cyclic antidepressants: it’s all good. toxicology core rounds jan 15, 2004 rob hall pgy4 randall...

Cyclic Antidepressants: Cyclic Antidepressants: it’s all good.it’s all good.

Toxicology Core RoundsToxicology Core Rounds

Jan 15, 2004Jan 15, 2004

Rob Hall PGY4Rob Hall PGY4

Randall Berlin (Randall Berlin (toxicologist extrodinaretoxicologist extrodinare!)!)

ObjectivesObjectives

Walk through a case………………Walk through a case……………… We need to know the presentation, We need to know the presentation,

diagnosis, disposition, and general diagnosis, disposition, and general management of TCA overdoses INSIDE management of TCA overdoses INSIDE and OUT!and OUT!

Specifically, we will focus on the Specifically, we will focus on the complications of TCA overdosescomplications of TCA overdoses

Case of the day!Case of the day!

EMS patches in ………EMS patches in ……… ETA 10 min ETA 10 min 42yo female42yo female Amitriptyline overdoseAmitriptyline overdose Decreased LOC, hypotensive, tachycardicDecreased LOC, hypotensive, tachycardic


How would you How would you prepare?prepare?

List four List four complications of TCA complications of TCA overdose that you overdose that you should be prepared should be prepared for?for?

Resusc room, be ready Resusc room, be ready to intubate, have ECG to intubate, have ECG there, approach will be there, approach will be ABCs/monitor/iv/etcABCs/monitor/iv/etc

Four predictable Four predictable complicationscomplications– HypotensionHypotension– Wide complex tachWide complex tach– SeizuresSeizures– Decreased LOCDecreased LOC


EMS arrivesEMS arrives Story = 42yo female, previous overdoses, found Story = 42yo female, previous overdoses, found

on floor in bathroom, amitriptyline bottle empty, on floor in bathroom, amitriptyline bottle empty, estimated time since ingestion is 1.5 hours ago, no estimated time since ingestion is 1.5 hours ago, no coingestants known coingestants known

T 38.1, HR 120, BP 85/60, C/S normal, sat 95% T 38.1, HR 120, BP 85/60, C/S normal, sat 95% NRB, RR 15, GCS E1V2M4, dry red skin, no NRB, RR 15, GCS E1V2M4, dry red skin, no bowel sounds, motor X 4, pupils 5mm, bowel sounds, motor X 4, pupils 5mm, hyporeflexic, no clonus, no rigidity, no signs of hyporeflexic, no clonus, no rigidity, no signs of traumatrauma

What’s your management?What’s your management?


How would you How would you intubate?intubate?

PEARLS of intubating the PEARLS of intubating the TCA overdoseTCA overdose– Preoxygenate Preoxygenate

– Hyperventilate before you Hyperventilate before you push drugspush drugs

– AVOID resp acidosisAVOID resp acidosis

– Give a bolus dose of bicarb Give a bolus dose of bicarb with your pretreatmentwith your pretreatment

– Best intubator!Best intubator!

Case of the day:Case of the day:What is the role of gastric lavage?What is the role of gastric lavage?

Evidence against lavageEvidence against lavage– Pond 1995: Gastric lavage can be omitted from the treatment Pond 1995: Gastric lavage can be omitted from the treatment

protocol for acute overdosesprotocol for acute overdoses

– Merigan 1990: No benefit of gastric lavageMerigan 1990: No benefit of gastric lavage

– Kulig 1985: No benefit of gastric lavage unless performed < 1hrKulig 1985: No benefit of gastric lavage unless performed < 1hr

All three studies either excluded the critically ill or were All three studies either excluded the critically ill or were underpowered to evaluate that subgroupunderpowered to evaluate that subgroup

This patient This patient SHOULD SHOULD be lavaged, why?be lavaged, why?– Potentially lethal overdose, no good antidote, delayed gastric Potentially lethal overdose, no good antidote, delayed gastric

emptying b/c of anticholinergic effect emptying b/c of anticholinergic effect

Case of the day:Case of the day:When do you expect toxicity?When do you expect toxicity?

TCA overdoses will develop toxicity within TCA overdoses will develop toxicity within 6 hours6 hours

– Rapidly absorbedRapidly absorbed

– Peak levels 6-8hrsPeak levels 6-8hrs

– Highly lipophilic thus rapid delivery to Highly lipophilic thus rapid delivery to heart, brainheart, brain

– Has relevance to when patient is Has relevance to when patient is “medically cleared”“medically cleared”

TCA mechanisms of ToxicityTCA mechanisms of Toxicity

Anti-cholinergicAnti-cholinergic Na+ channel blockadeNa+ channel blockade K+ channel blockadeK+ channel blockade Alpha 1 antagonismAlpha 1 antagonism Serotonin and NE Serotonin and NE

reuptake inhibitionreuptake inhibition GABA antagonism, etcGABA antagonism, etc

Anticholinergic toxidromeAnticholinergic toxidrome Wide QRSWide QRS Prolonged QTProlonged QT HypotensionHypotension Seritonin syndrome Seritonin syndrome SeizuresSeizures


After you intubate, patient has a generalized After you intubate, patient has a generalized seizureseizure

Why?Why?– Anticholinergic effectAnticholinergic effect– Gaba antagonismGaba antagonism– HypotensionHypotension– Exact mechanism unknown!Exact mechanism unknown!

Why are seizures so bad?Why are seizures so bad? Management?Management?

TCA overdoses and seizuresTCA overdoses and seizures

Seizure

Acidosis

Cardiac toxicity

Shock

DEATH

TCA toxicity and SeizuresTCA toxicity and Seizures

ManagementManagement– First line: benzodiazepinesFirst line: benzodiazepines

– Second line: phenobarbitalSecond line: phenobarbital

– Third line agents: propofolThird line agents: propofol

– Avoid dilantin (Na+ channel blockade)Avoid dilantin (Na+ channel blockade) Should you give bicarb? YesShould you give bicarb? Yes

FlumazenilFlumazenil

Why is flumazenil contraindicated in a patient Why is flumazenil contraindicated in a patient with BZD + TCA overdose?with BZD + TCA overdose?

Will precipitate seizures ----> Will precipitate seizures ----> acidosis, cardiac toxicity, acidosis, cardiac toxicity, death, call CMPAdeath, call CMPA

Flumazenil is generally not indicated in the Flumazenil is generally not indicated in the overdose setting for this reasonoverdose setting for this reason– One exception may be a pediatric ingestion of BZD One exception may be a pediatric ingestion of BZD

with absolutely no suspicion of coingestantwith absolutely no suspicion of coingestant

– OK with therapeutic useOK with therapeutic use

Any role for physostigmine in Any role for physostigmine in TCA overdoses??TCA overdoses??

TheoryTheory– Block acetylcholinesterase, increases Ach at Block acetylcholinesterase, increases Ach at

synapse, initially used to treat agitated deliriumsynapse, initially used to treat agitated delirium ResultsResults

– Brady, asystolic arrestsBrady, asystolic arrests– Do not useDo not use


HR 120, BP 80/50HR 120, BP 80/50 What is your management?What is your management? Why?Why?

TCAs and HypotensionTCAs and Hypotension

Fluids, go early to pressorsFluids, go early to pressors Norepinephrine is the pressor of choiceNorepinephrine is the pressor of choice If you are going to use dopamine, titrate up If you are going to use dopamine, titrate up

to alpha range (15 - 20 ug/kg/min) quicklyto alpha range (15 - 20 ug/kg/min) quickly Why is norepinephrine better theoretically Why is norepinephrine better theoretically

than dopamine?than dopamine?


How does dopamine How does dopamine work?work?– Dopamine is a Dopamine is a

precursor to precursor to norepinephrinenorepinephrine

– Dopamine stimulates Dopamine stimulates the release of stored the release of stored norepinephrinenorepinephrine

– Dopamine stimulates Dopamine stimulates adrenergic receptorsadrenergic receptors


TCAs block alpha receptors


NO controlled human studies comparing NO controlled human studies comparing pressors for hypotensionpressors for hypotension

Animal studies are conflictingAnimal studies are conflicting Teba. Am J Emerg Med 1988Teba. Am J Emerg Med 1988

– Best human dataBest human data– Retrospective review Retrospective review – 26 hypotensive TCA overdoses26 hypotensive TCA overdoses– Better response rates to norepi than dopamineBetter response rates to norepi than dopamine


Extreme options!Extreme options!– ECMOECMO– Cardiac bypassCardiac bypass– IABPIABP

Case of the day!Case of the day!Interpretation? Will she have a bad outcomeInterpretation? Will she have a bad outcome??

TCA toxicity and the ECGTCA toxicity and the ECG

Sinus tachycardiaSinus tachycardia Prolonged QTProlonged QT Wide QRSWide QRS Wide complex tachycardiaWide complex tachycardia

– SVT with aberrancy SVT with aberrancy – VtachVtach– VfibVfib

Right BBBRight BBB Tall R wave in aVRTall R wave in aVR R/S ratio in aVR >R/S ratio in aVR > Terminal 40 msec right axisTerminal 40 msec right axis


Tall R in aVR, R/S ratio in aVR > 0.7Tall R in aVR, R/S ratio in aVR > 0.7


Terminal 40 msec right axis: what does that Terminal 40 msec right axis: what does that mean????mean????


Terminal 40 msec Terminal 40 msec right axisright axis– What does a normal What does a normal

aVR look like?aVR look like?

– Why a right axis?Why a right axis?


Terminal 40 Terminal 40 msec right axis: msec right axis: the poor man’s the poor man’s wayway– S in lead IS in lead I– R in aVRR in aVR


What ECG features are predictive of TCA What ECG features are predictive of TCA toxicity?toxicity?– QRS widthQRS width– Tall R in aVRTall R in aVR– R/S ratio in aVRR/S ratio in aVR– Terminal 40 msec right axisTerminal 40 msec right axis

Which are the most sensitive/specific for Which are the most sensitive/specific for TCA toxicity?TCA toxicity?

QRS widthQRS width

Boehnert. NEJM 1985Boehnert. NEJM 1985– QRS > 100msec predictive of complicationsQRS > 100msec predictive of complications– 33% had seizures33% had seizures– 14% had ventricular dysrhythmias14% had ventricular dysrhythmias

QRS WidthQRS Width

Liebelt. Ann Emerg Med 1995.Liebelt. Ann Emerg Med 1995.– Prospective cohort of 79 TCA overdosesProspective cohort of 79 TCA overdoses– Used outcomes of seizures or arrythmiasUsed outcomes of seizures or arrythmias– SensitivitySensitivity SpecificitySpecificity– QRS > 100 msecQRS > 100 msec 82%82% 58%58%– QRS > 120 msecQRS > 120 msec 59%59% 87%87%

Tall R and R/S ratio in aVRTall R and R/S ratio in aVR

Liebelt. Ann Emerg Med 1995.Liebelt. Ann Emerg Med 1995.– Tall R wave and R/S ratio > 0.7 in aVR wasTall R wave and R/S ratio > 0.7 in aVR was– Used outcomes of seizures or arrythmiasUsed outcomes of seizures or arrythmias– SensitivitySensitivity SpecificitySpecificity– QRS > 100 msecQRS > 100 msec 82%82% 58%58%– QRS > 120 msecQRS > 120 msec 59%59% 87%87%– R > 3mm in aVRR > 3mm in aVR 81%81% 72%72%– R/S > 0.7 in aVRR/S > 0.7 in aVR 75%75% 77%77%

Terminal 40 msec right axisTerminal 40 msec right axis

Wolfe. Ann Emerg Med 1995Wolfe. Ann Emerg Med 1995– Retrospective chart reviewRetrospective chart review– Only looked at symptomatic TCA overdoses Only looked at symptomatic TCA overdoses – Outcome: seizure, arrythmia, vital sign Outcome: seizure, arrythmia, vital sign

changes, respiratory or level of consciousnous changes, respiratory or level of consciousnous changes ------------------pretty vague!!changes ------------------pretty vague!!

– Terminal 40 msec right axisTerminal 40 msec right axis» Sensitivity 83%Sensitivity 83%

» Specificity 63%Specificity 63%

ICU resident called to psych ward STATICU resident called to psych ward STAT (this isn’t going (this isn’t going

to be good!):to be good!): What is the differential dx of wide QRS in What is the differential dx of wide QRS in toxicology?toxicology?

ECG and ToxicologyECG and Toxicology

Wide QRS (Na+ Wide QRS (Na+ channel blockade)channel blockade)– TCAsTCAs– Antihistamines (Antihistamines (gravol,gravol,

benadryl)benadryl)– AmphetaminesAmphetamines– Cocaine Cocaine – CarbemazepineCarbemazepine– ChloroquineChloroquine– ProcainamideProcainamide– PropoxyphenePropoxyphene– PropranololPropranolol– DisopiramideDisopiramide– Quinine, quinidineQuinine, quinidine

Prolonged QTcProlonged QTc– TCATCA

– Haldol, Mellaril, etcHaldol, Mellaril, etc

– Ia: pdqIa: pdq

– Ic: flec, ecIc: flec, ec

– III: amio, sotalolIII: amio, sotalol

– CelexaCelexa

– Erythromycin, Erythromycin, Terfenidine, astemizoleTerfenidine, astemizole

– Lytes: Ca, Mg, KLytes: Ca, Mg, K

Case of the day!Case of the day!What do you want to do now?What do you want to do now?

TCA and Sodium BicarbonateTCA and Sodium Bicarbonate

Sodium Bicarbonate is the treatment of Sodium Bicarbonate is the treatment of choice for cardiac toxicitychoice for cardiac toxicity

Dose = 1-2 mEq/kg iv bolus q10 min prn Dose = 1-2 mEq/kg iv bolus q10 min prn End points = no indication, pH 7.50 - 7.55End points = no indication, pH 7.50 - 7.55 Monitor response with repeat ECGs and Monitor response with repeat ECGs and

ABGsABGs

TCA and Sodium Bicarbonate: TCA and Sodium Bicarbonate: How does it work?How does it work?

Increases protein bindingIncreases protein binding– TCAs are albumin bound which is pH sensitive; minor TCAs are albumin bound which is pH sensitive; minor

role b/c large Vd and lipophilic thus most TCA is in role b/c large Vd and lipophilic thus most TCA is in tissue not serumtissue not serum

AlkalosisAlkalosis– TCA binding to the voltage gated sodium channel is pH TCA binding to the voltage gated sodium channel is pH

dependent thus elevating the pH decreases the binding of dependent thus elevating the pH decreases the binding of the TCA molecule to the Na+ channelthe TCA molecule to the Na+ channel

Sodium loadingSodium loading– Na load with bicarb creates a larger gradient across the Na load with bicarb creates a larger gradient across the

Na+ channelNa+ channel

TCA and Sodium Bicarbonate: TCA and Sodium Bicarbonate: How does it work?How does it work?

TCA and Sodium Bicarbonate: TCA and Sodium Bicarbonate: What are the indications?What are the indications?

HypotensionHypotension Wide complex tachycardiaWide complex tachycardia Conduction blocksConduction blocks

– New/unexplained RBBBNew/unexplained RBBB

– R in aVR > 3mm, R/S ratio > 0.7, orR in aVR > 3mm, R/S ratio > 0.7, or terminal 40 msec right terminal 40 msec right axisaxis

– QRS > 100 msec (or > 120 msec) QRS > 100 msec (or > 120 msec) » Recommendations vary with sourceRecommendations vary with source» QRS width related to time from ingestion importantQRS width related to time from ingestion important

? Seizures? Seizures– Makes sense to me but isn’t classically listed as an Makes sense to me but isn’t classically listed as an

indication for bicarbindication for bicarb

TCA and Sodium Bicarbonate: TCA and Sodium Bicarbonate: Bolus versus infusionBolus versus infusion??

Boluses are preferred for initial indications: Why?Boluses are preferred for initial indications: Why?– Studies showing effect of bicarb have used a bolusStudies showing effect of bicarb have used a bolus– NOTE: bolus = Na+ load, bicarb drip will increase your NOTE: bolus = Na+ load, bicarb drip will increase your

pH but is not a large Na+ loadpH but is not a large Na+ load– Probably better b/c big Na load with bolus overcomes Probably better b/c big Na load with bolus overcomes

Na blockade; Na load likely more important than pH Na blockade; Na load likely more important than pH changechange

NO controlled human studies to compare repeat boluses vs NO controlled human studies to compare repeat boluses vs infusioninfusion

Bicarb infusion resonable for patient requiring repeat Bicarb infusion resonable for patient requiring repeat bolusesboluses

Controversies in the management Controversies in the management of wide complex tachycardia of wide complex tachycardia

with with TCA toxicity: TCA toxicity:

bicarb and then what??bicarb and then what??

You have given 3 amps bicarb and the ECG You have given 3 amps bicarb and the ECG still looks like this. Management?still looks like this. Management?

ControversyControversy

What if there is no What if there is no response to the bicarb response to the bicarb boluses despite pH being boluses despite pH being in target 7.50 – 7.55?in target 7.50 – 7.55?

ControversyControversy

Is there any role for Hypertonic Is there any role for Hypertonic Saline, Phenytoin, or Lidocaine, Saline, Phenytoin, or Lidocaine,

Magnesium, Amiodarone, or Magnesium, Amiodarone, or Propranolol in the management Propranolol in the management

of wide complex tach in TCA of wide complex tach in TCA overdoses?overdoses?

Hypertonic SalineHypertonic Saline

TheoryTheory– Na+ load to overcome Na+ channel blockade Na+ load to overcome Na+ channel blockade

by the TCA by the TCA – Na+ load without the adverse effects of Na+ load without the adverse effects of

alkalosis as seen with sodium bicarbonatealkalosis as seen with sodium bicarbonate– Able to give a lot more Na+ than with normal Able to give a lot more Na+ than with normal

saline saline » Normal Saline: 0.9% NaClNormal Saline: 0.9% NaCl

» Hypertonic Saline: 7.5% NaClHypertonic Saline: 7.5% NaCl


Goldfrank 2003Goldfrank 2003– Theoretical benefit but not adequately studiedTheoretical benefit but not adequately studied

Ford 2001Ford 2001– Not mentionedNot mentioned


Hoegholm. Clinical Toxicology. 1991Hoegholm. Clinical Toxicology. 1991– Case Report of TCA overdoseCase Report of TCA overdose– Hypotensive, wide QRS, recurrent VT and VFHypotensive, wide QRS, recurrent VT and VF– Intubated, lavagedIntubated, lavaged– Sodium bicarb, lidocaine, dopamine, and Sodium bicarb, lidocaine, dopamine, and

hyperventilation (how much of each???)hyperventilation (how much of each???)– Sodium chloride 170 mEq given over 5 minSodium chloride 170 mEq given over 5 min

» Immediate narrowing of the QRS, increased BP, no further VT Immediate narrowing of the QRS, increased BP, no further VT or VFor VF

One case report, not much for details, amount of One case report, not much for details, amount of bicarb could have been more importantbicarb could have been more important


McCabe. Acad Emerg Med. 1994McCabe. Acad Emerg Med. 1994– Swine model of TCA toxicitySwine model of TCA toxicity– Nortiptyline until SBP 50% of baseline and Nortiptyline until SBP 50% of baseline and

QRS > 120 msecQRS > 120 msec– Randomized groupsRandomized groups

» 10 ml/kg of 7.5% hypertonic saline + 6% dextran 10 ml/kg of 7.5% hypertonic saline + 6% dextran

» 10 ml/kg of 0.9% normal saline10 ml/kg of 0.9% normal saline

– NO bicarbonate treatment armNO bicarbonate treatment arm

Hypertonic Saline: Hypertonic Saline: McCabe. Acad Emerg Med. 1994McCabe. Acad Emerg Med. 1994

BP 10 min BP 10 min after txafter tx

QRS 10 QRS 10 min after txmin after tx

Survival at Survival at one hourone hour

Hypertonic Hypertonic

SalineSaline

115 +/- 12115 +/- 12 88 +/- 1388 +/- 13 4/54/5

Normal Normal

SalineSaline

45 +/- 845 +/- 8 180 +/- 8180 +/- 8 0/50/5


McKinney. Ann Emerg Med. 2003McKinney. Ann Emerg Med. 2003– Case ReportCase Report

– 29 yo female ingested 8 gm of nortryptylline29 yo female ingested 8 gm of nortryptylline

– Coma, BP 80/40, QRS 124 msecComa, BP 80/40, QRS 124 msec

– Intubated, lavaged, hyperventilation, 3L normal saline, Intubated, lavaged, hyperventilation, 3L normal saline, dopamine 20 ug/kg/min, norepinephrine 22 ug/min, 4 dopamine 20 ug/kg/min, norepinephrine 22 ug/min, 4 amps bolus sodium bicarb, pH 7.54amps bolus sodium bicarb, pH 7.54

– QRS 135 msecQRS 135 msec

– Given 200 ml of hypertonic saline (7.5%)Given 200 ml of hypertonic saline (7.5%)


McKinney. Ann Emerg Med. 2003McKinney. Ann Emerg Med. 2003– BP BP 00 33 55 10 10 30 min30 min

78/4278/42 85/5085/50 104/60104/60 112/68112/68 115/68115/68

– QRSQRS 136 msec136 msec 120msec120msec


McCabe. Ann Emerg Med 1998McCabe. Ann Emerg Med 1998– Swine model (N=24)Swine model (N=24)

– Nortyptyline until SBP < 50 and QRS > 120 msecNortyptyline until SBP < 50 and QRS > 120 msec

– Group 1 = D5W 10 ml/kgGroup 1 = D5W 10 ml/kg

– Group 2 = Hypertonic Saline 7.5% 10 ml/kgGroup 2 = Hypertonic Saline 7.5% 10 ml/kg

– Group 3 = Sodium Bicarb 8.4% 3mEq/kgGroup 3 = Sodium Bicarb 8.4% 3mEq/kg

– Group 4 = Hyperventilation to target pH 7.5-7.6 and Group 4 = Hyperventilation to target pH 7.5-7.6 and D5W 10 ml/kgD5W 10 ml/kg

Hypertonic saline looked pretty good!!Hypertonic saline looked pretty good!!

Hypertonic Saline:Hypertonic Saline: McCabe. Ann Emerg Med 1998 McCabe. Ann Emerg Med 1998

QRSQRS

BeforeBefore

txtx

QRS QRS

After txAfter tx

SBPSBP

BeforeBefore

txtx

SBP SBP After After

txtx

SurvivalSurvival

D5WD5W

N=6N=6

148148 144144 5656 5454 1/61/6

HTSHTS

N=6N=6

158158 8080 5757 134134 5/65/6

BicarbBicarb

N=6N=6

156156 105105 5252 8585 2/62/6

HyperVHyperV

N=6N=6

146146 125125 5050 6060 1/61/6

Hypertonic Saline: ConclusionsHypertonic Saline: Conclusions

There is animal evidence to support the use of There is animal evidence to support the use of hypertonic saline after other therapies have been hypertonic saline after other therapies have been maximizedmaximized

Human evidence is limited to case reportsHuman evidence is limited to case reports

Consider Hypertonic Saline for Consider Hypertonic Saline for TCA toxicity if sodium bicarbonate TCA toxicity if sodium bicarbonate ineffective and pH of 7.50-7.55 has ineffective and pH of 7.50-7.55 has been reachedbeen reached

Hypertonic Saline: ConclusionsHypertonic Saline: Conclusions

Should Hypertonic Saline be used Should Hypertonic Saline be used instead of sodium bicarbonate?instead of sodium bicarbonate?

NONO– Lots of evidence for sodium bicarb and not Lots of evidence for sodium bicarb and not

much for hypertonic salinemuch for hypertonic saline– Needs more studyNeeds more study

What about What about phenytoin?phenytoin?

PhenytoinPhenytoin

Theory: increases AV conduction thus Theory: increases AV conduction thus enhances delivery of supraventricular enhances delivery of supraventricular impulses and suppresses ventricular impulses and suppresses ventricular rhythms; also decreases re-entryrhythms; also decreases re-entry

BUT isn’t phenytoin a Na+ channel BUT isn’t phenytoin a Na+ channel blocker? blocker? – Different Na+ binding site than TCADifferent Na+ binding site than TCA– Thought to increase conduction rather than Thought to increase conduction rather than

block it although QRS prolongation can occurblock it although QRS prolongation can occur

PhenytoinPhenytoin

Goldfranks 2003Goldfranks 2003– Not recommendedNot recommended

Ford 2001 Ford 2001 – Not even discussedNot even discussed

So what evidence is there?So what evidence is there?

PhenytoinPhenytoin

Callaham. J Pharmacol Exp Ther. 1988Callaham. J Pharmacol Exp Ther. 1988– Dog modelDog model– Control group: amitriptyline infusionControl group: amitriptyline infusion– Experimental group: phenytoin loading before Experimental group: phenytoin loading before

amitriptyline infusionamitriptyline infusion– ResultsResults

» No differences in physiologic parametersNo differences in physiologic parameters

» Ventricular tachycardia dramatically increased in Ventricular tachycardia dramatically increased in phenytoin groupphenytoin group

PhenytoinPhenytoin

Kulig. Vet Hum Toxicol 1984 (abstract)Kulig. Vet Hum Toxicol 1984 (abstract)– Canine modelCanine model– Amitiptyline until QRS 160 msecAmitiptyline until QRS 160 msec– Phenytoin pretreatment and rescuePhenytoin pretreatment and rescue– No bicarb, no pressorsNo bicarb, no pressors– Phenytoin prevented ventricular arrythmias Phenytoin prevented ventricular arrythmias

only when given as pretreatmentonly when given as pretreatment– Details not providedDetails not provided

PhenytoinPhenytoin

Mayron. Ann Emerg Med 1986.Mayron. Ann Emerg Med 1986.– Rabbit modelRabbit model

– Amitripyline Amitripyline

– Looked at “prophylaxis” and “rescue” treatment with Looked at “prophylaxis” and “rescue” treatment with phenytoinphenytoin

– Outcome measure was dose of amitriptyline necessary Outcome measure was dose of amitriptyline necessary to cause wide QRS/arrythmia or deathto cause wide QRS/arrythmia or death

– NO BP dataNO BP data

– Specifics of QRS width not presentedSpecifics of QRS width not presented

PhenytoinPhenytoin

Mayron. Ann Emerg Med 1986.Mayron. Ann Emerg Med 1986.– Phenytoin had NO effect on the amitriptyline dose Phenytoin had NO effect on the amitriptyline dose

required to cause “toxicity”required to cause “toxicity”» No pretreatment: mean 11.4 mg/kg (2 – 39range)No pretreatment: mean 11.4 mg/kg (2 – 39range)

» Phenytoin pretx: mean 10.0 mg/kg (2.8-23.3 range)Phenytoin pretx: mean 10.0 mg/kg (2.8-23.3 range)

– Phenytoin had NO effect on the amitriptyline dose Phenytoin had NO effect on the amitriptyline dose required for lethalityrequired for lethality

– Phenytoin rescue dose after toxicity had an effect in Phenytoin rescue dose after toxicity had an effect in 2/12 (narrowed the QRS) and no effect in 10/122/12 (narrowed the QRS) and no effect in 10/12

Concluded: no effect with pretreatment or rescueConcluded: no effect with pretreatment or rescue

PhenytoinPhenytoin

Cantrill. J Emerg Med. 1983Cantrill. J Emerg Med. 1983– Case ReportCase Report

– 33yo female with amitripyline overdose33yo female with amitripyline overdose

– BP 70, QRS 170 msec, comatoseBP 70, QRS 170 msec, comatose

– Intubated, lavaged, charcoal, bicarb dripIntubated, lavaged, charcoal, bicarb drip

– Phenytoin givenPhenytoin given

– QRS narrowed to 90 msec on an ECG 30 minutes laterQRS narrowed to 90 msec on an ECG 30 minutes later

Concluded: Phenytoin is the drug of choice for Concluded: Phenytoin is the drug of choice for TCA toxicityTCA toxicity

PhenytoinPhenytoin

Several other case reports exist in the Several other case reports exist in the literatureliterature

PhenytoinPhenytoin

Hagerman. Ann Emerg Med. 1981Hagerman. Ann Emerg Med. 1981– 10 patients with TCA poisoning10 patients with TCA poisoning– 9/10 had wide QRS, 1/10 had normal QRS but 9/10 had wide QRS, 1/10 had normal QRS but

wide PR intervalwide PR interval– Phenytoin dose was 5 – 7 mg/kgPhenytoin dose was 5 – 7 mg/kg– Don’t mention the use of bicarb, Don’t mention the use of bicarb,

hyperventilation, normal or hypertonic salinehyperventilation, normal or hypertonic saline– Note: there is NO control groupNote: there is NO control group

PhenytoinPhenytoin

Hagerman. Ann Emerg Med. 1981Hagerman. Ann Emerg Med. 1981– Pre TreatmentPre Treatment Post TreatmentPost Treatment– Mean QRS Mean QRS 130 +/-7130 +/-7 106 +/-6106 +/-6– Range QRSRange QRS 100 – 160100 – 160 80 – 14080 – 140– Mean PRMean PR 204 +/- 12204 +/- 12 175 +/- 5175 +/- 5

Concluded that phenytoin was usefulConcluded that phenytoin was useful

Phenytoin:Phenytoin:ConclusionsConclusions

Animal Data is conflictingAnimal Data is conflicting Human data limited to case reports and case Human data limited to case reports and case

seriesseries No controlled human data existsNo controlled human data exists Bicarbonate is the treatment of choice for Bicarbonate is the treatment of choice for

QRS conduction abnormalitiesQRS conduction abnormalities Effect of phenytoin in cases refractory to Effect of phenytoin in cases refractory to

bicarb essentially unknownbicarb essentially unknown– Hypertonic saline seems like a better choiceHypertonic saline seems like a better choice

LidocaineLidocaine

Most commonly recommended Most commonly recommended antiarrythmic if refractory to bicarbantiarrythmic if refractory to bicarb

Doesn’t make sense because it is a Na+ Doesn’t make sense because it is a Na+ channel blocker thus has the potential to channel blocker thus has the potential to worsen the problemworsen the problem

Case reports are the “best” evidenceCase reports are the “best” evidence NO controlled human trialsNO controlled human trials Could try it if you are in a bindCould try it if you are in a bind

MagnesiumMagnesium

Case ReportsCase Reports– Citak. Eur J Citak. Eur J

Emerg Med. Emerg Med. 2002.2002.

Rat ModelRat Model– Knudsen. CCM 1994. Knudsen. CCM 1994.

– Norepinephrine pretreatmentNorepinephrine pretreatment

– Amitriptyline infusionAmitriptyline infusion

– Waited for Vtach to developWaited for Vtach to develop

– Got Mg, Lidocaine, or GlucoseGot Mg, Lidocaine, or Glucose

– Mg: 9/10 converted to sinus tachMg: 9/10 converted to sinus tach

– Lido: 1/10 converted to sinus tachLido: 1/10 converted to sinus tach

– Glucose: 1/10 converted to sinus Glucose: 1/10 converted to sinus tachtach

What other options What other options are there?are there?

Propranolol: Propranolol: few case reports of success, few case reports of success,

case series of crash and burn hypotensioncase series of crash and burn hypotension (Foulke. Am J Emerg Med 1986)(Foulke. Am J Emerg Med 1986)

Amiodarone: not studiedAmiodarone: not studied

Could Fab fragments be the cure Could Fab fragments be the cure for the TCA overdose??for the TCA overdose??

Watch for Fab fragments Watch for Fab fragments

in the future.in the future.

PEARL!PEARL!

Anything unique about AMOXAPINE and Anything unique about AMOXAPINE and MAPROTILINE?MAPROTILINE?– Bad, refractory seizuresBad, refractory seizures– Less cardiotoxicityLess cardiotoxicity


ICU resident order serum TCA level and ICU resident order serum TCA level and urine TCA screen ------> what do you say?urine TCA screen ------> what do you say?

TCA and lab testingTCA and lab testing

Urine TCA screenUrine TCA screen– Dip stick screen, Dip stick screen,

immunoassayimmunoassay

– HORRIBLE HORRIBLE specificity thus the specificity thus the lab doesn’t even lab doesn’t even do itdo it

Serum TCA levelsSerum TCA levels– Do NOT correlate with Do NOT correlate with

toxicitytoxicity

– False +vesFalse +ves» BenadrylBenadryl

» GravolGravol

» FlexerilFlexeril

» CarbemazepineCarbemazepine

» SeroquelSeroquel

» ClozapineClozapine

TCA overdose and dispositionTCA overdose and disposition

Toxicity develops within 6 hrsToxicity develops within 6 hrs Monitored for 6hrs: NO seizures, hypotension, Monitored for 6hrs: NO seizures, hypotension,

arrythmias, no bicarb Rxarrythmias, no bicarb Rx– Can d/c home or to psychCan d/c home or to psych

ICU for seizures, hypotension, arrythmias, ICU for seizures, hypotension, arrythmias, decreased LOCdecreased LOC

Telemetry for prolonged QTcTelemetry for prolonged QTc Duration of cardiac monitoringDuration of cardiac monitoring

– 24hrs after normalization of BP, off 24hrs after normalization of BP, off alkalinization/antidysrhythmics/pressorsalkalinization/antidysrhythmics/pressors

ADORA CriteriaADORA Criteria

AntiDepressant Overdose Risk AssessmentAntiDepressant Overdose Risk Assessment Foulke. Am J Emerg Med. 1995Foulke. Am J Emerg Med. 1995 High risk = any of QRS > 100 ms, High risk = any of QRS > 100 ms,

arrythmia, conduction defect, altered LOC, arrythmia, conduction defect, altered LOC, seizures, resp depression, hypotensionseizures, resp depression, hypotension

Prospective study of 67 patientsProspective study of 67 patients Any high risk feature predicted the Any high risk feature predicted the

development of complications (surprise!)development of complications (surprise!)

Key PointsKey Points

We need to know more about TCA overdoses than We need to know more about TCA overdoses than anybody (except toxicologist!!)anybody (except toxicologist!!)

Aggressive decontamination Aggressive decontamination Expect complications Expect complications Be able to manage complications appropriatelyBe able to manage complications appropriately Know how, why, when, and how much bicarb to Know how, why, when, and how much bicarb to

givegive Be aware of ECG features of TCA overdose and Be aware of ECG features of TCA overdose and

their predictive valuetheir predictive value Have a good approach to monitoring and disposition Have a good approach to monitoring and disposition

The end.The end.

Questions?Questions?

Comments?Comments?

cyclic antidepressants: it’s all good. toxicology core rounds jan 15, 2004 rob hall pgy4 randall...

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