staus epilepticus ;icu;nov 2004
DESCRIPTION
treatment of status epileptics,intensive therapy,2004TRANSCRIPT
Trattamento dello stato di
male
Il punto di vista del
rianimatore
Claudio Melloni
Anestesia e Rianimazione
Ospedale di Faenza
Tossicitagrave acuta da farmaci o brusca
sospensione
bull Sindrda astinenzaalcool(6 associate a
lesintracranica(40)Bdzoppiacei (11)bull Abbassamento livelli plasmatici up regulation del
sistglutamergico (46)
bull Occasionalmente le convulsioni da
astinenza potrebbero costituire la I
indicazione della dipendenza
Convulsioni indotte da farmaci1
bull In general medications rank low as precipitants of seizures The large Boston Collaborative Drug Surveillance Program evaluating the records of 32812 inpatients (ward and ICU) found drug-induced seizures to occur in only 008 of the group or approximately 05 of patients with neurologic side effects (204748) Nevertheless drugs with convulsant properties may precipitate seizures in high-risk inpatients and thus be particularly a problem in the ICU setting (49)
Schema delle modificazioni
neurofisiologicheparte I
Aum richieste
O2 cerebrali
Aum CBFAum Attivitagrave
autonomica
Aum PA
Aum glicemia
Sudorazione
Salivazione
iperpiressia
Schema delle modificazioni
neurofisiologicheparte II
Fallimento
Autoregolaz
cerebrale
Diminuz
CBF
Aum
ICP
Ipotensione
sistemicaDiminuz CPP
Disequilibrio
Apporto O2 cerebrale
E
richiesteDissociazione
Elettro EEG meccanica convuls
Mortalitagrave
bull overall mortality 21(Rochester)ndash Logroscino G Hesdorffer DC Cascino G Annegers
JF Hauser WA Short-term mortality after a first episode of status epilepticus Epilepsia 1997381344-1349
ndash Most of these deaths (89) occurred in those with an acute symptomatic aetiology especially anoxic encephalopathy or cerebrovascular disease
ndash When analysed for other factors only age (gt65 years) and sex (male) contributed significantly to the risk of death this appeared to be independent of aetiology In the overall analysis however length of status epilepticus was not an independent predictor of mortality Whether it is the underlying aetiology itself or the status epilepticus that has a major influence on mortality cannot be determined from this study
Mortalitagrave da CSE amp NCSE
0
10
20
30
40
50
60
70
80
90
DE Lorenzo 1998
Drislane 1994
Litt 1998
Labar 1998
Privitera 1994
10 elderly patients with
stroke tumors
head injury
electroconvulsive therapy
and metabolic derangements
3 died from infection 48 patients with
serious medical illnesses
but without prior epilepsy
coma after
convulsive SE
critic
ally
ill eld
erly
42 pts
Epilepsy
stroke
Generalized
SE
Morbilitagrave e mortalitagrave
bull Morte 10 -35 (Hauser 1983 DeLorenzo et
al 1996)
bull Morbilitagrave cognitiva e neurologica 10 - 35
(Hauser 1983 Dodrill and Wilensky 1990
DeLorenzo et al 1996 Cascino et al 1998)
bull Epilessia cronica (30 dei bambini che si
presentano inizialmente in status) (Shinnar et
al 1992)
bull SE ricorrente (15 - 20 dei bambini ) (Shinnar et
al 1992)
Morbiditagrave legata al trattamentodepressione
respiratoria
0
5
10
15
20
25
30
35
40
45
depr resp
diazepam
lorazepamWyeth
loraz Walker
loraz Levy
Incidenza di effetti collaterali nello studio
comparativo di Treiman et al
vs IrgantuaTreiman DM Meyers PD Walton NY et al A comparison of four treatments for
generalized convulsive status epilepticus N Engl J Med 1998339792-8
0
5
10
15
20
25
30
35
ipotensione ipoventilazione disturbi ritmo
cardiaco
diazepam+ fenitoina
fenitoina
lorazepam
fenobarbital
midazolam
prognosi
PrognosiSE vs NCSE
bull Necessitagrave di una attenta stratificazione
bull studies drawn from the intensive care setting (Drislane and Schomer 1994 DeLorenzo et al 1998 Litt et al 1998) are faced with the markedly greater task of determining the selective consequences and morbidity of the superadded insult of the epileptic electrical activity combined with the medical and neurologic problems that sent the patient to the intensive care setting or resulted in coma in the first place
Prognosi 2
NON Convulsive (NCSE) Status
Epilepticus(Hosford 1999)
bull 1 Generalized SE in nonconvulsing well-oxygenated animals produces brain damage (Wasterlain et al 1993) In paralyzed oxygen-ventilated baboons with over 3 hours of electrographic seizure activity there was neuronal necrosis in the hippocampal neocortex even when systemic complications and no convulsions were seen (Meldrum et al 1973) Flurothyl-induced seizures in O2-ventilated rats caused brain lesions that included infarction of the substantia nigra (Nevander et al 1985)
bull 2 Focal seizures can induce neuronal necrosis (Wasterlain et al 1993) Necrosis of hilar interneurons and CA3 pyramidal cells occurs with electrical stimulation of the afferent pathway for 2 to 24 hours (Sloviter 1983) with similar changes seen with intraventricular glutamate or aspartate injection (Sloviter and Dempster 1985)
bull 3 Limbic seizures can cause brain damage Cholinomimetics kainic acid and other methods to produce limbic SE can result in neuronal necrosis in the hippocampus amygdala piriform and entorhinal cortices the thalamus lateral septum substantia nigra and neocortex (Olney et al 1974 1983 Strain and Tasker 1991)
La prognosi finale dipende dalla eziologia
The possible relationships among seizure etiology
nonconvulsive status
epilepticus and outcome
Most patients with complex partial status epilepticus (CPSE)
have etiologies consistent with pathway [circled digit one]
(strokes anoxiaischemia head trauma encephalitis)
rather than [circled digit two]
The best example of [circled digit two] would be a patient with
temporal lobe epilepsy
who went into CPSE because of inadequate
antiepileptic drug levels
Fattori che influenzano la prognosi nello
SE(anche NCSE)
bull Causa dello stato
epilettico
bull Durata dello stato
bull Trattamento
bull Etagrave
bull Effetti dannosi sistemici metabolici e fisiologici (Meldrum et al 1973 Simon 1985)
bull Danno cerebrale secondario allrsquo insulto acuto che induce SE (Hauser 1983 Barry et al 1993)
bull Danno neuronale diretto dovuto alla abnorme attivitagrave elettrica del SE (Meldrum et al 1973 Knopman et al 1977 Lothman 1990)
Chin RFMVerhulst LNeville BGRPeters MJScott RC
Inappropriate emergency management of status epilepticus
in children contributes to need for intensive care Journal of
Neurology Neurosurgery amp Psychiatry 75(11)1584-
1588 2004
bull gt 2 dosi o dosi inadeguate di BDZ
bull Depressione respiratoria
bull Trattati in emergenza extraospedaliera
complicazioni
Complicazioni sistemiche dello status epilepticus
SNC cardiova
s
Resp metaboli
co
altro
Ipossiaanos
sia
IM Apneaipopnea Disidtrataz MOF
Edema Ipoipertens Insuff resp Disturbi
elettripoNaip
erK
DIC
Emorragia Aritmie Polmonite ab
ingestis
Acidosi metab Rabdomiolisi
Trombosi
venosa
Arresto Iprtens polm Necrosi
tubacutafratture
Shock
cardiogeno
EPA Necrosi
epatica acuta
Embolia polm Pancreatite
acuta
Complicazioni dello SE
bull Durata convulsioni gt 1 hrpredittore indipendente di poor outcome (mortality odds ratio di quasi 10) (4)
bull Convulsioni prolungate aumentano il rischio di danno neuronalendash Eccitotox
ndash Accumulo intracellulare di Ca++ e apoptosi
ndash Riorganizzazione sinaptica epilettogenica( e gemmazione)
ndash Deplezione di energia e inibizione della sintesi proteica e del DNA (5)
ndash ldquo Particularly vulnerable to injury are the neurons within the hippocampus cerebral cortical mantle and cerebellar Purkinje cells Selective neuronal loss has been described within the hilar area of the dentate gyrus of the hippocampus (areas CA1 and CA3) after prolonged seizures leading to the development of chronic temporal lobe epilepsy (6)rdquo
bull Manifestazioni autonomichemorte improvvisa ndash DeLorenzo RJ Status epilepticus Concepts in diagnosis and treatment Semin Neurol 1990 10396ndash
405
ndash Towne AR Pellock JM Ko D et al Determinants of mortality in status epilepticus Epilepsia 1994 3527ndash34
ndash Payne TA Bleck TP Status epilepticus Crit Care Clin 1997 13 (1)17ndash38
ndash Sloviter RS Status epilepticus-induced neuronal injury and network reorganization Epilepsia 1999 40S34ndash41
Complications of SE
bull Aminoff MJ Simon RP Status epilepticus causes clinical features and consequences in 98 patients Am J Med 198069657-666 Bibliographic Links [Context Link]
bull 25 Wasterlain CG Fujikawa DG Penix L Sankar R Pathophysiological mechanisms of brain damage from status epilepticus Epilepsia 199334(1)S37-S53 Bibliographic Links [Context Link]
bull 26 Singhal PC Chugh KS Golati DR Myoglobinuria and renal failure after status epilepticus Neurology 197828200-201 Bibliographic Links [Context Link]
bull 27 Fisher S Zatuchni J Greenberg J Disseminated intravascular coagulation in status epilepticus Thromb Haemost 197738909-913 Bibliographic Links [Context Link]
Neuroprotective effects of acidosis
bull some studies that suggest that hypoxia acidosis and hypoglycaemia may be neuroprotective [2829] To
study these phenomena further Sasahira and coworkers [30bull31bull] looked at a rat model of status epilepticus based upon repeated bicuculline injections and using heat shock protein as an indirect measure of neuronal injury Using high concentrations of inhaled carbon dioxide they were able to reduce the serum pH from 755 to 717 This resulted in a shorter seizure duration and less neuronal damage [30bull] Using multiple regression analysis they were able to show a neuroprotective effect of shortening seizure duration and an independent effect of acidosis [30bull] Acidosis and raised carbon dioxide tensions have a profound effect on cerebral blood flow and whether the neuroprotective effect is due to haemodynamic effects or to the effect of acidoisis on receptors or transmitter release is unknown
bull A further study from the same group [31bull] looked at the effects of moderate hypoxia (PaO2=50 mmHg) on neuronal damage in the same model compared with normoxic controls There was no difference in neuronal injury detected suggesting that moderate hypoxia has no effect on neuronal death in status epilepticus The authors rightly conclude however that the implications of their findings for the treatment of status epilepticus are unclear as more severe hypoxia could result in additional ischaemic injury to the brain
bull 28 Blennow G Brierley JB Meldrum BS Siesjouml BK Epileptic brain damage The role of sysemic factors that modify cerebral energy metabolism Brain 1978101687-700 Bibliographic Links [Context Link]
bull 29 Meldrum BS Brierley JB Prolonged epileptic seizures in primates Ischaemic cell change and its relation to ictal physiological events Arch Neurol 19732810-17 Bibliographic Links [Context Link]
bull 30 bull Sasahira M Lowry T Simon RP Neuronal injury in experimental status epilepticus in the rat role of acidosis Neurosci Lett 1997224177-180 Bibliographic Links See [31bull] [Context Link]
bull 31 bull Sasahira M Simon RP Greenberg DA Neuronal injury in experimental status epilepticus in the rat role of hypoxia Neurosci Lett 1997222207-209 Bibliographic Links Thie paper and [30bull] are excellent reports considering the influence of physiological parameters on neuronal damage induced by status epilepticus [Context Link]
Effetti collaterali della fenitoina ev
bull Lesioni dei tessuti mollicon o senza
stravasordquoPurple Handgt 40 casi con parecchie
amputazioni ( (Kilarski 1984 Rao et al 1988
Hanna 1992)
bull Problemi al sito di iniezione Earnest et al (1983)
30 su 200
bull Ipotensione in gt 25 dei pazcon aritmie
ndash In 3139 pazienti 1 FA (velocitagrave di infus 26 mgmin) 1
tachic sinusale 1 allungamento tratto PR
ndash (Gellerman and Martinex 1967 Goldschlager and
Karliner 1967 Louis et al 1967 Voigt 1968)
bull
Allen FH Runge JW Legarda S et al Multicenter open-label
study on safety tolerance and pharmacokinetics of
intravenous fosphenytoin (Cerebyx) in status epilepticus
[abstract] Epilepsia 199435(Suppl 18)93
bull Data have been published from 40 patients in status epilepticus who received fosphenytoin at a mean infusion rate of 92 mgmin ranging from 247 to 1113 mgmin) Status epilepticus was terminated in 37 of 40 patients (85) within 30 min of receiving fosphenytoin The rapid infusion was well tolerated with only mild or transient side effects Most of the side effects reported were attributable to the pharmacologic effect of phenytoin and included dizziness nystagmus and ataxia Most patients in this trial received a benzodiazepine before the infusion of fosphenytoin and no adverse drug interactions were found
Introduzione alla peculiaritagrave
dellrsquoambiente intensivistico
Convulsioni in ambiente intensivo
bull Sepsi
bull Cause mediche
bull Anormalitagrave metaboliche(30-35) (11)ndash Iponatremiaipocalcemiaipofosfatemiaipoglicemiauremia
ndash Alterazioni della osmolaritagrave specie correzione acuta bull Acute return from hyperosmolarity back to normal levels in a rat
neocortical slice preparation by lowering the D-glucose concentration increased the amplitude of evoked early and late excitatory postsynaptic potentials a situation reminiscent of the generalized convulsions that may follow acute reduction of glucose in diabetic nonketotic hyperglycemia (42)
ndash Ipoosmolaritagrave induce increased nervous system excitability by strengthening both excitatory synaptic communications in neocortex and field effects among the entire cortical population (41)
Problemi peculiari allrsquoambiente
intensivistico
bull Polifarmacologia
bull Insuff renale
bull Insuff epatica
bull Induzione enzimatica
bull Inibizione enzimatica
bull Ipodisprotidemiehellipfarmaci altamente
legati alle prot plasmatiche
Trattamento dello stato di
male
Allora
bull Terapia immediata
bull Aggressiva
bull Supporto vitale di base
bull AAirway
bull Breathing
bull CSupporto circolatorio
Status epilepticusfilosofia del trattamento
Disaccoppiamento
CMRO2CBF
Funzione cardiocircolatoriaFunzione resp
Supporto supernormale
Glucosio
Tiamina 100 mg
Dopaminanoradrenalina + fre con barbituricihellip
Indagine conoscitiva su 127 TI NCH europeeDauch WA Schutze M Guttinger M et al Posttraumatic seizure prevention - results of a
survey of 127 neurosurgery clinics Zentralbl Neurochir 1996 57190ndash5
0
10
20
30
40
50
60
profilassi
Profilassi con anticonvulsivi post trauma cranio-
encefalico
mai
sempre
secindicazione
substantial cortical
injurycerebral contusion
acute subdural
hemorrhage
depressed skull fracture
penetrating missile
injury
(141517)
Rischio convulsivo
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001bull Background It is uncertain whether the administration of benzodiazepines by paramedics is an
effective and safe treatment for out-of-hospital status epilepticus
Methods We conducted a randomized double-blind trial to evaluate intravenous benzodiazepines administered by paramedics for the treatment of out-of-hospital status epilepticus Adults with prolonged (lasting five minutes or more) or repetitive generalized convulsive seizures received intravenous diazepam (5 mg) lorazepam (2 mg) or placebo An identical second injection was given if needed
Results Of the 205 patients enrolled 66 received lorazepam 68 received diazepam and 71 received placebo Status epilepticus had been terminated on arrival at the emergency department in more patients treated with lorazepam (591 percent) or diazepam (426 percent) than patients given placebo (211 percent) (P=0001) After adjustment for covariates the odds ratio for termination of status epilepticus by the time of arrival in the lorazepam group as compared with the placebo group was 48 (95 percent confidence interval 19 to 130) The odds ratio was 19 (95 percent confidence interval 08 to 44) in the lorazepam group as compared with the diazepam group and 23 (95 percent confidence interval 10 to 59) in the diazepam group as compared with the placebo group The rates of respiratory or circulatory complications after the study treatment was administered were 106 percent for the lorazepam group 103 percent for the diazepam group and 225 percent for the placebo group (P=008)
Conclusions Benzodiazepines are safe and effective when administered by paramedics for out-of-hospital status epilepticus in adults Lorazepam is likely to be a better therapy than diazepam (N Engl J Med 2001345631-7)
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001
0
10
20
30
40
50
60
seizures stop complications
lorazepam
diazepam
placebo
randomized double-blind trial
to evaluate iv bdz
admin by paramedics
for the treatment of out-of-hospital status epilepticus
Adults with prolonged (lasting 5 minutes or +)
or repetitive generalized convulsive seizures
received iv diazepam (5 mg)
lorazepam (2 mg) or placebo
An identical second injection was given if needed
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
Treiman DM Meyers PD Walton NY Collins JF Colling C Rowan AJ et al A comparison of four treatments for generalized convulsive status epilepticus N Engl J Med 1998 339792-798
randomized double-blind trial that compared the following four regimens commonly used for the treatment of generalized convulsive status epilepticus diazepam followed by phenytoin phenytoin alone phenobarbital and lorazepam Although the doses and infusion rates chosen for study closely reflected common clinical practice at the time the study began the combination of lorazepam followed by phenytoin (the preferred regimen of many neurologists) was not included
This is a large well-controlled and important clinical trial The major limitation in its clinical relevance is the lack of inclusion of a regimen consisting of lorazepam followed by phenytoin
Veterans Affairs Status Epilepticus Cooperative
Study Group Treiman et al
SE aperto
diaz fenitoina fenobarbital lorazepam
2 o + convuls senza
ripresa di coscienza
Convuls continue = gt 10 min
fenitoina
Coma con scariche
ictali EEG
primary outcome measure
cessation of clinical and electrical
seizure activity
within 20min after initiation
of treatment and continuing for at least
60min after the start of treatment
lorazepam fenitoina
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
bull st treatment successful in 555 of patients with a verified diagnosis of overt status epilepticus (n=384) and in 149 of patients with subtle status epilepticus (n=134)
bull Comparisons between the 4 treatments showed that lorazepam was more effective than phenytoin alone in patients with overt status epilepticus (treatment success in 649 versus 436 of patients respectively)
bull other treatment comparisons in the overt group and all comparisons in the subtle group were not significantly different however
bull There were no significant differences between treatments in patient outcome rates of recurrence of status epilepticus or return of full consciousness over the 12-h observation period or in the frequency of adverse cardiac respiratory or hypotensive events
Treiman DM Meyers PD Walton NY et al A
comparison of four treatments for generalized
convulsive status epilepticus N Engl J Med 1998
339792-798
P 002
Percentage of successful treatment
grey bars overt patients black bars subtle patients
Alldredge Brian Kab Lowenstein Daniel HAC Status
epilepticus new concepts Current Opinion in Neurology
121999 183-190
Da ChapmanAnaesthesia 2004
Marik PEVaron J The Management of Status
Epilepticus Chest 126(2)582-591 August 2004
Status epilepticus is a major medical emergency associated with significant morbidity and mortality Status epilepticusis best defined as a continuous generalized convulsive seizure lasting gt 5 min or two or more seizures during which the patient does not return to baseline consciousness Lorazepam in a dose of 01 mgkg is the drug of first choice for terminating status epilepticus Patients who continue to have clinical or EEG evidence of seizure activity after treatment with lorazepam should be considered to have refractory status epileptics and should be treated with a continuous infusion of propofol or midazolam This article reviews current information regarding the management of status epilepticus in adults
Schema di Marik et al
Claassen JHirsch LJ Emerson R GBates
JE Thompson TBMayer SA Continuous EEG
monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042 bull The authors reviewed 33 episodes of RSE treated with cIV-MDZ in their neurologic intensive care
unit over 6 years All patients were monitored with continuous EEG (cEEG) MDZ infusion rates were titrated to eliminate clinical and EEG seizure activity cIV-MDZ was discontinued once patients were seizure-free for 24 hours Acute treatment failures (seizures 1 to 6 hours after starting cIV-MDZ) breakthrough seizures (after 6 hours of therapy) post-treatment seizures (within 48 hours of discontinuing therapy) and ultimate treatment failure (frequent seizures that led to treatment with pentobarbital or propofol) were identified
bull Results All patients were in nonconvulsive SE at the time cIV-MDZ was started the mean duration of SE before treatment was 39 days (range 0 to 17 days) In addition to benzodiazepines 94 of patients had received at least two antiepileptic drugs (AED) before starting cIV-MDZ The mean loading dose was 019 mgkg the mean maximal infusion rate was 022 mgkgh and the mean duration of cIV-MDZ therapy was 42 days (range 1 to 14 days) Acute treatment failure occurred in 18 (633) of episodes breakthrough seizures in 56 (1832) post-treatment seizures in 68 (1928) and ultimate treatment failure in 18 (633) Breakthrough seizures were clinically subtle or purely electrographic in 89 (1618) of cases and were associated with an increased risk of developing post-treatment seizures (p = 001)
bull Conclusions Although most patients with RSE initially responded to cIV-MDZ over half developed subsequent breakthrough seizures which were predictive of post-treatment seizures and were often detectable only with cEEG Titrating cIV-MDZ to burst suppression more aggressive treatment with concurrent AED or a longer period of initial treatment may reduce the high proportion of patients with RSE who relapse after cIV-MDZ is discontinued
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus Neurology 2001 57 25 1036-1042
0
10
20
30
40
50
60
70
80
non seizures
seizures lt30 min24h05-12 h
seizures 05-12 h24 hgt 12 h
seiz gt12 h24
burst suppression
periodic latdischarge
periodic gen discharge
prima
durante
dopo
33 episodes of RSE treated with cIV-MDZ neurologic ICU over 6 years
All patients were monitored with continuous EEG (cEEG)
Waterhouse Elizabeth J 1 2 DeLorenzo Robert J 1 3 4 2
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
bull Status epilepticus (SE) is a medical and neurological emergency that has been associated with significant morbidity and mortality The most widely accepted definition of SE is more than 30 minutes of either continuous seizure activity or intermittent seizures without full recovery of consciousness between seizures SE is a major clinical concern in the elderly population both because it has increased incidence in the elderly compared with the general population and because of concurrent medical conditions that are more likely to complicate therapy and worsen prognosis in elderly individuals
The incidence of SE in the elderly is almost twice that of the general population at 86 per 100 000 per year With the anticipated growth of the elderly population SE is likely to become an increasingly common problem facing clinicians and an important public health issue The elderly have the highest SE-associated mortality of any age group at 38 and the very old elderly (gt80 years of age) have a mortality of at least 50 Acute or remote stroke is the most common aetiology of SE in the elderly Nonconvulsive SE (NCSE) has a wide range of clinical presentations ranging from confusion to obtundation It occurs commonly in elderly patients who are critically ill and in the setting of coma Electroencephalogram is the only reliable method of diagnosing NCSE
The goal of treatment for SE is rapid cessation of clinical and electrical seizure activity Most treatment protocols call for the immediate administration of an intravenous benzodiazepine followed by phenytoin or fosphenytoin Recent studies suggest that when this initial treatment of SE fails little is gained by using additional standard drugs General anaesthetic agents (such as pentobarbital midazolam or propofol) should be expeditiously employed although these treatments have their own potential complications Intravenous valproic acid is a recent addition to the armamentarium of drugs for the treatment of SE with a low risk of hypotension respiratory depression and hypotension making it a potentially useful drug for the treatment of SE in the elderly However further information is needed to establish its role in the overall treatment of SE
Waterhouseet al
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
BDZ
Fenitoina
O fosfenitoina
GA
Midaz
Propof
pentobarb
Ac valproico
Ns proposta
Lorazepam
01 mgkg
Propofol
1-2 mgkgMidazolam01 mgkg
Inf cont 3-10 mgkgh Inf cont 001-005 mgkgh
Miorilassante solo
Per intubazione
Pentobarbital dose caricopoi 01-04 mgkgmin
fenobarbital
bull 10-20 mgkg iv
ndash Eccessiva sedazione
ndash Depressresp
ndash Ipotensione
ndash Interaz farmacol
ndash Hl gt48 hrhelliphelliphellip
tiopental
bull cumulativo
bull Inotropo neghellip
bull Pentobarbital
bull immunosoppressione
propofol
bull Vantaggi cineticodinamici
bull Titolazione continua possibile
bull TCIquale livello
bull Dosi 1 mgkgripetibile dopo 5rsquo-
ndash Infcont 2-10 mgkgh
bull Rapida emergenzafinestra neurologicaevitare la
brusca sospensione
bull + rapido controllo delle convuls gt barbituricindash Stecker MM Kramer TH Raps EC OMeeghan R Dulaney E Skaar DJ Treatment of
refractory status epilepticus with propofol clinical and pharmacokinetic findings Epilepsia 1998
39 18-26
AG
bull Non ci sono dati che indichino quanto a lungo i paz debbano rimanere senza convuls prima di poter alleggerire il piano di AG24 h96h (Treiman DM Convulsive status
epilepticus Current Treatment Options in Neurology 1999 1 359-69)
bull Anest alogenatiisofluranogtsevofluranogtdesflurane
bull Ma vaporizzatori
bull Contaminazione ambientale
bull Costihellip
Studi comparativi1
bull Midazolamgt tiopental
ndash Lohr A Jr Werneck LC Comparative non-randomized study with
midazolam versus thiopental in children with refractory status
epilepticus [Portuguese] Arq Neuropsiquiatr 2000 58282-287
ndash non-randomized comparison
ndash of historical data (thiopental) and prospectively
acquired data (midazolam)
ndash Midazolam was no more often effective than
thiopental but was associated with less cyanosis and
less respiratory distress in this study of 50 children
Studi comparativi2
Valproatobull Valproate(ivrdquoDepaconrdquo) has been used for the treatment of refractory SE
in children and myoclonic SE ndash Sheth RD Gidal BE Intravenous valproic acid for myoclonic status epilepticus
Neurology 2000 541201
ndash Uberall MA Trollmann R Wunsiedler U Wenzel D Intravenous valproate in pediatric epilepsy patients with refractory status epilepticus Neurology 2000 542188-2189 ]
bull Valproate has also been used in SE in the elderly and appears to be safe even in the presence of cardiovascular instability and hypotension no significant change in blood pressure pulse or the need for vasopressors in 13 patients with SE and hypotension given a loading dose of 147-327 mgkg Depacon intravenouslyndash Sinha S Naritoku DK Intravenous valproate is well tolerated in unstable patients
with status epilepticus Neurology 2000 55722-724
bull However there is a case report of severe hypotension in an 11-year-old child after treatment of SE with 30 mgkg intravenous valproate ndash White JR Santos CS Intravenous valproate associated with significant
hypotension in the treatment of status epilepticus J Child Neurol 1999 14822-823
FINE
Percheacute non ne possiamo
piugravehelliphelliphellip
Tossicitagrave acuta da farmaci o brusca
sospensione
bull Sindrda astinenzaalcool(6 associate a
lesintracranica(40)Bdzoppiacei (11)bull Abbassamento livelli plasmatici up regulation del
sistglutamergico (46)
bull Occasionalmente le convulsioni da
astinenza potrebbero costituire la I
indicazione della dipendenza
Convulsioni indotte da farmaci1
bull In general medications rank low as precipitants of seizures The large Boston Collaborative Drug Surveillance Program evaluating the records of 32812 inpatients (ward and ICU) found drug-induced seizures to occur in only 008 of the group or approximately 05 of patients with neurologic side effects (204748) Nevertheless drugs with convulsant properties may precipitate seizures in high-risk inpatients and thus be particularly a problem in the ICU setting (49)
Schema delle modificazioni
neurofisiologicheparte I
Aum richieste
O2 cerebrali
Aum CBFAum Attivitagrave
autonomica
Aum PA
Aum glicemia
Sudorazione
Salivazione
iperpiressia
Schema delle modificazioni
neurofisiologicheparte II
Fallimento
Autoregolaz
cerebrale
Diminuz
CBF
Aum
ICP
Ipotensione
sistemicaDiminuz CPP
Disequilibrio
Apporto O2 cerebrale
E
richiesteDissociazione
Elettro EEG meccanica convuls
Mortalitagrave
bull overall mortality 21(Rochester)ndash Logroscino G Hesdorffer DC Cascino G Annegers
JF Hauser WA Short-term mortality after a first episode of status epilepticus Epilepsia 1997381344-1349
ndash Most of these deaths (89) occurred in those with an acute symptomatic aetiology especially anoxic encephalopathy or cerebrovascular disease
ndash When analysed for other factors only age (gt65 years) and sex (male) contributed significantly to the risk of death this appeared to be independent of aetiology In the overall analysis however length of status epilepticus was not an independent predictor of mortality Whether it is the underlying aetiology itself or the status epilepticus that has a major influence on mortality cannot be determined from this study
Mortalitagrave da CSE amp NCSE
0
10
20
30
40
50
60
70
80
90
DE Lorenzo 1998
Drislane 1994
Litt 1998
Labar 1998
Privitera 1994
10 elderly patients with
stroke tumors
head injury
electroconvulsive therapy
and metabolic derangements
3 died from infection 48 patients with
serious medical illnesses
but without prior epilepsy
coma after
convulsive SE
critic
ally
ill eld
erly
42 pts
Epilepsy
stroke
Generalized
SE
Morbilitagrave e mortalitagrave
bull Morte 10 -35 (Hauser 1983 DeLorenzo et
al 1996)
bull Morbilitagrave cognitiva e neurologica 10 - 35
(Hauser 1983 Dodrill and Wilensky 1990
DeLorenzo et al 1996 Cascino et al 1998)
bull Epilessia cronica (30 dei bambini che si
presentano inizialmente in status) (Shinnar et
al 1992)
bull SE ricorrente (15 - 20 dei bambini ) (Shinnar et
al 1992)
Morbiditagrave legata al trattamentodepressione
respiratoria
0
5
10
15
20
25
30
35
40
45
depr resp
diazepam
lorazepamWyeth
loraz Walker
loraz Levy
Incidenza di effetti collaterali nello studio
comparativo di Treiman et al
vs IrgantuaTreiman DM Meyers PD Walton NY et al A comparison of four treatments for
generalized convulsive status epilepticus N Engl J Med 1998339792-8
0
5
10
15
20
25
30
35
ipotensione ipoventilazione disturbi ritmo
cardiaco
diazepam+ fenitoina
fenitoina
lorazepam
fenobarbital
midazolam
prognosi
PrognosiSE vs NCSE
bull Necessitagrave di una attenta stratificazione
bull studies drawn from the intensive care setting (Drislane and Schomer 1994 DeLorenzo et al 1998 Litt et al 1998) are faced with the markedly greater task of determining the selective consequences and morbidity of the superadded insult of the epileptic electrical activity combined with the medical and neurologic problems that sent the patient to the intensive care setting or resulted in coma in the first place
Prognosi 2
NON Convulsive (NCSE) Status
Epilepticus(Hosford 1999)
bull 1 Generalized SE in nonconvulsing well-oxygenated animals produces brain damage (Wasterlain et al 1993) In paralyzed oxygen-ventilated baboons with over 3 hours of electrographic seizure activity there was neuronal necrosis in the hippocampal neocortex even when systemic complications and no convulsions were seen (Meldrum et al 1973) Flurothyl-induced seizures in O2-ventilated rats caused brain lesions that included infarction of the substantia nigra (Nevander et al 1985)
bull 2 Focal seizures can induce neuronal necrosis (Wasterlain et al 1993) Necrosis of hilar interneurons and CA3 pyramidal cells occurs with electrical stimulation of the afferent pathway for 2 to 24 hours (Sloviter 1983) with similar changes seen with intraventricular glutamate or aspartate injection (Sloviter and Dempster 1985)
bull 3 Limbic seizures can cause brain damage Cholinomimetics kainic acid and other methods to produce limbic SE can result in neuronal necrosis in the hippocampus amygdala piriform and entorhinal cortices the thalamus lateral septum substantia nigra and neocortex (Olney et al 1974 1983 Strain and Tasker 1991)
La prognosi finale dipende dalla eziologia
The possible relationships among seizure etiology
nonconvulsive status
epilepticus and outcome
Most patients with complex partial status epilepticus (CPSE)
have etiologies consistent with pathway [circled digit one]
(strokes anoxiaischemia head trauma encephalitis)
rather than [circled digit two]
The best example of [circled digit two] would be a patient with
temporal lobe epilepsy
who went into CPSE because of inadequate
antiepileptic drug levels
Fattori che influenzano la prognosi nello
SE(anche NCSE)
bull Causa dello stato
epilettico
bull Durata dello stato
bull Trattamento
bull Etagrave
bull Effetti dannosi sistemici metabolici e fisiologici (Meldrum et al 1973 Simon 1985)
bull Danno cerebrale secondario allrsquo insulto acuto che induce SE (Hauser 1983 Barry et al 1993)
bull Danno neuronale diretto dovuto alla abnorme attivitagrave elettrica del SE (Meldrum et al 1973 Knopman et al 1977 Lothman 1990)
Chin RFMVerhulst LNeville BGRPeters MJScott RC
Inappropriate emergency management of status epilepticus
in children contributes to need for intensive care Journal of
Neurology Neurosurgery amp Psychiatry 75(11)1584-
1588 2004
bull gt 2 dosi o dosi inadeguate di BDZ
bull Depressione respiratoria
bull Trattati in emergenza extraospedaliera
complicazioni
Complicazioni sistemiche dello status epilepticus
SNC cardiova
s
Resp metaboli
co
altro
Ipossiaanos
sia
IM Apneaipopnea Disidtrataz MOF
Edema Ipoipertens Insuff resp Disturbi
elettripoNaip
erK
DIC
Emorragia Aritmie Polmonite ab
ingestis
Acidosi metab Rabdomiolisi
Trombosi
venosa
Arresto Iprtens polm Necrosi
tubacutafratture
Shock
cardiogeno
EPA Necrosi
epatica acuta
Embolia polm Pancreatite
acuta
Complicazioni dello SE
bull Durata convulsioni gt 1 hrpredittore indipendente di poor outcome (mortality odds ratio di quasi 10) (4)
bull Convulsioni prolungate aumentano il rischio di danno neuronalendash Eccitotox
ndash Accumulo intracellulare di Ca++ e apoptosi
ndash Riorganizzazione sinaptica epilettogenica( e gemmazione)
ndash Deplezione di energia e inibizione della sintesi proteica e del DNA (5)
ndash ldquo Particularly vulnerable to injury are the neurons within the hippocampus cerebral cortical mantle and cerebellar Purkinje cells Selective neuronal loss has been described within the hilar area of the dentate gyrus of the hippocampus (areas CA1 and CA3) after prolonged seizures leading to the development of chronic temporal lobe epilepsy (6)rdquo
bull Manifestazioni autonomichemorte improvvisa ndash DeLorenzo RJ Status epilepticus Concepts in diagnosis and treatment Semin Neurol 1990 10396ndash
405
ndash Towne AR Pellock JM Ko D et al Determinants of mortality in status epilepticus Epilepsia 1994 3527ndash34
ndash Payne TA Bleck TP Status epilepticus Crit Care Clin 1997 13 (1)17ndash38
ndash Sloviter RS Status epilepticus-induced neuronal injury and network reorganization Epilepsia 1999 40S34ndash41
Complications of SE
bull Aminoff MJ Simon RP Status epilepticus causes clinical features and consequences in 98 patients Am J Med 198069657-666 Bibliographic Links [Context Link]
bull 25 Wasterlain CG Fujikawa DG Penix L Sankar R Pathophysiological mechanisms of brain damage from status epilepticus Epilepsia 199334(1)S37-S53 Bibliographic Links [Context Link]
bull 26 Singhal PC Chugh KS Golati DR Myoglobinuria and renal failure after status epilepticus Neurology 197828200-201 Bibliographic Links [Context Link]
bull 27 Fisher S Zatuchni J Greenberg J Disseminated intravascular coagulation in status epilepticus Thromb Haemost 197738909-913 Bibliographic Links [Context Link]
Neuroprotective effects of acidosis
bull some studies that suggest that hypoxia acidosis and hypoglycaemia may be neuroprotective [2829] To
study these phenomena further Sasahira and coworkers [30bull31bull] looked at a rat model of status epilepticus based upon repeated bicuculline injections and using heat shock protein as an indirect measure of neuronal injury Using high concentrations of inhaled carbon dioxide they were able to reduce the serum pH from 755 to 717 This resulted in a shorter seizure duration and less neuronal damage [30bull] Using multiple regression analysis they were able to show a neuroprotective effect of shortening seizure duration and an independent effect of acidosis [30bull] Acidosis and raised carbon dioxide tensions have a profound effect on cerebral blood flow and whether the neuroprotective effect is due to haemodynamic effects or to the effect of acidoisis on receptors or transmitter release is unknown
bull A further study from the same group [31bull] looked at the effects of moderate hypoxia (PaO2=50 mmHg) on neuronal damage in the same model compared with normoxic controls There was no difference in neuronal injury detected suggesting that moderate hypoxia has no effect on neuronal death in status epilepticus The authors rightly conclude however that the implications of their findings for the treatment of status epilepticus are unclear as more severe hypoxia could result in additional ischaemic injury to the brain
bull 28 Blennow G Brierley JB Meldrum BS Siesjouml BK Epileptic brain damage The role of sysemic factors that modify cerebral energy metabolism Brain 1978101687-700 Bibliographic Links [Context Link]
bull 29 Meldrum BS Brierley JB Prolonged epileptic seizures in primates Ischaemic cell change and its relation to ictal physiological events Arch Neurol 19732810-17 Bibliographic Links [Context Link]
bull 30 bull Sasahira M Lowry T Simon RP Neuronal injury in experimental status epilepticus in the rat role of acidosis Neurosci Lett 1997224177-180 Bibliographic Links See [31bull] [Context Link]
bull 31 bull Sasahira M Simon RP Greenberg DA Neuronal injury in experimental status epilepticus in the rat role of hypoxia Neurosci Lett 1997222207-209 Bibliographic Links Thie paper and [30bull] are excellent reports considering the influence of physiological parameters on neuronal damage induced by status epilepticus [Context Link]
Effetti collaterali della fenitoina ev
bull Lesioni dei tessuti mollicon o senza
stravasordquoPurple Handgt 40 casi con parecchie
amputazioni ( (Kilarski 1984 Rao et al 1988
Hanna 1992)
bull Problemi al sito di iniezione Earnest et al (1983)
30 su 200
bull Ipotensione in gt 25 dei pazcon aritmie
ndash In 3139 pazienti 1 FA (velocitagrave di infus 26 mgmin) 1
tachic sinusale 1 allungamento tratto PR
ndash (Gellerman and Martinex 1967 Goldschlager and
Karliner 1967 Louis et al 1967 Voigt 1968)
bull
Allen FH Runge JW Legarda S et al Multicenter open-label
study on safety tolerance and pharmacokinetics of
intravenous fosphenytoin (Cerebyx) in status epilepticus
[abstract] Epilepsia 199435(Suppl 18)93
bull Data have been published from 40 patients in status epilepticus who received fosphenytoin at a mean infusion rate of 92 mgmin ranging from 247 to 1113 mgmin) Status epilepticus was terminated in 37 of 40 patients (85) within 30 min of receiving fosphenytoin The rapid infusion was well tolerated with only mild or transient side effects Most of the side effects reported were attributable to the pharmacologic effect of phenytoin and included dizziness nystagmus and ataxia Most patients in this trial received a benzodiazepine before the infusion of fosphenytoin and no adverse drug interactions were found
Introduzione alla peculiaritagrave
dellrsquoambiente intensivistico
Convulsioni in ambiente intensivo
bull Sepsi
bull Cause mediche
bull Anormalitagrave metaboliche(30-35) (11)ndash Iponatremiaipocalcemiaipofosfatemiaipoglicemiauremia
ndash Alterazioni della osmolaritagrave specie correzione acuta bull Acute return from hyperosmolarity back to normal levels in a rat
neocortical slice preparation by lowering the D-glucose concentration increased the amplitude of evoked early and late excitatory postsynaptic potentials a situation reminiscent of the generalized convulsions that may follow acute reduction of glucose in diabetic nonketotic hyperglycemia (42)
ndash Ipoosmolaritagrave induce increased nervous system excitability by strengthening both excitatory synaptic communications in neocortex and field effects among the entire cortical population (41)
Problemi peculiari allrsquoambiente
intensivistico
bull Polifarmacologia
bull Insuff renale
bull Insuff epatica
bull Induzione enzimatica
bull Inibizione enzimatica
bull Ipodisprotidemiehellipfarmaci altamente
legati alle prot plasmatiche
Trattamento dello stato di
male
Allora
bull Terapia immediata
bull Aggressiva
bull Supporto vitale di base
bull AAirway
bull Breathing
bull CSupporto circolatorio
Status epilepticusfilosofia del trattamento
Disaccoppiamento
CMRO2CBF
Funzione cardiocircolatoriaFunzione resp
Supporto supernormale
Glucosio
Tiamina 100 mg
Dopaminanoradrenalina + fre con barbituricihellip
Indagine conoscitiva su 127 TI NCH europeeDauch WA Schutze M Guttinger M et al Posttraumatic seizure prevention - results of a
survey of 127 neurosurgery clinics Zentralbl Neurochir 1996 57190ndash5
0
10
20
30
40
50
60
profilassi
Profilassi con anticonvulsivi post trauma cranio-
encefalico
mai
sempre
secindicazione
substantial cortical
injurycerebral contusion
acute subdural
hemorrhage
depressed skull fracture
penetrating missile
injury
(141517)
Rischio convulsivo
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001bull Background It is uncertain whether the administration of benzodiazepines by paramedics is an
effective and safe treatment for out-of-hospital status epilepticus
Methods We conducted a randomized double-blind trial to evaluate intravenous benzodiazepines administered by paramedics for the treatment of out-of-hospital status epilepticus Adults with prolonged (lasting five minutes or more) or repetitive generalized convulsive seizures received intravenous diazepam (5 mg) lorazepam (2 mg) or placebo An identical second injection was given if needed
Results Of the 205 patients enrolled 66 received lorazepam 68 received diazepam and 71 received placebo Status epilepticus had been terminated on arrival at the emergency department in more patients treated with lorazepam (591 percent) or diazepam (426 percent) than patients given placebo (211 percent) (P=0001) After adjustment for covariates the odds ratio for termination of status epilepticus by the time of arrival in the lorazepam group as compared with the placebo group was 48 (95 percent confidence interval 19 to 130) The odds ratio was 19 (95 percent confidence interval 08 to 44) in the lorazepam group as compared with the diazepam group and 23 (95 percent confidence interval 10 to 59) in the diazepam group as compared with the placebo group The rates of respiratory or circulatory complications after the study treatment was administered were 106 percent for the lorazepam group 103 percent for the diazepam group and 225 percent for the placebo group (P=008)
Conclusions Benzodiazepines are safe and effective when administered by paramedics for out-of-hospital status epilepticus in adults Lorazepam is likely to be a better therapy than diazepam (N Engl J Med 2001345631-7)
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001
0
10
20
30
40
50
60
seizures stop complications
lorazepam
diazepam
placebo
randomized double-blind trial
to evaluate iv bdz
admin by paramedics
for the treatment of out-of-hospital status epilepticus
Adults with prolonged (lasting 5 minutes or +)
or repetitive generalized convulsive seizures
received iv diazepam (5 mg)
lorazepam (2 mg) or placebo
An identical second injection was given if needed
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
Treiman DM Meyers PD Walton NY Collins JF Colling C Rowan AJ et al A comparison of four treatments for generalized convulsive status epilepticus N Engl J Med 1998 339792-798
randomized double-blind trial that compared the following four regimens commonly used for the treatment of generalized convulsive status epilepticus diazepam followed by phenytoin phenytoin alone phenobarbital and lorazepam Although the doses and infusion rates chosen for study closely reflected common clinical practice at the time the study began the combination of lorazepam followed by phenytoin (the preferred regimen of many neurologists) was not included
This is a large well-controlled and important clinical trial The major limitation in its clinical relevance is the lack of inclusion of a regimen consisting of lorazepam followed by phenytoin
Veterans Affairs Status Epilepticus Cooperative
Study Group Treiman et al
SE aperto
diaz fenitoina fenobarbital lorazepam
2 o + convuls senza
ripresa di coscienza
Convuls continue = gt 10 min
fenitoina
Coma con scariche
ictali EEG
primary outcome measure
cessation of clinical and electrical
seizure activity
within 20min after initiation
of treatment and continuing for at least
60min after the start of treatment
lorazepam fenitoina
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
bull st treatment successful in 555 of patients with a verified diagnosis of overt status epilepticus (n=384) and in 149 of patients with subtle status epilepticus (n=134)
bull Comparisons between the 4 treatments showed that lorazepam was more effective than phenytoin alone in patients with overt status epilepticus (treatment success in 649 versus 436 of patients respectively)
bull other treatment comparisons in the overt group and all comparisons in the subtle group were not significantly different however
bull There were no significant differences between treatments in patient outcome rates of recurrence of status epilepticus or return of full consciousness over the 12-h observation period or in the frequency of adverse cardiac respiratory or hypotensive events
Treiman DM Meyers PD Walton NY et al A
comparison of four treatments for generalized
convulsive status epilepticus N Engl J Med 1998
339792-798
P 002
Percentage of successful treatment
grey bars overt patients black bars subtle patients
Alldredge Brian Kab Lowenstein Daniel HAC Status
epilepticus new concepts Current Opinion in Neurology
121999 183-190
Da ChapmanAnaesthesia 2004
Marik PEVaron J The Management of Status
Epilepticus Chest 126(2)582-591 August 2004
Status epilepticus is a major medical emergency associated with significant morbidity and mortality Status epilepticusis best defined as a continuous generalized convulsive seizure lasting gt 5 min or two or more seizures during which the patient does not return to baseline consciousness Lorazepam in a dose of 01 mgkg is the drug of first choice for terminating status epilepticus Patients who continue to have clinical or EEG evidence of seizure activity after treatment with lorazepam should be considered to have refractory status epileptics and should be treated with a continuous infusion of propofol or midazolam This article reviews current information regarding the management of status epilepticus in adults
Schema di Marik et al
Claassen JHirsch LJ Emerson R GBates
JE Thompson TBMayer SA Continuous EEG
monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042 bull The authors reviewed 33 episodes of RSE treated with cIV-MDZ in their neurologic intensive care
unit over 6 years All patients were monitored with continuous EEG (cEEG) MDZ infusion rates were titrated to eliminate clinical and EEG seizure activity cIV-MDZ was discontinued once patients were seizure-free for 24 hours Acute treatment failures (seizures 1 to 6 hours after starting cIV-MDZ) breakthrough seizures (after 6 hours of therapy) post-treatment seizures (within 48 hours of discontinuing therapy) and ultimate treatment failure (frequent seizures that led to treatment with pentobarbital or propofol) were identified
bull Results All patients were in nonconvulsive SE at the time cIV-MDZ was started the mean duration of SE before treatment was 39 days (range 0 to 17 days) In addition to benzodiazepines 94 of patients had received at least two antiepileptic drugs (AED) before starting cIV-MDZ The mean loading dose was 019 mgkg the mean maximal infusion rate was 022 mgkgh and the mean duration of cIV-MDZ therapy was 42 days (range 1 to 14 days) Acute treatment failure occurred in 18 (633) of episodes breakthrough seizures in 56 (1832) post-treatment seizures in 68 (1928) and ultimate treatment failure in 18 (633) Breakthrough seizures were clinically subtle or purely electrographic in 89 (1618) of cases and were associated with an increased risk of developing post-treatment seizures (p = 001)
bull Conclusions Although most patients with RSE initially responded to cIV-MDZ over half developed subsequent breakthrough seizures which were predictive of post-treatment seizures and were often detectable only with cEEG Titrating cIV-MDZ to burst suppression more aggressive treatment with concurrent AED or a longer period of initial treatment may reduce the high proportion of patients with RSE who relapse after cIV-MDZ is discontinued
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus Neurology 2001 57 25 1036-1042
0
10
20
30
40
50
60
70
80
non seizures
seizures lt30 min24h05-12 h
seizures 05-12 h24 hgt 12 h
seiz gt12 h24
burst suppression
periodic latdischarge
periodic gen discharge
prima
durante
dopo
33 episodes of RSE treated with cIV-MDZ neurologic ICU over 6 years
All patients were monitored with continuous EEG (cEEG)
Waterhouse Elizabeth J 1 2 DeLorenzo Robert J 1 3 4 2
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
bull Status epilepticus (SE) is a medical and neurological emergency that has been associated with significant morbidity and mortality The most widely accepted definition of SE is more than 30 minutes of either continuous seizure activity or intermittent seizures without full recovery of consciousness between seizures SE is a major clinical concern in the elderly population both because it has increased incidence in the elderly compared with the general population and because of concurrent medical conditions that are more likely to complicate therapy and worsen prognosis in elderly individuals
The incidence of SE in the elderly is almost twice that of the general population at 86 per 100 000 per year With the anticipated growth of the elderly population SE is likely to become an increasingly common problem facing clinicians and an important public health issue The elderly have the highest SE-associated mortality of any age group at 38 and the very old elderly (gt80 years of age) have a mortality of at least 50 Acute or remote stroke is the most common aetiology of SE in the elderly Nonconvulsive SE (NCSE) has a wide range of clinical presentations ranging from confusion to obtundation It occurs commonly in elderly patients who are critically ill and in the setting of coma Electroencephalogram is the only reliable method of diagnosing NCSE
The goal of treatment for SE is rapid cessation of clinical and electrical seizure activity Most treatment protocols call for the immediate administration of an intravenous benzodiazepine followed by phenytoin or fosphenytoin Recent studies suggest that when this initial treatment of SE fails little is gained by using additional standard drugs General anaesthetic agents (such as pentobarbital midazolam or propofol) should be expeditiously employed although these treatments have their own potential complications Intravenous valproic acid is a recent addition to the armamentarium of drugs for the treatment of SE with a low risk of hypotension respiratory depression and hypotension making it a potentially useful drug for the treatment of SE in the elderly However further information is needed to establish its role in the overall treatment of SE
Waterhouseet al
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
BDZ
Fenitoina
O fosfenitoina
GA
Midaz
Propof
pentobarb
Ac valproico
Ns proposta
Lorazepam
01 mgkg
Propofol
1-2 mgkgMidazolam01 mgkg
Inf cont 3-10 mgkgh Inf cont 001-005 mgkgh
Miorilassante solo
Per intubazione
Pentobarbital dose caricopoi 01-04 mgkgmin
fenobarbital
bull 10-20 mgkg iv
ndash Eccessiva sedazione
ndash Depressresp
ndash Ipotensione
ndash Interaz farmacol
ndash Hl gt48 hrhelliphelliphellip
tiopental
bull cumulativo
bull Inotropo neghellip
bull Pentobarbital
bull immunosoppressione
propofol
bull Vantaggi cineticodinamici
bull Titolazione continua possibile
bull TCIquale livello
bull Dosi 1 mgkgripetibile dopo 5rsquo-
ndash Infcont 2-10 mgkgh
bull Rapida emergenzafinestra neurologicaevitare la
brusca sospensione
bull + rapido controllo delle convuls gt barbituricindash Stecker MM Kramer TH Raps EC OMeeghan R Dulaney E Skaar DJ Treatment of
refractory status epilepticus with propofol clinical and pharmacokinetic findings Epilepsia 1998
39 18-26
AG
bull Non ci sono dati che indichino quanto a lungo i paz debbano rimanere senza convuls prima di poter alleggerire il piano di AG24 h96h (Treiman DM Convulsive status
epilepticus Current Treatment Options in Neurology 1999 1 359-69)
bull Anest alogenatiisofluranogtsevofluranogtdesflurane
bull Ma vaporizzatori
bull Contaminazione ambientale
bull Costihellip
Studi comparativi1
bull Midazolamgt tiopental
ndash Lohr A Jr Werneck LC Comparative non-randomized study with
midazolam versus thiopental in children with refractory status
epilepticus [Portuguese] Arq Neuropsiquiatr 2000 58282-287
ndash non-randomized comparison
ndash of historical data (thiopental) and prospectively
acquired data (midazolam)
ndash Midazolam was no more often effective than
thiopental but was associated with less cyanosis and
less respiratory distress in this study of 50 children
Studi comparativi2
Valproatobull Valproate(ivrdquoDepaconrdquo) has been used for the treatment of refractory SE
in children and myoclonic SE ndash Sheth RD Gidal BE Intravenous valproic acid for myoclonic status epilepticus
Neurology 2000 541201
ndash Uberall MA Trollmann R Wunsiedler U Wenzel D Intravenous valproate in pediatric epilepsy patients with refractory status epilepticus Neurology 2000 542188-2189 ]
bull Valproate has also been used in SE in the elderly and appears to be safe even in the presence of cardiovascular instability and hypotension no significant change in blood pressure pulse or the need for vasopressors in 13 patients with SE and hypotension given a loading dose of 147-327 mgkg Depacon intravenouslyndash Sinha S Naritoku DK Intravenous valproate is well tolerated in unstable patients
with status epilepticus Neurology 2000 55722-724
bull However there is a case report of severe hypotension in an 11-year-old child after treatment of SE with 30 mgkg intravenous valproate ndash White JR Santos CS Intravenous valproate associated with significant
hypotension in the treatment of status epilepticus J Child Neurol 1999 14822-823
FINE
Percheacute non ne possiamo
piugravehelliphelliphellip
Convulsioni indotte da farmaci1
bull In general medications rank low as precipitants of seizures The large Boston Collaborative Drug Surveillance Program evaluating the records of 32812 inpatients (ward and ICU) found drug-induced seizures to occur in only 008 of the group or approximately 05 of patients with neurologic side effects (204748) Nevertheless drugs with convulsant properties may precipitate seizures in high-risk inpatients and thus be particularly a problem in the ICU setting (49)
Schema delle modificazioni
neurofisiologicheparte I
Aum richieste
O2 cerebrali
Aum CBFAum Attivitagrave
autonomica
Aum PA
Aum glicemia
Sudorazione
Salivazione
iperpiressia
Schema delle modificazioni
neurofisiologicheparte II
Fallimento
Autoregolaz
cerebrale
Diminuz
CBF
Aum
ICP
Ipotensione
sistemicaDiminuz CPP
Disequilibrio
Apporto O2 cerebrale
E
richiesteDissociazione
Elettro EEG meccanica convuls
Mortalitagrave
bull overall mortality 21(Rochester)ndash Logroscino G Hesdorffer DC Cascino G Annegers
JF Hauser WA Short-term mortality after a first episode of status epilepticus Epilepsia 1997381344-1349
ndash Most of these deaths (89) occurred in those with an acute symptomatic aetiology especially anoxic encephalopathy or cerebrovascular disease
ndash When analysed for other factors only age (gt65 years) and sex (male) contributed significantly to the risk of death this appeared to be independent of aetiology In the overall analysis however length of status epilepticus was not an independent predictor of mortality Whether it is the underlying aetiology itself or the status epilepticus that has a major influence on mortality cannot be determined from this study
Mortalitagrave da CSE amp NCSE
0
10
20
30
40
50
60
70
80
90
DE Lorenzo 1998
Drislane 1994
Litt 1998
Labar 1998
Privitera 1994
10 elderly patients with
stroke tumors
head injury
electroconvulsive therapy
and metabolic derangements
3 died from infection 48 patients with
serious medical illnesses
but without prior epilepsy
coma after
convulsive SE
critic
ally
ill eld
erly
42 pts
Epilepsy
stroke
Generalized
SE
Morbilitagrave e mortalitagrave
bull Morte 10 -35 (Hauser 1983 DeLorenzo et
al 1996)
bull Morbilitagrave cognitiva e neurologica 10 - 35
(Hauser 1983 Dodrill and Wilensky 1990
DeLorenzo et al 1996 Cascino et al 1998)
bull Epilessia cronica (30 dei bambini che si
presentano inizialmente in status) (Shinnar et
al 1992)
bull SE ricorrente (15 - 20 dei bambini ) (Shinnar et
al 1992)
Morbiditagrave legata al trattamentodepressione
respiratoria
0
5
10
15
20
25
30
35
40
45
depr resp
diazepam
lorazepamWyeth
loraz Walker
loraz Levy
Incidenza di effetti collaterali nello studio
comparativo di Treiman et al
vs IrgantuaTreiman DM Meyers PD Walton NY et al A comparison of four treatments for
generalized convulsive status epilepticus N Engl J Med 1998339792-8
0
5
10
15
20
25
30
35
ipotensione ipoventilazione disturbi ritmo
cardiaco
diazepam+ fenitoina
fenitoina
lorazepam
fenobarbital
midazolam
prognosi
PrognosiSE vs NCSE
bull Necessitagrave di una attenta stratificazione
bull studies drawn from the intensive care setting (Drislane and Schomer 1994 DeLorenzo et al 1998 Litt et al 1998) are faced with the markedly greater task of determining the selective consequences and morbidity of the superadded insult of the epileptic electrical activity combined with the medical and neurologic problems that sent the patient to the intensive care setting or resulted in coma in the first place
Prognosi 2
NON Convulsive (NCSE) Status
Epilepticus(Hosford 1999)
bull 1 Generalized SE in nonconvulsing well-oxygenated animals produces brain damage (Wasterlain et al 1993) In paralyzed oxygen-ventilated baboons with over 3 hours of electrographic seizure activity there was neuronal necrosis in the hippocampal neocortex even when systemic complications and no convulsions were seen (Meldrum et al 1973) Flurothyl-induced seizures in O2-ventilated rats caused brain lesions that included infarction of the substantia nigra (Nevander et al 1985)
bull 2 Focal seizures can induce neuronal necrosis (Wasterlain et al 1993) Necrosis of hilar interneurons and CA3 pyramidal cells occurs with electrical stimulation of the afferent pathway for 2 to 24 hours (Sloviter 1983) with similar changes seen with intraventricular glutamate or aspartate injection (Sloviter and Dempster 1985)
bull 3 Limbic seizures can cause brain damage Cholinomimetics kainic acid and other methods to produce limbic SE can result in neuronal necrosis in the hippocampus amygdala piriform and entorhinal cortices the thalamus lateral septum substantia nigra and neocortex (Olney et al 1974 1983 Strain and Tasker 1991)
La prognosi finale dipende dalla eziologia
The possible relationships among seizure etiology
nonconvulsive status
epilepticus and outcome
Most patients with complex partial status epilepticus (CPSE)
have etiologies consistent with pathway [circled digit one]
(strokes anoxiaischemia head trauma encephalitis)
rather than [circled digit two]
The best example of [circled digit two] would be a patient with
temporal lobe epilepsy
who went into CPSE because of inadequate
antiepileptic drug levels
Fattori che influenzano la prognosi nello
SE(anche NCSE)
bull Causa dello stato
epilettico
bull Durata dello stato
bull Trattamento
bull Etagrave
bull Effetti dannosi sistemici metabolici e fisiologici (Meldrum et al 1973 Simon 1985)
bull Danno cerebrale secondario allrsquo insulto acuto che induce SE (Hauser 1983 Barry et al 1993)
bull Danno neuronale diretto dovuto alla abnorme attivitagrave elettrica del SE (Meldrum et al 1973 Knopman et al 1977 Lothman 1990)
Chin RFMVerhulst LNeville BGRPeters MJScott RC
Inappropriate emergency management of status epilepticus
in children contributes to need for intensive care Journal of
Neurology Neurosurgery amp Psychiatry 75(11)1584-
1588 2004
bull gt 2 dosi o dosi inadeguate di BDZ
bull Depressione respiratoria
bull Trattati in emergenza extraospedaliera
complicazioni
Complicazioni sistemiche dello status epilepticus
SNC cardiova
s
Resp metaboli
co
altro
Ipossiaanos
sia
IM Apneaipopnea Disidtrataz MOF
Edema Ipoipertens Insuff resp Disturbi
elettripoNaip
erK
DIC
Emorragia Aritmie Polmonite ab
ingestis
Acidosi metab Rabdomiolisi
Trombosi
venosa
Arresto Iprtens polm Necrosi
tubacutafratture
Shock
cardiogeno
EPA Necrosi
epatica acuta
Embolia polm Pancreatite
acuta
Complicazioni dello SE
bull Durata convulsioni gt 1 hrpredittore indipendente di poor outcome (mortality odds ratio di quasi 10) (4)
bull Convulsioni prolungate aumentano il rischio di danno neuronalendash Eccitotox
ndash Accumulo intracellulare di Ca++ e apoptosi
ndash Riorganizzazione sinaptica epilettogenica( e gemmazione)
ndash Deplezione di energia e inibizione della sintesi proteica e del DNA (5)
ndash ldquo Particularly vulnerable to injury are the neurons within the hippocampus cerebral cortical mantle and cerebellar Purkinje cells Selective neuronal loss has been described within the hilar area of the dentate gyrus of the hippocampus (areas CA1 and CA3) after prolonged seizures leading to the development of chronic temporal lobe epilepsy (6)rdquo
bull Manifestazioni autonomichemorte improvvisa ndash DeLorenzo RJ Status epilepticus Concepts in diagnosis and treatment Semin Neurol 1990 10396ndash
405
ndash Towne AR Pellock JM Ko D et al Determinants of mortality in status epilepticus Epilepsia 1994 3527ndash34
ndash Payne TA Bleck TP Status epilepticus Crit Care Clin 1997 13 (1)17ndash38
ndash Sloviter RS Status epilepticus-induced neuronal injury and network reorganization Epilepsia 1999 40S34ndash41
Complications of SE
bull Aminoff MJ Simon RP Status epilepticus causes clinical features and consequences in 98 patients Am J Med 198069657-666 Bibliographic Links [Context Link]
bull 25 Wasterlain CG Fujikawa DG Penix L Sankar R Pathophysiological mechanisms of brain damage from status epilepticus Epilepsia 199334(1)S37-S53 Bibliographic Links [Context Link]
bull 26 Singhal PC Chugh KS Golati DR Myoglobinuria and renal failure after status epilepticus Neurology 197828200-201 Bibliographic Links [Context Link]
bull 27 Fisher S Zatuchni J Greenberg J Disseminated intravascular coagulation in status epilepticus Thromb Haemost 197738909-913 Bibliographic Links [Context Link]
Neuroprotective effects of acidosis
bull some studies that suggest that hypoxia acidosis and hypoglycaemia may be neuroprotective [2829] To
study these phenomena further Sasahira and coworkers [30bull31bull] looked at a rat model of status epilepticus based upon repeated bicuculline injections and using heat shock protein as an indirect measure of neuronal injury Using high concentrations of inhaled carbon dioxide they were able to reduce the serum pH from 755 to 717 This resulted in a shorter seizure duration and less neuronal damage [30bull] Using multiple regression analysis they were able to show a neuroprotective effect of shortening seizure duration and an independent effect of acidosis [30bull] Acidosis and raised carbon dioxide tensions have a profound effect on cerebral blood flow and whether the neuroprotective effect is due to haemodynamic effects or to the effect of acidoisis on receptors or transmitter release is unknown
bull A further study from the same group [31bull] looked at the effects of moderate hypoxia (PaO2=50 mmHg) on neuronal damage in the same model compared with normoxic controls There was no difference in neuronal injury detected suggesting that moderate hypoxia has no effect on neuronal death in status epilepticus The authors rightly conclude however that the implications of their findings for the treatment of status epilepticus are unclear as more severe hypoxia could result in additional ischaemic injury to the brain
bull 28 Blennow G Brierley JB Meldrum BS Siesjouml BK Epileptic brain damage The role of sysemic factors that modify cerebral energy metabolism Brain 1978101687-700 Bibliographic Links [Context Link]
bull 29 Meldrum BS Brierley JB Prolonged epileptic seizures in primates Ischaemic cell change and its relation to ictal physiological events Arch Neurol 19732810-17 Bibliographic Links [Context Link]
bull 30 bull Sasahira M Lowry T Simon RP Neuronal injury in experimental status epilepticus in the rat role of acidosis Neurosci Lett 1997224177-180 Bibliographic Links See [31bull] [Context Link]
bull 31 bull Sasahira M Simon RP Greenberg DA Neuronal injury in experimental status epilepticus in the rat role of hypoxia Neurosci Lett 1997222207-209 Bibliographic Links Thie paper and [30bull] are excellent reports considering the influence of physiological parameters on neuronal damage induced by status epilepticus [Context Link]
Effetti collaterali della fenitoina ev
bull Lesioni dei tessuti mollicon o senza
stravasordquoPurple Handgt 40 casi con parecchie
amputazioni ( (Kilarski 1984 Rao et al 1988
Hanna 1992)
bull Problemi al sito di iniezione Earnest et al (1983)
30 su 200
bull Ipotensione in gt 25 dei pazcon aritmie
ndash In 3139 pazienti 1 FA (velocitagrave di infus 26 mgmin) 1
tachic sinusale 1 allungamento tratto PR
ndash (Gellerman and Martinex 1967 Goldschlager and
Karliner 1967 Louis et al 1967 Voigt 1968)
bull
Allen FH Runge JW Legarda S et al Multicenter open-label
study on safety tolerance and pharmacokinetics of
intravenous fosphenytoin (Cerebyx) in status epilepticus
[abstract] Epilepsia 199435(Suppl 18)93
bull Data have been published from 40 patients in status epilepticus who received fosphenytoin at a mean infusion rate of 92 mgmin ranging from 247 to 1113 mgmin) Status epilepticus was terminated in 37 of 40 patients (85) within 30 min of receiving fosphenytoin The rapid infusion was well tolerated with only mild or transient side effects Most of the side effects reported were attributable to the pharmacologic effect of phenytoin and included dizziness nystagmus and ataxia Most patients in this trial received a benzodiazepine before the infusion of fosphenytoin and no adverse drug interactions were found
Introduzione alla peculiaritagrave
dellrsquoambiente intensivistico
Convulsioni in ambiente intensivo
bull Sepsi
bull Cause mediche
bull Anormalitagrave metaboliche(30-35) (11)ndash Iponatremiaipocalcemiaipofosfatemiaipoglicemiauremia
ndash Alterazioni della osmolaritagrave specie correzione acuta bull Acute return from hyperosmolarity back to normal levels in a rat
neocortical slice preparation by lowering the D-glucose concentration increased the amplitude of evoked early and late excitatory postsynaptic potentials a situation reminiscent of the generalized convulsions that may follow acute reduction of glucose in diabetic nonketotic hyperglycemia (42)
ndash Ipoosmolaritagrave induce increased nervous system excitability by strengthening both excitatory synaptic communications in neocortex and field effects among the entire cortical population (41)
Problemi peculiari allrsquoambiente
intensivistico
bull Polifarmacologia
bull Insuff renale
bull Insuff epatica
bull Induzione enzimatica
bull Inibizione enzimatica
bull Ipodisprotidemiehellipfarmaci altamente
legati alle prot plasmatiche
Trattamento dello stato di
male
Allora
bull Terapia immediata
bull Aggressiva
bull Supporto vitale di base
bull AAirway
bull Breathing
bull CSupporto circolatorio
Status epilepticusfilosofia del trattamento
Disaccoppiamento
CMRO2CBF
Funzione cardiocircolatoriaFunzione resp
Supporto supernormale
Glucosio
Tiamina 100 mg
Dopaminanoradrenalina + fre con barbituricihellip
Indagine conoscitiva su 127 TI NCH europeeDauch WA Schutze M Guttinger M et al Posttraumatic seizure prevention - results of a
survey of 127 neurosurgery clinics Zentralbl Neurochir 1996 57190ndash5
0
10
20
30
40
50
60
profilassi
Profilassi con anticonvulsivi post trauma cranio-
encefalico
mai
sempre
secindicazione
substantial cortical
injurycerebral contusion
acute subdural
hemorrhage
depressed skull fracture
penetrating missile
injury
(141517)
Rischio convulsivo
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001bull Background It is uncertain whether the administration of benzodiazepines by paramedics is an
effective and safe treatment for out-of-hospital status epilepticus
Methods We conducted a randomized double-blind trial to evaluate intravenous benzodiazepines administered by paramedics for the treatment of out-of-hospital status epilepticus Adults with prolonged (lasting five minutes or more) or repetitive generalized convulsive seizures received intravenous diazepam (5 mg) lorazepam (2 mg) or placebo An identical second injection was given if needed
Results Of the 205 patients enrolled 66 received lorazepam 68 received diazepam and 71 received placebo Status epilepticus had been terminated on arrival at the emergency department in more patients treated with lorazepam (591 percent) or diazepam (426 percent) than patients given placebo (211 percent) (P=0001) After adjustment for covariates the odds ratio for termination of status epilepticus by the time of arrival in the lorazepam group as compared with the placebo group was 48 (95 percent confidence interval 19 to 130) The odds ratio was 19 (95 percent confidence interval 08 to 44) in the lorazepam group as compared with the diazepam group and 23 (95 percent confidence interval 10 to 59) in the diazepam group as compared with the placebo group The rates of respiratory or circulatory complications after the study treatment was administered were 106 percent for the lorazepam group 103 percent for the diazepam group and 225 percent for the placebo group (P=008)
Conclusions Benzodiazepines are safe and effective when administered by paramedics for out-of-hospital status epilepticus in adults Lorazepam is likely to be a better therapy than diazepam (N Engl J Med 2001345631-7)
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001
0
10
20
30
40
50
60
seizures stop complications
lorazepam
diazepam
placebo
randomized double-blind trial
to evaluate iv bdz
admin by paramedics
for the treatment of out-of-hospital status epilepticus
Adults with prolonged (lasting 5 minutes or +)
or repetitive generalized convulsive seizures
received iv diazepam (5 mg)
lorazepam (2 mg) or placebo
An identical second injection was given if needed
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
Treiman DM Meyers PD Walton NY Collins JF Colling C Rowan AJ et al A comparison of four treatments for generalized convulsive status epilepticus N Engl J Med 1998 339792-798
randomized double-blind trial that compared the following four regimens commonly used for the treatment of generalized convulsive status epilepticus diazepam followed by phenytoin phenytoin alone phenobarbital and lorazepam Although the doses and infusion rates chosen for study closely reflected common clinical practice at the time the study began the combination of lorazepam followed by phenytoin (the preferred regimen of many neurologists) was not included
This is a large well-controlled and important clinical trial The major limitation in its clinical relevance is the lack of inclusion of a regimen consisting of lorazepam followed by phenytoin
Veterans Affairs Status Epilepticus Cooperative
Study Group Treiman et al
SE aperto
diaz fenitoina fenobarbital lorazepam
2 o + convuls senza
ripresa di coscienza
Convuls continue = gt 10 min
fenitoina
Coma con scariche
ictali EEG
primary outcome measure
cessation of clinical and electrical
seizure activity
within 20min after initiation
of treatment and continuing for at least
60min after the start of treatment
lorazepam fenitoina
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
bull st treatment successful in 555 of patients with a verified diagnosis of overt status epilepticus (n=384) and in 149 of patients with subtle status epilepticus (n=134)
bull Comparisons between the 4 treatments showed that lorazepam was more effective than phenytoin alone in patients with overt status epilepticus (treatment success in 649 versus 436 of patients respectively)
bull other treatment comparisons in the overt group and all comparisons in the subtle group were not significantly different however
bull There were no significant differences between treatments in patient outcome rates of recurrence of status epilepticus or return of full consciousness over the 12-h observation period or in the frequency of adverse cardiac respiratory or hypotensive events
Treiman DM Meyers PD Walton NY et al A
comparison of four treatments for generalized
convulsive status epilepticus N Engl J Med 1998
339792-798
P 002
Percentage of successful treatment
grey bars overt patients black bars subtle patients
Alldredge Brian Kab Lowenstein Daniel HAC Status
epilepticus new concepts Current Opinion in Neurology
121999 183-190
Da ChapmanAnaesthesia 2004
Marik PEVaron J The Management of Status
Epilepticus Chest 126(2)582-591 August 2004
Status epilepticus is a major medical emergency associated with significant morbidity and mortality Status epilepticusis best defined as a continuous generalized convulsive seizure lasting gt 5 min or two or more seizures during which the patient does not return to baseline consciousness Lorazepam in a dose of 01 mgkg is the drug of first choice for terminating status epilepticus Patients who continue to have clinical or EEG evidence of seizure activity after treatment with lorazepam should be considered to have refractory status epileptics and should be treated with a continuous infusion of propofol or midazolam This article reviews current information regarding the management of status epilepticus in adults
Schema di Marik et al
Claassen JHirsch LJ Emerson R GBates
JE Thompson TBMayer SA Continuous EEG
monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042 bull The authors reviewed 33 episodes of RSE treated with cIV-MDZ in their neurologic intensive care
unit over 6 years All patients were monitored with continuous EEG (cEEG) MDZ infusion rates were titrated to eliminate clinical and EEG seizure activity cIV-MDZ was discontinued once patients were seizure-free for 24 hours Acute treatment failures (seizures 1 to 6 hours after starting cIV-MDZ) breakthrough seizures (after 6 hours of therapy) post-treatment seizures (within 48 hours of discontinuing therapy) and ultimate treatment failure (frequent seizures that led to treatment with pentobarbital or propofol) were identified
bull Results All patients were in nonconvulsive SE at the time cIV-MDZ was started the mean duration of SE before treatment was 39 days (range 0 to 17 days) In addition to benzodiazepines 94 of patients had received at least two antiepileptic drugs (AED) before starting cIV-MDZ The mean loading dose was 019 mgkg the mean maximal infusion rate was 022 mgkgh and the mean duration of cIV-MDZ therapy was 42 days (range 1 to 14 days) Acute treatment failure occurred in 18 (633) of episodes breakthrough seizures in 56 (1832) post-treatment seizures in 68 (1928) and ultimate treatment failure in 18 (633) Breakthrough seizures were clinically subtle or purely electrographic in 89 (1618) of cases and were associated with an increased risk of developing post-treatment seizures (p = 001)
bull Conclusions Although most patients with RSE initially responded to cIV-MDZ over half developed subsequent breakthrough seizures which were predictive of post-treatment seizures and were often detectable only with cEEG Titrating cIV-MDZ to burst suppression more aggressive treatment with concurrent AED or a longer period of initial treatment may reduce the high proportion of patients with RSE who relapse after cIV-MDZ is discontinued
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus Neurology 2001 57 25 1036-1042
0
10
20
30
40
50
60
70
80
non seizures
seizures lt30 min24h05-12 h
seizures 05-12 h24 hgt 12 h
seiz gt12 h24
burst suppression
periodic latdischarge
periodic gen discharge
prima
durante
dopo
33 episodes of RSE treated with cIV-MDZ neurologic ICU over 6 years
All patients were monitored with continuous EEG (cEEG)
Waterhouse Elizabeth J 1 2 DeLorenzo Robert J 1 3 4 2
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
bull Status epilepticus (SE) is a medical and neurological emergency that has been associated with significant morbidity and mortality The most widely accepted definition of SE is more than 30 minutes of either continuous seizure activity or intermittent seizures without full recovery of consciousness between seizures SE is a major clinical concern in the elderly population both because it has increased incidence in the elderly compared with the general population and because of concurrent medical conditions that are more likely to complicate therapy and worsen prognosis in elderly individuals
The incidence of SE in the elderly is almost twice that of the general population at 86 per 100 000 per year With the anticipated growth of the elderly population SE is likely to become an increasingly common problem facing clinicians and an important public health issue The elderly have the highest SE-associated mortality of any age group at 38 and the very old elderly (gt80 years of age) have a mortality of at least 50 Acute or remote stroke is the most common aetiology of SE in the elderly Nonconvulsive SE (NCSE) has a wide range of clinical presentations ranging from confusion to obtundation It occurs commonly in elderly patients who are critically ill and in the setting of coma Electroencephalogram is the only reliable method of diagnosing NCSE
The goal of treatment for SE is rapid cessation of clinical and electrical seizure activity Most treatment protocols call for the immediate administration of an intravenous benzodiazepine followed by phenytoin or fosphenytoin Recent studies suggest that when this initial treatment of SE fails little is gained by using additional standard drugs General anaesthetic agents (such as pentobarbital midazolam or propofol) should be expeditiously employed although these treatments have their own potential complications Intravenous valproic acid is a recent addition to the armamentarium of drugs for the treatment of SE with a low risk of hypotension respiratory depression and hypotension making it a potentially useful drug for the treatment of SE in the elderly However further information is needed to establish its role in the overall treatment of SE
Waterhouseet al
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
BDZ
Fenitoina
O fosfenitoina
GA
Midaz
Propof
pentobarb
Ac valproico
Ns proposta
Lorazepam
01 mgkg
Propofol
1-2 mgkgMidazolam01 mgkg
Inf cont 3-10 mgkgh Inf cont 001-005 mgkgh
Miorilassante solo
Per intubazione
Pentobarbital dose caricopoi 01-04 mgkgmin
fenobarbital
bull 10-20 mgkg iv
ndash Eccessiva sedazione
ndash Depressresp
ndash Ipotensione
ndash Interaz farmacol
ndash Hl gt48 hrhelliphelliphellip
tiopental
bull cumulativo
bull Inotropo neghellip
bull Pentobarbital
bull immunosoppressione
propofol
bull Vantaggi cineticodinamici
bull Titolazione continua possibile
bull TCIquale livello
bull Dosi 1 mgkgripetibile dopo 5rsquo-
ndash Infcont 2-10 mgkgh
bull Rapida emergenzafinestra neurologicaevitare la
brusca sospensione
bull + rapido controllo delle convuls gt barbituricindash Stecker MM Kramer TH Raps EC OMeeghan R Dulaney E Skaar DJ Treatment of
refractory status epilepticus with propofol clinical and pharmacokinetic findings Epilepsia 1998
39 18-26
AG
bull Non ci sono dati che indichino quanto a lungo i paz debbano rimanere senza convuls prima di poter alleggerire il piano di AG24 h96h (Treiman DM Convulsive status
epilepticus Current Treatment Options in Neurology 1999 1 359-69)
bull Anest alogenatiisofluranogtsevofluranogtdesflurane
bull Ma vaporizzatori
bull Contaminazione ambientale
bull Costihellip
Studi comparativi1
bull Midazolamgt tiopental
ndash Lohr A Jr Werneck LC Comparative non-randomized study with
midazolam versus thiopental in children with refractory status
epilepticus [Portuguese] Arq Neuropsiquiatr 2000 58282-287
ndash non-randomized comparison
ndash of historical data (thiopental) and prospectively
acquired data (midazolam)
ndash Midazolam was no more often effective than
thiopental but was associated with less cyanosis and
less respiratory distress in this study of 50 children
Studi comparativi2
Valproatobull Valproate(ivrdquoDepaconrdquo) has been used for the treatment of refractory SE
in children and myoclonic SE ndash Sheth RD Gidal BE Intravenous valproic acid for myoclonic status epilepticus
Neurology 2000 541201
ndash Uberall MA Trollmann R Wunsiedler U Wenzel D Intravenous valproate in pediatric epilepsy patients with refractory status epilepticus Neurology 2000 542188-2189 ]
bull Valproate has also been used in SE in the elderly and appears to be safe even in the presence of cardiovascular instability and hypotension no significant change in blood pressure pulse or the need for vasopressors in 13 patients with SE and hypotension given a loading dose of 147-327 mgkg Depacon intravenouslyndash Sinha S Naritoku DK Intravenous valproate is well tolerated in unstable patients
with status epilepticus Neurology 2000 55722-724
bull However there is a case report of severe hypotension in an 11-year-old child after treatment of SE with 30 mgkg intravenous valproate ndash White JR Santos CS Intravenous valproate associated with significant
hypotension in the treatment of status epilepticus J Child Neurol 1999 14822-823
FINE
Percheacute non ne possiamo
piugravehelliphelliphellip
Schema delle modificazioni
neurofisiologicheparte I
Aum richieste
O2 cerebrali
Aum CBFAum Attivitagrave
autonomica
Aum PA
Aum glicemia
Sudorazione
Salivazione
iperpiressia
Schema delle modificazioni
neurofisiologicheparte II
Fallimento
Autoregolaz
cerebrale
Diminuz
CBF
Aum
ICP
Ipotensione
sistemicaDiminuz CPP
Disequilibrio
Apporto O2 cerebrale
E
richiesteDissociazione
Elettro EEG meccanica convuls
Mortalitagrave
bull overall mortality 21(Rochester)ndash Logroscino G Hesdorffer DC Cascino G Annegers
JF Hauser WA Short-term mortality after a first episode of status epilepticus Epilepsia 1997381344-1349
ndash Most of these deaths (89) occurred in those with an acute symptomatic aetiology especially anoxic encephalopathy or cerebrovascular disease
ndash When analysed for other factors only age (gt65 years) and sex (male) contributed significantly to the risk of death this appeared to be independent of aetiology In the overall analysis however length of status epilepticus was not an independent predictor of mortality Whether it is the underlying aetiology itself or the status epilepticus that has a major influence on mortality cannot be determined from this study
Mortalitagrave da CSE amp NCSE
0
10
20
30
40
50
60
70
80
90
DE Lorenzo 1998
Drislane 1994
Litt 1998
Labar 1998
Privitera 1994
10 elderly patients with
stroke tumors
head injury
electroconvulsive therapy
and metabolic derangements
3 died from infection 48 patients with
serious medical illnesses
but without prior epilepsy
coma after
convulsive SE
critic
ally
ill eld
erly
42 pts
Epilepsy
stroke
Generalized
SE
Morbilitagrave e mortalitagrave
bull Morte 10 -35 (Hauser 1983 DeLorenzo et
al 1996)
bull Morbilitagrave cognitiva e neurologica 10 - 35
(Hauser 1983 Dodrill and Wilensky 1990
DeLorenzo et al 1996 Cascino et al 1998)
bull Epilessia cronica (30 dei bambini che si
presentano inizialmente in status) (Shinnar et
al 1992)
bull SE ricorrente (15 - 20 dei bambini ) (Shinnar et
al 1992)
Morbiditagrave legata al trattamentodepressione
respiratoria
0
5
10
15
20
25
30
35
40
45
depr resp
diazepam
lorazepamWyeth
loraz Walker
loraz Levy
Incidenza di effetti collaterali nello studio
comparativo di Treiman et al
vs IrgantuaTreiman DM Meyers PD Walton NY et al A comparison of four treatments for
generalized convulsive status epilepticus N Engl J Med 1998339792-8
0
5
10
15
20
25
30
35
ipotensione ipoventilazione disturbi ritmo
cardiaco
diazepam+ fenitoina
fenitoina
lorazepam
fenobarbital
midazolam
prognosi
PrognosiSE vs NCSE
bull Necessitagrave di una attenta stratificazione
bull studies drawn from the intensive care setting (Drislane and Schomer 1994 DeLorenzo et al 1998 Litt et al 1998) are faced with the markedly greater task of determining the selective consequences and morbidity of the superadded insult of the epileptic electrical activity combined with the medical and neurologic problems that sent the patient to the intensive care setting or resulted in coma in the first place
Prognosi 2
NON Convulsive (NCSE) Status
Epilepticus(Hosford 1999)
bull 1 Generalized SE in nonconvulsing well-oxygenated animals produces brain damage (Wasterlain et al 1993) In paralyzed oxygen-ventilated baboons with over 3 hours of electrographic seizure activity there was neuronal necrosis in the hippocampal neocortex even when systemic complications and no convulsions were seen (Meldrum et al 1973) Flurothyl-induced seizures in O2-ventilated rats caused brain lesions that included infarction of the substantia nigra (Nevander et al 1985)
bull 2 Focal seizures can induce neuronal necrosis (Wasterlain et al 1993) Necrosis of hilar interneurons and CA3 pyramidal cells occurs with electrical stimulation of the afferent pathway for 2 to 24 hours (Sloviter 1983) with similar changes seen with intraventricular glutamate or aspartate injection (Sloviter and Dempster 1985)
bull 3 Limbic seizures can cause brain damage Cholinomimetics kainic acid and other methods to produce limbic SE can result in neuronal necrosis in the hippocampus amygdala piriform and entorhinal cortices the thalamus lateral septum substantia nigra and neocortex (Olney et al 1974 1983 Strain and Tasker 1991)
La prognosi finale dipende dalla eziologia
The possible relationships among seizure etiology
nonconvulsive status
epilepticus and outcome
Most patients with complex partial status epilepticus (CPSE)
have etiologies consistent with pathway [circled digit one]
(strokes anoxiaischemia head trauma encephalitis)
rather than [circled digit two]
The best example of [circled digit two] would be a patient with
temporal lobe epilepsy
who went into CPSE because of inadequate
antiepileptic drug levels
Fattori che influenzano la prognosi nello
SE(anche NCSE)
bull Causa dello stato
epilettico
bull Durata dello stato
bull Trattamento
bull Etagrave
bull Effetti dannosi sistemici metabolici e fisiologici (Meldrum et al 1973 Simon 1985)
bull Danno cerebrale secondario allrsquo insulto acuto che induce SE (Hauser 1983 Barry et al 1993)
bull Danno neuronale diretto dovuto alla abnorme attivitagrave elettrica del SE (Meldrum et al 1973 Knopman et al 1977 Lothman 1990)
Chin RFMVerhulst LNeville BGRPeters MJScott RC
Inappropriate emergency management of status epilepticus
in children contributes to need for intensive care Journal of
Neurology Neurosurgery amp Psychiatry 75(11)1584-
1588 2004
bull gt 2 dosi o dosi inadeguate di BDZ
bull Depressione respiratoria
bull Trattati in emergenza extraospedaliera
complicazioni
Complicazioni sistemiche dello status epilepticus
SNC cardiova
s
Resp metaboli
co
altro
Ipossiaanos
sia
IM Apneaipopnea Disidtrataz MOF
Edema Ipoipertens Insuff resp Disturbi
elettripoNaip
erK
DIC
Emorragia Aritmie Polmonite ab
ingestis
Acidosi metab Rabdomiolisi
Trombosi
venosa
Arresto Iprtens polm Necrosi
tubacutafratture
Shock
cardiogeno
EPA Necrosi
epatica acuta
Embolia polm Pancreatite
acuta
Complicazioni dello SE
bull Durata convulsioni gt 1 hrpredittore indipendente di poor outcome (mortality odds ratio di quasi 10) (4)
bull Convulsioni prolungate aumentano il rischio di danno neuronalendash Eccitotox
ndash Accumulo intracellulare di Ca++ e apoptosi
ndash Riorganizzazione sinaptica epilettogenica( e gemmazione)
ndash Deplezione di energia e inibizione della sintesi proteica e del DNA (5)
ndash ldquo Particularly vulnerable to injury are the neurons within the hippocampus cerebral cortical mantle and cerebellar Purkinje cells Selective neuronal loss has been described within the hilar area of the dentate gyrus of the hippocampus (areas CA1 and CA3) after prolonged seizures leading to the development of chronic temporal lobe epilepsy (6)rdquo
bull Manifestazioni autonomichemorte improvvisa ndash DeLorenzo RJ Status epilepticus Concepts in diagnosis and treatment Semin Neurol 1990 10396ndash
405
ndash Towne AR Pellock JM Ko D et al Determinants of mortality in status epilepticus Epilepsia 1994 3527ndash34
ndash Payne TA Bleck TP Status epilepticus Crit Care Clin 1997 13 (1)17ndash38
ndash Sloviter RS Status epilepticus-induced neuronal injury and network reorganization Epilepsia 1999 40S34ndash41
Complications of SE
bull Aminoff MJ Simon RP Status epilepticus causes clinical features and consequences in 98 patients Am J Med 198069657-666 Bibliographic Links [Context Link]
bull 25 Wasterlain CG Fujikawa DG Penix L Sankar R Pathophysiological mechanisms of brain damage from status epilepticus Epilepsia 199334(1)S37-S53 Bibliographic Links [Context Link]
bull 26 Singhal PC Chugh KS Golati DR Myoglobinuria and renal failure after status epilepticus Neurology 197828200-201 Bibliographic Links [Context Link]
bull 27 Fisher S Zatuchni J Greenberg J Disseminated intravascular coagulation in status epilepticus Thromb Haemost 197738909-913 Bibliographic Links [Context Link]
Neuroprotective effects of acidosis
bull some studies that suggest that hypoxia acidosis and hypoglycaemia may be neuroprotective [2829] To
study these phenomena further Sasahira and coworkers [30bull31bull] looked at a rat model of status epilepticus based upon repeated bicuculline injections and using heat shock protein as an indirect measure of neuronal injury Using high concentrations of inhaled carbon dioxide they were able to reduce the serum pH from 755 to 717 This resulted in a shorter seizure duration and less neuronal damage [30bull] Using multiple regression analysis they were able to show a neuroprotective effect of shortening seizure duration and an independent effect of acidosis [30bull] Acidosis and raised carbon dioxide tensions have a profound effect on cerebral blood flow and whether the neuroprotective effect is due to haemodynamic effects or to the effect of acidoisis on receptors or transmitter release is unknown
bull A further study from the same group [31bull] looked at the effects of moderate hypoxia (PaO2=50 mmHg) on neuronal damage in the same model compared with normoxic controls There was no difference in neuronal injury detected suggesting that moderate hypoxia has no effect on neuronal death in status epilepticus The authors rightly conclude however that the implications of their findings for the treatment of status epilepticus are unclear as more severe hypoxia could result in additional ischaemic injury to the brain
bull 28 Blennow G Brierley JB Meldrum BS Siesjouml BK Epileptic brain damage The role of sysemic factors that modify cerebral energy metabolism Brain 1978101687-700 Bibliographic Links [Context Link]
bull 29 Meldrum BS Brierley JB Prolonged epileptic seizures in primates Ischaemic cell change and its relation to ictal physiological events Arch Neurol 19732810-17 Bibliographic Links [Context Link]
bull 30 bull Sasahira M Lowry T Simon RP Neuronal injury in experimental status epilepticus in the rat role of acidosis Neurosci Lett 1997224177-180 Bibliographic Links See [31bull] [Context Link]
bull 31 bull Sasahira M Simon RP Greenberg DA Neuronal injury in experimental status epilepticus in the rat role of hypoxia Neurosci Lett 1997222207-209 Bibliographic Links Thie paper and [30bull] are excellent reports considering the influence of physiological parameters on neuronal damage induced by status epilepticus [Context Link]
Effetti collaterali della fenitoina ev
bull Lesioni dei tessuti mollicon o senza
stravasordquoPurple Handgt 40 casi con parecchie
amputazioni ( (Kilarski 1984 Rao et al 1988
Hanna 1992)
bull Problemi al sito di iniezione Earnest et al (1983)
30 su 200
bull Ipotensione in gt 25 dei pazcon aritmie
ndash In 3139 pazienti 1 FA (velocitagrave di infus 26 mgmin) 1
tachic sinusale 1 allungamento tratto PR
ndash (Gellerman and Martinex 1967 Goldschlager and
Karliner 1967 Louis et al 1967 Voigt 1968)
bull
Allen FH Runge JW Legarda S et al Multicenter open-label
study on safety tolerance and pharmacokinetics of
intravenous fosphenytoin (Cerebyx) in status epilepticus
[abstract] Epilepsia 199435(Suppl 18)93
bull Data have been published from 40 patients in status epilepticus who received fosphenytoin at a mean infusion rate of 92 mgmin ranging from 247 to 1113 mgmin) Status epilepticus was terminated in 37 of 40 patients (85) within 30 min of receiving fosphenytoin The rapid infusion was well tolerated with only mild or transient side effects Most of the side effects reported were attributable to the pharmacologic effect of phenytoin and included dizziness nystagmus and ataxia Most patients in this trial received a benzodiazepine before the infusion of fosphenytoin and no adverse drug interactions were found
Introduzione alla peculiaritagrave
dellrsquoambiente intensivistico
Convulsioni in ambiente intensivo
bull Sepsi
bull Cause mediche
bull Anormalitagrave metaboliche(30-35) (11)ndash Iponatremiaipocalcemiaipofosfatemiaipoglicemiauremia
ndash Alterazioni della osmolaritagrave specie correzione acuta bull Acute return from hyperosmolarity back to normal levels in a rat
neocortical slice preparation by lowering the D-glucose concentration increased the amplitude of evoked early and late excitatory postsynaptic potentials a situation reminiscent of the generalized convulsions that may follow acute reduction of glucose in diabetic nonketotic hyperglycemia (42)
ndash Ipoosmolaritagrave induce increased nervous system excitability by strengthening both excitatory synaptic communications in neocortex and field effects among the entire cortical population (41)
Problemi peculiari allrsquoambiente
intensivistico
bull Polifarmacologia
bull Insuff renale
bull Insuff epatica
bull Induzione enzimatica
bull Inibizione enzimatica
bull Ipodisprotidemiehellipfarmaci altamente
legati alle prot plasmatiche
Trattamento dello stato di
male
Allora
bull Terapia immediata
bull Aggressiva
bull Supporto vitale di base
bull AAirway
bull Breathing
bull CSupporto circolatorio
Status epilepticusfilosofia del trattamento
Disaccoppiamento
CMRO2CBF
Funzione cardiocircolatoriaFunzione resp
Supporto supernormale
Glucosio
Tiamina 100 mg
Dopaminanoradrenalina + fre con barbituricihellip
Indagine conoscitiva su 127 TI NCH europeeDauch WA Schutze M Guttinger M et al Posttraumatic seizure prevention - results of a
survey of 127 neurosurgery clinics Zentralbl Neurochir 1996 57190ndash5
0
10
20
30
40
50
60
profilassi
Profilassi con anticonvulsivi post trauma cranio-
encefalico
mai
sempre
secindicazione
substantial cortical
injurycerebral contusion
acute subdural
hemorrhage
depressed skull fracture
penetrating missile
injury
(141517)
Rischio convulsivo
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001bull Background It is uncertain whether the administration of benzodiazepines by paramedics is an
effective and safe treatment for out-of-hospital status epilepticus
Methods We conducted a randomized double-blind trial to evaluate intravenous benzodiazepines administered by paramedics for the treatment of out-of-hospital status epilepticus Adults with prolonged (lasting five minutes or more) or repetitive generalized convulsive seizures received intravenous diazepam (5 mg) lorazepam (2 mg) or placebo An identical second injection was given if needed
Results Of the 205 patients enrolled 66 received lorazepam 68 received diazepam and 71 received placebo Status epilepticus had been terminated on arrival at the emergency department in more patients treated with lorazepam (591 percent) or diazepam (426 percent) than patients given placebo (211 percent) (P=0001) After adjustment for covariates the odds ratio for termination of status epilepticus by the time of arrival in the lorazepam group as compared with the placebo group was 48 (95 percent confidence interval 19 to 130) The odds ratio was 19 (95 percent confidence interval 08 to 44) in the lorazepam group as compared with the diazepam group and 23 (95 percent confidence interval 10 to 59) in the diazepam group as compared with the placebo group The rates of respiratory or circulatory complications after the study treatment was administered were 106 percent for the lorazepam group 103 percent for the diazepam group and 225 percent for the placebo group (P=008)
Conclusions Benzodiazepines are safe and effective when administered by paramedics for out-of-hospital status epilepticus in adults Lorazepam is likely to be a better therapy than diazepam (N Engl J Med 2001345631-7)
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001
0
10
20
30
40
50
60
seizures stop complications
lorazepam
diazepam
placebo
randomized double-blind trial
to evaluate iv bdz
admin by paramedics
for the treatment of out-of-hospital status epilepticus
Adults with prolonged (lasting 5 minutes or +)
or repetitive generalized convulsive seizures
received iv diazepam (5 mg)
lorazepam (2 mg) or placebo
An identical second injection was given if needed
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
Treiman DM Meyers PD Walton NY Collins JF Colling C Rowan AJ et al A comparison of four treatments for generalized convulsive status epilepticus N Engl J Med 1998 339792-798
randomized double-blind trial that compared the following four regimens commonly used for the treatment of generalized convulsive status epilepticus diazepam followed by phenytoin phenytoin alone phenobarbital and lorazepam Although the doses and infusion rates chosen for study closely reflected common clinical practice at the time the study began the combination of lorazepam followed by phenytoin (the preferred regimen of many neurologists) was not included
This is a large well-controlled and important clinical trial The major limitation in its clinical relevance is the lack of inclusion of a regimen consisting of lorazepam followed by phenytoin
Veterans Affairs Status Epilepticus Cooperative
Study Group Treiman et al
SE aperto
diaz fenitoina fenobarbital lorazepam
2 o + convuls senza
ripresa di coscienza
Convuls continue = gt 10 min
fenitoina
Coma con scariche
ictali EEG
primary outcome measure
cessation of clinical and electrical
seizure activity
within 20min after initiation
of treatment and continuing for at least
60min after the start of treatment
lorazepam fenitoina
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
bull st treatment successful in 555 of patients with a verified diagnosis of overt status epilepticus (n=384) and in 149 of patients with subtle status epilepticus (n=134)
bull Comparisons between the 4 treatments showed that lorazepam was more effective than phenytoin alone in patients with overt status epilepticus (treatment success in 649 versus 436 of patients respectively)
bull other treatment comparisons in the overt group and all comparisons in the subtle group were not significantly different however
bull There were no significant differences between treatments in patient outcome rates of recurrence of status epilepticus or return of full consciousness over the 12-h observation period or in the frequency of adverse cardiac respiratory or hypotensive events
Treiman DM Meyers PD Walton NY et al A
comparison of four treatments for generalized
convulsive status epilepticus N Engl J Med 1998
339792-798
P 002
Percentage of successful treatment
grey bars overt patients black bars subtle patients
Alldredge Brian Kab Lowenstein Daniel HAC Status
epilepticus new concepts Current Opinion in Neurology
121999 183-190
Da ChapmanAnaesthesia 2004
Marik PEVaron J The Management of Status
Epilepticus Chest 126(2)582-591 August 2004
Status epilepticus is a major medical emergency associated with significant morbidity and mortality Status epilepticusis best defined as a continuous generalized convulsive seizure lasting gt 5 min or two or more seizures during which the patient does not return to baseline consciousness Lorazepam in a dose of 01 mgkg is the drug of first choice for terminating status epilepticus Patients who continue to have clinical or EEG evidence of seizure activity after treatment with lorazepam should be considered to have refractory status epileptics and should be treated with a continuous infusion of propofol or midazolam This article reviews current information regarding the management of status epilepticus in adults
Schema di Marik et al
Claassen JHirsch LJ Emerson R GBates
JE Thompson TBMayer SA Continuous EEG
monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042 bull The authors reviewed 33 episodes of RSE treated with cIV-MDZ in their neurologic intensive care
unit over 6 years All patients were monitored with continuous EEG (cEEG) MDZ infusion rates were titrated to eliminate clinical and EEG seizure activity cIV-MDZ was discontinued once patients were seizure-free for 24 hours Acute treatment failures (seizures 1 to 6 hours after starting cIV-MDZ) breakthrough seizures (after 6 hours of therapy) post-treatment seizures (within 48 hours of discontinuing therapy) and ultimate treatment failure (frequent seizures that led to treatment with pentobarbital or propofol) were identified
bull Results All patients were in nonconvulsive SE at the time cIV-MDZ was started the mean duration of SE before treatment was 39 days (range 0 to 17 days) In addition to benzodiazepines 94 of patients had received at least two antiepileptic drugs (AED) before starting cIV-MDZ The mean loading dose was 019 mgkg the mean maximal infusion rate was 022 mgkgh and the mean duration of cIV-MDZ therapy was 42 days (range 1 to 14 days) Acute treatment failure occurred in 18 (633) of episodes breakthrough seizures in 56 (1832) post-treatment seizures in 68 (1928) and ultimate treatment failure in 18 (633) Breakthrough seizures were clinically subtle or purely electrographic in 89 (1618) of cases and were associated with an increased risk of developing post-treatment seizures (p = 001)
bull Conclusions Although most patients with RSE initially responded to cIV-MDZ over half developed subsequent breakthrough seizures which were predictive of post-treatment seizures and were often detectable only with cEEG Titrating cIV-MDZ to burst suppression more aggressive treatment with concurrent AED or a longer period of initial treatment may reduce the high proportion of patients with RSE who relapse after cIV-MDZ is discontinued
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus Neurology 2001 57 25 1036-1042
0
10
20
30
40
50
60
70
80
non seizures
seizures lt30 min24h05-12 h
seizures 05-12 h24 hgt 12 h
seiz gt12 h24
burst suppression
periodic latdischarge
periodic gen discharge
prima
durante
dopo
33 episodes of RSE treated with cIV-MDZ neurologic ICU over 6 years
All patients were monitored with continuous EEG (cEEG)
Waterhouse Elizabeth J 1 2 DeLorenzo Robert J 1 3 4 2
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
bull Status epilepticus (SE) is a medical and neurological emergency that has been associated with significant morbidity and mortality The most widely accepted definition of SE is more than 30 minutes of either continuous seizure activity or intermittent seizures without full recovery of consciousness between seizures SE is a major clinical concern in the elderly population both because it has increased incidence in the elderly compared with the general population and because of concurrent medical conditions that are more likely to complicate therapy and worsen prognosis in elderly individuals
The incidence of SE in the elderly is almost twice that of the general population at 86 per 100 000 per year With the anticipated growth of the elderly population SE is likely to become an increasingly common problem facing clinicians and an important public health issue The elderly have the highest SE-associated mortality of any age group at 38 and the very old elderly (gt80 years of age) have a mortality of at least 50 Acute or remote stroke is the most common aetiology of SE in the elderly Nonconvulsive SE (NCSE) has a wide range of clinical presentations ranging from confusion to obtundation It occurs commonly in elderly patients who are critically ill and in the setting of coma Electroencephalogram is the only reliable method of diagnosing NCSE
The goal of treatment for SE is rapid cessation of clinical and electrical seizure activity Most treatment protocols call for the immediate administration of an intravenous benzodiazepine followed by phenytoin or fosphenytoin Recent studies suggest that when this initial treatment of SE fails little is gained by using additional standard drugs General anaesthetic agents (such as pentobarbital midazolam or propofol) should be expeditiously employed although these treatments have their own potential complications Intravenous valproic acid is a recent addition to the armamentarium of drugs for the treatment of SE with a low risk of hypotension respiratory depression and hypotension making it a potentially useful drug for the treatment of SE in the elderly However further information is needed to establish its role in the overall treatment of SE
Waterhouseet al
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
BDZ
Fenitoina
O fosfenitoina
GA
Midaz
Propof
pentobarb
Ac valproico
Ns proposta
Lorazepam
01 mgkg
Propofol
1-2 mgkgMidazolam01 mgkg
Inf cont 3-10 mgkgh Inf cont 001-005 mgkgh
Miorilassante solo
Per intubazione
Pentobarbital dose caricopoi 01-04 mgkgmin
fenobarbital
bull 10-20 mgkg iv
ndash Eccessiva sedazione
ndash Depressresp
ndash Ipotensione
ndash Interaz farmacol
ndash Hl gt48 hrhelliphelliphellip
tiopental
bull cumulativo
bull Inotropo neghellip
bull Pentobarbital
bull immunosoppressione
propofol
bull Vantaggi cineticodinamici
bull Titolazione continua possibile
bull TCIquale livello
bull Dosi 1 mgkgripetibile dopo 5rsquo-
ndash Infcont 2-10 mgkgh
bull Rapida emergenzafinestra neurologicaevitare la
brusca sospensione
bull + rapido controllo delle convuls gt barbituricindash Stecker MM Kramer TH Raps EC OMeeghan R Dulaney E Skaar DJ Treatment of
refractory status epilepticus with propofol clinical and pharmacokinetic findings Epilepsia 1998
39 18-26
AG
bull Non ci sono dati che indichino quanto a lungo i paz debbano rimanere senza convuls prima di poter alleggerire il piano di AG24 h96h (Treiman DM Convulsive status
epilepticus Current Treatment Options in Neurology 1999 1 359-69)
bull Anest alogenatiisofluranogtsevofluranogtdesflurane
bull Ma vaporizzatori
bull Contaminazione ambientale
bull Costihellip
Studi comparativi1
bull Midazolamgt tiopental
ndash Lohr A Jr Werneck LC Comparative non-randomized study with
midazolam versus thiopental in children with refractory status
epilepticus [Portuguese] Arq Neuropsiquiatr 2000 58282-287
ndash non-randomized comparison
ndash of historical data (thiopental) and prospectively
acquired data (midazolam)
ndash Midazolam was no more often effective than
thiopental but was associated with less cyanosis and
less respiratory distress in this study of 50 children
Studi comparativi2
Valproatobull Valproate(ivrdquoDepaconrdquo) has been used for the treatment of refractory SE
in children and myoclonic SE ndash Sheth RD Gidal BE Intravenous valproic acid for myoclonic status epilepticus
Neurology 2000 541201
ndash Uberall MA Trollmann R Wunsiedler U Wenzel D Intravenous valproate in pediatric epilepsy patients with refractory status epilepticus Neurology 2000 542188-2189 ]
bull Valproate has also been used in SE in the elderly and appears to be safe even in the presence of cardiovascular instability and hypotension no significant change in blood pressure pulse or the need for vasopressors in 13 patients with SE and hypotension given a loading dose of 147-327 mgkg Depacon intravenouslyndash Sinha S Naritoku DK Intravenous valproate is well tolerated in unstable patients
with status epilepticus Neurology 2000 55722-724
bull However there is a case report of severe hypotension in an 11-year-old child after treatment of SE with 30 mgkg intravenous valproate ndash White JR Santos CS Intravenous valproate associated with significant
hypotension in the treatment of status epilepticus J Child Neurol 1999 14822-823
FINE
Percheacute non ne possiamo
piugravehelliphelliphellip
Schema delle modificazioni
neurofisiologicheparte II
Fallimento
Autoregolaz
cerebrale
Diminuz
CBF
Aum
ICP
Ipotensione
sistemicaDiminuz CPP
Disequilibrio
Apporto O2 cerebrale
E
richiesteDissociazione
Elettro EEG meccanica convuls
Mortalitagrave
bull overall mortality 21(Rochester)ndash Logroscino G Hesdorffer DC Cascino G Annegers
JF Hauser WA Short-term mortality after a first episode of status epilepticus Epilepsia 1997381344-1349
ndash Most of these deaths (89) occurred in those with an acute symptomatic aetiology especially anoxic encephalopathy or cerebrovascular disease
ndash When analysed for other factors only age (gt65 years) and sex (male) contributed significantly to the risk of death this appeared to be independent of aetiology In the overall analysis however length of status epilepticus was not an independent predictor of mortality Whether it is the underlying aetiology itself or the status epilepticus that has a major influence on mortality cannot be determined from this study
Mortalitagrave da CSE amp NCSE
0
10
20
30
40
50
60
70
80
90
DE Lorenzo 1998
Drislane 1994
Litt 1998
Labar 1998
Privitera 1994
10 elderly patients with
stroke tumors
head injury
electroconvulsive therapy
and metabolic derangements
3 died from infection 48 patients with
serious medical illnesses
but without prior epilepsy
coma after
convulsive SE
critic
ally
ill eld
erly
42 pts
Epilepsy
stroke
Generalized
SE
Morbilitagrave e mortalitagrave
bull Morte 10 -35 (Hauser 1983 DeLorenzo et
al 1996)
bull Morbilitagrave cognitiva e neurologica 10 - 35
(Hauser 1983 Dodrill and Wilensky 1990
DeLorenzo et al 1996 Cascino et al 1998)
bull Epilessia cronica (30 dei bambini che si
presentano inizialmente in status) (Shinnar et
al 1992)
bull SE ricorrente (15 - 20 dei bambini ) (Shinnar et
al 1992)
Morbiditagrave legata al trattamentodepressione
respiratoria
0
5
10
15
20
25
30
35
40
45
depr resp
diazepam
lorazepamWyeth
loraz Walker
loraz Levy
Incidenza di effetti collaterali nello studio
comparativo di Treiman et al
vs IrgantuaTreiman DM Meyers PD Walton NY et al A comparison of four treatments for
generalized convulsive status epilepticus N Engl J Med 1998339792-8
0
5
10
15
20
25
30
35
ipotensione ipoventilazione disturbi ritmo
cardiaco
diazepam+ fenitoina
fenitoina
lorazepam
fenobarbital
midazolam
prognosi
PrognosiSE vs NCSE
bull Necessitagrave di una attenta stratificazione
bull studies drawn from the intensive care setting (Drislane and Schomer 1994 DeLorenzo et al 1998 Litt et al 1998) are faced with the markedly greater task of determining the selective consequences and morbidity of the superadded insult of the epileptic electrical activity combined with the medical and neurologic problems that sent the patient to the intensive care setting or resulted in coma in the first place
Prognosi 2
NON Convulsive (NCSE) Status
Epilepticus(Hosford 1999)
bull 1 Generalized SE in nonconvulsing well-oxygenated animals produces brain damage (Wasterlain et al 1993) In paralyzed oxygen-ventilated baboons with over 3 hours of electrographic seizure activity there was neuronal necrosis in the hippocampal neocortex even when systemic complications and no convulsions were seen (Meldrum et al 1973) Flurothyl-induced seizures in O2-ventilated rats caused brain lesions that included infarction of the substantia nigra (Nevander et al 1985)
bull 2 Focal seizures can induce neuronal necrosis (Wasterlain et al 1993) Necrosis of hilar interneurons and CA3 pyramidal cells occurs with electrical stimulation of the afferent pathway for 2 to 24 hours (Sloviter 1983) with similar changes seen with intraventricular glutamate or aspartate injection (Sloviter and Dempster 1985)
bull 3 Limbic seizures can cause brain damage Cholinomimetics kainic acid and other methods to produce limbic SE can result in neuronal necrosis in the hippocampus amygdala piriform and entorhinal cortices the thalamus lateral septum substantia nigra and neocortex (Olney et al 1974 1983 Strain and Tasker 1991)
La prognosi finale dipende dalla eziologia
The possible relationships among seizure etiology
nonconvulsive status
epilepticus and outcome
Most patients with complex partial status epilepticus (CPSE)
have etiologies consistent with pathway [circled digit one]
(strokes anoxiaischemia head trauma encephalitis)
rather than [circled digit two]
The best example of [circled digit two] would be a patient with
temporal lobe epilepsy
who went into CPSE because of inadequate
antiepileptic drug levels
Fattori che influenzano la prognosi nello
SE(anche NCSE)
bull Causa dello stato
epilettico
bull Durata dello stato
bull Trattamento
bull Etagrave
bull Effetti dannosi sistemici metabolici e fisiologici (Meldrum et al 1973 Simon 1985)
bull Danno cerebrale secondario allrsquo insulto acuto che induce SE (Hauser 1983 Barry et al 1993)
bull Danno neuronale diretto dovuto alla abnorme attivitagrave elettrica del SE (Meldrum et al 1973 Knopman et al 1977 Lothman 1990)
Chin RFMVerhulst LNeville BGRPeters MJScott RC
Inappropriate emergency management of status epilepticus
in children contributes to need for intensive care Journal of
Neurology Neurosurgery amp Psychiatry 75(11)1584-
1588 2004
bull gt 2 dosi o dosi inadeguate di BDZ
bull Depressione respiratoria
bull Trattati in emergenza extraospedaliera
complicazioni
Complicazioni sistemiche dello status epilepticus
SNC cardiova
s
Resp metaboli
co
altro
Ipossiaanos
sia
IM Apneaipopnea Disidtrataz MOF
Edema Ipoipertens Insuff resp Disturbi
elettripoNaip
erK
DIC
Emorragia Aritmie Polmonite ab
ingestis
Acidosi metab Rabdomiolisi
Trombosi
venosa
Arresto Iprtens polm Necrosi
tubacutafratture
Shock
cardiogeno
EPA Necrosi
epatica acuta
Embolia polm Pancreatite
acuta
Complicazioni dello SE
bull Durata convulsioni gt 1 hrpredittore indipendente di poor outcome (mortality odds ratio di quasi 10) (4)
bull Convulsioni prolungate aumentano il rischio di danno neuronalendash Eccitotox
ndash Accumulo intracellulare di Ca++ e apoptosi
ndash Riorganizzazione sinaptica epilettogenica( e gemmazione)
ndash Deplezione di energia e inibizione della sintesi proteica e del DNA (5)
ndash ldquo Particularly vulnerable to injury are the neurons within the hippocampus cerebral cortical mantle and cerebellar Purkinje cells Selective neuronal loss has been described within the hilar area of the dentate gyrus of the hippocampus (areas CA1 and CA3) after prolonged seizures leading to the development of chronic temporal lobe epilepsy (6)rdquo
bull Manifestazioni autonomichemorte improvvisa ndash DeLorenzo RJ Status epilepticus Concepts in diagnosis and treatment Semin Neurol 1990 10396ndash
405
ndash Towne AR Pellock JM Ko D et al Determinants of mortality in status epilepticus Epilepsia 1994 3527ndash34
ndash Payne TA Bleck TP Status epilepticus Crit Care Clin 1997 13 (1)17ndash38
ndash Sloviter RS Status epilepticus-induced neuronal injury and network reorganization Epilepsia 1999 40S34ndash41
Complications of SE
bull Aminoff MJ Simon RP Status epilepticus causes clinical features and consequences in 98 patients Am J Med 198069657-666 Bibliographic Links [Context Link]
bull 25 Wasterlain CG Fujikawa DG Penix L Sankar R Pathophysiological mechanisms of brain damage from status epilepticus Epilepsia 199334(1)S37-S53 Bibliographic Links [Context Link]
bull 26 Singhal PC Chugh KS Golati DR Myoglobinuria and renal failure after status epilepticus Neurology 197828200-201 Bibliographic Links [Context Link]
bull 27 Fisher S Zatuchni J Greenberg J Disseminated intravascular coagulation in status epilepticus Thromb Haemost 197738909-913 Bibliographic Links [Context Link]
Neuroprotective effects of acidosis
bull some studies that suggest that hypoxia acidosis and hypoglycaemia may be neuroprotective [2829] To
study these phenomena further Sasahira and coworkers [30bull31bull] looked at a rat model of status epilepticus based upon repeated bicuculline injections and using heat shock protein as an indirect measure of neuronal injury Using high concentrations of inhaled carbon dioxide they were able to reduce the serum pH from 755 to 717 This resulted in a shorter seizure duration and less neuronal damage [30bull] Using multiple regression analysis they were able to show a neuroprotective effect of shortening seizure duration and an independent effect of acidosis [30bull] Acidosis and raised carbon dioxide tensions have a profound effect on cerebral blood flow and whether the neuroprotective effect is due to haemodynamic effects or to the effect of acidoisis on receptors or transmitter release is unknown
bull A further study from the same group [31bull] looked at the effects of moderate hypoxia (PaO2=50 mmHg) on neuronal damage in the same model compared with normoxic controls There was no difference in neuronal injury detected suggesting that moderate hypoxia has no effect on neuronal death in status epilepticus The authors rightly conclude however that the implications of their findings for the treatment of status epilepticus are unclear as more severe hypoxia could result in additional ischaemic injury to the brain
bull 28 Blennow G Brierley JB Meldrum BS Siesjouml BK Epileptic brain damage The role of sysemic factors that modify cerebral energy metabolism Brain 1978101687-700 Bibliographic Links [Context Link]
bull 29 Meldrum BS Brierley JB Prolonged epileptic seizures in primates Ischaemic cell change and its relation to ictal physiological events Arch Neurol 19732810-17 Bibliographic Links [Context Link]
bull 30 bull Sasahira M Lowry T Simon RP Neuronal injury in experimental status epilepticus in the rat role of acidosis Neurosci Lett 1997224177-180 Bibliographic Links See [31bull] [Context Link]
bull 31 bull Sasahira M Simon RP Greenberg DA Neuronal injury in experimental status epilepticus in the rat role of hypoxia Neurosci Lett 1997222207-209 Bibliographic Links Thie paper and [30bull] are excellent reports considering the influence of physiological parameters on neuronal damage induced by status epilepticus [Context Link]
Effetti collaterali della fenitoina ev
bull Lesioni dei tessuti mollicon o senza
stravasordquoPurple Handgt 40 casi con parecchie
amputazioni ( (Kilarski 1984 Rao et al 1988
Hanna 1992)
bull Problemi al sito di iniezione Earnest et al (1983)
30 su 200
bull Ipotensione in gt 25 dei pazcon aritmie
ndash In 3139 pazienti 1 FA (velocitagrave di infus 26 mgmin) 1
tachic sinusale 1 allungamento tratto PR
ndash (Gellerman and Martinex 1967 Goldschlager and
Karliner 1967 Louis et al 1967 Voigt 1968)
bull
Allen FH Runge JW Legarda S et al Multicenter open-label
study on safety tolerance and pharmacokinetics of
intravenous fosphenytoin (Cerebyx) in status epilepticus
[abstract] Epilepsia 199435(Suppl 18)93
bull Data have been published from 40 patients in status epilepticus who received fosphenytoin at a mean infusion rate of 92 mgmin ranging from 247 to 1113 mgmin) Status epilepticus was terminated in 37 of 40 patients (85) within 30 min of receiving fosphenytoin The rapid infusion was well tolerated with only mild or transient side effects Most of the side effects reported were attributable to the pharmacologic effect of phenytoin and included dizziness nystagmus and ataxia Most patients in this trial received a benzodiazepine before the infusion of fosphenytoin and no adverse drug interactions were found
Introduzione alla peculiaritagrave
dellrsquoambiente intensivistico
Convulsioni in ambiente intensivo
bull Sepsi
bull Cause mediche
bull Anormalitagrave metaboliche(30-35) (11)ndash Iponatremiaipocalcemiaipofosfatemiaipoglicemiauremia
ndash Alterazioni della osmolaritagrave specie correzione acuta bull Acute return from hyperosmolarity back to normal levels in a rat
neocortical slice preparation by lowering the D-glucose concentration increased the amplitude of evoked early and late excitatory postsynaptic potentials a situation reminiscent of the generalized convulsions that may follow acute reduction of glucose in diabetic nonketotic hyperglycemia (42)
ndash Ipoosmolaritagrave induce increased nervous system excitability by strengthening both excitatory synaptic communications in neocortex and field effects among the entire cortical population (41)
Problemi peculiari allrsquoambiente
intensivistico
bull Polifarmacologia
bull Insuff renale
bull Insuff epatica
bull Induzione enzimatica
bull Inibizione enzimatica
bull Ipodisprotidemiehellipfarmaci altamente
legati alle prot plasmatiche
Trattamento dello stato di
male
Allora
bull Terapia immediata
bull Aggressiva
bull Supporto vitale di base
bull AAirway
bull Breathing
bull CSupporto circolatorio
Status epilepticusfilosofia del trattamento
Disaccoppiamento
CMRO2CBF
Funzione cardiocircolatoriaFunzione resp
Supporto supernormale
Glucosio
Tiamina 100 mg
Dopaminanoradrenalina + fre con barbituricihellip
Indagine conoscitiva su 127 TI NCH europeeDauch WA Schutze M Guttinger M et al Posttraumatic seizure prevention - results of a
survey of 127 neurosurgery clinics Zentralbl Neurochir 1996 57190ndash5
0
10
20
30
40
50
60
profilassi
Profilassi con anticonvulsivi post trauma cranio-
encefalico
mai
sempre
secindicazione
substantial cortical
injurycerebral contusion
acute subdural
hemorrhage
depressed skull fracture
penetrating missile
injury
(141517)
Rischio convulsivo
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001bull Background It is uncertain whether the administration of benzodiazepines by paramedics is an
effective and safe treatment for out-of-hospital status epilepticus
Methods We conducted a randomized double-blind trial to evaluate intravenous benzodiazepines administered by paramedics for the treatment of out-of-hospital status epilepticus Adults with prolonged (lasting five minutes or more) or repetitive generalized convulsive seizures received intravenous diazepam (5 mg) lorazepam (2 mg) or placebo An identical second injection was given if needed
Results Of the 205 patients enrolled 66 received lorazepam 68 received diazepam and 71 received placebo Status epilepticus had been terminated on arrival at the emergency department in more patients treated with lorazepam (591 percent) or diazepam (426 percent) than patients given placebo (211 percent) (P=0001) After adjustment for covariates the odds ratio for termination of status epilepticus by the time of arrival in the lorazepam group as compared with the placebo group was 48 (95 percent confidence interval 19 to 130) The odds ratio was 19 (95 percent confidence interval 08 to 44) in the lorazepam group as compared with the diazepam group and 23 (95 percent confidence interval 10 to 59) in the diazepam group as compared with the placebo group The rates of respiratory or circulatory complications after the study treatment was administered were 106 percent for the lorazepam group 103 percent for the diazepam group and 225 percent for the placebo group (P=008)
Conclusions Benzodiazepines are safe and effective when administered by paramedics for out-of-hospital status epilepticus in adults Lorazepam is likely to be a better therapy than diazepam (N Engl J Med 2001345631-7)
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001
0
10
20
30
40
50
60
seizures stop complications
lorazepam
diazepam
placebo
randomized double-blind trial
to evaluate iv bdz
admin by paramedics
for the treatment of out-of-hospital status epilepticus
Adults with prolonged (lasting 5 minutes or +)
or repetitive generalized convulsive seizures
received iv diazepam (5 mg)
lorazepam (2 mg) or placebo
An identical second injection was given if needed
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
Treiman DM Meyers PD Walton NY Collins JF Colling C Rowan AJ et al A comparison of four treatments for generalized convulsive status epilepticus N Engl J Med 1998 339792-798
randomized double-blind trial that compared the following four regimens commonly used for the treatment of generalized convulsive status epilepticus diazepam followed by phenytoin phenytoin alone phenobarbital and lorazepam Although the doses and infusion rates chosen for study closely reflected common clinical practice at the time the study began the combination of lorazepam followed by phenytoin (the preferred regimen of many neurologists) was not included
This is a large well-controlled and important clinical trial The major limitation in its clinical relevance is the lack of inclusion of a regimen consisting of lorazepam followed by phenytoin
Veterans Affairs Status Epilepticus Cooperative
Study Group Treiman et al
SE aperto
diaz fenitoina fenobarbital lorazepam
2 o + convuls senza
ripresa di coscienza
Convuls continue = gt 10 min
fenitoina
Coma con scariche
ictali EEG
primary outcome measure
cessation of clinical and electrical
seizure activity
within 20min after initiation
of treatment and continuing for at least
60min after the start of treatment
lorazepam fenitoina
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
bull st treatment successful in 555 of patients with a verified diagnosis of overt status epilepticus (n=384) and in 149 of patients with subtle status epilepticus (n=134)
bull Comparisons between the 4 treatments showed that lorazepam was more effective than phenytoin alone in patients with overt status epilepticus (treatment success in 649 versus 436 of patients respectively)
bull other treatment comparisons in the overt group and all comparisons in the subtle group were not significantly different however
bull There were no significant differences between treatments in patient outcome rates of recurrence of status epilepticus or return of full consciousness over the 12-h observation period or in the frequency of adverse cardiac respiratory or hypotensive events
Treiman DM Meyers PD Walton NY et al A
comparison of four treatments for generalized
convulsive status epilepticus N Engl J Med 1998
339792-798
P 002
Percentage of successful treatment
grey bars overt patients black bars subtle patients
Alldredge Brian Kab Lowenstein Daniel HAC Status
epilepticus new concepts Current Opinion in Neurology
121999 183-190
Da ChapmanAnaesthesia 2004
Marik PEVaron J The Management of Status
Epilepticus Chest 126(2)582-591 August 2004
Status epilepticus is a major medical emergency associated with significant morbidity and mortality Status epilepticusis best defined as a continuous generalized convulsive seizure lasting gt 5 min or two or more seizures during which the patient does not return to baseline consciousness Lorazepam in a dose of 01 mgkg is the drug of first choice for terminating status epilepticus Patients who continue to have clinical or EEG evidence of seizure activity after treatment with lorazepam should be considered to have refractory status epileptics and should be treated with a continuous infusion of propofol or midazolam This article reviews current information regarding the management of status epilepticus in adults
Schema di Marik et al
Claassen JHirsch LJ Emerson R GBates
JE Thompson TBMayer SA Continuous EEG
monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042 bull The authors reviewed 33 episodes of RSE treated with cIV-MDZ in their neurologic intensive care
unit over 6 years All patients were monitored with continuous EEG (cEEG) MDZ infusion rates were titrated to eliminate clinical and EEG seizure activity cIV-MDZ was discontinued once patients were seizure-free for 24 hours Acute treatment failures (seizures 1 to 6 hours after starting cIV-MDZ) breakthrough seizures (after 6 hours of therapy) post-treatment seizures (within 48 hours of discontinuing therapy) and ultimate treatment failure (frequent seizures that led to treatment with pentobarbital or propofol) were identified
bull Results All patients were in nonconvulsive SE at the time cIV-MDZ was started the mean duration of SE before treatment was 39 days (range 0 to 17 days) In addition to benzodiazepines 94 of patients had received at least two antiepileptic drugs (AED) before starting cIV-MDZ The mean loading dose was 019 mgkg the mean maximal infusion rate was 022 mgkgh and the mean duration of cIV-MDZ therapy was 42 days (range 1 to 14 days) Acute treatment failure occurred in 18 (633) of episodes breakthrough seizures in 56 (1832) post-treatment seizures in 68 (1928) and ultimate treatment failure in 18 (633) Breakthrough seizures were clinically subtle or purely electrographic in 89 (1618) of cases and were associated with an increased risk of developing post-treatment seizures (p = 001)
bull Conclusions Although most patients with RSE initially responded to cIV-MDZ over half developed subsequent breakthrough seizures which were predictive of post-treatment seizures and were often detectable only with cEEG Titrating cIV-MDZ to burst suppression more aggressive treatment with concurrent AED or a longer period of initial treatment may reduce the high proportion of patients with RSE who relapse after cIV-MDZ is discontinued
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus Neurology 2001 57 25 1036-1042
0
10
20
30
40
50
60
70
80
non seizures
seizures lt30 min24h05-12 h
seizures 05-12 h24 hgt 12 h
seiz gt12 h24
burst suppression
periodic latdischarge
periodic gen discharge
prima
durante
dopo
33 episodes of RSE treated with cIV-MDZ neurologic ICU over 6 years
All patients were monitored with continuous EEG (cEEG)
Waterhouse Elizabeth J 1 2 DeLorenzo Robert J 1 3 4 2
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
bull Status epilepticus (SE) is a medical and neurological emergency that has been associated with significant morbidity and mortality The most widely accepted definition of SE is more than 30 minutes of either continuous seizure activity or intermittent seizures without full recovery of consciousness between seizures SE is a major clinical concern in the elderly population both because it has increased incidence in the elderly compared with the general population and because of concurrent medical conditions that are more likely to complicate therapy and worsen prognosis in elderly individuals
The incidence of SE in the elderly is almost twice that of the general population at 86 per 100 000 per year With the anticipated growth of the elderly population SE is likely to become an increasingly common problem facing clinicians and an important public health issue The elderly have the highest SE-associated mortality of any age group at 38 and the very old elderly (gt80 years of age) have a mortality of at least 50 Acute or remote stroke is the most common aetiology of SE in the elderly Nonconvulsive SE (NCSE) has a wide range of clinical presentations ranging from confusion to obtundation It occurs commonly in elderly patients who are critically ill and in the setting of coma Electroencephalogram is the only reliable method of diagnosing NCSE
The goal of treatment for SE is rapid cessation of clinical and electrical seizure activity Most treatment protocols call for the immediate administration of an intravenous benzodiazepine followed by phenytoin or fosphenytoin Recent studies suggest that when this initial treatment of SE fails little is gained by using additional standard drugs General anaesthetic agents (such as pentobarbital midazolam or propofol) should be expeditiously employed although these treatments have their own potential complications Intravenous valproic acid is a recent addition to the armamentarium of drugs for the treatment of SE with a low risk of hypotension respiratory depression and hypotension making it a potentially useful drug for the treatment of SE in the elderly However further information is needed to establish its role in the overall treatment of SE
Waterhouseet al
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
BDZ
Fenitoina
O fosfenitoina
GA
Midaz
Propof
pentobarb
Ac valproico
Ns proposta
Lorazepam
01 mgkg
Propofol
1-2 mgkgMidazolam01 mgkg
Inf cont 3-10 mgkgh Inf cont 001-005 mgkgh
Miorilassante solo
Per intubazione
Pentobarbital dose caricopoi 01-04 mgkgmin
fenobarbital
bull 10-20 mgkg iv
ndash Eccessiva sedazione
ndash Depressresp
ndash Ipotensione
ndash Interaz farmacol
ndash Hl gt48 hrhelliphelliphellip
tiopental
bull cumulativo
bull Inotropo neghellip
bull Pentobarbital
bull immunosoppressione
propofol
bull Vantaggi cineticodinamici
bull Titolazione continua possibile
bull TCIquale livello
bull Dosi 1 mgkgripetibile dopo 5rsquo-
ndash Infcont 2-10 mgkgh
bull Rapida emergenzafinestra neurologicaevitare la
brusca sospensione
bull + rapido controllo delle convuls gt barbituricindash Stecker MM Kramer TH Raps EC OMeeghan R Dulaney E Skaar DJ Treatment of
refractory status epilepticus with propofol clinical and pharmacokinetic findings Epilepsia 1998
39 18-26
AG
bull Non ci sono dati che indichino quanto a lungo i paz debbano rimanere senza convuls prima di poter alleggerire il piano di AG24 h96h (Treiman DM Convulsive status
epilepticus Current Treatment Options in Neurology 1999 1 359-69)
bull Anest alogenatiisofluranogtsevofluranogtdesflurane
bull Ma vaporizzatori
bull Contaminazione ambientale
bull Costihellip
Studi comparativi1
bull Midazolamgt tiopental
ndash Lohr A Jr Werneck LC Comparative non-randomized study with
midazolam versus thiopental in children with refractory status
epilepticus [Portuguese] Arq Neuropsiquiatr 2000 58282-287
ndash non-randomized comparison
ndash of historical data (thiopental) and prospectively
acquired data (midazolam)
ndash Midazolam was no more often effective than
thiopental but was associated with less cyanosis and
less respiratory distress in this study of 50 children
Studi comparativi2
Valproatobull Valproate(ivrdquoDepaconrdquo) has been used for the treatment of refractory SE
in children and myoclonic SE ndash Sheth RD Gidal BE Intravenous valproic acid for myoclonic status epilepticus
Neurology 2000 541201
ndash Uberall MA Trollmann R Wunsiedler U Wenzel D Intravenous valproate in pediatric epilepsy patients with refractory status epilepticus Neurology 2000 542188-2189 ]
bull Valproate has also been used in SE in the elderly and appears to be safe even in the presence of cardiovascular instability and hypotension no significant change in blood pressure pulse or the need for vasopressors in 13 patients with SE and hypotension given a loading dose of 147-327 mgkg Depacon intravenouslyndash Sinha S Naritoku DK Intravenous valproate is well tolerated in unstable patients
with status epilepticus Neurology 2000 55722-724
bull However there is a case report of severe hypotension in an 11-year-old child after treatment of SE with 30 mgkg intravenous valproate ndash White JR Santos CS Intravenous valproate associated with significant
hypotension in the treatment of status epilepticus J Child Neurol 1999 14822-823
FINE
Percheacute non ne possiamo
piugravehelliphelliphellip
Mortalitagrave
bull overall mortality 21(Rochester)ndash Logroscino G Hesdorffer DC Cascino G Annegers
JF Hauser WA Short-term mortality after a first episode of status epilepticus Epilepsia 1997381344-1349
ndash Most of these deaths (89) occurred in those with an acute symptomatic aetiology especially anoxic encephalopathy or cerebrovascular disease
ndash When analysed for other factors only age (gt65 years) and sex (male) contributed significantly to the risk of death this appeared to be independent of aetiology In the overall analysis however length of status epilepticus was not an independent predictor of mortality Whether it is the underlying aetiology itself or the status epilepticus that has a major influence on mortality cannot be determined from this study
Mortalitagrave da CSE amp NCSE
0
10
20
30
40
50
60
70
80
90
DE Lorenzo 1998
Drislane 1994
Litt 1998
Labar 1998
Privitera 1994
10 elderly patients with
stroke tumors
head injury
electroconvulsive therapy
and metabolic derangements
3 died from infection 48 patients with
serious medical illnesses
but without prior epilepsy
coma after
convulsive SE
critic
ally
ill eld
erly
42 pts
Epilepsy
stroke
Generalized
SE
Morbilitagrave e mortalitagrave
bull Morte 10 -35 (Hauser 1983 DeLorenzo et
al 1996)
bull Morbilitagrave cognitiva e neurologica 10 - 35
(Hauser 1983 Dodrill and Wilensky 1990
DeLorenzo et al 1996 Cascino et al 1998)
bull Epilessia cronica (30 dei bambini che si
presentano inizialmente in status) (Shinnar et
al 1992)
bull SE ricorrente (15 - 20 dei bambini ) (Shinnar et
al 1992)
Morbiditagrave legata al trattamentodepressione
respiratoria
0
5
10
15
20
25
30
35
40
45
depr resp
diazepam
lorazepamWyeth
loraz Walker
loraz Levy
Incidenza di effetti collaterali nello studio
comparativo di Treiman et al
vs IrgantuaTreiman DM Meyers PD Walton NY et al A comparison of four treatments for
generalized convulsive status epilepticus N Engl J Med 1998339792-8
0
5
10
15
20
25
30
35
ipotensione ipoventilazione disturbi ritmo
cardiaco
diazepam+ fenitoina
fenitoina
lorazepam
fenobarbital
midazolam
prognosi
PrognosiSE vs NCSE
bull Necessitagrave di una attenta stratificazione
bull studies drawn from the intensive care setting (Drislane and Schomer 1994 DeLorenzo et al 1998 Litt et al 1998) are faced with the markedly greater task of determining the selective consequences and morbidity of the superadded insult of the epileptic electrical activity combined with the medical and neurologic problems that sent the patient to the intensive care setting or resulted in coma in the first place
Prognosi 2
NON Convulsive (NCSE) Status
Epilepticus(Hosford 1999)
bull 1 Generalized SE in nonconvulsing well-oxygenated animals produces brain damage (Wasterlain et al 1993) In paralyzed oxygen-ventilated baboons with over 3 hours of electrographic seizure activity there was neuronal necrosis in the hippocampal neocortex even when systemic complications and no convulsions were seen (Meldrum et al 1973) Flurothyl-induced seizures in O2-ventilated rats caused brain lesions that included infarction of the substantia nigra (Nevander et al 1985)
bull 2 Focal seizures can induce neuronal necrosis (Wasterlain et al 1993) Necrosis of hilar interneurons and CA3 pyramidal cells occurs with electrical stimulation of the afferent pathway for 2 to 24 hours (Sloviter 1983) with similar changes seen with intraventricular glutamate or aspartate injection (Sloviter and Dempster 1985)
bull 3 Limbic seizures can cause brain damage Cholinomimetics kainic acid and other methods to produce limbic SE can result in neuronal necrosis in the hippocampus amygdala piriform and entorhinal cortices the thalamus lateral septum substantia nigra and neocortex (Olney et al 1974 1983 Strain and Tasker 1991)
La prognosi finale dipende dalla eziologia
The possible relationships among seizure etiology
nonconvulsive status
epilepticus and outcome
Most patients with complex partial status epilepticus (CPSE)
have etiologies consistent with pathway [circled digit one]
(strokes anoxiaischemia head trauma encephalitis)
rather than [circled digit two]
The best example of [circled digit two] would be a patient with
temporal lobe epilepsy
who went into CPSE because of inadequate
antiepileptic drug levels
Fattori che influenzano la prognosi nello
SE(anche NCSE)
bull Causa dello stato
epilettico
bull Durata dello stato
bull Trattamento
bull Etagrave
bull Effetti dannosi sistemici metabolici e fisiologici (Meldrum et al 1973 Simon 1985)
bull Danno cerebrale secondario allrsquo insulto acuto che induce SE (Hauser 1983 Barry et al 1993)
bull Danno neuronale diretto dovuto alla abnorme attivitagrave elettrica del SE (Meldrum et al 1973 Knopman et al 1977 Lothman 1990)
Chin RFMVerhulst LNeville BGRPeters MJScott RC
Inappropriate emergency management of status epilepticus
in children contributes to need for intensive care Journal of
Neurology Neurosurgery amp Psychiatry 75(11)1584-
1588 2004
bull gt 2 dosi o dosi inadeguate di BDZ
bull Depressione respiratoria
bull Trattati in emergenza extraospedaliera
complicazioni
Complicazioni sistemiche dello status epilepticus
SNC cardiova
s
Resp metaboli
co
altro
Ipossiaanos
sia
IM Apneaipopnea Disidtrataz MOF
Edema Ipoipertens Insuff resp Disturbi
elettripoNaip
erK
DIC
Emorragia Aritmie Polmonite ab
ingestis
Acidosi metab Rabdomiolisi
Trombosi
venosa
Arresto Iprtens polm Necrosi
tubacutafratture
Shock
cardiogeno
EPA Necrosi
epatica acuta
Embolia polm Pancreatite
acuta
Complicazioni dello SE
bull Durata convulsioni gt 1 hrpredittore indipendente di poor outcome (mortality odds ratio di quasi 10) (4)
bull Convulsioni prolungate aumentano il rischio di danno neuronalendash Eccitotox
ndash Accumulo intracellulare di Ca++ e apoptosi
ndash Riorganizzazione sinaptica epilettogenica( e gemmazione)
ndash Deplezione di energia e inibizione della sintesi proteica e del DNA (5)
ndash ldquo Particularly vulnerable to injury are the neurons within the hippocampus cerebral cortical mantle and cerebellar Purkinje cells Selective neuronal loss has been described within the hilar area of the dentate gyrus of the hippocampus (areas CA1 and CA3) after prolonged seizures leading to the development of chronic temporal lobe epilepsy (6)rdquo
bull Manifestazioni autonomichemorte improvvisa ndash DeLorenzo RJ Status epilepticus Concepts in diagnosis and treatment Semin Neurol 1990 10396ndash
405
ndash Towne AR Pellock JM Ko D et al Determinants of mortality in status epilepticus Epilepsia 1994 3527ndash34
ndash Payne TA Bleck TP Status epilepticus Crit Care Clin 1997 13 (1)17ndash38
ndash Sloviter RS Status epilepticus-induced neuronal injury and network reorganization Epilepsia 1999 40S34ndash41
Complications of SE
bull Aminoff MJ Simon RP Status epilepticus causes clinical features and consequences in 98 patients Am J Med 198069657-666 Bibliographic Links [Context Link]
bull 25 Wasterlain CG Fujikawa DG Penix L Sankar R Pathophysiological mechanisms of brain damage from status epilepticus Epilepsia 199334(1)S37-S53 Bibliographic Links [Context Link]
bull 26 Singhal PC Chugh KS Golati DR Myoglobinuria and renal failure after status epilepticus Neurology 197828200-201 Bibliographic Links [Context Link]
bull 27 Fisher S Zatuchni J Greenberg J Disseminated intravascular coagulation in status epilepticus Thromb Haemost 197738909-913 Bibliographic Links [Context Link]
Neuroprotective effects of acidosis
bull some studies that suggest that hypoxia acidosis and hypoglycaemia may be neuroprotective [2829] To
study these phenomena further Sasahira and coworkers [30bull31bull] looked at a rat model of status epilepticus based upon repeated bicuculline injections and using heat shock protein as an indirect measure of neuronal injury Using high concentrations of inhaled carbon dioxide they were able to reduce the serum pH from 755 to 717 This resulted in a shorter seizure duration and less neuronal damage [30bull] Using multiple regression analysis they were able to show a neuroprotective effect of shortening seizure duration and an independent effect of acidosis [30bull] Acidosis and raised carbon dioxide tensions have a profound effect on cerebral blood flow and whether the neuroprotective effect is due to haemodynamic effects or to the effect of acidoisis on receptors or transmitter release is unknown
bull A further study from the same group [31bull] looked at the effects of moderate hypoxia (PaO2=50 mmHg) on neuronal damage in the same model compared with normoxic controls There was no difference in neuronal injury detected suggesting that moderate hypoxia has no effect on neuronal death in status epilepticus The authors rightly conclude however that the implications of their findings for the treatment of status epilepticus are unclear as more severe hypoxia could result in additional ischaemic injury to the brain
bull 28 Blennow G Brierley JB Meldrum BS Siesjouml BK Epileptic brain damage The role of sysemic factors that modify cerebral energy metabolism Brain 1978101687-700 Bibliographic Links [Context Link]
bull 29 Meldrum BS Brierley JB Prolonged epileptic seizures in primates Ischaemic cell change and its relation to ictal physiological events Arch Neurol 19732810-17 Bibliographic Links [Context Link]
bull 30 bull Sasahira M Lowry T Simon RP Neuronal injury in experimental status epilepticus in the rat role of acidosis Neurosci Lett 1997224177-180 Bibliographic Links See [31bull] [Context Link]
bull 31 bull Sasahira M Simon RP Greenberg DA Neuronal injury in experimental status epilepticus in the rat role of hypoxia Neurosci Lett 1997222207-209 Bibliographic Links Thie paper and [30bull] are excellent reports considering the influence of physiological parameters on neuronal damage induced by status epilepticus [Context Link]
Effetti collaterali della fenitoina ev
bull Lesioni dei tessuti mollicon o senza
stravasordquoPurple Handgt 40 casi con parecchie
amputazioni ( (Kilarski 1984 Rao et al 1988
Hanna 1992)
bull Problemi al sito di iniezione Earnest et al (1983)
30 su 200
bull Ipotensione in gt 25 dei pazcon aritmie
ndash In 3139 pazienti 1 FA (velocitagrave di infus 26 mgmin) 1
tachic sinusale 1 allungamento tratto PR
ndash (Gellerman and Martinex 1967 Goldschlager and
Karliner 1967 Louis et al 1967 Voigt 1968)
bull
Allen FH Runge JW Legarda S et al Multicenter open-label
study on safety tolerance and pharmacokinetics of
intravenous fosphenytoin (Cerebyx) in status epilepticus
[abstract] Epilepsia 199435(Suppl 18)93
bull Data have been published from 40 patients in status epilepticus who received fosphenytoin at a mean infusion rate of 92 mgmin ranging from 247 to 1113 mgmin) Status epilepticus was terminated in 37 of 40 patients (85) within 30 min of receiving fosphenytoin The rapid infusion was well tolerated with only mild or transient side effects Most of the side effects reported were attributable to the pharmacologic effect of phenytoin and included dizziness nystagmus and ataxia Most patients in this trial received a benzodiazepine before the infusion of fosphenytoin and no adverse drug interactions were found
Introduzione alla peculiaritagrave
dellrsquoambiente intensivistico
Convulsioni in ambiente intensivo
bull Sepsi
bull Cause mediche
bull Anormalitagrave metaboliche(30-35) (11)ndash Iponatremiaipocalcemiaipofosfatemiaipoglicemiauremia
ndash Alterazioni della osmolaritagrave specie correzione acuta bull Acute return from hyperosmolarity back to normal levels in a rat
neocortical slice preparation by lowering the D-glucose concentration increased the amplitude of evoked early and late excitatory postsynaptic potentials a situation reminiscent of the generalized convulsions that may follow acute reduction of glucose in diabetic nonketotic hyperglycemia (42)
ndash Ipoosmolaritagrave induce increased nervous system excitability by strengthening both excitatory synaptic communications in neocortex and field effects among the entire cortical population (41)
Problemi peculiari allrsquoambiente
intensivistico
bull Polifarmacologia
bull Insuff renale
bull Insuff epatica
bull Induzione enzimatica
bull Inibizione enzimatica
bull Ipodisprotidemiehellipfarmaci altamente
legati alle prot plasmatiche
Trattamento dello stato di
male
Allora
bull Terapia immediata
bull Aggressiva
bull Supporto vitale di base
bull AAirway
bull Breathing
bull CSupporto circolatorio
Status epilepticusfilosofia del trattamento
Disaccoppiamento
CMRO2CBF
Funzione cardiocircolatoriaFunzione resp
Supporto supernormale
Glucosio
Tiamina 100 mg
Dopaminanoradrenalina + fre con barbituricihellip
Indagine conoscitiva su 127 TI NCH europeeDauch WA Schutze M Guttinger M et al Posttraumatic seizure prevention - results of a
survey of 127 neurosurgery clinics Zentralbl Neurochir 1996 57190ndash5
0
10
20
30
40
50
60
profilassi
Profilassi con anticonvulsivi post trauma cranio-
encefalico
mai
sempre
secindicazione
substantial cortical
injurycerebral contusion
acute subdural
hemorrhage
depressed skull fracture
penetrating missile
injury
(141517)
Rischio convulsivo
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001bull Background It is uncertain whether the administration of benzodiazepines by paramedics is an
effective and safe treatment for out-of-hospital status epilepticus
Methods We conducted a randomized double-blind trial to evaluate intravenous benzodiazepines administered by paramedics for the treatment of out-of-hospital status epilepticus Adults with prolonged (lasting five minutes or more) or repetitive generalized convulsive seizures received intravenous diazepam (5 mg) lorazepam (2 mg) or placebo An identical second injection was given if needed
Results Of the 205 patients enrolled 66 received lorazepam 68 received diazepam and 71 received placebo Status epilepticus had been terminated on arrival at the emergency department in more patients treated with lorazepam (591 percent) or diazepam (426 percent) than patients given placebo (211 percent) (P=0001) After adjustment for covariates the odds ratio for termination of status epilepticus by the time of arrival in the lorazepam group as compared with the placebo group was 48 (95 percent confidence interval 19 to 130) The odds ratio was 19 (95 percent confidence interval 08 to 44) in the lorazepam group as compared with the diazepam group and 23 (95 percent confidence interval 10 to 59) in the diazepam group as compared with the placebo group The rates of respiratory or circulatory complications after the study treatment was administered were 106 percent for the lorazepam group 103 percent for the diazepam group and 225 percent for the placebo group (P=008)
Conclusions Benzodiazepines are safe and effective when administered by paramedics for out-of-hospital status epilepticus in adults Lorazepam is likely to be a better therapy than diazepam (N Engl J Med 2001345631-7)
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001
0
10
20
30
40
50
60
seizures stop complications
lorazepam
diazepam
placebo
randomized double-blind trial
to evaluate iv bdz
admin by paramedics
for the treatment of out-of-hospital status epilepticus
Adults with prolonged (lasting 5 minutes or +)
or repetitive generalized convulsive seizures
received iv diazepam (5 mg)
lorazepam (2 mg) or placebo
An identical second injection was given if needed
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
Treiman DM Meyers PD Walton NY Collins JF Colling C Rowan AJ et al A comparison of four treatments for generalized convulsive status epilepticus N Engl J Med 1998 339792-798
randomized double-blind trial that compared the following four regimens commonly used for the treatment of generalized convulsive status epilepticus diazepam followed by phenytoin phenytoin alone phenobarbital and lorazepam Although the doses and infusion rates chosen for study closely reflected common clinical practice at the time the study began the combination of lorazepam followed by phenytoin (the preferred regimen of many neurologists) was not included
This is a large well-controlled and important clinical trial The major limitation in its clinical relevance is the lack of inclusion of a regimen consisting of lorazepam followed by phenytoin
Veterans Affairs Status Epilepticus Cooperative
Study Group Treiman et al
SE aperto
diaz fenitoina fenobarbital lorazepam
2 o + convuls senza
ripresa di coscienza
Convuls continue = gt 10 min
fenitoina
Coma con scariche
ictali EEG
primary outcome measure
cessation of clinical and electrical
seizure activity
within 20min after initiation
of treatment and continuing for at least
60min after the start of treatment
lorazepam fenitoina
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
bull st treatment successful in 555 of patients with a verified diagnosis of overt status epilepticus (n=384) and in 149 of patients with subtle status epilepticus (n=134)
bull Comparisons between the 4 treatments showed that lorazepam was more effective than phenytoin alone in patients with overt status epilepticus (treatment success in 649 versus 436 of patients respectively)
bull other treatment comparisons in the overt group and all comparisons in the subtle group were not significantly different however
bull There were no significant differences between treatments in patient outcome rates of recurrence of status epilepticus or return of full consciousness over the 12-h observation period or in the frequency of adverse cardiac respiratory or hypotensive events
Treiman DM Meyers PD Walton NY et al A
comparison of four treatments for generalized
convulsive status epilepticus N Engl J Med 1998
339792-798
P 002
Percentage of successful treatment
grey bars overt patients black bars subtle patients
Alldredge Brian Kab Lowenstein Daniel HAC Status
epilepticus new concepts Current Opinion in Neurology
121999 183-190
Da ChapmanAnaesthesia 2004
Marik PEVaron J The Management of Status
Epilepticus Chest 126(2)582-591 August 2004
Status epilepticus is a major medical emergency associated with significant morbidity and mortality Status epilepticusis best defined as a continuous generalized convulsive seizure lasting gt 5 min or two or more seizures during which the patient does not return to baseline consciousness Lorazepam in a dose of 01 mgkg is the drug of first choice for terminating status epilepticus Patients who continue to have clinical or EEG evidence of seizure activity after treatment with lorazepam should be considered to have refractory status epileptics and should be treated with a continuous infusion of propofol or midazolam This article reviews current information regarding the management of status epilepticus in adults
Schema di Marik et al
Claassen JHirsch LJ Emerson R GBates
JE Thompson TBMayer SA Continuous EEG
monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042 bull The authors reviewed 33 episodes of RSE treated with cIV-MDZ in their neurologic intensive care
unit over 6 years All patients were monitored with continuous EEG (cEEG) MDZ infusion rates were titrated to eliminate clinical and EEG seizure activity cIV-MDZ was discontinued once patients were seizure-free for 24 hours Acute treatment failures (seizures 1 to 6 hours after starting cIV-MDZ) breakthrough seizures (after 6 hours of therapy) post-treatment seizures (within 48 hours of discontinuing therapy) and ultimate treatment failure (frequent seizures that led to treatment with pentobarbital or propofol) were identified
bull Results All patients were in nonconvulsive SE at the time cIV-MDZ was started the mean duration of SE before treatment was 39 days (range 0 to 17 days) In addition to benzodiazepines 94 of patients had received at least two antiepileptic drugs (AED) before starting cIV-MDZ The mean loading dose was 019 mgkg the mean maximal infusion rate was 022 mgkgh and the mean duration of cIV-MDZ therapy was 42 days (range 1 to 14 days) Acute treatment failure occurred in 18 (633) of episodes breakthrough seizures in 56 (1832) post-treatment seizures in 68 (1928) and ultimate treatment failure in 18 (633) Breakthrough seizures were clinically subtle or purely electrographic in 89 (1618) of cases and were associated with an increased risk of developing post-treatment seizures (p = 001)
bull Conclusions Although most patients with RSE initially responded to cIV-MDZ over half developed subsequent breakthrough seizures which were predictive of post-treatment seizures and were often detectable only with cEEG Titrating cIV-MDZ to burst suppression more aggressive treatment with concurrent AED or a longer period of initial treatment may reduce the high proportion of patients with RSE who relapse after cIV-MDZ is discontinued
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus Neurology 2001 57 25 1036-1042
0
10
20
30
40
50
60
70
80
non seizures
seizures lt30 min24h05-12 h
seizures 05-12 h24 hgt 12 h
seiz gt12 h24
burst suppression
periodic latdischarge
periodic gen discharge
prima
durante
dopo
33 episodes of RSE treated with cIV-MDZ neurologic ICU over 6 years
All patients were monitored with continuous EEG (cEEG)
Waterhouse Elizabeth J 1 2 DeLorenzo Robert J 1 3 4 2
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
bull Status epilepticus (SE) is a medical and neurological emergency that has been associated with significant morbidity and mortality The most widely accepted definition of SE is more than 30 minutes of either continuous seizure activity or intermittent seizures without full recovery of consciousness between seizures SE is a major clinical concern in the elderly population both because it has increased incidence in the elderly compared with the general population and because of concurrent medical conditions that are more likely to complicate therapy and worsen prognosis in elderly individuals
The incidence of SE in the elderly is almost twice that of the general population at 86 per 100 000 per year With the anticipated growth of the elderly population SE is likely to become an increasingly common problem facing clinicians and an important public health issue The elderly have the highest SE-associated mortality of any age group at 38 and the very old elderly (gt80 years of age) have a mortality of at least 50 Acute or remote stroke is the most common aetiology of SE in the elderly Nonconvulsive SE (NCSE) has a wide range of clinical presentations ranging from confusion to obtundation It occurs commonly in elderly patients who are critically ill and in the setting of coma Electroencephalogram is the only reliable method of diagnosing NCSE
The goal of treatment for SE is rapid cessation of clinical and electrical seizure activity Most treatment protocols call for the immediate administration of an intravenous benzodiazepine followed by phenytoin or fosphenytoin Recent studies suggest that when this initial treatment of SE fails little is gained by using additional standard drugs General anaesthetic agents (such as pentobarbital midazolam or propofol) should be expeditiously employed although these treatments have their own potential complications Intravenous valproic acid is a recent addition to the armamentarium of drugs for the treatment of SE with a low risk of hypotension respiratory depression and hypotension making it a potentially useful drug for the treatment of SE in the elderly However further information is needed to establish its role in the overall treatment of SE
Waterhouseet al
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
BDZ
Fenitoina
O fosfenitoina
GA
Midaz
Propof
pentobarb
Ac valproico
Ns proposta
Lorazepam
01 mgkg
Propofol
1-2 mgkgMidazolam01 mgkg
Inf cont 3-10 mgkgh Inf cont 001-005 mgkgh
Miorilassante solo
Per intubazione
Pentobarbital dose caricopoi 01-04 mgkgmin
fenobarbital
bull 10-20 mgkg iv
ndash Eccessiva sedazione
ndash Depressresp
ndash Ipotensione
ndash Interaz farmacol
ndash Hl gt48 hrhelliphelliphellip
tiopental
bull cumulativo
bull Inotropo neghellip
bull Pentobarbital
bull immunosoppressione
propofol
bull Vantaggi cineticodinamici
bull Titolazione continua possibile
bull TCIquale livello
bull Dosi 1 mgkgripetibile dopo 5rsquo-
ndash Infcont 2-10 mgkgh
bull Rapida emergenzafinestra neurologicaevitare la
brusca sospensione
bull + rapido controllo delle convuls gt barbituricindash Stecker MM Kramer TH Raps EC OMeeghan R Dulaney E Skaar DJ Treatment of
refractory status epilepticus with propofol clinical and pharmacokinetic findings Epilepsia 1998
39 18-26
AG
bull Non ci sono dati che indichino quanto a lungo i paz debbano rimanere senza convuls prima di poter alleggerire il piano di AG24 h96h (Treiman DM Convulsive status
epilepticus Current Treatment Options in Neurology 1999 1 359-69)
bull Anest alogenatiisofluranogtsevofluranogtdesflurane
bull Ma vaporizzatori
bull Contaminazione ambientale
bull Costihellip
Studi comparativi1
bull Midazolamgt tiopental
ndash Lohr A Jr Werneck LC Comparative non-randomized study with
midazolam versus thiopental in children with refractory status
epilepticus [Portuguese] Arq Neuropsiquiatr 2000 58282-287
ndash non-randomized comparison
ndash of historical data (thiopental) and prospectively
acquired data (midazolam)
ndash Midazolam was no more often effective than
thiopental but was associated with less cyanosis and
less respiratory distress in this study of 50 children
Studi comparativi2
Valproatobull Valproate(ivrdquoDepaconrdquo) has been used for the treatment of refractory SE
in children and myoclonic SE ndash Sheth RD Gidal BE Intravenous valproic acid for myoclonic status epilepticus
Neurology 2000 541201
ndash Uberall MA Trollmann R Wunsiedler U Wenzel D Intravenous valproate in pediatric epilepsy patients with refractory status epilepticus Neurology 2000 542188-2189 ]
bull Valproate has also been used in SE in the elderly and appears to be safe even in the presence of cardiovascular instability and hypotension no significant change in blood pressure pulse or the need for vasopressors in 13 patients with SE and hypotension given a loading dose of 147-327 mgkg Depacon intravenouslyndash Sinha S Naritoku DK Intravenous valproate is well tolerated in unstable patients
with status epilepticus Neurology 2000 55722-724
bull However there is a case report of severe hypotension in an 11-year-old child after treatment of SE with 30 mgkg intravenous valproate ndash White JR Santos CS Intravenous valproate associated with significant
hypotension in the treatment of status epilepticus J Child Neurol 1999 14822-823
FINE
Percheacute non ne possiamo
piugravehelliphelliphellip
Mortalitagrave da CSE amp NCSE
0
10
20
30
40
50
60
70
80
90
DE Lorenzo 1998
Drislane 1994
Litt 1998
Labar 1998
Privitera 1994
10 elderly patients with
stroke tumors
head injury
electroconvulsive therapy
and metabolic derangements
3 died from infection 48 patients with
serious medical illnesses
but without prior epilepsy
coma after
convulsive SE
critic
ally
ill eld
erly
42 pts
Epilepsy
stroke
Generalized
SE
Morbilitagrave e mortalitagrave
bull Morte 10 -35 (Hauser 1983 DeLorenzo et
al 1996)
bull Morbilitagrave cognitiva e neurologica 10 - 35
(Hauser 1983 Dodrill and Wilensky 1990
DeLorenzo et al 1996 Cascino et al 1998)
bull Epilessia cronica (30 dei bambini che si
presentano inizialmente in status) (Shinnar et
al 1992)
bull SE ricorrente (15 - 20 dei bambini ) (Shinnar et
al 1992)
Morbiditagrave legata al trattamentodepressione
respiratoria
0
5
10
15
20
25
30
35
40
45
depr resp
diazepam
lorazepamWyeth
loraz Walker
loraz Levy
Incidenza di effetti collaterali nello studio
comparativo di Treiman et al
vs IrgantuaTreiman DM Meyers PD Walton NY et al A comparison of four treatments for
generalized convulsive status epilepticus N Engl J Med 1998339792-8
0
5
10
15
20
25
30
35
ipotensione ipoventilazione disturbi ritmo
cardiaco
diazepam+ fenitoina
fenitoina
lorazepam
fenobarbital
midazolam
prognosi
PrognosiSE vs NCSE
bull Necessitagrave di una attenta stratificazione
bull studies drawn from the intensive care setting (Drislane and Schomer 1994 DeLorenzo et al 1998 Litt et al 1998) are faced with the markedly greater task of determining the selective consequences and morbidity of the superadded insult of the epileptic electrical activity combined with the medical and neurologic problems that sent the patient to the intensive care setting or resulted in coma in the first place
Prognosi 2
NON Convulsive (NCSE) Status
Epilepticus(Hosford 1999)
bull 1 Generalized SE in nonconvulsing well-oxygenated animals produces brain damage (Wasterlain et al 1993) In paralyzed oxygen-ventilated baboons with over 3 hours of electrographic seizure activity there was neuronal necrosis in the hippocampal neocortex even when systemic complications and no convulsions were seen (Meldrum et al 1973) Flurothyl-induced seizures in O2-ventilated rats caused brain lesions that included infarction of the substantia nigra (Nevander et al 1985)
bull 2 Focal seizures can induce neuronal necrosis (Wasterlain et al 1993) Necrosis of hilar interneurons and CA3 pyramidal cells occurs with electrical stimulation of the afferent pathway for 2 to 24 hours (Sloviter 1983) with similar changes seen with intraventricular glutamate or aspartate injection (Sloviter and Dempster 1985)
bull 3 Limbic seizures can cause brain damage Cholinomimetics kainic acid and other methods to produce limbic SE can result in neuronal necrosis in the hippocampus amygdala piriform and entorhinal cortices the thalamus lateral septum substantia nigra and neocortex (Olney et al 1974 1983 Strain and Tasker 1991)
La prognosi finale dipende dalla eziologia
The possible relationships among seizure etiology
nonconvulsive status
epilepticus and outcome
Most patients with complex partial status epilepticus (CPSE)
have etiologies consistent with pathway [circled digit one]
(strokes anoxiaischemia head trauma encephalitis)
rather than [circled digit two]
The best example of [circled digit two] would be a patient with
temporal lobe epilepsy
who went into CPSE because of inadequate
antiepileptic drug levels
Fattori che influenzano la prognosi nello
SE(anche NCSE)
bull Causa dello stato
epilettico
bull Durata dello stato
bull Trattamento
bull Etagrave
bull Effetti dannosi sistemici metabolici e fisiologici (Meldrum et al 1973 Simon 1985)
bull Danno cerebrale secondario allrsquo insulto acuto che induce SE (Hauser 1983 Barry et al 1993)
bull Danno neuronale diretto dovuto alla abnorme attivitagrave elettrica del SE (Meldrum et al 1973 Knopman et al 1977 Lothman 1990)
Chin RFMVerhulst LNeville BGRPeters MJScott RC
Inappropriate emergency management of status epilepticus
in children contributes to need for intensive care Journal of
Neurology Neurosurgery amp Psychiatry 75(11)1584-
1588 2004
bull gt 2 dosi o dosi inadeguate di BDZ
bull Depressione respiratoria
bull Trattati in emergenza extraospedaliera
complicazioni
Complicazioni sistemiche dello status epilepticus
SNC cardiova
s
Resp metaboli
co
altro
Ipossiaanos
sia
IM Apneaipopnea Disidtrataz MOF
Edema Ipoipertens Insuff resp Disturbi
elettripoNaip
erK
DIC
Emorragia Aritmie Polmonite ab
ingestis
Acidosi metab Rabdomiolisi
Trombosi
venosa
Arresto Iprtens polm Necrosi
tubacutafratture
Shock
cardiogeno
EPA Necrosi
epatica acuta
Embolia polm Pancreatite
acuta
Complicazioni dello SE
bull Durata convulsioni gt 1 hrpredittore indipendente di poor outcome (mortality odds ratio di quasi 10) (4)
bull Convulsioni prolungate aumentano il rischio di danno neuronalendash Eccitotox
ndash Accumulo intracellulare di Ca++ e apoptosi
ndash Riorganizzazione sinaptica epilettogenica( e gemmazione)
ndash Deplezione di energia e inibizione della sintesi proteica e del DNA (5)
ndash ldquo Particularly vulnerable to injury are the neurons within the hippocampus cerebral cortical mantle and cerebellar Purkinje cells Selective neuronal loss has been described within the hilar area of the dentate gyrus of the hippocampus (areas CA1 and CA3) after prolonged seizures leading to the development of chronic temporal lobe epilepsy (6)rdquo
bull Manifestazioni autonomichemorte improvvisa ndash DeLorenzo RJ Status epilepticus Concepts in diagnosis and treatment Semin Neurol 1990 10396ndash
405
ndash Towne AR Pellock JM Ko D et al Determinants of mortality in status epilepticus Epilepsia 1994 3527ndash34
ndash Payne TA Bleck TP Status epilepticus Crit Care Clin 1997 13 (1)17ndash38
ndash Sloviter RS Status epilepticus-induced neuronal injury and network reorganization Epilepsia 1999 40S34ndash41
Complications of SE
bull Aminoff MJ Simon RP Status epilepticus causes clinical features and consequences in 98 patients Am J Med 198069657-666 Bibliographic Links [Context Link]
bull 25 Wasterlain CG Fujikawa DG Penix L Sankar R Pathophysiological mechanisms of brain damage from status epilepticus Epilepsia 199334(1)S37-S53 Bibliographic Links [Context Link]
bull 26 Singhal PC Chugh KS Golati DR Myoglobinuria and renal failure after status epilepticus Neurology 197828200-201 Bibliographic Links [Context Link]
bull 27 Fisher S Zatuchni J Greenberg J Disseminated intravascular coagulation in status epilepticus Thromb Haemost 197738909-913 Bibliographic Links [Context Link]
Neuroprotective effects of acidosis
bull some studies that suggest that hypoxia acidosis and hypoglycaemia may be neuroprotective [2829] To
study these phenomena further Sasahira and coworkers [30bull31bull] looked at a rat model of status epilepticus based upon repeated bicuculline injections and using heat shock protein as an indirect measure of neuronal injury Using high concentrations of inhaled carbon dioxide they were able to reduce the serum pH from 755 to 717 This resulted in a shorter seizure duration and less neuronal damage [30bull] Using multiple regression analysis they were able to show a neuroprotective effect of shortening seizure duration and an independent effect of acidosis [30bull] Acidosis and raised carbon dioxide tensions have a profound effect on cerebral blood flow and whether the neuroprotective effect is due to haemodynamic effects or to the effect of acidoisis on receptors or transmitter release is unknown
bull A further study from the same group [31bull] looked at the effects of moderate hypoxia (PaO2=50 mmHg) on neuronal damage in the same model compared with normoxic controls There was no difference in neuronal injury detected suggesting that moderate hypoxia has no effect on neuronal death in status epilepticus The authors rightly conclude however that the implications of their findings for the treatment of status epilepticus are unclear as more severe hypoxia could result in additional ischaemic injury to the brain
bull 28 Blennow G Brierley JB Meldrum BS Siesjouml BK Epileptic brain damage The role of sysemic factors that modify cerebral energy metabolism Brain 1978101687-700 Bibliographic Links [Context Link]
bull 29 Meldrum BS Brierley JB Prolonged epileptic seizures in primates Ischaemic cell change and its relation to ictal physiological events Arch Neurol 19732810-17 Bibliographic Links [Context Link]
bull 30 bull Sasahira M Lowry T Simon RP Neuronal injury in experimental status epilepticus in the rat role of acidosis Neurosci Lett 1997224177-180 Bibliographic Links See [31bull] [Context Link]
bull 31 bull Sasahira M Simon RP Greenberg DA Neuronal injury in experimental status epilepticus in the rat role of hypoxia Neurosci Lett 1997222207-209 Bibliographic Links Thie paper and [30bull] are excellent reports considering the influence of physiological parameters on neuronal damage induced by status epilepticus [Context Link]
Effetti collaterali della fenitoina ev
bull Lesioni dei tessuti mollicon o senza
stravasordquoPurple Handgt 40 casi con parecchie
amputazioni ( (Kilarski 1984 Rao et al 1988
Hanna 1992)
bull Problemi al sito di iniezione Earnest et al (1983)
30 su 200
bull Ipotensione in gt 25 dei pazcon aritmie
ndash In 3139 pazienti 1 FA (velocitagrave di infus 26 mgmin) 1
tachic sinusale 1 allungamento tratto PR
ndash (Gellerman and Martinex 1967 Goldschlager and
Karliner 1967 Louis et al 1967 Voigt 1968)
bull
Allen FH Runge JW Legarda S et al Multicenter open-label
study on safety tolerance and pharmacokinetics of
intravenous fosphenytoin (Cerebyx) in status epilepticus
[abstract] Epilepsia 199435(Suppl 18)93
bull Data have been published from 40 patients in status epilepticus who received fosphenytoin at a mean infusion rate of 92 mgmin ranging from 247 to 1113 mgmin) Status epilepticus was terminated in 37 of 40 patients (85) within 30 min of receiving fosphenytoin The rapid infusion was well tolerated with only mild or transient side effects Most of the side effects reported were attributable to the pharmacologic effect of phenytoin and included dizziness nystagmus and ataxia Most patients in this trial received a benzodiazepine before the infusion of fosphenytoin and no adverse drug interactions were found
Introduzione alla peculiaritagrave
dellrsquoambiente intensivistico
Convulsioni in ambiente intensivo
bull Sepsi
bull Cause mediche
bull Anormalitagrave metaboliche(30-35) (11)ndash Iponatremiaipocalcemiaipofosfatemiaipoglicemiauremia
ndash Alterazioni della osmolaritagrave specie correzione acuta bull Acute return from hyperosmolarity back to normal levels in a rat
neocortical slice preparation by lowering the D-glucose concentration increased the amplitude of evoked early and late excitatory postsynaptic potentials a situation reminiscent of the generalized convulsions that may follow acute reduction of glucose in diabetic nonketotic hyperglycemia (42)
ndash Ipoosmolaritagrave induce increased nervous system excitability by strengthening both excitatory synaptic communications in neocortex and field effects among the entire cortical population (41)
Problemi peculiari allrsquoambiente
intensivistico
bull Polifarmacologia
bull Insuff renale
bull Insuff epatica
bull Induzione enzimatica
bull Inibizione enzimatica
bull Ipodisprotidemiehellipfarmaci altamente
legati alle prot plasmatiche
Trattamento dello stato di
male
Allora
bull Terapia immediata
bull Aggressiva
bull Supporto vitale di base
bull AAirway
bull Breathing
bull CSupporto circolatorio
Status epilepticusfilosofia del trattamento
Disaccoppiamento
CMRO2CBF
Funzione cardiocircolatoriaFunzione resp
Supporto supernormale
Glucosio
Tiamina 100 mg
Dopaminanoradrenalina + fre con barbituricihellip
Indagine conoscitiva su 127 TI NCH europeeDauch WA Schutze M Guttinger M et al Posttraumatic seizure prevention - results of a
survey of 127 neurosurgery clinics Zentralbl Neurochir 1996 57190ndash5
0
10
20
30
40
50
60
profilassi
Profilassi con anticonvulsivi post trauma cranio-
encefalico
mai
sempre
secindicazione
substantial cortical
injurycerebral contusion
acute subdural
hemorrhage
depressed skull fracture
penetrating missile
injury
(141517)
Rischio convulsivo
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001bull Background It is uncertain whether the administration of benzodiazepines by paramedics is an
effective and safe treatment for out-of-hospital status epilepticus
Methods We conducted a randomized double-blind trial to evaluate intravenous benzodiazepines administered by paramedics for the treatment of out-of-hospital status epilepticus Adults with prolonged (lasting five minutes or more) or repetitive generalized convulsive seizures received intravenous diazepam (5 mg) lorazepam (2 mg) or placebo An identical second injection was given if needed
Results Of the 205 patients enrolled 66 received lorazepam 68 received diazepam and 71 received placebo Status epilepticus had been terminated on arrival at the emergency department in more patients treated with lorazepam (591 percent) or diazepam (426 percent) than patients given placebo (211 percent) (P=0001) After adjustment for covariates the odds ratio for termination of status epilepticus by the time of arrival in the lorazepam group as compared with the placebo group was 48 (95 percent confidence interval 19 to 130) The odds ratio was 19 (95 percent confidence interval 08 to 44) in the lorazepam group as compared with the diazepam group and 23 (95 percent confidence interval 10 to 59) in the diazepam group as compared with the placebo group The rates of respiratory or circulatory complications after the study treatment was administered were 106 percent for the lorazepam group 103 percent for the diazepam group and 225 percent for the placebo group (P=008)
Conclusions Benzodiazepines are safe and effective when administered by paramedics for out-of-hospital status epilepticus in adults Lorazepam is likely to be a better therapy than diazepam (N Engl J Med 2001345631-7)
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001
0
10
20
30
40
50
60
seizures stop complications
lorazepam
diazepam
placebo
randomized double-blind trial
to evaluate iv bdz
admin by paramedics
for the treatment of out-of-hospital status epilepticus
Adults with prolonged (lasting 5 minutes or +)
or repetitive generalized convulsive seizures
received iv diazepam (5 mg)
lorazepam (2 mg) or placebo
An identical second injection was given if needed
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
Treiman DM Meyers PD Walton NY Collins JF Colling C Rowan AJ et al A comparison of four treatments for generalized convulsive status epilepticus N Engl J Med 1998 339792-798
randomized double-blind trial that compared the following four regimens commonly used for the treatment of generalized convulsive status epilepticus diazepam followed by phenytoin phenytoin alone phenobarbital and lorazepam Although the doses and infusion rates chosen for study closely reflected common clinical practice at the time the study began the combination of lorazepam followed by phenytoin (the preferred regimen of many neurologists) was not included
This is a large well-controlled and important clinical trial The major limitation in its clinical relevance is the lack of inclusion of a regimen consisting of lorazepam followed by phenytoin
Veterans Affairs Status Epilepticus Cooperative
Study Group Treiman et al
SE aperto
diaz fenitoina fenobarbital lorazepam
2 o + convuls senza
ripresa di coscienza
Convuls continue = gt 10 min
fenitoina
Coma con scariche
ictali EEG
primary outcome measure
cessation of clinical and electrical
seizure activity
within 20min after initiation
of treatment and continuing for at least
60min after the start of treatment
lorazepam fenitoina
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
bull st treatment successful in 555 of patients with a verified diagnosis of overt status epilepticus (n=384) and in 149 of patients with subtle status epilepticus (n=134)
bull Comparisons between the 4 treatments showed that lorazepam was more effective than phenytoin alone in patients with overt status epilepticus (treatment success in 649 versus 436 of patients respectively)
bull other treatment comparisons in the overt group and all comparisons in the subtle group were not significantly different however
bull There were no significant differences between treatments in patient outcome rates of recurrence of status epilepticus or return of full consciousness over the 12-h observation period or in the frequency of adverse cardiac respiratory or hypotensive events
Treiman DM Meyers PD Walton NY et al A
comparison of four treatments for generalized
convulsive status epilepticus N Engl J Med 1998
339792-798
P 002
Percentage of successful treatment
grey bars overt patients black bars subtle patients
Alldredge Brian Kab Lowenstein Daniel HAC Status
epilepticus new concepts Current Opinion in Neurology
121999 183-190
Da ChapmanAnaesthesia 2004
Marik PEVaron J The Management of Status
Epilepticus Chest 126(2)582-591 August 2004
Status epilepticus is a major medical emergency associated with significant morbidity and mortality Status epilepticusis best defined as a continuous generalized convulsive seizure lasting gt 5 min or two or more seizures during which the patient does not return to baseline consciousness Lorazepam in a dose of 01 mgkg is the drug of first choice for terminating status epilepticus Patients who continue to have clinical or EEG evidence of seizure activity after treatment with lorazepam should be considered to have refractory status epileptics and should be treated with a continuous infusion of propofol or midazolam This article reviews current information regarding the management of status epilepticus in adults
Schema di Marik et al
Claassen JHirsch LJ Emerson R GBates
JE Thompson TBMayer SA Continuous EEG
monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042 bull The authors reviewed 33 episodes of RSE treated with cIV-MDZ in their neurologic intensive care
unit over 6 years All patients were monitored with continuous EEG (cEEG) MDZ infusion rates were titrated to eliminate clinical and EEG seizure activity cIV-MDZ was discontinued once patients were seizure-free for 24 hours Acute treatment failures (seizures 1 to 6 hours after starting cIV-MDZ) breakthrough seizures (after 6 hours of therapy) post-treatment seizures (within 48 hours of discontinuing therapy) and ultimate treatment failure (frequent seizures that led to treatment with pentobarbital or propofol) were identified
bull Results All patients were in nonconvulsive SE at the time cIV-MDZ was started the mean duration of SE before treatment was 39 days (range 0 to 17 days) In addition to benzodiazepines 94 of patients had received at least two antiepileptic drugs (AED) before starting cIV-MDZ The mean loading dose was 019 mgkg the mean maximal infusion rate was 022 mgkgh and the mean duration of cIV-MDZ therapy was 42 days (range 1 to 14 days) Acute treatment failure occurred in 18 (633) of episodes breakthrough seizures in 56 (1832) post-treatment seizures in 68 (1928) and ultimate treatment failure in 18 (633) Breakthrough seizures were clinically subtle or purely electrographic in 89 (1618) of cases and were associated with an increased risk of developing post-treatment seizures (p = 001)
bull Conclusions Although most patients with RSE initially responded to cIV-MDZ over half developed subsequent breakthrough seizures which were predictive of post-treatment seizures and were often detectable only with cEEG Titrating cIV-MDZ to burst suppression more aggressive treatment with concurrent AED or a longer period of initial treatment may reduce the high proportion of patients with RSE who relapse after cIV-MDZ is discontinued
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus Neurology 2001 57 25 1036-1042
0
10
20
30
40
50
60
70
80
non seizures
seizures lt30 min24h05-12 h
seizures 05-12 h24 hgt 12 h
seiz gt12 h24
burst suppression
periodic latdischarge
periodic gen discharge
prima
durante
dopo
33 episodes of RSE treated with cIV-MDZ neurologic ICU over 6 years
All patients were monitored with continuous EEG (cEEG)
Waterhouse Elizabeth J 1 2 DeLorenzo Robert J 1 3 4 2
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
bull Status epilepticus (SE) is a medical and neurological emergency that has been associated with significant morbidity and mortality The most widely accepted definition of SE is more than 30 minutes of either continuous seizure activity or intermittent seizures without full recovery of consciousness between seizures SE is a major clinical concern in the elderly population both because it has increased incidence in the elderly compared with the general population and because of concurrent medical conditions that are more likely to complicate therapy and worsen prognosis in elderly individuals
The incidence of SE in the elderly is almost twice that of the general population at 86 per 100 000 per year With the anticipated growth of the elderly population SE is likely to become an increasingly common problem facing clinicians and an important public health issue The elderly have the highest SE-associated mortality of any age group at 38 and the very old elderly (gt80 years of age) have a mortality of at least 50 Acute or remote stroke is the most common aetiology of SE in the elderly Nonconvulsive SE (NCSE) has a wide range of clinical presentations ranging from confusion to obtundation It occurs commonly in elderly patients who are critically ill and in the setting of coma Electroencephalogram is the only reliable method of diagnosing NCSE
The goal of treatment for SE is rapid cessation of clinical and electrical seizure activity Most treatment protocols call for the immediate administration of an intravenous benzodiazepine followed by phenytoin or fosphenytoin Recent studies suggest that when this initial treatment of SE fails little is gained by using additional standard drugs General anaesthetic agents (such as pentobarbital midazolam or propofol) should be expeditiously employed although these treatments have their own potential complications Intravenous valproic acid is a recent addition to the armamentarium of drugs for the treatment of SE with a low risk of hypotension respiratory depression and hypotension making it a potentially useful drug for the treatment of SE in the elderly However further information is needed to establish its role in the overall treatment of SE
Waterhouseet al
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
BDZ
Fenitoina
O fosfenitoina
GA
Midaz
Propof
pentobarb
Ac valproico
Ns proposta
Lorazepam
01 mgkg
Propofol
1-2 mgkgMidazolam01 mgkg
Inf cont 3-10 mgkgh Inf cont 001-005 mgkgh
Miorilassante solo
Per intubazione
Pentobarbital dose caricopoi 01-04 mgkgmin
fenobarbital
bull 10-20 mgkg iv
ndash Eccessiva sedazione
ndash Depressresp
ndash Ipotensione
ndash Interaz farmacol
ndash Hl gt48 hrhelliphelliphellip
tiopental
bull cumulativo
bull Inotropo neghellip
bull Pentobarbital
bull immunosoppressione
propofol
bull Vantaggi cineticodinamici
bull Titolazione continua possibile
bull TCIquale livello
bull Dosi 1 mgkgripetibile dopo 5rsquo-
ndash Infcont 2-10 mgkgh
bull Rapida emergenzafinestra neurologicaevitare la
brusca sospensione
bull + rapido controllo delle convuls gt barbituricindash Stecker MM Kramer TH Raps EC OMeeghan R Dulaney E Skaar DJ Treatment of
refractory status epilepticus with propofol clinical and pharmacokinetic findings Epilepsia 1998
39 18-26
AG
bull Non ci sono dati che indichino quanto a lungo i paz debbano rimanere senza convuls prima di poter alleggerire il piano di AG24 h96h (Treiman DM Convulsive status
epilepticus Current Treatment Options in Neurology 1999 1 359-69)
bull Anest alogenatiisofluranogtsevofluranogtdesflurane
bull Ma vaporizzatori
bull Contaminazione ambientale
bull Costihellip
Studi comparativi1
bull Midazolamgt tiopental
ndash Lohr A Jr Werneck LC Comparative non-randomized study with
midazolam versus thiopental in children with refractory status
epilepticus [Portuguese] Arq Neuropsiquiatr 2000 58282-287
ndash non-randomized comparison
ndash of historical data (thiopental) and prospectively
acquired data (midazolam)
ndash Midazolam was no more often effective than
thiopental but was associated with less cyanosis and
less respiratory distress in this study of 50 children
Studi comparativi2
Valproatobull Valproate(ivrdquoDepaconrdquo) has been used for the treatment of refractory SE
in children and myoclonic SE ndash Sheth RD Gidal BE Intravenous valproic acid for myoclonic status epilepticus
Neurology 2000 541201
ndash Uberall MA Trollmann R Wunsiedler U Wenzel D Intravenous valproate in pediatric epilepsy patients with refractory status epilepticus Neurology 2000 542188-2189 ]
bull Valproate has also been used in SE in the elderly and appears to be safe even in the presence of cardiovascular instability and hypotension no significant change in blood pressure pulse or the need for vasopressors in 13 patients with SE and hypotension given a loading dose of 147-327 mgkg Depacon intravenouslyndash Sinha S Naritoku DK Intravenous valproate is well tolerated in unstable patients
with status epilepticus Neurology 2000 55722-724
bull However there is a case report of severe hypotension in an 11-year-old child after treatment of SE with 30 mgkg intravenous valproate ndash White JR Santos CS Intravenous valproate associated with significant
hypotension in the treatment of status epilepticus J Child Neurol 1999 14822-823
FINE
Percheacute non ne possiamo
piugravehelliphelliphellip
Morbilitagrave e mortalitagrave
bull Morte 10 -35 (Hauser 1983 DeLorenzo et
al 1996)
bull Morbilitagrave cognitiva e neurologica 10 - 35
(Hauser 1983 Dodrill and Wilensky 1990
DeLorenzo et al 1996 Cascino et al 1998)
bull Epilessia cronica (30 dei bambini che si
presentano inizialmente in status) (Shinnar et
al 1992)
bull SE ricorrente (15 - 20 dei bambini ) (Shinnar et
al 1992)
Morbiditagrave legata al trattamentodepressione
respiratoria
0
5
10
15
20
25
30
35
40
45
depr resp
diazepam
lorazepamWyeth
loraz Walker
loraz Levy
Incidenza di effetti collaterali nello studio
comparativo di Treiman et al
vs IrgantuaTreiman DM Meyers PD Walton NY et al A comparison of four treatments for
generalized convulsive status epilepticus N Engl J Med 1998339792-8
0
5
10
15
20
25
30
35
ipotensione ipoventilazione disturbi ritmo
cardiaco
diazepam+ fenitoina
fenitoina
lorazepam
fenobarbital
midazolam
prognosi
PrognosiSE vs NCSE
bull Necessitagrave di una attenta stratificazione
bull studies drawn from the intensive care setting (Drislane and Schomer 1994 DeLorenzo et al 1998 Litt et al 1998) are faced with the markedly greater task of determining the selective consequences and morbidity of the superadded insult of the epileptic electrical activity combined with the medical and neurologic problems that sent the patient to the intensive care setting or resulted in coma in the first place
Prognosi 2
NON Convulsive (NCSE) Status
Epilepticus(Hosford 1999)
bull 1 Generalized SE in nonconvulsing well-oxygenated animals produces brain damage (Wasterlain et al 1993) In paralyzed oxygen-ventilated baboons with over 3 hours of electrographic seizure activity there was neuronal necrosis in the hippocampal neocortex even when systemic complications and no convulsions were seen (Meldrum et al 1973) Flurothyl-induced seizures in O2-ventilated rats caused brain lesions that included infarction of the substantia nigra (Nevander et al 1985)
bull 2 Focal seizures can induce neuronal necrosis (Wasterlain et al 1993) Necrosis of hilar interneurons and CA3 pyramidal cells occurs with electrical stimulation of the afferent pathway for 2 to 24 hours (Sloviter 1983) with similar changes seen with intraventricular glutamate or aspartate injection (Sloviter and Dempster 1985)
bull 3 Limbic seizures can cause brain damage Cholinomimetics kainic acid and other methods to produce limbic SE can result in neuronal necrosis in the hippocampus amygdala piriform and entorhinal cortices the thalamus lateral septum substantia nigra and neocortex (Olney et al 1974 1983 Strain and Tasker 1991)
La prognosi finale dipende dalla eziologia
The possible relationships among seizure etiology
nonconvulsive status
epilepticus and outcome
Most patients with complex partial status epilepticus (CPSE)
have etiologies consistent with pathway [circled digit one]
(strokes anoxiaischemia head trauma encephalitis)
rather than [circled digit two]
The best example of [circled digit two] would be a patient with
temporal lobe epilepsy
who went into CPSE because of inadequate
antiepileptic drug levels
Fattori che influenzano la prognosi nello
SE(anche NCSE)
bull Causa dello stato
epilettico
bull Durata dello stato
bull Trattamento
bull Etagrave
bull Effetti dannosi sistemici metabolici e fisiologici (Meldrum et al 1973 Simon 1985)
bull Danno cerebrale secondario allrsquo insulto acuto che induce SE (Hauser 1983 Barry et al 1993)
bull Danno neuronale diretto dovuto alla abnorme attivitagrave elettrica del SE (Meldrum et al 1973 Knopman et al 1977 Lothman 1990)
Chin RFMVerhulst LNeville BGRPeters MJScott RC
Inappropriate emergency management of status epilepticus
in children contributes to need for intensive care Journal of
Neurology Neurosurgery amp Psychiatry 75(11)1584-
1588 2004
bull gt 2 dosi o dosi inadeguate di BDZ
bull Depressione respiratoria
bull Trattati in emergenza extraospedaliera
complicazioni
Complicazioni sistemiche dello status epilepticus
SNC cardiova
s
Resp metaboli
co
altro
Ipossiaanos
sia
IM Apneaipopnea Disidtrataz MOF
Edema Ipoipertens Insuff resp Disturbi
elettripoNaip
erK
DIC
Emorragia Aritmie Polmonite ab
ingestis
Acidosi metab Rabdomiolisi
Trombosi
venosa
Arresto Iprtens polm Necrosi
tubacutafratture
Shock
cardiogeno
EPA Necrosi
epatica acuta
Embolia polm Pancreatite
acuta
Complicazioni dello SE
bull Durata convulsioni gt 1 hrpredittore indipendente di poor outcome (mortality odds ratio di quasi 10) (4)
bull Convulsioni prolungate aumentano il rischio di danno neuronalendash Eccitotox
ndash Accumulo intracellulare di Ca++ e apoptosi
ndash Riorganizzazione sinaptica epilettogenica( e gemmazione)
ndash Deplezione di energia e inibizione della sintesi proteica e del DNA (5)
ndash ldquo Particularly vulnerable to injury are the neurons within the hippocampus cerebral cortical mantle and cerebellar Purkinje cells Selective neuronal loss has been described within the hilar area of the dentate gyrus of the hippocampus (areas CA1 and CA3) after prolonged seizures leading to the development of chronic temporal lobe epilepsy (6)rdquo
bull Manifestazioni autonomichemorte improvvisa ndash DeLorenzo RJ Status epilepticus Concepts in diagnosis and treatment Semin Neurol 1990 10396ndash
405
ndash Towne AR Pellock JM Ko D et al Determinants of mortality in status epilepticus Epilepsia 1994 3527ndash34
ndash Payne TA Bleck TP Status epilepticus Crit Care Clin 1997 13 (1)17ndash38
ndash Sloviter RS Status epilepticus-induced neuronal injury and network reorganization Epilepsia 1999 40S34ndash41
Complications of SE
bull Aminoff MJ Simon RP Status epilepticus causes clinical features and consequences in 98 patients Am J Med 198069657-666 Bibliographic Links [Context Link]
bull 25 Wasterlain CG Fujikawa DG Penix L Sankar R Pathophysiological mechanisms of brain damage from status epilepticus Epilepsia 199334(1)S37-S53 Bibliographic Links [Context Link]
bull 26 Singhal PC Chugh KS Golati DR Myoglobinuria and renal failure after status epilepticus Neurology 197828200-201 Bibliographic Links [Context Link]
bull 27 Fisher S Zatuchni J Greenberg J Disseminated intravascular coagulation in status epilepticus Thromb Haemost 197738909-913 Bibliographic Links [Context Link]
Neuroprotective effects of acidosis
bull some studies that suggest that hypoxia acidosis and hypoglycaemia may be neuroprotective [2829] To
study these phenomena further Sasahira and coworkers [30bull31bull] looked at a rat model of status epilepticus based upon repeated bicuculline injections and using heat shock protein as an indirect measure of neuronal injury Using high concentrations of inhaled carbon dioxide they were able to reduce the serum pH from 755 to 717 This resulted in a shorter seizure duration and less neuronal damage [30bull] Using multiple regression analysis they were able to show a neuroprotective effect of shortening seizure duration and an independent effect of acidosis [30bull] Acidosis and raised carbon dioxide tensions have a profound effect on cerebral blood flow and whether the neuroprotective effect is due to haemodynamic effects or to the effect of acidoisis on receptors or transmitter release is unknown
bull A further study from the same group [31bull] looked at the effects of moderate hypoxia (PaO2=50 mmHg) on neuronal damage in the same model compared with normoxic controls There was no difference in neuronal injury detected suggesting that moderate hypoxia has no effect on neuronal death in status epilepticus The authors rightly conclude however that the implications of their findings for the treatment of status epilepticus are unclear as more severe hypoxia could result in additional ischaemic injury to the brain
bull 28 Blennow G Brierley JB Meldrum BS Siesjouml BK Epileptic brain damage The role of sysemic factors that modify cerebral energy metabolism Brain 1978101687-700 Bibliographic Links [Context Link]
bull 29 Meldrum BS Brierley JB Prolonged epileptic seizures in primates Ischaemic cell change and its relation to ictal physiological events Arch Neurol 19732810-17 Bibliographic Links [Context Link]
bull 30 bull Sasahira M Lowry T Simon RP Neuronal injury in experimental status epilepticus in the rat role of acidosis Neurosci Lett 1997224177-180 Bibliographic Links See [31bull] [Context Link]
bull 31 bull Sasahira M Simon RP Greenberg DA Neuronal injury in experimental status epilepticus in the rat role of hypoxia Neurosci Lett 1997222207-209 Bibliographic Links Thie paper and [30bull] are excellent reports considering the influence of physiological parameters on neuronal damage induced by status epilepticus [Context Link]
Effetti collaterali della fenitoina ev
bull Lesioni dei tessuti mollicon o senza
stravasordquoPurple Handgt 40 casi con parecchie
amputazioni ( (Kilarski 1984 Rao et al 1988
Hanna 1992)
bull Problemi al sito di iniezione Earnest et al (1983)
30 su 200
bull Ipotensione in gt 25 dei pazcon aritmie
ndash In 3139 pazienti 1 FA (velocitagrave di infus 26 mgmin) 1
tachic sinusale 1 allungamento tratto PR
ndash (Gellerman and Martinex 1967 Goldschlager and
Karliner 1967 Louis et al 1967 Voigt 1968)
bull
Allen FH Runge JW Legarda S et al Multicenter open-label
study on safety tolerance and pharmacokinetics of
intravenous fosphenytoin (Cerebyx) in status epilepticus
[abstract] Epilepsia 199435(Suppl 18)93
bull Data have been published from 40 patients in status epilepticus who received fosphenytoin at a mean infusion rate of 92 mgmin ranging from 247 to 1113 mgmin) Status epilepticus was terminated in 37 of 40 patients (85) within 30 min of receiving fosphenytoin The rapid infusion was well tolerated with only mild or transient side effects Most of the side effects reported were attributable to the pharmacologic effect of phenytoin and included dizziness nystagmus and ataxia Most patients in this trial received a benzodiazepine before the infusion of fosphenytoin and no adverse drug interactions were found
Introduzione alla peculiaritagrave
dellrsquoambiente intensivistico
Convulsioni in ambiente intensivo
bull Sepsi
bull Cause mediche
bull Anormalitagrave metaboliche(30-35) (11)ndash Iponatremiaipocalcemiaipofosfatemiaipoglicemiauremia
ndash Alterazioni della osmolaritagrave specie correzione acuta bull Acute return from hyperosmolarity back to normal levels in a rat
neocortical slice preparation by lowering the D-glucose concentration increased the amplitude of evoked early and late excitatory postsynaptic potentials a situation reminiscent of the generalized convulsions that may follow acute reduction of glucose in diabetic nonketotic hyperglycemia (42)
ndash Ipoosmolaritagrave induce increased nervous system excitability by strengthening both excitatory synaptic communications in neocortex and field effects among the entire cortical population (41)
Problemi peculiari allrsquoambiente
intensivistico
bull Polifarmacologia
bull Insuff renale
bull Insuff epatica
bull Induzione enzimatica
bull Inibizione enzimatica
bull Ipodisprotidemiehellipfarmaci altamente
legati alle prot plasmatiche
Trattamento dello stato di
male
Allora
bull Terapia immediata
bull Aggressiva
bull Supporto vitale di base
bull AAirway
bull Breathing
bull CSupporto circolatorio
Status epilepticusfilosofia del trattamento
Disaccoppiamento
CMRO2CBF
Funzione cardiocircolatoriaFunzione resp
Supporto supernormale
Glucosio
Tiamina 100 mg
Dopaminanoradrenalina + fre con barbituricihellip
Indagine conoscitiva su 127 TI NCH europeeDauch WA Schutze M Guttinger M et al Posttraumatic seizure prevention - results of a
survey of 127 neurosurgery clinics Zentralbl Neurochir 1996 57190ndash5
0
10
20
30
40
50
60
profilassi
Profilassi con anticonvulsivi post trauma cranio-
encefalico
mai
sempre
secindicazione
substantial cortical
injurycerebral contusion
acute subdural
hemorrhage
depressed skull fracture
penetrating missile
injury
(141517)
Rischio convulsivo
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001bull Background It is uncertain whether the administration of benzodiazepines by paramedics is an
effective and safe treatment for out-of-hospital status epilepticus
Methods We conducted a randomized double-blind trial to evaluate intravenous benzodiazepines administered by paramedics for the treatment of out-of-hospital status epilepticus Adults with prolonged (lasting five minutes or more) or repetitive generalized convulsive seizures received intravenous diazepam (5 mg) lorazepam (2 mg) or placebo An identical second injection was given if needed
Results Of the 205 patients enrolled 66 received lorazepam 68 received diazepam and 71 received placebo Status epilepticus had been terminated on arrival at the emergency department in more patients treated with lorazepam (591 percent) or diazepam (426 percent) than patients given placebo (211 percent) (P=0001) After adjustment for covariates the odds ratio for termination of status epilepticus by the time of arrival in the lorazepam group as compared with the placebo group was 48 (95 percent confidence interval 19 to 130) The odds ratio was 19 (95 percent confidence interval 08 to 44) in the lorazepam group as compared with the diazepam group and 23 (95 percent confidence interval 10 to 59) in the diazepam group as compared with the placebo group The rates of respiratory or circulatory complications after the study treatment was administered were 106 percent for the lorazepam group 103 percent for the diazepam group and 225 percent for the placebo group (P=008)
Conclusions Benzodiazepines are safe and effective when administered by paramedics for out-of-hospital status epilepticus in adults Lorazepam is likely to be a better therapy than diazepam (N Engl J Med 2001345631-7)
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001
0
10
20
30
40
50
60
seizures stop complications
lorazepam
diazepam
placebo
randomized double-blind trial
to evaluate iv bdz
admin by paramedics
for the treatment of out-of-hospital status epilepticus
Adults with prolonged (lasting 5 minutes or +)
or repetitive generalized convulsive seizures
received iv diazepam (5 mg)
lorazepam (2 mg) or placebo
An identical second injection was given if needed
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
Treiman DM Meyers PD Walton NY Collins JF Colling C Rowan AJ et al A comparison of four treatments for generalized convulsive status epilepticus N Engl J Med 1998 339792-798
randomized double-blind trial that compared the following four regimens commonly used for the treatment of generalized convulsive status epilepticus diazepam followed by phenytoin phenytoin alone phenobarbital and lorazepam Although the doses and infusion rates chosen for study closely reflected common clinical practice at the time the study began the combination of lorazepam followed by phenytoin (the preferred regimen of many neurologists) was not included
This is a large well-controlled and important clinical trial The major limitation in its clinical relevance is the lack of inclusion of a regimen consisting of lorazepam followed by phenytoin
Veterans Affairs Status Epilepticus Cooperative
Study Group Treiman et al
SE aperto
diaz fenitoina fenobarbital lorazepam
2 o + convuls senza
ripresa di coscienza
Convuls continue = gt 10 min
fenitoina
Coma con scariche
ictali EEG
primary outcome measure
cessation of clinical and electrical
seizure activity
within 20min after initiation
of treatment and continuing for at least
60min after the start of treatment
lorazepam fenitoina
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
bull st treatment successful in 555 of patients with a verified diagnosis of overt status epilepticus (n=384) and in 149 of patients with subtle status epilepticus (n=134)
bull Comparisons between the 4 treatments showed that lorazepam was more effective than phenytoin alone in patients with overt status epilepticus (treatment success in 649 versus 436 of patients respectively)
bull other treatment comparisons in the overt group and all comparisons in the subtle group were not significantly different however
bull There were no significant differences between treatments in patient outcome rates of recurrence of status epilepticus or return of full consciousness over the 12-h observation period or in the frequency of adverse cardiac respiratory or hypotensive events
Treiman DM Meyers PD Walton NY et al A
comparison of four treatments for generalized
convulsive status epilepticus N Engl J Med 1998
339792-798
P 002
Percentage of successful treatment
grey bars overt patients black bars subtle patients
Alldredge Brian Kab Lowenstein Daniel HAC Status
epilepticus new concepts Current Opinion in Neurology
121999 183-190
Da ChapmanAnaesthesia 2004
Marik PEVaron J The Management of Status
Epilepticus Chest 126(2)582-591 August 2004
Status epilepticus is a major medical emergency associated with significant morbidity and mortality Status epilepticusis best defined as a continuous generalized convulsive seizure lasting gt 5 min or two or more seizures during which the patient does not return to baseline consciousness Lorazepam in a dose of 01 mgkg is the drug of first choice for terminating status epilepticus Patients who continue to have clinical or EEG evidence of seizure activity after treatment with lorazepam should be considered to have refractory status epileptics and should be treated with a continuous infusion of propofol or midazolam This article reviews current information regarding the management of status epilepticus in adults
Schema di Marik et al
Claassen JHirsch LJ Emerson R GBates
JE Thompson TBMayer SA Continuous EEG
monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042 bull The authors reviewed 33 episodes of RSE treated with cIV-MDZ in their neurologic intensive care
unit over 6 years All patients were monitored with continuous EEG (cEEG) MDZ infusion rates were titrated to eliminate clinical and EEG seizure activity cIV-MDZ was discontinued once patients were seizure-free for 24 hours Acute treatment failures (seizures 1 to 6 hours after starting cIV-MDZ) breakthrough seizures (after 6 hours of therapy) post-treatment seizures (within 48 hours of discontinuing therapy) and ultimate treatment failure (frequent seizures that led to treatment with pentobarbital or propofol) were identified
bull Results All patients were in nonconvulsive SE at the time cIV-MDZ was started the mean duration of SE before treatment was 39 days (range 0 to 17 days) In addition to benzodiazepines 94 of patients had received at least two antiepileptic drugs (AED) before starting cIV-MDZ The mean loading dose was 019 mgkg the mean maximal infusion rate was 022 mgkgh and the mean duration of cIV-MDZ therapy was 42 days (range 1 to 14 days) Acute treatment failure occurred in 18 (633) of episodes breakthrough seizures in 56 (1832) post-treatment seizures in 68 (1928) and ultimate treatment failure in 18 (633) Breakthrough seizures were clinically subtle or purely electrographic in 89 (1618) of cases and were associated with an increased risk of developing post-treatment seizures (p = 001)
bull Conclusions Although most patients with RSE initially responded to cIV-MDZ over half developed subsequent breakthrough seizures which were predictive of post-treatment seizures and were often detectable only with cEEG Titrating cIV-MDZ to burst suppression more aggressive treatment with concurrent AED or a longer period of initial treatment may reduce the high proportion of patients with RSE who relapse after cIV-MDZ is discontinued
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus Neurology 2001 57 25 1036-1042
0
10
20
30
40
50
60
70
80
non seizures
seizures lt30 min24h05-12 h
seizures 05-12 h24 hgt 12 h
seiz gt12 h24
burst suppression
periodic latdischarge
periodic gen discharge
prima
durante
dopo
33 episodes of RSE treated with cIV-MDZ neurologic ICU over 6 years
All patients were monitored with continuous EEG (cEEG)
Waterhouse Elizabeth J 1 2 DeLorenzo Robert J 1 3 4 2
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
bull Status epilepticus (SE) is a medical and neurological emergency that has been associated with significant morbidity and mortality The most widely accepted definition of SE is more than 30 minutes of either continuous seizure activity or intermittent seizures without full recovery of consciousness between seizures SE is a major clinical concern in the elderly population both because it has increased incidence in the elderly compared with the general population and because of concurrent medical conditions that are more likely to complicate therapy and worsen prognosis in elderly individuals
The incidence of SE in the elderly is almost twice that of the general population at 86 per 100 000 per year With the anticipated growth of the elderly population SE is likely to become an increasingly common problem facing clinicians and an important public health issue The elderly have the highest SE-associated mortality of any age group at 38 and the very old elderly (gt80 years of age) have a mortality of at least 50 Acute or remote stroke is the most common aetiology of SE in the elderly Nonconvulsive SE (NCSE) has a wide range of clinical presentations ranging from confusion to obtundation It occurs commonly in elderly patients who are critically ill and in the setting of coma Electroencephalogram is the only reliable method of diagnosing NCSE
The goal of treatment for SE is rapid cessation of clinical and electrical seizure activity Most treatment protocols call for the immediate administration of an intravenous benzodiazepine followed by phenytoin or fosphenytoin Recent studies suggest that when this initial treatment of SE fails little is gained by using additional standard drugs General anaesthetic agents (such as pentobarbital midazolam or propofol) should be expeditiously employed although these treatments have their own potential complications Intravenous valproic acid is a recent addition to the armamentarium of drugs for the treatment of SE with a low risk of hypotension respiratory depression and hypotension making it a potentially useful drug for the treatment of SE in the elderly However further information is needed to establish its role in the overall treatment of SE
Waterhouseet al
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
BDZ
Fenitoina
O fosfenitoina
GA
Midaz
Propof
pentobarb
Ac valproico
Ns proposta
Lorazepam
01 mgkg
Propofol
1-2 mgkgMidazolam01 mgkg
Inf cont 3-10 mgkgh Inf cont 001-005 mgkgh
Miorilassante solo
Per intubazione
Pentobarbital dose caricopoi 01-04 mgkgmin
fenobarbital
bull 10-20 mgkg iv
ndash Eccessiva sedazione
ndash Depressresp
ndash Ipotensione
ndash Interaz farmacol
ndash Hl gt48 hrhelliphelliphellip
tiopental
bull cumulativo
bull Inotropo neghellip
bull Pentobarbital
bull immunosoppressione
propofol
bull Vantaggi cineticodinamici
bull Titolazione continua possibile
bull TCIquale livello
bull Dosi 1 mgkgripetibile dopo 5rsquo-
ndash Infcont 2-10 mgkgh
bull Rapida emergenzafinestra neurologicaevitare la
brusca sospensione
bull + rapido controllo delle convuls gt barbituricindash Stecker MM Kramer TH Raps EC OMeeghan R Dulaney E Skaar DJ Treatment of
refractory status epilepticus with propofol clinical and pharmacokinetic findings Epilepsia 1998
39 18-26
AG
bull Non ci sono dati che indichino quanto a lungo i paz debbano rimanere senza convuls prima di poter alleggerire il piano di AG24 h96h (Treiman DM Convulsive status
epilepticus Current Treatment Options in Neurology 1999 1 359-69)
bull Anest alogenatiisofluranogtsevofluranogtdesflurane
bull Ma vaporizzatori
bull Contaminazione ambientale
bull Costihellip
Studi comparativi1
bull Midazolamgt tiopental
ndash Lohr A Jr Werneck LC Comparative non-randomized study with
midazolam versus thiopental in children with refractory status
epilepticus [Portuguese] Arq Neuropsiquiatr 2000 58282-287
ndash non-randomized comparison
ndash of historical data (thiopental) and prospectively
acquired data (midazolam)
ndash Midazolam was no more often effective than
thiopental but was associated with less cyanosis and
less respiratory distress in this study of 50 children
Studi comparativi2
Valproatobull Valproate(ivrdquoDepaconrdquo) has been used for the treatment of refractory SE
in children and myoclonic SE ndash Sheth RD Gidal BE Intravenous valproic acid for myoclonic status epilepticus
Neurology 2000 541201
ndash Uberall MA Trollmann R Wunsiedler U Wenzel D Intravenous valproate in pediatric epilepsy patients with refractory status epilepticus Neurology 2000 542188-2189 ]
bull Valproate has also been used in SE in the elderly and appears to be safe even in the presence of cardiovascular instability and hypotension no significant change in blood pressure pulse or the need for vasopressors in 13 patients with SE and hypotension given a loading dose of 147-327 mgkg Depacon intravenouslyndash Sinha S Naritoku DK Intravenous valproate is well tolerated in unstable patients
with status epilepticus Neurology 2000 55722-724
bull However there is a case report of severe hypotension in an 11-year-old child after treatment of SE with 30 mgkg intravenous valproate ndash White JR Santos CS Intravenous valproate associated with significant
hypotension in the treatment of status epilepticus J Child Neurol 1999 14822-823
FINE
Percheacute non ne possiamo
piugravehelliphelliphellip
Morbiditagrave legata al trattamentodepressione
respiratoria
0
5
10
15
20
25
30
35
40
45
depr resp
diazepam
lorazepamWyeth
loraz Walker
loraz Levy
Incidenza di effetti collaterali nello studio
comparativo di Treiman et al
vs IrgantuaTreiman DM Meyers PD Walton NY et al A comparison of four treatments for
generalized convulsive status epilepticus N Engl J Med 1998339792-8
0
5
10
15
20
25
30
35
ipotensione ipoventilazione disturbi ritmo
cardiaco
diazepam+ fenitoina
fenitoina
lorazepam
fenobarbital
midazolam
prognosi
PrognosiSE vs NCSE
bull Necessitagrave di una attenta stratificazione
bull studies drawn from the intensive care setting (Drislane and Schomer 1994 DeLorenzo et al 1998 Litt et al 1998) are faced with the markedly greater task of determining the selective consequences and morbidity of the superadded insult of the epileptic electrical activity combined with the medical and neurologic problems that sent the patient to the intensive care setting or resulted in coma in the first place
Prognosi 2
NON Convulsive (NCSE) Status
Epilepticus(Hosford 1999)
bull 1 Generalized SE in nonconvulsing well-oxygenated animals produces brain damage (Wasterlain et al 1993) In paralyzed oxygen-ventilated baboons with over 3 hours of electrographic seizure activity there was neuronal necrosis in the hippocampal neocortex even when systemic complications and no convulsions were seen (Meldrum et al 1973) Flurothyl-induced seizures in O2-ventilated rats caused brain lesions that included infarction of the substantia nigra (Nevander et al 1985)
bull 2 Focal seizures can induce neuronal necrosis (Wasterlain et al 1993) Necrosis of hilar interneurons and CA3 pyramidal cells occurs with electrical stimulation of the afferent pathway for 2 to 24 hours (Sloviter 1983) with similar changes seen with intraventricular glutamate or aspartate injection (Sloviter and Dempster 1985)
bull 3 Limbic seizures can cause brain damage Cholinomimetics kainic acid and other methods to produce limbic SE can result in neuronal necrosis in the hippocampus amygdala piriform and entorhinal cortices the thalamus lateral septum substantia nigra and neocortex (Olney et al 1974 1983 Strain and Tasker 1991)
La prognosi finale dipende dalla eziologia
The possible relationships among seizure etiology
nonconvulsive status
epilepticus and outcome
Most patients with complex partial status epilepticus (CPSE)
have etiologies consistent with pathway [circled digit one]
(strokes anoxiaischemia head trauma encephalitis)
rather than [circled digit two]
The best example of [circled digit two] would be a patient with
temporal lobe epilepsy
who went into CPSE because of inadequate
antiepileptic drug levels
Fattori che influenzano la prognosi nello
SE(anche NCSE)
bull Causa dello stato
epilettico
bull Durata dello stato
bull Trattamento
bull Etagrave
bull Effetti dannosi sistemici metabolici e fisiologici (Meldrum et al 1973 Simon 1985)
bull Danno cerebrale secondario allrsquo insulto acuto che induce SE (Hauser 1983 Barry et al 1993)
bull Danno neuronale diretto dovuto alla abnorme attivitagrave elettrica del SE (Meldrum et al 1973 Knopman et al 1977 Lothman 1990)
Chin RFMVerhulst LNeville BGRPeters MJScott RC
Inappropriate emergency management of status epilepticus
in children contributes to need for intensive care Journal of
Neurology Neurosurgery amp Psychiatry 75(11)1584-
1588 2004
bull gt 2 dosi o dosi inadeguate di BDZ
bull Depressione respiratoria
bull Trattati in emergenza extraospedaliera
complicazioni
Complicazioni sistemiche dello status epilepticus
SNC cardiova
s
Resp metaboli
co
altro
Ipossiaanos
sia
IM Apneaipopnea Disidtrataz MOF
Edema Ipoipertens Insuff resp Disturbi
elettripoNaip
erK
DIC
Emorragia Aritmie Polmonite ab
ingestis
Acidosi metab Rabdomiolisi
Trombosi
venosa
Arresto Iprtens polm Necrosi
tubacutafratture
Shock
cardiogeno
EPA Necrosi
epatica acuta
Embolia polm Pancreatite
acuta
Complicazioni dello SE
bull Durata convulsioni gt 1 hrpredittore indipendente di poor outcome (mortality odds ratio di quasi 10) (4)
bull Convulsioni prolungate aumentano il rischio di danno neuronalendash Eccitotox
ndash Accumulo intracellulare di Ca++ e apoptosi
ndash Riorganizzazione sinaptica epilettogenica( e gemmazione)
ndash Deplezione di energia e inibizione della sintesi proteica e del DNA (5)
ndash ldquo Particularly vulnerable to injury are the neurons within the hippocampus cerebral cortical mantle and cerebellar Purkinje cells Selective neuronal loss has been described within the hilar area of the dentate gyrus of the hippocampus (areas CA1 and CA3) after prolonged seizures leading to the development of chronic temporal lobe epilepsy (6)rdquo
bull Manifestazioni autonomichemorte improvvisa ndash DeLorenzo RJ Status epilepticus Concepts in diagnosis and treatment Semin Neurol 1990 10396ndash
405
ndash Towne AR Pellock JM Ko D et al Determinants of mortality in status epilepticus Epilepsia 1994 3527ndash34
ndash Payne TA Bleck TP Status epilepticus Crit Care Clin 1997 13 (1)17ndash38
ndash Sloviter RS Status epilepticus-induced neuronal injury and network reorganization Epilepsia 1999 40S34ndash41
Complications of SE
bull Aminoff MJ Simon RP Status epilepticus causes clinical features and consequences in 98 patients Am J Med 198069657-666 Bibliographic Links [Context Link]
bull 25 Wasterlain CG Fujikawa DG Penix L Sankar R Pathophysiological mechanisms of brain damage from status epilepticus Epilepsia 199334(1)S37-S53 Bibliographic Links [Context Link]
bull 26 Singhal PC Chugh KS Golati DR Myoglobinuria and renal failure after status epilepticus Neurology 197828200-201 Bibliographic Links [Context Link]
bull 27 Fisher S Zatuchni J Greenberg J Disseminated intravascular coagulation in status epilepticus Thromb Haemost 197738909-913 Bibliographic Links [Context Link]
Neuroprotective effects of acidosis
bull some studies that suggest that hypoxia acidosis and hypoglycaemia may be neuroprotective [2829] To
study these phenomena further Sasahira and coworkers [30bull31bull] looked at a rat model of status epilepticus based upon repeated bicuculline injections and using heat shock protein as an indirect measure of neuronal injury Using high concentrations of inhaled carbon dioxide they were able to reduce the serum pH from 755 to 717 This resulted in a shorter seizure duration and less neuronal damage [30bull] Using multiple regression analysis they were able to show a neuroprotective effect of shortening seizure duration and an independent effect of acidosis [30bull] Acidosis and raised carbon dioxide tensions have a profound effect on cerebral blood flow and whether the neuroprotective effect is due to haemodynamic effects or to the effect of acidoisis on receptors or transmitter release is unknown
bull A further study from the same group [31bull] looked at the effects of moderate hypoxia (PaO2=50 mmHg) on neuronal damage in the same model compared with normoxic controls There was no difference in neuronal injury detected suggesting that moderate hypoxia has no effect on neuronal death in status epilepticus The authors rightly conclude however that the implications of their findings for the treatment of status epilepticus are unclear as more severe hypoxia could result in additional ischaemic injury to the brain
bull 28 Blennow G Brierley JB Meldrum BS Siesjouml BK Epileptic brain damage The role of sysemic factors that modify cerebral energy metabolism Brain 1978101687-700 Bibliographic Links [Context Link]
bull 29 Meldrum BS Brierley JB Prolonged epileptic seizures in primates Ischaemic cell change and its relation to ictal physiological events Arch Neurol 19732810-17 Bibliographic Links [Context Link]
bull 30 bull Sasahira M Lowry T Simon RP Neuronal injury in experimental status epilepticus in the rat role of acidosis Neurosci Lett 1997224177-180 Bibliographic Links See [31bull] [Context Link]
bull 31 bull Sasahira M Simon RP Greenberg DA Neuronal injury in experimental status epilepticus in the rat role of hypoxia Neurosci Lett 1997222207-209 Bibliographic Links Thie paper and [30bull] are excellent reports considering the influence of physiological parameters on neuronal damage induced by status epilepticus [Context Link]
Effetti collaterali della fenitoina ev
bull Lesioni dei tessuti mollicon o senza
stravasordquoPurple Handgt 40 casi con parecchie
amputazioni ( (Kilarski 1984 Rao et al 1988
Hanna 1992)
bull Problemi al sito di iniezione Earnest et al (1983)
30 su 200
bull Ipotensione in gt 25 dei pazcon aritmie
ndash In 3139 pazienti 1 FA (velocitagrave di infus 26 mgmin) 1
tachic sinusale 1 allungamento tratto PR
ndash (Gellerman and Martinex 1967 Goldschlager and
Karliner 1967 Louis et al 1967 Voigt 1968)
bull
Allen FH Runge JW Legarda S et al Multicenter open-label
study on safety tolerance and pharmacokinetics of
intravenous fosphenytoin (Cerebyx) in status epilepticus
[abstract] Epilepsia 199435(Suppl 18)93
bull Data have been published from 40 patients in status epilepticus who received fosphenytoin at a mean infusion rate of 92 mgmin ranging from 247 to 1113 mgmin) Status epilepticus was terminated in 37 of 40 patients (85) within 30 min of receiving fosphenytoin The rapid infusion was well tolerated with only mild or transient side effects Most of the side effects reported were attributable to the pharmacologic effect of phenytoin and included dizziness nystagmus and ataxia Most patients in this trial received a benzodiazepine before the infusion of fosphenytoin and no adverse drug interactions were found
Introduzione alla peculiaritagrave
dellrsquoambiente intensivistico
Convulsioni in ambiente intensivo
bull Sepsi
bull Cause mediche
bull Anormalitagrave metaboliche(30-35) (11)ndash Iponatremiaipocalcemiaipofosfatemiaipoglicemiauremia
ndash Alterazioni della osmolaritagrave specie correzione acuta bull Acute return from hyperosmolarity back to normal levels in a rat
neocortical slice preparation by lowering the D-glucose concentration increased the amplitude of evoked early and late excitatory postsynaptic potentials a situation reminiscent of the generalized convulsions that may follow acute reduction of glucose in diabetic nonketotic hyperglycemia (42)
ndash Ipoosmolaritagrave induce increased nervous system excitability by strengthening both excitatory synaptic communications in neocortex and field effects among the entire cortical population (41)
Problemi peculiari allrsquoambiente
intensivistico
bull Polifarmacologia
bull Insuff renale
bull Insuff epatica
bull Induzione enzimatica
bull Inibizione enzimatica
bull Ipodisprotidemiehellipfarmaci altamente
legati alle prot plasmatiche
Trattamento dello stato di
male
Allora
bull Terapia immediata
bull Aggressiva
bull Supporto vitale di base
bull AAirway
bull Breathing
bull CSupporto circolatorio
Status epilepticusfilosofia del trattamento
Disaccoppiamento
CMRO2CBF
Funzione cardiocircolatoriaFunzione resp
Supporto supernormale
Glucosio
Tiamina 100 mg
Dopaminanoradrenalina + fre con barbituricihellip
Indagine conoscitiva su 127 TI NCH europeeDauch WA Schutze M Guttinger M et al Posttraumatic seizure prevention - results of a
survey of 127 neurosurgery clinics Zentralbl Neurochir 1996 57190ndash5
0
10
20
30
40
50
60
profilassi
Profilassi con anticonvulsivi post trauma cranio-
encefalico
mai
sempre
secindicazione
substantial cortical
injurycerebral contusion
acute subdural
hemorrhage
depressed skull fracture
penetrating missile
injury
(141517)
Rischio convulsivo
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001bull Background It is uncertain whether the administration of benzodiazepines by paramedics is an
effective and safe treatment for out-of-hospital status epilepticus
Methods We conducted a randomized double-blind trial to evaluate intravenous benzodiazepines administered by paramedics for the treatment of out-of-hospital status epilepticus Adults with prolonged (lasting five minutes or more) or repetitive generalized convulsive seizures received intravenous diazepam (5 mg) lorazepam (2 mg) or placebo An identical second injection was given if needed
Results Of the 205 patients enrolled 66 received lorazepam 68 received diazepam and 71 received placebo Status epilepticus had been terminated on arrival at the emergency department in more patients treated with lorazepam (591 percent) or diazepam (426 percent) than patients given placebo (211 percent) (P=0001) After adjustment for covariates the odds ratio for termination of status epilepticus by the time of arrival in the lorazepam group as compared with the placebo group was 48 (95 percent confidence interval 19 to 130) The odds ratio was 19 (95 percent confidence interval 08 to 44) in the lorazepam group as compared with the diazepam group and 23 (95 percent confidence interval 10 to 59) in the diazepam group as compared with the placebo group The rates of respiratory or circulatory complications after the study treatment was administered were 106 percent for the lorazepam group 103 percent for the diazepam group and 225 percent for the placebo group (P=008)
Conclusions Benzodiazepines are safe and effective when administered by paramedics for out-of-hospital status epilepticus in adults Lorazepam is likely to be a better therapy than diazepam (N Engl J Med 2001345631-7)
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001
0
10
20
30
40
50
60
seizures stop complications
lorazepam
diazepam
placebo
randomized double-blind trial
to evaluate iv bdz
admin by paramedics
for the treatment of out-of-hospital status epilepticus
Adults with prolonged (lasting 5 minutes or +)
or repetitive generalized convulsive seizures
received iv diazepam (5 mg)
lorazepam (2 mg) or placebo
An identical second injection was given if needed
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
Treiman DM Meyers PD Walton NY Collins JF Colling C Rowan AJ et al A comparison of four treatments for generalized convulsive status epilepticus N Engl J Med 1998 339792-798
randomized double-blind trial that compared the following four regimens commonly used for the treatment of generalized convulsive status epilepticus diazepam followed by phenytoin phenytoin alone phenobarbital and lorazepam Although the doses and infusion rates chosen for study closely reflected common clinical practice at the time the study began the combination of lorazepam followed by phenytoin (the preferred regimen of many neurologists) was not included
This is a large well-controlled and important clinical trial The major limitation in its clinical relevance is the lack of inclusion of a regimen consisting of lorazepam followed by phenytoin
Veterans Affairs Status Epilepticus Cooperative
Study Group Treiman et al
SE aperto
diaz fenitoina fenobarbital lorazepam
2 o + convuls senza
ripresa di coscienza
Convuls continue = gt 10 min
fenitoina
Coma con scariche
ictali EEG
primary outcome measure
cessation of clinical and electrical
seizure activity
within 20min after initiation
of treatment and continuing for at least
60min after the start of treatment
lorazepam fenitoina
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
bull st treatment successful in 555 of patients with a verified diagnosis of overt status epilepticus (n=384) and in 149 of patients with subtle status epilepticus (n=134)
bull Comparisons between the 4 treatments showed that lorazepam was more effective than phenytoin alone in patients with overt status epilepticus (treatment success in 649 versus 436 of patients respectively)
bull other treatment comparisons in the overt group and all comparisons in the subtle group were not significantly different however
bull There were no significant differences between treatments in patient outcome rates of recurrence of status epilepticus or return of full consciousness over the 12-h observation period or in the frequency of adverse cardiac respiratory or hypotensive events
Treiman DM Meyers PD Walton NY et al A
comparison of four treatments for generalized
convulsive status epilepticus N Engl J Med 1998
339792-798
P 002
Percentage of successful treatment
grey bars overt patients black bars subtle patients
Alldredge Brian Kab Lowenstein Daniel HAC Status
epilepticus new concepts Current Opinion in Neurology
121999 183-190
Da ChapmanAnaesthesia 2004
Marik PEVaron J The Management of Status
Epilepticus Chest 126(2)582-591 August 2004
Status epilepticus is a major medical emergency associated with significant morbidity and mortality Status epilepticusis best defined as a continuous generalized convulsive seizure lasting gt 5 min or two or more seizures during which the patient does not return to baseline consciousness Lorazepam in a dose of 01 mgkg is the drug of first choice for terminating status epilepticus Patients who continue to have clinical or EEG evidence of seizure activity after treatment with lorazepam should be considered to have refractory status epileptics and should be treated with a continuous infusion of propofol or midazolam This article reviews current information regarding the management of status epilepticus in adults
Schema di Marik et al
Claassen JHirsch LJ Emerson R GBates
JE Thompson TBMayer SA Continuous EEG
monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042 bull The authors reviewed 33 episodes of RSE treated with cIV-MDZ in their neurologic intensive care
unit over 6 years All patients were monitored with continuous EEG (cEEG) MDZ infusion rates were titrated to eliminate clinical and EEG seizure activity cIV-MDZ was discontinued once patients were seizure-free for 24 hours Acute treatment failures (seizures 1 to 6 hours after starting cIV-MDZ) breakthrough seizures (after 6 hours of therapy) post-treatment seizures (within 48 hours of discontinuing therapy) and ultimate treatment failure (frequent seizures that led to treatment with pentobarbital or propofol) were identified
bull Results All patients were in nonconvulsive SE at the time cIV-MDZ was started the mean duration of SE before treatment was 39 days (range 0 to 17 days) In addition to benzodiazepines 94 of patients had received at least two antiepileptic drugs (AED) before starting cIV-MDZ The mean loading dose was 019 mgkg the mean maximal infusion rate was 022 mgkgh and the mean duration of cIV-MDZ therapy was 42 days (range 1 to 14 days) Acute treatment failure occurred in 18 (633) of episodes breakthrough seizures in 56 (1832) post-treatment seizures in 68 (1928) and ultimate treatment failure in 18 (633) Breakthrough seizures were clinically subtle or purely electrographic in 89 (1618) of cases and were associated with an increased risk of developing post-treatment seizures (p = 001)
bull Conclusions Although most patients with RSE initially responded to cIV-MDZ over half developed subsequent breakthrough seizures which were predictive of post-treatment seizures and were often detectable only with cEEG Titrating cIV-MDZ to burst suppression more aggressive treatment with concurrent AED or a longer period of initial treatment may reduce the high proportion of patients with RSE who relapse after cIV-MDZ is discontinued
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus Neurology 2001 57 25 1036-1042
0
10
20
30
40
50
60
70
80
non seizures
seizures lt30 min24h05-12 h
seizures 05-12 h24 hgt 12 h
seiz gt12 h24
burst suppression
periodic latdischarge
periodic gen discharge
prima
durante
dopo
33 episodes of RSE treated with cIV-MDZ neurologic ICU over 6 years
All patients were monitored with continuous EEG (cEEG)
Waterhouse Elizabeth J 1 2 DeLorenzo Robert J 1 3 4 2
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
bull Status epilepticus (SE) is a medical and neurological emergency that has been associated with significant morbidity and mortality The most widely accepted definition of SE is more than 30 minutes of either continuous seizure activity or intermittent seizures without full recovery of consciousness between seizures SE is a major clinical concern in the elderly population both because it has increased incidence in the elderly compared with the general population and because of concurrent medical conditions that are more likely to complicate therapy and worsen prognosis in elderly individuals
The incidence of SE in the elderly is almost twice that of the general population at 86 per 100 000 per year With the anticipated growth of the elderly population SE is likely to become an increasingly common problem facing clinicians and an important public health issue The elderly have the highest SE-associated mortality of any age group at 38 and the very old elderly (gt80 years of age) have a mortality of at least 50 Acute or remote stroke is the most common aetiology of SE in the elderly Nonconvulsive SE (NCSE) has a wide range of clinical presentations ranging from confusion to obtundation It occurs commonly in elderly patients who are critically ill and in the setting of coma Electroencephalogram is the only reliable method of diagnosing NCSE
The goal of treatment for SE is rapid cessation of clinical and electrical seizure activity Most treatment protocols call for the immediate administration of an intravenous benzodiazepine followed by phenytoin or fosphenytoin Recent studies suggest that when this initial treatment of SE fails little is gained by using additional standard drugs General anaesthetic agents (such as pentobarbital midazolam or propofol) should be expeditiously employed although these treatments have their own potential complications Intravenous valproic acid is a recent addition to the armamentarium of drugs for the treatment of SE with a low risk of hypotension respiratory depression and hypotension making it a potentially useful drug for the treatment of SE in the elderly However further information is needed to establish its role in the overall treatment of SE
Waterhouseet al
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
BDZ
Fenitoina
O fosfenitoina
GA
Midaz
Propof
pentobarb
Ac valproico
Ns proposta
Lorazepam
01 mgkg
Propofol
1-2 mgkgMidazolam01 mgkg
Inf cont 3-10 mgkgh Inf cont 001-005 mgkgh
Miorilassante solo
Per intubazione
Pentobarbital dose caricopoi 01-04 mgkgmin
fenobarbital
bull 10-20 mgkg iv
ndash Eccessiva sedazione
ndash Depressresp
ndash Ipotensione
ndash Interaz farmacol
ndash Hl gt48 hrhelliphelliphellip
tiopental
bull cumulativo
bull Inotropo neghellip
bull Pentobarbital
bull immunosoppressione
propofol
bull Vantaggi cineticodinamici
bull Titolazione continua possibile
bull TCIquale livello
bull Dosi 1 mgkgripetibile dopo 5rsquo-
ndash Infcont 2-10 mgkgh
bull Rapida emergenzafinestra neurologicaevitare la
brusca sospensione
bull + rapido controllo delle convuls gt barbituricindash Stecker MM Kramer TH Raps EC OMeeghan R Dulaney E Skaar DJ Treatment of
refractory status epilepticus with propofol clinical and pharmacokinetic findings Epilepsia 1998
39 18-26
AG
bull Non ci sono dati che indichino quanto a lungo i paz debbano rimanere senza convuls prima di poter alleggerire il piano di AG24 h96h (Treiman DM Convulsive status
epilepticus Current Treatment Options in Neurology 1999 1 359-69)
bull Anest alogenatiisofluranogtsevofluranogtdesflurane
bull Ma vaporizzatori
bull Contaminazione ambientale
bull Costihellip
Studi comparativi1
bull Midazolamgt tiopental
ndash Lohr A Jr Werneck LC Comparative non-randomized study with
midazolam versus thiopental in children with refractory status
epilepticus [Portuguese] Arq Neuropsiquiatr 2000 58282-287
ndash non-randomized comparison
ndash of historical data (thiopental) and prospectively
acquired data (midazolam)
ndash Midazolam was no more often effective than
thiopental but was associated with less cyanosis and
less respiratory distress in this study of 50 children
Studi comparativi2
Valproatobull Valproate(ivrdquoDepaconrdquo) has been used for the treatment of refractory SE
in children and myoclonic SE ndash Sheth RD Gidal BE Intravenous valproic acid for myoclonic status epilepticus
Neurology 2000 541201
ndash Uberall MA Trollmann R Wunsiedler U Wenzel D Intravenous valproate in pediatric epilepsy patients with refractory status epilepticus Neurology 2000 542188-2189 ]
bull Valproate has also been used in SE in the elderly and appears to be safe even in the presence of cardiovascular instability and hypotension no significant change in blood pressure pulse or the need for vasopressors in 13 patients with SE and hypotension given a loading dose of 147-327 mgkg Depacon intravenouslyndash Sinha S Naritoku DK Intravenous valproate is well tolerated in unstable patients
with status epilepticus Neurology 2000 55722-724
bull However there is a case report of severe hypotension in an 11-year-old child after treatment of SE with 30 mgkg intravenous valproate ndash White JR Santos CS Intravenous valproate associated with significant
hypotension in the treatment of status epilepticus J Child Neurol 1999 14822-823
FINE
Percheacute non ne possiamo
piugravehelliphelliphellip
Incidenza di effetti collaterali nello studio
comparativo di Treiman et al
vs IrgantuaTreiman DM Meyers PD Walton NY et al A comparison of four treatments for
generalized convulsive status epilepticus N Engl J Med 1998339792-8
0
5
10
15
20
25
30
35
ipotensione ipoventilazione disturbi ritmo
cardiaco
diazepam+ fenitoina
fenitoina
lorazepam
fenobarbital
midazolam
prognosi
PrognosiSE vs NCSE
bull Necessitagrave di una attenta stratificazione
bull studies drawn from the intensive care setting (Drislane and Schomer 1994 DeLorenzo et al 1998 Litt et al 1998) are faced with the markedly greater task of determining the selective consequences and morbidity of the superadded insult of the epileptic electrical activity combined with the medical and neurologic problems that sent the patient to the intensive care setting or resulted in coma in the first place
Prognosi 2
NON Convulsive (NCSE) Status
Epilepticus(Hosford 1999)
bull 1 Generalized SE in nonconvulsing well-oxygenated animals produces brain damage (Wasterlain et al 1993) In paralyzed oxygen-ventilated baboons with over 3 hours of electrographic seizure activity there was neuronal necrosis in the hippocampal neocortex even when systemic complications and no convulsions were seen (Meldrum et al 1973) Flurothyl-induced seizures in O2-ventilated rats caused brain lesions that included infarction of the substantia nigra (Nevander et al 1985)
bull 2 Focal seizures can induce neuronal necrosis (Wasterlain et al 1993) Necrosis of hilar interneurons and CA3 pyramidal cells occurs with electrical stimulation of the afferent pathway for 2 to 24 hours (Sloviter 1983) with similar changes seen with intraventricular glutamate or aspartate injection (Sloviter and Dempster 1985)
bull 3 Limbic seizures can cause brain damage Cholinomimetics kainic acid and other methods to produce limbic SE can result in neuronal necrosis in the hippocampus amygdala piriform and entorhinal cortices the thalamus lateral septum substantia nigra and neocortex (Olney et al 1974 1983 Strain and Tasker 1991)
La prognosi finale dipende dalla eziologia
The possible relationships among seizure etiology
nonconvulsive status
epilepticus and outcome
Most patients with complex partial status epilepticus (CPSE)
have etiologies consistent with pathway [circled digit one]
(strokes anoxiaischemia head trauma encephalitis)
rather than [circled digit two]
The best example of [circled digit two] would be a patient with
temporal lobe epilepsy
who went into CPSE because of inadequate
antiepileptic drug levels
Fattori che influenzano la prognosi nello
SE(anche NCSE)
bull Causa dello stato
epilettico
bull Durata dello stato
bull Trattamento
bull Etagrave
bull Effetti dannosi sistemici metabolici e fisiologici (Meldrum et al 1973 Simon 1985)
bull Danno cerebrale secondario allrsquo insulto acuto che induce SE (Hauser 1983 Barry et al 1993)
bull Danno neuronale diretto dovuto alla abnorme attivitagrave elettrica del SE (Meldrum et al 1973 Knopman et al 1977 Lothman 1990)
Chin RFMVerhulst LNeville BGRPeters MJScott RC
Inappropriate emergency management of status epilepticus
in children contributes to need for intensive care Journal of
Neurology Neurosurgery amp Psychiatry 75(11)1584-
1588 2004
bull gt 2 dosi o dosi inadeguate di BDZ
bull Depressione respiratoria
bull Trattati in emergenza extraospedaliera
complicazioni
Complicazioni sistemiche dello status epilepticus
SNC cardiova
s
Resp metaboli
co
altro
Ipossiaanos
sia
IM Apneaipopnea Disidtrataz MOF
Edema Ipoipertens Insuff resp Disturbi
elettripoNaip
erK
DIC
Emorragia Aritmie Polmonite ab
ingestis
Acidosi metab Rabdomiolisi
Trombosi
venosa
Arresto Iprtens polm Necrosi
tubacutafratture
Shock
cardiogeno
EPA Necrosi
epatica acuta
Embolia polm Pancreatite
acuta
Complicazioni dello SE
bull Durata convulsioni gt 1 hrpredittore indipendente di poor outcome (mortality odds ratio di quasi 10) (4)
bull Convulsioni prolungate aumentano il rischio di danno neuronalendash Eccitotox
ndash Accumulo intracellulare di Ca++ e apoptosi
ndash Riorganizzazione sinaptica epilettogenica( e gemmazione)
ndash Deplezione di energia e inibizione della sintesi proteica e del DNA (5)
ndash ldquo Particularly vulnerable to injury are the neurons within the hippocampus cerebral cortical mantle and cerebellar Purkinje cells Selective neuronal loss has been described within the hilar area of the dentate gyrus of the hippocampus (areas CA1 and CA3) after prolonged seizures leading to the development of chronic temporal lobe epilepsy (6)rdquo
bull Manifestazioni autonomichemorte improvvisa ndash DeLorenzo RJ Status epilepticus Concepts in diagnosis and treatment Semin Neurol 1990 10396ndash
405
ndash Towne AR Pellock JM Ko D et al Determinants of mortality in status epilepticus Epilepsia 1994 3527ndash34
ndash Payne TA Bleck TP Status epilepticus Crit Care Clin 1997 13 (1)17ndash38
ndash Sloviter RS Status epilepticus-induced neuronal injury and network reorganization Epilepsia 1999 40S34ndash41
Complications of SE
bull Aminoff MJ Simon RP Status epilepticus causes clinical features and consequences in 98 patients Am J Med 198069657-666 Bibliographic Links [Context Link]
bull 25 Wasterlain CG Fujikawa DG Penix L Sankar R Pathophysiological mechanisms of brain damage from status epilepticus Epilepsia 199334(1)S37-S53 Bibliographic Links [Context Link]
bull 26 Singhal PC Chugh KS Golati DR Myoglobinuria and renal failure after status epilepticus Neurology 197828200-201 Bibliographic Links [Context Link]
bull 27 Fisher S Zatuchni J Greenberg J Disseminated intravascular coagulation in status epilepticus Thromb Haemost 197738909-913 Bibliographic Links [Context Link]
Neuroprotective effects of acidosis
bull some studies that suggest that hypoxia acidosis and hypoglycaemia may be neuroprotective [2829] To
study these phenomena further Sasahira and coworkers [30bull31bull] looked at a rat model of status epilepticus based upon repeated bicuculline injections and using heat shock protein as an indirect measure of neuronal injury Using high concentrations of inhaled carbon dioxide they were able to reduce the serum pH from 755 to 717 This resulted in a shorter seizure duration and less neuronal damage [30bull] Using multiple regression analysis they were able to show a neuroprotective effect of shortening seizure duration and an independent effect of acidosis [30bull] Acidosis and raised carbon dioxide tensions have a profound effect on cerebral blood flow and whether the neuroprotective effect is due to haemodynamic effects or to the effect of acidoisis on receptors or transmitter release is unknown
bull A further study from the same group [31bull] looked at the effects of moderate hypoxia (PaO2=50 mmHg) on neuronal damage in the same model compared with normoxic controls There was no difference in neuronal injury detected suggesting that moderate hypoxia has no effect on neuronal death in status epilepticus The authors rightly conclude however that the implications of their findings for the treatment of status epilepticus are unclear as more severe hypoxia could result in additional ischaemic injury to the brain
bull 28 Blennow G Brierley JB Meldrum BS Siesjouml BK Epileptic brain damage The role of sysemic factors that modify cerebral energy metabolism Brain 1978101687-700 Bibliographic Links [Context Link]
bull 29 Meldrum BS Brierley JB Prolonged epileptic seizures in primates Ischaemic cell change and its relation to ictal physiological events Arch Neurol 19732810-17 Bibliographic Links [Context Link]
bull 30 bull Sasahira M Lowry T Simon RP Neuronal injury in experimental status epilepticus in the rat role of acidosis Neurosci Lett 1997224177-180 Bibliographic Links See [31bull] [Context Link]
bull 31 bull Sasahira M Simon RP Greenberg DA Neuronal injury in experimental status epilepticus in the rat role of hypoxia Neurosci Lett 1997222207-209 Bibliographic Links Thie paper and [30bull] are excellent reports considering the influence of physiological parameters on neuronal damage induced by status epilepticus [Context Link]
Effetti collaterali della fenitoina ev
bull Lesioni dei tessuti mollicon o senza
stravasordquoPurple Handgt 40 casi con parecchie
amputazioni ( (Kilarski 1984 Rao et al 1988
Hanna 1992)
bull Problemi al sito di iniezione Earnest et al (1983)
30 su 200
bull Ipotensione in gt 25 dei pazcon aritmie
ndash In 3139 pazienti 1 FA (velocitagrave di infus 26 mgmin) 1
tachic sinusale 1 allungamento tratto PR
ndash (Gellerman and Martinex 1967 Goldschlager and
Karliner 1967 Louis et al 1967 Voigt 1968)
bull
Allen FH Runge JW Legarda S et al Multicenter open-label
study on safety tolerance and pharmacokinetics of
intravenous fosphenytoin (Cerebyx) in status epilepticus
[abstract] Epilepsia 199435(Suppl 18)93
bull Data have been published from 40 patients in status epilepticus who received fosphenytoin at a mean infusion rate of 92 mgmin ranging from 247 to 1113 mgmin) Status epilepticus was terminated in 37 of 40 patients (85) within 30 min of receiving fosphenytoin The rapid infusion was well tolerated with only mild or transient side effects Most of the side effects reported were attributable to the pharmacologic effect of phenytoin and included dizziness nystagmus and ataxia Most patients in this trial received a benzodiazepine before the infusion of fosphenytoin and no adverse drug interactions were found
Introduzione alla peculiaritagrave
dellrsquoambiente intensivistico
Convulsioni in ambiente intensivo
bull Sepsi
bull Cause mediche
bull Anormalitagrave metaboliche(30-35) (11)ndash Iponatremiaipocalcemiaipofosfatemiaipoglicemiauremia
ndash Alterazioni della osmolaritagrave specie correzione acuta bull Acute return from hyperosmolarity back to normal levels in a rat
neocortical slice preparation by lowering the D-glucose concentration increased the amplitude of evoked early and late excitatory postsynaptic potentials a situation reminiscent of the generalized convulsions that may follow acute reduction of glucose in diabetic nonketotic hyperglycemia (42)
ndash Ipoosmolaritagrave induce increased nervous system excitability by strengthening both excitatory synaptic communications in neocortex and field effects among the entire cortical population (41)
Problemi peculiari allrsquoambiente
intensivistico
bull Polifarmacologia
bull Insuff renale
bull Insuff epatica
bull Induzione enzimatica
bull Inibizione enzimatica
bull Ipodisprotidemiehellipfarmaci altamente
legati alle prot plasmatiche
Trattamento dello stato di
male
Allora
bull Terapia immediata
bull Aggressiva
bull Supporto vitale di base
bull AAirway
bull Breathing
bull CSupporto circolatorio
Status epilepticusfilosofia del trattamento
Disaccoppiamento
CMRO2CBF
Funzione cardiocircolatoriaFunzione resp
Supporto supernormale
Glucosio
Tiamina 100 mg
Dopaminanoradrenalina + fre con barbituricihellip
Indagine conoscitiva su 127 TI NCH europeeDauch WA Schutze M Guttinger M et al Posttraumatic seizure prevention - results of a
survey of 127 neurosurgery clinics Zentralbl Neurochir 1996 57190ndash5
0
10
20
30
40
50
60
profilassi
Profilassi con anticonvulsivi post trauma cranio-
encefalico
mai
sempre
secindicazione
substantial cortical
injurycerebral contusion
acute subdural
hemorrhage
depressed skull fracture
penetrating missile
injury
(141517)
Rischio convulsivo
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001bull Background It is uncertain whether the administration of benzodiazepines by paramedics is an
effective and safe treatment for out-of-hospital status epilepticus
Methods We conducted a randomized double-blind trial to evaluate intravenous benzodiazepines administered by paramedics for the treatment of out-of-hospital status epilepticus Adults with prolonged (lasting five minutes or more) or repetitive generalized convulsive seizures received intravenous diazepam (5 mg) lorazepam (2 mg) or placebo An identical second injection was given if needed
Results Of the 205 patients enrolled 66 received lorazepam 68 received diazepam and 71 received placebo Status epilepticus had been terminated on arrival at the emergency department in more patients treated with lorazepam (591 percent) or diazepam (426 percent) than patients given placebo (211 percent) (P=0001) After adjustment for covariates the odds ratio for termination of status epilepticus by the time of arrival in the lorazepam group as compared with the placebo group was 48 (95 percent confidence interval 19 to 130) The odds ratio was 19 (95 percent confidence interval 08 to 44) in the lorazepam group as compared with the diazepam group and 23 (95 percent confidence interval 10 to 59) in the diazepam group as compared with the placebo group The rates of respiratory or circulatory complications after the study treatment was administered were 106 percent for the lorazepam group 103 percent for the diazepam group and 225 percent for the placebo group (P=008)
Conclusions Benzodiazepines are safe and effective when administered by paramedics for out-of-hospital status epilepticus in adults Lorazepam is likely to be a better therapy than diazepam (N Engl J Med 2001345631-7)
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001
0
10
20
30
40
50
60
seizures stop complications
lorazepam
diazepam
placebo
randomized double-blind trial
to evaluate iv bdz
admin by paramedics
for the treatment of out-of-hospital status epilepticus
Adults with prolonged (lasting 5 minutes or +)
or repetitive generalized convulsive seizures
received iv diazepam (5 mg)
lorazepam (2 mg) or placebo
An identical second injection was given if needed
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
Treiman DM Meyers PD Walton NY Collins JF Colling C Rowan AJ et al A comparison of four treatments for generalized convulsive status epilepticus N Engl J Med 1998 339792-798
randomized double-blind trial that compared the following four regimens commonly used for the treatment of generalized convulsive status epilepticus diazepam followed by phenytoin phenytoin alone phenobarbital and lorazepam Although the doses and infusion rates chosen for study closely reflected common clinical practice at the time the study began the combination of lorazepam followed by phenytoin (the preferred regimen of many neurologists) was not included
This is a large well-controlled and important clinical trial The major limitation in its clinical relevance is the lack of inclusion of a regimen consisting of lorazepam followed by phenytoin
Veterans Affairs Status Epilepticus Cooperative
Study Group Treiman et al
SE aperto
diaz fenitoina fenobarbital lorazepam
2 o + convuls senza
ripresa di coscienza
Convuls continue = gt 10 min
fenitoina
Coma con scariche
ictali EEG
primary outcome measure
cessation of clinical and electrical
seizure activity
within 20min after initiation
of treatment and continuing for at least
60min after the start of treatment
lorazepam fenitoina
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
bull st treatment successful in 555 of patients with a verified diagnosis of overt status epilepticus (n=384) and in 149 of patients with subtle status epilepticus (n=134)
bull Comparisons between the 4 treatments showed that lorazepam was more effective than phenytoin alone in patients with overt status epilepticus (treatment success in 649 versus 436 of patients respectively)
bull other treatment comparisons in the overt group and all comparisons in the subtle group were not significantly different however
bull There were no significant differences between treatments in patient outcome rates of recurrence of status epilepticus or return of full consciousness over the 12-h observation period or in the frequency of adverse cardiac respiratory or hypotensive events
Treiman DM Meyers PD Walton NY et al A
comparison of four treatments for generalized
convulsive status epilepticus N Engl J Med 1998
339792-798
P 002
Percentage of successful treatment
grey bars overt patients black bars subtle patients
Alldredge Brian Kab Lowenstein Daniel HAC Status
epilepticus new concepts Current Opinion in Neurology
121999 183-190
Da ChapmanAnaesthesia 2004
Marik PEVaron J The Management of Status
Epilepticus Chest 126(2)582-591 August 2004
Status epilepticus is a major medical emergency associated with significant morbidity and mortality Status epilepticusis best defined as a continuous generalized convulsive seizure lasting gt 5 min or two or more seizures during which the patient does not return to baseline consciousness Lorazepam in a dose of 01 mgkg is the drug of first choice for terminating status epilepticus Patients who continue to have clinical or EEG evidence of seizure activity after treatment with lorazepam should be considered to have refractory status epileptics and should be treated with a continuous infusion of propofol or midazolam This article reviews current information regarding the management of status epilepticus in adults
Schema di Marik et al
Claassen JHirsch LJ Emerson R GBates
JE Thompson TBMayer SA Continuous EEG
monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042 bull The authors reviewed 33 episodes of RSE treated with cIV-MDZ in their neurologic intensive care
unit over 6 years All patients were monitored with continuous EEG (cEEG) MDZ infusion rates were titrated to eliminate clinical and EEG seizure activity cIV-MDZ was discontinued once patients were seizure-free for 24 hours Acute treatment failures (seizures 1 to 6 hours after starting cIV-MDZ) breakthrough seizures (after 6 hours of therapy) post-treatment seizures (within 48 hours of discontinuing therapy) and ultimate treatment failure (frequent seizures that led to treatment with pentobarbital or propofol) were identified
bull Results All patients were in nonconvulsive SE at the time cIV-MDZ was started the mean duration of SE before treatment was 39 days (range 0 to 17 days) In addition to benzodiazepines 94 of patients had received at least two antiepileptic drugs (AED) before starting cIV-MDZ The mean loading dose was 019 mgkg the mean maximal infusion rate was 022 mgkgh and the mean duration of cIV-MDZ therapy was 42 days (range 1 to 14 days) Acute treatment failure occurred in 18 (633) of episodes breakthrough seizures in 56 (1832) post-treatment seizures in 68 (1928) and ultimate treatment failure in 18 (633) Breakthrough seizures were clinically subtle or purely electrographic in 89 (1618) of cases and were associated with an increased risk of developing post-treatment seizures (p = 001)
bull Conclusions Although most patients with RSE initially responded to cIV-MDZ over half developed subsequent breakthrough seizures which were predictive of post-treatment seizures and were often detectable only with cEEG Titrating cIV-MDZ to burst suppression more aggressive treatment with concurrent AED or a longer period of initial treatment may reduce the high proportion of patients with RSE who relapse after cIV-MDZ is discontinued
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus Neurology 2001 57 25 1036-1042
0
10
20
30
40
50
60
70
80
non seizures
seizures lt30 min24h05-12 h
seizures 05-12 h24 hgt 12 h
seiz gt12 h24
burst suppression
periodic latdischarge
periodic gen discharge
prima
durante
dopo
33 episodes of RSE treated with cIV-MDZ neurologic ICU over 6 years
All patients were monitored with continuous EEG (cEEG)
Waterhouse Elizabeth J 1 2 DeLorenzo Robert J 1 3 4 2
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
bull Status epilepticus (SE) is a medical and neurological emergency that has been associated with significant morbidity and mortality The most widely accepted definition of SE is more than 30 minutes of either continuous seizure activity or intermittent seizures without full recovery of consciousness between seizures SE is a major clinical concern in the elderly population both because it has increased incidence in the elderly compared with the general population and because of concurrent medical conditions that are more likely to complicate therapy and worsen prognosis in elderly individuals
The incidence of SE in the elderly is almost twice that of the general population at 86 per 100 000 per year With the anticipated growth of the elderly population SE is likely to become an increasingly common problem facing clinicians and an important public health issue The elderly have the highest SE-associated mortality of any age group at 38 and the very old elderly (gt80 years of age) have a mortality of at least 50 Acute or remote stroke is the most common aetiology of SE in the elderly Nonconvulsive SE (NCSE) has a wide range of clinical presentations ranging from confusion to obtundation It occurs commonly in elderly patients who are critically ill and in the setting of coma Electroencephalogram is the only reliable method of diagnosing NCSE
The goal of treatment for SE is rapid cessation of clinical and electrical seizure activity Most treatment protocols call for the immediate administration of an intravenous benzodiazepine followed by phenytoin or fosphenytoin Recent studies suggest that when this initial treatment of SE fails little is gained by using additional standard drugs General anaesthetic agents (such as pentobarbital midazolam or propofol) should be expeditiously employed although these treatments have their own potential complications Intravenous valproic acid is a recent addition to the armamentarium of drugs for the treatment of SE with a low risk of hypotension respiratory depression and hypotension making it a potentially useful drug for the treatment of SE in the elderly However further information is needed to establish its role in the overall treatment of SE
Waterhouseet al
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
BDZ
Fenitoina
O fosfenitoina
GA
Midaz
Propof
pentobarb
Ac valproico
Ns proposta
Lorazepam
01 mgkg
Propofol
1-2 mgkgMidazolam01 mgkg
Inf cont 3-10 mgkgh Inf cont 001-005 mgkgh
Miorilassante solo
Per intubazione
Pentobarbital dose caricopoi 01-04 mgkgmin
fenobarbital
bull 10-20 mgkg iv
ndash Eccessiva sedazione
ndash Depressresp
ndash Ipotensione
ndash Interaz farmacol
ndash Hl gt48 hrhelliphelliphellip
tiopental
bull cumulativo
bull Inotropo neghellip
bull Pentobarbital
bull immunosoppressione
propofol
bull Vantaggi cineticodinamici
bull Titolazione continua possibile
bull TCIquale livello
bull Dosi 1 mgkgripetibile dopo 5rsquo-
ndash Infcont 2-10 mgkgh
bull Rapida emergenzafinestra neurologicaevitare la
brusca sospensione
bull + rapido controllo delle convuls gt barbituricindash Stecker MM Kramer TH Raps EC OMeeghan R Dulaney E Skaar DJ Treatment of
refractory status epilepticus with propofol clinical and pharmacokinetic findings Epilepsia 1998
39 18-26
AG
bull Non ci sono dati che indichino quanto a lungo i paz debbano rimanere senza convuls prima di poter alleggerire il piano di AG24 h96h (Treiman DM Convulsive status
epilepticus Current Treatment Options in Neurology 1999 1 359-69)
bull Anest alogenatiisofluranogtsevofluranogtdesflurane
bull Ma vaporizzatori
bull Contaminazione ambientale
bull Costihellip
Studi comparativi1
bull Midazolamgt tiopental
ndash Lohr A Jr Werneck LC Comparative non-randomized study with
midazolam versus thiopental in children with refractory status
epilepticus [Portuguese] Arq Neuropsiquiatr 2000 58282-287
ndash non-randomized comparison
ndash of historical data (thiopental) and prospectively
acquired data (midazolam)
ndash Midazolam was no more often effective than
thiopental but was associated with less cyanosis and
less respiratory distress in this study of 50 children
Studi comparativi2
Valproatobull Valproate(ivrdquoDepaconrdquo) has been used for the treatment of refractory SE
in children and myoclonic SE ndash Sheth RD Gidal BE Intravenous valproic acid for myoclonic status epilepticus
Neurology 2000 541201
ndash Uberall MA Trollmann R Wunsiedler U Wenzel D Intravenous valproate in pediatric epilepsy patients with refractory status epilepticus Neurology 2000 542188-2189 ]
bull Valproate has also been used in SE in the elderly and appears to be safe even in the presence of cardiovascular instability and hypotension no significant change in blood pressure pulse or the need for vasopressors in 13 patients with SE and hypotension given a loading dose of 147-327 mgkg Depacon intravenouslyndash Sinha S Naritoku DK Intravenous valproate is well tolerated in unstable patients
with status epilepticus Neurology 2000 55722-724
bull However there is a case report of severe hypotension in an 11-year-old child after treatment of SE with 30 mgkg intravenous valproate ndash White JR Santos CS Intravenous valproate associated with significant
hypotension in the treatment of status epilepticus J Child Neurol 1999 14822-823
FINE
Percheacute non ne possiamo
piugravehelliphelliphellip
prognosi
PrognosiSE vs NCSE
bull Necessitagrave di una attenta stratificazione
bull studies drawn from the intensive care setting (Drislane and Schomer 1994 DeLorenzo et al 1998 Litt et al 1998) are faced with the markedly greater task of determining the selective consequences and morbidity of the superadded insult of the epileptic electrical activity combined with the medical and neurologic problems that sent the patient to the intensive care setting or resulted in coma in the first place
Prognosi 2
NON Convulsive (NCSE) Status
Epilepticus(Hosford 1999)
bull 1 Generalized SE in nonconvulsing well-oxygenated animals produces brain damage (Wasterlain et al 1993) In paralyzed oxygen-ventilated baboons with over 3 hours of electrographic seizure activity there was neuronal necrosis in the hippocampal neocortex even when systemic complications and no convulsions were seen (Meldrum et al 1973) Flurothyl-induced seizures in O2-ventilated rats caused brain lesions that included infarction of the substantia nigra (Nevander et al 1985)
bull 2 Focal seizures can induce neuronal necrosis (Wasterlain et al 1993) Necrosis of hilar interneurons and CA3 pyramidal cells occurs with electrical stimulation of the afferent pathway for 2 to 24 hours (Sloviter 1983) with similar changes seen with intraventricular glutamate or aspartate injection (Sloviter and Dempster 1985)
bull 3 Limbic seizures can cause brain damage Cholinomimetics kainic acid and other methods to produce limbic SE can result in neuronal necrosis in the hippocampus amygdala piriform and entorhinal cortices the thalamus lateral septum substantia nigra and neocortex (Olney et al 1974 1983 Strain and Tasker 1991)
La prognosi finale dipende dalla eziologia
The possible relationships among seizure etiology
nonconvulsive status
epilepticus and outcome
Most patients with complex partial status epilepticus (CPSE)
have etiologies consistent with pathway [circled digit one]
(strokes anoxiaischemia head trauma encephalitis)
rather than [circled digit two]
The best example of [circled digit two] would be a patient with
temporal lobe epilepsy
who went into CPSE because of inadequate
antiepileptic drug levels
Fattori che influenzano la prognosi nello
SE(anche NCSE)
bull Causa dello stato
epilettico
bull Durata dello stato
bull Trattamento
bull Etagrave
bull Effetti dannosi sistemici metabolici e fisiologici (Meldrum et al 1973 Simon 1985)
bull Danno cerebrale secondario allrsquo insulto acuto che induce SE (Hauser 1983 Barry et al 1993)
bull Danno neuronale diretto dovuto alla abnorme attivitagrave elettrica del SE (Meldrum et al 1973 Knopman et al 1977 Lothman 1990)
Chin RFMVerhulst LNeville BGRPeters MJScott RC
Inappropriate emergency management of status epilepticus
in children contributes to need for intensive care Journal of
Neurology Neurosurgery amp Psychiatry 75(11)1584-
1588 2004
bull gt 2 dosi o dosi inadeguate di BDZ
bull Depressione respiratoria
bull Trattati in emergenza extraospedaliera
complicazioni
Complicazioni sistemiche dello status epilepticus
SNC cardiova
s
Resp metaboli
co
altro
Ipossiaanos
sia
IM Apneaipopnea Disidtrataz MOF
Edema Ipoipertens Insuff resp Disturbi
elettripoNaip
erK
DIC
Emorragia Aritmie Polmonite ab
ingestis
Acidosi metab Rabdomiolisi
Trombosi
venosa
Arresto Iprtens polm Necrosi
tubacutafratture
Shock
cardiogeno
EPA Necrosi
epatica acuta
Embolia polm Pancreatite
acuta
Complicazioni dello SE
bull Durata convulsioni gt 1 hrpredittore indipendente di poor outcome (mortality odds ratio di quasi 10) (4)
bull Convulsioni prolungate aumentano il rischio di danno neuronalendash Eccitotox
ndash Accumulo intracellulare di Ca++ e apoptosi
ndash Riorganizzazione sinaptica epilettogenica( e gemmazione)
ndash Deplezione di energia e inibizione della sintesi proteica e del DNA (5)
ndash ldquo Particularly vulnerable to injury are the neurons within the hippocampus cerebral cortical mantle and cerebellar Purkinje cells Selective neuronal loss has been described within the hilar area of the dentate gyrus of the hippocampus (areas CA1 and CA3) after prolonged seizures leading to the development of chronic temporal lobe epilepsy (6)rdquo
bull Manifestazioni autonomichemorte improvvisa ndash DeLorenzo RJ Status epilepticus Concepts in diagnosis and treatment Semin Neurol 1990 10396ndash
405
ndash Towne AR Pellock JM Ko D et al Determinants of mortality in status epilepticus Epilepsia 1994 3527ndash34
ndash Payne TA Bleck TP Status epilepticus Crit Care Clin 1997 13 (1)17ndash38
ndash Sloviter RS Status epilepticus-induced neuronal injury and network reorganization Epilepsia 1999 40S34ndash41
Complications of SE
bull Aminoff MJ Simon RP Status epilepticus causes clinical features and consequences in 98 patients Am J Med 198069657-666 Bibliographic Links [Context Link]
bull 25 Wasterlain CG Fujikawa DG Penix L Sankar R Pathophysiological mechanisms of brain damage from status epilepticus Epilepsia 199334(1)S37-S53 Bibliographic Links [Context Link]
bull 26 Singhal PC Chugh KS Golati DR Myoglobinuria and renal failure after status epilepticus Neurology 197828200-201 Bibliographic Links [Context Link]
bull 27 Fisher S Zatuchni J Greenberg J Disseminated intravascular coagulation in status epilepticus Thromb Haemost 197738909-913 Bibliographic Links [Context Link]
Neuroprotective effects of acidosis
bull some studies that suggest that hypoxia acidosis and hypoglycaemia may be neuroprotective [2829] To
study these phenomena further Sasahira and coworkers [30bull31bull] looked at a rat model of status epilepticus based upon repeated bicuculline injections and using heat shock protein as an indirect measure of neuronal injury Using high concentrations of inhaled carbon dioxide they were able to reduce the serum pH from 755 to 717 This resulted in a shorter seizure duration and less neuronal damage [30bull] Using multiple regression analysis they were able to show a neuroprotective effect of shortening seizure duration and an independent effect of acidosis [30bull] Acidosis and raised carbon dioxide tensions have a profound effect on cerebral blood flow and whether the neuroprotective effect is due to haemodynamic effects or to the effect of acidoisis on receptors or transmitter release is unknown
bull A further study from the same group [31bull] looked at the effects of moderate hypoxia (PaO2=50 mmHg) on neuronal damage in the same model compared with normoxic controls There was no difference in neuronal injury detected suggesting that moderate hypoxia has no effect on neuronal death in status epilepticus The authors rightly conclude however that the implications of their findings for the treatment of status epilepticus are unclear as more severe hypoxia could result in additional ischaemic injury to the brain
bull 28 Blennow G Brierley JB Meldrum BS Siesjouml BK Epileptic brain damage The role of sysemic factors that modify cerebral energy metabolism Brain 1978101687-700 Bibliographic Links [Context Link]
bull 29 Meldrum BS Brierley JB Prolonged epileptic seizures in primates Ischaemic cell change and its relation to ictal physiological events Arch Neurol 19732810-17 Bibliographic Links [Context Link]
bull 30 bull Sasahira M Lowry T Simon RP Neuronal injury in experimental status epilepticus in the rat role of acidosis Neurosci Lett 1997224177-180 Bibliographic Links See [31bull] [Context Link]
bull 31 bull Sasahira M Simon RP Greenberg DA Neuronal injury in experimental status epilepticus in the rat role of hypoxia Neurosci Lett 1997222207-209 Bibliographic Links Thie paper and [30bull] are excellent reports considering the influence of physiological parameters on neuronal damage induced by status epilepticus [Context Link]
Effetti collaterali della fenitoina ev
bull Lesioni dei tessuti mollicon o senza
stravasordquoPurple Handgt 40 casi con parecchie
amputazioni ( (Kilarski 1984 Rao et al 1988
Hanna 1992)
bull Problemi al sito di iniezione Earnest et al (1983)
30 su 200
bull Ipotensione in gt 25 dei pazcon aritmie
ndash In 3139 pazienti 1 FA (velocitagrave di infus 26 mgmin) 1
tachic sinusale 1 allungamento tratto PR
ndash (Gellerman and Martinex 1967 Goldschlager and
Karliner 1967 Louis et al 1967 Voigt 1968)
bull
Allen FH Runge JW Legarda S et al Multicenter open-label
study on safety tolerance and pharmacokinetics of
intravenous fosphenytoin (Cerebyx) in status epilepticus
[abstract] Epilepsia 199435(Suppl 18)93
bull Data have been published from 40 patients in status epilepticus who received fosphenytoin at a mean infusion rate of 92 mgmin ranging from 247 to 1113 mgmin) Status epilepticus was terminated in 37 of 40 patients (85) within 30 min of receiving fosphenytoin The rapid infusion was well tolerated with only mild or transient side effects Most of the side effects reported were attributable to the pharmacologic effect of phenytoin and included dizziness nystagmus and ataxia Most patients in this trial received a benzodiazepine before the infusion of fosphenytoin and no adverse drug interactions were found
Introduzione alla peculiaritagrave
dellrsquoambiente intensivistico
Convulsioni in ambiente intensivo
bull Sepsi
bull Cause mediche
bull Anormalitagrave metaboliche(30-35) (11)ndash Iponatremiaipocalcemiaipofosfatemiaipoglicemiauremia
ndash Alterazioni della osmolaritagrave specie correzione acuta bull Acute return from hyperosmolarity back to normal levels in a rat
neocortical slice preparation by lowering the D-glucose concentration increased the amplitude of evoked early and late excitatory postsynaptic potentials a situation reminiscent of the generalized convulsions that may follow acute reduction of glucose in diabetic nonketotic hyperglycemia (42)
ndash Ipoosmolaritagrave induce increased nervous system excitability by strengthening both excitatory synaptic communications in neocortex and field effects among the entire cortical population (41)
Problemi peculiari allrsquoambiente
intensivistico
bull Polifarmacologia
bull Insuff renale
bull Insuff epatica
bull Induzione enzimatica
bull Inibizione enzimatica
bull Ipodisprotidemiehellipfarmaci altamente
legati alle prot plasmatiche
Trattamento dello stato di
male
Allora
bull Terapia immediata
bull Aggressiva
bull Supporto vitale di base
bull AAirway
bull Breathing
bull CSupporto circolatorio
Status epilepticusfilosofia del trattamento
Disaccoppiamento
CMRO2CBF
Funzione cardiocircolatoriaFunzione resp
Supporto supernormale
Glucosio
Tiamina 100 mg
Dopaminanoradrenalina + fre con barbituricihellip
Indagine conoscitiva su 127 TI NCH europeeDauch WA Schutze M Guttinger M et al Posttraumatic seizure prevention - results of a
survey of 127 neurosurgery clinics Zentralbl Neurochir 1996 57190ndash5
0
10
20
30
40
50
60
profilassi
Profilassi con anticonvulsivi post trauma cranio-
encefalico
mai
sempre
secindicazione
substantial cortical
injurycerebral contusion
acute subdural
hemorrhage
depressed skull fracture
penetrating missile
injury
(141517)
Rischio convulsivo
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001bull Background It is uncertain whether the administration of benzodiazepines by paramedics is an
effective and safe treatment for out-of-hospital status epilepticus
Methods We conducted a randomized double-blind trial to evaluate intravenous benzodiazepines administered by paramedics for the treatment of out-of-hospital status epilepticus Adults with prolonged (lasting five minutes or more) or repetitive generalized convulsive seizures received intravenous diazepam (5 mg) lorazepam (2 mg) or placebo An identical second injection was given if needed
Results Of the 205 patients enrolled 66 received lorazepam 68 received diazepam and 71 received placebo Status epilepticus had been terminated on arrival at the emergency department in more patients treated with lorazepam (591 percent) or diazepam (426 percent) than patients given placebo (211 percent) (P=0001) After adjustment for covariates the odds ratio for termination of status epilepticus by the time of arrival in the lorazepam group as compared with the placebo group was 48 (95 percent confidence interval 19 to 130) The odds ratio was 19 (95 percent confidence interval 08 to 44) in the lorazepam group as compared with the diazepam group and 23 (95 percent confidence interval 10 to 59) in the diazepam group as compared with the placebo group The rates of respiratory or circulatory complications after the study treatment was administered were 106 percent for the lorazepam group 103 percent for the diazepam group and 225 percent for the placebo group (P=008)
Conclusions Benzodiazepines are safe and effective when administered by paramedics for out-of-hospital status epilepticus in adults Lorazepam is likely to be a better therapy than diazepam (N Engl J Med 2001345631-7)
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001
0
10
20
30
40
50
60
seizures stop complications
lorazepam
diazepam
placebo
randomized double-blind trial
to evaluate iv bdz
admin by paramedics
for the treatment of out-of-hospital status epilepticus
Adults with prolonged (lasting 5 minutes or +)
or repetitive generalized convulsive seizures
received iv diazepam (5 mg)
lorazepam (2 mg) or placebo
An identical second injection was given if needed
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
Treiman DM Meyers PD Walton NY Collins JF Colling C Rowan AJ et al A comparison of four treatments for generalized convulsive status epilepticus N Engl J Med 1998 339792-798
randomized double-blind trial that compared the following four regimens commonly used for the treatment of generalized convulsive status epilepticus diazepam followed by phenytoin phenytoin alone phenobarbital and lorazepam Although the doses and infusion rates chosen for study closely reflected common clinical practice at the time the study began the combination of lorazepam followed by phenytoin (the preferred regimen of many neurologists) was not included
This is a large well-controlled and important clinical trial The major limitation in its clinical relevance is the lack of inclusion of a regimen consisting of lorazepam followed by phenytoin
Veterans Affairs Status Epilepticus Cooperative
Study Group Treiman et al
SE aperto
diaz fenitoina fenobarbital lorazepam
2 o + convuls senza
ripresa di coscienza
Convuls continue = gt 10 min
fenitoina
Coma con scariche
ictali EEG
primary outcome measure
cessation of clinical and electrical
seizure activity
within 20min after initiation
of treatment and continuing for at least
60min after the start of treatment
lorazepam fenitoina
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
bull st treatment successful in 555 of patients with a verified diagnosis of overt status epilepticus (n=384) and in 149 of patients with subtle status epilepticus (n=134)
bull Comparisons between the 4 treatments showed that lorazepam was more effective than phenytoin alone in patients with overt status epilepticus (treatment success in 649 versus 436 of patients respectively)
bull other treatment comparisons in the overt group and all comparisons in the subtle group were not significantly different however
bull There were no significant differences between treatments in patient outcome rates of recurrence of status epilepticus or return of full consciousness over the 12-h observation period or in the frequency of adverse cardiac respiratory or hypotensive events
Treiman DM Meyers PD Walton NY et al A
comparison of four treatments for generalized
convulsive status epilepticus N Engl J Med 1998
339792-798
P 002
Percentage of successful treatment
grey bars overt patients black bars subtle patients
Alldredge Brian Kab Lowenstein Daniel HAC Status
epilepticus new concepts Current Opinion in Neurology
121999 183-190
Da ChapmanAnaesthesia 2004
Marik PEVaron J The Management of Status
Epilepticus Chest 126(2)582-591 August 2004
Status epilepticus is a major medical emergency associated with significant morbidity and mortality Status epilepticusis best defined as a continuous generalized convulsive seizure lasting gt 5 min or two or more seizures during which the patient does not return to baseline consciousness Lorazepam in a dose of 01 mgkg is the drug of first choice for terminating status epilepticus Patients who continue to have clinical or EEG evidence of seizure activity after treatment with lorazepam should be considered to have refractory status epileptics and should be treated with a continuous infusion of propofol or midazolam This article reviews current information regarding the management of status epilepticus in adults
Schema di Marik et al
Claassen JHirsch LJ Emerson R GBates
JE Thompson TBMayer SA Continuous EEG
monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042 bull The authors reviewed 33 episodes of RSE treated with cIV-MDZ in their neurologic intensive care
unit over 6 years All patients were monitored with continuous EEG (cEEG) MDZ infusion rates were titrated to eliminate clinical and EEG seizure activity cIV-MDZ was discontinued once patients were seizure-free for 24 hours Acute treatment failures (seizures 1 to 6 hours after starting cIV-MDZ) breakthrough seizures (after 6 hours of therapy) post-treatment seizures (within 48 hours of discontinuing therapy) and ultimate treatment failure (frequent seizures that led to treatment with pentobarbital or propofol) were identified
bull Results All patients were in nonconvulsive SE at the time cIV-MDZ was started the mean duration of SE before treatment was 39 days (range 0 to 17 days) In addition to benzodiazepines 94 of patients had received at least two antiepileptic drugs (AED) before starting cIV-MDZ The mean loading dose was 019 mgkg the mean maximal infusion rate was 022 mgkgh and the mean duration of cIV-MDZ therapy was 42 days (range 1 to 14 days) Acute treatment failure occurred in 18 (633) of episodes breakthrough seizures in 56 (1832) post-treatment seizures in 68 (1928) and ultimate treatment failure in 18 (633) Breakthrough seizures were clinically subtle or purely electrographic in 89 (1618) of cases and were associated with an increased risk of developing post-treatment seizures (p = 001)
bull Conclusions Although most patients with RSE initially responded to cIV-MDZ over half developed subsequent breakthrough seizures which were predictive of post-treatment seizures and were often detectable only with cEEG Titrating cIV-MDZ to burst suppression more aggressive treatment with concurrent AED or a longer period of initial treatment may reduce the high proportion of patients with RSE who relapse after cIV-MDZ is discontinued
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus Neurology 2001 57 25 1036-1042
0
10
20
30
40
50
60
70
80
non seizures
seizures lt30 min24h05-12 h
seizures 05-12 h24 hgt 12 h
seiz gt12 h24
burst suppression
periodic latdischarge
periodic gen discharge
prima
durante
dopo
33 episodes of RSE treated with cIV-MDZ neurologic ICU over 6 years
All patients were monitored with continuous EEG (cEEG)
Waterhouse Elizabeth J 1 2 DeLorenzo Robert J 1 3 4 2
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
bull Status epilepticus (SE) is a medical and neurological emergency that has been associated with significant morbidity and mortality The most widely accepted definition of SE is more than 30 minutes of either continuous seizure activity or intermittent seizures without full recovery of consciousness between seizures SE is a major clinical concern in the elderly population both because it has increased incidence in the elderly compared with the general population and because of concurrent medical conditions that are more likely to complicate therapy and worsen prognosis in elderly individuals
The incidence of SE in the elderly is almost twice that of the general population at 86 per 100 000 per year With the anticipated growth of the elderly population SE is likely to become an increasingly common problem facing clinicians and an important public health issue The elderly have the highest SE-associated mortality of any age group at 38 and the very old elderly (gt80 years of age) have a mortality of at least 50 Acute or remote stroke is the most common aetiology of SE in the elderly Nonconvulsive SE (NCSE) has a wide range of clinical presentations ranging from confusion to obtundation It occurs commonly in elderly patients who are critically ill and in the setting of coma Electroencephalogram is the only reliable method of diagnosing NCSE
The goal of treatment for SE is rapid cessation of clinical and electrical seizure activity Most treatment protocols call for the immediate administration of an intravenous benzodiazepine followed by phenytoin or fosphenytoin Recent studies suggest that when this initial treatment of SE fails little is gained by using additional standard drugs General anaesthetic agents (such as pentobarbital midazolam or propofol) should be expeditiously employed although these treatments have their own potential complications Intravenous valproic acid is a recent addition to the armamentarium of drugs for the treatment of SE with a low risk of hypotension respiratory depression and hypotension making it a potentially useful drug for the treatment of SE in the elderly However further information is needed to establish its role in the overall treatment of SE
Waterhouseet al
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
BDZ
Fenitoina
O fosfenitoina
GA
Midaz
Propof
pentobarb
Ac valproico
Ns proposta
Lorazepam
01 mgkg
Propofol
1-2 mgkgMidazolam01 mgkg
Inf cont 3-10 mgkgh Inf cont 001-005 mgkgh
Miorilassante solo
Per intubazione
Pentobarbital dose caricopoi 01-04 mgkgmin
fenobarbital
bull 10-20 mgkg iv
ndash Eccessiva sedazione
ndash Depressresp
ndash Ipotensione
ndash Interaz farmacol
ndash Hl gt48 hrhelliphelliphellip
tiopental
bull cumulativo
bull Inotropo neghellip
bull Pentobarbital
bull immunosoppressione
propofol
bull Vantaggi cineticodinamici
bull Titolazione continua possibile
bull TCIquale livello
bull Dosi 1 mgkgripetibile dopo 5rsquo-
ndash Infcont 2-10 mgkgh
bull Rapida emergenzafinestra neurologicaevitare la
brusca sospensione
bull + rapido controllo delle convuls gt barbituricindash Stecker MM Kramer TH Raps EC OMeeghan R Dulaney E Skaar DJ Treatment of
refractory status epilepticus with propofol clinical and pharmacokinetic findings Epilepsia 1998
39 18-26
AG
bull Non ci sono dati che indichino quanto a lungo i paz debbano rimanere senza convuls prima di poter alleggerire il piano di AG24 h96h (Treiman DM Convulsive status
epilepticus Current Treatment Options in Neurology 1999 1 359-69)
bull Anest alogenatiisofluranogtsevofluranogtdesflurane
bull Ma vaporizzatori
bull Contaminazione ambientale
bull Costihellip
Studi comparativi1
bull Midazolamgt tiopental
ndash Lohr A Jr Werneck LC Comparative non-randomized study with
midazolam versus thiopental in children with refractory status
epilepticus [Portuguese] Arq Neuropsiquiatr 2000 58282-287
ndash non-randomized comparison
ndash of historical data (thiopental) and prospectively
acquired data (midazolam)
ndash Midazolam was no more often effective than
thiopental but was associated with less cyanosis and
less respiratory distress in this study of 50 children
Studi comparativi2
Valproatobull Valproate(ivrdquoDepaconrdquo) has been used for the treatment of refractory SE
in children and myoclonic SE ndash Sheth RD Gidal BE Intravenous valproic acid for myoclonic status epilepticus
Neurology 2000 541201
ndash Uberall MA Trollmann R Wunsiedler U Wenzel D Intravenous valproate in pediatric epilepsy patients with refractory status epilepticus Neurology 2000 542188-2189 ]
bull Valproate has also been used in SE in the elderly and appears to be safe even in the presence of cardiovascular instability and hypotension no significant change in blood pressure pulse or the need for vasopressors in 13 patients with SE and hypotension given a loading dose of 147-327 mgkg Depacon intravenouslyndash Sinha S Naritoku DK Intravenous valproate is well tolerated in unstable patients
with status epilepticus Neurology 2000 55722-724
bull However there is a case report of severe hypotension in an 11-year-old child after treatment of SE with 30 mgkg intravenous valproate ndash White JR Santos CS Intravenous valproate associated with significant
hypotension in the treatment of status epilepticus J Child Neurol 1999 14822-823
FINE
Percheacute non ne possiamo
piugravehelliphelliphellip
PrognosiSE vs NCSE
bull Necessitagrave di una attenta stratificazione
bull studies drawn from the intensive care setting (Drislane and Schomer 1994 DeLorenzo et al 1998 Litt et al 1998) are faced with the markedly greater task of determining the selective consequences and morbidity of the superadded insult of the epileptic electrical activity combined with the medical and neurologic problems that sent the patient to the intensive care setting or resulted in coma in the first place
Prognosi 2
NON Convulsive (NCSE) Status
Epilepticus(Hosford 1999)
bull 1 Generalized SE in nonconvulsing well-oxygenated animals produces brain damage (Wasterlain et al 1993) In paralyzed oxygen-ventilated baboons with over 3 hours of electrographic seizure activity there was neuronal necrosis in the hippocampal neocortex even when systemic complications and no convulsions were seen (Meldrum et al 1973) Flurothyl-induced seizures in O2-ventilated rats caused brain lesions that included infarction of the substantia nigra (Nevander et al 1985)
bull 2 Focal seizures can induce neuronal necrosis (Wasterlain et al 1993) Necrosis of hilar interneurons and CA3 pyramidal cells occurs with electrical stimulation of the afferent pathway for 2 to 24 hours (Sloviter 1983) with similar changes seen with intraventricular glutamate or aspartate injection (Sloviter and Dempster 1985)
bull 3 Limbic seizures can cause brain damage Cholinomimetics kainic acid and other methods to produce limbic SE can result in neuronal necrosis in the hippocampus amygdala piriform and entorhinal cortices the thalamus lateral septum substantia nigra and neocortex (Olney et al 1974 1983 Strain and Tasker 1991)
La prognosi finale dipende dalla eziologia
The possible relationships among seizure etiology
nonconvulsive status
epilepticus and outcome
Most patients with complex partial status epilepticus (CPSE)
have etiologies consistent with pathway [circled digit one]
(strokes anoxiaischemia head trauma encephalitis)
rather than [circled digit two]
The best example of [circled digit two] would be a patient with
temporal lobe epilepsy
who went into CPSE because of inadequate
antiepileptic drug levels
Fattori che influenzano la prognosi nello
SE(anche NCSE)
bull Causa dello stato
epilettico
bull Durata dello stato
bull Trattamento
bull Etagrave
bull Effetti dannosi sistemici metabolici e fisiologici (Meldrum et al 1973 Simon 1985)
bull Danno cerebrale secondario allrsquo insulto acuto che induce SE (Hauser 1983 Barry et al 1993)
bull Danno neuronale diretto dovuto alla abnorme attivitagrave elettrica del SE (Meldrum et al 1973 Knopman et al 1977 Lothman 1990)
Chin RFMVerhulst LNeville BGRPeters MJScott RC
Inappropriate emergency management of status epilepticus
in children contributes to need for intensive care Journal of
Neurology Neurosurgery amp Psychiatry 75(11)1584-
1588 2004
bull gt 2 dosi o dosi inadeguate di BDZ
bull Depressione respiratoria
bull Trattati in emergenza extraospedaliera
complicazioni
Complicazioni sistemiche dello status epilepticus
SNC cardiova
s
Resp metaboli
co
altro
Ipossiaanos
sia
IM Apneaipopnea Disidtrataz MOF
Edema Ipoipertens Insuff resp Disturbi
elettripoNaip
erK
DIC
Emorragia Aritmie Polmonite ab
ingestis
Acidosi metab Rabdomiolisi
Trombosi
venosa
Arresto Iprtens polm Necrosi
tubacutafratture
Shock
cardiogeno
EPA Necrosi
epatica acuta
Embolia polm Pancreatite
acuta
Complicazioni dello SE
bull Durata convulsioni gt 1 hrpredittore indipendente di poor outcome (mortality odds ratio di quasi 10) (4)
bull Convulsioni prolungate aumentano il rischio di danno neuronalendash Eccitotox
ndash Accumulo intracellulare di Ca++ e apoptosi
ndash Riorganizzazione sinaptica epilettogenica( e gemmazione)
ndash Deplezione di energia e inibizione della sintesi proteica e del DNA (5)
ndash ldquo Particularly vulnerable to injury are the neurons within the hippocampus cerebral cortical mantle and cerebellar Purkinje cells Selective neuronal loss has been described within the hilar area of the dentate gyrus of the hippocampus (areas CA1 and CA3) after prolonged seizures leading to the development of chronic temporal lobe epilepsy (6)rdquo
bull Manifestazioni autonomichemorte improvvisa ndash DeLorenzo RJ Status epilepticus Concepts in diagnosis and treatment Semin Neurol 1990 10396ndash
405
ndash Towne AR Pellock JM Ko D et al Determinants of mortality in status epilepticus Epilepsia 1994 3527ndash34
ndash Payne TA Bleck TP Status epilepticus Crit Care Clin 1997 13 (1)17ndash38
ndash Sloviter RS Status epilepticus-induced neuronal injury and network reorganization Epilepsia 1999 40S34ndash41
Complications of SE
bull Aminoff MJ Simon RP Status epilepticus causes clinical features and consequences in 98 patients Am J Med 198069657-666 Bibliographic Links [Context Link]
bull 25 Wasterlain CG Fujikawa DG Penix L Sankar R Pathophysiological mechanisms of brain damage from status epilepticus Epilepsia 199334(1)S37-S53 Bibliographic Links [Context Link]
bull 26 Singhal PC Chugh KS Golati DR Myoglobinuria and renal failure after status epilepticus Neurology 197828200-201 Bibliographic Links [Context Link]
bull 27 Fisher S Zatuchni J Greenberg J Disseminated intravascular coagulation in status epilepticus Thromb Haemost 197738909-913 Bibliographic Links [Context Link]
Neuroprotective effects of acidosis
bull some studies that suggest that hypoxia acidosis and hypoglycaemia may be neuroprotective [2829] To
study these phenomena further Sasahira and coworkers [30bull31bull] looked at a rat model of status epilepticus based upon repeated bicuculline injections and using heat shock protein as an indirect measure of neuronal injury Using high concentrations of inhaled carbon dioxide they were able to reduce the serum pH from 755 to 717 This resulted in a shorter seizure duration and less neuronal damage [30bull] Using multiple regression analysis they were able to show a neuroprotective effect of shortening seizure duration and an independent effect of acidosis [30bull] Acidosis and raised carbon dioxide tensions have a profound effect on cerebral blood flow and whether the neuroprotective effect is due to haemodynamic effects or to the effect of acidoisis on receptors or transmitter release is unknown
bull A further study from the same group [31bull] looked at the effects of moderate hypoxia (PaO2=50 mmHg) on neuronal damage in the same model compared with normoxic controls There was no difference in neuronal injury detected suggesting that moderate hypoxia has no effect on neuronal death in status epilepticus The authors rightly conclude however that the implications of their findings for the treatment of status epilepticus are unclear as more severe hypoxia could result in additional ischaemic injury to the brain
bull 28 Blennow G Brierley JB Meldrum BS Siesjouml BK Epileptic brain damage The role of sysemic factors that modify cerebral energy metabolism Brain 1978101687-700 Bibliographic Links [Context Link]
bull 29 Meldrum BS Brierley JB Prolonged epileptic seizures in primates Ischaemic cell change and its relation to ictal physiological events Arch Neurol 19732810-17 Bibliographic Links [Context Link]
bull 30 bull Sasahira M Lowry T Simon RP Neuronal injury in experimental status epilepticus in the rat role of acidosis Neurosci Lett 1997224177-180 Bibliographic Links See [31bull] [Context Link]
bull 31 bull Sasahira M Simon RP Greenberg DA Neuronal injury in experimental status epilepticus in the rat role of hypoxia Neurosci Lett 1997222207-209 Bibliographic Links Thie paper and [30bull] are excellent reports considering the influence of physiological parameters on neuronal damage induced by status epilepticus [Context Link]
Effetti collaterali della fenitoina ev
bull Lesioni dei tessuti mollicon o senza
stravasordquoPurple Handgt 40 casi con parecchie
amputazioni ( (Kilarski 1984 Rao et al 1988
Hanna 1992)
bull Problemi al sito di iniezione Earnest et al (1983)
30 su 200
bull Ipotensione in gt 25 dei pazcon aritmie
ndash In 3139 pazienti 1 FA (velocitagrave di infus 26 mgmin) 1
tachic sinusale 1 allungamento tratto PR
ndash (Gellerman and Martinex 1967 Goldschlager and
Karliner 1967 Louis et al 1967 Voigt 1968)
bull
Allen FH Runge JW Legarda S et al Multicenter open-label
study on safety tolerance and pharmacokinetics of
intravenous fosphenytoin (Cerebyx) in status epilepticus
[abstract] Epilepsia 199435(Suppl 18)93
bull Data have been published from 40 patients in status epilepticus who received fosphenytoin at a mean infusion rate of 92 mgmin ranging from 247 to 1113 mgmin) Status epilepticus was terminated in 37 of 40 patients (85) within 30 min of receiving fosphenytoin The rapid infusion was well tolerated with only mild or transient side effects Most of the side effects reported were attributable to the pharmacologic effect of phenytoin and included dizziness nystagmus and ataxia Most patients in this trial received a benzodiazepine before the infusion of fosphenytoin and no adverse drug interactions were found
Introduzione alla peculiaritagrave
dellrsquoambiente intensivistico
Convulsioni in ambiente intensivo
bull Sepsi
bull Cause mediche
bull Anormalitagrave metaboliche(30-35) (11)ndash Iponatremiaipocalcemiaipofosfatemiaipoglicemiauremia
ndash Alterazioni della osmolaritagrave specie correzione acuta bull Acute return from hyperosmolarity back to normal levels in a rat
neocortical slice preparation by lowering the D-glucose concentration increased the amplitude of evoked early and late excitatory postsynaptic potentials a situation reminiscent of the generalized convulsions that may follow acute reduction of glucose in diabetic nonketotic hyperglycemia (42)
ndash Ipoosmolaritagrave induce increased nervous system excitability by strengthening both excitatory synaptic communications in neocortex and field effects among the entire cortical population (41)
Problemi peculiari allrsquoambiente
intensivistico
bull Polifarmacologia
bull Insuff renale
bull Insuff epatica
bull Induzione enzimatica
bull Inibizione enzimatica
bull Ipodisprotidemiehellipfarmaci altamente
legati alle prot plasmatiche
Trattamento dello stato di
male
Allora
bull Terapia immediata
bull Aggressiva
bull Supporto vitale di base
bull AAirway
bull Breathing
bull CSupporto circolatorio
Status epilepticusfilosofia del trattamento
Disaccoppiamento
CMRO2CBF
Funzione cardiocircolatoriaFunzione resp
Supporto supernormale
Glucosio
Tiamina 100 mg
Dopaminanoradrenalina + fre con barbituricihellip
Indagine conoscitiva su 127 TI NCH europeeDauch WA Schutze M Guttinger M et al Posttraumatic seizure prevention - results of a
survey of 127 neurosurgery clinics Zentralbl Neurochir 1996 57190ndash5
0
10
20
30
40
50
60
profilassi
Profilassi con anticonvulsivi post trauma cranio-
encefalico
mai
sempre
secindicazione
substantial cortical
injurycerebral contusion
acute subdural
hemorrhage
depressed skull fracture
penetrating missile
injury
(141517)
Rischio convulsivo
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001bull Background It is uncertain whether the administration of benzodiazepines by paramedics is an
effective and safe treatment for out-of-hospital status epilepticus
Methods We conducted a randomized double-blind trial to evaluate intravenous benzodiazepines administered by paramedics for the treatment of out-of-hospital status epilepticus Adults with prolonged (lasting five minutes or more) or repetitive generalized convulsive seizures received intravenous diazepam (5 mg) lorazepam (2 mg) or placebo An identical second injection was given if needed
Results Of the 205 patients enrolled 66 received lorazepam 68 received diazepam and 71 received placebo Status epilepticus had been terminated on arrival at the emergency department in more patients treated with lorazepam (591 percent) or diazepam (426 percent) than patients given placebo (211 percent) (P=0001) After adjustment for covariates the odds ratio for termination of status epilepticus by the time of arrival in the lorazepam group as compared with the placebo group was 48 (95 percent confidence interval 19 to 130) The odds ratio was 19 (95 percent confidence interval 08 to 44) in the lorazepam group as compared with the diazepam group and 23 (95 percent confidence interval 10 to 59) in the diazepam group as compared with the placebo group The rates of respiratory or circulatory complications after the study treatment was administered were 106 percent for the lorazepam group 103 percent for the diazepam group and 225 percent for the placebo group (P=008)
Conclusions Benzodiazepines are safe and effective when administered by paramedics for out-of-hospital status epilepticus in adults Lorazepam is likely to be a better therapy than diazepam (N Engl J Med 2001345631-7)
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001
0
10
20
30
40
50
60
seizures stop complications
lorazepam
diazepam
placebo
randomized double-blind trial
to evaluate iv bdz
admin by paramedics
for the treatment of out-of-hospital status epilepticus
Adults with prolonged (lasting 5 minutes or +)
or repetitive generalized convulsive seizures
received iv diazepam (5 mg)
lorazepam (2 mg) or placebo
An identical second injection was given if needed
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
Treiman DM Meyers PD Walton NY Collins JF Colling C Rowan AJ et al A comparison of four treatments for generalized convulsive status epilepticus N Engl J Med 1998 339792-798
randomized double-blind trial that compared the following four regimens commonly used for the treatment of generalized convulsive status epilepticus diazepam followed by phenytoin phenytoin alone phenobarbital and lorazepam Although the doses and infusion rates chosen for study closely reflected common clinical practice at the time the study began the combination of lorazepam followed by phenytoin (the preferred regimen of many neurologists) was not included
This is a large well-controlled and important clinical trial The major limitation in its clinical relevance is the lack of inclusion of a regimen consisting of lorazepam followed by phenytoin
Veterans Affairs Status Epilepticus Cooperative
Study Group Treiman et al
SE aperto
diaz fenitoina fenobarbital lorazepam
2 o + convuls senza
ripresa di coscienza
Convuls continue = gt 10 min
fenitoina
Coma con scariche
ictali EEG
primary outcome measure
cessation of clinical and electrical
seizure activity
within 20min after initiation
of treatment and continuing for at least
60min after the start of treatment
lorazepam fenitoina
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
bull st treatment successful in 555 of patients with a verified diagnosis of overt status epilepticus (n=384) and in 149 of patients with subtle status epilepticus (n=134)
bull Comparisons between the 4 treatments showed that lorazepam was more effective than phenytoin alone in patients with overt status epilepticus (treatment success in 649 versus 436 of patients respectively)
bull other treatment comparisons in the overt group and all comparisons in the subtle group were not significantly different however
bull There were no significant differences between treatments in patient outcome rates of recurrence of status epilepticus or return of full consciousness over the 12-h observation period or in the frequency of adverse cardiac respiratory or hypotensive events
Treiman DM Meyers PD Walton NY et al A
comparison of four treatments for generalized
convulsive status epilepticus N Engl J Med 1998
339792-798
P 002
Percentage of successful treatment
grey bars overt patients black bars subtle patients
Alldredge Brian Kab Lowenstein Daniel HAC Status
epilepticus new concepts Current Opinion in Neurology
121999 183-190
Da ChapmanAnaesthesia 2004
Marik PEVaron J The Management of Status
Epilepticus Chest 126(2)582-591 August 2004
Status epilepticus is a major medical emergency associated with significant morbidity and mortality Status epilepticusis best defined as a continuous generalized convulsive seizure lasting gt 5 min or two or more seizures during which the patient does not return to baseline consciousness Lorazepam in a dose of 01 mgkg is the drug of first choice for terminating status epilepticus Patients who continue to have clinical or EEG evidence of seizure activity after treatment with lorazepam should be considered to have refractory status epileptics and should be treated with a continuous infusion of propofol or midazolam This article reviews current information regarding the management of status epilepticus in adults
Schema di Marik et al
Claassen JHirsch LJ Emerson R GBates
JE Thompson TBMayer SA Continuous EEG
monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042 bull The authors reviewed 33 episodes of RSE treated with cIV-MDZ in their neurologic intensive care
unit over 6 years All patients were monitored with continuous EEG (cEEG) MDZ infusion rates were titrated to eliminate clinical and EEG seizure activity cIV-MDZ was discontinued once patients were seizure-free for 24 hours Acute treatment failures (seizures 1 to 6 hours after starting cIV-MDZ) breakthrough seizures (after 6 hours of therapy) post-treatment seizures (within 48 hours of discontinuing therapy) and ultimate treatment failure (frequent seizures that led to treatment with pentobarbital or propofol) were identified
bull Results All patients were in nonconvulsive SE at the time cIV-MDZ was started the mean duration of SE before treatment was 39 days (range 0 to 17 days) In addition to benzodiazepines 94 of patients had received at least two antiepileptic drugs (AED) before starting cIV-MDZ The mean loading dose was 019 mgkg the mean maximal infusion rate was 022 mgkgh and the mean duration of cIV-MDZ therapy was 42 days (range 1 to 14 days) Acute treatment failure occurred in 18 (633) of episodes breakthrough seizures in 56 (1832) post-treatment seizures in 68 (1928) and ultimate treatment failure in 18 (633) Breakthrough seizures were clinically subtle or purely electrographic in 89 (1618) of cases and were associated with an increased risk of developing post-treatment seizures (p = 001)
bull Conclusions Although most patients with RSE initially responded to cIV-MDZ over half developed subsequent breakthrough seizures which were predictive of post-treatment seizures and were often detectable only with cEEG Titrating cIV-MDZ to burst suppression more aggressive treatment with concurrent AED or a longer period of initial treatment may reduce the high proportion of patients with RSE who relapse after cIV-MDZ is discontinued
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus Neurology 2001 57 25 1036-1042
0
10
20
30
40
50
60
70
80
non seizures
seizures lt30 min24h05-12 h
seizures 05-12 h24 hgt 12 h
seiz gt12 h24
burst suppression
periodic latdischarge
periodic gen discharge
prima
durante
dopo
33 episodes of RSE treated with cIV-MDZ neurologic ICU over 6 years
All patients were monitored with continuous EEG (cEEG)
Waterhouse Elizabeth J 1 2 DeLorenzo Robert J 1 3 4 2
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
bull Status epilepticus (SE) is a medical and neurological emergency that has been associated with significant morbidity and mortality The most widely accepted definition of SE is more than 30 minutes of either continuous seizure activity or intermittent seizures without full recovery of consciousness between seizures SE is a major clinical concern in the elderly population both because it has increased incidence in the elderly compared with the general population and because of concurrent medical conditions that are more likely to complicate therapy and worsen prognosis in elderly individuals
The incidence of SE in the elderly is almost twice that of the general population at 86 per 100 000 per year With the anticipated growth of the elderly population SE is likely to become an increasingly common problem facing clinicians and an important public health issue The elderly have the highest SE-associated mortality of any age group at 38 and the very old elderly (gt80 years of age) have a mortality of at least 50 Acute or remote stroke is the most common aetiology of SE in the elderly Nonconvulsive SE (NCSE) has a wide range of clinical presentations ranging from confusion to obtundation It occurs commonly in elderly patients who are critically ill and in the setting of coma Electroencephalogram is the only reliable method of diagnosing NCSE
The goal of treatment for SE is rapid cessation of clinical and electrical seizure activity Most treatment protocols call for the immediate administration of an intravenous benzodiazepine followed by phenytoin or fosphenytoin Recent studies suggest that when this initial treatment of SE fails little is gained by using additional standard drugs General anaesthetic agents (such as pentobarbital midazolam or propofol) should be expeditiously employed although these treatments have their own potential complications Intravenous valproic acid is a recent addition to the armamentarium of drugs for the treatment of SE with a low risk of hypotension respiratory depression and hypotension making it a potentially useful drug for the treatment of SE in the elderly However further information is needed to establish its role in the overall treatment of SE
Waterhouseet al
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
BDZ
Fenitoina
O fosfenitoina
GA
Midaz
Propof
pentobarb
Ac valproico
Ns proposta
Lorazepam
01 mgkg
Propofol
1-2 mgkgMidazolam01 mgkg
Inf cont 3-10 mgkgh Inf cont 001-005 mgkgh
Miorilassante solo
Per intubazione
Pentobarbital dose caricopoi 01-04 mgkgmin
fenobarbital
bull 10-20 mgkg iv
ndash Eccessiva sedazione
ndash Depressresp
ndash Ipotensione
ndash Interaz farmacol
ndash Hl gt48 hrhelliphelliphellip
tiopental
bull cumulativo
bull Inotropo neghellip
bull Pentobarbital
bull immunosoppressione
propofol
bull Vantaggi cineticodinamici
bull Titolazione continua possibile
bull TCIquale livello
bull Dosi 1 mgkgripetibile dopo 5rsquo-
ndash Infcont 2-10 mgkgh
bull Rapida emergenzafinestra neurologicaevitare la
brusca sospensione
bull + rapido controllo delle convuls gt barbituricindash Stecker MM Kramer TH Raps EC OMeeghan R Dulaney E Skaar DJ Treatment of
refractory status epilepticus with propofol clinical and pharmacokinetic findings Epilepsia 1998
39 18-26
AG
bull Non ci sono dati che indichino quanto a lungo i paz debbano rimanere senza convuls prima di poter alleggerire il piano di AG24 h96h (Treiman DM Convulsive status
epilepticus Current Treatment Options in Neurology 1999 1 359-69)
bull Anest alogenatiisofluranogtsevofluranogtdesflurane
bull Ma vaporizzatori
bull Contaminazione ambientale
bull Costihellip
Studi comparativi1
bull Midazolamgt tiopental
ndash Lohr A Jr Werneck LC Comparative non-randomized study with
midazolam versus thiopental in children with refractory status
epilepticus [Portuguese] Arq Neuropsiquiatr 2000 58282-287
ndash non-randomized comparison
ndash of historical data (thiopental) and prospectively
acquired data (midazolam)
ndash Midazolam was no more often effective than
thiopental but was associated with less cyanosis and
less respiratory distress in this study of 50 children
Studi comparativi2
Valproatobull Valproate(ivrdquoDepaconrdquo) has been used for the treatment of refractory SE
in children and myoclonic SE ndash Sheth RD Gidal BE Intravenous valproic acid for myoclonic status epilepticus
Neurology 2000 541201
ndash Uberall MA Trollmann R Wunsiedler U Wenzel D Intravenous valproate in pediatric epilepsy patients with refractory status epilepticus Neurology 2000 542188-2189 ]
bull Valproate has also been used in SE in the elderly and appears to be safe even in the presence of cardiovascular instability and hypotension no significant change in blood pressure pulse or the need for vasopressors in 13 patients with SE and hypotension given a loading dose of 147-327 mgkg Depacon intravenouslyndash Sinha S Naritoku DK Intravenous valproate is well tolerated in unstable patients
with status epilepticus Neurology 2000 55722-724
bull However there is a case report of severe hypotension in an 11-year-old child after treatment of SE with 30 mgkg intravenous valproate ndash White JR Santos CS Intravenous valproate associated with significant
hypotension in the treatment of status epilepticus J Child Neurol 1999 14822-823
FINE
Percheacute non ne possiamo
piugravehelliphelliphellip
Prognosi 2
NON Convulsive (NCSE) Status
Epilepticus(Hosford 1999)
bull 1 Generalized SE in nonconvulsing well-oxygenated animals produces brain damage (Wasterlain et al 1993) In paralyzed oxygen-ventilated baboons with over 3 hours of electrographic seizure activity there was neuronal necrosis in the hippocampal neocortex even when systemic complications and no convulsions were seen (Meldrum et al 1973) Flurothyl-induced seizures in O2-ventilated rats caused brain lesions that included infarction of the substantia nigra (Nevander et al 1985)
bull 2 Focal seizures can induce neuronal necrosis (Wasterlain et al 1993) Necrosis of hilar interneurons and CA3 pyramidal cells occurs with electrical stimulation of the afferent pathway for 2 to 24 hours (Sloviter 1983) with similar changes seen with intraventricular glutamate or aspartate injection (Sloviter and Dempster 1985)
bull 3 Limbic seizures can cause brain damage Cholinomimetics kainic acid and other methods to produce limbic SE can result in neuronal necrosis in the hippocampus amygdala piriform and entorhinal cortices the thalamus lateral septum substantia nigra and neocortex (Olney et al 1974 1983 Strain and Tasker 1991)
La prognosi finale dipende dalla eziologia
The possible relationships among seizure etiology
nonconvulsive status
epilepticus and outcome
Most patients with complex partial status epilepticus (CPSE)
have etiologies consistent with pathway [circled digit one]
(strokes anoxiaischemia head trauma encephalitis)
rather than [circled digit two]
The best example of [circled digit two] would be a patient with
temporal lobe epilepsy
who went into CPSE because of inadequate
antiepileptic drug levels
Fattori che influenzano la prognosi nello
SE(anche NCSE)
bull Causa dello stato
epilettico
bull Durata dello stato
bull Trattamento
bull Etagrave
bull Effetti dannosi sistemici metabolici e fisiologici (Meldrum et al 1973 Simon 1985)
bull Danno cerebrale secondario allrsquo insulto acuto che induce SE (Hauser 1983 Barry et al 1993)
bull Danno neuronale diretto dovuto alla abnorme attivitagrave elettrica del SE (Meldrum et al 1973 Knopman et al 1977 Lothman 1990)
Chin RFMVerhulst LNeville BGRPeters MJScott RC
Inappropriate emergency management of status epilepticus
in children contributes to need for intensive care Journal of
Neurology Neurosurgery amp Psychiatry 75(11)1584-
1588 2004
bull gt 2 dosi o dosi inadeguate di BDZ
bull Depressione respiratoria
bull Trattati in emergenza extraospedaliera
complicazioni
Complicazioni sistemiche dello status epilepticus
SNC cardiova
s
Resp metaboli
co
altro
Ipossiaanos
sia
IM Apneaipopnea Disidtrataz MOF
Edema Ipoipertens Insuff resp Disturbi
elettripoNaip
erK
DIC
Emorragia Aritmie Polmonite ab
ingestis
Acidosi metab Rabdomiolisi
Trombosi
venosa
Arresto Iprtens polm Necrosi
tubacutafratture
Shock
cardiogeno
EPA Necrosi
epatica acuta
Embolia polm Pancreatite
acuta
Complicazioni dello SE
bull Durata convulsioni gt 1 hrpredittore indipendente di poor outcome (mortality odds ratio di quasi 10) (4)
bull Convulsioni prolungate aumentano il rischio di danno neuronalendash Eccitotox
ndash Accumulo intracellulare di Ca++ e apoptosi
ndash Riorganizzazione sinaptica epilettogenica( e gemmazione)
ndash Deplezione di energia e inibizione della sintesi proteica e del DNA (5)
ndash ldquo Particularly vulnerable to injury are the neurons within the hippocampus cerebral cortical mantle and cerebellar Purkinje cells Selective neuronal loss has been described within the hilar area of the dentate gyrus of the hippocampus (areas CA1 and CA3) after prolonged seizures leading to the development of chronic temporal lobe epilepsy (6)rdquo
bull Manifestazioni autonomichemorte improvvisa ndash DeLorenzo RJ Status epilepticus Concepts in diagnosis and treatment Semin Neurol 1990 10396ndash
405
ndash Towne AR Pellock JM Ko D et al Determinants of mortality in status epilepticus Epilepsia 1994 3527ndash34
ndash Payne TA Bleck TP Status epilepticus Crit Care Clin 1997 13 (1)17ndash38
ndash Sloviter RS Status epilepticus-induced neuronal injury and network reorganization Epilepsia 1999 40S34ndash41
Complications of SE
bull Aminoff MJ Simon RP Status epilepticus causes clinical features and consequences in 98 patients Am J Med 198069657-666 Bibliographic Links [Context Link]
bull 25 Wasterlain CG Fujikawa DG Penix L Sankar R Pathophysiological mechanisms of brain damage from status epilepticus Epilepsia 199334(1)S37-S53 Bibliographic Links [Context Link]
bull 26 Singhal PC Chugh KS Golati DR Myoglobinuria and renal failure after status epilepticus Neurology 197828200-201 Bibliographic Links [Context Link]
bull 27 Fisher S Zatuchni J Greenberg J Disseminated intravascular coagulation in status epilepticus Thromb Haemost 197738909-913 Bibliographic Links [Context Link]
Neuroprotective effects of acidosis
bull some studies that suggest that hypoxia acidosis and hypoglycaemia may be neuroprotective [2829] To
study these phenomena further Sasahira and coworkers [30bull31bull] looked at a rat model of status epilepticus based upon repeated bicuculline injections and using heat shock protein as an indirect measure of neuronal injury Using high concentrations of inhaled carbon dioxide they were able to reduce the serum pH from 755 to 717 This resulted in a shorter seizure duration and less neuronal damage [30bull] Using multiple regression analysis they were able to show a neuroprotective effect of shortening seizure duration and an independent effect of acidosis [30bull] Acidosis and raised carbon dioxide tensions have a profound effect on cerebral blood flow and whether the neuroprotective effect is due to haemodynamic effects or to the effect of acidoisis on receptors or transmitter release is unknown
bull A further study from the same group [31bull] looked at the effects of moderate hypoxia (PaO2=50 mmHg) on neuronal damage in the same model compared with normoxic controls There was no difference in neuronal injury detected suggesting that moderate hypoxia has no effect on neuronal death in status epilepticus The authors rightly conclude however that the implications of their findings for the treatment of status epilepticus are unclear as more severe hypoxia could result in additional ischaemic injury to the brain
bull 28 Blennow G Brierley JB Meldrum BS Siesjouml BK Epileptic brain damage The role of sysemic factors that modify cerebral energy metabolism Brain 1978101687-700 Bibliographic Links [Context Link]
bull 29 Meldrum BS Brierley JB Prolonged epileptic seizures in primates Ischaemic cell change and its relation to ictal physiological events Arch Neurol 19732810-17 Bibliographic Links [Context Link]
bull 30 bull Sasahira M Lowry T Simon RP Neuronal injury in experimental status epilepticus in the rat role of acidosis Neurosci Lett 1997224177-180 Bibliographic Links See [31bull] [Context Link]
bull 31 bull Sasahira M Simon RP Greenberg DA Neuronal injury in experimental status epilepticus in the rat role of hypoxia Neurosci Lett 1997222207-209 Bibliographic Links Thie paper and [30bull] are excellent reports considering the influence of physiological parameters on neuronal damage induced by status epilepticus [Context Link]
Effetti collaterali della fenitoina ev
bull Lesioni dei tessuti mollicon o senza
stravasordquoPurple Handgt 40 casi con parecchie
amputazioni ( (Kilarski 1984 Rao et al 1988
Hanna 1992)
bull Problemi al sito di iniezione Earnest et al (1983)
30 su 200
bull Ipotensione in gt 25 dei pazcon aritmie
ndash In 3139 pazienti 1 FA (velocitagrave di infus 26 mgmin) 1
tachic sinusale 1 allungamento tratto PR
ndash (Gellerman and Martinex 1967 Goldschlager and
Karliner 1967 Louis et al 1967 Voigt 1968)
bull
Allen FH Runge JW Legarda S et al Multicenter open-label
study on safety tolerance and pharmacokinetics of
intravenous fosphenytoin (Cerebyx) in status epilepticus
[abstract] Epilepsia 199435(Suppl 18)93
bull Data have been published from 40 patients in status epilepticus who received fosphenytoin at a mean infusion rate of 92 mgmin ranging from 247 to 1113 mgmin) Status epilepticus was terminated in 37 of 40 patients (85) within 30 min of receiving fosphenytoin The rapid infusion was well tolerated with only mild or transient side effects Most of the side effects reported were attributable to the pharmacologic effect of phenytoin and included dizziness nystagmus and ataxia Most patients in this trial received a benzodiazepine before the infusion of fosphenytoin and no adverse drug interactions were found
Introduzione alla peculiaritagrave
dellrsquoambiente intensivistico
Convulsioni in ambiente intensivo
bull Sepsi
bull Cause mediche
bull Anormalitagrave metaboliche(30-35) (11)ndash Iponatremiaipocalcemiaipofosfatemiaipoglicemiauremia
ndash Alterazioni della osmolaritagrave specie correzione acuta bull Acute return from hyperosmolarity back to normal levels in a rat
neocortical slice preparation by lowering the D-glucose concentration increased the amplitude of evoked early and late excitatory postsynaptic potentials a situation reminiscent of the generalized convulsions that may follow acute reduction of glucose in diabetic nonketotic hyperglycemia (42)
ndash Ipoosmolaritagrave induce increased nervous system excitability by strengthening both excitatory synaptic communications in neocortex and field effects among the entire cortical population (41)
Problemi peculiari allrsquoambiente
intensivistico
bull Polifarmacologia
bull Insuff renale
bull Insuff epatica
bull Induzione enzimatica
bull Inibizione enzimatica
bull Ipodisprotidemiehellipfarmaci altamente
legati alle prot plasmatiche
Trattamento dello stato di
male
Allora
bull Terapia immediata
bull Aggressiva
bull Supporto vitale di base
bull AAirway
bull Breathing
bull CSupporto circolatorio
Status epilepticusfilosofia del trattamento
Disaccoppiamento
CMRO2CBF
Funzione cardiocircolatoriaFunzione resp
Supporto supernormale
Glucosio
Tiamina 100 mg
Dopaminanoradrenalina + fre con barbituricihellip
Indagine conoscitiva su 127 TI NCH europeeDauch WA Schutze M Guttinger M et al Posttraumatic seizure prevention - results of a
survey of 127 neurosurgery clinics Zentralbl Neurochir 1996 57190ndash5
0
10
20
30
40
50
60
profilassi
Profilassi con anticonvulsivi post trauma cranio-
encefalico
mai
sempre
secindicazione
substantial cortical
injurycerebral contusion
acute subdural
hemorrhage
depressed skull fracture
penetrating missile
injury
(141517)
Rischio convulsivo
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001bull Background It is uncertain whether the administration of benzodiazepines by paramedics is an
effective and safe treatment for out-of-hospital status epilepticus
Methods We conducted a randomized double-blind trial to evaluate intravenous benzodiazepines administered by paramedics for the treatment of out-of-hospital status epilepticus Adults with prolonged (lasting five minutes or more) or repetitive generalized convulsive seizures received intravenous diazepam (5 mg) lorazepam (2 mg) or placebo An identical second injection was given if needed
Results Of the 205 patients enrolled 66 received lorazepam 68 received diazepam and 71 received placebo Status epilepticus had been terminated on arrival at the emergency department in more patients treated with lorazepam (591 percent) or diazepam (426 percent) than patients given placebo (211 percent) (P=0001) After adjustment for covariates the odds ratio for termination of status epilepticus by the time of arrival in the lorazepam group as compared with the placebo group was 48 (95 percent confidence interval 19 to 130) The odds ratio was 19 (95 percent confidence interval 08 to 44) in the lorazepam group as compared with the diazepam group and 23 (95 percent confidence interval 10 to 59) in the diazepam group as compared with the placebo group The rates of respiratory or circulatory complications after the study treatment was administered were 106 percent for the lorazepam group 103 percent for the diazepam group and 225 percent for the placebo group (P=008)
Conclusions Benzodiazepines are safe and effective when administered by paramedics for out-of-hospital status epilepticus in adults Lorazepam is likely to be a better therapy than diazepam (N Engl J Med 2001345631-7)
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001
0
10
20
30
40
50
60
seizures stop complications
lorazepam
diazepam
placebo
randomized double-blind trial
to evaluate iv bdz
admin by paramedics
for the treatment of out-of-hospital status epilepticus
Adults with prolonged (lasting 5 minutes or +)
or repetitive generalized convulsive seizures
received iv diazepam (5 mg)
lorazepam (2 mg) or placebo
An identical second injection was given if needed
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
Treiman DM Meyers PD Walton NY Collins JF Colling C Rowan AJ et al A comparison of four treatments for generalized convulsive status epilepticus N Engl J Med 1998 339792-798
randomized double-blind trial that compared the following four regimens commonly used for the treatment of generalized convulsive status epilepticus diazepam followed by phenytoin phenytoin alone phenobarbital and lorazepam Although the doses and infusion rates chosen for study closely reflected common clinical practice at the time the study began the combination of lorazepam followed by phenytoin (the preferred regimen of many neurologists) was not included
This is a large well-controlled and important clinical trial The major limitation in its clinical relevance is the lack of inclusion of a regimen consisting of lorazepam followed by phenytoin
Veterans Affairs Status Epilepticus Cooperative
Study Group Treiman et al
SE aperto
diaz fenitoina fenobarbital lorazepam
2 o + convuls senza
ripresa di coscienza
Convuls continue = gt 10 min
fenitoina
Coma con scariche
ictali EEG
primary outcome measure
cessation of clinical and electrical
seizure activity
within 20min after initiation
of treatment and continuing for at least
60min after the start of treatment
lorazepam fenitoina
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
bull st treatment successful in 555 of patients with a verified diagnosis of overt status epilepticus (n=384) and in 149 of patients with subtle status epilepticus (n=134)
bull Comparisons between the 4 treatments showed that lorazepam was more effective than phenytoin alone in patients with overt status epilepticus (treatment success in 649 versus 436 of patients respectively)
bull other treatment comparisons in the overt group and all comparisons in the subtle group were not significantly different however
bull There were no significant differences between treatments in patient outcome rates of recurrence of status epilepticus or return of full consciousness over the 12-h observation period or in the frequency of adverse cardiac respiratory or hypotensive events
Treiman DM Meyers PD Walton NY et al A
comparison of four treatments for generalized
convulsive status epilepticus N Engl J Med 1998
339792-798
P 002
Percentage of successful treatment
grey bars overt patients black bars subtle patients
Alldredge Brian Kab Lowenstein Daniel HAC Status
epilepticus new concepts Current Opinion in Neurology
121999 183-190
Da ChapmanAnaesthesia 2004
Marik PEVaron J The Management of Status
Epilepticus Chest 126(2)582-591 August 2004
Status epilepticus is a major medical emergency associated with significant morbidity and mortality Status epilepticusis best defined as a continuous generalized convulsive seizure lasting gt 5 min or two or more seizures during which the patient does not return to baseline consciousness Lorazepam in a dose of 01 mgkg is the drug of first choice for terminating status epilepticus Patients who continue to have clinical or EEG evidence of seizure activity after treatment with lorazepam should be considered to have refractory status epileptics and should be treated with a continuous infusion of propofol or midazolam This article reviews current information regarding the management of status epilepticus in adults
Schema di Marik et al
Claassen JHirsch LJ Emerson R GBates
JE Thompson TBMayer SA Continuous EEG
monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042 bull The authors reviewed 33 episodes of RSE treated with cIV-MDZ in their neurologic intensive care
unit over 6 years All patients were monitored with continuous EEG (cEEG) MDZ infusion rates were titrated to eliminate clinical and EEG seizure activity cIV-MDZ was discontinued once patients were seizure-free for 24 hours Acute treatment failures (seizures 1 to 6 hours after starting cIV-MDZ) breakthrough seizures (after 6 hours of therapy) post-treatment seizures (within 48 hours of discontinuing therapy) and ultimate treatment failure (frequent seizures that led to treatment with pentobarbital or propofol) were identified
bull Results All patients were in nonconvulsive SE at the time cIV-MDZ was started the mean duration of SE before treatment was 39 days (range 0 to 17 days) In addition to benzodiazepines 94 of patients had received at least two antiepileptic drugs (AED) before starting cIV-MDZ The mean loading dose was 019 mgkg the mean maximal infusion rate was 022 mgkgh and the mean duration of cIV-MDZ therapy was 42 days (range 1 to 14 days) Acute treatment failure occurred in 18 (633) of episodes breakthrough seizures in 56 (1832) post-treatment seizures in 68 (1928) and ultimate treatment failure in 18 (633) Breakthrough seizures were clinically subtle or purely electrographic in 89 (1618) of cases and were associated with an increased risk of developing post-treatment seizures (p = 001)
bull Conclusions Although most patients with RSE initially responded to cIV-MDZ over half developed subsequent breakthrough seizures which were predictive of post-treatment seizures and were often detectable only with cEEG Titrating cIV-MDZ to burst suppression more aggressive treatment with concurrent AED or a longer period of initial treatment may reduce the high proportion of patients with RSE who relapse after cIV-MDZ is discontinued
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus Neurology 2001 57 25 1036-1042
0
10
20
30
40
50
60
70
80
non seizures
seizures lt30 min24h05-12 h
seizures 05-12 h24 hgt 12 h
seiz gt12 h24
burst suppression
periodic latdischarge
periodic gen discharge
prima
durante
dopo
33 episodes of RSE treated with cIV-MDZ neurologic ICU over 6 years
All patients were monitored with continuous EEG (cEEG)
Waterhouse Elizabeth J 1 2 DeLorenzo Robert J 1 3 4 2
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
bull Status epilepticus (SE) is a medical and neurological emergency that has been associated with significant morbidity and mortality The most widely accepted definition of SE is more than 30 minutes of either continuous seizure activity or intermittent seizures without full recovery of consciousness between seizures SE is a major clinical concern in the elderly population both because it has increased incidence in the elderly compared with the general population and because of concurrent medical conditions that are more likely to complicate therapy and worsen prognosis in elderly individuals
The incidence of SE in the elderly is almost twice that of the general population at 86 per 100 000 per year With the anticipated growth of the elderly population SE is likely to become an increasingly common problem facing clinicians and an important public health issue The elderly have the highest SE-associated mortality of any age group at 38 and the very old elderly (gt80 years of age) have a mortality of at least 50 Acute or remote stroke is the most common aetiology of SE in the elderly Nonconvulsive SE (NCSE) has a wide range of clinical presentations ranging from confusion to obtundation It occurs commonly in elderly patients who are critically ill and in the setting of coma Electroencephalogram is the only reliable method of diagnosing NCSE
The goal of treatment for SE is rapid cessation of clinical and electrical seizure activity Most treatment protocols call for the immediate administration of an intravenous benzodiazepine followed by phenytoin or fosphenytoin Recent studies suggest that when this initial treatment of SE fails little is gained by using additional standard drugs General anaesthetic agents (such as pentobarbital midazolam or propofol) should be expeditiously employed although these treatments have their own potential complications Intravenous valproic acid is a recent addition to the armamentarium of drugs for the treatment of SE with a low risk of hypotension respiratory depression and hypotension making it a potentially useful drug for the treatment of SE in the elderly However further information is needed to establish its role in the overall treatment of SE
Waterhouseet al
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
BDZ
Fenitoina
O fosfenitoina
GA
Midaz
Propof
pentobarb
Ac valproico
Ns proposta
Lorazepam
01 mgkg
Propofol
1-2 mgkgMidazolam01 mgkg
Inf cont 3-10 mgkgh Inf cont 001-005 mgkgh
Miorilassante solo
Per intubazione
Pentobarbital dose caricopoi 01-04 mgkgmin
fenobarbital
bull 10-20 mgkg iv
ndash Eccessiva sedazione
ndash Depressresp
ndash Ipotensione
ndash Interaz farmacol
ndash Hl gt48 hrhelliphelliphellip
tiopental
bull cumulativo
bull Inotropo neghellip
bull Pentobarbital
bull immunosoppressione
propofol
bull Vantaggi cineticodinamici
bull Titolazione continua possibile
bull TCIquale livello
bull Dosi 1 mgkgripetibile dopo 5rsquo-
ndash Infcont 2-10 mgkgh
bull Rapida emergenzafinestra neurologicaevitare la
brusca sospensione
bull + rapido controllo delle convuls gt barbituricindash Stecker MM Kramer TH Raps EC OMeeghan R Dulaney E Skaar DJ Treatment of
refractory status epilepticus with propofol clinical and pharmacokinetic findings Epilepsia 1998
39 18-26
AG
bull Non ci sono dati che indichino quanto a lungo i paz debbano rimanere senza convuls prima di poter alleggerire il piano di AG24 h96h (Treiman DM Convulsive status
epilepticus Current Treatment Options in Neurology 1999 1 359-69)
bull Anest alogenatiisofluranogtsevofluranogtdesflurane
bull Ma vaporizzatori
bull Contaminazione ambientale
bull Costihellip
Studi comparativi1
bull Midazolamgt tiopental
ndash Lohr A Jr Werneck LC Comparative non-randomized study with
midazolam versus thiopental in children with refractory status
epilepticus [Portuguese] Arq Neuropsiquiatr 2000 58282-287
ndash non-randomized comparison
ndash of historical data (thiopental) and prospectively
acquired data (midazolam)
ndash Midazolam was no more often effective than
thiopental but was associated with less cyanosis and
less respiratory distress in this study of 50 children
Studi comparativi2
Valproatobull Valproate(ivrdquoDepaconrdquo) has been used for the treatment of refractory SE
in children and myoclonic SE ndash Sheth RD Gidal BE Intravenous valproic acid for myoclonic status epilepticus
Neurology 2000 541201
ndash Uberall MA Trollmann R Wunsiedler U Wenzel D Intravenous valproate in pediatric epilepsy patients with refractory status epilepticus Neurology 2000 542188-2189 ]
bull Valproate has also been used in SE in the elderly and appears to be safe even in the presence of cardiovascular instability and hypotension no significant change in blood pressure pulse or the need for vasopressors in 13 patients with SE and hypotension given a loading dose of 147-327 mgkg Depacon intravenouslyndash Sinha S Naritoku DK Intravenous valproate is well tolerated in unstable patients
with status epilepticus Neurology 2000 55722-724
bull However there is a case report of severe hypotension in an 11-year-old child after treatment of SE with 30 mgkg intravenous valproate ndash White JR Santos CS Intravenous valproate associated with significant
hypotension in the treatment of status epilepticus J Child Neurol 1999 14822-823
FINE
Percheacute non ne possiamo
piugravehelliphelliphellip
La prognosi finale dipende dalla eziologia
The possible relationships among seizure etiology
nonconvulsive status
epilepticus and outcome
Most patients with complex partial status epilepticus (CPSE)
have etiologies consistent with pathway [circled digit one]
(strokes anoxiaischemia head trauma encephalitis)
rather than [circled digit two]
The best example of [circled digit two] would be a patient with
temporal lobe epilepsy
who went into CPSE because of inadequate
antiepileptic drug levels
Fattori che influenzano la prognosi nello
SE(anche NCSE)
bull Causa dello stato
epilettico
bull Durata dello stato
bull Trattamento
bull Etagrave
bull Effetti dannosi sistemici metabolici e fisiologici (Meldrum et al 1973 Simon 1985)
bull Danno cerebrale secondario allrsquo insulto acuto che induce SE (Hauser 1983 Barry et al 1993)
bull Danno neuronale diretto dovuto alla abnorme attivitagrave elettrica del SE (Meldrum et al 1973 Knopman et al 1977 Lothman 1990)
Chin RFMVerhulst LNeville BGRPeters MJScott RC
Inappropriate emergency management of status epilepticus
in children contributes to need for intensive care Journal of
Neurology Neurosurgery amp Psychiatry 75(11)1584-
1588 2004
bull gt 2 dosi o dosi inadeguate di BDZ
bull Depressione respiratoria
bull Trattati in emergenza extraospedaliera
complicazioni
Complicazioni sistemiche dello status epilepticus
SNC cardiova
s
Resp metaboli
co
altro
Ipossiaanos
sia
IM Apneaipopnea Disidtrataz MOF
Edema Ipoipertens Insuff resp Disturbi
elettripoNaip
erK
DIC
Emorragia Aritmie Polmonite ab
ingestis
Acidosi metab Rabdomiolisi
Trombosi
venosa
Arresto Iprtens polm Necrosi
tubacutafratture
Shock
cardiogeno
EPA Necrosi
epatica acuta
Embolia polm Pancreatite
acuta
Complicazioni dello SE
bull Durata convulsioni gt 1 hrpredittore indipendente di poor outcome (mortality odds ratio di quasi 10) (4)
bull Convulsioni prolungate aumentano il rischio di danno neuronalendash Eccitotox
ndash Accumulo intracellulare di Ca++ e apoptosi
ndash Riorganizzazione sinaptica epilettogenica( e gemmazione)
ndash Deplezione di energia e inibizione della sintesi proteica e del DNA (5)
ndash ldquo Particularly vulnerable to injury are the neurons within the hippocampus cerebral cortical mantle and cerebellar Purkinje cells Selective neuronal loss has been described within the hilar area of the dentate gyrus of the hippocampus (areas CA1 and CA3) after prolonged seizures leading to the development of chronic temporal lobe epilepsy (6)rdquo
bull Manifestazioni autonomichemorte improvvisa ndash DeLorenzo RJ Status epilepticus Concepts in diagnosis and treatment Semin Neurol 1990 10396ndash
405
ndash Towne AR Pellock JM Ko D et al Determinants of mortality in status epilepticus Epilepsia 1994 3527ndash34
ndash Payne TA Bleck TP Status epilepticus Crit Care Clin 1997 13 (1)17ndash38
ndash Sloviter RS Status epilepticus-induced neuronal injury and network reorganization Epilepsia 1999 40S34ndash41
Complications of SE
bull Aminoff MJ Simon RP Status epilepticus causes clinical features and consequences in 98 patients Am J Med 198069657-666 Bibliographic Links [Context Link]
bull 25 Wasterlain CG Fujikawa DG Penix L Sankar R Pathophysiological mechanisms of brain damage from status epilepticus Epilepsia 199334(1)S37-S53 Bibliographic Links [Context Link]
bull 26 Singhal PC Chugh KS Golati DR Myoglobinuria and renal failure after status epilepticus Neurology 197828200-201 Bibliographic Links [Context Link]
bull 27 Fisher S Zatuchni J Greenberg J Disseminated intravascular coagulation in status epilepticus Thromb Haemost 197738909-913 Bibliographic Links [Context Link]
Neuroprotective effects of acidosis
bull some studies that suggest that hypoxia acidosis and hypoglycaemia may be neuroprotective [2829] To
study these phenomena further Sasahira and coworkers [30bull31bull] looked at a rat model of status epilepticus based upon repeated bicuculline injections and using heat shock protein as an indirect measure of neuronal injury Using high concentrations of inhaled carbon dioxide they were able to reduce the serum pH from 755 to 717 This resulted in a shorter seizure duration and less neuronal damage [30bull] Using multiple regression analysis they were able to show a neuroprotective effect of shortening seizure duration and an independent effect of acidosis [30bull] Acidosis and raised carbon dioxide tensions have a profound effect on cerebral blood flow and whether the neuroprotective effect is due to haemodynamic effects or to the effect of acidoisis on receptors or transmitter release is unknown
bull A further study from the same group [31bull] looked at the effects of moderate hypoxia (PaO2=50 mmHg) on neuronal damage in the same model compared with normoxic controls There was no difference in neuronal injury detected suggesting that moderate hypoxia has no effect on neuronal death in status epilepticus The authors rightly conclude however that the implications of their findings for the treatment of status epilepticus are unclear as more severe hypoxia could result in additional ischaemic injury to the brain
bull 28 Blennow G Brierley JB Meldrum BS Siesjouml BK Epileptic brain damage The role of sysemic factors that modify cerebral energy metabolism Brain 1978101687-700 Bibliographic Links [Context Link]
bull 29 Meldrum BS Brierley JB Prolonged epileptic seizures in primates Ischaemic cell change and its relation to ictal physiological events Arch Neurol 19732810-17 Bibliographic Links [Context Link]
bull 30 bull Sasahira M Lowry T Simon RP Neuronal injury in experimental status epilepticus in the rat role of acidosis Neurosci Lett 1997224177-180 Bibliographic Links See [31bull] [Context Link]
bull 31 bull Sasahira M Simon RP Greenberg DA Neuronal injury in experimental status epilepticus in the rat role of hypoxia Neurosci Lett 1997222207-209 Bibliographic Links Thie paper and [30bull] are excellent reports considering the influence of physiological parameters on neuronal damage induced by status epilepticus [Context Link]
Effetti collaterali della fenitoina ev
bull Lesioni dei tessuti mollicon o senza
stravasordquoPurple Handgt 40 casi con parecchie
amputazioni ( (Kilarski 1984 Rao et al 1988
Hanna 1992)
bull Problemi al sito di iniezione Earnest et al (1983)
30 su 200
bull Ipotensione in gt 25 dei pazcon aritmie
ndash In 3139 pazienti 1 FA (velocitagrave di infus 26 mgmin) 1
tachic sinusale 1 allungamento tratto PR
ndash (Gellerman and Martinex 1967 Goldschlager and
Karliner 1967 Louis et al 1967 Voigt 1968)
bull
Allen FH Runge JW Legarda S et al Multicenter open-label
study on safety tolerance and pharmacokinetics of
intravenous fosphenytoin (Cerebyx) in status epilepticus
[abstract] Epilepsia 199435(Suppl 18)93
bull Data have been published from 40 patients in status epilepticus who received fosphenytoin at a mean infusion rate of 92 mgmin ranging from 247 to 1113 mgmin) Status epilepticus was terminated in 37 of 40 patients (85) within 30 min of receiving fosphenytoin The rapid infusion was well tolerated with only mild or transient side effects Most of the side effects reported were attributable to the pharmacologic effect of phenytoin and included dizziness nystagmus and ataxia Most patients in this trial received a benzodiazepine before the infusion of fosphenytoin and no adverse drug interactions were found
Introduzione alla peculiaritagrave
dellrsquoambiente intensivistico
Convulsioni in ambiente intensivo
bull Sepsi
bull Cause mediche
bull Anormalitagrave metaboliche(30-35) (11)ndash Iponatremiaipocalcemiaipofosfatemiaipoglicemiauremia
ndash Alterazioni della osmolaritagrave specie correzione acuta bull Acute return from hyperosmolarity back to normal levels in a rat
neocortical slice preparation by lowering the D-glucose concentration increased the amplitude of evoked early and late excitatory postsynaptic potentials a situation reminiscent of the generalized convulsions that may follow acute reduction of glucose in diabetic nonketotic hyperglycemia (42)
ndash Ipoosmolaritagrave induce increased nervous system excitability by strengthening both excitatory synaptic communications in neocortex and field effects among the entire cortical population (41)
Problemi peculiari allrsquoambiente
intensivistico
bull Polifarmacologia
bull Insuff renale
bull Insuff epatica
bull Induzione enzimatica
bull Inibizione enzimatica
bull Ipodisprotidemiehellipfarmaci altamente
legati alle prot plasmatiche
Trattamento dello stato di
male
Allora
bull Terapia immediata
bull Aggressiva
bull Supporto vitale di base
bull AAirway
bull Breathing
bull CSupporto circolatorio
Status epilepticusfilosofia del trattamento
Disaccoppiamento
CMRO2CBF
Funzione cardiocircolatoriaFunzione resp
Supporto supernormale
Glucosio
Tiamina 100 mg
Dopaminanoradrenalina + fre con barbituricihellip
Indagine conoscitiva su 127 TI NCH europeeDauch WA Schutze M Guttinger M et al Posttraumatic seizure prevention - results of a
survey of 127 neurosurgery clinics Zentralbl Neurochir 1996 57190ndash5
0
10
20
30
40
50
60
profilassi
Profilassi con anticonvulsivi post trauma cranio-
encefalico
mai
sempre
secindicazione
substantial cortical
injurycerebral contusion
acute subdural
hemorrhage
depressed skull fracture
penetrating missile
injury
(141517)
Rischio convulsivo
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001bull Background It is uncertain whether the administration of benzodiazepines by paramedics is an
effective and safe treatment for out-of-hospital status epilepticus
Methods We conducted a randomized double-blind trial to evaluate intravenous benzodiazepines administered by paramedics for the treatment of out-of-hospital status epilepticus Adults with prolonged (lasting five minutes or more) or repetitive generalized convulsive seizures received intravenous diazepam (5 mg) lorazepam (2 mg) or placebo An identical second injection was given if needed
Results Of the 205 patients enrolled 66 received lorazepam 68 received diazepam and 71 received placebo Status epilepticus had been terminated on arrival at the emergency department in more patients treated with lorazepam (591 percent) or diazepam (426 percent) than patients given placebo (211 percent) (P=0001) After adjustment for covariates the odds ratio for termination of status epilepticus by the time of arrival in the lorazepam group as compared with the placebo group was 48 (95 percent confidence interval 19 to 130) The odds ratio was 19 (95 percent confidence interval 08 to 44) in the lorazepam group as compared with the diazepam group and 23 (95 percent confidence interval 10 to 59) in the diazepam group as compared with the placebo group The rates of respiratory or circulatory complications after the study treatment was administered were 106 percent for the lorazepam group 103 percent for the diazepam group and 225 percent for the placebo group (P=008)
Conclusions Benzodiazepines are safe and effective when administered by paramedics for out-of-hospital status epilepticus in adults Lorazepam is likely to be a better therapy than diazepam (N Engl J Med 2001345631-7)
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001
0
10
20
30
40
50
60
seizures stop complications
lorazepam
diazepam
placebo
randomized double-blind trial
to evaluate iv bdz
admin by paramedics
for the treatment of out-of-hospital status epilepticus
Adults with prolonged (lasting 5 minutes or +)
or repetitive generalized convulsive seizures
received iv diazepam (5 mg)
lorazepam (2 mg) or placebo
An identical second injection was given if needed
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
Treiman DM Meyers PD Walton NY Collins JF Colling C Rowan AJ et al A comparison of four treatments for generalized convulsive status epilepticus N Engl J Med 1998 339792-798
randomized double-blind trial that compared the following four regimens commonly used for the treatment of generalized convulsive status epilepticus diazepam followed by phenytoin phenytoin alone phenobarbital and lorazepam Although the doses and infusion rates chosen for study closely reflected common clinical practice at the time the study began the combination of lorazepam followed by phenytoin (the preferred regimen of many neurologists) was not included
This is a large well-controlled and important clinical trial The major limitation in its clinical relevance is the lack of inclusion of a regimen consisting of lorazepam followed by phenytoin
Veterans Affairs Status Epilepticus Cooperative
Study Group Treiman et al
SE aperto
diaz fenitoina fenobarbital lorazepam
2 o + convuls senza
ripresa di coscienza
Convuls continue = gt 10 min
fenitoina
Coma con scariche
ictali EEG
primary outcome measure
cessation of clinical and electrical
seizure activity
within 20min after initiation
of treatment and continuing for at least
60min after the start of treatment
lorazepam fenitoina
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
bull st treatment successful in 555 of patients with a verified diagnosis of overt status epilepticus (n=384) and in 149 of patients with subtle status epilepticus (n=134)
bull Comparisons between the 4 treatments showed that lorazepam was more effective than phenytoin alone in patients with overt status epilepticus (treatment success in 649 versus 436 of patients respectively)
bull other treatment comparisons in the overt group and all comparisons in the subtle group were not significantly different however
bull There were no significant differences between treatments in patient outcome rates of recurrence of status epilepticus or return of full consciousness over the 12-h observation period or in the frequency of adverse cardiac respiratory or hypotensive events
Treiman DM Meyers PD Walton NY et al A
comparison of four treatments for generalized
convulsive status epilepticus N Engl J Med 1998
339792-798
P 002
Percentage of successful treatment
grey bars overt patients black bars subtle patients
Alldredge Brian Kab Lowenstein Daniel HAC Status
epilepticus new concepts Current Opinion in Neurology
121999 183-190
Da ChapmanAnaesthesia 2004
Marik PEVaron J The Management of Status
Epilepticus Chest 126(2)582-591 August 2004
Status epilepticus is a major medical emergency associated with significant morbidity and mortality Status epilepticusis best defined as a continuous generalized convulsive seizure lasting gt 5 min or two or more seizures during which the patient does not return to baseline consciousness Lorazepam in a dose of 01 mgkg is the drug of first choice for terminating status epilepticus Patients who continue to have clinical or EEG evidence of seizure activity after treatment with lorazepam should be considered to have refractory status epileptics and should be treated with a continuous infusion of propofol or midazolam This article reviews current information regarding the management of status epilepticus in adults
Schema di Marik et al
Claassen JHirsch LJ Emerson R GBates
JE Thompson TBMayer SA Continuous EEG
monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042 bull The authors reviewed 33 episodes of RSE treated with cIV-MDZ in their neurologic intensive care
unit over 6 years All patients were monitored with continuous EEG (cEEG) MDZ infusion rates were titrated to eliminate clinical and EEG seizure activity cIV-MDZ was discontinued once patients were seizure-free for 24 hours Acute treatment failures (seizures 1 to 6 hours after starting cIV-MDZ) breakthrough seizures (after 6 hours of therapy) post-treatment seizures (within 48 hours of discontinuing therapy) and ultimate treatment failure (frequent seizures that led to treatment with pentobarbital or propofol) were identified
bull Results All patients were in nonconvulsive SE at the time cIV-MDZ was started the mean duration of SE before treatment was 39 days (range 0 to 17 days) In addition to benzodiazepines 94 of patients had received at least two antiepileptic drugs (AED) before starting cIV-MDZ The mean loading dose was 019 mgkg the mean maximal infusion rate was 022 mgkgh and the mean duration of cIV-MDZ therapy was 42 days (range 1 to 14 days) Acute treatment failure occurred in 18 (633) of episodes breakthrough seizures in 56 (1832) post-treatment seizures in 68 (1928) and ultimate treatment failure in 18 (633) Breakthrough seizures were clinically subtle or purely electrographic in 89 (1618) of cases and were associated with an increased risk of developing post-treatment seizures (p = 001)
bull Conclusions Although most patients with RSE initially responded to cIV-MDZ over half developed subsequent breakthrough seizures which were predictive of post-treatment seizures and were often detectable only with cEEG Titrating cIV-MDZ to burst suppression more aggressive treatment with concurrent AED or a longer period of initial treatment may reduce the high proportion of patients with RSE who relapse after cIV-MDZ is discontinued
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus Neurology 2001 57 25 1036-1042
0
10
20
30
40
50
60
70
80
non seizures
seizures lt30 min24h05-12 h
seizures 05-12 h24 hgt 12 h
seiz gt12 h24
burst suppression
periodic latdischarge
periodic gen discharge
prima
durante
dopo
33 episodes of RSE treated with cIV-MDZ neurologic ICU over 6 years
All patients were monitored with continuous EEG (cEEG)
Waterhouse Elizabeth J 1 2 DeLorenzo Robert J 1 3 4 2
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
bull Status epilepticus (SE) is a medical and neurological emergency that has been associated with significant morbidity and mortality The most widely accepted definition of SE is more than 30 minutes of either continuous seizure activity or intermittent seizures without full recovery of consciousness between seizures SE is a major clinical concern in the elderly population both because it has increased incidence in the elderly compared with the general population and because of concurrent medical conditions that are more likely to complicate therapy and worsen prognosis in elderly individuals
The incidence of SE in the elderly is almost twice that of the general population at 86 per 100 000 per year With the anticipated growth of the elderly population SE is likely to become an increasingly common problem facing clinicians and an important public health issue The elderly have the highest SE-associated mortality of any age group at 38 and the very old elderly (gt80 years of age) have a mortality of at least 50 Acute or remote stroke is the most common aetiology of SE in the elderly Nonconvulsive SE (NCSE) has a wide range of clinical presentations ranging from confusion to obtundation It occurs commonly in elderly patients who are critically ill and in the setting of coma Electroencephalogram is the only reliable method of diagnosing NCSE
The goal of treatment for SE is rapid cessation of clinical and electrical seizure activity Most treatment protocols call for the immediate administration of an intravenous benzodiazepine followed by phenytoin or fosphenytoin Recent studies suggest that when this initial treatment of SE fails little is gained by using additional standard drugs General anaesthetic agents (such as pentobarbital midazolam or propofol) should be expeditiously employed although these treatments have their own potential complications Intravenous valproic acid is a recent addition to the armamentarium of drugs for the treatment of SE with a low risk of hypotension respiratory depression and hypotension making it a potentially useful drug for the treatment of SE in the elderly However further information is needed to establish its role in the overall treatment of SE
Waterhouseet al
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
BDZ
Fenitoina
O fosfenitoina
GA
Midaz
Propof
pentobarb
Ac valproico
Ns proposta
Lorazepam
01 mgkg
Propofol
1-2 mgkgMidazolam01 mgkg
Inf cont 3-10 mgkgh Inf cont 001-005 mgkgh
Miorilassante solo
Per intubazione
Pentobarbital dose caricopoi 01-04 mgkgmin
fenobarbital
bull 10-20 mgkg iv
ndash Eccessiva sedazione
ndash Depressresp
ndash Ipotensione
ndash Interaz farmacol
ndash Hl gt48 hrhelliphelliphellip
tiopental
bull cumulativo
bull Inotropo neghellip
bull Pentobarbital
bull immunosoppressione
propofol
bull Vantaggi cineticodinamici
bull Titolazione continua possibile
bull TCIquale livello
bull Dosi 1 mgkgripetibile dopo 5rsquo-
ndash Infcont 2-10 mgkgh
bull Rapida emergenzafinestra neurologicaevitare la
brusca sospensione
bull + rapido controllo delle convuls gt barbituricindash Stecker MM Kramer TH Raps EC OMeeghan R Dulaney E Skaar DJ Treatment of
refractory status epilepticus with propofol clinical and pharmacokinetic findings Epilepsia 1998
39 18-26
AG
bull Non ci sono dati che indichino quanto a lungo i paz debbano rimanere senza convuls prima di poter alleggerire il piano di AG24 h96h (Treiman DM Convulsive status
epilepticus Current Treatment Options in Neurology 1999 1 359-69)
bull Anest alogenatiisofluranogtsevofluranogtdesflurane
bull Ma vaporizzatori
bull Contaminazione ambientale
bull Costihellip
Studi comparativi1
bull Midazolamgt tiopental
ndash Lohr A Jr Werneck LC Comparative non-randomized study with
midazolam versus thiopental in children with refractory status
epilepticus [Portuguese] Arq Neuropsiquiatr 2000 58282-287
ndash non-randomized comparison
ndash of historical data (thiopental) and prospectively
acquired data (midazolam)
ndash Midazolam was no more often effective than
thiopental but was associated with less cyanosis and
less respiratory distress in this study of 50 children
Studi comparativi2
Valproatobull Valproate(ivrdquoDepaconrdquo) has been used for the treatment of refractory SE
in children and myoclonic SE ndash Sheth RD Gidal BE Intravenous valproic acid for myoclonic status epilepticus
Neurology 2000 541201
ndash Uberall MA Trollmann R Wunsiedler U Wenzel D Intravenous valproate in pediatric epilepsy patients with refractory status epilepticus Neurology 2000 542188-2189 ]
bull Valproate has also been used in SE in the elderly and appears to be safe even in the presence of cardiovascular instability and hypotension no significant change in blood pressure pulse or the need for vasopressors in 13 patients with SE and hypotension given a loading dose of 147-327 mgkg Depacon intravenouslyndash Sinha S Naritoku DK Intravenous valproate is well tolerated in unstable patients
with status epilepticus Neurology 2000 55722-724
bull However there is a case report of severe hypotension in an 11-year-old child after treatment of SE with 30 mgkg intravenous valproate ndash White JR Santos CS Intravenous valproate associated with significant
hypotension in the treatment of status epilepticus J Child Neurol 1999 14822-823
FINE
Percheacute non ne possiamo
piugravehelliphelliphellip
Fattori che influenzano la prognosi nello
SE(anche NCSE)
bull Causa dello stato
epilettico
bull Durata dello stato
bull Trattamento
bull Etagrave
bull Effetti dannosi sistemici metabolici e fisiologici (Meldrum et al 1973 Simon 1985)
bull Danno cerebrale secondario allrsquo insulto acuto che induce SE (Hauser 1983 Barry et al 1993)
bull Danno neuronale diretto dovuto alla abnorme attivitagrave elettrica del SE (Meldrum et al 1973 Knopman et al 1977 Lothman 1990)
Chin RFMVerhulst LNeville BGRPeters MJScott RC
Inappropriate emergency management of status epilepticus
in children contributes to need for intensive care Journal of
Neurology Neurosurgery amp Psychiatry 75(11)1584-
1588 2004
bull gt 2 dosi o dosi inadeguate di BDZ
bull Depressione respiratoria
bull Trattati in emergenza extraospedaliera
complicazioni
Complicazioni sistemiche dello status epilepticus
SNC cardiova
s
Resp metaboli
co
altro
Ipossiaanos
sia
IM Apneaipopnea Disidtrataz MOF
Edema Ipoipertens Insuff resp Disturbi
elettripoNaip
erK
DIC
Emorragia Aritmie Polmonite ab
ingestis
Acidosi metab Rabdomiolisi
Trombosi
venosa
Arresto Iprtens polm Necrosi
tubacutafratture
Shock
cardiogeno
EPA Necrosi
epatica acuta
Embolia polm Pancreatite
acuta
Complicazioni dello SE
bull Durata convulsioni gt 1 hrpredittore indipendente di poor outcome (mortality odds ratio di quasi 10) (4)
bull Convulsioni prolungate aumentano il rischio di danno neuronalendash Eccitotox
ndash Accumulo intracellulare di Ca++ e apoptosi
ndash Riorganizzazione sinaptica epilettogenica( e gemmazione)
ndash Deplezione di energia e inibizione della sintesi proteica e del DNA (5)
ndash ldquo Particularly vulnerable to injury are the neurons within the hippocampus cerebral cortical mantle and cerebellar Purkinje cells Selective neuronal loss has been described within the hilar area of the dentate gyrus of the hippocampus (areas CA1 and CA3) after prolonged seizures leading to the development of chronic temporal lobe epilepsy (6)rdquo
bull Manifestazioni autonomichemorte improvvisa ndash DeLorenzo RJ Status epilepticus Concepts in diagnosis and treatment Semin Neurol 1990 10396ndash
405
ndash Towne AR Pellock JM Ko D et al Determinants of mortality in status epilepticus Epilepsia 1994 3527ndash34
ndash Payne TA Bleck TP Status epilepticus Crit Care Clin 1997 13 (1)17ndash38
ndash Sloviter RS Status epilepticus-induced neuronal injury and network reorganization Epilepsia 1999 40S34ndash41
Complications of SE
bull Aminoff MJ Simon RP Status epilepticus causes clinical features and consequences in 98 patients Am J Med 198069657-666 Bibliographic Links [Context Link]
bull 25 Wasterlain CG Fujikawa DG Penix L Sankar R Pathophysiological mechanisms of brain damage from status epilepticus Epilepsia 199334(1)S37-S53 Bibliographic Links [Context Link]
bull 26 Singhal PC Chugh KS Golati DR Myoglobinuria and renal failure after status epilepticus Neurology 197828200-201 Bibliographic Links [Context Link]
bull 27 Fisher S Zatuchni J Greenberg J Disseminated intravascular coagulation in status epilepticus Thromb Haemost 197738909-913 Bibliographic Links [Context Link]
Neuroprotective effects of acidosis
bull some studies that suggest that hypoxia acidosis and hypoglycaemia may be neuroprotective [2829] To
study these phenomena further Sasahira and coworkers [30bull31bull] looked at a rat model of status epilepticus based upon repeated bicuculline injections and using heat shock protein as an indirect measure of neuronal injury Using high concentrations of inhaled carbon dioxide they were able to reduce the serum pH from 755 to 717 This resulted in a shorter seizure duration and less neuronal damage [30bull] Using multiple regression analysis they were able to show a neuroprotective effect of shortening seizure duration and an independent effect of acidosis [30bull] Acidosis and raised carbon dioxide tensions have a profound effect on cerebral blood flow and whether the neuroprotective effect is due to haemodynamic effects or to the effect of acidoisis on receptors or transmitter release is unknown
bull A further study from the same group [31bull] looked at the effects of moderate hypoxia (PaO2=50 mmHg) on neuronal damage in the same model compared with normoxic controls There was no difference in neuronal injury detected suggesting that moderate hypoxia has no effect on neuronal death in status epilepticus The authors rightly conclude however that the implications of their findings for the treatment of status epilepticus are unclear as more severe hypoxia could result in additional ischaemic injury to the brain
bull 28 Blennow G Brierley JB Meldrum BS Siesjouml BK Epileptic brain damage The role of sysemic factors that modify cerebral energy metabolism Brain 1978101687-700 Bibliographic Links [Context Link]
bull 29 Meldrum BS Brierley JB Prolonged epileptic seizures in primates Ischaemic cell change and its relation to ictal physiological events Arch Neurol 19732810-17 Bibliographic Links [Context Link]
bull 30 bull Sasahira M Lowry T Simon RP Neuronal injury in experimental status epilepticus in the rat role of acidosis Neurosci Lett 1997224177-180 Bibliographic Links See [31bull] [Context Link]
bull 31 bull Sasahira M Simon RP Greenberg DA Neuronal injury in experimental status epilepticus in the rat role of hypoxia Neurosci Lett 1997222207-209 Bibliographic Links Thie paper and [30bull] are excellent reports considering the influence of physiological parameters on neuronal damage induced by status epilepticus [Context Link]
Effetti collaterali della fenitoina ev
bull Lesioni dei tessuti mollicon o senza
stravasordquoPurple Handgt 40 casi con parecchie
amputazioni ( (Kilarski 1984 Rao et al 1988
Hanna 1992)
bull Problemi al sito di iniezione Earnest et al (1983)
30 su 200
bull Ipotensione in gt 25 dei pazcon aritmie
ndash In 3139 pazienti 1 FA (velocitagrave di infus 26 mgmin) 1
tachic sinusale 1 allungamento tratto PR
ndash (Gellerman and Martinex 1967 Goldschlager and
Karliner 1967 Louis et al 1967 Voigt 1968)
bull
Allen FH Runge JW Legarda S et al Multicenter open-label
study on safety tolerance and pharmacokinetics of
intravenous fosphenytoin (Cerebyx) in status epilepticus
[abstract] Epilepsia 199435(Suppl 18)93
bull Data have been published from 40 patients in status epilepticus who received fosphenytoin at a mean infusion rate of 92 mgmin ranging from 247 to 1113 mgmin) Status epilepticus was terminated in 37 of 40 patients (85) within 30 min of receiving fosphenytoin The rapid infusion was well tolerated with only mild or transient side effects Most of the side effects reported were attributable to the pharmacologic effect of phenytoin and included dizziness nystagmus and ataxia Most patients in this trial received a benzodiazepine before the infusion of fosphenytoin and no adverse drug interactions were found
Introduzione alla peculiaritagrave
dellrsquoambiente intensivistico
Convulsioni in ambiente intensivo
bull Sepsi
bull Cause mediche
bull Anormalitagrave metaboliche(30-35) (11)ndash Iponatremiaipocalcemiaipofosfatemiaipoglicemiauremia
ndash Alterazioni della osmolaritagrave specie correzione acuta bull Acute return from hyperosmolarity back to normal levels in a rat
neocortical slice preparation by lowering the D-glucose concentration increased the amplitude of evoked early and late excitatory postsynaptic potentials a situation reminiscent of the generalized convulsions that may follow acute reduction of glucose in diabetic nonketotic hyperglycemia (42)
ndash Ipoosmolaritagrave induce increased nervous system excitability by strengthening both excitatory synaptic communications in neocortex and field effects among the entire cortical population (41)
Problemi peculiari allrsquoambiente
intensivistico
bull Polifarmacologia
bull Insuff renale
bull Insuff epatica
bull Induzione enzimatica
bull Inibizione enzimatica
bull Ipodisprotidemiehellipfarmaci altamente
legati alle prot plasmatiche
Trattamento dello stato di
male
Allora
bull Terapia immediata
bull Aggressiva
bull Supporto vitale di base
bull AAirway
bull Breathing
bull CSupporto circolatorio
Status epilepticusfilosofia del trattamento
Disaccoppiamento
CMRO2CBF
Funzione cardiocircolatoriaFunzione resp
Supporto supernormale
Glucosio
Tiamina 100 mg
Dopaminanoradrenalina + fre con barbituricihellip
Indagine conoscitiva su 127 TI NCH europeeDauch WA Schutze M Guttinger M et al Posttraumatic seizure prevention - results of a
survey of 127 neurosurgery clinics Zentralbl Neurochir 1996 57190ndash5
0
10
20
30
40
50
60
profilassi
Profilassi con anticonvulsivi post trauma cranio-
encefalico
mai
sempre
secindicazione
substantial cortical
injurycerebral contusion
acute subdural
hemorrhage
depressed skull fracture
penetrating missile
injury
(141517)
Rischio convulsivo
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001bull Background It is uncertain whether the administration of benzodiazepines by paramedics is an
effective and safe treatment for out-of-hospital status epilepticus
Methods We conducted a randomized double-blind trial to evaluate intravenous benzodiazepines administered by paramedics for the treatment of out-of-hospital status epilepticus Adults with prolonged (lasting five minutes or more) or repetitive generalized convulsive seizures received intravenous diazepam (5 mg) lorazepam (2 mg) or placebo An identical second injection was given if needed
Results Of the 205 patients enrolled 66 received lorazepam 68 received diazepam and 71 received placebo Status epilepticus had been terminated on arrival at the emergency department in more patients treated with lorazepam (591 percent) or diazepam (426 percent) than patients given placebo (211 percent) (P=0001) After adjustment for covariates the odds ratio for termination of status epilepticus by the time of arrival in the lorazepam group as compared with the placebo group was 48 (95 percent confidence interval 19 to 130) The odds ratio was 19 (95 percent confidence interval 08 to 44) in the lorazepam group as compared with the diazepam group and 23 (95 percent confidence interval 10 to 59) in the diazepam group as compared with the placebo group The rates of respiratory or circulatory complications after the study treatment was administered were 106 percent for the lorazepam group 103 percent for the diazepam group and 225 percent for the placebo group (P=008)
Conclusions Benzodiazepines are safe and effective when administered by paramedics for out-of-hospital status epilepticus in adults Lorazepam is likely to be a better therapy than diazepam (N Engl J Med 2001345631-7)
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001
0
10
20
30
40
50
60
seizures stop complications
lorazepam
diazepam
placebo
randomized double-blind trial
to evaluate iv bdz
admin by paramedics
for the treatment of out-of-hospital status epilepticus
Adults with prolonged (lasting 5 minutes or +)
or repetitive generalized convulsive seizures
received iv diazepam (5 mg)
lorazepam (2 mg) or placebo
An identical second injection was given if needed
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
Treiman DM Meyers PD Walton NY Collins JF Colling C Rowan AJ et al A comparison of four treatments for generalized convulsive status epilepticus N Engl J Med 1998 339792-798
randomized double-blind trial that compared the following four regimens commonly used for the treatment of generalized convulsive status epilepticus diazepam followed by phenytoin phenytoin alone phenobarbital and lorazepam Although the doses and infusion rates chosen for study closely reflected common clinical practice at the time the study began the combination of lorazepam followed by phenytoin (the preferred regimen of many neurologists) was not included
This is a large well-controlled and important clinical trial The major limitation in its clinical relevance is the lack of inclusion of a regimen consisting of lorazepam followed by phenytoin
Veterans Affairs Status Epilepticus Cooperative
Study Group Treiman et al
SE aperto
diaz fenitoina fenobarbital lorazepam
2 o + convuls senza
ripresa di coscienza
Convuls continue = gt 10 min
fenitoina
Coma con scariche
ictali EEG
primary outcome measure
cessation of clinical and electrical
seizure activity
within 20min after initiation
of treatment and continuing for at least
60min after the start of treatment
lorazepam fenitoina
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
bull st treatment successful in 555 of patients with a verified diagnosis of overt status epilepticus (n=384) and in 149 of patients with subtle status epilepticus (n=134)
bull Comparisons between the 4 treatments showed that lorazepam was more effective than phenytoin alone in patients with overt status epilepticus (treatment success in 649 versus 436 of patients respectively)
bull other treatment comparisons in the overt group and all comparisons in the subtle group were not significantly different however
bull There were no significant differences between treatments in patient outcome rates of recurrence of status epilepticus or return of full consciousness over the 12-h observation period or in the frequency of adverse cardiac respiratory or hypotensive events
Treiman DM Meyers PD Walton NY et al A
comparison of four treatments for generalized
convulsive status epilepticus N Engl J Med 1998
339792-798
P 002
Percentage of successful treatment
grey bars overt patients black bars subtle patients
Alldredge Brian Kab Lowenstein Daniel HAC Status
epilepticus new concepts Current Opinion in Neurology
121999 183-190
Da ChapmanAnaesthesia 2004
Marik PEVaron J The Management of Status
Epilepticus Chest 126(2)582-591 August 2004
Status epilepticus is a major medical emergency associated with significant morbidity and mortality Status epilepticusis best defined as a continuous generalized convulsive seizure lasting gt 5 min or two or more seizures during which the patient does not return to baseline consciousness Lorazepam in a dose of 01 mgkg is the drug of first choice for terminating status epilepticus Patients who continue to have clinical or EEG evidence of seizure activity after treatment with lorazepam should be considered to have refractory status epileptics and should be treated with a continuous infusion of propofol or midazolam This article reviews current information regarding the management of status epilepticus in adults
Schema di Marik et al
Claassen JHirsch LJ Emerson R GBates
JE Thompson TBMayer SA Continuous EEG
monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042 bull The authors reviewed 33 episodes of RSE treated with cIV-MDZ in their neurologic intensive care
unit over 6 years All patients were monitored with continuous EEG (cEEG) MDZ infusion rates were titrated to eliminate clinical and EEG seizure activity cIV-MDZ was discontinued once patients were seizure-free for 24 hours Acute treatment failures (seizures 1 to 6 hours after starting cIV-MDZ) breakthrough seizures (after 6 hours of therapy) post-treatment seizures (within 48 hours of discontinuing therapy) and ultimate treatment failure (frequent seizures that led to treatment with pentobarbital or propofol) were identified
bull Results All patients were in nonconvulsive SE at the time cIV-MDZ was started the mean duration of SE before treatment was 39 days (range 0 to 17 days) In addition to benzodiazepines 94 of patients had received at least two antiepileptic drugs (AED) before starting cIV-MDZ The mean loading dose was 019 mgkg the mean maximal infusion rate was 022 mgkgh and the mean duration of cIV-MDZ therapy was 42 days (range 1 to 14 days) Acute treatment failure occurred in 18 (633) of episodes breakthrough seizures in 56 (1832) post-treatment seizures in 68 (1928) and ultimate treatment failure in 18 (633) Breakthrough seizures were clinically subtle or purely electrographic in 89 (1618) of cases and were associated with an increased risk of developing post-treatment seizures (p = 001)
bull Conclusions Although most patients with RSE initially responded to cIV-MDZ over half developed subsequent breakthrough seizures which were predictive of post-treatment seizures and were often detectable only with cEEG Titrating cIV-MDZ to burst suppression more aggressive treatment with concurrent AED or a longer period of initial treatment may reduce the high proportion of patients with RSE who relapse after cIV-MDZ is discontinued
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus Neurology 2001 57 25 1036-1042
0
10
20
30
40
50
60
70
80
non seizures
seizures lt30 min24h05-12 h
seizures 05-12 h24 hgt 12 h
seiz gt12 h24
burst suppression
periodic latdischarge
periodic gen discharge
prima
durante
dopo
33 episodes of RSE treated with cIV-MDZ neurologic ICU over 6 years
All patients were monitored with continuous EEG (cEEG)
Waterhouse Elizabeth J 1 2 DeLorenzo Robert J 1 3 4 2
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
bull Status epilepticus (SE) is a medical and neurological emergency that has been associated with significant morbidity and mortality The most widely accepted definition of SE is more than 30 minutes of either continuous seizure activity or intermittent seizures without full recovery of consciousness between seizures SE is a major clinical concern in the elderly population both because it has increased incidence in the elderly compared with the general population and because of concurrent medical conditions that are more likely to complicate therapy and worsen prognosis in elderly individuals
The incidence of SE in the elderly is almost twice that of the general population at 86 per 100 000 per year With the anticipated growth of the elderly population SE is likely to become an increasingly common problem facing clinicians and an important public health issue The elderly have the highest SE-associated mortality of any age group at 38 and the very old elderly (gt80 years of age) have a mortality of at least 50 Acute or remote stroke is the most common aetiology of SE in the elderly Nonconvulsive SE (NCSE) has a wide range of clinical presentations ranging from confusion to obtundation It occurs commonly in elderly patients who are critically ill and in the setting of coma Electroencephalogram is the only reliable method of diagnosing NCSE
The goal of treatment for SE is rapid cessation of clinical and electrical seizure activity Most treatment protocols call for the immediate administration of an intravenous benzodiazepine followed by phenytoin or fosphenytoin Recent studies suggest that when this initial treatment of SE fails little is gained by using additional standard drugs General anaesthetic agents (such as pentobarbital midazolam or propofol) should be expeditiously employed although these treatments have their own potential complications Intravenous valproic acid is a recent addition to the armamentarium of drugs for the treatment of SE with a low risk of hypotension respiratory depression and hypotension making it a potentially useful drug for the treatment of SE in the elderly However further information is needed to establish its role in the overall treatment of SE
Waterhouseet al
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
BDZ
Fenitoina
O fosfenitoina
GA
Midaz
Propof
pentobarb
Ac valproico
Ns proposta
Lorazepam
01 mgkg
Propofol
1-2 mgkgMidazolam01 mgkg
Inf cont 3-10 mgkgh Inf cont 001-005 mgkgh
Miorilassante solo
Per intubazione
Pentobarbital dose caricopoi 01-04 mgkgmin
fenobarbital
bull 10-20 mgkg iv
ndash Eccessiva sedazione
ndash Depressresp
ndash Ipotensione
ndash Interaz farmacol
ndash Hl gt48 hrhelliphelliphellip
tiopental
bull cumulativo
bull Inotropo neghellip
bull Pentobarbital
bull immunosoppressione
propofol
bull Vantaggi cineticodinamici
bull Titolazione continua possibile
bull TCIquale livello
bull Dosi 1 mgkgripetibile dopo 5rsquo-
ndash Infcont 2-10 mgkgh
bull Rapida emergenzafinestra neurologicaevitare la
brusca sospensione
bull + rapido controllo delle convuls gt barbituricindash Stecker MM Kramer TH Raps EC OMeeghan R Dulaney E Skaar DJ Treatment of
refractory status epilepticus with propofol clinical and pharmacokinetic findings Epilepsia 1998
39 18-26
AG
bull Non ci sono dati che indichino quanto a lungo i paz debbano rimanere senza convuls prima di poter alleggerire il piano di AG24 h96h (Treiman DM Convulsive status
epilepticus Current Treatment Options in Neurology 1999 1 359-69)
bull Anest alogenatiisofluranogtsevofluranogtdesflurane
bull Ma vaporizzatori
bull Contaminazione ambientale
bull Costihellip
Studi comparativi1
bull Midazolamgt tiopental
ndash Lohr A Jr Werneck LC Comparative non-randomized study with
midazolam versus thiopental in children with refractory status
epilepticus [Portuguese] Arq Neuropsiquiatr 2000 58282-287
ndash non-randomized comparison
ndash of historical data (thiopental) and prospectively
acquired data (midazolam)
ndash Midazolam was no more often effective than
thiopental but was associated with less cyanosis and
less respiratory distress in this study of 50 children
Studi comparativi2
Valproatobull Valproate(ivrdquoDepaconrdquo) has been used for the treatment of refractory SE
in children and myoclonic SE ndash Sheth RD Gidal BE Intravenous valproic acid for myoclonic status epilepticus
Neurology 2000 541201
ndash Uberall MA Trollmann R Wunsiedler U Wenzel D Intravenous valproate in pediatric epilepsy patients with refractory status epilepticus Neurology 2000 542188-2189 ]
bull Valproate has also been used in SE in the elderly and appears to be safe even in the presence of cardiovascular instability and hypotension no significant change in blood pressure pulse or the need for vasopressors in 13 patients with SE and hypotension given a loading dose of 147-327 mgkg Depacon intravenouslyndash Sinha S Naritoku DK Intravenous valproate is well tolerated in unstable patients
with status epilepticus Neurology 2000 55722-724
bull However there is a case report of severe hypotension in an 11-year-old child after treatment of SE with 30 mgkg intravenous valproate ndash White JR Santos CS Intravenous valproate associated with significant
hypotension in the treatment of status epilepticus J Child Neurol 1999 14822-823
FINE
Percheacute non ne possiamo
piugravehelliphelliphellip
Chin RFMVerhulst LNeville BGRPeters MJScott RC
Inappropriate emergency management of status epilepticus
in children contributes to need for intensive care Journal of
Neurology Neurosurgery amp Psychiatry 75(11)1584-
1588 2004
bull gt 2 dosi o dosi inadeguate di BDZ
bull Depressione respiratoria
bull Trattati in emergenza extraospedaliera
complicazioni
Complicazioni sistemiche dello status epilepticus
SNC cardiova
s
Resp metaboli
co
altro
Ipossiaanos
sia
IM Apneaipopnea Disidtrataz MOF
Edema Ipoipertens Insuff resp Disturbi
elettripoNaip
erK
DIC
Emorragia Aritmie Polmonite ab
ingestis
Acidosi metab Rabdomiolisi
Trombosi
venosa
Arresto Iprtens polm Necrosi
tubacutafratture
Shock
cardiogeno
EPA Necrosi
epatica acuta
Embolia polm Pancreatite
acuta
Complicazioni dello SE
bull Durata convulsioni gt 1 hrpredittore indipendente di poor outcome (mortality odds ratio di quasi 10) (4)
bull Convulsioni prolungate aumentano il rischio di danno neuronalendash Eccitotox
ndash Accumulo intracellulare di Ca++ e apoptosi
ndash Riorganizzazione sinaptica epilettogenica( e gemmazione)
ndash Deplezione di energia e inibizione della sintesi proteica e del DNA (5)
ndash ldquo Particularly vulnerable to injury are the neurons within the hippocampus cerebral cortical mantle and cerebellar Purkinje cells Selective neuronal loss has been described within the hilar area of the dentate gyrus of the hippocampus (areas CA1 and CA3) after prolonged seizures leading to the development of chronic temporal lobe epilepsy (6)rdquo
bull Manifestazioni autonomichemorte improvvisa ndash DeLorenzo RJ Status epilepticus Concepts in diagnosis and treatment Semin Neurol 1990 10396ndash
405
ndash Towne AR Pellock JM Ko D et al Determinants of mortality in status epilepticus Epilepsia 1994 3527ndash34
ndash Payne TA Bleck TP Status epilepticus Crit Care Clin 1997 13 (1)17ndash38
ndash Sloviter RS Status epilepticus-induced neuronal injury and network reorganization Epilepsia 1999 40S34ndash41
Complications of SE
bull Aminoff MJ Simon RP Status epilepticus causes clinical features and consequences in 98 patients Am J Med 198069657-666 Bibliographic Links [Context Link]
bull 25 Wasterlain CG Fujikawa DG Penix L Sankar R Pathophysiological mechanisms of brain damage from status epilepticus Epilepsia 199334(1)S37-S53 Bibliographic Links [Context Link]
bull 26 Singhal PC Chugh KS Golati DR Myoglobinuria and renal failure after status epilepticus Neurology 197828200-201 Bibliographic Links [Context Link]
bull 27 Fisher S Zatuchni J Greenberg J Disseminated intravascular coagulation in status epilepticus Thromb Haemost 197738909-913 Bibliographic Links [Context Link]
Neuroprotective effects of acidosis
bull some studies that suggest that hypoxia acidosis and hypoglycaemia may be neuroprotective [2829] To
study these phenomena further Sasahira and coworkers [30bull31bull] looked at a rat model of status epilepticus based upon repeated bicuculline injections and using heat shock protein as an indirect measure of neuronal injury Using high concentrations of inhaled carbon dioxide they were able to reduce the serum pH from 755 to 717 This resulted in a shorter seizure duration and less neuronal damage [30bull] Using multiple regression analysis they were able to show a neuroprotective effect of shortening seizure duration and an independent effect of acidosis [30bull] Acidosis and raised carbon dioxide tensions have a profound effect on cerebral blood flow and whether the neuroprotective effect is due to haemodynamic effects or to the effect of acidoisis on receptors or transmitter release is unknown
bull A further study from the same group [31bull] looked at the effects of moderate hypoxia (PaO2=50 mmHg) on neuronal damage in the same model compared with normoxic controls There was no difference in neuronal injury detected suggesting that moderate hypoxia has no effect on neuronal death in status epilepticus The authors rightly conclude however that the implications of their findings for the treatment of status epilepticus are unclear as more severe hypoxia could result in additional ischaemic injury to the brain
bull 28 Blennow G Brierley JB Meldrum BS Siesjouml BK Epileptic brain damage The role of sysemic factors that modify cerebral energy metabolism Brain 1978101687-700 Bibliographic Links [Context Link]
bull 29 Meldrum BS Brierley JB Prolonged epileptic seizures in primates Ischaemic cell change and its relation to ictal physiological events Arch Neurol 19732810-17 Bibliographic Links [Context Link]
bull 30 bull Sasahira M Lowry T Simon RP Neuronal injury in experimental status epilepticus in the rat role of acidosis Neurosci Lett 1997224177-180 Bibliographic Links See [31bull] [Context Link]
bull 31 bull Sasahira M Simon RP Greenberg DA Neuronal injury in experimental status epilepticus in the rat role of hypoxia Neurosci Lett 1997222207-209 Bibliographic Links Thie paper and [30bull] are excellent reports considering the influence of physiological parameters on neuronal damage induced by status epilepticus [Context Link]
Effetti collaterali della fenitoina ev
bull Lesioni dei tessuti mollicon o senza
stravasordquoPurple Handgt 40 casi con parecchie
amputazioni ( (Kilarski 1984 Rao et al 1988
Hanna 1992)
bull Problemi al sito di iniezione Earnest et al (1983)
30 su 200
bull Ipotensione in gt 25 dei pazcon aritmie
ndash In 3139 pazienti 1 FA (velocitagrave di infus 26 mgmin) 1
tachic sinusale 1 allungamento tratto PR
ndash (Gellerman and Martinex 1967 Goldschlager and
Karliner 1967 Louis et al 1967 Voigt 1968)
bull
Allen FH Runge JW Legarda S et al Multicenter open-label
study on safety tolerance and pharmacokinetics of
intravenous fosphenytoin (Cerebyx) in status epilepticus
[abstract] Epilepsia 199435(Suppl 18)93
bull Data have been published from 40 patients in status epilepticus who received fosphenytoin at a mean infusion rate of 92 mgmin ranging from 247 to 1113 mgmin) Status epilepticus was terminated in 37 of 40 patients (85) within 30 min of receiving fosphenytoin The rapid infusion was well tolerated with only mild or transient side effects Most of the side effects reported were attributable to the pharmacologic effect of phenytoin and included dizziness nystagmus and ataxia Most patients in this trial received a benzodiazepine before the infusion of fosphenytoin and no adverse drug interactions were found
Introduzione alla peculiaritagrave
dellrsquoambiente intensivistico
Convulsioni in ambiente intensivo
bull Sepsi
bull Cause mediche
bull Anormalitagrave metaboliche(30-35) (11)ndash Iponatremiaipocalcemiaipofosfatemiaipoglicemiauremia
ndash Alterazioni della osmolaritagrave specie correzione acuta bull Acute return from hyperosmolarity back to normal levels in a rat
neocortical slice preparation by lowering the D-glucose concentration increased the amplitude of evoked early and late excitatory postsynaptic potentials a situation reminiscent of the generalized convulsions that may follow acute reduction of glucose in diabetic nonketotic hyperglycemia (42)
ndash Ipoosmolaritagrave induce increased nervous system excitability by strengthening both excitatory synaptic communications in neocortex and field effects among the entire cortical population (41)
Problemi peculiari allrsquoambiente
intensivistico
bull Polifarmacologia
bull Insuff renale
bull Insuff epatica
bull Induzione enzimatica
bull Inibizione enzimatica
bull Ipodisprotidemiehellipfarmaci altamente
legati alle prot plasmatiche
Trattamento dello stato di
male
Allora
bull Terapia immediata
bull Aggressiva
bull Supporto vitale di base
bull AAirway
bull Breathing
bull CSupporto circolatorio
Status epilepticusfilosofia del trattamento
Disaccoppiamento
CMRO2CBF
Funzione cardiocircolatoriaFunzione resp
Supporto supernormale
Glucosio
Tiamina 100 mg
Dopaminanoradrenalina + fre con barbituricihellip
Indagine conoscitiva su 127 TI NCH europeeDauch WA Schutze M Guttinger M et al Posttraumatic seizure prevention - results of a
survey of 127 neurosurgery clinics Zentralbl Neurochir 1996 57190ndash5
0
10
20
30
40
50
60
profilassi
Profilassi con anticonvulsivi post trauma cranio-
encefalico
mai
sempre
secindicazione
substantial cortical
injurycerebral contusion
acute subdural
hemorrhage
depressed skull fracture
penetrating missile
injury
(141517)
Rischio convulsivo
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001bull Background It is uncertain whether the administration of benzodiazepines by paramedics is an
effective and safe treatment for out-of-hospital status epilepticus
Methods We conducted a randomized double-blind trial to evaluate intravenous benzodiazepines administered by paramedics for the treatment of out-of-hospital status epilepticus Adults with prolonged (lasting five minutes or more) or repetitive generalized convulsive seizures received intravenous diazepam (5 mg) lorazepam (2 mg) or placebo An identical second injection was given if needed
Results Of the 205 patients enrolled 66 received lorazepam 68 received diazepam and 71 received placebo Status epilepticus had been terminated on arrival at the emergency department in more patients treated with lorazepam (591 percent) or diazepam (426 percent) than patients given placebo (211 percent) (P=0001) After adjustment for covariates the odds ratio for termination of status epilepticus by the time of arrival in the lorazepam group as compared with the placebo group was 48 (95 percent confidence interval 19 to 130) The odds ratio was 19 (95 percent confidence interval 08 to 44) in the lorazepam group as compared with the diazepam group and 23 (95 percent confidence interval 10 to 59) in the diazepam group as compared with the placebo group The rates of respiratory or circulatory complications after the study treatment was administered were 106 percent for the lorazepam group 103 percent for the diazepam group and 225 percent for the placebo group (P=008)
Conclusions Benzodiazepines are safe and effective when administered by paramedics for out-of-hospital status epilepticus in adults Lorazepam is likely to be a better therapy than diazepam (N Engl J Med 2001345631-7)
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001
0
10
20
30
40
50
60
seizures stop complications
lorazepam
diazepam
placebo
randomized double-blind trial
to evaluate iv bdz
admin by paramedics
for the treatment of out-of-hospital status epilepticus
Adults with prolonged (lasting 5 minutes or +)
or repetitive generalized convulsive seizures
received iv diazepam (5 mg)
lorazepam (2 mg) or placebo
An identical second injection was given if needed
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
Treiman DM Meyers PD Walton NY Collins JF Colling C Rowan AJ et al A comparison of four treatments for generalized convulsive status epilepticus N Engl J Med 1998 339792-798
randomized double-blind trial that compared the following four regimens commonly used for the treatment of generalized convulsive status epilepticus diazepam followed by phenytoin phenytoin alone phenobarbital and lorazepam Although the doses and infusion rates chosen for study closely reflected common clinical practice at the time the study began the combination of lorazepam followed by phenytoin (the preferred regimen of many neurologists) was not included
This is a large well-controlled and important clinical trial The major limitation in its clinical relevance is the lack of inclusion of a regimen consisting of lorazepam followed by phenytoin
Veterans Affairs Status Epilepticus Cooperative
Study Group Treiman et al
SE aperto
diaz fenitoina fenobarbital lorazepam
2 o + convuls senza
ripresa di coscienza
Convuls continue = gt 10 min
fenitoina
Coma con scariche
ictali EEG
primary outcome measure
cessation of clinical and electrical
seizure activity
within 20min after initiation
of treatment and continuing for at least
60min after the start of treatment
lorazepam fenitoina
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
bull st treatment successful in 555 of patients with a verified diagnosis of overt status epilepticus (n=384) and in 149 of patients with subtle status epilepticus (n=134)
bull Comparisons between the 4 treatments showed that lorazepam was more effective than phenytoin alone in patients with overt status epilepticus (treatment success in 649 versus 436 of patients respectively)
bull other treatment comparisons in the overt group and all comparisons in the subtle group were not significantly different however
bull There were no significant differences between treatments in patient outcome rates of recurrence of status epilepticus or return of full consciousness over the 12-h observation period or in the frequency of adverse cardiac respiratory or hypotensive events
Treiman DM Meyers PD Walton NY et al A
comparison of four treatments for generalized
convulsive status epilepticus N Engl J Med 1998
339792-798
P 002
Percentage of successful treatment
grey bars overt patients black bars subtle patients
Alldredge Brian Kab Lowenstein Daniel HAC Status
epilepticus new concepts Current Opinion in Neurology
121999 183-190
Da ChapmanAnaesthesia 2004
Marik PEVaron J The Management of Status
Epilepticus Chest 126(2)582-591 August 2004
Status epilepticus is a major medical emergency associated with significant morbidity and mortality Status epilepticusis best defined as a continuous generalized convulsive seizure lasting gt 5 min or two or more seizures during which the patient does not return to baseline consciousness Lorazepam in a dose of 01 mgkg is the drug of first choice for terminating status epilepticus Patients who continue to have clinical or EEG evidence of seizure activity after treatment with lorazepam should be considered to have refractory status epileptics and should be treated with a continuous infusion of propofol or midazolam This article reviews current information regarding the management of status epilepticus in adults
Schema di Marik et al
Claassen JHirsch LJ Emerson R GBates
JE Thompson TBMayer SA Continuous EEG
monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042 bull The authors reviewed 33 episodes of RSE treated with cIV-MDZ in their neurologic intensive care
unit over 6 years All patients were monitored with continuous EEG (cEEG) MDZ infusion rates were titrated to eliminate clinical and EEG seizure activity cIV-MDZ was discontinued once patients were seizure-free for 24 hours Acute treatment failures (seizures 1 to 6 hours after starting cIV-MDZ) breakthrough seizures (after 6 hours of therapy) post-treatment seizures (within 48 hours of discontinuing therapy) and ultimate treatment failure (frequent seizures that led to treatment with pentobarbital or propofol) were identified
bull Results All patients were in nonconvulsive SE at the time cIV-MDZ was started the mean duration of SE before treatment was 39 days (range 0 to 17 days) In addition to benzodiazepines 94 of patients had received at least two antiepileptic drugs (AED) before starting cIV-MDZ The mean loading dose was 019 mgkg the mean maximal infusion rate was 022 mgkgh and the mean duration of cIV-MDZ therapy was 42 days (range 1 to 14 days) Acute treatment failure occurred in 18 (633) of episodes breakthrough seizures in 56 (1832) post-treatment seizures in 68 (1928) and ultimate treatment failure in 18 (633) Breakthrough seizures were clinically subtle or purely electrographic in 89 (1618) of cases and were associated with an increased risk of developing post-treatment seizures (p = 001)
bull Conclusions Although most patients with RSE initially responded to cIV-MDZ over half developed subsequent breakthrough seizures which were predictive of post-treatment seizures and were often detectable only with cEEG Titrating cIV-MDZ to burst suppression more aggressive treatment with concurrent AED or a longer period of initial treatment may reduce the high proportion of patients with RSE who relapse after cIV-MDZ is discontinued
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus Neurology 2001 57 25 1036-1042
0
10
20
30
40
50
60
70
80
non seizures
seizures lt30 min24h05-12 h
seizures 05-12 h24 hgt 12 h
seiz gt12 h24
burst suppression
periodic latdischarge
periodic gen discharge
prima
durante
dopo
33 episodes of RSE treated with cIV-MDZ neurologic ICU over 6 years
All patients were monitored with continuous EEG (cEEG)
Waterhouse Elizabeth J 1 2 DeLorenzo Robert J 1 3 4 2
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
bull Status epilepticus (SE) is a medical and neurological emergency that has been associated with significant morbidity and mortality The most widely accepted definition of SE is more than 30 minutes of either continuous seizure activity or intermittent seizures without full recovery of consciousness between seizures SE is a major clinical concern in the elderly population both because it has increased incidence in the elderly compared with the general population and because of concurrent medical conditions that are more likely to complicate therapy and worsen prognosis in elderly individuals
The incidence of SE in the elderly is almost twice that of the general population at 86 per 100 000 per year With the anticipated growth of the elderly population SE is likely to become an increasingly common problem facing clinicians and an important public health issue The elderly have the highest SE-associated mortality of any age group at 38 and the very old elderly (gt80 years of age) have a mortality of at least 50 Acute or remote stroke is the most common aetiology of SE in the elderly Nonconvulsive SE (NCSE) has a wide range of clinical presentations ranging from confusion to obtundation It occurs commonly in elderly patients who are critically ill and in the setting of coma Electroencephalogram is the only reliable method of diagnosing NCSE
The goal of treatment for SE is rapid cessation of clinical and electrical seizure activity Most treatment protocols call for the immediate administration of an intravenous benzodiazepine followed by phenytoin or fosphenytoin Recent studies suggest that when this initial treatment of SE fails little is gained by using additional standard drugs General anaesthetic agents (such as pentobarbital midazolam or propofol) should be expeditiously employed although these treatments have their own potential complications Intravenous valproic acid is a recent addition to the armamentarium of drugs for the treatment of SE with a low risk of hypotension respiratory depression and hypotension making it a potentially useful drug for the treatment of SE in the elderly However further information is needed to establish its role in the overall treatment of SE
Waterhouseet al
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
BDZ
Fenitoina
O fosfenitoina
GA
Midaz
Propof
pentobarb
Ac valproico
Ns proposta
Lorazepam
01 mgkg
Propofol
1-2 mgkgMidazolam01 mgkg
Inf cont 3-10 mgkgh Inf cont 001-005 mgkgh
Miorilassante solo
Per intubazione
Pentobarbital dose caricopoi 01-04 mgkgmin
fenobarbital
bull 10-20 mgkg iv
ndash Eccessiva sedazione
ndash Depressresp
ndash Ipotensione
ndash Interaz farmacol
ndash Hl gt48 hrhelliphelliphellip
tiopental
bull cumulativo
bull Inotropo neghellip
bull Pentobarbital
bull immunosoppressione
propofol
bull Vantaggi cineticodinamici
bull Titolazione continua possibile
bull TCIquale livello
bull Dosi 1 mgkgripetibile dopo 5rsquo-
ndash Infcont 2-10 mgkgh
bull Rapida emergenzafinestra neurologicaevitare la
brusca sospensione
bull + rapido controllo delle convuls gt barbituricindash Stecker MM Kramer TH Raps EC OMeeghan R Dulaney E Skaar DJ Treatment of
refractory status epilepticus with propofol clinical and pharmacokinetic findings Epilepsia 1998
39 18-26
AG
bull Non ci sono dati che indichino quanto a lungo i paz debbano rimanere senza convuls prima di poter alleggerire il piano di AG24 h96h (Treiman DM Convulsive status
epilepticus Current Treatment Options in Neurology 1999 1 359-69)
bull Anest alogenatiisofluranogtsevofluranogtdesflurane
bull Ma vaporizzatori
bull Contaminazione ambientale
bull Costihellip
Studi comparativi1
bull Midazolamgt tiopental
ndash Lohr A Jr Werneck LC Comparative non-randomized study with
midazolam versus thiopental in children with refractory status
epilepticus [Portuguese] Arq Neuropsiquiatr 2000 58282-287
ndash non-randomized comparison
ndash of historical data (thiopental) and prospectively
acquired data (midazolam)
ndash Midazolam was no more often effective than
thiopental but was associated with less cyanosis and
less respiratory distress in this study of 50 children
Studi comparativi2
Valproatobull Valproate(ivrdquoDepaconrdquo) has been used for the treatment of refractory SE
in children and myoclonic SE ndash Sheth RD Gidal BE Intravenous valproic acid for myoclonic status epilepticus
Neurology 2000 541201
ndash Uberall MA Trollmann R Wunsiedler U Wenzel D Intravenous valproate in pediatric epilepsy patients with refractory status epilepticus Neurology 2000 542188-2189 ]
bull Valproate has also been used in SE in the elderly and appears to be safe even in the presence of cardiovascular instability and hypotension no significant change in blood pressure pulse or the need for vasopressors in 13 patients with SE and hypotension given a loading dose of 147-327 mgkg Depacon intravenouslyndash Sinha S Naritoku DK Intravenous valproate is well tolerated in unstable patients
with status epilepticus Neurology 2000 55722-724
bull However there is a case report of severe hypotension in an 11-year-old child after treatment of SE with 30 mgkg intravenous valproate ndash White JR Santos CS Intravenous valproate associated with significant
hypotension in the treatment of status epilepticus J Child Neurol 1999 14822-823
FINE
Percheacute non ne possiamo
piugravehelliphelliphellip
complicazioni
Complicazioni sistemiche dello status epilepticus
SNC cardiova
s
Resp metaboli
co
altro
Ipossiaanos
sia
IM Apneaipopnea Disidtrataz MOF
Edema Ipoipertens Insuff resp Disturbi
elettripoNaip
erK
DIC
Emorragia Aritmie Polmonite ab
ingestis
Acidosi metab Rabdomiolisi
Trombosi
venosa
Arresto Iprtens polm Necrosi
tubacutafratture
Shock
cardiogeno
EPA Necrosi
epatica acuta
Embolia polm Pancreatite
acuta
Complicazioni dello SE
bull Durata convulsioni gt 1 hrpredittore indipendente di poor outcome (mortality odds ratio di quasi 10) (4)
bull Convulsioni prolungate aumentano il rischio di danno neuronalendash Eccitotox
ndash Accumulo intracellulare di Ca++ e apoptosi
ndash Riorganizzazione sinaptica epilettogenica( e gemmazione)
ndash Deplezione di energia e inibizione della sintesi proteica e del DNA (5)
ndash ldquo Particularly vulnerable to injury are the neurons within the hippocampus cerebral cortical mantle and cerebellar Purkinje cells Selective neuronal loss has been described within the hilar area of the dentate gyrus of the hippocampus (areas CA1 and CA3) after prolonged seizures leading to the development of chronic temporal lobe epilepsy (6)rdquo
bull Manifestazioni autonomichemorte improvvisa ndash DeLorenzo RJ Status epilepticus Concepts in diagnosis and treatment Semin Neurol 1990 10396ndash
405
ndash Towne AR Pellock JM Ko D et al Determinants of mortality in status epilepticus Epilepsia 1994 3527ndash34
ndash Payne TA Bleck TP Status epilepticus Crit Care Clin 1997 13 (1)17ndash38
ndash Sloviter RS Status epilepticus-induced neuronal injury and network reorganization Epilepsia 1999 40S34ndash41
Complications of SE
bull Aminoff MJ Simon RP Status epilepticus causes clinical features and consequences in 98 patients Am J Med 198069657-666 Bibliographic Links [Context Link]
bull 25 Wasterlain CG Fujikawa DG Penix L Sankar R Pathophysiological mechanisms of brain damage from status epilepticus Epilepsia 199334(1)S37-S53 Bibliographic Links [Context Link]
bull 26 Singhal PC Chugh KS Golati DR Myoglobinuria and renal failure after status epilepticus Neurology 197828200-201 Bibliographic Links [Context Link]
bull 27 Fisher S Zatuchni J Greenberg J Disseminated intravascular coagulation in status epilepticus Thromb Haemost 197738909-913 Bibliographic Links [Context Link]
Neuroprotective effects of acidosis
bull some studies that suggest that hypoxia acidosis and hypoglycaemia may be neuroprotective [2829] To
study these phenomena further Sasahira and coworkers [30bull31bull] looked at a rat model of status epilepticus based upon repeated bicuculline injections and using heat shock protein as an indirect measure of neuronal injury Using high concentrations of inhaled carbon dioxide they were able to reduce the serum pH from 755 to 717 This resulted in a shorter seizure duration and less neuronal damage [30bull] Using multiple regression analysis they were able to show a neuroprotective effect of shortening seizure duration and an independent effect of acidosis [30bull] Acidosis and raised carbon dioxide tensions have a profound effect on cerebral blood flow and whether the neuroprotective effect is due to haemodynamic effects or to the effect of acidoisis on receptors or transmitter release is unknown
bull A further study from the same group [31bull] looked at the effects of moderate hypoxia (PaO2=50 mmHg) on neuronal damage in the same model compared with normoxic controls There was no difference in neuronal injury detected suggesting that moderate hypoxia has no effect on neuronal death in status epilepticus The authors rightly conclude however that the implications of their findings for the treatment of status epilepticus are unclear as more severe hypoxia could result in additional ischaemic injury to the brain
bull 28 Blennow G Brierley JB Meldrum BS Siesjouml BK Epileptic brain damage The role of sysemic factors that modify cerebral energy metabolism Brain 1978101687-700 Bibliographic Links [Context Link]
bull 29 Meldrum BS Brierley JB Prolonged epileptic seizures in primates Ischaemic cell change and its relation to ictal physiological events Arch Neurol 19732810-17 Bibliographic Links [Context Link]
bull 30 bull Sasahira M Lowry T Simon RP Neuronal injury in experimental status epilepticus in the rat role of acidosis Neurosci Lett 1997224177-180 Bibliographic Links See [31bull] [Context Link]
bull 31 bull Sasahira M Simon RP Greenberg DA Neuronal injury in experimental status epilepticus in the rat role of hypoxia Neurosci Lett 1997222207-209 Bibliographic Links Thie paper and [30bull] are excellent reports considering the influence of physiological parameters on neuronal damage induced by status epilepticus [Context Link]
Effetti collaterali della fenitoina ev
bull Lesioni dei tessuti mollicon o senza
stravasordquoPurple Handgt 40 casi con parecchie
amputazioni ( (Kilarski 1984 Rao et al 1988
Hanna 1992)
bull Problemi al sito di iniezione Earnest et al (1983)
30 su 200
bull Ipotensione in gt 25 dei pazcon aritmie
ndash In 3139 pazienti 1 FA (velocitagrave di infus 26 mgmin) 1
tachic sinusale 1 allungamento tratto PR
ndash (Gellerman and Martinex 1967 Goldschlager and
Karliner 1967 Louis et al 1967 Voigt 1968)
bull
Allen FH Runge JW Legarda S et al Multicenter open-label
study on safety tolerance and pharmacokinetics of
intravenous fosphenytoin (Cerebyx) in status epilepticus
[abstract] Epilepsia 199435(Suppl 18)93
bull Data have been published from 40 patients in status epilepticus who received fosphenytoin at a mean infusion rate of 92 mgmin ranging from 247 to 1113 mgmin) Status epilepticus was terminated in 37 of 40 patients (85) within 30 min of receiving fosphenytoin The rapid infusion was well tolerated with only mild or transient side effects Most of the side effects reported were attributable to the pharmacologic effect of phenytoin and included dizziness nystagmus and ataxia Most patients in this trial received a benzodiazepine before the infusion of fosphenytoin and no adverse drug interactions were found
Introduzione alla peculiaritagrave
dellrsquoambiente intensivistico
Convulsioni in ambiente intensivo
bull Sepsi
bull Cause mediche
bull Anormalitagrave metaboliche(30-35) (11)ndash Iponatremiaipocalcemiaipofosfatemiaipoglicemiauremia
ndash Alterazioni della osmolaritagrave specie correzione acuta bull Acute return from hyperosmolarity back to normal levels in a rat
neocortical slice preparation by lowering the D-glucose concentration increased the amplitude of evoked early and late excitatory postsynaptic potentials a situation reminiscent of the generalized convulsions that may follow acute reduction of glucose in diabetic nonketotic hyperglycemia (42)
ndash Ipoosmolaritagrave induce increased nervous system excitability by strengthening both excitatory synaptic communications in neocortex and field effects among the entire cortical population (41)
Problemi peculiari allrsquoambiente
intensivistico
bull Polifarmacologia
bull Insuff renale
bull Insuff epatica
bull Induzione enzimatica
bull Inibizione enzimatica
bull Ipodisprotidemiehellipfarmaci altamente
legati alle prot plasmatiche
Trattamento dello stato di
male
Allora
bull Terapia immediata
bull Aggressiva
bull Supporto vitale di base
bull AAirway
bull Breathing
bull CSupporto circolatorio
Status epilepticusfilosofia del trattamento
Disaccoppiamento
CMRO2CBF
Funzione cardiocircolatoriaFunzione resp
Supporto supernormale
Glucosio
Tiamina 100 mg
Dopaminanoradrenalina + fre con barbituricihellip
Indagine conoscitiva su 127 TI NCH europeeDauch WA Schutze M Guttinger M et al Posttraumatic seizure prevention - results of a
survey of 127 neurosurgery clinics Zentralbl Neurochir 1996 57190ndash5
0
10
20
30
40
50
60
profilassi
Profilassi con anticonvulsivi post trauma cranio-
encefalico
mai
sempre
secindicazione
substantial cortical
injurycerebral contusion
acute subdural
hemorrhage
depressed skull fracture
penetrating missile
injury
(141517)
Rischio convulsivo
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001bull Background It is uncertain whether the administration of benzodiazepines by paramedics is an
effective and safe treatment for out-of-hospital status epilepticus
Methods We conducted a randomized double-blind trial to evaluate intravenous benzodiazepines administered by paramedics for the treatment of out-of-hospital status epilepticus Adults with prolonged (lasting five minutes or more) or repetitive generalized convulsive seizures received intravenous diazepam (5 mg) lorazepam (2 mg) or placebo An identical second injection was given if needed
Results Of the 205 patients enrolled 66 received lorazepam 68 received diazepam and 71 received placebo Status epilepticus had been terminated on arrival at the emergency department in more patients treated with lorazepam (591 percent) or diazepam (426 percent) than patients given placebo (211 percent) (P=0001) After adjustment for covariates the odds ratio for termination of status epilepticus by the time of arrival in the lorazepam group as compared with the placebo group was 48 (95 percent confidence interval 19 to 130) The odds ratio was 19 (95 percent confidence interval 08 to 44) in the lorazepam group as compared with the diazepam group and 23 (95 percent confidence interval 10 to 59) in the diazepam group as compared with the placebo group The rates of respiratory or circulatory complications after the study treatment was administered were 106 percent for the lorazepam group 103 percent for the diazepam group and 225 percent for the placebo group (P=008)
Conclusions Benzodiazepines are safe and effective when administered by paramedics for out-of-hospital status epilepticus in adults Lorazepam is likely to be a better therapy than diazepam (N Engl J Med 2001345631-7)
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001
0
10
20
30
40
50
60
seizures stop complications
lorazepam
diazepam
placebo
randomized double-blind trial
to evaluate iv bdz
admin by paramedics
for the treatment of out-of-hospital status epilepticus
Adults with prolonged (lasting 5 minutes or +)
or repetitive generalized convulsive seizures
received iv diazepam (5 mg)
lorazepam (2 mg) or placebo
An identical second injection was given if needed
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
Treiman DM Meyers PD Walton NY Collins JF Colling C Rowan AJ et al A comparison of four treatments for generalized convulsive status epilepticus N Engl J Med 1998 339792-798
randomized double-blind trial that compared the following four regimens commonly used for the treatment of generalized convulsive status epilepticus diazepam followed by phenytoin phenytoin alone phenobarbital and lorazepam Although the doses and infusion rates chosen for study closely reflected common clinical practice at the time the study began the combination of lorazepam followed by phenytoin (the preferred regimen of many neurologists) was not included
This is a large well-controlled and important clinical trial The major limitation in its clinical relevance is the lack of inclusion of a regimen consisting of lorazepam followed by phenytoin
Veterans Affairs Status Epilepticus Cooperative
Study Group Treiman et al
SE aperto
diaz fenitoina fenobarbital lorazepam
2 o + convuls senza
ripresa di coscienza
Convuls continue = gt 10 min
fenitoina
Coma con scariche
ictali EEG
primary outcome measure
cessation of clinical and electrical
seizure activity
within 20min after initiation
of treatment and continuing for at least
60min after the start of treatment
lorazepam fenitoina
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
bull st treatment successful in 555 of patients with a verified diagnosis of overt status epilepticus (n=384) and in 149 of patients with subtle status epilepticus (n=134)
bull Comparisons between the 4 treatments showed that lorazepam was more effective than phenytoin alone in patients with overt status epilepticus (treatment success in 649 versus 436 of patients respectively)
bull other treatment comparisons in the overt group and all comparisons in the subtle group were not significantly different however
bull There were no significant differences between treatments in patient outcome rates of recurrence of status epilepticus or return of full consciousness over the 12-h observation period or in the frequency of adverse cardiac respiratory or hypotensive events
Treiman DM Meyers PD Walton NY et al A
comparison of four treatments for generalized
convulsive status epilepticus N Engl J Med 1998
339792-798
P 002
Percentage of successful treatment
grey bars overt patients black bars subtle patients
Alldredge Brian Kab Lowenstein Daniel HAC Status
epilepticus new concepts Current Opinion in Neurology
121999 183-190
Da ChapmanAnaesthesia 2004
Marik PEVaron J The Management of Status
Epilepticus Chest 126(2)582-591 August 2004
Status epilepticus is a major medical emergency associated with significant morbidity and mortality Status epilepticusis best defined as a continuous generalized convulsive seizure lasting gt 5 min or two or more seizures during which the patient does not return to baseline consciousness Lorazepam in a dose of 01 mgkg is the drug of first choice for terminating status epilepticus Patients who continue to have clinical or EEG evidence of seizure activity after treatment with lorazepam should be considered to have refractory status epileptics and should be treated with a continuous infusion of propofol or midazolam This article reviews current information regarding the management of status epilepticus in adults
Schema di Marik et al
Claassen JHirsch LJ Emerson R GBates
JE Thompson TBMayer SA Continuous EEG
monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042 bull The authors reviewed 33 episodes of RSE treated with cIV-MDZ in their neurologic intensive care
unit over 6 years All patients were monitored with continuous EEG (cEEG) MDZ infusion rates were titrated to eliminate clinical and EEG seizure activity cIV-MDZ was discontinued once patients were seizure-free for 24 hours Acute treatment failures (seizures 1 to 6 hours after starting cIV-MDZ) breakthrough seizures (after 6 hours of therapy) post-treatment seizures (within 48 hours of discontinuing therapy) and ultimate treatment failure (frequent seizures that led to treatment with pentobarbital or propofol) were identified
bull Results All patients were in nonconvulsive SE at the time cIV-MDZ was started the mean duration of SE before treatment was 39 days (range 0 to 17 days) In addition to benzodiazepines 94 of patients had received at least two antiepileptic drugs (AED) before starting cIV-MDZ The mean loading dose was 019 mgkg the mean maximal infusion rate was 022 mgkgh and the mean duration of cIV-MDZ therapy was 42 days (range 1 to 14 days) Acute treatment failure occurred in 18 (633) of episodes breakthrough seizures in 56 (1832) post-treatment seizures in 68 (1928) and ultimate treatment failure in 18 (633) Breakthrough seizures were clinically subtle or purely electrographic in 89 (1618) of cases and were associated with an increased risk of developing post-treatment seizures (p = 001)
bull Conclusions Although most patients with RSE initially responded to cIV-MDZ over half developed subsequent breakthrough seizures which were predictive of post-treatment seizures and were often detectable only with cEEG Titrating cIV-MDZ to burst suppression more aggressive treatment with concurrent AED or a longer period of initial treatment may reduce the high proportion of patients with RSE who relapse after cIV-MDZ is discontinued
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus Neurology 2001 57 25 1036-1042
0
10
20
30
40
50
60
70
80
non seizures
seizures lt30 min24h05-12 h
seizures 05-12 h24 hgt 12 h
seiz gt12 h24
burst suppression
periodic latdischarge
periodic gen discharge
prima
durante
dopo
33 episodes of RSE treated with cIV-MDZ neurologic ICU over 6 years
All patients were monitored with continuous EEG (cEEG)
Waterhouse Elizabeth J 1 2 DeLorenzo Robert J 1 3 4 2
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
bull Status epilepticus (SE) is a medical and neurological emergency that has been associated with significant morbidity and mortality The most widely accepted definition of SE is more than 30 minutes of either continuous seizure activity or intermittent seizures without full recovery of consciousness between seizures SE is a major clinical concern in the elderly population both because it has increased incidence in the elderly compared with the general population and because of concurrent medical conditions that are more likely to complicate therapy and worsen prognosis in elderly individuals
The incidence of SE in the elderly is almost twice that of the general population at 86 per 100 000 per year With the anticipated growth of the elderly population SE is likely to become an increasingly common problem facing clinicians and an important public health issue The elderly have the highest SE-associated mortality of any age group at 38 and the very old elderly (gt80 years of age) have a mortality of at least 50 Acute or remote stroke is the most common aetiology of SE in the elderly Nonconvulsive SE (NCSE) has a wide range of clinical presentations ranging from confusion to obtundation It occurs commonly in elderly patients who are critically ill and in the setting of coma Electroencephalogram is the only reliable method of diagnosing NCSE
The goal of treatment for SE is rapid cessation of clinical and electrical seizure activity Most treatment protocols call for the immediate administration of an intravenous benzodiazepine followed by phenytoin or fosphenytoin Recent studies suggest that when this initial treatment of SE fails little is gained by using additional standard drugs General anaesthetic agents (such as pentobarbital midazolam or propofol) should be expeditiously employed although these treatments have their own potential complications Intravenous valproic acid is a recent addition to the armamentarium of drugs for the treatment of SE with a low risk of hypotension respiratory depression and hypotension making it a potentially useful drug for the treatment of SE in the elderly However further information is needed to establish its role in the overall treatment of SE
Waterhouseet al
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
BDZ
Fenitoina
O fosfenitoina
GA
Midaz
Propof
pentobarb
Ac valproico
Ns proposta
Lorazepam
01 mgkg
Propofol
1-2 mgkgMidazolam01 mgkg
Inf cont 3-10 mgkgh Inf cont 001-005 mgkgh
Miorilassante solo
Per intubazione
Pentobarbital dose caricopoi 01-04 mgkgmin
fenobarbital
bull 10-20 mgkg iv
ndash Eccessiva sedazione
ndash Depressresp
ndash Ipotensione
ndash Interaz farmacol
ndash Hl gt48 hrhelliphelliphellip
tiopental
bull cumulativo
bull Inotropo neghellip
bull Pentobarbital
bull immunosoppressione
propofol
bull Vantaggi cineticodinamici
bull Titolazione continua possibile
bull TCIquale livello
bull Dosi 1 mgkgripetibile dopo 5rsquo-
ndash Infcont 2-10 mgkgh
bull Rapida emergenzafinestra neurologicaevitare la
brusca sospensione
bull + rapido controllo delle convuls gt barbituricindash Stecker MM Kramer TH Raps EC OMeeghan R Dulaney E Skaar DJ Treatment of
refractory status epilepticus with propofol clinical and pharmacokinetic findings Epilepsia 1998
39 18-26
AG
bull Non ci sono dati che indichino quanto a lungo i paz debbano rimanere senza convuls prima di poter alleggerire il piano di AG24 h96h (Treiman DM Convulsive status
epilepticus Current Treatment Options in Neurology 1999 1 359-69)
bull Anest alogenatiisofluranogtsevofluranogtdesflurane
bull Ma vaporizzatori
bull Contaminazione ambientale
bull Costihellip
Studi comparativi1
bull Midazolamgt tiopental
ndash Lohr A Jr Werneck LC Comparative non-randomized study with
midazolam versus thiopental in children with refractory status
epilepticus [Portuguese] Arq Neuropsiquiatr 2000 58282-287
ndash non-randomized comparison
ndash of historical data (thiopental) and prospectively
acquired data (midazolam)
ndash Midazolam was no more often effective than
thiopental but was associated with less cyanosis and
less respiratory distress in this study of 50 children
Studi comparativi2
Valproatobull Valproate(ivrdquoDepaconrdquo) has been used for the treatment of refractory SE
in children and myoclonic SE ndash Sheth RD Gidal BE Intravenous valproic acid for myoclonic status epilepticus
Neurology 2000 541201
ndash Uberall MA Trollmann R Wunsiedler U Wenzel D Intravenous valproate in pediatric epilepsy patients with refractory status epilepticus Neurology 2000 542188-2189 ]
bull Valproate has also been used in SE in the elderly and appears to be safe even in the presence of cardiovascular instability and hypotension no significant change in blood pressure pulse or the need for vasopressors in 13 patients with SE and hypotension given a loading dose of 147-327 mgkg Depacon intravenouslyndash Sinha S Naritoku DK Intravenous valproate is well tolerated in unstable patients
with status epilepticus Neurology 2000 55722-724
bull However there is a case report of severe hypotension in an 11-year-old child after treatment of SE with 30 mgkg intravenous valproate ndash White JR Santos CS Intravenous valproate associated with significant
hypotension in the treatment of status epilepticus J Child Neurol 1999 14822-823
FINE
Percheacute non ne possiamo
piugravehelliphelliphellip
Complicazioni sistemiche dello status epilepticus
SNC cardiova
s
Resp metaboli
co
altro
Ipossiaanos
sia
IM Apneaipopnea Disidtrataz MOF
Edema Ipoipertens Insuff resp Disturbi
elettripoNaip
erK
DIC
Emorragia Aritmie Polmonite ab
ingestis
Acidosi metab Rabdomiolisi
Trombosi
venosa
Arresto Iprtens polm Necrosi
tubacutafratture
Shock
cardiogeno
EPA Necrosi
epatica acuta
Embolia polm Pancreatite
acuta
Complicazioni dello SE
bull Durata convulsioni gt 1 hrpredittore indipendente di poor outcome (mortality odds ratio di quasi 10) (4)
bull Convulsioni prolungate aumentano il rischio di danno neuronalendash Eccitotox
ndash Accumulo intracellulare di Ca++ e apoptosi
ndash Riorganizzazione sinaptica epilettogenica( e gemmazione)
ndash Deplezione di energia e inibizione della sintesi proteica e del DNA (5)
ndash ldquo Particularly vulnerable to injury are the neurons within the hippocampus cerebral cortical mantle and cerebellar Purkinje cells Selective neuronal loss has been described within the hilar area of the dentate gyrus of the hippocampus (areas CA1 and CA3) after prolonged seizures leading to the development of chronic temporal lobe epilepsy (6)rdquo
bull Manifestazioni autonomichemorte improvvisa ndash DeLorenzo RJ Status epilepticus Concepts in diagnosis and treatment Semin Neurol 1990 10396ndash
405
ndash Towne AR Pellock JM Ko D et al Determinants of mortality in status epilepticus Epilepsia 1994 3527ndash34
ndash Payne TA Bleck TP Status epilepticus Crit Care Clin 1997 13 (1)17ndash38
ndash Sloviter RS Status epilepticus-induced neuronal injury and network reorganization Epilepsia 1999 40S34ndash41
Complications of SE
bull Aminoff MJ Simon RP Status epilepticus causes clinical features and consequences in 98 patients Am J Med 198069657-666 Bibliographic Links [Context Link]
bull 25 Wasterlain CG Fujikawa DG Penix L Sankar R Pathophysiological mechanisms of brain damage from status epilepticus Epilepsia 199334(1)S37-S53 Bibliographic Links [Context Link]
bull 26 Singhal PC Chugh KS Golati DR Myoglobinuria and renal failure after status epilepticus Neurology 197828200-201 Bibliographic Links [Context Link]
bull 27 Fisher S Zatuchni J Greenberg J Disseminated intravascular coagulation in status epilepticus Thromb Haemost 197738909-913 Bibliographic Links [Context Link]
Neuroprotective effects of acidosis
bull some studies that suggest that hypoxia acidosis and hypoglycaemia may be neuroprotective [2829] To
study these phenomena further Sasahira and coworkers [30bull31bull] looked at a rat model of status epilepticus based upon repeated bicuculline injections and using heat shock protein as an indirect measure of neuronal injury Using high concentrations of inhaled carbon dioxide they were able to reduce the serum pH from 755 to 717 This resulted in a shorter seizure duration and less neuronal damage [30bull] Using multiple regression analysis they were able to show a neuroprotective effect of shortening seizure duration and an independent effect of acidosis [30bull] Acidosis and raised carbon dioxide tensions have a profound effect on cerebral blood flow and whether the neuroprotective effect is due to haemodynamic effects or to the effect of acidoisis on receptors or transmitter release is unknown
bull A further study from the same group [31bull] looked at the effects of moderate hypoxia (PaO2=50 mmHg) on neuronal damage in the same model compared with normoxic controls There was no difference in neuronal injury detected suggesting that moderate hypoxia has no effect on neuronal death in status epilepticus The authors rightly conclude however that the implications of their findings for the treatment of status epilepticus are unclear as more severe hypoxia could result in additional ischaemic injury to the brain
bull 28 Blennow G Brierley JB Meldrum BS Siesjouml BK Epileptic brain damage The role of sysemic factors that modify cerebral energy metabolism Brain 1978101687-700 Bibliographic Links [Context Link]
bull 29 Meldrum BS Brierley JB Prolonged epileptic seizures in primates Ischaemic cell change and its relation to ictal physiological events Arch Neurol 19732810-17 Bibliographic Links [Context Link]
bull 30 bull Sasahira M Lowry T Simon RP Neuronal injury in experimental status epilepticus in the rat role of acidosis Neurosci Lett 1997224177-180 Bibliographic Links See [31bull] [Context Link]
bull 31 bull Sasahira M Simon RP Greenberg DA Neuronal injury in experimental status epilepticus in the rat role of hypoxia Neurosci Lett 1997222207-209 Bibliographic Links Thie paper and [30bull] are excellent reports considering the influence of physiological parameters on neuronal damage induced by status epilepticus [Context Link]
Effetti collaterali della fenitoina ev
bull Lesioni dei tessuti mollicon o senza
stravasordquoPurple Handgt 40 casi con parecchie
amputazioni ( (Kilarski 1984 Rao et al 1988
Hanna 1992)
bull Problemi al sito di iniezione Earnest et al (1983)
30 su 200
bull Ipotensione in gt 25 dei pazcon aritmie
ndash In 3139 pazienti 1 FA (velocitagrave di infus 26 mgmin) 1
tachic sinusale 1 allungamento tratto PR
ndash (Gellerman and Martinex 1967 Goldschlager and
Karliner 1967 Louis et al 1967 Voigt 1968)
bull
Allen FH Runge JW Legarda S et al Multicenter open-label
study on safety tolerance and pharmacokinetics of
intravenous fosphenytoin (Cerebyx) in status epilepticus
[abstract] Epilepsia 199435(Suppl 18)93
bull Data have been published from 40 patients in status epilepticus who received fosphenytoin at a mean infusion rate of 92 mgmin ranging from 247 to 1113 mgmin) Status epilepticus was terminated in 37 of 40 patients (85) within 30 min of receiving fosphenytoin The rapid infusion was well tolerated with only mild or transient side effects Most of the side effects reported were attributable to the pharmacologic effect of phenytoin and included dizziness nystagmus and ataxia Most patients in this trial received a benzodiazepine before the infusion of fosphenytoin and no adverse drug interactions were found
Introduzione alla peculiaritagrave
dellrsquoambiente intensivistico
Convulsioni in ambiente intensivo
bull Sepsi
bull Cause mediche
bull Anormalitagrave metaboliche(30-35) (11)ndash Iponatremiaipocalcemiaipofosfatemiaipoglicemiauremia
ndash Alterazioni della osmolaritagrave specie correzione acuta bull Acute return from hyperosmolarity back to normal levels in a rat
neocortical slice preparation by lowering the D-glucose concentration increased the amplitude of evoked early and late excitatory postsynaptic potentials a situation reminiscent of the generalized convulsions that may follow acute reduction of glucose in diabetic nonketotic hyperglycemia (42)
ndash Ipoosmolaritagrave induce increased nervous system excitability by strengthening both excitatory synaptic communications in neocortex and field effects among the entire cortical population (41)
Problemi peculiari allrsquoambiente
intensivistico
bull Polifarmacologia
bull Insuff renale
bull Insuff epatica
bull Induzione enzimatica
bull Inibizione enzimatica
bull Ipodisprotidemiehellipfarmaci altamente
legati alle prot plasmatiche
Trattamento dello stato di
male
Allora
bull Terapia immediata
bull Aggressiva
bull Supporto vitale di base
bull AAirway
bull Breathing
bull CSupporto circolatorio
Status epilepticusfilosofia del trattamento
Disaccoppiamento
CMRO2CBF
Funzione cardiocircolatoriaFunzione resp
Supporto supernormale
Glucosio
Tiamina 100 mg
Dopaminanoradrenalina + fre con barbituricihellip
Indagine conoscitiva su 127 TI NCH europeeDauch WA Schutze M Guttinger M et al Posttraumatic seizure prevention - results of a
survey of 127 neurosurgery clinics Zentralbl Neurochir 1996 57190ndash5
0
10
20
30
40
50
60
profilassi
Profilassi con anticonvulsivi post trauma cranio-
encefalico
mai
sempre
secindicazione
substantial cortical
injurycerebral contusion
acute subdural
hemorrhage
depressed skull fracture
penetrating missile
injury
(141517)
Rischio convulsivo
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001bull Background It is uncertain whether the administration of benzodiazepines by paramedics is an
effective and safe treatment for out-of-hospital status epilepticus
Methods We conducted a randomized double-blind trial to evaluate intravenous benzodiazepines administered by paramedics for the treatment of out-of-hospital status epilepticus Adults with prolonged (lasting five minutes or more) or repetitive generalized convulsive seizures received intravenous diazepam (5 mg) lorazepam (2 mg) or placebo An identical second injection was given if needed
Results Of the 205 patients enrolled 66 received lorazepam 68 received diazepam and 71 received placebo Status epilepticus had been terminated on arrival at the emergency department in more patients treated with lorazepam (591 percent) or diazepam (426 percent) than patients given placebo (211 percent) (P=0001) After adjustment for covariates the odds ratio for termination of status epilepticus by the time of arrival in the lorazepam group as compared with the placebo group was 48 (95 percent confidence interval 19 to 130) The odds ratio was 19 (95 percent confidence interval 08 to 44) in the lorazepam group as compared with the diazepam group and 23 (95 percent confidence interval 10 to 59) in the diazepam group as compared with the placebo group The rates of respiratory or circulatory complications after the study treatment was administered were 106 percent for the lorazepam group 103 percent for the diazepam group and 225 percent for the placebo group (P=008)
Conclusions Benzodiazepines are safe and effective when administered by paramedics for out-of-hospital status epilepticus in adults Lorazepam is likely to be a better therapy than diazepam (N Engl J Med 2001345631-7)
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001
0
10
20
30
40
50
60
seizures stop complications
lorazepam
diazepam
placebo
randomized double-blind trial
to evaluate iv bdz
admin by paramedics
for the treatment of out-of-hospital status epilepticus
Adults with prolonged (lasting 5 minutes or +)
or repetitive generalized convulsive seizures
received iv diazepam (5 mg)
lorazepam (2 mg) or placebo
An identical second injection was given if needed
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
Treiman DM Meyers PD Walton NY Collins JF Colling C Rowan AJ et al A comparison of four treatments for generalized convulsive status epilepticus N Engl J Med 1998 339792-798
randomized double-blind trial that compared the following four regimens commonly used for the treatment of generalized convulsive status epilepticus diazepam followed by phenytoin phenytoin alone phenobarbital and lorazepam Although the doses and infusion rates chosen for study closely reflected common clinical practice at the time the study began the combination of lorazepam followed by phenytoin (the preferred regimen of many neurologists) was not included
This is a large well-controlled and important clinical trial The major limitation in its clinical relevance is the lack of inclusion of a regimen consisting of lorazepam followed by phenytoin
Veterans Affairs Status Epilepticus Cooperative
Study Group Treiman et al
SE aperto
diaz fenitoina fenobarbital lorazepam
2 o + convuls senza
ripresa di coscienza
Convuls continue = gt 10 min
fenitoina
Coma con scariche
ictali EEG
primary outcome measure
cessation of clinical and electrical
seizure activity
within 20min after initiation
of treatment and continuing for at least
60min after the start of treatment
lorazepam fenitoina
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
bull st treatment successful in 555 of patients with a verified diagnosis of overt status epilepticus (n=384) and in 149 of patients with subtle status epilepticus (n=134)
bull Comparisons between the 4 treatments showed that lorazepam was more effective than phenytoin alone in patients with overt status epilepticus (treatment success in 649 versus 436 of patients respectively)
bull other treatment comparisons in the overt group and all comparisons in the subtle group were not significantly different however
bull There were no significant differences between treatments in patient outcome rates of recurrence of status epilepticus or return of full consciousness over the 12-h observation period or in the frequency of adverse cardiac respiratory or hypotensive events
Treiman DM Meyers PD Walton NY et al A
comparison of four treatments for generalized
convulsive status epilepticus N Engl J Med 1998
339792-798
P 002
Percentage of successful treatment
grey bars overt patients black bars subtle patients
Alldredge Brian Kab Lowenstein Daniel HAC Status
epilepticus new concepts Current Opinion in Neurology
121999 183-190
Da ChapmanAnaesthesia 2004
Marik PEVaron J The Management of Status
Epilepticus Chest 126(2)582-591 August 2004
Status epilepticus is a major medical emergency associated with significant morbidity and mortality Status epilepticusis best defined as a continuous generalized convulsive seizure lasting gt 5 min or two or more seizures during which the patient does not return to baseline consciousness Lorazepam in a dose of 01 mgkg is the drug of first choice for terminating status epilepticus Patients who continue to have clinical or EEG evidence of seizure activity after treatment with lorazepam should be considered to have refractory status epileptics and should be treated with a continuous infusion of propofol or midazolam This article reviews current information regarding the management of status epilepticus in adults
Schema di Marik et al
Claassen JHirsch LJ Emerson R GBates
JE Thompson TBMayer SA Continuous EEG
monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042 bull The authors reviewed 33 episodes of RSE treated with cIV-MDZ in their neurologic intensive care
unit over 6 years All patients were monitored with continuous EEG (cEEG) MDZ infusion rates were titrated to eliminate clinical and EEG seizure activity cIV-MDZ was discontinued once patients were seizure-free for 24 hours Acute treatment failures (seizures 1 to 6 hours after starting cIV-MDZ) breakthrough seizures (after 6 hours of therapy) post-treatment seizures (within 48 hours of discontinuing therapy) and ultimate treatment failure (frequent seizures that led to treatment with pentobarbital or propofol) were identified
bull Results All patients were in nonconvulsive SE at the time cIV-MDZ was started the mean duration of SE before treatment was 39 days (range 0 to 17 days) In addition to benzodiazepines 94 of patients had received at least two antiepileptic drugs (AED) before starting cIV-MDZ The mean loading dose was 019 mgkg the mean maximal infusion rate was 022 mgkgh and the mean duration of cIV-MDZ therapy was 42 days (range 1 to 14 days) Acute treatment failure occurred in 18 (633) of episodes breakthrough seizures in 56 (1832) post-treatment seizures in 68 (1928) and ultimate treatment failure in 18 (633) Breakthrough seizures were clinically subtle or purely electrographic in 89 (1618) of cases and were associated with an increased risk of developing post-treatment seizures (p = 001)
bull Conclusions Although most patients with RSE initially responded to cIV-MDZ over half developed subsequent breakthrough seizures which were predictive of post-treatment seizures and were often detectable only with cEEG Titrating cIV-MDZ to burst suppression more aggressive treatment with concurrent AED or a longer period of initial treatment may reduce the high proportion of patients with RSE who relapse after cIV-MDZ is discontinued
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus Neurology 2001 57 25 1036-1042
0
10
20
30
40
50
60
70
80
non seizures
seizures lt30 min24h05-12 h
seizures 05-12 h24 hgt 12 h
seiz gt12 h24
burst suppression
periodic latdischarge
periodic gen discharge
prima
durante
dopo
33 episodes of RSE treated with cIV-MDZ neurologic ICU over 6 years
All patients were monitored with continuous EEG (cEEG)
Waterhouse Elizabeth J 1 2 DeLorenzo Robert J 1 3 4 2
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
bull Status epilepticus (SE) is a medical and neurological emergency that has been associated with significant morbidity and mortality The most widely accepted definition of SE is more than 30 minutes of either continuous seizure activity or intermittent seizures without full recovery of consciousness between seizures SE is a major clinical concern in the elderly population both because it has increased incidence in the elderly compared with the general population and because of concurrent medical conditions that are more likely to complicate therapy and worsen prognosis in elderly individuals
The incidence of SE in the elderly is almost twice that of the general population at 86 per 100 000 per year With the anticipated growth of the elderly population SE is likely to become an increasingly common problem facing clinicians and an important public health issue The elderly have the highest SE-associated mortality of any age group at 38 and the very old elderly (gt80 years of age) have a mortality of at least 50 Acute or remote stroke is the most common aetiology of SE in the elderly Nonconvulsive SE (NCSE) has a wide range of clinical presentations ranging from confusion to obtundation It occurs commonly in elderly patients who are critically ill and in the setting of coma Electroencephalogram is the only reliable method of diagnosing NCSE
The goal of treatment for SE is rapid cessation of clinical and electrical seizure activity Most treatment protocols call for the immediate administration of an intravenous benzodiazepine followed by phenytoin or fosphenytoin Recent studies suggest that when this initial treatment of SE fails little is gained by using additional standard drugs General anaesthetic agents (such as pentobarbital midazolam or propofol) should be expeditiously employed although these treatments have their own potential complications Intravenous valproic acid is a recent addition to the armamentarium of drugs for the treatment of SE with a low risk of hypotension respiratory depression and hypotension making it a potentially useful drug for the treatment of SE in the elderly However further information is needed to establish its role in the overall treatment of SE
Waterhouseet al
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
BDZ
Fenitoina
O fosfenitoina
GA
Midaz
Propof
pentobarb
Ac valproico
Ns proposta
Lorazepam
01 mgkg
Propofol
1-2 mgkgMidazolam01 mgkg
Inf cont 3-10 mgkgh Inf cont 001-005 mgkgh
Miorilassante solo
Per intubazione
Pentobarbital dose caricopoi 01-04 mgkgmin
fenobarbital
bull 10-20 mgkg iv
ndash Eccessiva sedazione
ndash Depressresp
ndash Ipotensione
ndash Interaz farmacol
ndash Hl gt48 hrhelliphelliphellip
tiopental
bull cumulativo
bull Inotropo neghellip
bull Pentobarbital
bull immunosoppressione
propofol
bull Vantaggi cineticodinamici
bull Titolazione continua possibile
bull TCIquale livello
bull Dosi 1 mgkgripetibile dopo 5rsquo-
ndash Infcont 2-10 mgkgh
bull Rapida emergenzafinestra neurologicaevitare la
brusca sospensione
bull + rapido controllo delle convuls gt barbituricindash Stecker MM Kramer TH Raps EC OMeeghan R Dulaney E Skaar DJ Treatment of
refractory status epilepticus with propofol clinical and pharmacokinetic findings Epilepsia 1998
39 18-26
AG
bull Non ci sono dati che indichino quanto a lungo i paz debbano rimanere senza convuls prima di poter alleggerire il piano di AG24 h96h (Treiman DM Convulsive status
epilepticus Current Treatment Options in Neurology 1999 1 359-69)
bull Anest alogenatiisofluranogtsevofluranogtdesflurane
bull Ma vaporizzatori
bull Contaminazione ambientale
bull Costihellip
Studi comparativi1
bull Midazolamgt tiopental
ndash Lohr A Jr Werneck LC Comparative non-randomized study with
midazolam versus thiopental in children with refractory status
epilepticus [Portuguese] Arq Neuropsiquiatr 2000 58282-287
ndash non-randomized comparison
ndash of historical data (thiopental) and prospectively
acquired data (midazolam)
ndash Midazolam was no more often effective than
thiopental but was associated with less cyanosis and
less respiratory distress in this study of 50 children
Studi comparativi2
Valproatobull Valproate(ivrdquoDepaconrdquo) has been used for the treatment of refractory SE
in children and myoclonic SE ndash Sheth RD Gidal BE Intravenous valproic acid for myoclonic status epilepticus
Neurology 2000 541201
ndash Uberall MA Trollmann R Wunsiedler U Wenzel D Intravenous valproate in pediatric epilepsy patients with refractory status epilepticus Neurology 2000 542188-2189 ]
bull Valproate has also been used in SE in the elderly and appears to be safe even in the presence of cardiovascular instability and hypotension no significant change in blood pressure pulse or the need for vasopressors in 13 patients with SE and hypotension given a loading dose of 147-327 mgkg Depacon intravenouslyndash Sinha S Naritoku DK Intravenous valproate is well tolerated in unstable patients
with status epilepticus Neurology 2000 55722-724
bull However there is a case report of severe hypotension in an 11-year-old child after treatment of SE with 30 mgkg intravenous valproate ndash White JR Santos CS Intravenous valproate associated with significant
hypotension in the treatment of status epilepticus J Child Neurol 1999 14822-823
FINE
Percheacute non ne possiamo
piugravehelliphelliphellip
Complicazioni dello SE
bull Durata convulsioni gt 1 hrpredittore indipendente di poor outcome (mortality odds ratio di quasi 10) (4)
bull Convulsioni prolungate aumentano il rischio di danno neuronalendash Eccitotox
ndash Accumulo intracellulare di Ca++ e apoptosi
ndash Riorganizzazione sinaptica epilettogenica( e gemmazione)
ndash Deplezione di energia e inibizione della sintesi proteica e del DNA (5)
ndash ldquo Particularly vulnerable to injury are the neurons within the hippocampus cerebral cortical mantle and cerebellar Purkinje cells Selective neuronal loss has been described within the hilar area of the dentate gyrus of the hippocampus (areas CA1 and CA3) after prolonged seizures leading to the development of chronic temporal lobe epilepsy (6)rdquo
bull Manifestazioni autonomichemorte improvvisa ndash DeLorenzo RJ Status epilepticus Concepts in diagnosis and treatment Semin Neurol 1990 10396ndash
405
ndash Towne AR Pellock JM Ko D et al Determinants of mortality in status epilepticus Epilepsia 1994 3527ndash34
ndash Payne TA Bleck TP Status epilepticus Crit Care Clin 1997 13 (1)17ndash38
ndash Sloviter RS Status epilepticus-induced neuronal injury and network reorganization Epilepsia 1999 40S34ndash41
Complications of SE
bull Aminoff MJ Simon RP Status epilepticus causes clinical features and consequences in 98 patients Am J Med 198069657-666 Bibliographic Links [Context Link]
bull 25 Wasterlain CG Fujikawa DG Penix L Sankar R Pathophysiological mechanisms of brain damage from status epilepticus Epilepsia 199334(1)S37-S53 Bibliographic Links [Context Link]
bull 26 Singhal PC Chugh KS Golati DR Myoglobinuria and renal failure after status epilepticus Neurology 197828200-201 Bibliographic Links [Context Link]
bull 27 Fisher S Zatuchni J Greenberg J Disseminated intravascular coagulation in status epilepticus Thromb Haemost 197738909-913 Bibliographic Links [Context Link]
Neuroprotective effects of acidosis
bull some studies that suggest that hypoxia acidosis and hypoglycaemia may be neuroprotective [2829] To
study these phenomena further Sasahira and coworkers [30bull31bull] looked at a rat model of status epilepticus based upon repeated bicuculline injections and using heat shock protein as an indirect measure of neuronal injury Using high concentrations of inhaled carbon dioxide they were able to reduce the serum pH from 755 to 717 This resulted in a shorter seizure duration and less neuronal damage [30bull] Using multiple regression analysis they were able to show a neuroprotective effect of shortening seizure duration and an independent effect of acidosis [30bull] Acidosis and raised carbon dioxide tensions have a profound effect on cerebral blood flow and whether the neuroprotective effect is due to haemodynamic effects or to the effect of acidoisis on receptors or transmitter release is unknown
bull A further study from the same group [31bull] looked at the effects of moderate hypoxia (PaO2=50 mmHg) on neuronal damage in the same model compared with normoxic controls There was no difference in neuronal injury detected suggesting that moderate hypoxia has no effect on neuronal death in status epilepticus The authors rightly conclude however that the implications of their findings for the treatment of status epilepticus are unclear as more severe hypoxia could result in additional ischaemic injury to the brain
bull 28 Blennow G Brierley JB Meldrum BS Siesjouml BK Epileptic brain damage The role of sysemic factors that modify cerebral energy metabolism Brain 1978101687-700 Bibliographic Links [Context Link]
bull 29 Meldrum BS Brierley JB Prolonged epileptic seizures in primates Ischaemic cell change and its relation to ictal physiological events Arch Neurol 19732810-17 Bibliographic Links [Context Link]
bull 30 bull Sasahira M Lowry T Simon RP Neuronal injury in experimental status epilepticus in the rat role of acidosis Neurosci Lett 1997224177-180 Bibliographic Links See [31bull] [Context Link]
bull 31 bull Sasahira M Simon RP Greenberg DA Neuronal injury in experimental status epilepticus in the rat role of hypoxia Neurosci Lett 1997222207-209 Bibliographic Links Thie paper and [30bull] are excellent reports considering the influence of physiological parameters on neuronal damage induced by status epilepticus [Context Link]
Effetti collaterali della fenitoina ev
bull Lesioni dei tessuti mollicon o senza
stravasordquoPurple Handgt 40 casi con parecchie
amputazioni ( (Kilarski 1984 Rao et al 1988
Hanna 1992)
bull Problemi al sito di iniezione Earnest et al (1983)
30 su 200
bull Ipotensione in gt 25 dei pazcon aritmie
ndash In 3139 pazienti 1 FA (velocitagrave di infus 26 mgmin) 1
tachic sinusale 1 allungamento tratto PR
ndash (Gellerman and Martinex 1967 Goldschlager and
Karliner 1967 Louis et al 1967 Voigt 1968)
bull
Allen FH Runge JW Legarda S et al Multicenter open-label
study on safety tolerance and pharmacokinetics of
intravenous fosphenytoin (Cerebyx) in status epilepticus
[abstract] Epilepsia 199435(Suppl 18)93
bull Data have been published from 40 patients in status epilepticus who received fosphenytoin at a mean infusion rate of 92 mgmin ranging from 247 to 1113 mgmin) Status epilepticus was terminated in 37 of 40 patients (85) within 30 min of receiving fosphenytoin The rapid infusion was well tolerated with only mild or transient side effects Most of the side effects reported were attributable to the pharmacologic effect of phenytoin and included dizziness nystagmus and ataxia Most patients in this trial received a benzodiazepine before the infusion of fosphenytoin and no adverse drug interactions were found
Introduzione alla peculiaritagrave
dellrsquoambiente intensivistico
Convulsioni in ambiente intensivo
bull Sepsi
bull Cause mediche
bull Anormalitagrave metaboliche(30-35) (11)ndash Iponatremiaipocalcemiaipofosfatemiaipoglicemiauremia
ndash Alterazioni della osmolaritagrave specie correzione acuta bull Acute return from hyperosmolarity back to normal levels in a rat
neocortical slice preparation by lowering the D-glucose concentration increased the amplitude of evoked early and late excitatory postsynaptic potentials a situation reminiscent of the generalized convulsions that may follow acute reduction of glucose in diabetic nonketotic hyperglycemia (42)
ndash Ipoosmolaritagrave induce increased nervous system excitability by strengthening both excitatory synaptic communications in neocortex and field effects among the entire cortical population (41)
Problemi peculiari allrsquoambiente
intensivistico
bull Polifarmacologia
bull Insuff renale
bull Insuff epatica
bull Induzione enzimatica
bull Inibizione enzimatica
bull Ipodisprotidemiehellipfarmaci altamente
legati alle prot plasmatiche
Trattamento dello stato di
male
Allora
bull Terapia immediata
bull Aggressiva
bull Supporto vitale di base
bull AAirway
bull Breathing
bull CSupporto circolatorio
Status epilepticusfilosofia del trattamento
Disaccoppiamento
CMRO2CBF
Funzione cardiocircolatoriaFunzione resp
Supporto supernormale
Glucosio
Tiamina 100 mg
Dopaminanoradrenalina + fre con barbituricihellip
Indagine conoscitiva su 127 TI NCH europeeDauch WA Schutze M Guttinger M et al Posttraumatic seizure prevention - results of a
survey of 127 neurosurgery clinics Zentralbl Neurochir 1996 57190ndash5
0
10
20
30
40
50
60
profilassi
Profilassi con anticonvulsivi post trauma cranio-
encefalico
mai
sempre
secindicazione
substantial cortical
injurycerebral contusion
acute subdural
hemorrhage
depressed skull fracture
penetrating missile
injury
(141517)
Rischio convulsivo
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001bull Background It is uncertain whether the administration of benzodiazepines by paramedics is an
effective and safe treatment for out-of-hospital status epilepticus
Methods We conducted a randomized double-blind trial to evaluate intravenous benzodiazepines administered by paramedics for the treatment of out-of-hospital status epilepticus Adults with prolonged (lasting five minutes or more) or repetitive generalized convulsive seizures received intravenous diazepam (5 mg) lorazepam (2 mg) or placebo An identical second injection was given if needed
Results Of the 205 patients enrolled 66 received lorazepam 68 received diazepam and 71 received placebo Status epilepticus had been terminated on arrival at the emergency department in more patients treated with lorazepam (591 percent) or diazepam (426 percent) than patients given placebo (211 percent) (P=0001) After adjustment for covariates the odds ratio for termination of status epilepticus by the time of arrival in the lorazepam group as compared with the placebo group was 48 (95 percent confidence interval 19 to 130) The odds ratio was 19 (95 percent confidence interval 08 to 44) in the lorazepam group as compared with the diazepam group and 23 (95 percent confidence interval 10 to 59) in the diazepam group as compared with the placebo group The rates of respiratory or circulatory complications after the study treatment was administered were 106 percent for the lorazepam group 103 percent for the diazepam group and 225 percent for the placebo group (P=008)
Conclusions Benzodiazepines are safe and effective when administered by paramedics for out-of-hospital status epilepticus in adults Lorazepam is likely to be a better therapy than diazepam (N Engl J Med 2001345631-7)
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001
0
10
20
30
40
50
60
seizures stop complications
lorazepam
diazepam
placebo
randomized double-blind trial
to evaluate iv bdz
admin by paramedics
for the treatment of out-of-hospital status epilepticus
Adults with prolonged (lasting 5 minutes or +)
or repetitive generalized convulsive seizures
received iv diazepam (5 mg)
lorazepam (2 mg) or placebo
An identical second injection was given if needed
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
Treiman DM Meyers PD Walton NY Collins JF Colling C Rowan AJ et al A comparison of four treatments for generalized convulsive status epilepticus N Engl J Med 1998 339792-798
randomized double-blind trial that compared the following four regimens commonly used for the treatment of generalized convulsive status epilepticus diazepam followed by phenytoin phenytoin alone phenobarbital and lorazepam Although the doses and infusion rates chosen for study closely reflected common clinical practice at the time the study began the combination of lorazepam followed by phenytoin (the preferred regimen of many neurologists) was not included
This is a large well-controlled and important clinical trial The major limitation in its clinical relevance is the lack of inclusion of a regimen consisting of lorazepam followed by phenytoin
Veterans Affairs Status Epilepticus Cooperative
Study Group Treiman et al
SE aperto
diaz fenitoina fenobarbital lorazepam
2 o + convuls senza
ripresa di coscienza
Convuls continue = gt 10 min
fenitoina
Coma con scariche
ictali EEG
primary outcome measure
cessation of clinical and electrical
seizure activity
within 20min after initiation
of treatment and continuing for at least
60min after the start of treatment
lorazepam fenitoina
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
bull st treatment successful in 555 of patients with a verified diagnosis of overt status epilepticus (n=384) and in 149 of patients with subtle status epilepticus (n=134)
bull Comparisons between the 4 treatments showed that lorazepam was more effective than phenytoin alone in patients with overt status epilepticus (treatment success in 649 versus 436 of patients respectively)
bull other treatment comparisons in the overt group and all comparisons in the subtle group were not significantly different however
bull There were no significant differences between treatments in patient outcome rates of recurrence of status epilepticus or return of full consciousness over the 12-h observation period or in the frequency of adverse cardiac respiratory or hypotensive events
Treiman DM Meyers PD Walton NY et al A
comparison of four treatments for generalized
convulsive status epilepticus N Engl J Med 1998
339792-798
P 002
Percentage of successful treatment
grey bars overt patients black bars subtle patients
Alldredge Brian Kab Lowenstein Daniel HAC Status
epilepticus new concepts Current Opinion in Neurology
121999 183-190
Da ChapmanAnaesthesia 2004
Marik PEVaron J The Management of Status
Epilepticus Chest 126(2)582-591 August 2004
Status epilepticus is a major medical emergency associated with significant morbidity and mortality Status epilepticusis best defined as a continuous generalized convulsive seizure lasting gt 5 min or two or more seizures during which the patient does not return to baseline consciousness Lorazepam in a dose of 01 mgkg is the drug of first choice for terminating status epilepticus Patients who continue to have clinical or EEG evidence of seizure activity after treatment with lorazepam should be considered to have refractory status epileptics and should be treated with a continuous infusion of propofol or midazolam This article reviews current information regarding the management of status epilepticus in adults
Schema di Marik et al
Claassen JHirsch LJ Emerson R GBates
JE Thompson TBMayer SA Continuous EEG
monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042 bull The authors reviewed 33 episodes of RSE treated with cIV-MDZ in their neurologic intensive care
unit over 6 years All patients were monitored with continuous EEG (cEEG) MDZ infusion rates were titrated to eliminate clinical and EEG seizure activity cIV-MDZ was discontinued once patients were seizure-free for 24 hours Acute treatment failures (seizures 1 to 6 hours after starting cIV-MDZ) breakthrough seizures (after 6 hours of therapy) post-treatment seizures (within 48 hours of discontinuing therapy) and ultimate treatment failure (frequent seizures that led to treatment with pentobarbital or propofol) were identified
bull Results All patients were in nonconvulsive SE at the time cIV-MDZ was started the mean duration of SE before treatment was 39 days (range 0 to 17 days) In addition to benzodiazepines 94 of patients had received at least two antiepileptic drugs (AED) before starting cIV-MDZ The mean loading dose was 019 mgkg the mean maximal infusion rate was 022 mgkgh and the mean duration of cIV-MDZ therapy was 42 days (range 1 to 14 days) Acute treatment failure occurred in 18 (633) of episodes breakthrough seizures in 56 (1832) post-treatment seizures in 68 (1928) and ultimate treatment failure in 18 (633) Breakthrough seizures were clinically subtle or purely electrographic in 89 (1618) of cases and were associated with an increased risk of developing post-treatment seizures (p = 001)
bull Conclusions Although most patients with RSE initially responded to cIV-MDZ over half developed subsequent breakthrough seizures which were predictive of post-treatment seizures and were often detectable only with cEEG Titrating cIV-MDZ to burst suppression more aggressive treatment with concurrent AED or a longer period of initial treatment may reduce the high proportion of patients with RSE who relapse after cIV-MDZ is discontinued
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus Neurology 2001 57 25 1036-1042
0
10
20
30
40
50
60
70
80
non seizures
seizures lt30 min24h05-12 h
seizures 05-12 h24 hgt 12 h
seiz gt12 h24
burst suppression
periodic latdischarge
periodic gen discharge
prima
durante
dopo
33 episodes of RSE treated with cIV-MDZ neurologic ICU over 6 years
All patients were monitored with continuous EEG (cEEG)
Waterhouse Elizabeth J 1 2 DeLorenzo Robert J 1 3 4 2
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
bull Status epilepticus (SE) is a medical and neurological emergency that has been associated with significant morbidity and mortality The most widely accepted definition of SE is more than 30 minutes of either continuous seizure activity or intermittent seizures without full recovery of consciousness between seizures SE is a major clinical concern in the elderly population both because it has increased incidence in the elderly compared with the general population and because of concurrent medical conditions that are more likely to complicate therapy and worsen prognosis in elderly individuals
The incidence of SE in the elderly is almost twice that of the general population at 86 per 100 000 per year With the anticipated growth of the elderly population SE is likely to become an increasingly common problem facing clinicians and an important public health issue The elderly have the highest SE-associated mortality of any age group at 38 and the very old elderly (gt80 years of age) have a mortality of at least 50 Acute or remote stroke is the most common aetiology of SE in the elderly Nonconvulsive SE (NCSE) has a wide range of clinical presentations ranging from confusion to obtundation It occurs commonly in elderly patients who are critically ill and in the setting of coma Electroencephalogram is the only reliable method of diagnosing NCSE
The goal of treatment for SE is rapid cessation of clinical and electrical seizure activity Most treatment protocols call for the immediate administration of an intravenous benzodiazepine followed by phenytoin or fosphenytoin Recent studies suggest that when this initial treatment of SE fails little is gained by using additional standard drugs General anaesthetic agents (such as pentobarbital midazolam or propofol) should be expeditiously employed although these treatments have their own potential complications Intravenous valproic acid is a recent addition to the armamentarium of drugs for the treatment of SE with a low risk of hypotension respiratory depression and hypotension making it a potentially useful drug for the treatment of SE in the elderly However further information is needed to establish its role in the overall treatment of SE
Waterhouseet al
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
BDZ
Fenitoina
O fosfenitoina
GA
Midaz
Propof
pentobarb
Ac valproico
Ns proposta
Lorazepam
01 mgkg
Propofol
1-2 mgkgMidazolam01 mgkg
Inf cont 3-10 mgkgh Inf cont 001-005 mgkgh
Miorilassante solo
Per intubazione
Pentobarbital dose caricopoi 01-04 mgkgmin
fenobarbital
bull 10-20 mgkg iv
ndash Eccessiva sedazione
ndash Depressresp
ndash Ipotensione
ndash Interaz farmacol
ndash Hl gt48 hrhelliphelliphellip
tiopental
bull cumulativo
bull Inotropo neghellip
bull Pentobarbital
bull immunosoppressione
propofol
bull Vantaggi cineticodinamici
bull Titolazione continua possibile
bull TCIquale livello
bull Dosi 1 mgkgripetibile dopo 5rsquo-
ndash Infcont 2-10 mgkgh
bull Rapida emergenzafinestra neurologicaevitare la
brusca sospensione
bull + rapido controllo delle convuls gt barbituricindash Stecker MM Kramer TH Raps EC OMeeghan R Dulaney E Skaar DJ Treatment of
refractory status epilepticus with propofol clinical and pharmacokinetic findings Epilepsia 1998
39 18-26
AG
bull Non ci sono dati che indichino quanto a lungo i paz debbano rimanere senza convuls prima di poter alleggerire il piano di AG24 h96h (Treiman DM Convulsive status
epilepticus Current Treatment Options in Neurology 1999 1 359-69)
bull Anest alogenatiisofluranogtsevofluranogtdesflurane
bull Ma vaporizzatori
bull Contaminazione ambientale
bull Costihellip
Studi comparativi1
bull Midazolamgt tiopental
ndash Lohr A Jr Werneck LC Comparative non-randomized study with
midazolam versus thiopental in children with refractory status
epilepticus [Portuguese] Arq Neuropsiquiatr 2000 58282-287
ndash non-randomized comparison
ndash of historical data (thiopental) and prospectively
acquired data (midazolam)
ndash Midazolam was no more often effective than
thiopental but was associated with less cyanosis and
less respiratory distress in this study of 50 children
Studi comparativi2
Valproatobull Valproate(ivrdquoDepaconrdquo) has been used for the treatment of refractory SE
in children and myoclonic SE ndash Sheth RD Gidal BE Intravenous valproic acid for myoclonic status epilepticus
Neurology 2000 541201
ndash Uberall MA Trollmann R Wunsiedler U Wenzel D Intravenous valproate in pediatric epilepsy patients with refractory status epilepticus Neurology 2000 542188-2189 ]
bull Valproate has also been used in SE in the elderly and appears to be safe even in the presence of cardiovascular instability and hypotension no significant change in blood pressure pulse or the need for vasopressors in 13 patients with SE and hypotension given a loading dose of 147-327 mgkg Depacon intravenouslyndash Sinha S Naritoku DK Intravenous valproate is well tolerated in unstable patients
with status epilepticus Neurology 2000 55722-724
bull However there is a case report of severe hypotension in an 11-year-old child after treatment of SE with 30 mgkg intravenous valproate ndash White JR Santos CS Intravenous valproate associated with significant
hypotension in the treatment of status epilepticus J Child Neurol 1999 14822-823
FINE
Percheacute non ne possiamo
piugravehelliphelliphellip
Complications of SE
bull Aminoff MJ Simon RP Status epilepticus causes clinical features and consequences in 98 patients Am J Med 198069657-666 Bibliographic Links [Context Link]
bull 25 Wasterlain CG Fujikawa DG Penix L Sankar R Pathophysiological mechanisms of brain damage from status epilepticus Epilepsia 199334(1)S37-S53 Bibliographic Links [Context Link]
bull 26 Singhal PC Chugh KS Golati DR Myoglobinuria and renal failure after status epilepticus Neurology 197828200-201 Bibliographic Links [Context Link]
bull 27 Fisher S Zatuchni J Greenberg J Disseminated intravascular coagulation in status epilepticus Thromb Haemost 197738909-913 Bibliographic Links [Context Link]
Neuroprotective effects of acidosis
bull some studies that suggest that hypoxia acidosis and hypoglycaemia may be neuroprotective [2829] To
study these phenomena further Sasahira and coworkers [30bull31bull] looked at a rat model of status epilepticus based upon repeated bicuculline injections and using heat shock protein as an indirect measure of neuronal injury Using high concentrations of inhaled carbon dioxide they were able to reduce the serum pH from 755 to 717 This resulted in a shorter seizure duration and less neuronal damage [30bull] Using multiple regression analysis they were able to show a neuroprotective effect of shortening seizure duration and an independent effect of acidosis [30bull] Acidosis and raised carbon dioxide tensions have a profound effect on cerebral blood flow and whether the neuroprotective effect is due to haemodynamic effects or to the effect of acidoisis on receptors or transmitter release is unknown
bull A further study from the same group [31bull] looked at the effects of moderate hypoxia (PaO2=50 mmHg) on neuronal damage in the same model compared with normoxic controls There was no difference in neuronal injury detected suggesting that moderate hypoxia has no effect on neuronal death in status epilepticus The authors rightly conclude however that the implications of their findings for the treatment of status epilepticus are unclear as more severe hypoxia could result in additional ischaemic injury to the brain
bull 28 Blennow G Brierley JB Meldrum BS Siesjouml BK Epileptic brain damage The role of sysemic factors that modify cerebral energy metabolism Brain 1978101687-700 Bibliographic Links [Context Link]
bull 29 Meldrum BS Brierley JB Prolonged epileptic seizures in primates Ischaemic cell change and its relation to ictal physiological events Arch Neurol 19732810-17 Bibliographic Links [Context Link]
bull 30 bull Sasahira M Lowry T Simon RP Neuronal injury in experimental status epilepticus in the rat role of acidosis Neurosci Lett 1997224177-180 Bibliographic Links See [31bull] [Context Link]
bull 31 bull Sasahira M Simon RP Greenberg DA Neuronal injury in experimental status epilepticus in the rat role of hypoxia Neurosci Lett 1997222207-209 Bibliographic Links Thie paper and [30bull] are excellent reports considering the influence of physiological parameters on neuronal damage induced by status epilepticus [Context Link]
Effetti collaterali della fenitoina ev
bull Lesioni dei tessuti mollicon o senza
stravasordquoPurple Handgt 40 casi con parecchie
amputazioni ( (Kilarski 1984 Rao et al 1988
Hanna 1992)
bull Problemi al sito di iniezione Earnest et al (1983)
30 su 200
bull Ipotensione in gt 25 dei pazcon aritmie
ndash In 3139 pazienti 1 FA (velocitagrave di infus 26 mgmin) 1
tachic sinusale 1 allungamento tratto PR
ndash (Gellerman and Martinex 1967 Goldschlager and
Karliner 1967 Louis et al 1967 Voigt 1968)
bull
Allen FH Runge JW Legarda S et al Multicenter open-label
study on safety tolerance and pharmacokinetics of
intravenous fosphenytoin (Cerebyx) in status epilepticus
[abstract] Epilepsia 199435(Suppl 18)93
bull Data have been published from 40 patients in status epilepticus who received fosphenytoin at a mean infusion rate of 92 mgmin ranging from 247 to 1113 mgmin) Status epilepticus was terminated in 37 of 40 patients (85) within 30 min of receiving fosphenytoin The rapid infusion was well tolerated with only mild or transient side effects Most of the side effects reported were attributable to the pharmacologic effect of phenytoin and included dizziness nystagmus and ataxia Most patients in this trial received a benzodiazepine before the infusion of fosphenytoin and no adverse drug interactions were found
Introduzione alla peculiaritagrave
dellrsquoambiente intensivistico
Convulsioni in ambiente intensivo
bull Sepsi
bull Cause mediche
bull Anormalitagrave metaboliche(30-35) (11)ndash Iponatremiaipocalcemiaipofosfatemiaipoglicemiauremia
ndash Alterazioni della osmolaritagrave specie correzione acuta bull Acute return from hyperosmolarity back to normal levels in a rat
neocortical slice preparation by lowering the D-glucose concentration increased the amplitude of evoked early and late excitatory postsynaptic potentials a situation reminiscent of the generalized convulsions that may follow acute reduction of glucose in diabetic nonketotic hyperglycemia (42)
ndash Ipoosmolaritagrave induce increased nervous system excitability by strengthening both excitatory synaptic communications in neocortex and field effects among the entire cortical population (41)
Problemi peculiari allrsquoambiente
intensivistico
bull Polifarmacologia
bull Insuff renale
bull Insuff epatica
bull Induzione enzimatica
bull Inibizione enzimatica
bull Ipodisprotidemiehellipfarmaci altamente
legati alle prot plasmatiche
Trattamento dello stato di
male
Allora
bull Terapia immediata
bull Aggressiva
bull Supporto vitale di base
bull AAirway
bull Breathing
bull CSupporto circolatorio
Status epilepticusfilosofia del trattamento
Disaccoppiamento
CMRO2CBF
Funzione cardiocircolatoriaFunzione resp
Supporto supernormale
Glucosio
Tiamina 100 mg
Dopaminanoradrenalina + fre con barbituricihellip
Indagine conoscitiva su 127 TI NCH europeeDauch WA Schutze M Guttinger M et al Posttraumatic seizure prevention - results of a
survey of 127 neurosurgery clinics Zentralbl Neurochir 1996 57190ndash5
0
10
20
30
40
50
60
profilassi
Profilassi con anticonvulsivi post trauma cranio-
encefalico
mai
sempre
secindicazione
substantial cortical
injurycerebral contusion
acute subdural
hemorrhage
depressed skull fracture
penetrating missile
injury
(141517)
Rischio convulsivo
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001bull Background It is uncertain whether the administration of benzodiazepines by paramedics is an
effective and safe treatment for out-of-hospital status epilepticus
Methods We conducted a randomized double-blind trial to evaluate intravenous benzodiazepines administered by paramedics for the treatment of out-of-hospital status epilepticus Adults with prolonged (lasting five minutes or more) or repetitive generalized convulsive seizures received intravenous diazepam (5 mg) lorazepam (2 mg) or placebo An identical second injection was given if needed
Results Of the 205 patients enrolled 66 received lorazepam 68 received diazepam and 71 received placebo Status epilepticus had been terminated on arrival at the emergency department in more patients treated with lorazepam (591 percent) or diazepam (426 percent) than patients given placebo (211 percent) (P=0001) After adjustment for covariates the odds ratio for termination of status epilepticus by the time of arrival in the lorazepam group as compared with the placebo group was 48 (95 percent confidence interval 19 to 130) The odds ratio was 19 (95 percent confidence interval 08 to 44) in the lorazepam group as compared with the diazepam group and 23 (95 percent confidence interval 10 to 59) in the diazepam group as compared with the placebo group The rates of respiratory or circulatory complications after the study treatment was administered were 106 percent for the lorazepam group 103 percent for the diazepam group and 225 percent for the placebo group (P=008)
Conclusions Benzodiazepines are safe and effective when administered by paramedics for out-of-hospital status epilepticus in adults Lorazepam is likely to be a better therapy than diazepam (N Engl J Med 2001345631-7)
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001
0
10
20
30
40
50
60
seizures stop complications
lorazepam
diazepam
placebo
randomized double-blind trial
to evaluate iv bdz
admin by paramedics
for the treatment of out-of-hospital status epilepticus
Adults with prolonged (lasting 5 minutes or +)
or repetitive generalized convulsive seizures
received iv diazepam (5 mg)
lorazepam (2 mg) or placebo
An identical second injection was given if needed
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
Treiman DM Meyers PD Walton NY Collins JF Colling C Rowan AJ et al A comparison of four treatments for generalized convulsive status epilepticus N Engl J Med 1998 339792-798
randomized double-blind trial that compared the following four regimens commonly used for the treatment of generalized convulsive status epilepticus diazepam followed by phenytoin phenytoin alone phenobarbital and lorazepam Although the doses and infusion rates chosen for study closely reflected common clinical practice at the time the study began the combination of lorazepam followed by phenytoin (the preferred regimen of many neurologists) was not included
This is a large well-controlled and important clinical trial The major limitation in its clinical relevance is the lack of inclusion of a regimen consisting of lorazepam followed by phenytoin
Veterans Affairs Status Epilepticus Cooperative
Study Group Treiman et al
SE aperto
diaz fenitoina fenobarbital lorazepam
2 o + convuls senza
ripresa di coscienza
Convuls continue = gt 10 min
fenitoina
Coma con scariche
ictali EEG
primary outcome measure
cessation of clinical and electrical
seizure activity
within 20min after initiation
of treatment and continuing for at least
60min after the start of treatment
lorazepam fenitoina
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
bull st treatment successful in 555 of patients with a verified diagnosis of overt status epilepticus (n=384) and in 149 of patients with subtle status epilepticus (n=134)
bull Comparisons between the 4 treatments showed that lorazepam was more effective than phenytoin alone in patients with overt status epilepticus (treatment success in 649 versus 436 of patients respectively)
bull other treatment comparisons in the overt group and all comparisons in the subtle group were not significantly different however
bull There were no significant differences between treatments in patient outcome rates of recurrence of status epilepticus or return of full consciousness over the 12-h observation period or in the frequency of adverse cardiac respiratory or hypotensive events
Treiman DM Meyers PD Walton NY et al A
comparison of four treatments for generalized
convulsive status epilepticus N Engl J Med 1998
339792-798
P 002
Percentage of successful treatment
grey bars overt patients black bars subtle patients
Alldredge Brian Kab Lowenstein Daniel HAC Status
epilepticus new concepts Current Opinion in Neurology
121999 183-190
Da ChapmanAnaesthesia 2004
Marik PEVaron J The Management of Status
Epilepticus Chest 126(2)582-591 August 2004
Status epilepticus is a major medical emergency associated with significant morbidity and mortality Status epilepticusis best defined as a continuous generalized convulsive seizure lasting gt 5 min or two or more seizures during which the patient does not return to baseline consciousness Lorazepam in a dose of 01 mgkg is the drug of first choice for terminating status epilepticus Patients who continue to have clinical or EEG evidence of seizure activity after treatment with lorazepam should be considered to have refractory status epileptics and should be treated with a continuous infusion of propofol or midazolam This article reviews current information regarding the management of status epilepticus in adults
Schema di Marik et al
Claassen JHirsch LJ Emerson R GBates
JE Thompson TBMayer SA Continuous EEG
monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042 bull The authors reviewed 33 episodes of RSE treated with cIV-MDZ in their neurologic intensive care
unit over 6 years All patients were monitored with continuous EEG (cEEG) MDZ infusion rates were titrated to eliminate clinical and EEG seizure activity cIV-MDZ was discontinued once patients were seizure-free for 24 hours Acute treatment failures (seizures 1 to 6 hours after starting cIV-MDZ) breakthrough seizures (after 6 hours of therapy) post-treatment seizures (within 48 hours of discontinuing therapy) and ultimate treatment failure (frequent seizures that led to treatment with pentobarbital or propofol) were identified
bull Results All patients were in nonconvulsive SE at the time cIV-MDZ was started the mean duration of SE before treatment was 39 days (range 0 to 17 days) In addition to benzodiazepines 94 of patients had received at least two antiepileptic drugs (AED) before starting cIV-MDZ The mean loading dose was 019 mgkg the mean maximal infusion rate was 022 mgkgh and the mean duration of cIV-MDZ therapy was 42 days (range 1 to 14 days) Acute treatment failure occurred in 18 (633) of episodes breakthrough seizures in 56 (1832) post-treatment seizures in 68 (1928) and ultimate treatment failure in 18 (633) Breakthrough seizures were clinically subtle or purely electrographic in 89 (1618) of cases and were associated with an increased risk of developing post-treatment seizures (p = 001)
bull Conclusions Although most patients with RSE initially responded to cIV-MDZ over half developed subsequent breakthrough seizures which were predictive of post-treatment seizures and were often detectable only with cEEG Titrating cIV-MDZ to burst suppression more aggressive treatment with concurrent AED or a longer period of initial treatment may reduce the high proportion of patients with RSE who relapse after cIV-MDZ is discontinued
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus Neurology 2001 57 25 1036-1042
0
10
20
30
40
50
60
70
80
non seizures
seizures lt30 min24h05-12 h
seizures 05-12 h24 hgt 12 h
seiz gt12 h24
burst suppression
periodic latdischarge
periodic gen discharge
prima
durante
dopo
33 episodes of RSE treated with cIV-MDZ neurologic ICU over 6 years
All patients were monitored with continuous EEG (cEEG)
Waterhouse Elizabeth J 1 2 DeLorenzo Robert J 1 3 4 2
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
bull Status epilepticus (SE) is a medical and neurological emergency that has been associated with significant morbidity and mortality The most widely accepted definition of SE is more than 30 minutes of either continuous seizure activity or intermittent seizures without full recovery of consciousness between seizures SE is a major clinical concern in the elderly population both because it has increased incidence in the elderly compared with the general population and because of concurrent medical conditions that are more likely to complicate therapy and worsen prognosis in elderly individuals
The incidence of SE in the elderly is almost twice that of the general population at 86 per 100 000 per year With the anticipated growth of the elderly population SE is likely to become an increasingly common problem facing clinicians and an important public health issue The elderly have the highest SE-associated mortality of any age group at 38 and the very old elderly (gt80 years of age) have a mortality of at least 50 Acute or remote stroke is the most common aetiology of SE in the elderly Nonconvulsive SE (NCSE) has a wide range of clinical presentations ranging from confusion to obtundation It occurs commonly in elderly patients who are critically ill and in the setting of coma Electroencephalogram is the only reliable method of diagnosing NCSE
The goal of treatment for SE is rapid cessation of clinical and electrical seizure activity Most treatment protocols call for the immediate administration of an intravenous benzodiazepine followed by phenytoin or fosphenytoin Recent studies suggest that when this initial treatment of SE fails little is gained by using additional standard drugs General anaesthetic agents (such as pentobarbital midazolam or propofol) should be expeditiously employed although these treatments have their own potential complications Intravenous valproic acid is a recent addition to the armamentarium of drugs for the treatment of SE with a low risk of hypotension respiratory depression and hypotension making it a potentially useful drug for the treatment of SE in the elderly However further information is needed to establish its role in the overall treatment of SE
Waterhouseet al
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
BDZ
Fenitoina
O fosfenitoina
GA
Midaz
Propof
pentobarb
Ac valproico
Ns proposta
Lorazepam
01 mgkg
Propofol
1-2 mgkgMidazolam01 mgkg
Inf cont 3-10 mgkgh Inf cont 001-005 mgkgh
Miorilassante solo
Per intubazione
Pentobarbital dose caricopoi 01-04 mgkgmin
fenobarbital
bull 10-20 mgkg iv
ndash Eccessiva sedazione
ndash Depressresp
ndash Ipotensione
ndash Interaz farmacol
ndash Hl gt48 hrhelliphelliphellip
tiopental
bull cumulativo
bull Inotropo neghellip
bull Pentobarbital
bull immunosoppressione
propofol
bull Vantaggi cineticodinamici
bull Titolazione continua possibile
bull TCIquale livello
bull Dosi 1 mgkgripetibile dopo 5rsquo-
ndash Infcont 2-10 mgkgh
bull Rapida emergenzafinestra neurologicaevitare la
brusca sospensione
bull + rapido controllo delle convuls gt barbituricindash Stecker MM Kramer TH Raps EC OMeeghan R Dulaney E Skaar DJ Treatment of
refractory status epilepticus with propofol clinical and pharmacokinetic findings Epilepsia 1998
39 18-26
AG
bull Non ci sono dati che indichino quanto a lungo i paz debbano rimanere senza convuls prima di poter alleggerire il piano di AG24 h96h (Treiman DM Convulsive status
epilepticus Current Treatment Options in Neurology 1999 1 359-69)
bull Anest alogenatiisofluranogtsevofluranogtdesflurane
bull Ma vaporizzatori
bull Contaminazione ambientale
bull Costihellip
Studi comparativi1
bull Midazolamgt tiopental
ndash Lohr A Jr Werneck LC Comparative non-randomized study with
midazolam versus thiopental in children with refractory status
epilepticus [Portuguese] Arq Neuropsiquiatr 2000 58282-287
ndash non-randomized comparison
ndash of historical data (thiopental) and prospectively
acquired data (midazolam)
ndash Midazolam was no more often effective than
thiopental but was associated with less cyanosis and
less respiratory distress in this study of 50 children
Studi comparativi2
Valproatobull Valproate(ivrdquoDepaconrdquo) has been used for the treatment of refractory SE
in children and myoclonic SE ndash Sheth RD Gidal BE Intravenous valproic acid for myoclonic status epilepticus
Neurology 2000 541201
ndash Uberall MA Trollmann R Wunsiedler U Wenzel D Intravenous valproate in pediatric epilepsy patients with refractory status epilepticus Neurology 2000 542188-2189 ]
bull Valproate has also been used in SE in the elderly and appears to be safe even in the presence of cardiovascular instability and hypotension no significant change in blood pressure pulse or the need for vasopressors in 13 patients with SE and hypotension given a loading dose of 147-327 mgkg Depacon intravenouslyndash Sinha S Naritoku DK Intravenous valproate is well tolerated in unstable patients
with status epilepticus Neurology 2000 55722-724
bull However there is a case report of severe hypotension in an 11-year-old child after treatment of SE with 30 mgkg intravenous valproate ndash White JR Santos CS Intravenous valproate associated with significant
hypotension in the treatment of status epilepticus J Child Neurol 1999 14822-823
FINE
Percheacute non ne possiamo
piugravehelliphelliphellip
Neuroprotective effects of acidosis
bull some studies that suggest that hypoxia acidosis and hypoglycaemia may be neuroprotective [2829] To
study these phenomena further Sasahira and coworkers [30bull31bull] looked at a rat model of status epilepticus based upon repeated bicuculline injections and using heat shock protein as an indirect measure of neuronal injury Using high concentrations of inhaled carbon dioxide they were able to reduce the serum pH from 755 to 717 This resulted in a shorter seizure duration and less neuronal damage [30bull] Using multiple regression analysis they were able to show a neuroprotective effect of shortening seizure duration and an independent effect of acidosis [30bull] Acidosis and raised carbon dioxide tensions have a profound effect on cerebral blood flow and whether the neuroprotective effect is due to haemodynamic effects or to the effect of acidoisis on receptors or transmitter release is unknown
bull A further study from the same group [31bull] looked at the effects of moderate hypoxia (PaO2=50 mmHg) on neuronal damage in the same model compared with normoxic controls There was no difference in neuronal injury detected suggesting that moderate hypoxia has no effect on neuronal death in status epilepticus The authors rightly conclude however that the implications of their findings for the treatment of status epilepticus are unclear as more severe hypoxia could result in additional ischaemic injury to the brain
bull 28 Blennow G Brierley JB Meldrum BS Siesjouml BK Epileptic brain damage The role of sysemic factors that modify cerebral energy metabolism Brain 1978101687-700 Bibliographic Links [Context Link]
bull 29 Meldrum BS Brierley JB Prolonged epileptic seizures in primates Ischaemic cell change and its relation to ictal physiological events Arch Neurol 19732810-17 Bibliographic Links [Context Link]
bull 30 bull Sasahira M Lowry T Simon RP Neuronal injury in experimental status epilepticus in the rat role of acidosis Neurosci Lett 1997224177-180 Bibliographic Links See [31bull] [Context Link]
bull 31 bull Sasahira M Simon RP Greenberg DA Neuronal injury in experimental status epilepticus in the rat role of hypoxia Neurosci Lett 1997222207-209 Bibliographic Links Thie paper and [30bull] are excellent reports considering the influence of physiological parameters on neuronal damage induced by status epilepticus [Context Link]
Effetti collaterali della fenitoina ev
bull Lesioni dei tessuti mollicon o senza
stravasordquoPurple Handgt 40 casi con parecchie
amputazioni ( (Kilarski 1984 Rao et al 1988
Hanna 1992)
bull Problemi al sito di iniezione Earnest et al (1983)
30 su 200
bull Ipotensione in gt 25 dei pazcon aritmie
ndash In 3139 pazienti 1 FA (velocitagrave di infus 26 mgmin) 1
tachic sinusale 1 allungamento tratto PR
ndash (Gellerman and Martinex 1967 Goldschlager and
Karliner 1967 Louis et al 1967 Voigt 1968)
bull
Allen FH Runge JW Legarda S et al Multicenter open-label
study on safety tolerance and pharmacokinetics of
intravenous fosphenytoin (Cerebyx) in status epilepticus
[abstract] Epilepsia 199435(Suppl 18)93
bull Data have been published from 40 patients in status epilepticus who received fosphenytoin at a mean infusion rate of 92 mgmin ranging from 247 to 1113 mgmin) Status epilepticus was terminated in 37 of 40 patients (85) within 30 min of receiving fosphenytoin The rapid infusion was well tolerated with only mild or transient side effects Most of the side effects reported were attributable to the pharmacologic effect of phenytoin and included dizziness nystagmus and ataxia Most patients in this trial received a benzodiazepine before the infusion of fosphenytoin and no adverse drug interactions were found
Introduzione alla peculiaritagrave
dellrsquoambiente intensivistico
Convulsioni in ambiente intensivo
bull Sepsi
bull Cause mediche
bull Anormalitagrave metaboliche(30-35) (11)ndash Iponatremiaipocalcemiaipofosfatemiaipoglicemiauremia
ndash Alterazioni della osmolaritagrave specie correzione acuta bull Acute return from hyperosmolarity back to normal levels in a rat
neocortical slice preparation by lowering the D-glucose concentration increased the amplitude of evoked early and late excitatory postsynaptic potentials a situation reminiscent of the generalized convulsions that may follow acute reduction of glucose in diabetic nonketotic hyperglycemia (42)
ndash Ipoosmolaritagrave induce increased nervous system excitability by strengthening both excitatory synaptic communications in neocortex and field effects among the entire cortical population (41)
Problemi peculiari allrsquoambiente
intensivistico
bull Polifarmacologia
bull Insuff renale
bull Insuff epatica
bull Induzione enzimatica
bull Inibizione enzimatica
bull Ipodisprotidemiehellipfarmaci altamente
legati alle prot plasmatiche
Trattamento dello stato di
male
Allora
bull Terapia immediata
bull Aggressiva
bull Supporto vitale di base
bull AAirway
bull Breathing
bull CSupporto circolatorio
Status epilepticusfilosofia del trattamento
Disaccoppiamento
CMRO2CBF
Funzione cardiocircolatoriaFunzione resp
Supporto supernormale
Glucosio
Tiamina 100 mg
Dopaminanoradrenalina + fre con barbituricihellip
Indagine conoscitiva su 127 TI NCH europeeDauch WA Schutze M Guttinger M et al Posttraumatic seizure prevention - results of a
survey of 127 neurosurgery clinics Zentralbl Neurochir 1996 57190ndash5
0
10
20
30
40
50
60
profilassi
Profilassi con anticonvulsivi post trauma cranio-
encefalico
mai
sempre
secindicazione
substantial cortical
injurycerebral contusion
acute subdural
hemorrhage
depressed skull fracture
penetrating missile
injury
(141517)
Rischio convulsivo
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001bull Background It is uncertain whether the administration of benzodiazepines by paramedics is an
effective and safe treatment for out-of-hospital status epilepticus
Methods We conducted a randomized double-blind trial to evaluate intravenous benzodiazepines administered by paramedics for the treatment of out-of-hospital status epilepticus Adults with prolonged (lasting five minutes or more) or repetitive generalized convulsive seizures received intravenous diazepam (5 mg) lorazepam (2 mg) or placebo An identical second injection was given if needed
Results Of the 205 patients enrolled 66 received lorazepam 68 received diazepam and 71 received placebo Status epilepticus had been terminated on arrival at the emergency department in more patients treated with lorazepam (591 percent) or diazepam (426 percent) than patients given placebo (211 percent) (P=0001) After adjustment for covariates the odds ratio for termination of status epilepticus by the time of arrival in the lorazepam group as compared with the placebo group was 48 (95 percent confidence interval 19 to 130) The odds ratio was 19 (95 percent confidence interval 08 to 44) in the lorazepam group as compared with the diazepam group and 23 (95 percent confidence interval 10 to 59) in the diazepam group as compared with the placebo group The rates of respiratory or circulatory complications after the study treatment was administered were 106 percent for the lorazepam group 103 percent for the diazepam group and 225 percent for the placebo group (P=008)
Conclusions Benzodiazepines are safe and effective when administered by paramedics for out-of-hospital status epilepticus in adults Lorazepam is likely to be a better therapy than diazepam (N Engl J Med 2001345631-7)
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001
0
10
20
30
40
50
60
seizures stop complications
lorazepam
diazepam
placebo
randomized double-blind trial
to evaluate iv bdz
admin by paramedics
for the treatment of out-of-hospital status epilepticus
Adults with prolonged (lasting 5 minutes or +)
or repetitive generalized convulsive seizures
received iv diazepam (5 mg)
lorazepam (2 mg) or placebo
An identical second injection was given if needed
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
Treiman DM Meyers PD Walton NY Collins JF Colling C Rowan AJ et al A comparison of four treatments for generalized convulsive status epilepticus N Engl J Med 1998 339792-798
randomized double-blind trial that compared the following four regimens commonly used for the treatment of generalized convulsive status epilepticus diazepam followed by phenytoin phenytoin alone phenobarbital and lorazepam Although the doses and infusion rates chosen for study closely reflected common clinical practice at the time the study began the combination of lorazepam followed by phenytoin (the preferred regimen of many neurologists) was not included
This is a large well-controlled and important clinical trial The major limitation in its clinical relevance is the lack of inclusion of a regimen consisting of lorazepam followed by phenytoin
Veterans Affairs Status Epilepticus Cooperative
Study Group Treiman et al
SE aperto
diaz fenitoina fenobarbital lorazepam
2 o + convuls senza
ripresa di coscienza
Convuls continue = gt 10 min
fenitoina
Coma con scariche
ictali EEG
primary outcome measure
cessation of clinical and electrical
seizure activity
within 20min after initiation
of treatment and continuing for at least
60min after the start of treatment
lorazepam fenitoina
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
bull st treatment successful in 555 of patients with a verified diagnosis of overt status epilepticus (n=384) and in 149 of patients with subtle status epilepticus (n=134)
bull Comparisons between the 4 treatments showed that lorazepam was more effective than phenytoin alone in patients with overt status epilepticus (treatment success in 649 versus 436 of patients respectively)
bull other treatment comparisons in the overt group and all comparisons in the subtle group were not significantly different however
bull There were no significant differences between treatments in patient outcome rates of recurrence of status epilepticus or return of full consciousness over the 12-h observation period or in the frequency of adverse cardiac respiratory or hypotensive events
Treiman DM Meyers PD Walton NY et al A
comparison of four treatments for generalized
convulsive status epilepticus N Engl J Med 1998
339792-798
P 002
Percentage of successful treatment
grey bars overt patients black bars subtle patients
Alldredge Brian Kab Lowenstein Daniel HAC Status
epilepticus new concepts Current Opinion in Neurology
121999 183-190
Da ChapmanAnaesthesia 2004
Marik PEVaron J The Management of Status
Epilepticus Chest 126(2)582-591 August 2004
Status epilepticus is a major medical emergency associated with significant morbidity and mortality Status epilepticusis best defined as a continuous generalized convulsive seizure lasting gt 5 min or two or more seizures during which the patient does not return to baseline consciousness Lorazepam in a dose of 01 mgkg is the drug of first choice for terminating status epilepticus Patients who continue to have clinical or EEG evidence of seizure activity after treatment with lorazepam should be considered to have refractory status epileptics and should be treated with a continuous infusion of propofol or midazolam This article reviews current information regarding the management of status epilepticus in adults
Schema di Marik et al
Claassen JHirsch LJ Emerson R GBates
JE Thompson TBMayer SA Continuous EEG
monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042 bull The authors reviewed 33 episodes of RSE treated with cIV-MDZ in their neurologic intensive care
unit over 6 years All patients were monitored with continuous EEG (cEEG) MDZ infusion rates were titrated to eliminate clinical and EEG seizure activity cIV-MDZ was discontinued once patients were seizure-free for 24 hours Acute treatment failures (seizures 1 to 6 hours after starting cIV-MDZ) breakthrough seizures (after 6 hours of therapy) post-treatment seizures (within 48 hours of discontinuing therapy) and ultimate treatment failure (frequent seizures that led to treatment with pentobarbital or propofol) were identified
bull Results All patients were in nonconvulsive SE at the time cIV-MDZ was started the mean duration of SE before treatment was 39 days (range 0 to 17 days) In addition to benzodiazepines 94 of patients had received at least two antiepileptic drugs (AED) before starting cIV-MDZ The mean loading dose was 019 mgkg the mean maximal infusion rate was 022 mgkgh and the mean duration of cIV-MDZ therapy was 42 days (range 1 to 14 days) Acute treatment failure occurred in 18 (633) of episodes breakthrough seizures in 56 (1832) post-treatment seizures in 68 (1928) and ultimate treatment failure in 18 (633) Breakthrough seizures were clinically subtle or purely electrographic in 89 (1618) of cases and were associated with an increased risk of developing post-treatment seizures (p = 001)
bull Conclusions Although most patients with RSE initially responded to cIV-MDZ over half developed subsequent breakthrough seizures which were predictive of post-treatment seizures and were often detectable only with cEEG Titrating cIV-MDZ to burst suppression more aggressive treatment with concurrent AED or a longer period of initial treatment may reduce the high proportion of patients with RSE who relapse after cIV-MDZ is discontinued
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus Neurology 2001 57 25 1036-1042
0
10
20
30
40
50
60
70
80
non seizures
seizures lt30 min24h05-12 h
seizures 05-12 h24 hgt 12 h
seiz gt12 h24
burst suppression
periodic latdischarge
periodic gen discharge
prima
durante
dopo
33 episodes of RSE treated with cIV-MDZ neurologic ICU over 6 years
All patients were monitored with continuous EEG (cEEG)
Waterhouse Elizabeth J 1 2 DeLorenzo Robert J 1 3 4 2
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
bull Status epilepticus (SE) is a medical and neurological emergency that has been associated with significant morbidity and mortality The most widely accepted definition of SE is more than 30 minutes of either continuous seizure activity or intermittent seizures without full recovery of consciousness between seizures SE is a major clinical concern in the elderly population both because it has increased incidence in the elderly compared with the general population and because of concurrent medical conditions that are more likely to complicate therapy and worsen prognosis in elderly individuals
The incidence of SE in the elderly is almost twice that of the general population at 86 per 100 000 per year With the anticipated growth of the elderly population SE is likely to become an increasingly common problem facing clinicians and an important public health issue The elderly have the highest SE-associated mortality of any age group at 38 and the very old elderly (gt80 years of age) have a mortality of at least 50 Acute or remote stroke is the most common aetiology of SE in the elderly Nonconvulsive SE (NCSE) has a wide range of clinical presentations ranging from confusion to obtundation It occurs commonly in elderly patients who are critically ill and in the setting of coma Electroencephalogram is the only reliable method of diagnosing NCSE
The goal of treatment for SE is rapid cessation of clinical and electrical seizure activity Most treatment protocols call for the immediate administration of an intravenous benzodiazepine followed by phenytoin or fosphenytoin Recent studies suggest that when this initial treatment of SE fails little is gained by using additional standard drugs General anaesthetic agents (such as pentobarbital midazolam or propofol) should be expeditiously employed although these treatments have their own potential complications Intravenous valproic acid is a recent addition to the armamentarium of drugs for the treatment of SE with a low risk of hypotension respiratory depression and hypotension making it a potentially useful drug for the treatment of SE in the elderly However further information is needed to establish its role in the overall treatment of SE
Waterhouseet al
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
BDZ
Fenitoina
O fosfenitoina
GA
Midaz
Propof
pentobarb
Ac valproico
Ns proposta
Lorazepam
01 mgkg
Propofol
1-2 mgkgMidazolam01 mgkg
Inf cont 3-10 mgkgh Inf cont 001-005 mgkgh
Miorilassante solo
Per intubazione
Pentobarbital dose caricopoi 01-04 mgkgmin
fenobarbital
bull 10-20 mgkg iv
ndash Eccessiva sedazione
ndash Depressresp
ndash Ipotensione
ndash Interaz farmacol
ndash Hl gt48 hrhelliphelliphellip
tiopental
bull cumulativo
bull Inotropo neghellip
bull Pentobarbital
bull immunosoppressione
propofol
bull Vantaggi cineticodinamici
bull Titolazione continua possibile
bull TCIquale livello
bull Dosi 1 mgkgripetibile dopo 5rsquo-
ndash Infcont 2-10 mgkgh
bull Rapida emergenzafinestra neurologicaevitare la
brusca sospensione
bull + rapido controllo delle convuls gt barbituricindash Stecker MM Kramer TH Raps EC OMeeghan R Dulaney E Skaar DJ Treatment of
refractory status epilepticus with propofol clinical and pharmacokinetic findings Epilepsia 1998
39 18-26
AG
bull Non ci sono dati che indichino quanto a lungo i paz debbano rimanere senza convuls prima di poter alleggerire il piano di AG24 h96h (Treiman DM Convulsive status
epilepticus Current Treatment Options in Neurology 1999 1 359-69)
bull Anest alogenatiisofluranogtsevofluranogtdesflurane
bull Ma vaporizzatori
bull Contaminazione ambientale
bull Costihellip
Studi comparativi1
bull Midazolamgt tiopental
ndash Lohr A Jr Werneck LC Comparative non-randomized study with
midazolam versus thiopental in children with refractory status
epilepticus [Portuguese] Arq Neuropsiquiatr 2000 58282-287
ndash non-randomized comparison
ndash of historical data (thiopental) and prospectively
acquired data (midazolam)
ndash Midazolam was no more often effective than
thiopental but was associated with less cyanosis and
less respiratory distress in this study of 50 children
Studi comparativi2
Valproatobull Valproate(ivrdquoDepaconrdquo) has been used for the treatment of refractory SE
in children and myoclonic SE ndash Sheth RD Gidal BE Intravenous valproic acid for myoclonic status epilepticus
Neurology 2000 541201
ndash Uberall MA Trollmann R Wunsiedler U Wenzel D Intravenous valproate in pediatric epilepsy patients with refractory status epilepticus Neurology 2000 542188-2189 ]
bull Valproate has also been used in SE in the elderly and appears to be safe even in the presence of cardiovascular instability and hypotension no significant change in blood pressure pulse or the need for vasopressors in 13 patients with SE and hypotension given a loading dose of 147-327 mgkg Depacon intravenouslyndash Sinha S Naritoku DK Intravenous valproate is well tolerated in unstable patients
with status epilepticus Neurology 2000 55722-724
bull However there is a case report of severe hypotension in an 11-year-old child after treatment of SE with 30 mgkg intravenous valproate ndash White JR Santos CS Intravenous valproate associated with significant
hypotension in the treatment of status epilepticus J Child Neurol 1999 14822-823
FINE
Percheacute non ne possiamo
piugravehelliphelliphellip
Effetti collaterali della fenitoina ev
bull Lesioni dei tessuti mollicon o senza
stravasordquoPurple Handgt 40 casi con parecchie
amputazioni ( (Kilarski 1984 Rao et al 1988
Hanna 1992)
bull Problemi al sito di iniezione Earnest et al (1983)
30 su 200
bull Ipotensione in gt 25 dei pazcon aritmie
ndash In 3139 pazienti 1 FA (velocitagrave di infus 26 mgmin) 1
tachic sinusale 1 allungamento tratto PR
ndash (Gellerman and Martinex 1967 Goldschlager and
Karliner 1967 Louis et al 1967 Voigt 1968)
bull
Allen FH Runge JW Legarda S et al Multicenter open-label
study on safety tolerance and pharmacokinetics of
intravenous fosphenytoin (Cerebyx) in status epilepticus
[abstract] Epilepsia 199435(Suppl 18)93
bull Data have been published from 40 patients in status epilepticus who received fosphenytoin at a mean infusion rate of 92 mgmin ranging from 247 to 1113 mgmin) Status epilepticus was terminated in 37 of 40 patients (85) within 30 min of receiving fosphenytoin The rapid infusion was well tolerated with only mild or transient side effects Most of the side effects reported were attributable to the pharmacologic effect of phenytoin and included dizziness nystagmus and ataxia Most patients in this trial received a benzodiazepine before the infusion of fosphenytoin and no adverse drug interactions were found
Introduzione alla peculiaritagrave
dellrsquoambiente intensivistico
Convulsioni in ambiente intensivo
bull Sepsi
bull Cause mediche
bull Anormalitagrave metaboliche(30-35) (11)ndash Iponatremiaipocalcemiaipofosfatemiaipoglicemiauremia
ndash Alterazioni della osmolaritagrave specie correzione acuta bull Acute return from hyperosmolarity back to normal levels in a rat
neocortical slice preparation by lowering the D-glucose concentration increased the amplitude of evoked early and late excitatory postsynaptic potentials a situation reminiscent of the generalized convulsions that may follow acute reduction of glucose in diabetic nonketotic hyperglycemia (42)
ndash Ipoosmolaritagrave induce increased nervous system excitability by strengthening both excitatory synaptic communications in neocortex and field effects among the entire cortical population (41)
Problemi peculiari allrsquoambiente
intensivistico
bull Polifarmacologia
bull Insuff renale
bull Insuff epatica
bull Induzione enzimatica
bull Inibizione enzimatica
bull Ipodisprotidemiehellipfarmaci altamente
legati alle prot plasmatiche
Trattamento dello stato di
male
Allora
bull Terapia immediata
bull Aggressiva
bull Supporto vitale di base
bull AAirway
bull Breathing
bull CSupporto circolatorio
Status epilepticusfilosofia del trattamento
Disaccoppiamento
CMRO2CBF
Funzione cardiocircolatoriaFunzione resp
Supporto supernormale
Glucosio
Tiamina 100 mg
Dopaminanoradrenalina + fre con barbituricihellip
Indagine conoscitiva su 127 TI NCH europeeDauch WA Schutze M Guttinger M et al Posttraumatic seizure prevention - results of a
survey of 127 neurosurgery clinics Zentralbl Neurochir 1996 57190ndash5
0
10
20
30
40
50
60
profilassi
Profilassi con anticonvulsivi post trauma cranio-
encefalico
mai
sempre
secindicazione
substantial cortical
injurycerebral contusion
acute subdural
hemorrhage
depressed skull fracture
penetrating missile
injury
(141517)
Rischio convulsivo
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001bull Background It is uncertain whether the administration of benzodiazepines by paramedics is an
effective and safe treatment for out-of-hospital status epilepticus
Methods We conducted a randomized double-blind trial to evaluate intravenous benzodiazepines administered by paramedics for the treatment of out-of-hospital status epilepticus Adults with prolonged (lasting five minutes or more) or repetitive generalized convulsive seizures received intravenous diazepam (5 mg) lorazepam (2 mg) or placebo An identical second injection was given if needed
Results Of the 205 patients enrolled 66 received lorazepam 68 received diazepam and 71 received placebo Status epilepticus had been terminated on arrival at the emergency department in more patients treated with lorazepam (591 percent) or diazepam (426 percent) than patients given placebo (211 percent) (P=0001) After adjustment for covariates the odds ratio for termination of status epilepticus by the time of arrival in the lorazepam group as compared with the placebo group was 48 (95 percent confidence interval 19 to 130) The odds ratio was 19 (95 percent confidence interval 08 to 44) in the lorazepam group as compared with the diazepam group and 23 (95 percent confidence interval 10 to 59) in the diazepam group as compared with the placebo group The rates of respiratory or circulatory complications after the study treatment was administered were 106 percent for the lorazepam group 103 percent for the diazepam group and 225 percent for the placebo group (P=008)
Conclusions Benzodiazepines are safe and effective when administered by paramedics for out-of-hospital status epilepticus in adults Lorazepam is likely to be a better therapy than diazepam (N Engl J Med 2001345631-7)
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001
0
10
20
30
40
50
60
seizures stop complications
lorazepam
diazepam
placebo
randomized double-blind trial
to evaluate iv bdz
admin by paramedics
for the treatment of out-of-hospital status epilepticus
Adults with prolonged (lasting 5 minutes or +)
or repetitive generalized convulsive seizures
received iv diazepam (5 mg)
lorazepam (2 mg) or placebo
An identical second injection was given if needed
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
Treiman DM Meyers PD Walton NY Collins JF Colling C Rowan AJ et al A comparison of four treatments for generalized convulsive status epilepticus N Engl J Med 1998 339792-798
randomized double-blind trial that compared the following four regimens commonly used for the treatment of generalized convulsive status epilepticus diazepam followed by phenytoin phenytoin alone phenobarbital and lorazepam Although the doses and infusion rates chosen for study closely reflected common clinical practice at the time the study began the combination of lorazepam followed by phenytoin (the preferred regimen of many neurologists) was not included
This is a large well-controlled and important clinical trial The major limitation in its clinical relevance is the lack of inclusion of a regimen consisting of lorazepam followed by phenytoin
Veterans Affairs Status Epilepticus Cooperative
Study Group Treiman et al
SE aperto
diaz fenitoina fenobarbital lorazepam
2 o + convuls senza
ripresa di coscienza
Convuls continue = gt 10 min
fenitoina
Coma con scariche
ictali EEG
primary outcome measure
cessation of clinical and electrical
seizure activity
within 20min after initiation
of treatment and continuing for at least
60min after the start of treatment
lorazepam fenitoina
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
bull st treatment successful in 555 of patients with a verified diagnosis of overt status epilepticus (n=384) and in 149 of patients with subtle status epilepticus (n=134)
bull Comparisons between the 4 treatments showed that lorazepam was more effective than phenytoin alone in patients with overt status epilepticus (treatment success in 649 versus 436 of patients respectively)
bull other treatment comparisons in the overt group and all comparisons in the subtle group were not significantly different however
bull There were no significant differences between treatments in patient outcome rates of recurrence of status epilepticus or return of full consciousness over the 12-h observation period or in the frequency of adverse cardiac respiratory or hypotensive events
Treiman DM Meyers PD Walton NY et al A
comparison of four treatments for generalized
convulsive status epilepticus N Engl J Med 1998
339792-798
P 002
Percentage of successful treatment
grey bars overt patients black bars subtle patients
Alldredge Brian Kab Lowenstein Daniel HAC Status
epilepticus new concepts Current Opinion in Neurology
121999 183-190
Da ChapmanAnaesthesia 2004
Marik PEVaron J The Management of Status
Epilepticus Chest 126(2)582-591 August 2004
Status epilepticus is a major medical emergency associated with significant morbidity and mortality Status epilepticusis best defined as a continuous generalized convulsive seizure lasting gt 5 min or two or more seizures during which the patient does not return to baseline consciousness Lorazepam in a dose of 01 mgkg is the drug of first choice for terminating status epilepticus Patients who continue to have clinical or EEG evidence of seizure activity after treatment with lorazepam should be considered to have refractory status epileptics and should be treated with a continuous infusion of propofol or midazolam This article reviews current information regarding the management of status epilepticus in adults
Schema di Marik et al
Claassen JHirsch LJ Emerson R GBates
JE Thompson TBMayer SA Continuous EEG
monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042 bull The authors reviewed 33 episodes of RSE treated with cIV-MDZ in their neurologic intensive care
unit over 6 years All patients were monitored with continuous EEG (cEEG) MDZ infusion rates were titrated to eliminate clinical and EEG seizure activity cIV-MDZ was discontinued once patients were seizure-free for 24 hours Acute treatment failures (seizures 1 to 6 hours after starting cIV-MDZ) breakthrough seizures (after 6 hours of therapy) post-treatment seizures (within 48 hours of discontinuing therapy) and ultimate treatment failure (frequent seizures that led to treatment with pentobarbital or propofol) were identified
bull Results All patients were in nonconvulsive SE at the time cIV-MDZ was started the mean duration of SE before treatment was 39 days (range 0 to 17 days) In addition to benzodiazepines 94 of patients had received at least two antiepileptic drugs (AED) before starting cIV-MDZ The mean loading dose was 019 mgkg the mean maximal infusion rate was 022 mgkgh and the mean duration of cIV-MDZ therapy was 42 days (range 1 to 14 days) Acute treatment failure occurred in 18 (633) of episodes breakthrough seizures in 56 (1832) post-treatment seizures in 68 (1928) and ultimate treatment failure in 18 (633) Breakthrough seizures were clinically subtle or purely electrographic in 89 (1618) of cases and were associated with an increased risk of developing post-treatment seizures (p = 001)
bull Conclusions Although most patients with RSE initially responded to cIV-MDZ over half developed subsequent breakthrough seizures which were predictive of post-treatment seizures and were often detectable only with cEEG Titrating cIV-MDZ to burst suppression more aggressive treatment with concurrent AED or a longer period of initial treatment may reduce the high proportion of patients with RSE who relapse after cIV-MDZ is discontinued
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus Neurology 2001 57 25 1036-1042
0
10
20
30
40
50
60
70
80
non seizures
seizures lt30 min24h05-12 h
seizures 05-12 h24 hgt 12 h
seiz gt12 h24
burst suppression
periodic latdischarge
periodic gen discharge
prima
durante
dopo
33 episodes of RSE treated with cIV-MDZ neurologic ICU over 6 years
All patients were monitored with continuous EEG (cEEG)
Waterhouse Elizabeth J 1 2 DeLorenzo Robert J 1 3 4 2
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
bull Status epilepticus (SE) is a medical and neurological emergency that has been associated with significant morbidity and mortality The most widely accepted definition of SE is more than 30 minutes of either continuous seizure activity or intermittent seizures without full recovery of consciousness between seizures SE is a major clinical concern in the elderly population both because it has increased incidence in the elderly compared with the general population and because of concurrent medical conditions that are more likely to complicate therapy and worsen prognosis in elderly individuals
The incidence of SE in the elderly is almost twice that of the general population at 86 per 100 000 per year With the anticipated growth of the elderly population SE is likely to become an increasingly common problem facing clinicians and an important public health issue The elderly have the highest SE-associated mortality of any age group at 38 and the very old elderly (gt80 years of age) have a mortality of at least 50 Acute or remote stroke is the most common aetiology of SE in the elderly Nonconvulsive SE (NCSE) has a wide range of clinical presentations ranging from confusion to obtundation It occurs commonly in elderly patients who are critically ill and in the setting of coma Electroencephalogram is the only reliable method of diagnosing NCSE
The goal of treatment for SE is rapid cessation of clinical and electrical seizure activity Most treatment protocols call for the immediate administration of an intravenous benzodiazepine followed by phenytoin or fosphenytoin Recent studies suggest that when this initial treatment of SE fails little is gained by using additional standard drugs General anaesthetic agents (such as pentobarbital midazolam or propofol) should be expeditiously employed although these treatments have their own potential complications Intravenous valproic acid is a recent addition to the armamentarium of drugs for the treatment of SE with a low risk of hypotension respiratory depression and hypotension making it a potentially useful drug for the treatment of SE in the elderly However further information is needed to establish its role in the overall treatment of SE
Waterhouseet al
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
BDZ
Fenitoina
O fosfenitoina
GA
Midaz
Propof
pentobarb
Ac valproico
Ns proposta
Lorazepam
01 mgkg
Propofol
1-2 mgkgMidazolam01 mgkg
Inf cont 3-10 mgkgh Inf cont 001-005 mgkgh
Miorilassante solo
Per intubazione
Pentobarbital dose caricopoi 01-04 mgkgmin
fenobarbital
bull 10-20 mgkg iv
ndash Eccessiva sedazione
ndash Depressresp
ndash Ipotensione
ndash Interaz farmacol
ndash Hl gt48 hrhelliphelliphellip
tiopental
bull cumulativo
bull Inotropo neghellip
bull Pentobarbital
bull immunosoppressione
propofol
bull Vantaggi cineticodinamici
bull Titolazione continua possibile
bull TCIquale livello
bull Dosi 1 mgkgripetibile dopo 5rsquo-
ndash Infcont 2-10 mgkgh
bull Rapida emergenzafinestra neurologicaevitare la
brusca sospensione
bull + rapido controllo delle convuls gt barbituricindash Stecker MM Kramer TH Raps EC OMeeghan R Dulaney E Skaar DJ Treatment of
refractory status epilepticus with propofol clinical and pharmacokinetic findings Epilepsia 1998
39 18-26
AG
bull Non ci sono dati che indichino quanto a lungo i paz debbano rimanere senza convuls prima di poter alleggerire il piano di AG24 h96h (Treiman DM Convulsive status
epilepticus Current Treatment Options in Neurology 1999 1 359-69)
bull Anest alogenatiisofluranogtsevofluranogtdesflurane
bull Ma vaporizzatori
bull Contaminazione ambientale
bull Costihellip
Studi comparativi1
bull Midazolamgt tiopental
ndash Lohr A Jr Werneck LC Comparative non-randomized study with
midazolam versus thiopental in children with refractory status
epilepticus [Portuguese] Arq Neuropsiquiatr 2000 58282-287
ndash non-randomized comparison
ndash of historical data (thiopental) and prospectively
acquired data (midazolam)
ndash Midazolam was no more often effective than
thiopental but was associated with less cyanosis and
less respiratory distress in this study of 50 children
Studi comparativi2
Valproatobull Valproate(ivrdquoDepaconrdquo) has been used for the treatment of refractory SE
in children and myoclonic SE ndash Sheth RD Gidal BE Intravenous valproic acid for myoclonic status epilepticus
Neurology 2000 541201
ndash Uberall MA Trollmann R Wunsiedler U Wenzel D Intravenous valproate in pediatric epilepsy patients with refractory status epilepticus Neurology 2000 542188-2189 ]
bull Valproate has also been used in SE in the elderly and appears to be safe even in the presence of cardiovascular instability and hypotension no significant change in blood pressure pulse or the need for vasopressors in 13 patients with SE and hypotension given a loading dose of 147-327 mgkg Depacon intravenouslyndash Sinha S Naritoku DK Intravenous valproate is well tolerated in unstable patients
with status epilepticus Neurology 2000 55722-724
bull However there is a case report of severe hypotension in an 11-year-old child after treatment of SE with 30 mgkg intravenous valproate ndash White JR Santos CS Intravenous valproate associated with significant
hypotension in the treatment of status epilepticus J Child Neurol 1999 14822-823
FINE
Percheacute non ne possiamo
piugravehelliphelliphellip
Allen FH Runge JW Legarda S et al Multicenter open-label
study on safety tolerance and pharmacokinetics of
intravenous fosphenytoin (Cerebyx) in status epilepticus
[abstract] Epilepsia 199435(Suppl 18)93
bull Data have been published from 40 patients in status epilepticus who received fosphenytoin at a mean infusion rate of 92 mgmin ranging from 247 to 1113 mgmin) Status epilepticus was terminated in 37 of 40 patients (85) within 30 min of receiving fosphenytoin The rapid infusion was well tolerated with only mild or transient side effects Most of the side effects reported were attributable to the pharmacologic effect of phenytoin and included dizziness nystagmus and ataxia Most patients in this trial received a benzodiazepine before the infusion of fosphenytoin and no adverse drug interactions were found
Introduzione alla peculiaritagrave
dellrsquoambiente intensivistico
Convulsioni in ambiente intensivo
bull Sepsi
bull Cause mediche
bull Anormalitagrave metaboliche(30-35) (11)ndash Iponatremiaipocalcemiaipofosfatemiaipoglicemiauremia
ndash Alterazioni della osmolaritagrave specie correzione acuta bull Acute return from hyperosmolarity back to normal levels in a rat
neocortical slice preparation by lowering the D-glucose concentration increased the amplitude of evoked early and late excitatory postsynaptic potentials a situation reminiscent of the generalized convulsions that may follow acute reduction of glucose in diabetic nonketotic hyperglycemia (42)
ndash Ipoosmolaritagrave induce increased nervous system excitability by strengthening both excitatory synaptic communications in neocortex and field effects among the entire cortical population (41)
Problemi peculiari allrsquoambiente
intensivistico
bull Polifarmacologia
bull Insuff renale
bull Insuff epatica
bull Induzione enzimatica
bull Inibizione enzimatica
bull Ipodisprotidemiehellipfarmaci altamente
legati alle prot plasmatiche
Trattamento dello stato di
male
Allora
bull Terapia immediata
bull Aggressiva
bull Supporto vitale di base
bull AAirway
bull Breathing
bull CSupporto circolatorio
Status epilepticusfilosofia del trattamento
Disaccoppiamento
CMRO2CBF
Funzione cardiocircolatoriaFunzione resp
Supporto supernormale
Glucosio
Tiamina 100 mg
Dopaminanoradrenalina + fre con barbituricihellip
Indagine conoscitiva su 127 TI NCH europeeDauch WA Schutze M Guttinger M et al Posttraumatic seizure prevention - results of a
survey of 127 neurosurgery clinics Zentralbl Neurochir 1996 57190ndash5
0
10
20
30
40
50
60
profilassi
Profilassi con anticonvulsivi post trauma cranio-
encefalico
mai
sempre
secindicazione
substantial cortical
injurycerebral contusion
acute subdural
hemorrhage
depressed skull fracture
penetrating missile
injury
(141517)
Rischio convulsivo
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001bull Background It is uncertain whether the administration of benzodiazepines by paramedics is an
effective and safe treatment for out-of-hospital status epilepticus
Methods We conducted a randomized double-blind trial to evaluate intravenous benzodiazepines administered by paramedics for the treatment of out-of-hospital status epilepticus Adults with prolonged (lasting five minutes or more) or repetitive generalized convulsive seizures received intravenous diazepam (5 mg) lorazepam (2 mg) or placebo An identical second injection was given if needed
Results Of the 205 patients enrolled 66 received lorazepam 68 received diazepam and 71 received placebo Status epilepticus had been terminated on arrival at the emergency department in more patients treated with lorazepam (591 percent) or diazepam (426 percent) than patients given placebo (211 percent) (P=0001) After adjustment for covariates the odds ratio for termination of status epilepticus by the time of arrival in the lorazepam group as compared with the placebo group was 48 (95 percent confidence interval 19 to 130) The odds ratio was 19 (95 percent confidence interval 08 to 44) in the lorazepam group as compared with the diazepam group and 23 (95 percent confidence interval 10 to 59) in the diazepam group as compared with the placebo group The rates of respiratory or circulatory complications after the study treatment was administered were 106 percent for the lorazepam group 103 percent for the diazepam group and 225 percent for the placebo group (P=008)
Conclusions Benzodiazepines are safe and effective when administered by paramedics for out-of-hospital status epilepticus in adults Lorazepam is likely to be a better therapy than diazepam (N Engl J Med 2001345631-7)
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001
0
10
20
30
40
50
60
seizures stop complications
lorazepam
diazepam
placebo
randomized double-blind trial
to evaluate iv bdz
admin by paramedics
for the treatment of out-of-hospital status epilepticus
Adults with prolonged (lasting 5 minutes or +)
or repetitive generalized convulsive seizures
received iv diazepam (5 mg)
lorazepam (2 mg) or placebo
An identical second injection was given if needed
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
Treiman DM Meyers PD Walton NY Collins JF Colling C Rowan AJ et al A comparison of four treatments for generalized convulsive status epilepticus N Engl J Med 1998 339792-798
randomized double-blind trial that compared the following four regimens commonly used for the treatment of generalized convulsive status epilepticus diazepam followed by phenytoin phenytoin alone phenobarbital and lorazepam Although the doses and infusion rates chosen for study closely reflected common clinical practice at the time the study began the combination of lorazepam followed by phenytoin (the preferred regimen of many neurologists) was not included
This is a large well-controlled and important clinical trial The major limitation in its clinical relevance is the lack of inclusion of a regimen consisting of lorazepam followed by phenytoin
Veterans Affairs Status Epilepticus Cooperative
Study Group Treiman et al
SE aperto
diaz fenitoina fenobarbital lorazepam
2 o + convuls senza
ripresa di coscienza
Convuls continue = gt 10 min
fenitoina
Coma con scariche
ictali EEG
primary outcome measure
cessation of clinical and electrical
seizure activity
within 20min after initiation
of treatment and continuing for at least
60min after the start of treatment
lorazepam fenitoina
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
bull st treatment successful in 555 of patients with a verified diagnosis of overt status epilepticus (n=384) and in 149 of patients with subtle status epilepticus (n=134)
bull Comparisons between the 4 treatments showed that lorazepam was more effective than phenytoin alone in patients with overt status epilepticus (treatment success in 649 versus 436 of patients respectively)
bull other treatment comparisons in the overt group and all comparisons in the subtle group were not significantly different however
bull There were no significant differences between treatments in patient outcome rates of recurrence of status epilepticus or return of full consciousness over the 12-h observation period or in the frequency of adverse cardiac respiratory or hypotensive events
Treiman DM Meyers PD Walton NY et al A
comparison of four treatments for generalized
convulsive status epilepticus N Engl J Med 1998
339792-798
P 002
Percentage of successful treatment
grey bars overt patients black bars subtle patients
Alldredge Brian Kab Lowenstein Daniel HAC Status
epilepticus new concepts Current Opinion in Neurology
121999 183-190
Da ChapmanAnaesthesia 2004
Marik PEVaron J The Management of Status
Epilepticus Chest 126(2)582-591 August 2004
Status epilepticus is a major medical emergency associated with significant morbidity and mortality Status epilepticusis best defined as a continuous generalized convulsive seizure lasting gt 5 min or two or more seizures during which the patient does not return to baseline consciousness Lorazepam in a dose of 01 mgkg is the drug of first choice for terminating status epilepticus Patients who continue to have clinical or EEG evidence of seizure activity after treatment with lorazepam should be considered to have refractory status epileptics and should be treated with a continuous infusion of propofol or midazolam This article reviews current information regarding the management of status epilepticus in adults
Schema di Marik et al
Claassen JHirsch LJ Emerson R GBates
JE Thompson TBMayer SA Continuous EEG
monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042 bull The authors reviewed 33 episodes of RSE treated with cIV-MDZ in their neurologic intensive care
unit over 6 years All patients were monitored with continuous EEG (cEEG) MDZ infusion rates were titrated to eliminate clinical and EEG seizure activity cIV-MDZ was discontinued once patients were seizure-free for 24 hours Acute treatment failures (seizures 1 to 6 hours after starting cIV-MDZ) breakthrough seizures (after 6 hours of therapy) post-treatment seizures (within 48 hours of discontinuing therapy) and ultimate treatment failure (frequent seizures that led to treatment with pentobarbital or propofol) were identified
bull Results All patients were in nonconvulsive SE at the time cIV-MDZ was started the mean duration of SE before treatment was 39 days (range 0 to 17 days) In addition to benzodiazepines 94 of patients had received at least two antiepileptic drugs (AED) before starting cIV-MDZ The mean loading dose was 019 mgkg the mean maximal infusion rate was 022 mgkgh and the mean duration of cIV-MDZ therapy was 42 days (range 1 to 14 days) Acute treatment failure occurred in 18 (633) of episodes breakthrough seizures in 56 (1832) post-treatment seizures in 68 (1928) and ultimate treatment failure in 18 (633) Breakthrough seizures were clinically subtle or purely electrographic in 89 (1618) of cases and were associated with an increased risk of developing post-treatment seizures (p = 001)
bull Conclusions Although most patients with RSE initially responded to cIV-MDZ over half developed subsequent breakthrough seizures which were predictive of post-treatment seizures and were often detectable only with cEEG Titrating cIV-MDZ to burst suppression more aggressive treatment with concurrent AED or a longer period of initial treatment may reduce the high proportion of patients with RSE who relapse after cIV-MDZ is discontinued
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus Neurology 2001 57 25 1036-1042
0
10
20
30
40
50
60
70
80
non seizures
seizures lt30 min24h05-12 h
seizures 05-12 h24 hgt 12 h
seiz gt12 h24
burst suppression
periodic latdischarge
periodic gen discharge
prima
durante
dopo
33 episodes of RSE treated with cIV-MDZ neurologic ICU over 6 years
All patients were monitored with continuous EEG (cEEG)
Waterhouse Elizabeth J 1 2 DeLorenzo Robert J 1 3 4 2
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
bull Status epilepticus (SE) is a medical and neurological emergency that has been associated with significant morbidity and mortality The most widely accepted definition of SE is more than 30 minutes of either continuous seizure activity or intermittent seizures without full recovery of consciousness between seizures SE is a major clinical concern in the elderly population both because it has increased incidence in the elderly compared with the general population and because of concurrent medical conditions that are more likely to complicate therapy and worsen prognosis in elderly individuals
The incidence of SE in the elderly is almost twice that of the general population at 86 per 100 000 per year With the anticipated growth of the elderly population SE is likely to become an increasingly common problem facing clinicians and an important public health issue The elderly have the highest SE-associated mortality of any age group at 38 and the very old elderly (gt80 years of age) have a mortality of at least 50 Acute or remote stroke is the most common aetiology of SE in the elderly Nonconvulsive SE (NCSE) has a wide range of clinical presentations ranging from confusion to obtundation It occurs commonly in elderly patients who are critically ill and in the setting of coma Electroencephalogram is the only reliable method of diagnosing NCSE
The goal of treatment for SE is rapid cessation of clinical and electrical seizure activity Most treatment protocols call for the immediate administration of an intravenous benzodiazepine followed by phenytoin or fosphenytoin Recent studies suggest that when this initial treatment of SE fails little is gained by using additional standard drugs General anaesthetic agents (such as pentobarbital midazolam or propofol) should be expeditiously employed although these treatments have their own potential complications Intravenous valproic acid is a recent addition to the armamentarium of drugs for the treatment of SE with a low risk of hypotension respiratory depression and hypotension making it a potentially useful drug for the treatment of SE in the elderly However further information is needed to establish its role in the overall treatment of SE
Waterhouseet al
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
BDZ
Fenitoina
O fosfenitoina
GA
Midaz
Propof
pentobarb
Ac valproico
Ns proposta
Lorazepam
01 mgkg
Propofol
1-2 mgkgMidazolam01 mgkg
Inf cont 3-10 mgkgh Inf cont 001-005 mgkgh
Miorilassante solo
Per intubazione
Pentobarbital dose caricopoi 01-04 mgkgmin
fenobarbital
bull 10-20 mgkg iv
ndash Eccessiva sedazione
ndash Depressresp
ndash Ipotensione
ndash Interaz farmacol
ndash Hl gt48 hrhelliphelliphellip
tiopental
bull cumulativo
bull Inotropo neghellip
bull Pentobarbital
bull immunosoppressione
propofol
bull Vantaggi cineticodinamici
bull Titolazione continua possibile
bull TCIquale livello
bull Dosi 1 mgkgripetibile dopo 5rsquo-
ndash Infcont 2-10 mgkgh
bull Rapida emergenzafinestra neurologicaevitare la
brusca sospensione
bull + rapido controllo delle convuls gt barbituricindash Stecker MM Kramer TH Raps EC OMeeghan R Dulaney E Skaar DJ Treatment of
refractory status epilepticus with propofol clinical and pharmacokinetic findings Epilepsia 1998
39 18-26
AG
bull Non ci sono dati che indichino quanto a lungo i paz debbano rimanere senza convuls prima di poter alleggerire il piano di AG24 h96h (Treiman DM Convulsive status
epilepticus Current Treatment Options in Neurology 1999 1 359-69)
bull Anest alogenatiisofluranogtsevofluranogtdesflurane
bull Ma vaporizzatori
bull Contaminazione ambientale
bull Costihellip
Studi comparativi1
bull Midazolamgt tiopental
ndash Lohr A Jr Werneck LC Comparative non-randomized study with
midazolam versus thiopental in children with refractory status
epilepticus [Portuguese] Arq Neuropsiquiatr 2000 58282-287
ndash non-randomized comparison
ndash of historical data (thiopental) and prospectively
acquired data (midazolam)
ndash Midazolam was no more often effective than
thiopental but was associated with less cyanosis and
less respiratory distress in this study of 50 children
Studi comparativi2
Valproatobull Valproate(ivrdquoDepaconrdquo) has been used for the treatment of refractory SE
in children and myoclonic SE ndash Sheth RD Gidal BE Intravenous valproic acid for myoclonic status epilepticus
Neurology 2000 541201
ndash Uberall MA Trollmann R Wunsiedler U Wenzel D Intravenous valproate in pediatric epilepsy patients with refractory status epilepticus Neurology 2000 542188-2189 ]
bull Valproate has also been used in SE in the elderly and appears to be safe even in the presence of cardiovascular instability and hypotension no significant change in blood pressure pulse or the need for vasopressors in 13 patients with SE and hypotension given a loading dose of 147-327 mgkg Depacon intravenouslyndash Sinha S Naritoku DK Intravenous valproate is well tolerated in unstable patients
with status epilepticus Neurology 2000 55722-724
bull However there is a case report of severe hypotension in an 11-year-old child after treatment of SE with 30 mgkg intravenous valproate ndash White JR Santos CS Intravenous valproate associated with significant
hypotension in the treatment of status epilepticus J Child Neurol 1999 14822-823
FINE
Percheacute non ne possiamo
piugravehelliphelliphellip
Introduzione alla peculiaritagrave
dellrsquoambiente intensivistico
Convulsioni in ambiente intensivo
bull Sepsi
bull Cause mediche
bull Anormalitagrave metaboliche(30-35) (11)ndash Iponatremiaipocalcemiaipofosfatemiaipoglicemiauremia
ndash Alterazioni della osmolaritagrave specie correzione acuta bull Acute return from hyperosmolarity back to normal levels in a rat
neocortical slice preparation by lowering the D-glucose concentration increased the amplitude of evoked early and late excitatory postsynaptic potentials a situation reminiscent of the generalized convulsions that may follow acute reduction of glucose in diabetic nonketotic hyperglycemia (42)
ndash Ipoosmolaritagrave induce increased nervous system excitability by strengthening both excitatory synaptic communications in neocortex and field effects among the entire cortical population (41)
Problemi peculiari allrsquoambiente
intensivistico
bull Polifarmacologia
bull Insuff renale
bull Insuff epatica
bull Induzione enzimatica
bull Inibizione enzimatica
bull Ipodisprotidemiehellipfarmaci altamente
legati alle prot plasmatiche
Trattamento dello stato di
male
Allora
bull Terapia immediata
bull Aggressiva
bull Supporto vitale di base
bull AAirway
bull Breathing
bull CSupporto circolatorio
Status epilepticusfilosofia del trattamento
Disaccoppiamento
CMRO2CBF
Funzione cardiocircolatoriaFunzione resp
Supporto supernormale
Glucosio
Tiamina 100 mg
Dopaminanoradrenalina + fre con barbituricihellip
Indagine conoscitiva su 127 TI NCH europeeDauch WA Schutze M Guttinger M et al Posttraumatic seizure prevention - results of a
survey of 127 neurosurgery clinics Zentralbl Neurochir 1996 57190ndash5
0
10
20
30
40
50
60
profilassi
Profilassi con anticonvulsivi post trauma cranio-
encefalico
mai
sempre
secindicazione
substantial cortical
injurycerebral contusion
acute subdural
hemorrhage
depressed skull fracture
penetrating missile
injury
(141517)
Rischio convulsivo
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001bull Background It is uncertain whether the administration of benzodiazepines by paramedics is an
effective and safe treatment for out-of-hospital status epilepticus
Methods We conducted a randomized double-blind trial to evaluate intravenous benzodiazepines administered by paramedics for the treatment of out-of-hospital status epilepticus Adults with prolonged (lasting five minutes or more) or repetitive generalized convulsive seizures received intravenous diazepam (5 mg) lorazepam (2 mg) or placebo An identical second injection was given if needed
Results Of the 205 patients enrolled 66 received lorazepam 68 received diazepam and 71 received placebo Status epilepticus had been terminated on arrival at the emergency department in more patients treated with lorazepam (591 percent) or diazepam (426 percent) than patients given placebo (211 percent) (P=0001) After adjustment for covariates the odds ratio for termination of status epilepticus by the time of arrival in the lorazepam group as compared with the placebo group was 48 (95 percent confidence interval 19 to 130) The odds ratio was 19 (95 percent confidence interval 08 to 44) in the lorazepam group as compared with the diazepam group and 23 (95 percent confidence interval 10 to 59) in the diazepam group as compared with the placebo group The rates of respiratory or circulatory complications after the study treatment was administered were 106 percent for the lorazepam group 103 percent for the diazepam group and 225 percent for the placebo group (P=008)
Conclusions Benzodiazepines are safe and effective when administered by paramedics for out-of-hospital status epilepticus in adults Lorazepam is likely to be a better therapy than diazepam (N Engl J Med 2001345631-7)
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001
0
10
20
30
40
50
60
seizures stop complications
lorazepam
diazepam
placebo
randomized double-blind trial
to evaluate iv bdz
admin by paramedics
for the treatment of out-of-hospital status epilepticus
Adults with prolonged (lasting 5 minutes or +)
or repetitive generalized convulsive seizures
received iv diazepam (5 mg)
lorazepam (2 mg) or placebo
An identical second injection was given if needed
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
Treiman DM Meyers PD Walton NY Collins JF Colling C Rowan AJ et al A comparison of four treatments for generalized convulsive status epilepticus N Engl J Med 1998 339792-798
randomized double-blind trial that compared the following four regimens commonly used for the treatment of generalized convulsive status epilepticus diazepam followed by phenytoin phenytoin alone phenobarbital and lorazepam Although the doses and infusion rates chosen for study closely reflected common clinical practice at the time the study began the combination of lorazepam followed by phenytoin (the preferred regimen of many neurologists) was not included
This is a large well-controlled and important clinical trial The major limitation in its clinical relevance is the lack of inclusion of a regimen consisting of lorazepam followed by phenytoin
Veterans Affairs Status Epilepticus Cooperative
Study Group Treiman et al
SE aperto
diaz fenitoina fenobarbital lorazepam
2 o + convuls senza
ripresa di coscienza
Convuls continue = gt 10 min
fenitoina
Coma con scariche
ictali EEG
primary outcome measure
cessation of clinical and electrical
seizure activity
within 20min after initiation
of treatment and continuing for at least
60min after the start of treatment
lorazepam fenitoina
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
bull st treatment successful in 555 of patients with a verified diagnosis of overt status epilepticus (n=384) and in 149 of patients with subtle status epilepticus (n=134)
bull Comparisons between the 4 treatments showed that lorazepam was more effective than phenytoin alone in patients with overt status epilepticus (treatment success in 649 versus 436 of patients respectively)
bull other treatment comparisons in the overt group and all comparisons in the subtle group were not significantly different however
bull There were no significant differences between treatments in patient outcome rates of recurrence of status epilepticus or return of full consciousness over the 12-h observation period or in the frequency of adverse cardiac respiratory or hypotensive events
Treiman DM Meyers PD Walton NY et al A
comparison of four treatments for generalized
convulsive status epilepticus N Engl J Med 1998
339792-798
P 002
Percentage of successful treatment
grey bars overt patients black bars subtle patients
Alldredge Brian Kab Lowenstein Daniel HAC Status
epilepticus new concepts Current Opinion in Neurology
121999 183-190
Da ChapmanAnaesthesia 2004
Marik PEVaron J The Management of Status
Epilepticus Chest 126(2)582-591 August 2004
Status epilepticus is a major medical emergency associated with significant morbidity and mortality Status epilepticusis best defined as a continuous generalized convulsive seizure lasting gt 5 min or two or more seizures during which the patient does not return to baseline consciousness Lorazepam in a dose of 01 mgkg is the drug of first choice for terminating status epilepticus Patients who continue to have clinical or EEG evidence of seizure activity after treatment with lorazepam should be considered to have refractory status epileptics and should be treated with a continuous infusion of propofol or midazolam This article reviews current information regarding the management of status epilepticus in adults
Schema di Marik et al
Claassen JHirsch LJ Emerson R GBates
JE Thompson TBMayer SA Continuous EEG
monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042 bull The authors reviewed 33 episodes of RSE treated with cIV-MDZ in their neurologic intensive care
unit over 6 years All patients were monitored with continuous EEG (cEEG) MDZ infusion rates were titrated to eliminate clinical and EEG seizure activity cIV-MDZ was discontinued once patients were seizure-free for 24 hours Acute treatment failures (seizures 1 to 6 hours after starting cIV-MDZ) breakthrough seizures (after 6 hours of therapy) post-treatment seizures (within 48 hours of discontinuing therapy) and ultimate treatment failure (frequent seizures that led to treatment with pentobarbital or propofol) were identified
bull Results All patients were in nonconvulsive SE at the time cIV-MDZ was started the mean duration of SE before treatment was 39 days (range 0 to 17 days) In addition to benzodiazepines 94 of patients had received at least two antiepileptic drugs (AED) before starting cIV-MDZ The mean loading dose was 019 mgkg the mean maximal infusion rate was 022 mgkgh and the mean duration of cIV-MDZ therapy was 42 days (range 1 to 14 days) Acute treatment failure occurred in 18 (633) of episodes breakthrough seizures in 56 (1832) post-treatment seizures in 68 (1928) and ultimate treatment failure in 18 (633) Breakthrough seizures were clinically subtle or purely electrographic in 89 (1618) of cases and were associated with an increased risk of developing post-treatment seizures (p = 001)
bull Conclusions Although most patients with RSE initially responded to cIV-MDZ over half developed subsequent breakthrough seizures which were predictive of post-treatment seizures and were often detectable only with cEEG Titrating cIV-MDZ to burst suppression more aggressive treatment with concurrent AED or a longer period of initial treatment may reduce the high proportion of patients with RSE who relapse after cIV-MDZ is discontinued
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus Neurology 2001 57 25 1036-1042
0
10
20
30
40
50
60
70
80
non seizures
seizures lt30 min24h05-12 h
seizures 05-12 h24 hgt 12 h
seiz gt12 h24
burst suppression
periodic latdischarge
periodic gen discharge
prima
durante
dopo
33 episodes of RSE treated with cIV-MDZ neurologic ICU over 6 years
All patients were monitored with continuous EEG (cEEG)
Waterhouse Elizabeth J 1 2 DeLorenzo Robert J 1 3 4 2
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
bull Status epilepticus (SE) is a medical and neurological emergency that has been associated with significant morbidity and mortality The most widely accepted definition of SE is more than 30 minutes of either continuous seizure activity or intermittent seizures without full recovery of consciousness between seizures SE is a major clinical concern in the elderly population both because it has increased incidence in the elderly compared with the general population and because of concurrent medical conditions that are more likely to complicate therapy and worsen prognosis in elderly individuals
The incidence of SE in the elderly is almost twice that of the general population at 86 per 100 000 per year With the anticipated growth of the elderly population SE is likely to become an increasingly common problem facing clinicians and an important public health issue The elderly have the highest SE-associated mortality of any age group at 38 and the very old elderly (gt80 years of age) have a mortality of at least 50 Acute or remote stroke is the most common aetiology of SE in the elderly Nonconvulsive SE (NCSE) has a wide range of clinical presentations ranging from confusion to obtundation It occurs commonly in elderly patients who are critically ill and in the setting of coma Electroencephalogram is the only reliable method of diagnosing NCSE
The goal of treatment for SE is rapid cessation of clinical and electrical seizure activity Most treatment protocols call for the immediate administration of an intravenous benzodiazepine followed by phenytoin or fosphenytoin Recent studies suggest that when this initial treatment of SE fails little is gained by using additional standard drugs General anaesthetic agents (such as pentobarbital midazolam or propofol) should be expeditiously employed although these treatments have their own potential complications Intravenous valproic acid is a recent addition to the armamentarium of drugs for the treatment of SE with a low risk of hypotension respiratory depression and hypotension making it a potentially useful drug for the treatment of SE in the elderly However further information is needed to establish its role in the overall treatment of SE
Waterhouseet al
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
BDZ
Fenitoina
O fosfenitoina
GA
Midaz
Propof
pentobarb
Ac valproico
Ns proposta
Lorazepam
01 mgkg
Propofol
1-2 mgkgMidazolam01 mgkg
Inf cont 3-10 mgkgh Inf cont 001-005 mgkgh
Miorilassante solo
Per intubazione
Pentobarbital dose caricopoi 01-04 mgkgmin
fenobarbital
bull 10-20 mgkg iv
ndash Eccessiva sedazione
ndash Depressresp
ndash Ipotensione
ndash Interaz farmacol
ndash Hl gt48 hrhelliphelliphellip
tiopental
bull cumulativo
bull Inotropo neghellip
bull Pentobarbital
bull immunosoppressione
propofol
bull Vantaggi cineticodinamici
bull Titolazione continua possibile
bull TCIquale livello
bull Dosi 1 mgkgripetibile dopo 5rsquo-
ndash Infcont 2-10 mgkgh
bull Rapida emergenzafinestra neurologicaevitare la
brusca sospensione
bull + rapido controllo delle convuls gt barbituricindash Stecker MM Kramer TH Raps EC OMeeghan R Dulaney E Skaar DJ Treatment of
refractory status epilepticus with propofol clinical and pharmacokinetic findings Epilepsia 1998
39 18-26
AG
bull Non ci sono dati che indichino quanto a lungo i paz debbano rimanere senza convuls prima di poter alleggerire il piano di AG24 h96h (Treiman DM Convulsive status
epilepticus Current Treatment Options in Neurology 1999 1 359-69)
bull Anest alogenatiisofluranogtsevofluranogtdesflurane
bull Ma vaporizzatori
bull Contaminazione ambientale
bull Costihellip
Studi comparativi1
bull Midazolamgt tiopental
ndash Lohr A Jr Werneck LC Comparative non-randomized study with
midazolam versus thiopental in children with refractory status
epilepticus [Portuguese] Arq Neuropsiquiatr 2000 58282-287
ndash non-randomized comparison
ndash of historical data (thiopental) and prospectively
acquired data (midazolam)
ndash Midazolam was no more often effective than
thiopental but was associated with less cyanosis and
less respiratory distress in this study of 50 children
Studi comparativi2
Valproatobull Valproate(ivrdquoDepaconrdquo) has been used for the treatment of refractory SE
in children and myoclonic SE ndash Sheth RD Gidal BE Intravenous valproic acid for myoclonic status epilepticus
Neurology 2000 541201
ndash Uberall MA Trollmann R Wunsiedler U Wenzel D Intravenous valproate in pediatric epilepsy patients with refractory status epilepticus Neurology 2000 542188-2189 ]
bull Valproate has also been used in SE in the elderly and appears to be safe even in the presence of cardiovascular instability and hypotension no significant change in blood pressure pulse or the need for vasopressors in 13 patients with SE and hypotension given a loading dose of 147-327 mgkg Depacon intravenouslyndash Sinha S Naritoku DK Intravenous valproate is well tolerated in unstable patients
with status epilepticus Neurology 2000 55722-724
bull However there is a case report of severe hypotension in an 11-year-old child after treatment of SE with 30 mgkg intravenous valproate ndash White JR Santos CS Intravenous valproate associated with significant
hypotension in the treatment of status epilepticus J Child Neurol 1999 14822-823
FINE
Percheacute non ne possiamo
piugravehelliphelliphellip
Convulsioni in ambiente intensivo
bull Sepsi
bull Cause mediche
bull Anormalitagrave metaboliche(30-35) (11)ndash Iponatremiaipocalcemiaipofosfatemiaipoglicemiauremia
ndash Alterazioni della osmolaritagrave specie correzione acuta bull Acute return from hyperosmolarity back to normal levels in a rat
neocortical slice preparation by lowering the D-glucose concentration increased the amplitude of evoked early and late excitatory postsynaptic potentials a situation reminiscent of the generalized convulsions that may follow acute reduction of glucose in diabetic nonketotic hyperglycemia (42)
ndash Ipoosmolaritagrave induce increased nervous system excitability by strengthening both excitatory synaptic communications in neocortex and field effects among the entire cortical population (41)
Problemi peculiari allrsquoambiente
intensivistico
bull Polifarmacologia
bull Insuff renale
bull Insuff epatica
bull Induzione enzimatica
bull Inibizione enzimatica
bull Ipodisprotidemiehellipfarmaci altamente
legati alle prot plasmatiche
Trattamento dello stato di
male
Allora
bull Terapia immediata
bull Aggressiva
bull Supporto vitale di base
bull AAirway
bull Breathing
bull CSupporto circolatorio
Status epilepticusfilosofia del trattamento
Disaccoppiamento
CMRO2CBF
Funzione cardiocircolatoriaFunzione resp
Supporto supernormale
Glucosio
Tiamina 100 mg
Dopaminanoradrenalina + fre con barbituricihellip
Indagine conoscitiva su 127 TI NCH europeeDauch WA Schutze M Guttinger M et al Posttraumatic seizure prevention - results of a
survey of 127 neurosurgery clinics Zentralbl Neurochir 1996 57190ndash5
0
10
20
30
40
50
60
profilassi
Profilassi con anticonvulsivi post trauma cranio-
encefalico
mai
sempre
secindicazione
substantial cortical
injurycerebral contusion
acute subdural
hemorrhage
depressed skull fracture
penetrating missile
injury
(141517)
Rischio convulsivo
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001bull Background It is uncertain whether the administration of benzodiazepines by paramedics is an
effective and safe treatment for out-of-hospital status epilepticus
Methods We conducted a randomized double-blind trial to evaluate intravenous benzodiazepines administered by paramedics for the treatment of out-of-hospital status epilepticus Adults with prolonged (lasting five minutes or more) or repetitive generalized convulsive seizures received intravenous diazepam (5 mg) lorazepam (2 mg) or placebo An identical second injection was given if needed
Results Of the 205 patients enrolled 66 received lorazepam 68 received diazepam and 71 received placebo Status epilepticus had been terminated on arrival at the emergency department in more patients treated with lorazepam (591 percent) or diazepam (426 percent) than patients given placebo (211 percent) (P=0001) After adjustment for covariates the odds ratio for termination of status epilepticus by the time of arrival in the lorazepam group as compared with the placebo group was 48 (95 percent confidence interval 19 to 130) The odds ratio was 19 (95 percent confidence interval 08 to 44) in the lorazepam group as compared with the diazepam group and 23 (95 percent confidence interval 10 to 59) in the diazepam group as compared with the placebo group The rates of respiratory or circulatory complications after the study treatment was administered were 106 percent for the lorazepam group 103 percent for the diazepam group and 225 percent for the placebo group (P=008)
Conclusions Benzodiazepines are safe and effective when administered by paramedics for out-of-hospital status epilepticus in adults Lorazepam is likely to be a better therapy than diazepam (N Engl J Med 2001345631-7)
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001
0
10
20
30
40
50
60
seizures stop complications
lorazepam
diazepam
placebo
randomized double-blind trial
to evaluate iv bdz
admin by paramedics
for the treatment of out-of-hospital status epilepticus
Adults with prolonged (lasting 5 minutes or +)
or repetitive generalized convulsive seizures
received iv diazepam (5 mg)
lorazepam (2 mg) or placebo
An identical second injection was given if needed
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
Treiman DM Meyers PD Walton NY Collins JF Colling C Rowan AJ et al A comparison of four treatments for generalized convulsive status epilepticus N Engl J Med 1998 339792-798
randomized double-blind trial that compared the following four regimens commonly used for the treatment of generalized convulsive status epilepticus diazepam followed by phenytoin phenytoin alone phenobarbital and lorazepam Although the doses and infusion rates chosen for study closely reflected common clinical practice at the time the study began the combination of lorazepam followed by phenytoin (the preferred regimen of many neurologists) was not included
This is a large well-controlled and important clinical trial The major limitation in its clinical relevance is the lack of inclusion of a regimen consisting of lorazepam followed by phenytoin
Veterans Affairs Status Epilepticus Cooperative
Study Group Treiman et al
SE aperto
diaz fenitoina fenobarbital lorazepam
2 o + convuls senza
ripresa di coscienza
Convuls continue = gt 10 min
fenitoina
Coma con scariche
ictali EEG
primary outcome measure
cessation of clinical and electrical
seizure activity
within 20min after initiation
of treatment and continuing for at least
60min after the start of treatment
lorazepam fenitoina
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
bull st treatment successful in 555 of patients with a verified diagnosis of overt status epilepticus (n=384) and in 149 of patients with subtle status epilepticus (n=134)
bull Comparisons between the 4 treatments showed that lorazepam was more effective than phenytoin alone in patients with overt status epilepticus (treatment success in 649 versus 436 of patients respectively)
bull other treatment comparisons in the overt group and all comparisons in the subtle group were not significantly different however
bull There were no significant differences between treatments in patient outcome rates of recurrence of status epilepticus or return of full consciousness over the 12-h observation period or in the frequency of adverse cardiac respiratory or hypotensive events
Treiman DM Meyers PD Walton NY et al A
comparison of four treatments for generalized
convulsive status epilepticus N Engl J Med 1998
339792-798
P 002
Percentage of successful treatment
grey bars overt patients black bars subtle patients
Alldredge Brian Kab Lowenstein Daniel HAC Status
epilepticus new concepts Current Opinion in Neurology
121999 183-190
Da ChapmanAnaesthesia 2004
Marik PEVaron J The Management of Status
Epilepticus Chest 126(2)582-591 August 2004
Status epilepticus is a major medical emergency associated with significant morbidity and mortality Status epilepticusis best defined as a continuous generalized convulsive seizure lasting gt 5 min or two or more seizures during which the patient does not return to baseline consciousness Lorazepam in a dose of 01 mgkg is the drug of first choice for terminating status epilepticus Patients who continue to have clinical or EEG evidence of seizure activity after treatment with lorazepam should be considered to have refractory status epileptics and should be treated with a continuous infusion of propofol or midazolam This article reviews current information regarding the management of status epilepticus in adults
Schema di Marik et al
Claassen JHirsch LJ Emerson R GBates
JE Thompson TBMayer SA Continuous EEG
monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042 bull The authors reviewed 33 episodes of RSE treated with cIV-MDZ in their neurologic intensive care
unit over 6 years All patients were monitored with continuous EEG (cEEG) MDZ infusion rates were titrated to eliminate clinical and EEG seizure activity cIV-MDZ was discontinued once patients were seizure-free for 24 hours Acute treatment failures (seizures 1 to 6 hours after starting cIV-MDZ) breakthrough seizures (after 6 hours of therapy) post-treatment seizures (within 48 hours of discontinuing therapy) and ultimate treatment failure (frequent seizures that led to treatment with pentobarbital or propofol) were identified
bull Results All patients were in nonconvulsive SE at the time cIV-MDZ was started the mean duration of SE before treatment was 39 days (range 0 to 17 days) In addition to benzodiazepines 94 of patients had received at least two antiepileptic drugs (AED) before starting cIV-MDZ The mean loading dose was 019 mgkg the mean maximal infusion rate was 022 mgkgh and the mean duration of cIV-MDZ therapy was 42 days (range 1 to 14 days) Acute treatment failure occurred in 18 (633) of episodes breakthrough seizures in 56 (1832) post-treatment seizures in 68 (1928) and ultimate treatment failure in 18 (633) Breakthrough seizures were clinically subtle or purely electrographic in 89 (1618) of cases and were associated with an increased risk of developing post-treatment seizures (p = 001)
bull Conclusions Although most patients with RSE initially responded to cIV-MDZ over half developed subsequent breakthrough seizures which were predictive of post-treatment seizures and were often detectable only with cEEG Titrating cIV-MDZ to burst suppression more aggressive treatment with concurrent AED or a longer period of initial treatment may reduce the high proportion of patients with RSE who relapse after cIV-MDZ is discontinued
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus Neurology 2001 57 25 1036-1042
0
10
20
30
40
50
60
70
80
non seizures
seizures lt30 min24h05-12 h
seizures 05-12 h24 hgt 12 h
seiz gt12 h24
burst suppression
periodic latdischarge
periodic gen discharge
prima
durante
dopo
33 episodes of RSE treated with cIV-MDZ neurologic ICU over 6 years
All patients were monitored with continuous EEG (cEEG)
Waterhouse Elizabeth J 1 2 DeLorenzo Robert J 1 3 4 2
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
bull Status epilepticus (SE) is a medical and neurological emergency that has been associated with significant morbidity and mortality The most widely accepted definition of SE is more than 30 minutes of either continuous seizure activity or intermittent seizures without full recovery of consciousness between seizures SE is a major clinical concern in the elderly population both because it has increased incidence in the elderly compared with the general population and because of concurrent medical conditions that are more likely to complicate therapy and worsen prognosis in elderly individuals
The incidence of SE in the elderly is almost twice that of the general population at 86 per 100 000 per year With the anticipated growth of the elderly population SE is likely to become an increasingly common problem facing clinicians and an important public health issue The elderly have the highest SE-associated mortality of any age group at 38 and the very old elderly (gt80 years of age) have a mortality of at least 50 Acute or remote stroke is the most common aetiology of SE in the elderly Nonconvulsive SE (NCSE) has a wide range of clinical presentations ranging from confusion to obtundation It occurs commonly in elderly patients who are critically ill and in the setting of coma Electroencephalogram is the only reliable method of diagnosing NCSE
The goal of treatment for SE is rapid cessation of clinical and electrical seizure activity Most treatment protocols call for the immediate administration of an intravenous benzodiazepine followed by phenytoin or fosphenytoin Recent studies suggest that when this initial treatment of SE fails little is gained by using additional standard drugs General anaesthetic agents (such as pentobarbital midazolam or propofol) should be expeditiously employed although these treatments have their own potential complications Intravenous valproic acid is a recent addition to the armamentarium of drugs for the treatment of SE with a low risk of hypotension respiratory depression and hypotension making it a potentially useful drug for the treatment of SE in the elderly However further information is needed to establish its role in the overall treatment of SE
Waterhouseet al
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
BDZ
Fenitoina
O fosfenitoina
GA
Midaz
Propof
pentobarb
Ac valproico
Ns proposta
Lorazepam
01 mgkg
Propofol
1-2 mgkgMidazolam01 mgkg
Inf cont 3-10 mgkgh Inf cont 001-005 mgkgh
Miorilassante solo
Per intubazione
Pentobarbital dose caricopoi 01-04 mgkgmin
fenobarbital
bull 10-20 mgkg iv
ndash Eccessiva sedazione
ndash Depressresp
ndash Ipotensione
ndash Interaz farmacol
ndash Hl gt48 hrhelliphelliphellip
tiopental
bull cumulativo
bull Inotropo neghellip
bull Pentobarbital
bull immunosoppressione
propofol
bull Vantaggi cineticodinamici
bull Titolazione continua possibile
bull TCIquale livello
bull Dosi 1 mgkgripetibile dopo 5rsquo-
ndash Infcont 2-10 mgkgh
bull Rapida emergenzafinestra neurologicaevitare la
brusca sospensione
bull + rapido controllo delle convuls gt barbituricindash Stecker MM Kramer TH Raps EC OMeeghan R Dulaney E Skaar DJ Treatment of
refractory status epilepticus with propofol clinical and pharmacokinetic findings Epilepsia 1998
39 18-26
AG
bull Non ci sono dati che indichino quanto a lungo i paz debbano rimanere senza convuls prima di poter alleggerire il piano di AG24 h96h (Treiman DM Convulsive status
epilepticus Current Treatment Options in Neurology 1999 1 359-69)
bull Anest alogenatiisofluranogtsevofluranogtdesflurane
bull Ma vaporizzatori
bull Contaminazione ambientale
bull Costihellip
Studi comparativi1
bull Midazolamgt tiopental
ndash Lohr A Jr Werneck LC Comparative non-randomized study with
midazolam versus thiopental in children with refractory status
epilepticus [Portuguese] Arq Neuropsiquiatr 2000 58282-287
ndash non-randomized comparison
ndash of historical data (thiopental) and prospectively
acquired data (midazolam)
ndash Midazolam was no more often effective than
thiopental but was associated with less cyanosis and
less respiratory distress in this study of 50 children
Studi comparativi2
Valproatobull Valproate(ivrdquoDepaconrdquo) has been used for the treatment of refractory SE
in children and myoclonic SE ndash Sheth RD Gidal BE Intravenous valproic acid for myoclonic status epilepticus
Neurology 2000 541201
ndash Uberall MA Trollmann R Wunsiedler U Wenzel D Intravenous valproate in pediatric epilepsy patients with refractory status epilepticus Neurology 2000 542188-2189 ]
bull Valproate has also been used in SE in the elderly and appears to be safe even in the presence of cardiovascular instability and hypotension no significant change in blood pressure pulse or the need for vasopressors in 13 patients with SE and hypotension given a loading dose of 147-327 mgkg Depacon intravenouslyndash Sinha S Naritoku DK Intravenous valproate is well tolerated in unstable patients
with status epilepticus Neurology 2000 55722-724
bull However there is a case report of severe hypotension in an 11-year-old child after treatment of SE with 30 mgkg intravenous valproate ndash White JR Santos CS Intravenous valproate associated with significant
hypotension in the treatment of status epilepticus J Child Neurol 1999 14822-823
FINE
Percheacute non ne possiamo
piugravehelliphelliphellip
Problemi peculiari allrsquoambiente
intensivistico
bull Polifarmacologia
bull Insuff renale
bull Insuff epatica
bull Induzione enzimatica
bull Inibizione enzimatica
bull Ipodisprotidemiehellipfarmaci altamente
legati alle prot plasmatiche
Trattamento dello stato di
male
Allora
bull Terapia immediata
bull Aggressiva
bull Supporto vitale di base
bull AAirway
bull Breathing
bull CSupporto circolatorio
Status epilepticusfilosofia del trattamento
Disaccoppiamento
CMRO2CBF
Funzione cardiocircolatoriaFunzione resp
Supporto supernormale
Glucosio
Tiamina 100 mg
Dopaminanoradrenalina + fre con barbituricihellip
Indagine conoscitiva su 127 TI NCH europeeDauch WA Schutze M Guttinger M et al Posttraumatic seizure prevention - results of a
survey of 127 neurosurgery clinics Zentralbl Neurochir 1996 57190ndash5
0
10
20
30
40
50
60
profilassi
Profilassi con anticonvulsivi post trauma cranio-
encefalico
mai
sempre
secindicazione
substantial cortical
injurycerebral contusion
acute subdural
hemorrhage
depressed skull fracture
penetrating missile
injury
(141517)
Rischio convulsivo
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001bull Background It is uncertain whether the administration of benzodiazepines by paramedics is an
effective and safe treatment for out-of-hospital status epilepticus
Methods We conducted a randomized double-blind trial to evaluate intravenous benzodiazepines administered by paramedics for the treatment of out-of-hospital status epilepticus Adults with prolonged (lasting five minutes or more) or repetitive generalized convulsive seizures received intravenous diazepam (5 mg) lorazepam (2 mg) or placebo An identical second injection was given if needed
Results Of the 205 patients enrolled 66 received lorazepam 68 received diazepam and 71 received placebo Status epilepticus had been terminated on arrival at the emergency department in more patients treated with lorazepam (591 percent) or diazepam (426 percent) than patients given placebo (211 percent) (P=0001) After adjustment for covariates the odds ratio for termination of status epilepticus by the time of arrival in the lorazepam group as compared with the placebo group was 48 (95 percent confidence interval 19 to 130) The odds ratio was 19 (95 percent confidence interval 08 to 44) in the lorazepam group as compared with the diazepam group and 23 (95 percent confidence interval 10 to 59) in the diazepam group as compared with the placebo group The rates of respiratory or circulatory complications after the study treatment was administered were 106 percent for the lorazepam group 103 percent for the diazepam group and 225 percent for the placebo group (P=008)
Conclusions Benzodiazepines are safe and effective when administered by paramedics for out-of-hospital status epilepticus in adults Lorazepam is likely to be a better therapy than diazepam (N Engl J Med 2001345631-7)
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001
0
10
20
30
40
50
60
seizures stop complications
lorazepam
diazepam
placebo
randomized double-blind trial
to evaluate iv bdz
admin by paramedics
for the treatment of out-of-hospital status epilepticus
Adults with prolonged (lasting 5 minutes or +)
or repetitive generalized convulsive seizures
received iv diazepam (5 mg)
lorazepam (2 mg) or placebo
An identical second injection was given if needed
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
Treiman DM Meyers PD Walton NY Collins JF Colling C Rowan AJ et al A comparison of four treatments for generalized convulsive status epilepticus N Engl J Med 1998 339792-798
randomized double-blind trial that compared the following four regimens commonly used for the treatment of generalized convulsive status epilepticus diazepam followed by phenytoin phenytoin alone phenobarbital and lorazepam Although the doses and infusion rates chosen for study closely reflected common clinical practice at the time the study began the combination of lorazepam followed by phenytoin (the preferred regimen of many neurologists) was not included
This is a large well-controlled and important clinical trial The major limitation in its clinical relevance is the lack of inclusion of a regimen consisting of lorazepam followed by phenytoin
Veterans Affairs Status Epilepticus Cooperative
Study Group Treiman et al
SE aperto
diaz fenitoina fenobarbital lorazepam
2 o + convuls senza
ripresa di coscienza
Convuls continue = gt 10 min
fenitoina
Coma con scariche
ictali EEG
primary outcome measure
cessation of clinical and electrical
seizure activity
within 20min after initiation
of treatment and continuing for at least
60min after the start of treatment
lorazepam fenitoina
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
bull st treatment successful in 555 of patients with a verified diagnosis of overt status epilepticus (n=384) and in 149 of patients with subtle status epilepticus (n=134)
bull Comparisons between the 4 treatments showed that lorazepam was more effective than phenytoin alone in patients with overt status epilepticus (treatment success in 649 versus 436 of patients respectively)
bull other treatment comparisons in the overt group and all comparisons in the subtle group were not significantly different however
bull There were no significant differences between treatments in patient outcome rates of recurrence of status epilepticus or return of full consciousness over the 12-h observation period or in the frequency of adverse cardiac respiratory or hypotensive events
Treiman DM Meyers PD Walton NY et al A
comparison of four treatments for generalized
convulsive status epilepticus N Engl J Med 1998
339792-798
P 002
Percentage of successful treatment
grey bars overt patients black bars subtle patients
Alldredge Brian Kab Lowenstein Daniel HAC Status
epilepticus new concepts Current Opinion in Neurology
121999 183-190
Da ChapmanAnaesthesia 2004
Marik PEVaron J The Management of Status
Epilepticus Chest 126(2)582-591 August 2004
Status epilepticus is a major medical emergency associated with significant morbidity and mortality Status epilepticusis best defined as a continuous generalized convulsive seizure lasting gt 5 min or two or more seizures during which the patient does not return to baseline consciousness Lorazepam in a dose of 01 mgkg is the drug of first choice for terminating status epilepticus Patients who continue to have clinical or EEG evidence of seizure activity after treatment with lorazepam should be considered to have refractory status epileptics and should be treated with a continuous infusion of propofol or midazolam This article reviews current information regarding the management of status epilepticus in adults
Schema di Marik et al
Claassen JHirsch LJ Emerson R GBates
JE Thompson TBMayer SA Continuous EEG
monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042 bull The authors reviewed 33 episodes of RSE treated with cIV-MDZ in their neurologic intensive care
unit over 6 years All patients were monitored with continuous EEG (cEEG) MDZ infusion rates were titrated to eliminate clinical and EEG seizure activity cIV-MDZ was discontinued once patients were seizure-free for 24 hours Acute treatment failures (seizures 1 to 6 hours after starting cIV-MDZ) breakthrough seizures (after 6 hours of therapy) post-treatment seizures (within 48 hours of discontinuing therapy) and ultimate treatment failure (frequent seizures that led to treatment with pentobarbital or propofol) were identified
bull Results All patients were in nonconvulsive SE at the time cIV-MDZ was started the mean duration of SE before treatment was 39 days (range 0 to 17 days) In addition to benzodiazepines 94 of patients had received at least two antiepileptic drugs (AED) before starting cIV-MDZ The mean loading dose was 019 mgkg the mean maximal infusion rate was 022 mgkgh and the mean duration of cIV-MDZ therapy was 42 days (range 1 to 14 days) Acute treatment failure occurred in 18 (633) of episodes breakthrough seizures in 56 (1832) post-treatment seizures in 68 (1928) and ultimate treatment failure in 18 (633) Breakthrough seizures were clinically subtle or purely electrographic in 89 (1618) of cases and were associated with an increased risk of developing post-treatment seizures (p = 001)
bull Conclusions Although most patients with RSE initially responded to cIV-MDZ over half developed subsequent breakthrough seizures which were predictive of post-treatment seizures and were often detectable only with cEEG Titrating cIV-MDZ to burst suppression more aggressive treatment with concurrent AED or a longer period of initial treatment may reduce the high proportion of patients with RSE who relapse after cIV-MDZ is discontinued
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus Neurology 2001 57 25 1036-1042
0
10
20
30
40
50
60
70
80
non seizures
seizures lt30 min24h05-12 h
seizures 05-12 h24 hgt 12 h
seiz gt12 h24
burst suppression
periodic latdischarge
periodic gen discharge
prima
durante
dopo
33 episodes of RSE treated with cIV-MDZ neurologic ICU over 6 years
All patients were monitored with continuous EEG (cEEG)
Waterhouse Elizabeth J 1 2 DeLorenzo Robert J 1 3 4 2
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
bull Status epilepticus (SE) is a medical and neurological emergency that has been associated with significant morbidity and mortality The most widely accepted definition of SE is more than 30 minutes of either continuous seizure activity or intermittent seizures without full recovery of consciousness between seizures SE is a major clinical concern in the elderly population both because it has increased incidence in the elderly compared with the general population and because of concurrent medical conditions that are more likely to complicate therapy and worsen prognosis in elderly individuals
The incidence of SE in the elderly is almost twice that of the general population at 86 per 100 000 per year With the anticipated growth of the elderly population SE is likely to become an increasingly common problem facing clinicians and an important public health issue The elderly have the highest SE-associated mortality of any age group at 38 and the very old elderly (gt80 years of age) have a mortality of at least 50 Acute or remote stroke is the most common aetiology of SE in the elderly Nonconvulsive SE (NCSE) has a wide range of clinical presentations ranging from confusion to obtundation It occurs commonly in elderly patients who are critically ill and in the setting of coma Electroencephalogram is the only reliable method of diagnosing NCSE
The goal of treatment for SE is rapid cessation of clinical and electrical seizure activity Most treatment protocols call for the immediate administration of an intravenous benzodiazepine followed by phenytoin or fosphenytoin Recent studies suggest that when this initial treatment of SE fails little is gained by using additional standard drugs General anaesthetic agents (such as pentobarbital midazolam or propofol) should be expeditiously employed although these treatments have their own potential complications Intravenous valproic acid is a recent addition to the armamentarium of drugs for the treatment of SE with a low risk of hypotension respiratory depression and hypotension making it a potentially useful drug for the treatment of SE in the elderly However further information is needed to establish its role in the overall treatment of SE
Waterhouseet al
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
BDZ
Fenitoina
O fosfenitoina
GA
Midaz
Propof
pentobarb
Ac valproico
Ns proposta
Lorazepam
01 mgkg
Propofol
1-2 mgkgMidazolam01 mgkg
Inf cont 3-10 mgkgh Inf cont 001-005 mgkgh
Miorilassante solo
Per intubazione
Pentobarbital dose caricopoi 01-04 mgkgmin
fenobarbital
bull 10-20 mgkg iv
ndash Eccessiva sedazione
ndash Depressresp
ndash Ipotensione
ndash Interaz farmacol
ndash Hl gt48 hrhelliphelliphellip
tiopental
bull cumulativo
bull Inotropo neghellip
bull Pentobarbital
bull immunosoppressione
propofol
bull Vantaggi cineticodinamici
bull Titolazione continua possibile
bull TCIquale livello
bull Dosi 1 mgkgripetibile dopo 5rsquo-
ndash Infcont 2-10 mgkgh
bull Rapida emergenzafinestra neurologicaevitare la
brusca sospensione
bull + rapido controllo delle convuls gt barbituricindash Stecker MM Kramer TH Raps EC OMeeghan R Dulaney E Skaar DJ Treatment of
refractory status epilepticus with propofol clinical and pharmacokinetic findings Epilepsia 1998
39 18-26
AG
bull Non ci sono dati che indichino quanto a lungo i paz debbano rimanere senza convuls prima di poter alleggerire il piano di AG24 h96h (Treiman DM Convulsive status
epilepticus Current Treatment Options in Neurology 1999 1 359-69)
bull Anest alogenatiisofluranogtsevofluranogtdesflurane
bull Ma vaporizzatori
bull Contaminazione ambientale
bull Costihellip
Studi comparativi1
bull Midazolamgt tiopental
ndash Lohr A Jr Werneck LC Comparative non-randomized study with
midazolam versus thiopental in children with refractory status
epilepticus [Portuguese] Arq Neuropsiquiatr 2000 58282-287
ndash non-randomized comparison
ndash of historical data (thiopental) and prospectively
acquired data (midazolam)
ndash Midazolam was no more often effective than
thiopental but was associated with less cyanosis and
less respiratory distress in this study of 50 children
Studi comparativi2
Valproatobull Valproate(ivrdquoDepaconrdquo) has been used for the treatment of refractory SE
in children and myoclonic SE ndash Sheth RD Gidal BE Intravenous valproic acid for myoclonic status epilepticus
Neurology 2000 541201
ndash Uberall MA Trollmann R Wunsiedler U Wenzel D Intravenous valproate in pediatric epilepsy patients with refractory status epilepticus Neurology 2000 542188-2189 ]
bull Valproate has also been used in SE in the elderly and appears to be safe even in the presence of cardiovascular instability and hypotension no significant change in blood pressure pulse or the need for vasopressors in 13 patients with SE and hypotension given a loading dose of 147-327 mgkg Depacon intravenouslyndash Sinha S Naritoku DK Intravenous valproate is well tolerated in unstable patients
with status epilepticus Neurology 2000 55722-724
bull However there is a case report of severe hypotension in an 11-year-old child after treatment of SE with 30 mgkg intravenous valproate ndash White JR Santos CS Intravenous valproate associated with significant
hypotension in the treatment of status epilepticus J Child Neurol 1999 14822-823
FINE
Percheacute non ne possiamo
piugravehelliphelliphellip
Trattamento dello stato di
male
Allora
bull Terapia immediata
bull Aggressiva
bull Supporto vitale di base
bull AAirway
bull Breathing
bull CSupporto circolatorio
Status epilepticusfilosofia del trattamento
Disaccoppiamento
CMRO2CBF
Funzione cardiocircolatoriaFunzione resp
Supporto supernormale
Glucosio
Tiamina 100 mg
Dopaminanoradrenalina + fre con barbituricihellip
Indagine conoscitiva su 127 TI NCH europeeDauch WA Schutze M Guttinger M et al Posttraumatic seizure prevention - results of a
survey of 127 neurosurgery clinics Zentralbl Neurochir 1996 57190ndash5
0
10
20
30
40
50
60
profilassi
Profilassi con anticonvulsivi post trauma cranio-
encefalico
mai
sempre
secindicazione
substantial cortical
injurycerebral contusion
acute subdural
hemorrhage
depressed skull fracture
penetrating missile
injury
(141517)
Rischio convulsivo
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001bull Background It is uncertain whether the administration of benzodiazepines by paramedics is an
effective and safe treatment for out-of-hospital status epilepticus
Methods We conducted a randomized double-blind trial to evaluate intravenous benzodiazepines administered by paramedics for the treatment of out-of-hospital status epilepticus Adults with prolonged (lasting five minutes or more) or repetitive generalized convulsive seizures received intravenous diazepam (5 mg) lorazepam (2 mg) or placebo An identical second injection was given if needed
Results Of the 205 patients enrolled 66 received lorazepam 68 received diazepam and 71 received placebo Status epilepticus had been terminated on arrival at the emergency department in more patients treated with lorazepam (591 percent) or diazepam (426 percent) than patients given placebo (211 percent) (P=0001) After adjustment for covariates the odds ratio for termination of status epilepticus by the time of arrival in the lorazepam group as compared with the placebo group was 48 (95 percent confidence interval 19 to 130) The odds ratio was 19 (95 percent confidence interval 08 to 44) in the lorazepam group as compared with the diazepam group and 23 (95 percent confidence interval 10 to 59) in the diazepam group as compared with the placebo group The rates of respiratory or circulatory complications after the study treatment was administered were 106 percent for the lorazepam group 103 percent for the diazepam group and 225 percent for the placebo group (P=008)
Conclusions Benzodiazepines are safe and effective when administered by paramedics for out-of-hospital status epilepticus in adults Lorazepam is likely to be a better therapy than diazepam (N Engl J Med 2001345631-7)
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001
0
10
20
30
40
50
60
seizures stop complications
lorazepam
diazepam
placebo
randomized double-blind trial
to evaluate iv bdz
admin by paramedics
for the treatment of out-of-hospital status epilepticus
Adults with prolonged (lasting 5 minutes or +)
or repetitive generalized convulsive seizures
received iv diazepam (5 mg)
lorazepam (2 mg) or placebo
An identical second injection was given if needed
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
Treiman DM Meyers PD Walton NY Collins JF Colling C Rowan AJ et al A comparison of four treatments for generalized convulsive status epilepticus N Engl J Med 1998 339792-798
randomized double-blind trial that compared the following four regimens commonly used for the treatment of generalized convulsive status epilepticus diazepam followed by phenytoin phenytoin alone phenobarbital and lorazepam Although the doses and infusion rates chosen for study closely reflected common clinical practice at the time the study began the combination of lorazepam followed by phenytoin (the preferred regimen of many neurologists) was not included
This is a large well-controlled and important clinical trial The major limitation in its clinical relevance is the lack of inclusion of a regimen consisting of lorazepam followed by phenytoin
Veterans Affairs Status Epilepticus Cooperative
Study Group Treiman et al
SE aperto
diaz fenitoina fenobarbital lorazepam
2 o + convuls senza
ripresa di coscienza
Convuls continue = gt 10 min
fenitoina
Coma con scariche
ictali EEG
primary outcome measure
cessation of clinical and electrical
seizure activity
within 20min after initiation
of treatment and continuing for at least
60min after the start of treatment
lorazepam fenitoina
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
bull st treatment successful in 555 of patients with a verified diagnosis of overt status epilepticus (n=384) and in 149 of patients with subtle status epilepticus (n=134)
bull Comparisons between the 4 treatments showed that lorazepam was more effective than phenytoin alone in patients with overt status epilepticus (treatment success in 649 versus 436 of patients respectively)
bull other treatment comparisons in the overt group and all comparisons in the subtle group were not significantly different however
bull There were no significant differences between treatments in patient outcome rates of recurrence of status epilepticus or return of full consciousness over the 12-h observation period or in the frequency of adverse cardiac respiratory or hypotensive events
Treiman DM Meyers PD Walton NY et al A
comparison of four treatments for generalized
convulsive status epilepticus N Engl J Med 1998
339792-798
P 002
Percentage of successful treatment
grey bars overt patients black bars subtle patients
Alldredge Brian Kab Lowenstein Daniel HAC Status
epilepticus new concepts Current Opinion in Neurology
121999 183-190
Da ChapmanAnaesthesia 2004
Marik PEVaron J The Management of Status
Epilepticus Chest 126(2)582-591 August 2004
Status epilepticus is a major medical emergency associated with significant morbidity and mortality Status epilepticusis best defined as a continuous generalized convulsive seizure lasting gt 5 min or two or more seizures during which the patient does not return to baseline consciousness Lorazepam in a dose of 01 mgkg is the drug of first choice for terminating status epilepticus Patients who continue to have clinical or EEG evidence of seizure activity after treatment with lorazepam should be considered to have refractory status epileptics and should be treated with a continuous infusion of propofol or midazolam This article reviews current information regarding the management of status epilepticus in adults
Schema di Marik et al
Claassen JHirsch LJ Emerson R GBates
JE Thompson TBMayer SA Continuous EEG
monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042 bull The authors reviewed 33 episodes of RSE treated with cIV-MDZ in their neurologic intensive care
unit over 6 years All patients were monitored with continuous EEG (cEEG) MDZ infusion rates were titrated to eliminate clinical and EEG seizure activity cIV-MDZ was discontinued once patients were seizure-free for 24 hours Acute treatment failures (seizures 1 to 6 hours after starting cIV-MDZ) breakthrough seizures (after 6 hours of therapy) post-treatment seizures (within 48 hours of discontinuing therapy) and ultimate treatment failure (frequent seizures that led to treatment with pentobarbital or propofol) were identified
bull Results All patients were in nonconvulsive SE at the time cIV-MDZ was started the mean duration of SE before treatment was 39 days (range 0 to 17 days) In addition to benzodiazepines 94 of patients had received at least two antiepileptic drugs (AED) before starting cIV-MDZ The mean loading dose was 019 mgkg the mean maximal infusion rate was 022 mgkgh and the mean duration of cIV-MDZ therapy was 42 days (range 1 to 14 days) Acute treatment failure occurred in 18 (633) of episodes breakthrough seizures in 56 (1832) post-treatment seizures in 68 (1928) and ultimate treatment failure in 18 (633) Breakthrough seizures were clinically subtle or purely electrographic in 89 (1618) of cases and were associated with an increased risk of developing post-treatment seizures (p = 001)
bull Conclusions Although most patients with RSE initially responded to cIV-MDZ over half developed subsequent breakthrough seizures which were predictive of post-treatment seizures and were often detectable only with cEEG Titrating cIV-MDZ to burst suppression more aggressive treatment with concurrent AED or a longer period of initial treatment may reduce the high proportion of patients with RSE who relapse after cIV-MDZ is discontinued
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus Neurology 2001 57 25 1036-1042
0
10
20
30
40
50
60
70
80
non seizures
seizures lt30 min24h05-12 h
seizures 05-12 h24 hgt 12 h
seiz gt12 h24
burst suppression
periodic latdischarge
periodic gen discharge
prima
durante
dopo
33 episodes of RSE treated with cIV-MDZ neurologic ICU over 6 years
All patients were monitored with continuous EEG (cEEG)
Waterhouse Elizabeth J 1 2 DeLorenzo Robert J 1 3 4 2
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
bull Status epilepticus (SE) is a medical and neurological emergency that has been associated with significant morbidity and mortality The most widely accepted definition of SE is more than 30 minutes of either continuous seizure activity or intermittent seizures without full recovery of consciousness between seizures SE is a major clinical concern in the elderly population both because it has increased incidence in the elderly compared with the general population and because of concurrent medical conditions that are more likely to complicate therapy and worsen prognosis in elderly individuals
The incidence of SE in the elderly is almost twice that of the general population at 86 per 100 000 per year With the anticipated growth of the elderly population SE is likely to become an increasingly common problem facing clinicians and an important public health issue The elderly have the highest SE-associated mortality of any age group at 38 and the very old elderly (gt80 years of age) have a mortality of at least 50 Acute or remote stroke is the most common aetiology of SE in the elderly Nonconvulsive SE (NCSE) has a wide range of clinical presentations ranging from confusion to obtundation It occurs commonly in elderly patients who are critically ill and in the setting of coma Electroencephalogram is the only reliable method of diagnosing NCSE
The goal of treatment for SE is rapid cessation of clinical and electrical seizure activity Most treatment protocols call for the immediate administration of an intravenous benzodiazepine followed by phenytoin or fosphenytoin Recent studies suggest that when this initial treatment of SE fails little is gained by using additional standard drugs General anaesthetic agents (such as pentobarbital midazolam or propofol) should be expeditiously employed although these treatments have their own potential complications Intravenous valproic acid is a recent addition to the armamentarium of drugs for the treatment of SE with a low risk of hypotension respiratory depression and hypotension making it a potentially useful drug for the treatment of SE in the elderly However further information is needed to establish its role in the overall treatment of SE
Waterhouseet al
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
BDZ
Fenitoina
O fosfenitoina
GA
Midaz
Propof
pentobarb
Ac valproico
Ns proposta
Lorazepam
01 mgkg
Propofol
1-2 mgkgMidazolam01 mgkg
Inf cont 3-10 mgkgh Inf cont 001-005 mgkgh
Miorilassante solo
Per intubazione
Pentobarbital dose caricopoi 01-04 mgkgmin
fenobarbital
bull 10-20 mgkg iv
ndash Eccessiva sedazione
ndash Depressresp
ndash Ipotensione
ndash Interaz farmacol
ndash Hl gt48 hrhelliphelliphellip
tiopental
bull cumulativo
bull Inotropo neghellip
bull Pentobarbital
bull immunosoppressione
propofol
bull Vantaggi cineticodinamici
bull Titolazione continua possibile
bull TCIquale livello
bull Dosi 1 mgkgripetibile dopo 5rsquo-
ndash Infcont 2-10 mgkgh
bull Rapida emergenzafinestra neurologicaevitare la
brusca sospensione
bull + rapido controllo delle convuls gt barbituricindash Stecker MM Kramer TH Raps EC OMeeghan R Dulaney E Skaar DJ Treatment of
refractory status epilepticus with propofol clinical and pharmacokinetic findings Epilepsia 1998
39 18-26
AG
bull Non ci sono dati che indichino quanto a lungo i paz debbano rimanere senza convuls prima di poter alleggerire il piano di AG24 h96h (Treiman DM Convulsive status
epilepticus Current Treatment Options in Neurology 1999 1 359-69)
bull Anest alogenatiisofluranogtsevofluranogtdesflurane
bull Ma vaporizzatori
bull Contaminazione ambientale
bull Costihellip
Studi comparativi1
bull Midazolamgt tiopental
ndash Lohr A Jr Werneck LC Comparative non-randomized study with
midazolam versus thiopental in children with refractory status
epilepticus [Portuguese] Arq Neuropsiquiatr 2000 58282-287
ndash non-randomized comparison
ndash of historical data (thiopental) and prospectively
acquired data (midazolam)
ndash Midazolam was no more often effective than
thiopental but was associated with less cyanosis and
less respiratory distress in this study of 50 children
Studi comparativi2
Valproatobull Valproate(ivrdquoDepaconrdquo) has been used for the treatment of refractory SE
in children and myoclonic SE ndash Sheth RD Gidal BE Intravenous valproic acid for myoclonic status epilepticus
Neurology 2000 541201
ndash Uberall MA Trollmann R Wunsiedler U Wenzel D Intravenous valproate in pediatric epilepsy patients with refractory status epilepticus Neurology 2000 542188-2189 ]
bull Valproate has also been used in SE in the elderly and appears to be safe even in the presence of cardiovascular instability and hypotension no significant change in blood pressure pulse or the need for vasopressors in 13 patients with SE and hypotension given a loading dose of 147-327 mgkg Depacon intravenouslyndash Sinha S Naritoku DK Intravenous valproate is well tolerated in unstable patients
with status epilepticus Neurology 2000 55722-724
bull However there is a case report of severe hypotension in an 11-year-old child after treatment of SE with 30 mgkg intravenous valproate ndash White JR Santos CS Intravenous valproate associated with significant
hypotension in the treatment of status epilepticus J Child Neurol 1999 14822-823
FINE
Percheacute non ne possiamo
piugravehelliphelliphellip
Allora
bull Terapia immediata
bull Aggressiva
bull Supporto vitale di base
bull AAirway
bull Breathing
bull CSupporto circolatorio
Status epilepticusfilosofia del trattamento
Disaccoppiamento
CMRO2CBF
Funzione cardiocircolatoriaFunzione resp
Supporto supernormale
Glucosio
Tiamina 100 mg
Dopaminanoradrenalina + fre con barbituricihellip
Indagine conoscitiva su 127 TI NCH europeeDauch WA Schutze M Guttinger M et al Posttraumatic seizure prevention - results of a
survey of 127 neurosurgery clinics Zentralbl Neurochir 1996 57190ndash5
0
10
20
30
40
50
60
profilassi
Profilassi con anticonvulsivi post trauma cranio-
encefalico
mai
sempre
secindicazione
substantial cortical
injurycerebral contusion
acute subdural
hemorrhage
depressed skull fracture
penetrating missile
injury
(141517)
Rischio convulsivo
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001bull Background It is uncertain whether the administration of benzodiazepines by paramedics is an
effective and safe treatment for out-of-hospital status epilepticus
Methods We conducted a randomized double-blind trial to evaluate intravenous benzodiazepines administered by paramedics for the treatment of out-of-hospital status epilepticus Adults with prolonged (lasting five minutes or more) or repetitive generalized convulsive seizures received intravenous diazepam (5 mg) lorazepam (2 mg) or placebo An identical second injection was given if needed
Results Of the 205 patients enrolled 66 received lorazepam 68 received diazepam and 71 received placebo Status epilepticus had been terminated on arrival at the emergency department in more patients treated with lorazepam (591 percent) or diazepam (426 percent) than patients given placebo (211 percent) (P=0001) After adjustment for covariates the odds ratio for termination of status epilepticus by the time of arrival in the lorazepam group as compared with the placebo group was 48 (95 percent confidence interval 19 to 130) The odds ratio was 19 (95 percent confidence interval 08 to 44) in the lorazepam group as compared with the diazepam group and 23 (95 percent confidence interval 10 to 59) in the diazepam group as compared with the placebo group The rates of respiratory or circulatory complications after the study treatment was administered were 106 percent for the lorazepam group 103 percent for the diazepam group and 225 percent for the placebo group (P=008)
Conclusions Benzodiazepines are safe and effective when administered by paramedics for out-of-hospital status epilepticus in adults Lorazepam is likely to be a better therapy than diazepam (N Engl J Med 2001345631-7)
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001
0
10
20
30
40
50
60
seizures stop complications
lorazepam
diazepam
placebo
randomized double-blind trial
to evaluate iv bdz
admin by paramedics
for the treatment of out-of-hospital status epilepticus
Adults with prolonged (lasting 5 minutes or +)
or repetitive generalized convulsive seizures
received iv diazepam (5 mg)
lorazepam (2 mg) or placebo
An identical second injection was given if needed
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
Treiman DM Meyers PD Walton NY Collins JF Colling C Rowan AJ et al A comparison of four treatments for generalized convulsive status epilepticus N Engl J Med 1998 339792-798
randomized double-blind trial that compared the following four regimens commonly used for the treatment of generalized convulsive status epilepticus diazepam followed by phenytoin phenytoin alone phenobarbital and lorazepam Although the doses and infusion rates chosen for study closely reflected common clinical practice at the time the study began the combination of lorazepam followed by phenytoin (the preferred regimen of many neurologists) was not included
This is a large well-controlled and important clinical trial The major limitation in its clinical relevance is the lack of inclusion of a regimen consisting of lorazepam followed by phenytoin
Veterans Affairs Status Epilepticus Cooperative
Study Group Treiman et al
SE aperto
diaz fenitoina fenobarbital lorazepam
2 o + convuls senza
ripresa di coscienza
Convuls continue = gt 10 min
fenitoina
Coma con scariche
ictali EEG
primary outcome measure
cessation of clinical and electrical
seizure activity
within 20min after initiation
of treatment and continuing for at least
60min after the start of treatment
lorazepam fenitoina
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
bull st treatment successful in 555 of patients with a verified diagnosis of overt status epilepticus (n=384) and in 149 of patients with subtle status epilepticus (n=134)
bull Comparisons between the 4 treatments showed that lorazepam was more effective than phenytoin alone in patients with overt status epilepticus (treatment success in 649 versus 436 of patients respectively)
bull other treatment comparisons in the overt group and all comparisons in the subtle group were not significantly different however
bull There were no significant differences between treatments in patient outcome rates of recurrence of status epilepticus or return of full consciousness over the 12-h observation period or in the frequency of adverse cardiac respiratory or hypotensive events
Treiman DM Meyers PD Walton NY et al A
comparison of four treatments for generalized
convulsive status epilepticus N Engl J Med 1998
339792-798
P 002
Percentage of successful treatment
grey bars overt patients black bars subtle patients
Alldredge Brian Kab Lowenstein Daniel HAC Status
epilepticus new concepts Current Opinion in Neurology
121999 183-190
Da ChapmanAnaesthesia 2004
Marik PEVaron J The Management of Status
Epilepticus Chest 126(2)582-591 August 2004
Status epilepticus is a major medical emergency associated with significant morbidity and mortality Status epilepticusis best defined as a continuous generalized convulsive seizure lasting gt 5 min or two or more seizures during which the patient does not return to baseline consciousness Lorazepam in a dose of 01 mgkg is the drug of first choice for terminating status epilepticus Patients who continue to have clinical or EEG evidence of seizure activity after treatment with lorazepam should be considered to have refractory status epileptics and should be treated with a continuous infusion of propofol or midazolam This article reviews current information regarding the management of status epilepticus in adults
Schema di Marik et al
Claassen JHirsch LJ Emerson R GBates
JE Thompson TBMayer SA Continuous EEG
monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042 bull The authors reviewed 33 episodes of RSE treated with cIV-MDZ in their neurologic intensive care
unit over 6 years All patients were monitored with continuous EEG (cEEG) MDZ infusion rates were titrated to eliminate clinical and EEG seizure activity cIV-MDZ was discontinued once patients were seizure-free for 24 hours Acute treatment failures (seizures 1 to 6 hours after starting cIV-MDZ) breakthrough seizures (after 6 hours of therapy) post-treatment seizures (within 48 hours of discontinuing therapy) and ultimate treatment failure (frequent seizures that led to treatment with pentobarbital or propofol) were identified
bull Results All patients were in nonconvulsive SE at the time cIV-MDZ was started the mean duration of SE before treatment was 39 days (range 0 to 17 days) In addition to benzodiazepines 94 of patients had received at least two antiepileptic drugs (AED) before starting cIV-MDZ The mean loading dose was 019 mgkg the mean maximal infusion rate was 022 mgkgh and the mean duration of cIV-MDZ therapy was 42 days (range 1 to 14 days) Acute treatment failure occurred in 18 (633) of episodes breakthrough seizures in 56 (1832) post-treatment seizures in 68 (1928) and ultimate treatment failure in 18 (633) Breakthrough seizures were clinically subtle or purely electrographic in 89 (1618) of cases and were associated with an increased risk of developing post-treatment seizures (p = 001)
bull Conclusions Although most patients with RSE initially responded to cIV-MDZ over half developed subsequent breakthrough seizures which were predictive of post-treatment seizures and were often detectable only with cEEG Titrating cIV-MDZ to burst suppression more aggressive treatment with concurrent AED or a longer period of initial treatment may reduce the high proportion of patients with RSE who relapse after cIV-MDZ is discontinued
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus Neurology 2001 57 25 1036-1042
0
10
20
30
40
50
60
70
80
non seizures
seizures lt30 min24h05-12 h
seizures 05-12 h24 hgt 12 h
seiz gt12 h24
burst suppression
periodic latdischarge
periodic gen discharge
prima
durante
dopo
33 episodes of RSE treated with cIV-MDZ neurologic ICU over 6 years
All patients were monitored with continuous EEG (cEEG)
Waterhouse Elizabeth J 1 2 DeLorenzo Robert J 1 3 4 2
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
bull Status epilepticus (SE) is a medical and neurological emergency that has been associated with significant morbidity and mortality The most widely accepted definition of SE is more than 30 minutes of either continuous seizure activity or intermittent seizures without full recovery of consciousness between seizures SE is a major clinical concern in the elderly population both because it has increased incidence in the elderly compared with the general population and because of concurrent medical conditions that are more likely to complicate therapy and worsen prognosis in elderly individuals
The incidence of SE in the elderly is almost twice that of the general population at 86 per 100 000 per year With the anticipated growth of the elderly population SE is likely to become an increasingly common problem facing clinicians and an important public health issue The elderly have the highest SE-associated mortality of any age group at 38 and the very old elderly (gt80 years of age) have a mortality of at least 50 Acute or remote stroke is the most common aetiology of SE in the elderly Nonconvulsive SE (NCSE) has a wide range of clinical presentations ranging from confusion to obtundation It occurs commonly in elderly patients who are critically ill and in the setting of coma Electroencephalogram is the only reliable method of diagnosing NCSE
The goal of treatment for SE is rapid cessation of clinical and electrical seizure activity Most treatment protocols call for the immediate administration of an intravenous benzodiazepine followed by phenytoin or fosphenytoin Recent studies suggest that when this initial treatment of SE fails little is gained by using additional standard drugs General anaesthetic agents (such as pentobarbital midazolam or propofol) should be expeditiously employed although these treatments have their own potential complications Intravenous valproic acid is a recent addition to the armamentarium of drugs for the treatment of SE with a low risk of hypotension respiratory depression and hypotension making it a potentially useful drug for the treatment of SE in the elderly However further information is needed to establish its role in the overall treatment of SE
Waterhouseet al
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
BDZ
Fenitoina
O fosfenitoina
GA
Midaz
Propof
pentobarb
Ac valproico
Ns proposta
Lorazepam
01 mgkg
Propofol
1-2 mgkgMidazolam01 mgkg
Inf cont 3-10 mgkgh Inf cont 001-005 mgkgh
Miorilassante solo
Per intubazione
Pentobarbital dose caricopoi 01-04 mgkgmin
fenobarbital
bull 10-20 mgkg iv
ndash Eccessiva sedazione
ndash Depressresp
ndash Ipotensione
ndash Interaz farmacol
ndash Hl gt48 hrhelliphelliphellip
tiopental
bull cumulativo
bull Inotropo neghellip
bull Pentobarbital
bull immunosoppressione
propofol
bull Vantaggi cineticodinamici
bull Titolazione continua possibile
bull TCIquale livello
bull Dosi 1 mgkgripetibile dopo 5rsquo-
ndash Infcont 2-10 mgkgh
bull Rapida emergenzafinestra neurologicaevitare la
brusca sospensione
bull + rapido controllo delle convuls gt barbituricindash Stecker MM Kramer TH Raps EC OMeeghan R Dulaney E Skaar DJ Treatment of
refractory status epilepticus with propofol clinical and pharmacokinetic findings Epilepsia 1998
39 18-26
AG
bull Non ci sono dati che indichino quanto a lungo i paz debbano rimanere senza convuls prima di poter alleggerire il piano di AG24 h96h (Treiman DM Convulsive status
epilepticus Current Treatment Options in Neurology 1999 1 359-69)
bull Anest alogenatiisofluranogtsevofluranogtdesflurane
bull Ma vaporizzatori
bull Contaminazione ambientale
bull Costihellip
Studi comparativi1
bull Midazolamgt tiopental
ndash Lohr A Jr Werneck LC Comparative non-randomized study with
midazolam versus thiopental in children with refractory status
epilepticus [Portuguese] Arq Neuropsiquiatr 2000 58282-287
ndash non-randomized comparison
ndash of historical data (thiopental) and prospectively
acquired data (midazolam)
ndash Midazolam was no more often effective than
thiopental but was associated with less cyanosis and
less respiratory distress in this study of 50 children
Studi comparativi2
Valproatobull Valproate(ivrdquoDepaconrdquo) has been used for the treatment of refractory SE
in children and myoclonic SE ndash Sheth RD Gidal BE Intravenous valproic acid for myoclonic status epilepticus
Neurology 2000 541201
ndash Uberall MA Trollmann R Wunsiedler U Wenzel D Intravenous valproate in pediatric epilepsy patients with refractory status epilepticus Neurology 2000 542188-2189 ]
bull Valproate has also been used in SE in the elderly and appears to be safe even in the presence of cardiovascular instability and hypotension no significant change in blood pressure pulse or the need for vasopressors in 13 patients with SE and hypotension given a loading dose of 147-327 mgkg Depacon intravenouslyndash Sinha S Naritoku DK Intravenous valproate is well tolerated in unstable patients
with status epilepticus Neurology 2000 55722-724
bull However there is a case report of severe hypotension in an 11-year-old child after treatment of SE with 30 mgkg intravenous valproate ndash White JR Santos CS Intravenous valproate associated with significant
hypotension in the treatment of status epilepticus J Child Neurol 1999 14822-823
FINE
Percheacute non ne possiamo
piugravehelliphelliphellip
Status epilepticusfilosofia del trattamento
Disaccoppiamento
CMRO2CBF
Funzione cardiocircolatoriaFunzione resp
Supporto supernormale
Glucosio
Tiamina 100 mg
Dopaminanoradrenalina + fre con barbituricihellip
Indagine conoscitiva su 127 TI NCH europeeDauch WA Schutze M Guttinger M et al Posttraumatic seizure prevention - results of a
survey of 127 neurosurgery clinics Zentralbl Neurochir 1996 57190ndash5
0
10
20
30
40
50
60
profilassi
Profilassi con anticonvulsivi post trauma cranio-
encefalico
mai
sempre
secindicazione
substantial cortical
injurycerebral contusion
acute subdural
hemorrhage
depressed skull fracture
penetrating missile
injury
(141517)
Rischio convulsivo
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001bull Background It is uncertain whether the administration of benzodiazepines by paramedics is an
effective and safe treatment for out-of-hospital status epilepticus
Methods We conducted a randomized double-blind trial to evaluate intravenous benzodiazepines administered by paramedics for the treatment of out-of-hospital status epilepticus Adults with prolonged (lasting five minutes or more) or repetitive generalized convulsive seizures received intravenous diazepam (5 mg) lorazepam (2 mg) or placebo An identical second injection was given if needed
Results Of the 205 patients enrolled 66 received lorazepam 68 received diazepam and 71 received placebo Status epilepticus had been terminated on arrival at the emergency department in more patients treated with lorazepam (591 percent) or diazepam (426 percent) than patients given placebo (211 percent) (P=0001) After adjustment for covariates the odds ratio for termination of status epilepticus by the time of arrival in the lorazepam group as compared with the placebo group was 48 (95 percent confidence interval 19 to 130) The odds ratio was 19 (95 percent confidence interval 08 to 44) in the lorazepam group as compared with the diazepam group and 23 (95 percent confidence interval 10 to 59) in the diazepam group as compared with the placebo group The rates of respiratory or circulatory complications after the study treatment was administered were 106 percent for the lorazepam group 103 percent for the diazepam group and 225 percent for the placebo group (P=008)
Conclusions Benzodiazepines are safe and effective when administered by paramedics for out-of-hospital status epilepticus in adults Lorazepam is likely to be a better therapy than diazepam (N Engl J Med 2001345631-7)
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001
0
10
20
30
40
50
60
seizures stop complications
lorazepam
diazepam
placebo
randomized double-blind trial
to evaluate iv bdz
admin by paramedics
for the treatment of out-of-hospital status epilepticus
Adults with prolonged (lasting 5 minutes or +)
or repetitive generalized convulsive seizures
received iv diazepam (5 mg)
lorazepam (2 mg) or placebo
An identical second injection was given if needed
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
Treiman DM Meyers PD Walton NY Collins JF Colling C Rowan AJ et al A comparison of four treatments for generalized convulsive status epilepticus N Engl J Med 1998 339792-798
randomized double-blind trial that compared the following four regimens commonly used for the treatment of generalized convulsive status epilepticus diazepam followed by phenytoin phenytoin alone phenobarbital and lorazepam Although the doses and infusion rates chosen for study closely reflected common clinical practice at the time the study began the combination of lorazepam followed by phenytoin (the preferred regimen of many neurologists) was not included
This is a large well-controlled and important clinical trial The major limitation in its clinical relevance is the lack of inclusion of a regimen consisting of lorazepam followed by phenytoin
Veterans Affairs Status Epilepticus Cooperative
Study Group Treiman et al
SE aperto
diaz fenitoina fenobarbital lorazepam
2 o + convuls senza
ripresa di coscienza
Convuls continue = gt 10 min
fenitoina
Coma con scariche
ictali EEG
primary outcome measure
cessation of clinical and electrical
seizure activity
within 20min after initiation
of treatment and continuing for at least
60min after the start of treatment
lorazepam fenitoina
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
bull st treatment successful in 555 of patients with a verified diagnosis of overt status epilepticus (n=384) and in 149 of patients with subtle status epilepticus (n=134)
bull Comparisons between the 4 treatments showed that lorazepam was more effective than phenytoin alone in patients with overt status epilepticus (treatment success in 649 versus 436 of patients respectively)
bull other treatment comparisons in the overt group and all comparisons in the subtle group were not significantly different however
bull There were no significant differences between treatments in patient outcome rates of recurrence of status epilepticus or return of full consciousness over the 12-h observation period or in the frequency of adverse cardiac respiratory or hypotensive events
Treiman DM Meyers PD Walton NY et al A
comparison of four treatments for generalized
convulsive status epilepticus N Engl J Med 1998
339792-798
P 002
Percentage of successful treatment
grey bars overt patients black bars subtle patients
Alldredge Brian Kab Lowenstein Daniel HAC Status
epilepticus new concepts Current Opinion in Neurology
121999 183-190
Da ChapmanAnaesthesia 2004
Marik PEVaron J The Management of Status
Epilepticus Chest 126(2)582-591 August 2004
Status epilepticus is a major medical emergency associated with significant morbidity and mortality Status epilepticusis best defined as a continuous generalized convulsive seizure lasting gt 5 min or two or more seizures during which the patient does not return to baseline consciousness Lorazepam in a dose of 01 mgkg is the drug of first choice for terminating status epilepticus Patients who continue to have clinical or EEG evidence of seizure activity after treatment with lorazepam should be considered to have refractory status epileptics and should be treated with a continuous infusion of propofol or midazolam This article reviews current information regarding the management of status epilepticus in adults
Schema di Marik et al
Claassen JHirsch LJ Emerson R GBates
JE Thompson TBMayer SA Continuous EEG
monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042 bull The authors reviewed 33 episodes of RSE treated with cIV-MDZ in their neurologic intensive care
unit over 6 years All patients were monitored with continuous EEG (cEEG) MDZ infusion rates were titrated to eliminate clinical and EEG seizure activity cIV-MDZ was discontinued once patients were seizure-free for 24 hours Acute treatment failures (seizures 1 to 6 hours after starting cIV-MDZ) breakthrough seizures (after 6 hours of therapy) post-treatment seizures (within 48 hours of discontinuing therapy) and ultimate treatment failure (frequent seizures that led to treatment with pentobarbital or propofol) were identified
bull Results All patients were in nonconvulsive SE at the time cIV-MDZ was started the mean duration of SE before treatment was 39 days (range 0 to 17 days) In addition to benzodiazepines 94 of patients had received at least two antiepileptic drugs (AED) before starting cIV-MDZ The mean loading dose was 019 mgkg the mean maximal infusion rate was 022 mgkgh and the mean duration of cIV-MDZ therapy was 42 days (range 1 to 14 days) Acute treatment failure occurred in 18 (633) of episodes breakthrough seizures in 56 (1832) post-treatment seizures in 68 (1928) and ultimate treatment failure in 18 (633) Breakthrough seizures were clinically subtle or purely electrographic in 89 (1618) of cases and were associated with an increased risk of developing post-treatment seizures (p = 001)
bull Conclusions Although most patients with RSE initially responded to cIV-MDZ over half developed subsequent breakthrough seizures which were predictive of post-treatment seizures and were often detectable only with cEEG Titrating cIV-MDZ to burst suppression more aggressive treatment with concurrent AED or a longer period of initial treatment may reduce the high proportion of patients with RSE who relapse after cIV-MDZ is discontinued
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus Neurology 2001 57 25 1036-1042
0
10
20
30
40
50
60
70
80
non seizures
seizures lt30 min24h05-12 h
seizures 05-12 h24 hgt 12 h
seiz gt12 h24
burst suppression
periodic latdischarge
periodic gen discharge
prima
durante
dopo
33 episodes of RSE treated with cIV-MDZ neurologic ICU over 6 years
All patients were monitored with continuous EEG (cEEG)
Waterhouse Elizabeth J 1 2 DeLorenzo Robert J 1 3 4 2
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
bull Status epilepticus (SE) is a medical and neurological emergency that has been associated with significant morbidity and mortality The most widely accepted definition of SE is more than 30 minutes of either continuous seizure activity or intermittent seizures without full recovery of consciousness between seizures SE is a major clinical concern in the elderly population both because it has increased incidence in the elderly compared with the general population and because of concurrent medical conditions that are more likely to complicate therapy and worsen prognosis in elderly individuals
The incidence of SE in the elderly is almost twice that of the general population at 86 per 100 000 per year With the anticipated growth of the elderly population SE is likely to become an increasingly common problem facing clinicians and an important public health issue The elderly have the highest SE-associated mortality of any age group at 38 and the very old elderly (gt80 years of age) have a mortality of at least 50 Acute or remote stroke is the most common aetiology of SE in the elderly Nonconvulsive SE (NCSE) has a wide range of clinical presentations ranging from confusion to obtundation It occurs commonly in elderly patients who are critically ill and in the setting of coma Electroencephalogram is the only reliable method of diagnosing NCSE
The goal of treatment for SE is rapid cessation of clinical and electrical seizure activity Most treatment protocols call for the immediate administration of an intravenous benzodiazepine followed by phenytoin or fosphenytoin Recent studies suggest that when this initial treatment of SE fails little is gained by using additional standard drugs General anaesthetic agents (such as pentobarbital midazolam or propofol) should be expeditiously employed although these treatments have their own potential complications Intravenous valproic acid is a recent addition to the armamentarium of drugs for the treatment of SE with a low risk of hypotension respiratory depression and hypotension making it a potentially useful drug for the treatment of SE in the elderly However further information is needed to establish its role in the overall treatment of SE
Waterhouseet al
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
BDZ
Fenitoina
O fosfenitoina
GA
Midaz
Propof
pentobarb
Ac valproico
Ns proposta
Lorazepam
01 mgkg
Propofol
1-2 mgkgMidazolam01 mgkg
Inf cont 3-10 mgkgh Inf cont 001-005 mgkgh
Miorilassante solo
Per intubazione
Pentobarbital dose caricopoi 01-04 mgkgmin
fenobarbital
bull 10-20 mgkg iv
ndash Eccessiva sedazione
ndash Depressresp
ndash Ipotensione
ndash Interaz farmacol
ndash Hl gt48 hrhelliphelliphellip
tiopental
bull cumulativo
bull Inotropo neghellip
bull Pentobarbital
bull immunosoppressione
propofol
bull Vantaggi cineticodinamici
bull Titolazione continua possibile
bull TCIquale livello
bull Dosi 1 mgkgripetibile dopo 5rsquo-
ndash Infcont 2-10 mgkgh
bull Rapida emergenzafinestra neurologicaevitare la
brusca sospensione
bull + rapido controllo delle convuls gt barbituricindash Stecker MM Kramer TH Raps EC OMeeghan R Dulaney E Skaar DJ Treatment of
refractory status epilepticus with propofol clinical and pharmacokinetic findings Epilepsia 1998
39 18-26
AG
bull Non ci sono dati che indichino quanto a lungo i paz debbano rimanere senza convuls prima di poter alleggerire il piano di AG24 h96h (Treiman DM Convulsive status
epilepticus Current Treatment Options in Neurology 1999 1 359-69)
bull Anest alogenatiisofluranogtsevofluranogtdesflurane
bull Ma vaporizzatori
bull Contaminazione ambientale
bull Costihellip
Studi comparativi1
bull Midazolamgt tiopental
ndash Lohr A Jr Werneck LC Comparative non-randomized study with
midazolam versus thiopental in children with refractory status
epilepticus [Portuguese] Arq Neuropsiquiatr 2000 58282-287
ndash non-randomized comparison
ndash of historical data (thiopental) and prospectively
acquired data (midazolam)
ndash Midazolam was no more often effective than
thiopental but was associated with less cyanosis and
less respiratory distress in this study of 50 children
Studi comparativi2
Valproatobull Valproate(ivrdquoDepaconrdquo) has been used for the treatment of refractory SE
in children and myoclonic SE ndash Sheth RD Gidal BE Intravenous valproic acid for myoclonic status epilepticus
Neurology 2000 541201
ndash Uberall MA Trollmann R Wunsiedler U Wenzel D Intravenous valproate in pediatric epilepsy patients with refractory status epilepticus Neurology 2000 542188-2189 ]
bull Valproate has also been used in SE in the elderly and appears to be safe even in the presence of cardiovascular instability and hypotension no significant change in blood pressure pulse or the need for vasopressors in 13 patients with SE and hypotension given a loading dose of 147-327 mgkg Depacon intravenouslyndash Sinha S Naritoku DK Intravenous valproate is well tolerated in unstable patients
with status epilepticus Neurology 2000 55722-724
bull However there is a case report of severe hypotension in an 11-year-old child after treatment of SE with 30 mgkg intravenous valproate ndash White JR Santos CS Intravenous valproate associated with significant
hypotension in the treatment of status epilepticus J Child Neurol 1999 14822-823
FINE
Percheacute non ne possiamo
piugravehelliphelliphellip
Indagine conoscitiva su 127 TI NCH europeeDauch WA Schutze M Guttinger M et al Posttraumatic seizure prevention - results of a
survey of 127 neurosurgery clinics Zentralbl Neurochir 1996 57190ndash5
0
10
20
30
40
50
60
profilassi
Profilassi con anticonvulsivi post trauma cranio-
encefalico
mai
sempre
secindicazione
substantial cortical
injurycerebral contusion
acute subdural
hemorrhage
depressed skull fracture
penetrating missile
injury
(141517)
Rischio convulsivo
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001bull Background It is uncertain whether the administration of benzodiazepines by paramedics is an
effective and safe treatment for out-of-hospital status epilepticus
Methods We conducted a randomized double-blind trial to evaluate intravenous benzodiazepines administered by paramedics for the treatment of out-of-hospital status epilepticus Adults with prolonged (lasting five minutes or more) or repetitive generalized convulsive seizures received intravenous diazepam (5 mg) lorazepam (2 mg) or placebo An identical second injection was given if needed
Results Of the 205 patients enrolled 66 received lorazepam 68 received diazepam and 71 received placebo Status epilepticus had been terminated on arrival at the emergency department in more patients treated with lorazepam (591 percent) or diazepam (426 percent) than patients given placebo (211 percent) (P=0001) After adjustment for covariates the odds ratio for termination of status epilepticus by the time of arrival in the lorazepam group as compared with the placebo group was 48 (95 percent confidence interval 19 to 130) The odds ratio was 19 (95 percent confidence interval 08 to 44) in the lorazepam group as compared with the diazepam group and 23 (95 percent confidence interval 10 to 59) in the diazepam group as compared with the placebo group The rates of respiratory or circulatory complications after the study treatment was administered were 106 percent for the lorazepam group 103 percent for the diazepam group and 225 percent for the placebo group (P=008)
Conclusions Benzodiazepines are safe and effective when administered by paramedics for out-of-hospital status epilepticus in adults Lorazepam is likely to be a better therapy than diazepam (N Engl J Med 2001345631-7)
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001
0
10
20
30
40
50
60
seizures stop complications
lorazepam
diazepam
placebo
randomized double-blind trial
to evaluate iv bdz
admin by paramedics
for the treatment of out-of-hospital status epilepticus
Adults with prolonged (lasting 5 minutes or +)
or repetitive generalized convulsive seizures
received iv diazepam (5 mg)
lorazepam (2 mg) or placebo
An identical second injection was given if needed
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
Treiman DM Meyers PD Walton NY Collins JF Colling C Rowan AJ et al A comparison of four treatments for generalized convulsive status epilepticus N Engl J Med 1998 339792-798
randomized double-blind trial that compared the following four regimens commonly used for the treatment of generalized convulsive status epilepticus diazepam followed by phenytoin phenytoin alone phenobarbital and lorazepam Although the doses and infusion rates chosen for study closely reflected common clinical practice at the time the study began the combination of lorazepam followed by phenytoin (the preferred regimen of many neurologists) was not included
This is a large well-controlled and important clinical trial The major limitation in its clinical relevance is the lack of inclusion of a regimen consisting of lorazepam followed by phenytoin
Veterans Affairs Status Epilepticus Cooperative
Study Group Treiman et al
SE aperto
diaz fenitoina fenobarbital lorazepam
2 o + convuls senza
ripresa di coscienza
Convuls continue = gt 10 min
fenitoina
Coma con scariche
ictali EEG
primary outcome measure
cessation of clinical and electrical
seizure activity
within 20min after initiation
of treatment and continuing for at least
60min after the start of treatment
lorazepam fenitoina
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
bull st treatment successful in 555 of patients with a verified diagnosis of overt status epilepticus (n=384) and in 149 of patients with subtle status epilepticus (n=134)
bull Comparisons between the 4 treatments showed that lorazepam was more effective than phenytoin alone in patients with overt status epilepticus (treatment success in 649 versus 436 of patients respectively)
bull other treatment comparisons in the overt group and all comparisons in the subtle group were not significantly different however
bull There were no significant differences between treatments in patient outcome rates of recurrence of status epilepticus or return of full consciousness over the 12-h observation period or in the frequency of adverse cardiac respiratory or hypotensive events
Treiman DM Meyers PD Walton NY et al A
comparison of four treatments for generalized
convulsive status epilepticus N Engl J Med 1998
339792-798
P 002
Percentage of successful treatment
grey bars overt patients black bars subtle patients
Alldredge Brian Kab Lowenstein Daniel HAC Status
epilepticus new concepts Current Opinion in Neurology
121999 183-190
Da ChapmanAnaesthesia 2004
Marik PEVaron J The Management of Status
Epilepticus Chest 126(2)582-591 August 2004
Status epilepticus is a major medical emergency associated with significant morbidity and mortality Status epilepticusis best defined as a continuous generalized convulsive seizure lasting gt 5 min or two or more seizures during which the patient does not return to baseline consciousness Lorazepam in a dose of 01 mgkg is the drug of first choice for terminating status epilepticus Patients who continue to have clinical or EEG evidence of seizure activity after treatment with lorazepam should be considered to have refractory status epileptics and should be treated with a continuous infusion of propofol or midazolam This article reviews current information regarding the management of status epilepticus in adults
Schema di Marik et al
Claassen JHirsch LJ Emerson R GBates
JE Thompson TBMayer SA Continuous EEG
monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042 bull The authors reviewed 33 episodes of RSE treated with cIV-MDZ in their neurologic intensive care
unit over 6 years All patients were monitored with continuous EEG (cEEG) MDZ infusion rates were titrated to eliminate clinical and EEG seizure activity cIV-MDZ was discontinued once patients were seizure-free for 24 hours Acute treatment failures (seizures 1 to 6 hours after starting cIV-MDZ) breakthrough seizures (after 6 hours of therapy) post-treatment seizures (within 48 hours of discontinuing therapy) and ultimate treatment failure (frequent seizures that led to treatment with pentobarbital or propofol) were identified
bull Results All patients were in nonconvulsive SE at the time cIV-MDZ was started the mean duration of SE before treatment was 39 days (range 0 to 17 days) In addition to benzodiazepines 94 of patients had received at least two antiepileptic drugs (AED) before starting cIV-MDZ The mean loading dose was 019 mgkg the mean maximal infusion rate was 022 mgkgh and the mean duration of cIV-MDZ therapy was 42 days (range 1 to 14 days) Acute treatment failure occurred in 18 (633) of episodes breakthrough seizures in 56 (1832) post-treatment seizures in 68 (1928) and ultimate treatment failure in 18 (633) Breakthrough seizures were clinically subtle or purely electrographic in 89 (1618) of cases and were associated with an increased risk of developing post-treatment seizures (p = 001)
bull Conclusions Although most patients with RSE initially responded to cIV-MDZ over half developed subsequent breakthrough seizures which were predictive of post-treatment seizures and were often detectable only with cEEG Titrating cIV-MDZ to burst suppression more aggressive treatment with concurrent AED or a longer period of initial treatment may reduce the high proportion of patients with RSE who relapse after cIV-MDZ is discontinued
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus Neurology 2001 57 25 1036-1042
0
10
20
30
40
50
60
70
80
non seizures
seizures lt30 min24h05-12 h
seizures 05-12 h24 hgt 12 h
seiz gt12 h24
burst suppression
periodic latdischarge
periodic gen discharge
prima
durante
dopo
33 episodes of RSE treated with cIV-MDZ neurologic ICU over 6 years
All patients were monitored with continuous EEG (cEEG)
Waterhouse Elizabeth J 1 2 DeLorenzo Robert J 1 3 4 2
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
bull Status epilepticus (SE) is a medical and neurological emergency that has been associated with significant morbidity and mortality The most widely accepted definition of SE is more than 30 minutes of either continuous seizure activity or intermittent seizures without full recovery of consciousness between seizures SE is a major clinical concern in the elderly population both because it has increased incidence in the elderly compared with the general population and because of concurrent medical conditions that are more likely to complicate therapy and worsen prognosis in elderly individuals
The incidence of SE in the elderly is almost twice that of the general population at 86 per 100 000 per year With the anticipated growth of the elderly population SE is likely to become an increasingly common problem facing clinicians and an important public health issue The elderly have the highest SE-associated mortality of any age group at 38 and the very old elderly (gt80 years of age) have a mortality of at least 50 Acute or remote stroke is the most common aetiology of SE in the elderly Nonconvulsive SE (NCSE) has a wide range of clinical presentations ranging from confusion to obtundation It occurs commonly in elderly patients who are critically ill and in the setting of coma Electroencephalogram is the only reliable method of diagnosing NCSE
The goal of treatment for SE is rapid cessation of clinical and electrical seizure activity Most treatment protocols call for the immediate administration of an intravenous benzodiazepine followed by phenytoin or fosphenytoin Recent studies suggest that when this initial treatment of SE fails little is gained by using additional standard drugs General anaesthetic agents (such as pentobarbital midazolam or propofol) should be expeditiously employed although these treatments have their own potential complications Intravenous valproic acid is a recent addition to the armamentarium of drugs for the treatment of SE with a low risk of hypotension respiratory depression and hypotension making it a potentially useful drug for the treatment of SE in the elderly However further information is needed to establish its role in the overall treatment of SE
Waterhouseet al
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
BDZ
Fenitoina
O fosfenitoina
GA
Midaz
Propof
pentobarb
Ac valproico
Ns proposta
Lorazepam
01 mgkg
Propofol
1-2 mgkgMidazolam01 mgkg
Inf cont 3-10 mgkgh Inf cont 001-005 mgkgh
Miorilassante solo
Per intubazione
Pentobarbital dose caricopoi 01-04 mgkgmin
fenobarbital
bull 10-20 mgkg iv
ndash Eccessiva sedazione
ndash Depressresp
ndash Ipotensione
ndash Interaz farmacol
ndash Hl gt48 hrhelliphelliphellip
tiopental
bull cumulativo
bull Inotropo neghellip
bull Pentobarbital
bull immunosoppressione
propofol
bull Vantaggi cineticodinamici
bull Titolazione continua possibile
bull TCIquale livello
bull Dosi 1 mgkgripetibile dopo 5rsquo-
ndash Infcont 2-10 mgkgh
bull Rapida emergenzafinestra neurologicaevitare la
brusca sospensione
bull + rapido controllo delle convuls gt barbituricindash Stecker MM Kramer TH Raps EC OMeeghan R Dulaney E Skaar DJ Treatment of
refractory status epilepticus with propofol clinical and pharmacokinetic findings Epilepsia 1998
39 18-26
AG
bull Non ci sono dati che indichino quanto a lungo i paz debbano rimanere senza convuls prima di poter alleggerire il piano di AG24 h96h (Treiman DM Convulsive status
epilepticus Current Treatment Options in Neurology 1999 1 359-69)
bull Anest alogenatiisofluranogtsevofluranogtdesflurane
bull Ma vaporizzatori
bull Contaminazione ambientale
bull Costihellip
Studi comparativi1
bull Midazolamgt tiopental
ndash Lohr A Jr Werneck LC Comparative non-randomized study with
midazolam versus thiopental in children with refractory status
epilepticus [Portuguese] Arq Neuropsiquiatr 2000 58282-287
ndash non-randomized comparison
ndash of historical data (thiopental) and prospectively
acquired data (midazolam)
ndash Midazolam was no more often effective than
thiopental but was associated with less cyanosis and
less respiratory distress in this study of 50 children
Studi comparativi2
Valproatobull Valproate(ivrdquoDepaconrdquo) has been used for the treatment of refractory SE
in children and myoclonic SE ndash Sheth RD Gidal BE Intravenous valproic acid for myoclonic status epilepticus
Neurology 2000 541201
ndash Uberall MA Trollmann R Wunsiedler U Wenzel D Intravenous valproate in pediatric epilepsy patients with refractory status epilepticus Neurology 2000 542188-2189 ]
bull Valproate has also been used in SE in the elderly and appears to be safe even in the presence of cardiovascular instability and hypotension no significant change in blood pressure pulse or the need for vasopressors in 13 patients with SE and hypotension given a loading dose of 147-327 mgkg Depacon intravenouslyndash Sinha S Naritoku DK Intravenous valproate is well tolerated in unstable patients
with status epilepticus Neurology 2000 55722-724
bull However there is a case report of severe hypotension in an 11-year-old child after treatment of SE with 30 mgkg intravenous valproate ndash White JR Santos CS Intravenous valproate associated with significant
hypotension in the treatment of status epilepticus J Child Neurol 1999 14822-823
FINE
Percheacute non ne possiamo
piugravehelliphelliphellip
Rischio convulsivo
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001bull Background It is uncertain whether the administration of benzodiazepines by paramedics is an
effective and safe treatment for out-of-hospital status epilepticus
Methods We conducted a randomized double-blind trial to evaluate intravenous benzodiazepines administered by paramedics for the treatment of out-of-hospital status epilepticus Adults with prolonged (lasting five minutes or more) or repetitive generalized convulsive seizures received intravenous diazepam (5 mg) lorazepam (2 mg) or placebo An identical second injection was given if needed
Results Of the 205 patients enrolled 66 received lorazepam 68 received diazepam and 71 received placebo Status epilepticus had been terminated on arrival at the emergency department in more patients treated with lorazepam (591 percent) or diazepam (426 percent) than patients given placebo (211 percent) (P=0001) After adjustment for covariates the odds ratio for termination of status epilepticus by the time of arrival in the lorazepam group as compared with the placebo group was 48 (95 percent confidence interval 19 to 130) The odds ratio was 19 (95 percent confidence interval 08 to 44) in the lorazepam group as compared with the diazepam group and 23 (95 percent confidence interval 10 to 59) in the diazepam group as compared with the placebo group The rates of respiratory or circulatory complications after the study treatment was administered were 106 percent for the lorazepam group 103 percent for the diazepam group and 225 percent for the placebo group (P=008)
Conclusions Benzodiazepines are safe and effective when administered by paramedics for out-of-hospital status epilepticus in adults Lorazepam is likely to be a better therapy than diazepam (N Engl J Med 2001345631-7)
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001
0
10
20
30
40
50
60
seizures stop complications
lorazepam
diazepam
placebo
randomized double-blind trial
to evaluate iv bdz
admin by paramedics
for the treatment of out-of-hospital status epilepticus
Adults with prolonged (lasting 5 minutes or +)
or repetitive generalized convulsive seizures
received iv diazepam (5 mg)
lorazepam (2 mg) or placebo
An identical second injection was given if needed
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
Treiman DM Meyers PD Walton NY Collins JF Colling C Rowan AJ et al A comparison of four treatments for generalized convulsive status epilepticus N Engl J Med 1998 339792-798
randomized double-blind trial that compared the following four regimens commonly used for the treatment of generalized convulsive status epilepticus diazepam followed by phenytoin phenytoin alone phenobarbital and lorazepam Although the doses and infusion rates chosen for study closely reflected common clinical practice at the time the study began the combination of lorazepam followed by phenytoin (the preferred regimen of many neurologists) was not included
This is a large well-controlled and important clinical trial The major limitation in its clinical relevance is the lack of inclusion of a regimen consisting of lorazepam followed by phenytoin
Veterans Affairs Status Epilepticus Cooperative
Study Group Treiman et al
SE aperto
diaz fenitoina fenobarbital lorazepam
2 o + convuls senza
ripresa di coscienza
Convuls continue = gt 10 min
fenitoina
Coma con scariche
ictali EEG
primary outcome measure
cessation of clinical and electrical
seizure activity
within 20min after initiation
of treatment and continuing for at least
60min after the start of treatment
lorazepam fenitoina
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
bull st treatment successful in 555 of patients with a verified diagnosis of overt status epilepticus (n=384) and in 149 of patients with subtle status epilepticus (n=134)
bull Comparisons between the 4 treatments showed that lorazepam was more effective than phenytoin alone in patients with overt status epilepticus (treatment success in 649 versus 436 of patients respectively)
bull other treatment comparisons in the overt group and all comparisons in the subtle group were not significantly different however
bull There were no significant differences between treatments in patient outcome rates of recurrence of status epilepticus or return of full consciousness over the 12-h observation period or in the frequency of adverse cardiac respiratory or hypotensive events
Treiman DM Meyers PD Walton NY et al A
comparison of four treatments for generalized
convulsive status epilepticus N Engl J Med 1998
339792-798
P 002
Percentage of successful treatment
grey bars overt patients black bars subtle patients
Alldredge Brian Kab Lowenstein Daniel HAC Status
epilepticus new concepts Current Opinion in Neurology
121999 183-190
Da ChapmanAnaesthesia 2004
Marik PEVaron J The Management of Status
Epilepticus Chest 126(2)582-591 August 2004
Status epilepticus is a major medical emergency associated with significant morbidity and mortality Status epilepticusis best defined as a continuous generalized convulsive seizure lasting gt 5 min or two or more seizures during which the patient does not return to baseline consciousness Lorazepam in a dose of 01 mgkg is the drug of first choice for terminating status epilepticus Patients who continue to have clinical or EEG evidence of seizure activity after treatment with lorazepam should be considered to have refractory status epileptics and should be treated with a continuous infusion of propofol or midazolam This article reviews current information regarding the management of status epilepticus in adults
Schema di Marik et al
Claassen JHirsch LJ Emerson R GBates
JE Thompson TBMayer SA Continuous EEG
monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042 bull The authors reviewed 33 episodes of RSE treated with cIV-MDZ in their neurologic intensive care
unit over 6 years All patients were monitored with continuous EEG (cEEG) MDZ infusion rates were titrated to eliminate clinical and EEG seizure activity cIV-MDZ was discontinued once patients were seizure-free for 24 hours Acute treatment failures (seizures 1 to 6 hours after starting cIV-MDZ) breakthrough seizures (after 6 hours of therapy) post-treatment seizures (within 48 hours of discontinuing therapy) and ultimate treatment failure (frequent seizures that led to treatment with pentobarbital or propofol) were identified
bull Results All patients were in nonconvulsive SE at the time cIV-MDZ was started the mean duration of SE before treatment was 39 days (range 0 to 17 days) In addition to benzodiazepines 94 of patients had received at least two antiepileptic drugs (AED) before starting cIV-MDZ The mean loading dose was 019 mgkg the mean maximal infusion rate was 022 mgkgh and the mean duration of cIV-MDZ therapy was 42 days (range 1 to 14 days) Acute treatment failure occurred in 18 (633) of episodes breakthrough seizures in 56 (1832) post-treatment seizures in 68 (1928) and ultimate treatment failure in 18 (633) Breakthrough seizures were clinically subtle or purely electrographic in 89 (1618) of cases and were associated with an increased risk of developing post-treatment seizures (p = 001)
bull Conclusions Although most patients with RSE initially responded to cIV-MDZ over half developed subsequent breakthrough seizures which were predictive of post-treatment seizures and were often detectable only with cEEG Titrating cIV-MDZ to burst suppression more aggressive treatment with concurrent AED or a longer period of initial treatment may reduce the high proportion of patients with RSE who relapse after cIV-MDZ is discontinued
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus Neurology 2001 57 25 1036-1042
0
10
20
30
40
50
60
70
80
non seizures
seizures lt30 min24h05-12 h
seizures 05-12 h24 hgt 12 h
seiz gt12 h24
burst suppression
periodic latdischarge
periodic gen discharge
prima
durante
dopo
33 episodes of RSE treated with cIV-MDZ neurologic ICU over 6 years
All patients were monitored with continuous EEG (cEEG)
Waterhouse Elizabeth J 1 2 DeLorenzo Robert J 1 3 4 2
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
bull Status epilepticus (SE) is a medical and neurological emergency that has been associated with significant morbidity and mortality The most widely accepted definition of SE is more than 30 minutes of either continuous seizure activity or intermittent seizures without full recovery of consciousness between seizures SE is a major clinical concern in the elderly population both because it has increased incidence in the elderly compared with the general population and because of concurrent medical conditions that are more likely to complicate therapy and worsen prognosis in elderly individuals
The incidence of SE in the elderly is almost twice that of the general population at 86 per 100 000 per year With the anticipated growth of the elderly population SE is likely to become an increasingly common problem facing clinicians and an important public health issue The elderly have the highest SE-associated mortality of any age group at 38 and the very old elderly (gt80 years of age) have a mortality of at least 50 Acute or remote stroke is the most common aetiology of SE in the elderly Nonconvulsive SE (NCSE) has a wide range of clinical presentations ranging from confusion to obtundation It occurs commonly in elderly patients who are critically ill and in the setting of coma Electroencephalogram is the only reliable method of diagnosing NCSE
The goal of treatment for SE is rapid cessation of clinical and electrical seizure activity Most treatment protocols call for the immediate administration of an intravenous benzodiazepine followed by phenytoin or fosphenytoin Recent studies suggest that when this initial treatment of SE fails little is gained by using additional standard drugs General anaesthetic agents (such as pentobarbital midazolam or propofol) should be expeditiously employed although these treatments have their own potential complications Intravenous valproic acid is a recent addition to the armamentarium of drugs for the treatment of SE with a low risk of hypotension respiratory depression and hypotension making it a potentially useful drug for the treatment of SE in the elderly However further information is needed to establish its role in the overall treatment of SE
Waterhouseet al
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
BDZ
Fenitoina
O fosfenitoina
GA
Midaz
Propof
pentobarb
Ac valproico
Ns proposta
Lorazepam
01 mgkg
Propofol
1-2 mgkgMidazolam01 mgkg
Inf cont 3-10 mgkgh Inf cont 001-005 mgkgh
Miorilassante solo
Per intubazione
Pentobarbital dose caricopoi 01-04 mgkgmin
fenobarbital
bull 10-20 mgkg iv
ndash Eccessiva sedazione
ndash Depressresp
ndash Ipotensione
ndash Interaz farmacol
ndash Hl gt48 hrhelliphelliphellip
tiopental
bull cumulativo
bull Inotropo neghellip
bull Pentobarbital
bull immunosoppressione
propofol
bull Vantaggi cineticodinamici
bull Titolazione continua possibile
bull TCIquale livello
bull Dosi 1 mgkgripetibile dopo 5rsquo-
ndash Infcont 2-10 mgkgh
bull Rapida emergenzafinestra neurologicaevitare la
brusca sospensione
bull + rapido controllo delle convuls gt barbituricindash Stecker MM Kramer TH Raps EC OMeeghan R Dulaney E Skaar DJ Treatment of
refractory status epilepticus with propofol clinical and pharmacokinetic findings Epilepsia 1998
39 18-26
AG
bull Non ci sono dati che indichino quanto a lungo i paz debbano rimanere senza convuls prima di poter alleggerire il piano di AG24 h96h (Treiman DM Convulsive status
epilepticus Current Treatment Options in Neurology 1999 1 359-69)
bull Anest alogenatiisofluranogtsevofluranogtdesflurane
bull Ma vaporizzatori
bull Contaminazione ambientale
bull Costihellip
Studi comparativi1
bull Midazolamgt tiopental
ndash Lohr A Jr Werneck LC Comparative non-randomized study with
midazolam versus thiopental in children with refractory status
epilepticus [Portuguese] Arq Neuropsiquiatr 2000 58282-287
ndash non-randomized comparison
ndash of historical data (thiopental) and prospectively
acquired data (midazolam)
ndash Midazolam was no more often effective than
thiopental but was associated with less cyanosis and
less respiratory distress in this study of 50 children
Studi comparativi2
Valproatobull Valproate(ivrdquoDepaconrdquo) has been used for the treatment of refractory SE
in children and myoclonic SE ndash Sheth RD Gidal BE Intravenous valproic acid for myoclonic status epilepticus
Neurology 2000 541201
ndash Uberall MA Trollmann R Wunsiedler U Wenzel D Intravenous valproate in pediatric epilepsy patients with refractory status epilepticus Neurology 2000 542188-2189 ]
bull Valproate has also been used in SE in the elderly and appears to be safe even in the presence of cardiovascular instability and hypotension no significant change in blood pressure pulse or the need for vasopressors in 13 patients with SE and hypotension given a loading dose of 147-327 mgkg Depacon intravenouslyndash Sinha S Naritoku DK Intravenous valproate is well tolerated in unstable patients
with status epilepticus Neurology 2000 55722-724
bull However there is a case report of severe hypotension in an 11-year-old child after treatment of SE with 30 mgkg intravenous valproate ndash White JR Santos CS Intravenous valproate associated with significant
hypotension in the treatment of status epilepticus J Child Neurol 1999 14822-823
FINE
Percheacute non ne possiamo
piugravehelliphelliphellip
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001bull Background It is uncertain whether the administration of benzodiazepines by paramedics is an
effective and safe treatment for out-of-hospital status epilepticus
Methods We conducted a randomized double-blind trial to evaluate intravenous benzodiazepines administered by paramedics for the treatment of out-of-hospital status epilepticus Adults with prolonged (lasting five minutes or more) or repetitive generalized convulsive seizures received intravenous diazepam (5 mg) lorazepam (2 mg) or placebo An identical second injection was given if needed
Results Of the 205 patients enrolled 66 received lorazepam 68 received diazepam and 71 received placebo Status epilepticus had been terminated on arrival at the emergency department in more patients treated with lorazepam (591 percent) or diazepam (426 percent) than patients given placebo (211 percent) (P=0001) After adjustment for covariates the odds ratio for termination of status epilepticus by the time of arrival in the lorazepam group as compared with the placebo group was 48 (95 percent confidence interval 19 to 130) The odds ratio was 19 (95 percent confidence interval 08 to 44) in the lorazepam group as compared with the diazepam group and 23 (95 percent confidence interval 10 to 59) in the diazepam group as compared with the placebo group The rates of respiratory or circulatory complications after the study treatment was administered were 106 percent for the lorazepam group 103 percent for the diazepam group and 225 percent for the placebo group (P=008)
Conclusions Benzodiazepines are safe and effective when administered by paramedics for out-of-hospital status epilepticus in adults Lorazepam is likely to be a better therapy than diazepam (N Engl J Med 2001345631-7)
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001
0
10
20
30
40
50
60
seizures stop complications
lorazepam
diazepam
placebo
randomized double-blind trial
to evaluate iv bdz
admin by paramedics
for the treatment of out-of-hospital status epilepticus
Adults with prolonged (lasting 5 minutes or +)
or repetitive generalized convulsive seizures
received iv diazepam (5 mg)
lorazepam (2 mg) or placebo
An identical second injection was given if needed
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
Treiman DM Meyers PD Walton NY Collins JF Colling C Rowan AJ et al A comparison of four treatments for generalized convulsive status epilepticus N Engl J Med 1998 339792-798
randomized double-blind trial that compared the following four regimens commonly used for the treatment of generalized convulsive status epilepticus diazepam followed by phenytoin phenytoin alone phenobarbital and lorazepam Although the doses and infusion rates chosen for study closely reflected common clinical practice at the time the study began the combination of lorazepam followed by phenytoin (the preferred regimen of many neurologists) was not included
This is a large well-controlled and important clinical trial The major limitation in its clinical relevance is the lack of inclusion of a regimen consisting of lorazepam followed by phenytoin
Veterans Affairs Status Epilepticus Cooperative
Study Group Treiman et al
SE aperto
diaz fenitoina fenobarbital lorazepam
2 o + convuls senza
ripresa di coscienza
Convuls continue = gt 10 min
fenitoina
Coma con scariche
ictali EEG
primary outcome measure
cessation of clinical and electrical
seizure activity
within 20min after initiation
of treatment and continuing for at least
60min after the start of treatment
lorazepam fenitoina
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
bull st treatment successful in 555 of patients with a verified diagnosis of overt status epilepticus (n=384) and in 149 of patients with subtle status epilepticus (n=134)
bull Comparisons between the 4 treatments showed that lorazepam was more effective than phenytoin alone in patients with overt status epilepticus (treatment success in 649 versus 436 of patients respectively)
bull other treatment comparisons in the overt group and all comparisons in the subtle group were not significantly different however
bull There were no significant differences between treatments in patient outcome rates of recurrence of status epilepticus or return of full consciousness over the 12-h observation period or in the frequency of adverse cardiac respiratory or hypotensive events
Treiman DM Meyers PD Walton NY et al A
comparison of four treatments for generalized
convulsive status epilepticus N Engl J Med 1998
339792-798
P 002
Percentage of successful treatment
grey bars overt patients black bars subtle patients
Alldredge Brian Kab Lowenstein Daniel HAC Status
epilepticus new concepts Current Opinion in Neurology
121999 183-190
Da ChapmanAnaesthesia 2004
Marik PEVaron J The Management of Status
Epilepticus Chest 126(2)582-591 August 2004
Status epilepticus is a major medical emergency associated with significant morbidity and mortality Status epilepticusis best defined as a continuous generalized convulsive seizure lasting gt 5 min or two or more seizures during which the patient does not return to baseline consciousness Lorazepam in a dose of 01 mgkg is the drug of first choice for terminating status epilepticus Patients who continue to have clinical or EEG evidence of seizure activity after treatment with lorazepam should be considered to have refractory status epileptics and should be treated with a continuous infusion of propofol or midazolam This article reviews current information regarding the management of status epilepticus in adults
Schema di Marik et al
Claassen JHirsch LJ Emerson R GBates
JE Thompson TBMayer SA Continuous EEG
monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042 bull The authors reviewed 33 episodes of RSE treated with cIV-MDZ in their neurologic intensive care
unit over 6 years All patients were monitored with continuous EEG (cEEG) MDZ infusion rates were titrated to eliminate clinical and EEG seizure activity cIV-MDZ was discontinued once patients were seizure-free for 24 hours Acute treatment failures (seizures 1 to 6 hours after starting cIV-MDZ) breakthrough seizures (after 6 hours of therapy) post-treatment seizures (within 48 hours of discontinuing therapy) and ultimate treatment failure (frequent seizures that led to treatment with pentobarbital or propofol) were identified
bull Results All patients were in nonconvulsive SE at the time cIV-MDZ was started the mean duration of SE before treatment was 39 days (range 0 to 17 days) In addition to benzodiazepines 94 of patients had received at least two antiepileptic drugs (AED) before starting cIV-MDZ The mean loading dose was 019 mgkg the mean maximal infusion rate was 022 mgkgh and the mean duration of cIV-MDZ therapy was 42 days (range 1 to 14 days) Acute treatment failure occurred in 18 (633) of episodes breakthrough seizures in 56 (1832) post-treatment seizures in 68 (1928) and ultimate treatment failure in 18 (633) Breakthrough seizures were clinically subtle or purely electrographic in 89 (1618) of cases and were associated with an increased risk of developing post-treatment seizures (p = 001)
bull Conclusions Although most patients with RSE initially responded to cIV-MDZ over half developed subsequent breakthrough seizures which were predictive of post-treatment seizures and were often detectable only with cEEG Titrating cIV-MDZ to burst suppression more aggressive treatment with concurrent AED or a longer period of initial treatment may reduce the high proportion of patients with RSE who relapse after cIV-MDZ is discontinued
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus Neurology 2001 57 25 1036-1042
0
10
20
30
40
50
60
70
80
non seizures
seizures lt30 min24h05-12 h
seizures 05-12 h24 hgt 12 h
seiz gt12 h24
burst suppression
periodic latdischarge
periodic gen discharge
prima
durante
dopo
33 episodes of RSE treated with cIV-MDZ neurologic ICU over 6 years
All patients were monitored with continuous EEG (cEEG)
Waterhouse Elizabeth J 1 2 DeLorenzo Robert J 1 3 4 2
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
bull Status epilepticus (SE) is a medical and neurological emergency that has been associated with significant morbidity and mortality The most widely accepted definition of SE is more than 30 minutes of either continuous seizure activity or intermittent seizures without full recovery of consciousness between seizures SE is a major clinical concern in the elderly population both because it has increased incidence in the elderly compared with the general population and because of concurrent medical conditions that are more likely to complicate therapy and worsen prognosis in elderly individuals
The incidence of SE in the elderly is almost twice that of the general population at 86 per 100 000 per year With the anticipated growth of the elderly population SE is likely to become an increasingly common problem facing clinicians and an important public health issue The elderly have the highest SE-associated mortality of any age group at 38 and the very old elderly (gt80 years of age) have a mortality of at least 50 Acute or remote stroke is the most common aetiology of SE in the elderly Nonconvulsive SE (NCSE) has a wide range of clinical presentations ranging from confusion to obtundation It occurs commonly in elderly patients who are critically ill and in the setting of coma Electroencephalogram is the only reliable method of diagnosing NCSE
The goal of treatment for SE is rapid cessation of clinical and electrical seizure activity Most treatment protocols call for the immediate administration of an intravenous benzodiazepine followed by phenytoin or fosphenytoin Recent studies suggest that when this initial treatment of SE fails little is gained by using additional standard drugs General anaesthetic agents (such as pentobarbital midazolam or propofol) should be expeditiously employed although these treatments have their own potential complications Intravenous valproic acid is a recent addition to the armamentarium of drugs for the treatment of SE with a low risk of hypotension respiratory depression and hypotension making it a potentially useful drug for the treatment of SE in the elderly However further information is needed to establish its role in the overall treatment of SE
Waterhouseet al
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
BDZ
Fenitoina
O fosfenitoina
GA
Midaz
Propof
pentobarb
Ac valproico
Ns proposta
Lorazepam
01 mgkg
Propofol
1-2 mgkgMidazolam01 mgkg
Inf cont 3-10 mgkgh Inf cont 001-005 mgkgh
Miorilassante solo
Per intubazione
Pentobarbital dose caricopoi 01-04 mgkgmin
fenobarbital
bull 10-20 mgkg iv
ndash Eccessiva sedazione
ndash Depressresp
ndash Ipotensione
ndash Interaz farmacol
ndash Hl gt48 hrhelliphelliphellip
tiopental
bull cumulativo
bull Inotropo neghellip
bull Pentobarbital
bull immunosoppressione
propofol
bull Vantaggi cineticodinamici
bull Titolazione continua possibile
bull TCIquale livello
bull Dosi 1 mgkgripetibile dopo 5rsquo-
ndash Infcont 2-10 mgkgh
bull Rapida emergenzafinestra neurologicaevitare la
brusca sospensione
bull + rapido controllo delle convuls gt barbituricindash Stecker MM Kramer TH Raps EC OMeeghan R Dulaney E Skaar DJ Treatment of
refractory status epilepticus with propofol clinical and pharmacokinetic findings Epilepsia 1998
39 18-26
AG
bull Non ci sono dati che indichino quanto a lungo i paz debbano rimanere senza convuls prima di poter alleggerire il piano di AG24 h96h (Treiman DM Convulsive status
epilepticus Current Treatment Options in Neurology 1999 1 359-69)
bull Anest alogenatiisofluranogtsevofluranogtdesflurane
bull Ma vaporizzatori
bull Contaminazione ambientale
bull Costihellip
Studi comparativi1
bull Midazolamgt tiopental
ndash Lohr A Jr Werneck LC Comparative non-randomized study with
midazolam versus thiopental in children with refractory status
epilepticus [Portuguese] Arq Neuropsiquiatr 2000 58282-287
ndash non-randomized comparison
ndash of historical data (thiopental) and prospectively
acquired data (midazolam)
ndash Midazolam was no more often effective than
thiopental but was associated with less cyanosis and
less respiratory distress in this study of 50 children
Studi comparativi2
Valproatobull Valproate(ivrdquoDepaconrdquo) has been used for the treatment of refractory SE
in children and myoclonic SE ndash Sheth RD Gidal BE Intravenous valproic acid for myoclonic status epilepticus
Neurology 2000 541201
ndash Uberall MA Trollmann R Wunsiedler U Wenzel D Intravenous valproate in pediatric epilepsy patients with refractory status epilepticus Neurology 2000 542188-2189 ]
bull Valproate has also been used in SE in the elderly and appears to be safe even in the presence of cardiovascular instability and hypotension no significant change in blood pressure pulse or the need for vasopressors in 13 patients with SE and hypotension given a loading dose of 147-327 mgkg Depacon intravenouslyndash Sinha S Naritoku DK Intravenous valproate is well tolerated in unstable patients
with status epilepticus Neurology 2000 55722-724
bull However there is a case report of severe hypotension in an 11-year-old child after treatment of SE with 30 mgkg intravenous valproate ndash White JR Santos CS Intravenous valproate associated with significant
hypotension in the treatment of status epilepticus J Child Neurol 1999 14822-823
FINE
Percheacute non ne possiamo
piugravehelliphelliphellip
Alldredge BK Gelb AMIsaacs S MCorry MDAllen FUlrich SK Gottwald
MDONeil N Neuhaus JM Segal MRLowenstein DH
Comparison of Lorazepam Diazepam and Placebo for the Treatment of
Out-of-Hospital Status Epilepticus
New England Journal of Medicine 345(9)631-637 August 30 2001
0
10
20
30
40
50
60
seizures stop complications
lorazepam
diazepam
placebo
randomized double-blind trial
to evaluate iv bdz
admin by paramedics
for the treatment of out-of-hospital status epilepticus
Adults with prolonged (lasting 5 minutes or +)
or repetitive generalized convulsive seizures
received iv diazepam (5 mg)
lorazepam (2 mg) or placebo
An identical second injection was given if needed
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
Treiman DM Meyers PD Walton NY Collins JF Colling C Rowan AJ et al A comparison of four treatments for generalized convulsive status epilepticus N Engl J Med 1998 339792-798
randomized double-blind trial that compared the following four regimens commonly used for the treatment of generalized convulsive status epilepticus diazepam followed by phenytoin phenytoin alone phenobarbital and lorazepam Although the doses and infusion rates chosen for study closely reflected common clinical practice at the time the study began the combination of lorazepam followed by phenytoin (the preferred regimen of many neurologists) was not included
This is a large well-controlled and important clinical trial The major limitation in its clinical relevance is the lack of inclusion of a regimen consisting of lorazepam followed by phenytoin
Veterans Affairs Status Epilepticus Cooperative
Study Group Treiman et al
SE aperto
diaz fenitoina fenobarbital lorazepam
2 o + convuls senza
ripresa di coscienza
Convuls continue = gt 10 min
fenitoina
Coma con scariche
ictali EEG
primary outcome measure
cessation of clinical and electrical
seizure activity
within 20min after initiation
of treatment and continuing for at least
60min after the start of treatment
lorazepam fenitoina
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
bull st treatment successful in 555 of patients with a verified diagnosis of overt status epilepticus (n=384) and in 149 of patients with subtle status epilepticus (n=134)
bull Comparisons between the 4 treatments showed that lorazepam was more effective than phenytoin alone in patients with overt status epilepticus (treatment success in 649 versus 436 of patients respectively)
bull other treatment comparisons in the overt group and all comparisons in the subtle group were not significantly different however
bull There were no significant differences between treatments in patient outcome rates of recurrence of status epilepticus or return of full consciousness over the 12-h observation period or in the frequency of adverse cardiac respiratory or hypotensive events
Treiman DM Meyers PD Walton NY et al A
comparison of four treatments for generalized
convulsive status epilepticus N Engl J Med 1998
339792-798
P 002
Percentage of successful treatment
grey bars overt patients black bars subtle patients
Alldredge Brian Kab Lowenstein Daniel HAC Status
epilepticus new concepts Current Opinion in Neurology
121999 183-190
Da ChapmanAnaesthesia 2004
Marik PEVaron J The Management of Status
Epilepticus Chest 126(2)582-591 August 2004
Status epilepticus is a major medical emergency associated with significant morbidity and mortality Status epilepticusis best defined as a continuous generalized convulsive seizure lasting gt 5 min or two or more seizures during which the patient does not return to baseline consciousness Lorazepam in a dose of 01 mgkg is the drug of first choice for terminating status epilepticus Patients who continue to have clinical or EEG evidence of seizure activity after treatment with lorazepam should be considered to have refractory status epileptics and should be treated with a continuous infusion of propofol or midazolam This article reviews current information regarding the management of status epilepticus in adults
Schema di Marik et al
Claassen JHirsch LJ Emerson R GBates
JE Thompson TBMayer SA Continuous EEG
monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042 bull The authors reviewed 33 episodes of RSE treated with cIV-MDZ in their neurologic intensive care
unit over 6 years All patients were monitored with continuous EEG (cEEG) MDZ infusion rates were titrated to eliminate clinical and EEG seizure activity cIV-MDZ was discontinued once patients were seizure-free for 24 hours Acute treatment failures (seizures 1 to 6 hours after starting cIV-MDZ) breakthrough seizures (after 6 hours of therapy) post-treatment seizures (within 48 hours of discontinuing therapy) and ultimate treatment failure (frequent seizures that led to treatment with pentobarbital or propofol) were identified
bull Results All patients were in nonconvulsive SE at the time cIV-MDZ was started the mean duration of SE before treatment was 39 days (range 0 to 17 days) In addition to benzodiazepines 94 of patients had received at least two antiepileptic drugs (AED) before starting cIV-MDZ The mean loading dose was 019 mgkg the mean maximal infusion rate was 022 mgkgh and the mean duration of cIV-MDZ therapy was 42 days (range 1 to 14 days) Acute treatment failure occurred in 18 (633) of episodes breakthrough seizures in 56 (1832) post-treatment seizures in 68 (1928) and ultimate treatment failure in 18 (633) Breakthrough seizures were clinically subtle or purely electrographic in 89 (1618) of cases and were associated with an increased risk of developing post-treatment seizures (p = 001)
bull Conclusions Although most patients with RSE initially responded to cIV-MDZ over half developed subsequent breakthrough seizures which were predictive of post-treatment seizures and were often detectable only with cEEG Titrating cIV-MDZ to burst suppression more aggressive treatment with concurrent AED or a longer period of initial treatment may reduce the high proportion of patients with RSE who relapse after cIV-MDZ is discontinued
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus Neurology 2001 57 25 1036-1042
0
10
20
30
40
50
60
70
80
non seizures
seizures lt30 min24h05-12 h
seizures 05-12 h24 hgt 12 h
seiz gt12 h24
burst suppression
periodic latdischarge
periodic gen discharge
prima
durante
dopo
33 episodes of RSE treated with cIV-MDZ neurologic ICU over 6 years
All patients were monitored with continuous EEG (cEEG)
Waterhouse Elizabeth J 1 2 DeLorenzo Robert J 1 3 4 2
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
bull Status epilepticus (SE) is a medical and neurological emergency that has been associated with significant morbidity and mortality The most widely accepted definition of SE is more than 30 minutes of either continuous seizure activity or intermittent seizures without full recovery of consciousness between seizures SE is a major clinical concern in the elderly population both because it has increased incidence in the elderly compared with the general population and because of concurrent medical conditions that are more likely to complicate therapy and worsen prognosis in elderly individuals
The incidence of SE in the elderly is almost twice that of the general population at 86 per 100 000 per year With the anticipated growth of the elderly population SE is likely to become an increasingly common problem facing clinicians and an important public health issue The elderly have the highest SE-associated mortality of any age group at 38 and the very old elderly (gt80 years of age) have a mortality of at least 50 Acute or remote stroke is the most common aetiology of SE in the elderly Nonconvulsive SE (NCSE) has a wide range of clinical presentations ranging from confusion to obtundation It occurs commonly in elderly patients who are critically ill and in the setting of coma Electroencephalogram is the only reliable method of diagnosing NCSE
The goal of treatment for SE is rapid cessation of clinical and electrical seizure activity Most treatment protocols call for the immediate administration of an intravenous benzodiazepine followed by phenytoin or fosphenytoin Recent studies suggest that when this initial treatment of SE fails little is gained by using additional standard drugs General anaesthetic agents (such as pentobarbital midazolam or propofol) should be expeditiously employed although these treatments have their own potential complications Intravenous valproic acid is a recent addition to the armamentarium of drugs for the treatment of SE with a low risk of hypotension respiratory depression and hypotension making it a potentially useful drug for the treatment of SE in the elderly However further information is needed to establish its role in the overall treatment of SE
Waterhouseet al
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
BDZ
Fenitoina
O fosfenitoina
GA
Midaz
Propof
pentobarb
Ac valproico
Ns proposta
Lorazepam
01 mgkg
Propofol
1-2 mgkgMidazolam01 mgkg
Inf cont 3-10 mgkgh Inf cont 001-005 mgkgh
Miorilassante solo
Per intubazione
Pentobarbital dose caricopoi 01-04 mgkgmin
fenobarbital
bull 10-20 mgkg iv
ndash Eccessiva sedazione
ndash Depressresp
ndash Ipotensione
ndash Interaz farmacol
ndash Hl gt48 hrhelliphelliphellip
tiopental
bull cumulativo
bull Inotropo neghellip
bull Pentobarbital
bull immunosoppressione
propofol
bull Vantaggi cineticodinamici
bull Titolazione continua possibile
bull TCIquale livello
bull Dosi 1 mgkgripetibile dopo 5rsquo-
ndash Infcont 2-10 mgkgh
bull Rapida emergenzafinestra neurologicaevitare la
brusca sospensione
bull + rapido controllo delle convuls gt barbituricindash Stecker MM Kramer TH Raps EC OMeeghan R Dulaney E Skaar DJ Treatment of
refractory status epilepticus with propofol clinical and pharmacokinetic findings Epilepsia 1998
39 18-26
AG
bull Non ci sono dati che indichino quanto a lungo i paz debbano rimanere senza convuls prima di poter alleggerire il piano di AG24 h96h (Treiman DM Convulsive status
epilepticus Current Treatment Options in Neurology 1999 1 359-69)
bull Anest alogenatiisofluranogtsevofluranogtdesflurane
bull Ma vaporizzatori
bull Contaminazione ambientale
bull Costihellip
Studi comparativi1
bull Midazolamgt tiopental
ndash Lohr A Jr Werneck LC Comparative non-randomized study with
midazolam versus thiopental in children with refractory status
epilepticus [Portuguese] Arq Neuropsiquiatr 2000 58282-287
ndash non-randomized comparison
ndash of historical data (thiopental) and prospectively
acquired data (midazolam)
ndash Midazolam was no more often effective than
thiopental but was associated with less cyanosis and
less respiratory distress in this study of 50 children
Studi comparativi2
Valproatobull Valproate(ivrdquoDepaconrdquo) has been used for the treatment of refractory SE
in children and myoclonic SE ndash Sheth RD Gidal BE Intravenous valproic acid for myoclonic status epilepticus
Neurology 2000 541201
ndash Uberall MA Trollmann R Wunsiedler U Wenzel D Intravenous valproate in pediatric epilepsy patients with refractory status epilepticus Neurology 2000 542188-2189 ]
bull Valproate has also been used in SE in the elderly and appears to be safe even in the presence of cardiovascular instability and hypotension no significant change in blood pressure pulse or the need for vasopressors in 13 patients with SE and hypotension given a loading dose of 147-327 mgkg Depacon intravenouslyndash Sinha S Naritoku DK Intravenous valproate is well tolerated in unstable patients
with status epilepticus Neurology 2000 55722-724
bull However there is a case report of severe hypotension in an 11-year-old child after treatment of SE with 30 mgkg intravenous valproate ndash White JR Santos CS Intravenous valproate associated with significant
hypotension in the treatment of status epilepticus J Child Neurol 1999 14822-823
FINE
Percheacute non ne possiamo
piugravehelliphelliphellip
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
Treiman DM Meyers PD Walton NY Collins JF Colling C Rowan AJ et al A comparison of four treatments for generalized convulsive status epilepticus N Engl J Med 1998 339792-798
randomized double-blind trial that compared the following four regimens commonly used for the treatment of generalized convulsive status epilepticus diazepam followed by phenytoin phenytoin alone phenobarbital and lorazepam Although the doses and infusion rates chosen for study closely reflected common clinical practice at the time the study began the combination of lorazepam followed by phenytoin (the preferred regimen of many neurologists) was not included
This is a large well-controlled and important clinical trial The major limitation in its clinical relevance is the lack of inclusion of a regimen consisting of lorazepam followed by phenytoin
Veterans Affairs Status Epilepticus Cooperative
Study Group Treiman et al
SE aperto
diaz fenitoina fenobarbital lorazepam
2 o + convuls senza
ripresa di coscienza
Convuls continue = gt 10 min
fenitoina
Coma con scariche
ictali EEG
primary outcome measure
cessation of clinical and electrical
seizure activity
within 20min after initiation
of treatment and continuing for at least
60min after the start of treatment
lorazepam fenitoina
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
bull st treatment successful in 555 of patients with a verified diagnosis of overt status epilepticus (n=384) and in 149 of patients with subtle status epilepticus (n=134)
bull Comparisons between the 4 treatments showed that lorazepam was more effective than phenytoin alone in patients with overt status epilepticus (treatment success in 649 versus 436 of patients respectively)
bull other treatment comparisons in the overt group and all comparisons in the subtle group were not significantly different however
bull There were no significant differences between treatments in patient outcome rates of recurrence of status epilepticus or return of full consciousness over the 12-h observation period or in the frequency of adverse cardiac respiratory or hypotensive events
Treiman DM Meyers PD Walton NY et al A
comparison of four treatments for generalized
convulsive status epilepticus N Engl J Med 1998
339792-798
P 002
Percentage of successful treatment
grey bars overt patients black bars subtle patients
Alldredge Brian Kab Lowenstein Daniel HAC Status
epilepticus new concepts Current Opinion in Neurology
121999 183-190
Da ChapmanAnaesthesia 2004
Marik PEVaron J The Management of Status
Epilepticus Chest 126(2)582-591 August 2004
Status epilepticus is a major medical emergency associated with significant morbidity and mortality Status epilepticusis best defined as a continuous generalized convulsive seizure lasting gt 5 min or two or more seizures during which the patient does not return to baseline consciousness Lorazepam in a dose of 01 mgkg is the drug of first choice for terminating status epilepticus Patients who continue to have clinical or EEG evidence of seizure activity after treatment with lorazepam should be considered to have refractory status epileptics and should be treated with a continuous infusion of propofol or midazolam This article reviews current information regarding the management of status epilepticus in adults
Schema di Marik et al
Claassen JHirsch LJ Emerson R GBates
JE Thompson TBMayer SA Continuous EEG
monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042 bull The authors reviewed 33 episodes of RSE treated with cIV-MDZ in their neurologic intensive care
unit over 6 years All patients were monitored with continuous EEG (cEEG) MDZ infusion rates were titrated to eliminate clinical and EEG seizure activity cIV-MDZ was discontinued once patients were seizure-free for 24 hours Acute treatment failures (seizures 1 to 6 hours after starting cIV-MDZ) breakthrough seizures (after 6 hours of therapy) post-treatment seizures (within 48 hours of discontinuing therapy) and ultimate treatment failure (frequent seizures that led to treatment with pentobarbital or propofol) were identified
bull Results All patients were in nonconvulsive SE at the time cIV-MDZ was started the mean duration of SE before treatment was 39 days (range 0 to 17 days) In addition to benzodiazepines 94 of patients had received at least two antiepileptic drugs (AED) before starting cIV-MDZ The mean loading dose was 019 mgkg the mean maximal infusion rate was 022 mgkgh and the mean duration of cIV-MDZ therapy was 42 days (range 1 to 14 days) Acute treatment failure occurred in 18 (633) of episodes breakthrough seizures in 56 (1832) post-treatment seizures in 68 (1928) and ultimate treatment failure in 18 (633) Breakthrough seizures were clinically subtle or purely electrographic in 89 (1618) of cases and were associated with an increased risk of developing post-treatment seizures (p = 001)
bull Conclusions Although most patients with RSE initially responded to cIV-MDZ over half developed subsequent breakthrough seizures which were predictive of post-treatment seizures and were often detectable only with cEEG Titrating cIV-MDZ to burst suppression more aggressive treatment with concurrent AED or a longer period of initial treatment may reduce the high proportion of patients with RSE who relapse after cIV-MDZ is discontinued
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus Neurology 2001 57 25 1036-1042
0
10
20
30
40
50
60
70
80
non seizures
seizures lt30 min24h05-12 h
seizures 05-12 h24 hgt 12 h
seiz gt12 h24
burst suppression
periodic latdischarge
periodic gen discharge
prima
durante
dopo
33 episodes of RSE treated with cIV-MDZ neurologic ICU over 6 years
All patients were monitored with continuous EEG (cEEG)
Waterhouse Elizabeth J 1 2 DeLorenzo Robert J 1 3 4 2
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
bull Status epilepticus (SE) is a medical and neurological emergency that has been associated with significant morbidity and mortality The most widely accepted definition of SE is more than 30 minutes of either continuous seizure activity or intermittent seizures without full recovery of consciousness between seizures SE is a major clinical concern in the elderly population both because it has increased incidence in the elderly compared with the general population and because of concurrent medical conditions that are more likely to complicate therapy and worsen prognosis in elderly individuals
The incidence of SE in the elderly is almost twice that of the general population at 86 per 100 000 per year With the anticipated growth of the elderly population SE is likely to become an increasingly common problem facing clinicians and an important public health issue The elderly have the highest SE-associated mortality of any age group at 38 and the very old elderly (gt80 years of age) have a mortality of at least 50 Acute or remote stroke is the most common aetiology of SE in the elderly Nonconvulsive SE (NCSE) has a wide range of clinical presentations ranging from confusion to obtundation It occurs commonly in elderly patients who are critically ill and in the setting of coma Electroencephalogram is the only reliable method of diagnosing NCSE
The goal of treatment for SE is rapid cessation of clinical and electrical seizure activity Most treatment protocols call for the immediate administration of an intravenous benzodiazepine followed by phenytoin or fosphenytoin Recent studies suggest that when this initial treatment of SE fails little is gained by using additional standard drugs General anaesthetic agents (such as pentobarbital midazolam or propofol) should be expeditiously employed although these treatments have their own potential complications Intravenous valproic acid is a recent addition to the armamentarium of drugs for the treatment of SE with a low risk of hypotension respiratory depression and hypotension making it a potentially useful drug for the treatment of SE in the elderly However further information is needed to establish its role in the overall treatment of SE
Waterhouseet al
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
BDZ
Fenitoina
O fosfenitoina
GA
Midaz
Propof
pentobarb
Ac valproico
Ns proposta
Lorazepam
01 mgkg
Propofol
1-2 mgkgMidazolam01 mgkg
Inf cont 3-10 mgkgh Inf cont 001-005 mgkgh
Miorilassante solo
Per intubazione
Pentobarbital dose caricopoi 01-04 mgkgmin
fenobarbital
bull 10-20 mgkg iv
ndash Eccessiva sedazione
ndash Depressresp
ndash Ipotensione
ndash Interaz farmacol
ndash Hl gt48 hrhelliphelliphellip
tiopental
bull cumulativo
bull Inotropo neghellip
bull Pentobarbital
bull immunosoppressione
propofol
bull Vantaggi cineticodinamici
bull Titolazione continua possibile
bull TCIquale livello
bull Dosi 1 mgkgripetibile dopo 5rsquo-
ndash Infcont 2-10 mgkgh
bull Rapida emergenzafinestra neurologicaevitare la
brusca sospensione
bull + rapido controllo delle convuls gt barbituricindash Stecker MM Kramer TH Raps EC OMeeghan R Dulaney E Skaar DJ Treatment of
refractory status epilepticus with propofol clinical and pharmacokinetic findings Epilepsia 1998
39 18-26
AG
bull Non ci sono dati che indichino quanto a lungo i paz debbano rimanere senza convuls prima di poter alleggerire il piano di AG24 h96h (Treiman DM Convulsive status
epilepticus Current Treatment Options in Neurology 1999 1 359-69)
bull Anest alogenatiisofluranogtsevofluranogtdesflurane
bull Ma vaporizzatori
bull Contaminazione ambientale
bull Costihellip
Studi comparativi1
bull Midazolamgt tiopental
ndash Lohr A Jr Werneck LC Comparative non-randomized study with
midazolam versus thiopental in children with refractory status
epilepticus [Portuguese] Arq Neuropsiquiatr 2000 58282-287
ndash non-randomized comparison
ndash of historical data (thiopental) and prospectively
acquired data (midazolam)
ndash Midazolam was no more often effective than
thiopental but was associated with less cyanosis and
less respiratory distress in this study of 50 children
Studi comparativi2
Valproatobull Valproate(ivrdquoDepaconrdquo) has been used for the treatment of refractory SE
in children and myoclonic SE ndash Sheth RD Gidal BE Intravenous valproic acid for myoclonic status epilepticus
Neurology 2000 541201
ndash Uberall MA Trollmann R Wunsiedler U Wenzel D Intravenous valproate in pediatric epilepsy patients with refractory status epilepticus Neurology 2000 542188-2189 ]
bull Valproate has also been used in SE in the elderly and appears to be safe even in the presence of cardiovascular instability and hypotension no significant change in blood pressure pulse or the need for vasopressors in 13 patients with SE and hypotension given a loading dose of 147-327 mgkg Depacon intravenouslyndash Sinha S Naritoku DK Intravenous valproate is well tolerated in unstable patients
with status epilepticus Neurology 2000 55722-724
bull However there is a case report of severe hypotension in an 11-year-old child after treatment of SE with 30 mgkg intravenous valproate ndash White JR Santos CS Intravenous valproate associated with significant
hypotension in the treatment of status epilepticus J Child Neurol 1999 14822-823
FINE
Percheacute non ne possiamo
piugravehelliphelliphellip
Veterans Affairs Status Epilepticus Cooperative
Study Group Treiman et al
SE aperto
diaz fenitoina fenobarbital lorazepam
2 o + convuls senza
ripresa di coscienza
Convuls continue = gt 10 min
fenitoina
Coma con scariche
ictali EEG
primary outcome measure
cessation of clinical and electrical
seizure activity
within 20min after initiation
of treatment and continuing for at least
60min after the start of treatment
lorazepam fenitoina
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
bull st treatment successful in 555 of patients with a verified diagnosis of overt status epilepticus (n=384) and in 149 of patients with subtle status epilepticus (n=134)
bull Comparisons between the 4 treatments showed that lorazepam was more effective than phenytoin alone in patients with overt status epilepticus (treatment success in 649 versus 436 of patients respectively)
bull other treatment comparisons in the overt group and all comparisons in the subtle group were not significantly different however
bull There were no significant differences between treatments in patient outcome rates of recurrence of status epilepticus or return of full consciousness over the 12-h observation period or in the frequency of adverse cardiac respiratory or hypotensive events
Treiman DM Meyers PD Walton NY et al A
comparison of four treatments for generalized
convulsive status epilepticus N Engl J Med 1998
339792-798
P 002
Percentage of successful treatment
grey bars overt patients black bars subtle patients
Alldredge Brian Kab Lowenstein Daniel HAC Status
epilepticus new concepts Current Opinion in Neurology
121999 183-190
Da ChapmanAnaesthesia 2004
Marik PEVaron J The Management of Status
Epilepticus Chest 126(2)582-591 August 2004
Status epilepticus is a major medical emergency associated with significant morbidity and mortality Status epilepticusis best defined as a continuous generalized convulsive seizure lasting gt 5 min or two or more seizures during which the patient does not return to baseline consciousness Lorazepam in a dose of 01 mgkg is the drug of first choice for terminating status epilepticus Patients who continue to have clinical or EEG evidence of seizure activity after treatment with lorazepam should be considered to have refractory status epileptics and should be treated with a continuous infusion of propofol or midazolam This article reviews current information regarding the management of status epilepticus in adults
Schema di Marik et al
Claassen JHirsch LJ Emerson R GBates
JE Thompson TBMayer SA Continuous EEG
monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042 bull The authors reviewed 33 episodes of RSE treated with cIV-MDZ in their neurologic intensive care
unit over 6 years All patients were monitored with continuous EEG (cEEG) MDZ infusion rates were titrated to eliminate clinical and EEG seizure activity cIV-MDZ was discontinued once patients were seizure-free for 24 hours Acute treatment failures (seizures 1 to 6 hours after starting cIV-MDZ) breakthrough seizures (after 6 hours of therapy) post-treatment seizures (within 48 hours of discontinuing therapy) and ultimate treatment failure (frequent seizures that led to treatment with pentobarbital or propofol) were identified
bull Results All patients were in nonconvulsive SE at the time cIV-MDZ was started the mean duration of SE before treatment was 39 days (range 0 to 17 days) In addition to benzodiazepines 94 of patients had received at least two antiepileptic drugs (AED) before starting cIV-MDZ The mean loading dose was 019 mgkg the mean maximal infusion rate was 022 mgkgh and the mean duration of cIV-MDZ therapy was 42 days (range 1 to 14 days) Acute treatment failure occurred in 18 (633) of episodes breakthrough seizures in 56 (1832) post-treatment seizures in 68 (1928) and ultimate treatment failure in 18 (633) Breakthrough seizures were clinically subtle or purely electrographic in 89 (1618) of cases and were associated with an increased risk of developing post-treatment seizures (p = 001)
bull Conclusions Although most patients with RSE initially responded to cIV-MDZ over half developed subsequent breakthrough seizures which were predictive of post-treatment seizures and were often detectable only with cEEG Titrating cIV-MDZ to burst suppression more aggressive treatment with concurrent AED or a longer period of initial treatment may reduce the high proportion of patients with RSE who relapse after cIV-MDZ is discontinued
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus Neurology 2001 57 25 1036-1042
0
10
20
30
40
50
60
70
80
non seizures
seizures lt30 min24h05-12 h
seizures 05-12 h24 hgt 12 h
seiz gt12 h24
burst suppression
periodic latdischarge
periodic gen discharge
prima
durante
dopo
33 episodes of RSE treated with cIV-MDZ neurologic ICU over 6 years
All patients were monitored with continuous EEG (cEEG)
Waterhouse Elizabeth J 1 2 DeLorenzo Robert J 1 3 4 2
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
bull Status epilepticus (SE) is a medical and neurological emergency that has been associated with significant morbidity and mortality The most widely accepted definition of SE is more than 30 minutes of either continuous seizure activity or intermittent seizures without full recovery of consciousness between seizures SE is a major clinical concern in the elderly population both because it has increased incidence in the elderly compared with the general population and because of concurrent medical conditions that are more likely to complicate therapy and worsen prognosis in elderly individuals
The incidence of SE in the elderly is almost twice that of the general population at 86 per 100 000 per year With the anticipated growth of the elderly population SE is likely to become an increasingly common problem facing clinicians and an important public health issue The elderly have the highest SE-associated mortality of any age group at 38 and the very old elderly (gt80 years of age) have a mortality of at least 50 Acute or remote stroke is the most common aetiology of SE in the elderly Nonconvulsive SE (NCSE) has a wide range of clinical presentations ranging from confusion to obtundation It occurs commonly in elderly patients who are critically ill and in the setting of coma Electroencephalogram is the only reliable method of diagnosing NCSE
The goal of treatment for SE is rapid cessation of clinical and electrical seizure activity Most treatment protocols call for the immediate administration of an intravenous benzodiazepine followed by phenytoin or fosphenytoin Recent studies suggest that when this initial treatment of SE fails little is gained by using additional standard drugs General anaesthetic agents (such as pentobarbital midazolam or propofol) should be expeditiously employed although these treatments have their own potential complications Intravenous valproic acid is a recent addition to the armamentarium of drugs for the treatment of SE with a low risk of hypotension respiratory depression and hypotension making it a potentially useful drug for the treatment of SE in the elderly However further information is needed to establish its role in the overall treatment of SE
Waterhouseet al
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
BDZ
Fenitoina
O fosfenitoina
GA
Midaz
Propof
pentobarb
Ac valproico
Ns proposta
Lorazepam
01 mgkg
Propofol
1-2 mgkgMidazolam01 mgkg
Inf cont 3-10 mgkgh Inf cont 001-005 mgkgh
Miorilassante solo
Per intubazione
Pentobarbital dose caricopoi 01-04 mgkgmin
fenobarbital
bull 10-20 mgkg iv
ndash Eccessiva sedazione
ndash Depressresp
ndash Ipotensione
ndash Interaz farmacol
ndash Hl gt48 hrhelliphelliphellip
tiopental
bull cumulativo
bull Inotropo neghellip
bull Pentobarbital
bull immunosoppressione
propofol
bull Vantaggi cineticodinamici
bull Titolazione continua possibile
bull TCIquale livello
bull Dosi 1 mgkgripetibile dopo 5rsquo-
ndash Infcont 2-10 mgkgh
bull Rapida emergenzafinestra neurologicaevitare la
brusca sospensione
bull + rapido controllo delle convuls gt barbituricindash Stecker MM Kramer TH Raps EC OMeeghan R Dulaney E Skaar DJ Treatment of
refractory status epilepticus with propofol clinical and pharmacokinetic findings Epilepsia 1998
39 18-26
AG
bull Non ci sono dati che indichino quanto a lungo i paz debbano rimanere senza convuls prima di poter alleggerire il piano di AG24 h96h (Treiman DM Convulsive status
epilepticus Current Treatment Options in Neurology 1999 1 359-69)
bull Anest alogenatiisofluranogtsevofluranogtdesflurane
bull Ma vaporizzatori
bull Contaminazione ambientale
bull Costihellip
Studi comparativi1
bull Midazolamgt tiopental
ndash Lohr A Jr Werneck LC Comparative non-randomized study with
midazolam versus thiopental in children with refractory status
epilepticus [Portuguese] Arq Neuropsiquiatr 2000 58282-287
ndash non-randomized comparison
ndash of historical data (thiopental) and prospectively
acquired data (midazolam)
ndash Midazolam was no more often effective than
thiopental but was associated with less cyanosis and
less respiratory distress in this study of 50 children
Studi comparativi2
Valproatobull Valproate(ivrdquoDepaconrdquo) has been used for the treatment of refractory SE
in children and myoclonic SE ndash Sheth RD Gidal BE Intravenous valproic acid for myoclonic status epilepticus
Neurology 2000 541201
ndash Uberall MA Trollmann R Wunsiedler U Wenzel D Intravenous valproate in pediatric epilepsy patients with refractory status epilepticus Neurology 2000 542188-2189 ]
bull Valproate has also been used in SE in the elderly and appears to be safe even in the presence of cardiovascular instability and hypotension no significant change in blood pressure pulse or the need for vasopressors in 13 patients with SE and hypotension given a loading dose of 147-327 mgkg Depacon intravenouslyndash Sinha S Naritoku DK Intravenous valproate is well tolerated in unstable patients
with status epilepticus Neurology 2000 55722-724
bull However there is a case report of severe hypotension in an 11-year-old child after treatment of SE with 30 mgkg intravenous valproate ndash White JR Santos CS Intravenous valproate associated with significant
hypotension in the treatment of status epilepticus J Child Neurol 1999 14822-823
FINE
Percheacute non ne possiamo
piugravehelliphelliphellip
Veterans Affairs Status Epilepticus
Cooperative Study Group Treiman et al
bull st treatment successful in 555 of patients with a verified diagnosis of overt status epilepticus (n=384) and in 149 of patients with subtle status epilepticus (n=134)
bull Comparisons between the 4 treatments showed that lorazepam was more effective than phenytoin alone in patients with overt status epilepticus (treatment success in 649 versus 436 of patients respectively)
bull other treatment comparisons in the overt group and all comparisons in the subtle group were not significantly different however
bull There were no significant differences between treatments in patient outcome rates of recurrence of status epilepticus or return of full consciousness over the 12-h observation period or in the frequency of adverse cardiac respiratory or hypotensive events
Treiman DM Meyers PD Walton NY et al A
comparison of four treatments for generalized
convulsive status epilepticus N Engl J Med 1998
339792-798
P 002
Percentage of successful treatment
grey bars overt patients black bars subtle patients
Alldredge Brian Kab Lowenstein Daniel HAC Status
epilepticus new concepts Current Opinion in Neurology
121999 183-190
Da ChapmanAnaesthesia 2004
Marik PEVaron J The Management of Status
Epilepticus Chest 126(2)582-591 August 2004
Status epilepticus is a major medical emergency associated with significant morbidity and mortality Status epilepticusis best defined as a continuous generalized convulsive seizure lasting gt 5 min or two or more seizures during which the patient does not return to baseline consciousness Lorazepam in a dose of 01 mgkg is the drug of first choice for terminating status epilepticus Patients who continue to have clinical or EEG evidence of seizure activity after treatment with lorazepam should be considered to have refractory status epileptics and should be treated with a continuous infusion of propofol or midazolam This article reviews current information regarding the management of status epilepticus in adults
Schema di Marik et al
Claassen JHirsch LJ Emerson R GBates
JE Thompson TBMayer SA Continuous EEG
monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042 bull The authors reviewed 33 episodes of RSE treated with cIV-MDZ in their neurologic intensive care
unit over 6 years All patients were monitored with continuous EEG (cEEG) MDZ infusion rates were titrated to eliminate clinical and EEG seizure activity cIV-MDZ was discontinued once patients were seizure-free for 24 hours Acute treatment failures (seizures 1 to 6 hours after starting cIV-MDZ) breakthrough seizures (after 6 hours of therapy) post-treatment seizures (within 48 hours of discontinuing therapy) and ultimate treatment failure (frequent seizures that led to treatment with pentobarbital or propofol) were identified
bull Results All patients were in nonconvulsive SE at the time cIV-MDZ was started the mean duration of SE before treatment was 39 days (range 0 to 17 days) In addition to benzodiazepines 94 of patients had received at least two antiepileptic drugs (AED) before starting cIV-MDZ The mean loading dose was 019 mgkg the mean maximal infusion rate was 022 mgkgh and the mean duration of cIV-MDZ therapy was 42 days (range 1 to 14 days) Acute treatment failure occurred in 18 (633) of episodes breakthrough seizures in 56 (1832) post-treatment seizures in 68 (1928) and ultimate treatment failure in 18 (633) Breakthrough seizures were clinically subtle or purely electrographic in 89 (1618) of cases and were associated with an increased risk of developing post-treatment seizures (p = 001)
bull Conclusions Although most patients with RSE initially responded to cIV-MDZ over half developed subsequent breakthrough seizures which were predictive of post-treatment seizures and were often detectable only with cEEG Titrating cIV-MDZ to burst suppression more aggressive treatment with concurrent AED or a longer period of initial treatment may reduce the high proportion of patients with RSE who relapse after cIV-MDZ is discontinued
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus Neurology 2001 57 25 1036-1042
0
10
20
30
40
50
60
70
80
non seizures
seizures lt30 min24h05-12 h
seizures 05-12 h24 hgt 12 h
seiz gt12 h24
burst suppression
periodic latdischarge
periodic gen discharge
prima
durante
dopo
33 episodes of RSE treated with cIV-MDZ neurologic ICU over 6 years
All patients were monitored with continuous EEG (cEEG)
Waterhouse Elizabeth J 1 2 DeLorenzo Robert J 1 3 4 2
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
bull Status epilepticus (SE) is a medical and neurological emergency that has been associated with significant morbidity and mortality The most widely accepted definition of SE is more than 30 minutes of either continuous seizure activity or intermittent seizures without full recovery of consciousness between seizures SE is a major clinical concern in the elderly population both because it has increased incidence in the elderly compared with the general population and because of concurrent medical conditions that are more likely to complicate therapy and worsen prognosis in elderly individuals
The incidence of SE in the elderly is almost twice that of the general population at 86 per 100 000 per year With the anticipated growth of the elderly population SE is likely to become an increasingly common problem facing clinicians and an important public health issue The elderly have the highest SE-associated mortality of any age group at 38 and the very old elderly (gt80 years of age) have a mortality of at least 50 Acute or remote stroke is the most common aetiology of SE in the elderly Nonconvulsive SE (NCSE) has a wide range of clinical presentations ranging from confusion to obtundation It occurs commonly in elderly patients who are critically ill and in the setting of coma Electroencephalogram is the only reliable method of diagnosing NCSE
The goal of treatment for SE is rapid cessation of clinical and electrical seizure activity Most treatment protocols call for the immediate administration of an intravenous benzodiazepine followed by phenytoin or fosphenytoin Recent studies suggest that when this initial treatment of SE fails little is gained by using additional standard drugs General anaesthetic agents (such as pentobarbital midazolam or propofol) should be expeditiously employed although these treatments have their own potential complications Intravenous valproic acid is a recent addition to the armamentarium of drugs for the treatment of SE with a low risk of hypotension respiratory depression and hypotension making it a potentially useful drug for the treatment of SE in the elderly However further information is needed to establish its role in the overall treatment of SE
Waterhouseet al
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
BDZ
Fenitoina
O fosfenitoina
GA
Midaz
Propof
pentobarb
Ac valproico
Ns proposta
Lorazepam
01 mgkg
Propofol
1-2 mgkgMidazolam01 mgkg
Inf cont 3-10 mgkgh Inf cont 001-005 mgkgh
Miorilassante solo
Per intubazione
Pentobarbital dose caricopoi 01-04 mgkgmin
fenobarbital
bull 10-20 mgkg iv
ndash Eccessiva sedazione
ndash Depressresp
ndash Ipotensione
ndash Interaz farmacol
ndash Hl gt48 hrhelliphelliphellip
tiopental
bull cumulativo
bull Inotropo neghellip
bull Pentobarbital
bull immunosoppressione
propofol
bull Vantaggi cineticodinamici
bull Titolazione continua possibile
bull TCIquale livello
bull Dosi 1 mgkgripetibile dopo 5rsquo-
ndash Infcont 2-10 mgkgh
bull Rapida emergenzafinestra neurologicaevitare la
brusca sospensione
bull + rapido controllo delle convuls gt barbituricindash Stecker MM Kramer TH Raps EC OMeeghan R Dulaney E Skaar DJ Treatment of
refractory status epilepticus with propofol clinical and pharmacokinetic findings Epilepsia 1998
39 18-26
AG
bull Non ci sono dati che indichino quanto a lungo i paz debbano rimanere senza convuls prima di poter alleggerire il piano di AG24 h96h (Treiman DM Convulsive status
epilepticus Current Treatment Options in Neurology 1999 1 359-69)
bull Anest alogenatiisofluranogtsevofluranogtdesflurane
bull Ma vaporizzatori
bull Contaminazione ambientale
bull Costihellip
Studi comparativi1
bull Midazolamgt tiopental
ndash Lohr A Jr Werneck LC Comparative non-randomized study with
midazolam versus thiopental in children with refractory status
epilepticus [Portuguese] Arq Neuropsiquiatr 2000 58282-287
ndash non-randomized comparison
ndash of historical data (thiopental) and prospectively
acquired data (midazolam)
ndash Midazolam was no more often effective than
thiopental but was associated with less cyanosis and
less respiratory distress in this study of 50 children
Studi comparativi2
Valproatobull Valproate(ivrdquoDepaconrdquo) has been used for the treatment of refractory SE
in children and myoclonic SE ndash Sheth RD Gidal BE Intravenous valproic acid for myoclonic status epilepticus
Neurology 2000 541201
ndash Uberall MA Trollmann R Wunsiedler U Wenzel D Intravenous valproate in pediatric epilepsy patients with refractory status epilepticus Neurology 2000 542188-2189 ]
bull Valproate has also been used in SE in the elderly and appears to be safe even in the presence of cardiovascular instability and hypotension no significant change in blood pressure pulse or the need for vasopressors in 13 patients with SE and hypotension given a loading dose of 147-327 mgkg Depacon intravenouslyndash Sinha S Naritoku DK Intravenous valproate is well tolerated in unstable patients
with status epilepticus Neurology 2000 55722-724
bull However there is a case report of severe hypotension in an 11-year-old child after treatment of SE with 30 mgkg intravenous valproate ndash White JR Santos CS Intravenous valproate associated with significant
hypotension in the treatment of status epilepticus J Child Neurol 1999 14822-823
FINE
Percheacute non ne possiamo
piugravehelliphelliphellip
Treiman DM Meyers PD Walton NY et al A
comparison of four treatments for generalized
convulsive status epilepticus N Engl J Med 1998
339792-798
P 002
Percentage of successful treatment
grey bars overt patients black bars subtle patients
Alldredge Brian Kab Lowenstein Daniel HAC Status
epilepticus new concepts Current Opinion in Neurology
121999 183-190
Da ChapmanAnaesthesia 2004
Marik PEVaron J The Management of Status
Epilepticus Chest 126(2)582-591 August 2004
Status epilepticus is a major medical emergency associated with significant morbidity and mortality Status epilepticusis best defined as a continuous generalized convulsive seizure lasting gt 5 min or two or more seizures during which the patient does not return to baseline consciousness Lorazepam in a dose of 01 mgkg is the drug of first choice for terminating status epilepticus Patients who continue to have clinical or EEG evidence of seizure activity after treatment with lorazepam should be considered to have refractory status epileptics and should be treated with a continuous infusion of propofol or midazolam This article reviews current information regarding the management of status epilepticus in adults
Schema di Marik et al
Claassen JHirsch LJ Emerson R GBates
JE Thompson TBMayer SA Continuous EEG
monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042 bull The authors reviewed 33 episodes of RSE treated with cIV-MDZ in their neurologic intensive care
unit over 6 years All patients were monitored with continuous EEG (cEEG) MDZ infusion rates were titrated to eliminate clinical and EEG seizure activity cIV-MDZ was discontinued once patients were seizure-free for 24 hours Acute treatment failures (seizures 1 to 6 hours after starting cIV-MDZ) breakthrough seizures (after 6 hours of therapy) post-treatment seizures (within 48 hours of discontinuing therapy) and ultimate treatment failure (frequent seizures that led to treatment with pentobarbital or propofol) were identified
bull Results All patients were in nonconvulsive SE at the time cIV-MDZ was started the mean duration of SE before treatment was 39 days (range 0 to 17 days) In addition to benzodiazepines 94 of patients had received at least two antiepileptic drugs (AED) before starting cIV-MDZ The mean loading dose was 019 mgkg the mean maximal infusion rate was 022 mgkgh and the mean duration of cIV-MDZ therapy was 42 days (range 1 to 14 days) Acute treatment failure occurred in 18 (633) of episodes breakthrough seizures in 56 (1832) post-treatment seizures in 68 (1928) and ultimate treatment failure in 18 (633) Breakthrough seizures were clinically subtle or purely electrographic in 89 (1618) of cases and were associated with an increased risk of developing post-treatment seizures (p = 001)
bull Conclusions Although most patients with RSE initially responded to cIV-MDZ over half developed subsequent breakthrough seizures which were predictive of post-treatment seizures and were often detectable only with cEEG Titrating cIV-MDZ to burst suppression more aggressive treatment with concurrent AED or a longer period of initial treatment may reduce the high proportion of patients with RSE who relapse after cIV-MDZ is discontinued
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus Neurology 2001 57 25 1036-1042
0
10
20
30
40
50
60
70
80
non seizures
seizures lt30 min24h05-12 h
seizures 05-12 h24 hgt 12 h
seiz gt12 h24
burst suppression
periodic latdischarge
periodic gen discharge
prima
durante
dopo
33 episodes of RSE treated with cIV-MDZ neurologic ICU over 6 years
All patients were monitored with continuous EEG (cEEG)
Waterhouse Elizabeth J 1 2 DeLorenzo Robert J 1 3 4 2
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
bull Status epilepticus (SE) is a medical and neurological emergency that has been associated with significant morbidity and mortality The most widely accepted definition of SE is more than 30 minutes of either continuous seizure activity or intermittent seizures without full recovery of consciousness between seizures SE is a major clinical concern in the elderly population both because it has increased incidence in the elderly compared with the general population and because of concurrent medical conditions that are more likely to complicate therapy and worsen prognosis in elderly individuals
The incidence of SE in the elderly is almost twice that of the general population at 86 per 100 000 per year With the anticipated growth of the elderly population SE is likely to become an increasingly common problem facing clinicians and an important public health issue The elderly have the highest SE-associated mortality of any age group at 38 and the very old elderly (gt80 years of age) have a mortality of at least 50 Acute or remote stroke is the most common aetiology of SE in the elderly Nonconvulsive SE (NCSE) has a wide range of clinical presentations ranging from confusion to obtundation It occurs commonly in elderly patients who are critically ill and in the setting of coma Electroencephalogram is the only reliable method of diagnosing NCSE
The goal of treatment for SE is rapid cessation of clinical and electrical seizure activity Most treatment protocols call for the immediate administration of an intravenous benzodiazepine followed by phenytoin or fosphenytoin Recent studies suggest that when this initial treatment of SE fails little is gained by using additional standard drugs General anaesthetic agents (such as pentobarbital midazolam or propofol) should be expeditiously employed although these treatments have their own potential complications Intravenous valproic acid is a recent addition to the armamentarium of drugs for the treatment of SE with a low risk of hypotension respiratory depression and hypotension making it a potentially useful drug for the treatment of SE in the elderly However further information is needed to establish its role in the overall treatment of SE
Waterhouseet al
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
BDZ
Fenitoina
O fosfenitoina
GA
Midaz
Propof
pentobarb
Ac valproico
Ns proposta
Lorazepam
01 mgkg
Propofol
1-2 mgkgMidazolam01 mgkg
Inf cont 3-10 mgkgh Inf cont 001-005 mgkgh
Miorilassante solo
Per intubazione
Pentobarbital dose caricopoi 01-04 mgkgmin
fenobarbital
bull 10-20 mgkg iv
ndash Eccessiva sedazione
ndash Depressresp
ndash Ipotensione
ndash Interaz farmacol
ndash Hl gt48 hrhelliphelliphellip
tiopental
bull cumulativo
bull Inotropo neghellip
bull Pentobarbital
bull immunosoppressione
propofol
bull Vantaggi cineticodinamici
bull Titolazione continua possibile
bull TCIquale livello
bull Dosi 1 mgkgripetibile dopo 5rsquo-
ndash Infcont 2-10 mgkgh
bull Rapida emergenzafinestra neurologicaevitare la
brusca sospensione
bull + rapido controllo delle convuls gt barbituricindash Stecker MM Kramer TH Raps EC OMeeghan R Dulaney E Skaar DJ Treatment of
refractory status epilepticus with propofol clinical and pharmacokinetic findings Epilepsia 1998
39 18-26
AG
bull Non ci sono dati che indichino quanto a lungo i paz debbano rimanere senza convuls prima di poter alleggerire il piano di AG24 h96h (Treiman DM Convulsive status
epilepticus Current Treatment Options in Neurology 1999 1 359-69)
bull Anest alogenatiisofluranogtsevofluranogtdesflurane
bull Ma vaporizzatori
bull Contaminazione ambientale
bull Costihellip
Studi comparativi1
bull Midazolamgt tiopental
ndash Lohr A Jr Werneck LC Comparative non-randomized study with
midazolam versus thiopental in children with refractory status
epilepticus [Portuguese] Arq Neuropsiquiatr 2000 58282-287
ndash non-randomized comparison
ndash of historical data (thiopental) and prospectively
acquired data (midazolam)
ndash Midazolam was no more often effective than
thiopental but was associated with less cyanosis and
less respiratory distress in this study of 50 children
Studi comparativi2
Valproatobull Valproate(ivrdquoDepaconrdquo) has been used for the treatment of refractory SE
in children and myoclonic SE ndash Sheth RD Gidal BE Intravenous valproic acid for myoclonic status epilepticus
Neurology 2000 541201
ndash Uberall MA Trollmann R Wunsiedler U Wenzel D Intravenous valproate in pediatric epilepsy patients with refractory status epilepticus Neurology 2000 542188-2189 ]
bull Valproate has also been used in SE in the elderly and appears to be safe even in the presence of cardiovascular instability and hypotension no significant change in blood pressure pulse or the need for vasopressors in 13 patients with SE and hypotension given a loading dose of 147-327 mgkg Depacon intravenouslyndash Sinha S Naritoku DK Intravenous valproate is well tolerated in unstable patients
with status epilepticus Neurology 2000 55722-724
bull However there is a case report of severe hypotension in an 11-year-old child after treatment of SE with 30 mgkg intravenous valproate ndash White JR Santos CS Intravenous valproate associated with significant
hypotension in the treatment of status epilepticus J Child Neurol 1999 14822-823
FINE
Percheacute non ne possiamo
piugravehelliphelliphellip
Alldredge Brian Kab Lowenstein Daniel HAC Status
epilepticus new concepts Current Opinion in Neurology
121999 183-190
Da ChapmanAnaesthesia 2004
Marik PEVaron J The Management of Status
Epilepticus Chest 126(2)582-591 August 2004
Status epilepticus is a major medical emergency associated with significant morbidity and mortality Status epilepticusis best defined as a continuous generalized convulsive seizure lasting gt 5 min or two or more seizures during which the patient does not return to baseline consciousness Lorazepam in a dose of 01 mgkg is the drug of first choice for terminating status epilepticus Patients who continue to have clinical or EEG evidence of seizure activity after treatment with lorazepam should be considered to have refractory status epileptics and should be treated with a continuous infusion of propofol or midazolam This article reviews current information regarding the management of status epilepticus in adults
Schema di Marik et al
Claassen JHirsch LJ Emerson R GBates
JE Thompson TBMayer SA Continuous EEG
monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042 bull The authors reviewed 33 episodes of RSE treated with cIV-MDZ in their neurologic intensive care
unit over 6 years All patients were monitored with continuous EEG (cEEG) MDZ infusion rates were titrated to eliminate clinical and EEG seizure activity cIV-MDZ was discontinued once patients were seizure-free for 24 hours Acute treatment failures (seizures 1 to 6 hours after starting cIV-MDZ) breakthrough seizures (after 6 hours of therapy) post-treatment seizures (within 48 hours of discontinuing therapy) and ultimate treatment failure (frequent seizures that led to treatment with pentobarbital or propofol) were identified
bull Results All patients were in nonconvulsive SE at the time cIV-MDZ was started the mean duration of SE before treatment was 39 days (range 0 to 17 days) In addition to benzodiazepines 94 of patients had received at least two antiepileptic drugs (AED) before starting cIV-MDZ The mean loading dose was 019 mgkg the mean maximal infusion rate was 022 mgkgh and the mean duration of cIV-MDZ therapy was 42 days (range 1 to 14 days) Acute treatment failure occurred in 18 (633) of episodes breakthrough seizures in 56 (1832) post-treatment seizures in 68 (1928) and ultimate treatment failure in 18 (633) Breakthrough seizures were clinically subtle or purely electrographic in 89 (1618) of cases and were associated with an increased risk of developing post-treatment seizures (p = 001)
bull Conclusions Although most patients with RSE initially responded to cIV-MDZ over half developed subsequent breakthrough seizures which were predictive of post-treatment seizures and were often detectable only with cEEG Titrating cIV-MDZ to burst suppression more aggressive treatment with concurrent AED or a longer period of initial treatment may reduce the high proportion of patients with RSE who relapse after cIV-MDZ is discontinued
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus Neurology 2001 57 25 1036-1042
0
10
20
30
40
50
60
70
80
non seizures
seizures lt30 min24h05-12 h
seizures 05-12 h24 hgt 12 h
seiz gt12 h24
burst suppression
periodic latdischarge
periodic gen discharge
prima
durante
dopo
33 episodes of RSE treated with cIV-MDZ neurologic ICU over 6 years
All patients were monitored with continuous EEG (cEEG)
Waterhouse Elizabeth J 1 2 DeLorenzo Robert J 1 3 4 2
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
bull Status epilepticus (SE) is a medical and neurological emergency that has been associated with significant morbidity and mortality The most widely accepted definition of SE is more than 30 minutes of either continuous seizure activity or intermittent seizures without full recovery of consciousness between seizures SE is a major clinical concern in the elderly population both because it has increased incidence in the elderly compared with the general population and because of concurrent medical conditions that are more likely to complicate therapy and worsen prognosis in elderly individuals
The incidence of SE in the elderly is almost twice that of the general population at 86 per 100 000 per year With the anticipated growth of the elderly population SE is likely to become an increasingly common problem facing clinicians and an important public health issue The elderly have the highest SE-associated mortality of any age group at 38 and the very old elderly (gt80 years of age) have a mortality of at least 50 Acute or remote stroke is the most common aetiology of SE in the elderly Nonconvulsive SE (NCSE) has a wide range of clinical presentations ranging from confusion to obtundation It occurs commonly in elderly patients who are critically ill and in the setting of coma Electroencephalogram is the only reliable method of diagnosing NCSE
The goal of treatment for SE is rapid cessation of clinical and electrical seizure activity Most treatment protocols call for the immediate administration of an intravenous benzodiazepine followed by phenytoin or fosphenytoin Recent studies suggest that when this initial treatment of SE fails little is gained by using additional standard drugs General anaesthetic agents (such as pentobarbital midazolam or propofol) should be expeditiously employed although these treatments have their own potential complications Intravenous valproic acid is a recent addition to the armamentarium of drugs for the treatment of SE with a low risk of hypotension respiratory depression and hypotension making it a potentially useful drug for the treatment of SE in the elderly However further information is needed to establish its role in the overall treatment of SE
Waterhouseet al
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
BDZ
Fenitoina
O fosfenitoina
GA
Midaz
Propof
pentobarb
Ac valproico
Ns proposta
Lorazepam
01 mgkg
Propofol
1-2 mgkgMidazolam01 mgkg
Inf cont 3-10 mgkgh Inf cont 001-005 mgkgh
Miorilassante solo
Per intubazione
Pentobarbital dose caricopoi 01-04 mgkgmin
fenobarbital
bull 10-20 mgkg iv
ndash Eccessiva sedazione
ndash Depressresp
ndash Ipotensione
ndash Interaz farmacol
ndash Hl gt48 hrhelliphelliphellip
tiopental
bull cumulativo
bull Inotropo neghellip
bull Pentobarbital
bull immunosoppressione
propofol
bull Vantaggi cineticodinamici
bull Titolazione continua possibile
bull TCIquale livello
bull Dosi 1 mgkgripetibile dopo 5rsquo-
ndash Infcont 2-10 mgkgh
bull Rapida emergenzafinestra neurologicaevitare la
brusca sospensione
bull + rapido controllo delle convuls gt barbituricindash Stecker MM Kramer TH Raps EC OMeeghan R Dulaney E Skaar DJ Treatment of
refractory status epilepticus with propofol clinical and pharmacokinetic findings Epilepsia 1998
39 18-26
AG
bull Non ci sono dati che indichino quanto a lungo i paz debbano rimanere senza convuls prima di poter alleggerire il piano di AG24 h96h (Treiman DM Convulsive status
epilepticus Current Treatment Options in Neurology 1999 1 359-69)
bull Anest alogenatiisofluranogtsevofluranogtdesflurane
bull Ma vaporizzatori
bull Contaminazione ambientale
bull Costihellip
Studi comparativi1
bull Midazolamgt tiopental
ndash Lohr A Jr Werneck LC Comparative non-randomized study with
midazolam versus thiopental in children with refractory status
epilepticus [Portuguese] Arq Neuropsiquiatr 2000 58282-287
ndash non-randomized comparison
ndash of historical data (thiopental) and prospectively
acquired data (midazolam)
ndash Midazolam was no more often effective than
thiopental but was associated with less cyanosis and
less respiratory distress in this study of 50 children
Studi comparativi2
Valproatobull Valproate(ivrdquoDepaconrdquo) has been used for the treatment of refractory SE
in children and myoclonic SE ndash Sheth RD Gidal BE Intravenous valproic acid for myoclonic status epilepticus
Neurology 2000 541201
ndash Uberall MA Trollmann R Wunsiedler U Wenzel D Intravenous valproate in pediatric epilepsy patients with refractory status epilepticus Neurology 2000 542188-2189 ]
bull Valproate has also been used in SE in the elderly and appears to be safe even in the presence of cardiovascular instability and hypotension no significant change in blood pressure pulse or the need for vasopressors in 13 patients with SE and hypotension given a loading dose of 147-327 mgkg Depacon intravenouslyndash Sinha S Naritoku DK Intravenous valproate is well tolerated in unstable patients
with status epilepticus Neurology 2000 55722-724
bull However there is a case report of severe hypotension in an 11-year-old child after treatment of SE with 30 mgkg intravenous valproate ndash White JR Santos CS Intravenous valproate associated with significant
hypotension in the treatment of status epilepticus J Child Neurol 1999 14822-823
FINE
Percheacute non ne possiamo
piugravehelliphelliphellip
Da ChapmanAnaesthesia 2004
Marik PEVaron J The Management of Status
Epilepticus Chest 126(2)582-591 August 2004
Status epilepticus is a major medical emergency associated with significant morbidity and mortality Status epilepticusis best defined as a continuous generalized convulsive seizure lasting gt 5 min or two or more seizures during which the patient does not return to baseline consciousness Lorazepam in a dose of 01 mgkg is the drug of first choice for terminating status epilepticus Patients who continue to have clinical or EEG evidence of seizure activity after treatment with lorazepam should be considered to have refractory status epileptics and should be treated with a continuous infusion of propofol or midazolam This article reviews current information regarding the management of status epilepticus in adults
Schema di Marik et al
Claassen JHirsch LJ Emerson R GBates
JE Thompson TBMayer SA Continuous EEG
monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042 bull The authors reviewed 33 episodes of RSE treated with cIV-MDZ in their neurologic intensive care
unit over 6 years All patients were monitored with continuous EEG (cEEG) MDZ infusion rates were titrated to eliminate clinical and EEG seizure activity cIV-MDZ was discontinued once patients were seizure-free for 24 hours Acute treatment failures (seizures 1 to 6 hours after starting cIV-MDZ) breakthrough seizures (after 6 hours of therapy) post-treatment seizures (within 48 hours of discontinuing therapy) and ultimate treatment failure (frequent seizures that led to treatment with pentobarbital or propofol) were identified
bull Results All patients were in nonconvulsive SE at the time cIV-MDZ was started the mean duration of SE before treatment was 39 days (range 0 to 17 days) In addition to benzodiazepines 94 of patients had received at least two antiepileptic drugs (AED) before starting cIV-MDZ The mean loading dose was 019 mgkg the mean maximal infusion rate was 022 mgkgh and the mean duration of cIV-MDZ therapy was 42 days (range 1 to 14 days) Acute treatment failure occurred in 18 (633) of episodes breakthrough seizures in 56 (1832) post-treatment seizures in 68 (1928) and ultimate treatment failure in 18 (633) Breakthrough seizures were clinically subtle or purely electrographic in 89 (1618) of cases and were associated with an increased risk of developing post-treatment seizures (p = 001)
bull Conclusions Although most patients with RSE initially responded to cIV-MDZ over half developed subsequent breakthrough seizures which were predictive of post-treatment seizures and were often detectable only with cEEG Titrating cIV-MDZ to burst suppression more aggressive treatment with concurrent AED or a longer period of initial treatment may reduce the high proportion of patients with RSE who relapse after cIV-MDZ is discontinued
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus Neurology 2001 57 25 1036-1042
0
10
20
30
40
50
60
70
80
non seizures
seizures lt30 min24h05-12 h
seizures 05-12 h24 hgt 12 h
seiz gt12 h24
burst suppression
periodic latdischarge
periodic gen discharge
prima
durante
dopo
33 episodes of RSE treated with cIV-MDZ neurologic ICU over 6 years
All patients were monitored with continuous EEG (cEEG)
Waterhouse Elizabeth J 1 2 DeLorenzo Robert J 1 3 4 2
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
bull Status epilepticus (SE) is a medical and neurological emergency that has been associated with significant morbidity and mortality The most widely accepted definition of SE is more than 30 minutes of either continuous seizure activity or intermittent seizures without full recovery of consciousness between seizures SE is a major clinical concern in the elderly population both because it has increased incidence in the elderly compared with the general population and because of concurrent medical conditions that are more likely to complicate therapy and worsen prognosis in elderly individuals
The incidence of SE in the elderly is almost twice that of the general population at 86 per 100 000 per year With the anticipated growth of the elderly population SE is likely to become an increasingly common problem facing clinicians and an important public health issue The elderly have the highest SE-associated mortality of any age group at 38 and the very old elderly (gt80 years of age) have a mortality of at least 50 Acute or remote stroke is the most common aetiology of SE in the elderly Nonconvulsive SE (NCSE) has a wide range of clinical presentations ranging from confusion to obtundation It occurs commonly in elderly patients who are critically ill and in the setting of coma Electroencephalogram is the only reliable method of diagnosing NCSE
The goal of treatment for SE is rapid cessation of clinical and electrical seizure activity Most treatment protocols call for the immediate administration of an intravenous benzodiazepine followed by phenytoin or fosphenytoin Recent studies suggest that when this initial treatment of SE fails little is gained by using additional standard drugs General anaesthetic agents (such as pentobarbital midazolam or propofol) should be expeditiously employed although these treatments have their own potential complications Intravenous valproic acid is a recent addition to the armamentarium of drugs for the treatment of SE with a low risk of hypotension respiratory depression and hypotension making it a potentially useful drug for the treatment of SE in the elderly However further information is needed to establish its role in the overall treatment of SE
Waterhouseet al
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
BDZ
Fenitoina
O fosfenitoina
GA
Midaz
Propof
pentobarb
Ac valproico
Ns proposta
Lorazepam
01 mgkg
Propofol
1-2 mgkgMidazolam01 mgkg
Inf cont 3-10 mgkgh Inf cont 001-005 mgkgh
Miorilassante solo
Per intubazione
Pentobarbital dose caricopoi 01-04 mgkgmin
fenobarbital
bull 10-20 mgkg iv
ndash Eccessiva sedazione
ndash Depressresp
ndash Ipotensione
ndash Interaz farmacol
ndash Hl gt48 hrhelliphelliphellip
tiopental
bull cumulativo
bull Inotropo neghellip
bull Pentobarbital
bull immunosoppressione
propofol
bull Vantaggi cineticodinamici
bull Titolazione continua possibile
bull TCIquale livello
bull Dosi 1 mgkgripetibile dopo 5rsquo-
ndash Infcont 2-10 mgkgh
bull Rapida emergenzafinestra neurologicaevitare la
brusca sospensione
bull + rapido controllo delle convuls gt barbituricindash Stecker MM Kramer TH Raps EC OMeeghan R Dulaney E Skaar DJ Treatment of
refractory status epilepticus with propofol clinical and pharmacokinetic findings Epilepsia 1998
39 18-26
AG
bull Non ci sono dati che indichino quanto a lungo i paz debbano rimanere senza convuls prima di poter alleggerire il piano di AG24 h96h (Treiman DM Convulsive status
epilepticus Current Treatment Options in Neurology 1999 1 359-69)
bull Anest alogenatiisofluranogtsevofluranogtdesflurane
bull Ma vaporizzatori
bull Contaminazione ambientale
bull Costihellip
Studi comparativi1
bull Midazolamgt tiopental
ndash Lohr A Jr Werneck LC Comparative non-randomized study with
midazolam versus thiopental in children with refractory status
epilepticus [Portuguese] Arq Neuropsiquiatr 2000 58282-287
ndash non-randomized comparison
ndash of historical data (thiopental) and prospectively
acquired data (midazolam)
ndash Midazolam was no more often effective than
thiopental but was associated with less cyanosis and
less respiratory distress in this study of 50 children
Studi comparativi2
Valproatobull Valproate(ivrdquoDepaconrdquo) has been used for the treatment of refractory SE
in children and myoclonic SE ndash Sheth RD Gidal BE Intravenous valproic acid for myoclonic status epilepticus
Neurology 2000 541201
ndash Uberall MA Trollmann R Wunsiedler U Wenzel D Intravenous valproate in pediatric epilepsy patients with refractory status epilepticus Neurology 2000 542188-2189 ]
bull Valproate has also been used in SE in the elderly and appears to be safe even in the presence of cardiovascular instability and hypotension no significant change in blood pressure pulse or the need for vasopressors in 13 patients with SE and hypotension given a loading dose of 147-327 mgkg Depacon intravenouslyndash Sinha S Naritoku DK Intravenous valproate is well tolerated in unstable patients
with status epilepticus Neurology 2000 55722-724
bull However there is a case report of severe hypotension in an 11-year-old child after treatment of SE with 30 mgkg intravenous valproate ndash White JR Santos CS Intravenous valproate associated with significant
hypotension in the treatment of status epilepticus J Child Neurol 1999 14822-823
FINE
Percheacute non ne possiamo
piugravehelliphelliphellip
Marik PEVaron J The Management of Status
Epilepticus Chest 126(2)582-591 August 2004
Status epilepticus is a major medical emergency associated with significant morbidity and mortality Status epilepticusis best defined as a continuous generalized convulsive seizure lasting gt 5 min or two or more seizures during which the patient does not return to baseline consciousness Lorazepam in a dose of 01 mgkg is the drug of first choice for terminating status epilepticus Patients who continue to have clinical or EEG evidence of seizure activity after treatment with lorazepam should be considered to have refractory status epileptics and should be treated with a continuous infusion of propofol or midazolam This article reviews current information regarding the management of status epilepticus in adults
Schema di Marik et al
Claassen JHirsch LJ Emerson R GBates
JE Thompson TBMayer SA Continuous EEG
monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042 bull The authors reviewed 33 episodes of RSE treated with cIV-MDZ in their neurologic intensive care
unit over 6 years All patients were monitored with continuous EEG (cEEG) MDZ infusion rates were titrated to eliminate clinical and EEG seizure activity cIV-MDZ was discontinued once patients were seizure-free for 24 hours Acute treatment failures (seizures 1 to 6 hours after starting cIV-MDZ) breakthrough seizures (after 6 hours of therapy) post-treatment seizures (within 48 hours of discontinuing therapy) and ultimate treatment failure (frequent seizures that led to treatment with pentobarbital or propofol) were identified
bull Results All patients were in nonconvulsive SE at the time cIV-MDZ was started the mean duration of SE before treatment was 39 days (range 0 to 17 days) In addition to benzodiazepines 94 of patients had received at least two antiepileptic drugs (AED) before starting cIV-MDZ The mean loading dose was 019 mgkg the mean maximal infusion rate was 022 mgkgh and the mean duration of cIV-MDZ therapy was 42 days (range 1 to 14 days) Acute treatment failure occurred in 18 (633) of episodes breakthrough seizures in 56 (1832) post-treatment seizures in 68 (1928) and ultimate treatment failure in 18 (633) Breakthrough seizures were clinically subtle or purely electrographic in 89 (1618) of cases and were associated with an increased risk of developing post-treatment seizures (p = 001)
bull Conclusions Although most patients with RSE initially responded to cIV-MDZ over half developed subsequent breakthrough seizures which were predictive of post-treatment seizures and were often detectable only with cEEG Titrating cIV-MDZ to burst suppression more aggressive treatment with concurrent AED or a longer period of initial treatment may reduce the high proportion of patients with RSE who relapse after cIV-MDZ is discontinued
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus Neurology 2001 57 25 1036-1042
0
10
20
30
40
50
60
70
80
non seizures
seizures lt30 min24h05-12 h
seizures 05-12 h24 hgt 12 h
seiz gt12 h24
burst suppression
periodic latdischarge
periodic gen discharge
prima
durante
dopo
33 episodes of RSE treated with cIV-MDZ neurologic ICU over 6 years
All patients were monitored with continuous EEG (cEEG)
Waterhouse Elizabeth J 1 2 DeLorenzo Robert J 1 3 4 2
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
bull Status epilepticus (SE) is a medical and neurological emergency that has been associated with significant morbidity and mortality The most widely accepted definition of SE is more than 30 minutes of either continuous seizure activity or intermittent seizures without full recovery of consciousness between seizures SE is a major clinical concern in the elderly population both because it has increased incidence in the elderly compared with the general population and because of concurrent medical conditions that are more likely to complicate therapy and worsen prognosis in elderly individuals
The incidence of SE in the elderly is almost twice that of the general population at 86 per 100 000 per year With the anticipated growth of the elderly population SE is likely to become an increasingly common problem facing clinicians and an important public health issue The elderly have the highest SE-associated mortality of any age group at 38 and the very old elderly (gt80 years of age) have a mortality of at least 50 Acute or remote stroke is the most common aetiology of SE in the elderly Nonconvulsive SE (NCSE) has a wide range of clinical presentations ranging from confusion to obtundation It occurs commonly in elderly patients who are critically ill and in the setting of coma Electroencephalogram is the only reliable method of diagnosing NCSE
The goal of treatment for SE is rapid cessation of clinical and electrical seizure activity Most treatment protocols call for the immediate administration of an intravenous benzodiazepine followed by phenytoin or fosphenytoin Recent studies suggest that when this initial treatment of SE fails little is gained by using additional standard drugs General anaesthetic agents (such as pentobarbital midazolam or propofol) should be expeditiously employed although these treatments have their own potential complications Intravenous valproic acid is a recent addition to the armamentarium of drugs for the treatment of SE with a low risk of hypotension respiratory depression and hypotension making it a potentially useful drug for the treatment of SE in the elderly However further information is needed to establish its role in the overall treatment of SE
Waterhouseet al
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
BDZ
Fenitoina
O fosfenitoina
GA
Midaz
Propof
pentobarb
Ac valproico
Ns proposta
Lorazepam
01 mgkg
Propofol
1-2 mgkgMidazolam01 mgkg
Inf cont 3-10 mgkgh Inf cont 001-005 mgkgh
Miorilassante solo
Per intubazione
Pentobarbital dose caricopoi 01-04 mgkgmin
fenobarbital
bull 10-20 mgkg iv
ndash Eccessiva sedazione
ndash Depressresp
ndash Ipotensione
ndash Interaz farmacol
ndash Hl gt48 hrhelliphelliphellip
tiopental
bull cumulativo
bull Inotropo neghellip
bull Pentobarbital
bull immunosoppressione
propofol
bull Vantaggi cineticodinamici
bull Titolazione continua possibile
bull TCIquale livello
bull Dosi 1 mgkgripetibile dopo 5rsquo-
ndash Infcont 2-10 mgkgh
bull Rapida emergenzafinestra neurologicaevitare la
brusca sospensione
bull + rapido controllo delle convuls gt barbituricindash Stecker MM Kramer TH Raps EC OMeeghan R Dulaney E Skaar DJ Treatment of
refractory status epilepticus with propofol clinical and pharmacokinetic findings Epilepsia 1998
39 18-26
AG
bull Non ci sono dati che indichino quanto a lungo i paz debbano rimanere senza convuls prima di poter alleggerire il piano di AG24 h96h (Treiman DM Convulsive status
epilepticus Current Treatment Options in Neurology 1999 1 359-69)
bull Anest alogenatiisofluranogtsevofluranogtdesflurane
bull Ma vaporizzatori
bull Contaminazione ambientale
bull Costihellip
Studi comparativi1
bull Midazolamgt tiopental
ndash Lohr A Jr Werneck LC Comparative non-randomized study with
midazolam versus thiopental in children with refractory status
epilepticus [Portuguese] Arq Neuropsiquiatr 2000 58282-287
ndash non-randomized comparison
ndash of historical data (thiopental) and prospectively
acquired data (midazolam)
ndash Midazolam was no more often effective than
thiopental but was associated with less cyanosis and
less respiratory distress in this study of 50 children
Studi comparativi2
Valproatobull Valproate(ivrdquoDepaconrdquo) has been used for the treatment of refractory SE
in children and myoclonic SE ndash Sheth RD Gidal BE Intravenous valproic acid for myoclonic status epilepticus
Neurology 2000 541201
ndash Uberall MA Trollmann R Wunsiedler U Wenzel D Intravenous valproate in pediatric epilepsy patients with refractory status epilepticus Neurology 2000 542188-2189 ]
bull Valproate has also been used in SE in the elderly and appears to be safe even in the presence of cardiovascular instability and hypotension no significant change in blood pressure pulse or the need for vasopressors in 13 patients with SE and hypotension given a loading dose of 147-327 mgkg Depacon intravenouslyndash Sinha S Naritoku DK Intravenous valproate is well tolerated in unstable patients
with status epilepticus Neurology 2000 55722-724
bull However there is a case report of severe hypotension in an 11-year-old child after treatment of SE with 30 mgkg intravenous valproate ndash White JR Santos CS Intravenous valproate associated with significant
hypotension in the treatment of status epilepticus J Child Neurol 1999 14822-823
FINE
Percheacute non ne possiamo
piugravehelliphelliphellip
Schema di Marik et al
Claassen JHirsch LJ Emerson R GBates
JE Thompson TBMayer SA Continuous EEG
monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042 bull The authors reviewed 33 episodes of RSE treated with cIV-MDZ in their neurologic intensive care
unit over 6 years All patients were monitored with continuous EEG (cEEG) MDZ infusion rates were titrated to eliminate clinical and EEG seizure activity cIV-MDZ was discontinued once patients were seizure-free for 24 hours Acute treatment failures (seizures 1 to 6 hours after starting cIV-MDZ) breakthrough seizures (after 6 hours of therapy) post-treatment seizures (within 48 hours of discontinuing therapy) and ultimate treatment failure (frequent seizures that led to treatment with pentobarbital or propofol) were identified
bull Results All patients were in nonconvulsive SE at the time cIV-MDZ was started the mean duration of SE before treatment was 39 days (range 0 to 17 days) In addition to benzodiazepines 94 of patients had received at least two antiepileptic drugs (AED) before starting cIV-MDZ The mean loading dose was 019 mgkg the mean maximal infusion rate was 022 mgkgh and the mean duration of cIV-MDZ therapy was 42 days (range 1 to 14 days) Acute treatment failure occurred in 18 (633) of episodes breakthrough seizures in 56 (1832) post-treatment seizures in 68 (1928) and ultimate treatment failure in 18 (633) Breakthrough seizures were clinically subtle or purely electrographic in 89 (1618) of cases and were associated with an increased risk of developing post-treatment seizures (p = 001)
bull Conclusions Although most patients with RSE initially responded to cIV-MDZ over half developed subsequent breakthrough seizures which were predictive of post-treatment seizures and were often detectable only with cEEG Titrating cIV-MDZ to burst suppression more aggressive treatment with concurrent AED or a longer period of initial treatment may reduce the high proportion of patients with RSE who relapse after cIV-MDZ is discontinued
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus Neurology 2001 57 25 1036-1042
0
10
20
30
40
50
60
70
80
non seizures
seizures lt30 min24h05-12 h
seizures 05-12 h24 hgt 12 h
seiz gt12 h24
burst suppression
periodic latdischarge
periodic gen discharge
prima
durante
dopo
33 episodes of RSE treated with cIV-MDZ neurologic ICU over 6 years
All patients were monitored with continuous EEG (cEEG)
Waterhouse Elizabeth J 1 2 DeLorenzo Robert J 1 3 4 2
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
bull Status epilepticus (SE) is a medical and neurological emergency that has been associated with significant morbidity and mortality The most widely accepted definition of SE is more than 30 minutes of either continuous seizure activity or intermittent seizures without full recovery of consciousness between seizures SE is a major clinical concern in the elderly population both because it has increased incidence in the elderly compared with the general population and because of concurrent medical conditions that are more likely to complicate therapy and worsen prognosis in elderly individuals
The incidence of SE in the elderly is almost twice that of the general population at 86 per 100 000 per year With the anticipated growth of the elderly population SE is likely to become an increasingly common problem facing clinicians and an important public health issue The elderly have the highest SE-associated mortality of any age group at 38 and the very old elderly (gt80 years of age) have a mortality of at least 50 Acute or remote stroke is the most common aetiology of SE in the elderly Nonconvulsive SE (NCSE) has a wide range of clinical presentations ranging from confusion to obtundation It occurs commonly in elderly patients who are critically ill and in the setting of coma Electroencephalogram is the only reliable method of diagnosing NCSE
The goal of treatment for SE is rapid cessation of clinical and electrical seizure activity Most treatment protocols call for the immediate administration of an intravenous benzodiazepine followed by phenytoin or fosphenytoin Recent studies suggest that when this initial treatment of SE fails little is gained by using additional standard drugs General anaesthetic agents (such as pentobarbital midazolam or propofol) should be expeditiously employed although these treatments have their own potential complications Intravenous valproic acid is a recent addition to the armamentarium of drugs for the treatment of SE with a low risk of hypotension respiratory depression and hypotension making it a potentially useful drug for the treatment of SE in the elderly However further information is needed to establish its role in the overall treatment of SE
Waterhouseet al
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
BDZ
Fenitoina
O fosfenitoina
GA
Midaz
Propof
pentobarb
Ac valproico
Ns proposta
Lorazepam
01 mgkg
Propofol
1-2 mgkgMidazolam01 mgkg
Inf cont 3-10 mgkgh Inf cont 001-005 mgkgh
Miorilassante solo
Per intubazione
Pentobarbital dose caricopoi 01-04 mgkgmin
fenobarbital
bull 10-20 mgkg iv
ndash Eccessiva sedazione
ndash Depressresp
ndash Ipotensione
ndash Interaz farmacol
ndash Hl gt48 hrhelliphelliphellip
tiopental
bull cumulativo
bull Inotropo neghellip
bull Pentobarbital
bull immunosoppressione
propofol
bull Vantaggi cineticodinamici
bull Titolazione continua possibile
bull TCIquale livello
bull Dosi 1 mgkgripetibile dopo 5rsquo-
ndash Infcont 2-10 mgkgh
bull Rapida emergenzafinestra neurologicaevitare la
brusca sospensione
bull + rapido controllo delle convuls gt barbituricindash Stecker MM Kramer TH Raps EC OMeeghan R Dulaney E Skaar DJ Treatment of
refractory status epilepticus with propofol clinical and pharmacokinetic findings Epilepsia 1998
39 18-26
AG
bull Non ci sono dati che indichino quanto a lungo i paz debbano rimanere senza convuls prima di poter alleggerire il piano di AG24 h96h (Treiman DM Convulsive status
epilepticus Current Treatment Options in Neurology 1999 1 359-69)
bull Anest alogenatiisofluranogtsevofluranogtdesflurane
bull Ma vaporizzatori
bull Contaminazione ambientale
bull Costihellip
Studi comparativi1
bull Midazolamgt tiopental
ndash Lohr A Jr Werneck LC Comparative non-randomized study with
midazolam versus thiopental in children with refractory status
epilepticus [Portuguese] Arq Neuropsiquiatr 2000 58282-287
ndash non-randomized comparison
ndash of historical data (thiopental) and prospectively
acquired data (midazolam)
ndash Midazolam was no more often effective than
thiopental but was associated with less cyanosis and
less respiratory distress in this study of 50 children
Studi comparativi2
Valproatobull Valproate(ivrdquoDepaconrdquo) has been used for the treatment of refractory SE
in children and myoclonic SE ndash Sheth RD Gidal BE Intravenous valproic acid for myoclonic status epilepticus
Neurology 2000 541201
ndash Uberall MA Trollmann R Wunsiedler U Wenzel D Intravenous valproate in pediatric epilepsy patients with refractory status epilepticus Neurology 2000 542188-2189 ]
bull Valproate has also been used in SE in the elderly and appears to be safe even in the presence of cardiovascular instability and hypotension no significant change in blood pressure pulse or the need for vasopressors in 13 patients with SE and hypotension given a loading dose of 147-327 mgkg Depacon intravenouslyndash Sinha S Naritoku DK Intravenous valproate is well tolerated in unstable patients
with status epilepticus Neurology 2000 55722-724
bull However there is a case report of severe hypotension in an 11-year-old child after treatment of SE with 30 mgkg intravenous valproate ndash White JR Santos CS Intravenous valproate associated with significant
hypotension in the treatment of status epilepticus J Child Neurol 1999 14822-823
FINE
Percheacute non ne possiamo
piugravehelliphelliphellip
Claassen JHirsch LJ Emerson R GBates
JE Thompson TBMayer SA Continuous EEG
monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042 bull The authors reviewed 33 episodes of RSE treated with cIV-MDZ in their neurologic intensive care
unit over 6 years All patients were monitored with continuous EEG (cEEG) MDZ infusion rates were titrated to eliminate clinical and EEG seizure activity cIV-MDZ was discontinued once patients were seizure-free for 24 hours Acute treatment failures (seizures 1 to 6 hours after starting cIV-MDZ) breakthrough seizures (after 6 hours of therapy) post-treatment seizures (within 48 hours of discontinuing therapy) and ultimate treatment failure (frequent seizures that led to treatment with pentobarbital or propofol) were identified
bull Results All patients were in nonconvulsive SE at the time cIV-MDZ was started the mean duration of SE before treatment was 39 days (range 0 to 17 days) In addition to benzodiazepines 94 of patients had received at least two antiepileptic drugs (AED) before starting cIV-MDZ The mean loading dose was 019 mgkg the mean maximal infusion rate was 022 mgkgh and the mean duration of cIV-MDZ therapy was 42 days (range 1 to 14 days) Acute treatment failure occurred in 18 (633) of episodes breakthrough seizures in 56 (1832) post-treatment seizures in 68 (1928) and ultimate treatment failure in 18 (633) Breakthrough seizures were clinically subtle or purely electrographic in 89 (1618) of cases and were associated with an increased risk of developing post-treatment seizures (p = 001)
bull Conclusions Although most patients with RSE initially responded to cIV-MDZ over half developed subsequent breakthrough seizures which were predictive of post-treatment seizures and were often detectable only with cEEG Titrating cIV-MDZ to burst suppression more aggressive treatment with concurrent AED or a longer period of initial treatment may reduce the high proportion of patients with RSE who relapse after cIV-MDZ is discontinued
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus Neurology 2001 57 25 1036-1042
0
10
20
30
40
50
60
70
80
non seizures
seizures lt30 min24h05-12 h
seizures 05-12 h24 hgt 12 h
seiz gt12 h24
burst suppression
periodic latdischarge
periodic gen discharge
prima
durante
dopo
33 episodes of RSE treated with cIV-MDZ neurologic ICU over 6 years
All patients were monitored with continuous EEG (cEEG)
Waterhouse Elizabeth J 1 2 DeLorenzo Robert J 1 3 4 2
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
bull Status epilepticus (SE) is a medical and neurological emergency that has been associated with significant morbidity and mortality The most widely accepted definition of SE is more than 30 minutes of either continuous seizure activity or intermittent seizures without full recovery of consciousness between seizures SE is a major clinical concern in the elderly population both because it has increased incidence in the elderly compared with the general population and because of concurrent medical conditions that are more likely to complicate therapy and worsen prognosis in elderly individuals
The incidence of SE in the elderly is almost twice that of the general population at 86 per 100 000 per year With the anticipated growth of the elderly population SE is likely to become an increasingly common problem facing clinicians and an important public health issue The elderly have the highest SE-associated mortality of any age group at 38 and the very old elderly (gt80 years of age) have a mortality of at least 50 Acute or remote stroke is the most common aetiology of SE in the elderly Nonconvulsive SE (NCSE) has a wide range of clinical presentations ranging from confusion to obtundation It occurs commonly in elderly patients who are critically ill and in the setting of coma Electroencephalogram is the only reliable method of diagnosing NCSE
The goal of treatment for SE is rapid cessation of clinical and electrical seizure activity Most treatment protocols call for the immediate administration of an intravenous benzodiazepine followed by phenytoin or fosphenytoin Recent studies suggest that when this initial treatment of SE fails little is gained by using additional standard drugs General anaesthetic agents (such as pentobarbital midazolam or propofol) should be expeditiously employed although these treatments have their own potential complications Intravenous valproic acid is a recent addition to the armamentarium of drugs for the treatment of SE with a low risk of hypotension respiratory depression and hypotension making it a potentially useful drug for the treatment of SE in the elderly However further information is needed to establish its role in the overall treatment of SE
Waterhouseet al
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
BDZ
Fenitoina
O fosfenitoina
GA
Midaz
Propof
pentobarb
Ac valproico
Ns proposta
Lorazepam
01 mgkg
Propofol
1-2 mgkgMidazolam01 mgkg
Inf cont 3-10 mgkgh Inf cont 001-005 mgkgh
Miorilassante solo
Per intubazione
Pentobarbital dose caricopoi 01-04 mgkgmin
fenobarbital
bull 10-20 mgkg iv
ndash Eccessiva sedazione
ndash Depressresp
ndash Ipotensione
ndash Interaz farmacol
ndash Hl gt48 hrhelliphelliphellip
tiopental
bull cumulativo
bull Inotropo neghellip
bull Pentobarbital
bull immunosoppressione
propofol
bull Vantaggi cineticodinamici
bull Titolazione continua possibile
bull TCIquale livello
bull Dosi 1 mgkgripetibile dopo 5rsquo-
ndash Infcont 2-10 mgkgh
bull Rapida emergenzafinestra neurologicaevitare la
brusca sospensione
bull + rapido controllo delle convuls gt barbituricindash Stecker MM Kramer TH Raps EC OMeeghan R Dulaney E Skaar DJ Treatment of
refractory status epilepticus with propofol clinical and pharmacokinetic findings Epilepsia 1998
39 18-26
AG
bull Non ci sono dati che indichino quanto a lungo i paz debbano rimanere senza convuls prima di poter alleggerire il piano di AG24 h96h (Treiman DM Convulsive status
epilepticus Current Treatment Options in Neurology 1999 1 359-69)
bull Anest alogenatiisofluranogtsevofluranogtdesflurane
bull Ma vaporizzatori
bull Contaminazione ambientale
bull Costihellip
Studi comparativi1
bull Midazolamgt tiopental
ndash Lohr A Jr Werneck LC Comparative non-randomized study with
midazolam versus thiopental in children with refractory status
epilepticus [Portuguese] Arq Neuropsiquiatr 2000 58282-287
ndash non-randomized comparison
ndash of historical data (thiopental) and prospectively
acquired data (midazolam)
ndash Midazolam was no more often effective than
thiopental but was associated with less cyanosis and
less respiratory distress in this study of 50 children
Studi comparativi2
Valproatobull Valproate(ivrdquoDepaconrdquo) has been used for the treatment of refractory SE
in children and myoclonic SE ndash Sheth RD Gidal BE Intravenous valproic acid for myoclonic status epilepticus
Neurology 2000 541201
ndash Uberall MA Trollmann R Wunsiedler U Wenzel D Intravenous valproate in pediatric epilepsy patients with refractory status epilepticus Neurology 2000 542188-2189 ]
bull Valproate has also been used in SE in the elderly and appears to be safe even in the presence of cardiovascular instability and hypotension no significant change in blood pressure pulse or the need for vasopressors in 13 patients with SE and hypotension given a loading dose of 147-327 mgkg Depacon intravenouslyndash Sinha S Naritoku DK Intravenous valproate is well tolerated in unstable patients
with status epilepticus Neurology 2000 55722-724
bull However there is a case report of severe hypotension in an 11-year-old child after treatment of SE with 30 mgkg intravenous valproate ndash White JR Santos CS Intravenous valproate associated with significant
hypotension in the treatment of status epilepticus J Child Neurol 1999 14822-823
FINE
Percheacute non ne possiamo
piugravehelliphelliphellip
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus
Neurology 2001 57 25 1036-1042
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus Neurology 2001 57 25 1036-1042
0
10
20
30
40
50
60
70
80
non seizures
seizures lt30 min24h05-12 h
seizures 05-12 h24 hgt 12 h
seiz gt12 h24
burst suppression
periodic latdischarge
periodic gen discharge
prima
durante
dopo
33 episodes of RSE treated with cIV-MDZ neurologic ICU over 6 years
All patients were monitored with continuous EEG (cEEG)
Waterhouse Elizabeth J 1 2 DeLorenzo Robert J 1 3 4 2
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
bull Status epilepticus (SE) is a medical and neurological emergency that has been associated with significant morbidity and mortality The most widely accepted definition of SE is more than 30 minutes of either continuous seizure activity or intermittent seizures without full recovery of consciousness between seizures SE is a major clinical concern in the elderly population both because it has increased incidence in the elderly compared with the general population and because of concurrent medical conditions that are more likely to complicate therapy and worsen prognosis in elderly individuals
The incidence of SE in the elderly is almost twice that of the general population at 86 per 100 000 per year With the anticipated growth of the elderly population SE is likely to become an increasingly common problem facing clinicians and an important public health issue The elderly have the highest SE-associated mortality of any age group at 38 and the very old elderly (gt80 years of age) have a mortality of at least 50 Acute or remote stroke is the most common aetiology of SE in the elderly Nonconvulsive SE (NCSE) has a wide range of clinical presentations ranging from confusion to obtundation It occurs commonly in elderly patients who are critically ill and in the setting of coma Electroencephalogram is the only reliable method of diagnosing NCSE
The goal of treatment for SE is rapid cessation of clinical and electrical seizure activity Most treatment protocols call for the immediate administration of an intravenous benzodiazepine followed by phenytoin or fosphenytoin Recent studies suggest that when this initial treatment of SE fails little is gained by using additional standard drugs General anaesthetic agents (such as pentobarbital midazolam or propofol) should be expeditiously employed although these treatments have their own potential complications Intravenous valproic acid is a recent addition to the armamentarium of drugs for the treatment of SE with a low risk of hypotension respiratory depression and hypotension making it a potentially useful drug for the treatment of SE in the elderly However further information is needed to establish its role in the overall treatment of SE
Waterhouseet al
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
BDZ
Fenitoina
O fosfenitoina
GA
Midaz
Propof
pentobarb
Ac valproico
Ns proposta
Lorazepam
01 mgkg
Propofol
1-2 mgkgMidazolam01 mgkg
Inf cont 3-10 mgkgh Inf cont 001-005 mgkgh
Miorilassante solo
Per intubazione
Pentobarbital dose caricopoi 01-04 mgkgmin
fenobarbital
bull 10-20 mgkg iv
ndash Eccessiva sedazione
ndash Depressresp
ndash Ipotensione
ndash Interaz farmacol
ndash Hl gt48 hrhelliphelliphellip
tiopental
bull cumulativo
bull Inotropo neghellip
bull Pentobarbital
bull immunosoppressione
propofol
bull Vantaggi cineticodinamici
bull Titolazione continua possibile
bull TCIquale livello
bull Dosi 1 mgkgripetibile dopo 5rsquo-
ndash Infcont 2-10 mgkgh
bull Rapida emergenzafinestra neurologicaevitare la
brusca sospensione
bull + rapido controllo delle convuls gt barbituricindash Stecker MM Kramer TH Raps EC OMeeghan R Dulaney E Skaar DJ Treatment of
refractory status epilepticus with propofol clinical and pharmacokinetic findings Epilepsia 1998
39 18-26
AG
bull Non ci sono dati che indichino quanto a lungo i paz debbano rimanere senza convuls prima di poter alleggerire il piano di AG24 h96h (Treiman DM Convulsive status
epilepticus Current Treatment Options in Neurology 1999 1 359-69)
bull Anest alogenatiisofluranogtsevofluranogtdesflurane
bull Ma vaporizzatori
bull Contaminazione ambientale
bull Costihellip
Studi comparativi1
bull Midazolamgt tiopental
ndash Lohr A Jr Werneck LC Comparative non-randomized study with
midazolam versus thiopental in children with refractory status
epilepticus [Portuguese] Arq Neuropsiquiatr 2000 58282-287
ndash non-randomized comparison
ndash of historical data (thiopental) and prospectively
acquired data (midazolam)
ndash Midazolam was no more often effective than
thiopental but was associated with less cyanosis and
less respiratory distress in this study of 50 children
Studi comparativi2
Valproatobull Valproate(ivrdquoDepaconrdquo) has been used for the treatment of refractory SE
in children and myoclonic SE ndash Sheth RD Gidal BE Intravenous valproic acid for myoclonic status epilepticus
Neurology 2000 541201
ndash Uberall MA Trollmann R Wunsiedler U Wenzel D Intravenous valproate in pediatric epilepsy patients with refractory status epilepticus Neurology 2000 542188-2189 ]
bull Valproate has also been used in SE in the elderly and appears to be safe even in the presence of cardiovascular instability and hypotension no significant change in blood pressure pulse or the need for vasopressors in 13 patients with SE and hypotension given a loading dose of 147-327 mgkg Depacon intravenouslyndash Sinha S Naritoku DK Intravenous valproate is well tolerated in unstable patients
with status epilepticus Neurology 2000 55722-724
bull However there is a case report of severe hypotension in an 11-year-old child after treatment of SE with 30 mgkg intravenous valproate ndash White JR Santos CS Intravenous valproate associated with significant
hypotension in the treatment of status epilepticus J Child Neurol 1999 14822-823
FINE
Percheacute non ne possiamo
piugravehelliphelliphellip
Claassen JHirsch LJ Emerson R GBates JE Thompson TBMayer
SA Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus Neurology 2001 57 25 1036-1042
0
10
20
30
40
50
60
70
80
non seizures
seizures lt30 min24h05-12 h
seizures 05-12 h24 hgt 12 h
seiz gt12 h24
burst suppression
periodic latdischarge
periodic gen discharge
prima
durante
dopo
33 episodes of RSE treated with cIV-MDZ neurologic ICU over 6 years
All patients were monitored with continuous EEG (cEEG)
Waterhouse Elizabeth J 1 2 DeLorenzo Robert J 1 3 4 2
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
bull Status epilepticus (SE) is a medical and neurological emergency that has been associated with significant morbidity and mortality The most widely accepted definition of SE is more than 30 minutes of either continuous seizure activity or intermittent seizures without full recovery of consciousness between seizures SE is a major clinical concern in the elderly population both because it has increased incidence in the elderly compared with the general population and because of concurrent medical conditions that are more likely to complicate therapy and worsen prognosis in elderly individuals
The incidence of SE in the elderly is almost twice that of the general population at 86 per 100 000 per year With the anticipated growth of the elderly population SE is likely to become an increasingly common problem facing clinicians and an important public health issue The elderly have the highest SE-associated mortality of any age group at 38 and the very old elderly (gt80 years of age) have a mortality of at least 50 Acute or remote stroke is the most common aetiology of SE in the elderly Nonconvulsive SE (NCSE) has a wide range of clinical presentations ranging from confusion to obtundation It occurs commonly in elderly patients who are critically ill and in the setting of coma Electroencephalogram is the only reliable method of diagnosing NCSE
The goal of treatment for SE is rapid cessation of clinical and electrical seizure activity Most treatment protocols call for the immediate administration of an intravenous benzodiazepine followed by phenytoin or fosphenytoin Recent studies suggest that when this initial treatment of SE fails little is gained by using additional standard drugs General anaesthetic agents (such as pentobarbital midazolam or propofol) should be expeditiously employed although these treatments have their own potential complications Intravenous valproic acid is a recent addition to the armamentarium of drugs for the treatment of SE with a low risk of hypotension respiratory depression and hypotension making it a potentially useful drug for the treatment of SE in the elderly However further information is needed to establish its role in the overall treatment of SE
Waterhouseet al
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
BDZ
Fenitoina
O fosfenitoina
GA
Midaz
Propof
pentobarb
Ac valproico
Ns proposta
Lorazepam
01 mgkg
Propofol
1-2 mgkgMidazolam01 mgkg
Inf cont 3-10 mgkgh Inf cont 001-005 mgkgh
Miorilassante solo
Per intubazione
Pentobarbital dose caricopoi 01-04 mgkgmin
fenobarbital
bull 10-20 mgkg iv
ndash Eccessiva sedazione
ndash Depressresp
ndash Ipotensione
ndash Interaz farmacol
ndash Hl gt48 hrhelliphelliphellip
tiopental
bull cumulativo
bull Inotropo neghellip
bull Pentobarbital
bull immunosoppressione
propofol
bull Vantaggi cineticodinamici
bull Titolazione continua possibile
bull TCIquale livello
bull Dosi 1 mgkgripetibile dopo 5rsquo-
ndash Infcont 2-10 mgkgh
bull Rapida emergenzafinestra neurologicaevitare la
brusca sospensione
bull + rapido controllo delle convuls gt barbituricindash Stecker MM Kramer TH Raps EC OMeeghan R Dulaney E Skaar DJ Treatment of
refractory status epilepticus with propofol clinical and pharmacokinetic findings Epilepsia 1998
39 18-26
AG
bull Non ci sono dati che indichino quanto a lungo i paz debbano rimanere senza convuls prima di poter alleggerire il piano di AG24 h96h (Treiman DM Convulsive status
epilepticus Current Treatment Options in Neurology 1999 1 359-69)
bull Anest alogenatiisofluranogtsevofluranogtdesflurane
bull Ma vaporizzatori
bull Contaminazione ambientale
bull Costihellip
Studi comparativi1
bull Midazolamgt tiopental
ndash Lohr A Jr Werneck LC Comparative non-randomized study with
midazolam versus thiopental in children with refractory status
epilepticus [Portuguese] Arq Neuropsiquiatr 2000 58282-287
ndash non-randomized comparison
ndash of historical data (thiopental) and prospectively
acquired data (midazolam)
ndash Midazolam was no more often effective than
thiopental but was associated with less cyanosis and
less respiratory distress in this study of 50 children
Studi comparativi2
Valproatobull Valproate(ivrdquoDepaconrdquo) has been used for the treatment of refractory SE
in children and myoclonic SE ndash Sheth RD Gidal BE Intravenous valproic acid for myoclonic status epilepticus
Neurology 2000 541201
ndash Uberall MA Trollmann R Wunsiedler U Wenzel D Intravenous valproate in pediatric epilepsy patients with refractory status epilepticus Neurology 2000 542188-2189 ]
bull Valproate has also been used in SE in the elderly and appears to be safe even in the presence of cardiovascular instability and hypotension no significant change in blood pressure pulse or the need for vasopressors in 13 patients with SE and hypotension given a loading dose of 147-327 mgkg Depacon intravenouslyndash Sinha S Naritoku DK Intravenous valproate is well tolerated in unstable patients
with status epilepticus Neurology 2000 55722-724
bull However there is a case report of severe hypotension in an 11-year-old child after treatment of SE with 30 mgkg intravenous valproate ndash White JR Santos CS Intravenous valproate associated with significant
hypotension in the treatment of status epilepticus J Child Neurol 1999 14822-823
FINE
Percheacute non ne possiamo
piugravehelliphelliphellip
Waterhouse Elizabeth J 1 2 DeLorenzo Robert J 1 3 4 2
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
bull Status epilepticus (SE) is a medical and neurological emergency that has been associated with significant morbidity and mortality The most widely accepted definition of SE is more than 30 minutes of either continuous seizure activity or intermittent seizures without full recovery of consciousness between seizures SE is a major clinical concern in the elderly population both because it has increased incidence in the elderly compared with the general population and because of concurrent medical conditions that are more likely to complicate therapy and worsen prognosis in elderly individuals
The incidence of SE in the elderly is almost twice that of the general population at 86 per 100 000 per year With the anticipated growth of the elderly population SE is likely to become an increasingly common problem facing clinicians and an important public health issue The elderly have the highest SE-associated mortality of any age group at 38 and the very old elderly (gt80 years of age) have a mortality of at least 50 Acute or remote stroke is the most common aetiology of SE in the elderly Nonconvulsive SE (NCSE) has a wide range of clinical presentations ranging from confusion to obtundation It occurs commonly in elderly patients who are critically ill and in the setting of coma Electroencephalogram is the only reliable method of diagnosing NCSE
The goal of treatment for SE is rapid cessation of clinical and electrical seizure activity Most treatment protocols call for the immediate administration of an intravenous benzodiazepine followed by phenytoin or fosphenytoin Recent studies suggest that when this initial treatment of SE fails little is gained by using additional standard drugs General anaesthetic agents (such as pentobarbital midazolam or propofol) should be expeditiously employed although these treatments have their own potential complications Intravenous valproic acid is a recent addition to the armamentarium of drugs for the treatment of SE with a low risk of hypotension respiratory depression and hypotension making it a potentially useful drug for the treatment of SE in the elderly However further information is needed to establish its role in the overall treatment of SE
Waterhouseet al
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
BDZ
Fenitoina
O fosfenitoina
GA
Midaz
Propof
pentobarb
Ac valproico
Ns proposta
Lorazepam
01 mgkg
Propofol
1-2 mgkgMidazolam01 mgkg
Inf cont 3-10 mgkgh Inf cont 001-005 mgkgh
Miorilassante solo
Per intubazione
Pentobarbital dose caricopoi 01-04 mgkgmin
fenobarbital
bull 10-20 mgkg iv
ndash Eccessiva sedazione
ndash Depressresp
ndash Ipotensione
ndash Interaz farmacol
ndash Hl gt48 hrhelliphelliphellip
tiopental
bull cumulativo
bull Inotropo neghellip
bull Pentobarbital
bull immunosoppressione
propofol
bull Vantaggi cineticodinamici
bull Titolazione continua possibile
bull TCIquale livello
bull Dosi 1 mgkgripetibile dopo 5rsquo-
ndash Infcont 2-10 mgkgh
bull Rapida emergenzafinestra neurologicaevitare la
brusca sospensione
bull + rapido controllo delle convuls gt barbituricindash Stecker MM Kramer TH Raps EC OMeeghan R Dulaney E Skaar DJ Treatment of
refractory status epilepticus with propofol clinical and pharmacokinetic findings Epilepsia 1998
39 18-26
AG
bull Non ci sono dati che indichino quanto a lungo i paz debbano rimanere senza convuls prima di poter alleggerire il piano di AG24 h96h (Treiman DM Convulsive status
epilepticus Current Treatment Options in Neurology 1999 1 359-69)
bull Anest alogenatiisofluranogtsevofluranogtdesflurane
bull Ma vaporizzatori
bull Contaminazione ambientale
bull Costihellip
Studi comparativi1
bull Midazolamgt tiopental
ndash Lohr A Jr Werneck LC Comparative non-randomized study with
midazolam versus thiopental in children with refractory status
epilepticus [Portuguese] Arq Neuropsiquiatr 2000 58282-287
ndash non-randomized comparison
ndash of historical data (thiopental) and prospectively
acquired data (midazolam)
ndash Midazolam was no more often effective than
thiopental but was associated with less cyanosis and
less respiratory distress in this study of 50 children
Studi comparativi2
Valproatobull Valproate(ivrdquoDepaconrdquo) has been used for the treatment of refractory SE
in children and myoclonic SE ndash Sheth RD Gidal BE Intravenous valproic acid for myoclonic status epilepticus
Neurology 2000 541201
ndash Uberall MA Trollmann R Wunsiedler U Wenzel D Intravenous valproate in pediatric epilepsy patients with refractory status epilepticus Neurology 2000 542188-2189 ]
bull Valproate has also been used in SE in the elderly and appears to be safe even in the presence of cardiovascular instability and hypotension no significant change in blood pressure pulse or the need for vasopressors in 13 patients with SE and hypotension given a loading dose of 147-327 mgkg Depacon intravenouslyndash Sinha S Naritoku DK Intravenous valproate is well tolerated in unstable patients
with status epilepticus Neurology 2000 55722-724
bull However there is a case report of severe hypotension in an 11-year-old child after treatment of SE with 30 mgkg intravenous valproate ndash White JR Santos CS Intravenous valproate associated with significant
hypotension in the treatment of status epilepticus J Child Neurol 1999 14822-823
FINE
Percheacute non ne possiamo
piugravehelliphelliphellip
Waterhouseet al
Status Epilepticus in Older Patients Epidemiology and
Treatment OptionsDrugs amp Aging 18(2)133-142 2001
BDZ
Fenitoina
O fosfenitoina
GA
Midaz
Propof
pentobarb
Ac valproico
Ns proposta
Lorazepam
01 mgkg
Propofol
1-2 mgkgMidazolam01 mgkg
Inf cont 3-10 mgkgh Inf cont 001-005 mgkgh
Miorilassante solo
Per intubazione
Pentobarbital dose caricopoi 01-04 mgkgmin
fenobarbital
bull 10-20 mgkg iv
ndash Eccessiva sedazione
ndash Depressresp
ndash Ipotensione
ndash Interaz farmacol
ndash Hl gt48 hrhelliphelliphellip
tiopental
bull cumulativo
bull Inotropo neghellip
bull Pentobarbital
bull immunosoppressione
propofol
bull Vantaggi cineticodinamici
bull Titolazione continua possibile
bull TCIquale livello
bull Dosi 1 mgkgripetibile dopo 5rsquo-
ndash Infcont 2-10 mgkgh
bull Rapida emergenzafinestra neurologicaevitare la
brusca sospensione
bull + rapido controllo delle convuls gt barbituricindash Stecker MM Kramer TH Raps EC OMeeghan R Dulaney E Skaar DJ Treatment of
refractory status epilepticus with propofol clinical and pharmacokinetic findings Epilepsia 1998
39 18-26
AG
bull Non ci sono dati che indichino quanto a lungo i paz debbano rimanere senza convuls prima di poter alleggerire il piano di AG24 h96h (Treiman DM Convulsive status
epilepticus Current Treatment Options in Neurology 1999 1 359-69)
bull Anest alogenatiisofluranogtsevofluranogtdesflurane
bull Ma vaporizzatori
bull Contaminazione ambientale
bull Costihellip
Studi comparativi1
bull Midazolamgt tiopental
ndash Lohr A Jr Werneck LC Comparative non-randomized study with
midazolam versus thiopental in children with refractory status
epilepticus [Portuguese] Arq Neuropsiquiatr 2000 58282-287
ndash non-randomized comparison
ndash of historical data (thiopental) and prospectively
acquired data (midazolam)
ndash Midazolam was no more often effective than
thiopental but was associated with less cyanosis and
less respiratory distress in this study of 50 children
Studi comparativi2
Valproatobull Valproate(ivrdquoDepaconrdquo) has been used for the treatment of refractory SE
in children and myoclonic SE ndash Sheth RD Gidal BE Intravenous valproic acid for myoclonic status epilepticus
Neurology 2000 541201
ndash Uberall MA Trollmann R Wunsiedler U Wenzel D Intravenous valproate in pediatric epilepsy patients with refractory status epilepticus Neurology 2000 542188-2189 ]
bull Valproate has also been used in SE in the elderly and appears to be safe even in the presence of cardiovascular instability and hypotension no significant change in blood pressure pulse or the need for vasopressors in 13 patients with SE and hypotension given a loading dose of 147-327 mgkg Depacon intravenouslyndash Sinha S Naritoku DK Intravenous valproate is well tolerated in unstable patients
with status epilepticus Neurology 2000 55722-724
bull However there is a case report of severe hypotension in an 11-year-old child after treatment of SE with 30 mgkg intravenous valproate ndash White JR Santos CS Intravenous valproate associated with significant
hypotension in the treatment of status epilepticus J Child Neurol 1999 14822-823
FINE
Percheacute non ne possiamo
piugravehelliphelliphellip
Ns proposta
Lorazepam
01 mgkg
Propofol
1-2 mgkgMidazolam01 mgkg
Inf cont 3-10 mgkgh Inf cont 001-005 mgkgh
Miorilassante solo
Per intubazione
Pentobarbital dose caricopoi 01-04 mgkgmin
fenobarbital
bull 10-20 mgkg iv
ndash Eccessiva sedazione
ndash Depressresp
ndash Ipotensione
ndash Interaz farmacol
ndash Hl gt48 hrhelliphelliphellip
tiopental
bull cumulativo
bull Inotropo neghellip
bull Pentobarbital
bull immunosoppressione
propofol
bull Vantaggi cineticodinamici
bull Titolazione continua possibile
bull TCIquale livello
bull Dosi 1 mgkgripetibile dopo 5rsquo-
ndash Infcont 2-10 mgkgh
bull Rapida emergenzafinestra neurologicaevitare la
brusca sospensione
bull + rapido controllo delle convuls gt barbituricindash Stecker MM Kramer TH Raps EC OMeeghan R Dulaney E Skaar DJ Treatment of
refractory status epilepticus with propofol clinical and pharmacokinetic findings Epilepsia 1998
39 18-26
AG
bull Non ci sono dati che indichino quanto a lungo i paz debbano rimanere senza convuls prima di poter alleggerire il piano di AG24 h96h (Treiman DM Convulsive status
epilepticus Current Treatment Options in Neurology 1999 1 359-69)
bull Anest alogenatiisofluranogtsevofluranogtdesflurane
bull Ma vaporizzatori
bull Contaminazione ambientale
bull Costihellip
Studi comparativi1
bull Midazolamgt tiopental
ndash Lohr A Jr Werneck LC Comparative non-randomized study with
midazolam versus thiopental in children with refractory status
epilepticus [Portuguese] Arq Neuropsiquiatr 2000 58282-287
ndash non-randomized comparison
ndash of historical data (thiopental) and prospectively
acquired data (midazolam)
ndash Midazolam was no more often effective than
thiopental but was associated with less cyanosis and
less respiratory distress in this study of 50 children
Studi comparativi2
Valproatobull Valproate(ivrdquoDepaconrdquo) has been used for the treatment of refractory SE
in children and myoclonic SE ndash Sheth RD Gidal BE Intravenous valproic acid for myoclonic status epilepticus
Neurology 2000 541201
ndash Uberall MA Trollmann R Wunsiedler U Wenzel D Intravenous valproate in pediatric epilepsy patients with refractory status epilepticus Neurology 2000 542188-2189 ]
bull Valproate has also been used in SE in the elderly and appears to be safe even in the presence of cardiovascular instability and hypotension no significant change in blood pressure pulse or the need for vasopressors in 13 patients with SE and hypotension given a loading dose of 147-327 mgkg Depacon intravenouslyndash Sinha S Naritoku DK Intravenous valproate is well tolerated in unstable patients
with status epilepticus Neurology 2000 55722-724
bull However there is a case report of severe hypotension in an 11-year-old child after treatment of SE with 30 mgkg intravenous valproate ndash White JR Santos CS Intravenous valproate associated with significant
hypotension in the treatment of status epilepticus J Child Neurol 1999 14822-823
FINE
Percheacute non ne possiamo
piugravehelliphelliphellip
fenobarbital
bull 10-20 mgkg iv
ndash Eccessiva sedazione
ndash Depressresp
ndash Ipotensione
ndash Interaz farmacol
ndash Hl gt48 hrhelliphelliphellip
tiopental
bull cumulativo
bull Inotropo neghellip
bull Pentobarbital
bull immunosoppressione
propofol
bull Vantaggi cineticodinamici
bull Titolazione continua possibile
bull TCIquale livello
bull Dosi 1 mgkgripetibile dopo 5rsquo-
ndash Infcont 2-10 mgkgh
bull Rapida emergenzafinestra neurologicaevitare la
brusca sospensione
bull + rapido controllo delle convuls gt barbituricindash Stecker MM Kramer TH Raps EC OMeeghan R Dulaney E Skaar DJ Treatment of
refractory status epilepticus with propofol clinical and pharmacokinetic findings Epilepsia 1998
39 18-26
AG
bull Non ci sono dati che indichino quanto a lungo i paz debbano rimanere senza convuls prima di poter alleggerire il piano di AG24 h96h (Treiman DM Convulsive status
epilepticus Current Treatment Options in Neurology 1999 1 359-69)
bull Anest alogenatiisofluranogtsevofluranogtdesflurane
bull Ma vaporizzatori
bull Contaminazione ambientale
bull Costihellip
Studi comparativi1
bull Midazolamgt tiopental
ndash Lohr A Jr Werneck LC Comparative non-randomized study with
midazolam versus thiopental in children with refractory status
epilepticus [Portuguese] Arq Neuropsiquiatr 2000 58282-287
ndash non-randomized comparison
ndash of historical data (thiopental) and prospectively
acquired data (midazolam)
ndash Midazolam was no more often effective than
thiopental but was associated with less cyanosis and
less respiratory distress in this study of 50 children
Studi comparativi2
Valproatobull Valproate(ivrdquoDepaconrdquo) has been used for the treatment of refractory SE
in children and myoclonic SE ndash Sheth RD Gidal BE Intravenous valproic acid for myoclonic status epilepticus
Neurology 2000 541201
ndash Uberall MA Trollmann R Wunsiedler U Wenzel D Intravenous valproate in pediatric epilepsy patients with refractory status epilepticus Neurology 2000 542188-2189 ]
bull Valproate has also been used in SE in the elderly and appears to be safe even in the presence of cardiovascular instability and hypotension no significant change in blood pressure pulse or the need for vasopressors in 13 patients with SE and hypotension given a loading dose of 147-327 mgkg Depacon intravenouslyndash Sinha S Naritoku DK Intravenous valproate is well tolerated in unstable patients
with status epilepticus Neurology 2000 55722-724
bull However there is a case report of severe hypotension in an 11-year-old child after treatment of SE with 30 mgkg intravenous valproate ndash White JR Santos CS Intravenous valproate associated with significant
hypotension in the treatment of status epilepticus J Child Neurol 1999 14822-823
FINE
Percheacute non ne possiamo
piugravehelliphelliphellip
tiopental
bull cumulativo
bull Inotropo neghellip
bull Pentobarbital
bull immunosoppressione
propofol
bull Vantaggi cineticodinamici
bull Titolazione continua possibile
bull TCIquale livello
bull Dosi 1 mgkgripetibile dopo 5rsquo-
ndash Infcont 2-10 mgkgh
bull Rapida emergenzafinestra neurologicaevitare la
brusca sospensione
bull + rapido controllo delle convuls gt barbituricindash Stecker MM Kramer TH Raps EC OMeeghan R Dulaney E Skaar DJ Treatment of
refractory status epilepticus with propofol clinical and pharmacokinetic findings Epilepsia 1998
39 18-26
AG
bull Non ci sono dati che indichino quanto a lungo i paz debbano rimanere senza convuls prima di poter alleggerire il piano di AG24 h96h (Treiman DM Convulsive status
epilepticus Current Treatment Options in Neurology 1999 1 359-69)
bull Anest alogenatiisofluranogtsevofluranogtdesflurane
bull Ma vaporizzatori
bull Contaminazione ambientale
bull Costihellip
Studi comparativi1
bull Midazolamgt tiopental
ndash Lohr A Jr Werneck LC Comparative non-randomized study with
midazolam versus thiopental in children with refractory status
epilepticus [Portuguese] Arq Neuropsiquiatr 2000 58282-287
ndash non-randomized comparison
ndash of historical data (thiopental) and prospectively
acquired data (midazolam)
ndash Midazolam was no more often effective than
thiopental but was associated with less cyanosis and
less respiratory distress in this study of 50 children
Studi comparativi2
Valproatobull Valproate(ivrdquoDepaconrdquo) has been used for the treatment of refractory SE
in children and myoclonic SE ndash Sheth RD Gidal BE Intravenous valproic acid for myoclonic status epilepticus
Neurology 2000 541201
ndash Uberall MA Trollmann R Wunsiedler U Wenzel D Intravenous valproate in pediatric epilepsy patients with refractory status epilepticus Neurology 2000 542188-2189 ]
bull Valproate has also been used in SE in the elderly and appears to be safe even in the presence of cardiovascular instability and hypotension no significant change in blood pressure pulse or the need for vasopressors in 13 patients with SE and hypotension given a loading dose of 147-327 mgkg Depacon intravenouslyndash Sinha S Naritoku DK Intravenous valproate is well tolerated in unstable patients
with status epilepticus Neurology 2000 55722-724
bull However there is a case report of severe hypotension in an 11-year-old child after treatment of SE with 30 mgkg intravenous valproate ndash White JR Santos CS Intravenous valproate associated with significant
hypotension in the treatment of status epilepticus J Child Neurol 1999 14822-823
FINE
Percheacute non ne possiamo
piugravehelliphelliphellip
propofol
bull Vantaggi cineticodinamici
bull Titolazione continua possibile
bull TCIquale livello
bull Dosi 1 mgkgripetibile dopo 5rsquo-
ndash Infcont 2-10 mgkgh
bull Rapida emergenzafinestra neurologicaevitare la
brusca sospensione
bull + rapido controllo delle convuls gt barbituricindash Stecker MM Kramer TH Raps EC OMeeghan R Dulaney E Skaar DJ Treatment of
refractory status epilepticus with propofol clinical and pharmacokinetic findings Epilepsia 1998
39 18-26
AG
bull Non ci sono dati che indichino quanto a lungo i paz debbano rimanere senza convuls prima di poter alleggerire il piano di AG24 h96h (Treiman DM Convulsive status
epilepticus Current Treatment Options in Neurology 1999 1 359-69)
bull Anest alogenatiisofluranogtsevofluranogtdesflurane
bull Ma vaporizzatori
bull Contaminazione ambientale
bull Costihellip
Studi comparativi1
bull Midazolamgt tiopental
ndash Lohr A Jr Werneck LC Comparative non-randomized study with
midazolam versus thiopental in children with refractory status
epilepticus [Portuguese] Arq Neuropsiquiatr 2000 58282-287
ndash non-randomized comparison
ndash of historical data (thiopental) and prospectively
acquired data (midazolam)
ndash Midazolam was no more often effective than
thiopental but was associated with less cyanosis and
less respiratory distress in this study of 50 children
Studi comparativi2
Valproatobull Valproate(ivrdquoDepaconrdquo) has been used for the treatment of refractory SE
in children and myoclonic SE ndash Sheth RD Gidal BE Intravenous valproic acid for myoclonic status epilepticus
Neurology 2000 541201
ndash Uberall MA Trollmann R Wunsiedler U Wenzel D Intravenous valproate in pediatric epilepsy patients with refractory status epilepticus Neurology 2000 542188-2189 ]
bull Valproate has also been used in SE in the elderly and appears to be safe even in the presence of cardiovascular instability and hypotension no significant change in blood pressure pulse or the need for vasopressors in 13 patients with SE and hypotension given a loading dose of 147-327 mgkg Depacon intravenouslyndash Sinha S Naritoku DK Intravenous valproate is well tolerated in unstable patients
with status epilepticus Neurology 2000 55722-724
bull However there is a case report of severe hypotension in an 11-year-old child after treatment of SE with 30 mgkg intravenous valproate ndash White JR Santos CS Intravenous valproate associated with significant
hypotension in the treatment of status epilepticus J Child Neurol 1999 14822-823
FINE
Percheacute non ne possiamo
piugravehelliphelliphellip
AG
bull Non ci sono dati che indichino quanto a lungo i paz debbano rimanere senza convuls prima di poter alleggerire il piano di AG24 h96h (Treiman DM Convulsive status
epilepticus Current Treatment Options in Neurology 1999 1 359-69)
bull Anest alogenatiisofluranogtsevofluranogtdesflurane
bull Ma vaporizzatori
bull Contaminazione ambientale
bull Costihellip
Studi comparativi1
bull Midazolamgt tiopental
ndash Lohr A Jr Werneck LC Comparative non-randomized study with
midazolam versus thiopental in children with refractory status
epilepticus [Portuguese] Arq Neuropsiquiatr 2000 58282-287
ndash non-randomized comparison
ndash of historical data (thiopental) and prospectively
acquired data (midazolam)
ndash Midazolam was no more often effective than
thiopental but was associated with less cyanosis and
less respiratory distress in this study of 50 children
Studi comparativi2
Valproatobull Valproate(ivrdquoDepaconrdquo) has been used for the treatment of refractory SE
in children and myoclonic SE ndash Sheth RD Gidal BE Intravenous valproic acid for myoclonic status epilepticus
Neurology 2000 541201
ndash Uberall MA Trollmann R Wunsiedler U Wenzel D Intravenous valproate in pediatric epilepsy patients with refractory status epilepticus Neurology 2000 542188-2189 ]
bull Valproate has also been used in SE in the elderly and appears to be safe even in the presence of cardiovascular instability and hypotension no significant change in blood pressure pulse or the need for vasopressors in 13 patients with SE and hypotension given a loading dose of 147-327 mgkg Depacon intravenouslyndash Sinha S Naritoku DK Intravenous valproate is well tolerated in unstable patients
with status epilepticus Neurology 2000 55722-724
bull However there is a case report of severe hypotension in an 11-year-old child after treatment of SE with 30 mgkg intravenous valproate ndash White JR Santos CS Intravenous valproate associated with significant
hypotension in the treatment of status epilepticus J Child Neurol 1999 14822-823
FINE
Percheacute non ne possiamo
piugravehelliphelliphellip
Studi comparativi1
bull Midazolamgt tiopental
ndash Lohr A Jr Werneck LC Comparative non-randomized study with
midazolam versus thiopental in children with refractory status
epilepticus [Portuguese] Arq Neuropsiquiatr 2000 58282-287
ndash non-randomized comparison
ndash of historical data (thiopental) and prospectively
acquired data (midazolam)
ndash Midazolam was no more often effective than
thiopental but was associated with less cyanosis and
less respiratory distress in this study of 50 children
Studi comparativi2
Valproatobull Valproate(ivrdquoDepaconrdquo) has been used for the treatment of refractory SE
in children and myoclonic SE ndash Sheth RD Gidal BE Intravenous valproic acid for myoclonic status epilepticus
Neurology 2000 541201
ndash Uberall MA Trollmann R Wunsiedler U Wenzel D Intravenous valproate in pediatric epilepsy patients with refractory status epilepticus Neurology 2000 542188-2189 ]
bull Valproate has also been used in SE in the elderly and appears to be safe even in the presence of cardiovascular instability and hypotension no significant change in blood pressure pulse or the need for vasopressors in 13 patients with SE and hypotension given a loading dose of 147-327 mgkg Depacon intravenouslyndash Sinha S Naritoku DK Intravenous valproate is well tolerated in unstable patients
with status epilepticus Neurology 2000 55722-724
bull However there is a case report of severe hypotension in an 11-year-old child after treatment of SE with 30 mgkg intravenous valproate ndash White JR Santos CS Intravenous valproate associated with significant
hypotension in the treatment of status epilepticus J Child Neurol 1999 14822-823
FINE
Percheacute non ne possiamo
piugravehelliphelliphellip
Studi comparativi2
Valproatobull Valproate(ivrdquoDepaconrdquo) has been used for the treatment of refractory SE
in children and myoclonic SE ndash Sheth RD Gidal BE Intravenous valproic acid for myoclonic status epilepticus
Neurology 2000 541201
ndash Uberall MA Trollmann R Wunsiedler U Wenzel D Intravenous valproate in pediatric epilepsy patients with refractory status epilepticus Neurology 2000 542188-2189 ]
bull Valproate has also been used in SE in the elderly and appears to be safe even in the presence of cardiovascular instability and hypotension no significant change in blood pressure pulse or the need for vasopressors in 13 patients with SE and hypotension given a loading dose of 147-327 mgkg Depacon intravenouslyndash Sinha S Naritoku DK Intravenous valproate is well tolerated in unstable patients
with status epilepticus Neurology 2000 55722-724
bull However there is a case report of severe hypotension in an 11-year-old child after treatment of SE with 30 mgkg intravenous valproate ndash White JR Santos CS Intravenous valproate associated with significant
hypotension in the treatment of status epilepticus J Child Neurol 1999 14822-823
FINE
Percheacute non ne possiamo
piugravehelliphelliphellip
FINE
Percheacute non ne possiamo
piugravehelliphelliphellip