Hypothermic Neuroprotection In The Newborn

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

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

Thank you!

Hypothermic Neuroprotection In The Newborn

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Transcript of Hypothermic Neuroprotection In The Newborn