hypothermic neuroprotection in the newborn
TRANSCRIPT
HYPOTHERMIC NEUROPROTECTION
IN THE NEWBORN:A COOL IDEA
HYPOTHERMIC NEUROPROTECTION
IN THE NEWBORN:A COOL IDEA
Steven M. Donn, M.D.Steven M. Donn, M.D.
Professor of PediatricsProfessor of PediatricsChief, Division of Neonatal-Perinatal MedicineChief, Division of Neonatal-Perinatal Medicine
C.S. Mott Children’s HospitalC.S. Mott Children’s HospitalUniversity of Michigan Health SystemUniversity of Michigan Health System
DISCLOSUREDISCLOSURE
Steven M. Donn, M.D. received grant Steven M. Donn, M.D. received grant support from Olympic Medical support from Olympic Medical (Seattle, WA) as an investigator for (Seattle, WA) as an investigator for the Cool Capthe Cool Cap®® trial.trial.
HYPOXIC-ISCHEMIC ENCEPHALOPATHY (HIE)
HYPOXIC-ISCHEMIC ENCEPHALOPATHY (HIE)
Estimated incidence: 1-4/1000 term Estimated incidence: 1-4/1000 term birthsbirths
Frequently associated with chronically Frequently associated with chronically disabling conditions including CP, MR, disabling conditions including CP, MR, and epilepsyand epilepsy
Abnormal neurologic behavior in neonatal Abnormal neurologic behavior in neonatal period (SZ, EEG abnormalities) best period (SZ, EEG abnormalities) best predictors of neurologic disability and deathpredictors of neurologic disability and death
NEONATAL PREDICTORS OF LTND: Patient Selection CriteriaNEONATAL PREDICTORS OF LTND: Patient Selection Criteria
NCPP (1988): 69% Death or Handicap if:NCPP (1988): 69% Death or Handicap if:Apgar < 6Apgar < 655
Neonatal encephalopathyNeonatal encephalopathySeizuresSeizures
Gunn and Gunn (1997): 60% LTND if: Gunn and Gunn (1997): 60% LTND if: HIEHIE
SeizuresSeizures
HIE PATHOPHYSIOLOGYHIE PATHOPHYSIOLOGY
Hypoxic-Ischemic Insult (transient)Hypoxic-Ischemic Insult (transient) Primary energy failurePrimary energy failure RecoveryRecovery Secondary energy failure (6-48 hours later)Secondary energy failure (6-48 hours later) Irreversible Neuronal InjuryIrreversible Neuronal Injury
Necrosis Necrosis vsvs. Apoptosis. Apoptosis
HUMAN NEONATAL TRIALS HUMAN NEONATAL TRIALS
Calcium channel antagonists and Calcium channel antagonists and
magnesium not effective, possibly magnesium not effective, possibly
dangerousdangerous
Some preliminary success with Some preliminary success with
cerebral cooling, phenobarbital, and cerebral cooling, phenobarbital, and
allopurinolallopurinol
BACKGROUNDBACKGROUND
In perinatal animal studies hypothermia can be neuroprotective when applied following asphyxial or ischemic insults Cooling needs to be started within ~ 6 h after
birth (and earlier is better) It needs to be continued for at least 24 h (72 h
is better) The brain needs to be cooled to 32 to 34ºC
Post-HI Hypothermia in P7 RatsPost-HI Hypothermia in P7 Rats
Study Study TimeTime T (T (°C)°C) OutcomeOutcome
ThoresenThoresen 3 hr.3 hr. 32.5 32.5 Less damage Less damage scores at 7 dscores at 7 d
YagerYager 3 hr.3 hr. 31/3431/34 No effect at 23 dNo effect at 23 d
TrescherTrescher 3 hr. 3 hr. 32/3532/35 7 d- protection7 d- protection
28 d- no morph. 28 d- no morph. ∆∆
BonaBona 6 hr.6 hr. 3232 7d- protection7d- protection
42 d –morph.prot. 42 d –morph.prot. Better motor fcn.Better motor fcn.
Prolonged Post-HI Hypothermia IProlonged Post-HI Hypothermia I
P21 rat HI (15 min = mild)P21 rat HI (15 min = mild) Post-HI temp 22Post-HI temp 22ooC v 34C v 34ooC (environment)C (environment) 0-72 h protective *0-72 h protective * 0-6 h not protective0-6 h not protective 6-72 h not protective6-72 h not protective
* cortex (72h and 21d - 66%) and striatum * cortex (72h and 21d - 66%) and striatum (72h), not hippocampus. No “neuro exam”(72h), not hippocampus. No “neuro exam”
Prolonged Post-HI Hypothermia II Prolonged Post-HI Hypothermia II
Late term fetal sheep (Gunn et al.)Late term fetal sheep (Gunn et al.) 30 min. BCO; 72 h selective head cooling 30 min. BCO; 72 h selective head cooling
starting 1.5 or 5.5 h later. Pathol. @ 5dstarting 1.5 or 5.5 h later. Pathol. @ 5d 1.5h: attenuation of neuron loss, all regions1.5h: attenuation of neuron loss, all regions 5.5h: attenuated neuron loss, except 5.5h: attenuated neuron loss, except
hippocampushippocampus Final EEG recovery better with 1.5h startFinal EEG recovery better with 1.5h start
EEG – dramatically improved
0 2 4
-20
-15
-10
-5
0
5
24 48 72 96 120
*
Hypothermia
Control
*
Cooling
Time (hours)
EEG(µV)
Seizures not suppressed
Slide c/o Alistair Gunn
SUMMARY of ANIMAL DATASUMMARY of ANIMAL DATA
The longer the hypothermia duration, the The longer the hypothermia duration, the better the protection, both %damage better the protection, both %damage reduction and “durability”reduction and “durability”
Window of opportunity may be several Window of opportunity may be several hours (up to 6-8)hours (up to 6-8)
Systemic toxicity not a major issue (mild Systemic toxicity not a major issue (mild reversable increases in BP, blood reversable increases in BP, blood glucose, lactate in fetal sheep model) glucose, lactate in fetal sheep model)
Mechanism still unclearMechanism still unclear
The Cool Cap Study
By parental permission, Dr Durand, Oakland
PRIMARY HYPOTHESISPRIMARY HYPOTHESIS
In term neonates with moderate to severe hypoxic-ischemic encephalopathy head cooling with mild systemic hypothermia will be associated with a reduction in death and severe neurodevelopmental disability
Anticipated Issues in Trial Design Anticipated Issues in Trial Design
Problem : heterogeneous population with HIE
Solution : aEEG based selection, to exclude milder cases that
would be expected to have high rate of good outcome aEEG stratification, to compare the effect in the most
severe cases vs. more ‘moderate’ cases, or effect of seizures vs. no seizures
Prospectively record other baseline data that may influence outcome, and thus may be used as covariates, e.g. gestational age, BW, Apgar scores, delay from birth to initiation of cooling
aEEG CRITERIAaEEG CRITERIA
Local physician read (central training by D. Azzopardi, Hammersmith, London, UK)
Selected for randomization if: aEEG diagnosed seizures
and/or Moderately or severely abnormal voltage on
aEEG (lower margin < 5 V)
Anticipated Issues in Trial Design Anticipated Issues in Trial Design
Problem: risk of complications from systemic cooling in neonates
Systemic hypothermia < 33-34C is associated with potential risks of coagulopathy, cardiovascular compromise, infection and metabolic acidosis
SOLUTIONSOLUTION While cooling the head directly, the body was
warmed by radiant heat to 34-35 C. Pilot studies in Auckland were used to develop the system and showed safety and hinted at efficacy (Gunn et al 1998). Nasopharyngeal temperatures fell by 0.8 C more than core temperature
By parental permission, Dr Durand, Oakland
The Cool Cap TrialThe Cool Cap Trial 28 centers: NZ, Canada, USA, UK Randomization, stratified by center, to selective head
cooling plus mild central hypothermia with rectal temperature maintained at 34.5 ± 0.5 °C for 72 h, then controlled warming @ 0.5 C/h or routine care
Term (36 weeks) infants, start within 6 h of birth Staged selection
Evidence of perinatal HIE (10 min Apgar<6 or resuscitation @ 10 min or pH<7 or BD>=16)
Moderate to severe clinical encephalopathy Moderate to severe EEG amplitude reduction (lower
margin < 5 V) on aEEG or seizures
MODERATE to SEVERE HIEMODERATE to SEVERE HIE
i.e., Sarnat stage II or III encephalopathy:i.e., Sarnat stage II or III encephalopathy: Altered state of consciousness (lethargy, Altered state of consciousness (lethargy,
stupor, coma), stupor, coma), + ≥+ ≥1 of1 of
HypotoniaHypotonia
Abnormal reflexes (include eyes)Abnormal reflexes (include eyes)
Absent or weak suckAbsent or weak suck
Clinical seizuresClinical seizures
PRIMARY OUTCOME PRIMARY OUTCOME At 17 to 22 months
Death or or Severe disability
- BSID II MDI < 70, or
- Gross Motor Function (GMF) neuromotor impairment Level 3-5 * (Level 3: non-
ambulatory, sits with support applied to the lower back;
Levels 4-5: infants who have limited or no self-mobility), or
- Bilateral cortical visual impairment
(* Palisano et al., Dev Med Child Neurol 39:214, 1997)
TRIAL STATISTICSTRIAL STATISTICS
234 infants studied (to Jan. 2002) 75% U.S. sites 25% UK, Canada, New Zealand
Safety reviews at 25, 50 and 75% enrolment revealed no major concerns
Follow up available on 218 (93%) infants 8 cooled and 8 control infants lost to follow up
Before primary analysis was initiated, neurodevelopmental outcome independently reviewed (DF, CR)
The primary analysis was initiated and performed independent of trial sponsor
Cooled ControlNumber 116 118Initial pH (mean, SD) 6.9 (0.2) 6.9 (0.2)Five min Apgar 0 – 3 77% 68%
Pre-randomization aEEG: Moderately Abnormal54% 64%Severely Abnormal 36% 27%
Seizures present 59% 64%Age at Randomization (h) 4.8 (2.6-6) 4.7 (2.1-6.1)
BASELINE DATABASELINE DATA
# Enrolled235
Final Count234
Cancelled1
Lost to Follow-up
16
18-Month Primary Outcome
218
Cooled108
Control110
Favorable49 (45%)
Unfavorable59 (55%)
Favorable37 (34%)
Unfavorable73 (66%)
PrimaryOutcomePrimaryOutcome
EFFICACY RESULTSEFFICACY RESULTS
All infants, intention-to-treat analysisAll infants, intention-to-treat analysis Pre-specified 6-Factor Logistic Regression: Pre-specified 6-Factor Logistic Regression:
aEEG backgroundaEEG background aEEG seizure statusaEEG seizure status Age at randomization Age at randomization Apgar scoreApgar score Birth weightBirth weight GenderGender
Statistically Significant Treatment Effect p=0.042, Statistically Significant Treatment Effect p=0.042, Odds Ratio = 0.53, when chance imbalances in Odds Ratio = 0.53, when chance imbalances in baseline factors were accounted for by Logistic baseline factors were accounted for by Logistic RegressionRegression
Excluding most severe abnormalities in aEEG < 6
hours
A priori – anticipated to respond172/218
In controls (n=88)66% unfavourable outcome
(39% mortality)
Most abnormal aEEG< 6 hours
A priori – unlikely to respond46/218
In controls (n=22)68% unfavourable outcome
(36% mortality)
Stratification by Baseline aEEG
To allow for multiple comparisons, p<0.025 required for significance
A priori defined group excluding infants
with severely abnormal aEEG with
seizure
n=172
Cooled84
Control88
Favorable44 (52%)
Unfavorable40 (48%)
Favorable30 (34%)
Unfavorable58 (66%)
Fisher’s exact p=0.02; logistic regression,
OR: 0.42 (0.22, 0.80), p=0.009
Cooling Improved Intact Survival Excluding the Most Abnormal Baseline aEEG
Cooling Improved Intact Survival Excluding the Most Abnormal Baseline aEEG
Mortality 39% (control) vs 29% (cooled), p=0.2
Severe neuromotor disability, defined as Gross Motor Function level 3-5 in survivors
27.8% of control infants , 11.7% of cooled infants (p=0.035)
BSID II MDI and PDI (treated as continuous variable) p<0.05
Note: p<0.025 required for significance
NUMBER NEEDED to TREAT(Per Survivor with Improved Outcome)NUMBER NEEDED to TREAT(Per Survivor with Improved Outcome)
Excluding most severe EEG 6 (95% CI: 3, 27)
aEEG entry, no exclusions 8.5
Infants with the Most Abnormal Baseline aEEG (Severe suppression of background
plus seizures, 46/218)
Infants with the Most Abnormal Baseline aEEG (Severe suppression of background
plus seizures, 46/218)
Unfavorable primary outcome 19/24 infants in cooled group (79.2%) vs 15/22 control infants (68.2%)
No evidence of a trend to improvement in any sub-components, p=0.51
ADVERSE EFFECTSADVERSE EFFECTS
No increase in severe hypotension despite full volume and inotrope support: 3 cooled vs 3 non-cooled infants (p=1.00)
Scalp edema common (32 cooled and 1 control infant, p<0.0001), but transient
One case of scalp damage under the cap in an infant dying of severe hypotension and coagulopathy
Sinus bradycardia, without hypotension, was very common during cooling and reversed on rewarming
PERINATAL COMPLICATIONSPERINATAL COMPLICATIONS
Cooled Non-Cooled P
Sinus Bradycardia/tachy 10 9% 1 1% 0.004*Hypotension (<40mmHg) 62 55% 64 52% 0.60Coagulopathy 21 19% 17 14% 0.38Prolonged coagulation 56 50% 50 42% 0.29Abnormal renal function 73 65% 83 70% 0.48Hyponatremia 49 44% 46 39% 0.50Hypokalemia 71 63% 73 62% 0.89Bone marrow depr. 36 32% 26 22% 0.10Elevated liver enzymes 42 38% 62 53% 0.02
PERINATAL COMPLICATIONSPERINATAL COMPLICATIONS
Cooled Non-Cooled P
Metabolic acidosis 22 20% 27 23% 0.63Respiratory distress 94 84% 92 78% 0.31Hypoglycemia 14 13% 20 17% 0.36Infection 1 1% 2 2% 1.00Acute Mortality 27 23% 26 22% 0.88
(Deaths in the first week of life are not defined an adverse event)
CONCLUSIONSCONCLUSIONS
Head cooling, with rectal temperature maintained at 34-35 ºC for 72 h, started soon after birth in term infants with HIE led to a modest improvement in outcome, in a mixed group of infants with moderate to severe encephalopathy
Head cooling had no clinically important adverse effects
CONCLUSIONS (II)CONCLUSIONS (II) In the large subgroup (172/218), defined a priori to exclude
those with the most severe aEEG changes, there was a statistically and clinically significant reduction in death and severe disability
There was a similar trend to improvement in most of the components of primary outcome, including mortality, motor disability and BSID – II scores in survivors
There was no improvement in primary outcome in infants who exhibited severe background suppression of the aEEG plus seizures at randomization
Other Neonatal Hypothermia Trials: “South Carolina Body Cooling Trial” (I)Other Neonatal Hypothermia Trials: “South Carolina Body Cooling Trial” (I)
RCT, N=65, 6 centers, primary outcome death RCT, N=65, 6 centers, primary outcome death or severe motor disability at 12 mo. or severe motor disability at 12 mo.
≥ ≥ 35 wks GA, ≥ 2000 gm BW35 wks GA, ≥ 2000 gm BW Evidence of perinatal or postnatal hypoxic-Evidence of perinatal or postnatal hypoxic-
ischemic event, followed by neonatal ischemic event, followed by neonatal encephalopathy encephalopathy
Cooling by 6h, ice bags to head and body Cooling by 6h, ice bags to head and body ~2h, then cooling blanket, servo controlled to ~2h, then cooling blanket, servo controlled to rectal temp. (Trectal temp. (Trr) 33 ±0.5˚C for 48 h (controls - ) 33 ±0.5˚C for 48 h (controls - radiant warmer, Tradiant warmer, Trr 37 ±0.5˚C) 37 ±0.5˚C)
Eicher Eicher et alet al, Pediatr Neurol 32:11 & 32:18, 2005, Pediatr Neurol 32:11 & 32:18, 2005
“South Carolina Body Cooling Trial” (II)“South Carolina Body Cooling Trial” (II)
OutcomeOutcome NormothermicNormothermic(n=33)(n=33)
HypothermicHypothermic(n=32)(n=32)
Death or severe Death or severe disabilitydisability
84%84% 52% (p=0.019)52% (p=0.019)
DeathDeath 14 (42%)14 (42%) 10 (31%) 10 (31%) (p=0.35)(p=0.35)
Severe motor Severe motor disabilitydisability
7/11 (64%)7/11 (64%) 4/17 (24%)4/17 (24%)(p=0.053)(p=0.053)
Severe cognitive Severe cognitive abnormalityabnormality
5/12 (42%)5/12 (42%) 4/17 (24%)4/17 (24%)(p=0.4)(p=0.4)
Lost/incomplete Lost/incomplete followupfollowup
88 55
“South Carolina Body Cooling Trial” (III)“South Carolina Body Cooling Trial” (III)
Mean TMean Trr 32.8 ± 1.4˚C at 2h in cooled group 32.8 ± 1.4˚C at 2h in cooled group Safety issues in body-cooled group:Safety issues in body-cooled group:
Lower mean BP in cooled group, only during Lower mean BP in cooled group, only during re-warming dayre-warming day
More PPHN needing iNO (5 vs. 1)More PPHN needing iNO (5 vs. 1) Greater median days on pressors (5 Greater median days on pressors (5 vsvs. 2). 2) More thrombocytopenia (105 ± 60 vs. 160 ± 65)More thrombocytopenia (105 ± 60 vs. 160 ± 65) More use of FFP (23 vs. 11; but highest PT, More use of FFP (23 vs. 11; but highest PT,
lowest fibrinogen no different)lowest fibrinogen no different)
Other Neonatal Hypothermia Trials: NICHD NRN Body Cooling Trial (I)Other Neonatal Hypothermia Trials: NICHD NRN Body Cooling Trial (I) Eligibility and exclusions similar to Cool Eligibility and exclusions similar to Cool
Cap, except no aEEG selection stepCap, except no aEEG selection step N=208 (NT=106, HT=102)N=208 (NT=106, HT=102) Primary outcome death or moderate-severe Primary outcome death or moderate-severe
disability at 18 mo.disability at 18 mo. Severe: MDI<70, GMF 3-5, hearing aid, Severe: MDI<70, GMF 3-5, hearing aid,
blindblind Mod: MDI 70-85, GMF 2, Mod: MDI 70-85, GMF 2, hearing, Sz hearing, Sz
disorderdisorder HT: 3 days target THT: 3 days target Teses 33.5 ˚C (servo cooling 33.5 ˚C (servo cooling
mattress)mattress)Shankaran Shankaran et alet al. NEJM 353:1574-84, 2005. NEJM 353:1574-84, 2005
Copyright ©2002 American Academy of Pediatrics
Shankaran, et al. Pediatrics 2002;110:377-385
The infant lies supine on the infant-size blanket
NICHD NRN Body Cooling Trial (II)NICHD NRN Body Cooling Trial (II)OutcomeOutcome NTNT HTHT OR (CI)OR (CI)
Death or mod/sev Death or mod/sev dis.dis.
62%62% 44%44% .72 (.54-.95).72 (.54-.95)
Disabling CPDisabling CP 30%30% 19%19% .68 (.38-1.22).68 (.38-1.22)
MDI >85MDI >85 40%40% 52%52%
MDI 70-84MDI 70-84 21%21% 23%23% NSNS
MDI < 70MDI < 70 39%39% 25%25%
Death by 18 mo.Death by 18 mo. 37%37% 24%24% .68 (.44-1.05).68 (.44-1.05)
Death/dis after Mod Death/dis after Mod HIEHIE
48%48% 32%32% .69 (.44-1.07).69 (.44-1.07)
Death/dis after Sev Death/dis after Sev HIEHIE
85%85% 72%72% .85 (.64-1.13).85 (.64-1.13)
Shankaran et al. NEJM 353:1574
NICHD vs. Cool Cap trialsNICHD vs. Cool Cap trials Broader definition of “bad outcome” in NICHD trial Broader definition of “bad outcome” in NICHD trial
made it statistically easier to detect a between-made it statistically easier to detect a between-group differencegroup difference
Active temperature management in the Cool Cap Active temperature management in the Cool Cap trial, resulting in less hyperthermia in controls, may trial, resulting in less hyperthermia in controls, may have decreased the apparent effect of coolinghave decreased the apparent effect of cooling
Cool Cap aEEG step excluded some infants with Cool Cap aEEG step excluded some infants with moderate HIE who would have qualified in NICHD moderate HIE who would have qualified in NICHD trialtrial
Worse outcome in control group of Cool Cap trial Worse outcome in control group of Cool Cap trial (66% death or severe disability) (66% death or severe disability) vsvs. control group of . control group of NICHD trial (62% death or moderate or severe NICHD trial (62% death or moderate or severe disability) suggests Cool Cap population had disability) suggests Cool Cap population had greater baseline severity of injurygreater baseline severity of injury
Summary of Three Large TrialsSummary of Three Large Trials
Hypothermia has a modest beneficial Hypothermia has a modest beneficial effect in term infants with moderate-to-effect in term infants with moderate-to-severe HIEsevere HIE
Babies with HIE have multiple organ Babies with HIE have multiple organ system complications, which are not system complications, which are not worse with cooling as used in the two worse with cooling as used in the two larger trialslarger trials
Sinus bradycardia is a physiologic Sinus bradycardia is a physiologic response to hypothermiaresponse to hypothermia
Skin complications with head or body Skin complications with head or body cooling resolved after re-warmingcooling resolved after re-warming
Limitations of All Three TrialsLimitations of All Three Trials
About 1/1000 live births could qualifyAbout 1/1000 live births could qualify Delay to onset of cooling - nearly 5hDelay to onset of cooling - nearly 5h
Stabilization and/or transport timeStabilization and/or transport time Time to obtain consentTime to obtain consent
Current standard of care is to warm Current standard of care is to warm all birth-depressed neonates to 37˚C all birth-depressed neonates to 37˚C
The Future of Neonatal CoolingThe Future of Neonatal Cooling Is it true?Is it true?
At least 3 ongoing RCTs of body cooling in UK, At least 3 ongoing RCTs of body cooling in UK, Australia, Canada, Europe, with ~270 recruits/3 Australia, Canada, Europe, with ~270 recruits/3 years (as of Jan 2005)years (as of Jan 2005)
Chinese head cooling trial results?Chinese head cooling trial results? Recruitment slowRecruitment slow
How do we improve upon results?How do we improve upon results? Cool sooner? Colder?Cool sooner? Colder? Combination with pharmacotherapy?Combination with pharmacotherapy?
Head cooling device under FDA reviewHead cooling device under FDA review
Remember:Remember:
=
PRACTICALITIES ofBRAIN COOLINGPRACTICALITIES ofBRAIN COOLING
Practical Issues for Referring Hospitals (I)Practical Issues for
Referring Hospitals (I)
Distance: Patients from Saginaw, Toledo, Holland, St. ClairDistance: Patients from Saginaw, Toledo, Holland, St. Clair ““How do I know they’ll meet EEG criteria?”How do I know they’ll meet EEG criteria?”
Sarnat III and Sarnat II with clinical SZ likely willSarnat III and Sarnat II with clinical SZ likely willSarnat II without clinical SZ - about 1/3 meet aEEG Sarnat II without clinical SZ - about 1/3 meet aEEG
criteria criteria What should you say to parents? They can have a therapy What should you say to parents? They can have a therapy
which may help their baby, and has no serious adverse effects which may help their baby, and has no serious adverse effects (studied in over 200 babies); better than conventional care (studied in over 200 babies); better than conventional care offers. Use analogy of icing a joint after a sports injuryoffers. Use analogy of icing a joint after a sports injury
No “prophylactic” phenobarb please (OK to treat SZ)No “prophylactic” phenobarb please (OK to treat SZ) Avoid hyperthermia - check rectal temperatureAvoid hyperthermia - check rectal temperature
Practical Issues for Referring Hospitals (II)Practical Issues for Referring Hospitals (II)
Prompt notification of study center is keyPrompt notification of study center is key Rapid mobilization of transport (ours or Rapid mobilization of transport (ours or yoursyours)) Consent signed on team arrival, or by fax/phone Consent signed on team arrival, or by fax/phone
with investigatorwith investigator Investigators will discuss cooling details with Investigators will discuss cooling details with
parent(s) by phone while team en route, to save parent(s) by phone while team en route, to save timetime
Remember: they need to arrive by 5.5 h Remember: they need to arrive by 5.5 h
Rectal TemperatureRectal Temperature
ImplicationsImplications Cerebral hypothermia is the first treatment
demonstrated in a major controlled trial to improve long term outcome of neonatal encephalopathy
Confirms experimental and clinical data showing that neonatal encephalopathy can be progressive and reversible, not necessarily fixed at birth
Trial design issues in perinatal encephalopathy Relatively large trials are needed for sufficient power aEEG helped address the problem of heterogeneity of
severity/timing and improved power of the study
Issues AheadIssues Ahead Head vs whole body cooling
Efficacy – unlikely to be specific to cranial cooling provided protective temperature reached
Safety – risks of cranial cooling may be less as higher rectal temperature can be maintained. The ease of systemic hypothermia may lead to uninformed use
Physiology – ?less thermogenesis with head cooling
Degree and duration of cooling Prematurity: greater risks? Time to treat: can we enroll earlier?
The Cool Cap Study GroupThe Cool Cap Study GroupExecutive committee: P.D.Gluckman (chair), J.S. Wyatt, A.J. Gunn (Scientific Officer)Scientific advisory committee: J.S. Wyatt (chair), R. Ballard, A.D. Edwards, D.M. Ferriero, P.D.
Gluckman, A.J. Gunn, R. Polin, C. Robertson, A. WhitelawStatistician: P.Y. LiuaEEG advisor: D. AzzopardiData safety committee: R. Soll (chair), M. Bracken, M. Heymann, C. Palmer, A.Wilkinson.Hospital investigators: J. Kaiser, M. Battin, J. Khan, T. Raju, R. Polin, R. Sahni, U. Sanocka, A.
Rosenberg, J. Paisley, R. Goldberg, M. Cotten, A. Peliowski, E. Phillipos, D. Azzopardi, A.D. Edwards, F. Northington, J. Barks, S. Donn, B. Couser, D. Durand, K. Sekar, D. Davis, M. Blayney, S. Adeniyi-Jones, T. Yanowitz, R. Guillet, N. Laroia, N. Finer, F. Mannino, J. Partridge, D. Davidson, A. Whitelaw, M. Thoresen, J.S. Wyatt, F. O’Brien, B. Walsh, J. Perciaccante, M. O'Shea
Manufacturer’s representatives - Olympic Medical : J. Jones, T. Weiler, J. Mullane, D. Hammond
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