Therapeutic Hypothermia: Disclosure - UT Health Science Center

Pediatrics Grand Rounds11 January 2013

University of Texas Health Science Center at San Antonio, School of Medicine

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Therapeutic Hypothermia:Therapeutic Hypothermia:Applications in the PICUApplications in the PICU

Theodore Wu MDPediatric Critical Care

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DisclosureDisclosure

I have no relationships with commercial companies to disclose.

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ObjectivesObjectivesReview the basic science of hypothermia and application in hypoxic- ischemic neuronal injurySummarize current clinical evidence for use of therapeutic hypothermia– Use in cardiac arrest, intrapartum asphyxia and

traumatic brain injury– limitations of available evidence

Introduction to the goals and objectives of the THAPCA trials

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BackgroundBackgroundCardiac arrest (CA) in children is a tragic event associated with high mortality and poor neurological outcomeEspecially true of out-of-hospital (OH) CAEspecially true of out-of-hospital (OH) CA where mortality and neurological sequelae commonCA in the in-hospital (IH) setting results in higher survival and neurologic sequelae are far less common in survivors

5 Nadkarni, 2006

History of HypothermiaHistory of HypothermiaConcept developed in the 1950s– Hypothermic dogs

survived 20min of cardiac arrest

1960s Neurosurgery for large aneurysms under cardiac arrest1970s Ascending aortic arch surgeryOutcome: not good

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Simplified scheme of the mechanism after ischemia

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Multiple Brain injury processesMultiple Brain injury processes

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Neuroprotective Effects of Neuroprotective Effects of HypothermiaHypothermia

In rat models: ↓ cerebral edema, blood brain barrier permeability, cerebral atrophyp yLowers CBF and ICPPotential as an anticonvulsant24hr hypothermia is safe

Marion et al. 199710

Neuroprotective Effects of Neuroprotective Effects of HypothermiaHypothermia

↓ Cerebral metabolic rate by 6-7% per ↓ 1oC body core temp; increase O2 supply to ischemic areas↓ lactate and excitatory amino acids such as↓ lactate and excitatory amino acids such as glutamate and glycerol↓ ICAM-1expression↓ neutrophil migration to ischemic tissue

Illievich UM Anesth Analg. 1994Berger C Stroke. 2002Inamasu J Neurol Res. 200111

Evidence for Hypothermia in Evidence for Hypothermia in Pediatric Cardiac ArrestPediatric Cardiac Arrest

Bohn DJ, et al. Influence of hypothermia, barbiturate therapy, and intracranial pressure monitoring on morbidity and mortality after near drowning Crit Care Med 1986; 14:529-34Hypothermic group – (target temp 30oC for 1 week)

Increased risk for neutropenia, sepsis, death in the hypothermia groupNo optimal core temperature determined

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Bernard ResultsBernard Results

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Hypothermia in Adult Arrest Hypothermia in Adult Arrest ––European trialEuropean trial

Randomized survivors OOH witnessedVF/VT with coma after ROSC– Goal was to cool to temp 32-34 OC within 4 hours

f ROSC b t di 8 hof ROSC but median was 8 hours– Sedated and Intermittent NMB for shivering– Blinded assessment of outcome at 6 months

3551 patients screened and 275 studied (only 7.7% of total arrest population)

HACA Study Group. NEJM 2002; 346: 549-56 14 15

Hypothermia after Pediatric Hypothermia after Pediatric Cardiac ArrestCardiac Arrest

CHOP, Retrospective cohortChildren w/o CHD with ROSC181 pts studied– 91% asphyxial cause; 55% in-hosp CA

40 pts received HT Similar mortality rates- 55%, p=1.0

16Fink et al., Peds Crit Care Med 2010

Hypothermia after Pediatric Hypothermia after Pediatric Cardiac ArrestCardiac Arrest

Hypothermia Pts – 78% survivors d/c home– Temp <32oC (15%); assoc with higher

mortalityo ta ty– More unwitnessed CA and out hosp CA;

Epi doses to ROSC– Received more Electrolytes

Normothermia Pts (68% survivors)– 2x more likely to fever; and re-arrest

17Fink et al., Peds Crit Care Med 2010

Canadian StudyCanadian Study5 center, retrospective study79 pts studied, 29 received HT – Cooled to 33.7± 1.3oC for 20.8± 11.9 hrs

HTHT assoc– Higher mortality, longer duration of CA,

more resus interventions, Higher lactacte, and ECMO use

No signif stat diff in Mortality when adjusted CA duration, ECMO, propensity scores18

Cool Cap Perinatal Asphyxia Cool Cap Perinatal Asphyxia StudyStudy

25 Center study in term newborns with HI-encephalopathyEvaluated use ofEvaluated use of selective head cooling using dedicated deviceRandom assignment w/in 6h of birth to head cooling for 72h or conventional care

Gluckman PD, et al. Lancet 2005: 365:663-7019



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Cool Cap Perinatal Asphyxia Cool Cap Perinatal Asphyxia StudyStudy

Inclusion: term infant w/clinical evidence of mod to severe encephalopathy or seizures and evidence of perinatal HI – (Apgar ≤ 5 at 10 min or severe acidosis w/in 1 hr

of birth) and abnormal aEEG w/in 6 hRectal temp maintained at 34-35oC for 72 hrPrimary outcome: death or severe disability at 18 mo

Gluckman PD, et al. Lancet 2005: 365:663-7020 21

HypothermiaHypothermia-- Perinatal AsphyxiaPerinatal AsphyxiaLogistic regression analysis controlling for pre-randomization severity of encephalopathy suggested a protective effect (p=0.05; OR 0.57; 0.32, 1.01)No effect in infants with most abnormal aEEG changesAdverse outcome reduced from 65.9% in controls (n=88) to 47.6% in cooled (n=84), p=0.01– ARR = 18.3%; NNT = 6 (95% CI:3 to 27)

Gluckman PD, et al. Lancet 2005: 365:663-7022

Whole Body Hypothermia for Whole Body Hypothermia for Neonatal HIENeonatal HIE

15 center NICHD Neonatal Network trial of systemic hypothermia initiated within 6 h and continued for 72 h in neonates with HIE

1o outcome: reduction of death or severe disability– 1 outcome: reduction of death or severe disability at 18-22 mo

– Cooled with servo-controlled blanket; monitored rectal temp to target of 33.5oC

Controls at 36.5-37oC skin temp– Randomized block design at each center; 798

screened, 239 eligible and 208 enrolled

Shankaran S, et al. NEJM 2005: 353: 1574-8423

Whole Body Hypothermia for Whole Body Hypothermia for Neonatal HIENeonatal HIE

Included if significant acidosis (pH<7, BD> 16 mm/L) by umbilical cord or blood sample w/in 1 h of birth + acute perinatal event and either 10 i A ≤ 5 OR i t d til ti t10 min Apgar ≤ 5 OR assisted ventilation at birth and continued > 10 minExcluded if > 6 hrs, major congenital abnormality, moribund, severe growth retardation

Shankaran S, et al. NEJM 2005: 353: 1574-8424 25



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TOBY StudyTOBY StudyProspective, multi-center, randomized neonatal trial in UK (325 pts recruited)Infants less than 6 hrs old, 36 weeks and perinatal encephalopathyC li 33 5oC f 72 h 37oCCooling 33.5oC for 72 hrs or 37oCRewarming no more than 0.5oC/hrPrimary outcome: death or severe disability (18 months)

26 Azzopardi NEJM 2009

TOBY ResultsTOBY ResultsCooled group– 42 deaths, 32 survival with severe

disability Noncooled group– 44 deaths, 42 survival with severe disability

Either outcome: RR 0.86, P 0.17Increased survival rate without neuro disability (RR 1.57; p=0.003)


ResultsResults

Cooled infants increased survival rate w/o neuro abn (RR 0.67, P 0.003)Cooling had reduced risk for cerebralCooling had reduced risk for cerebral palsy (RR 0.67 P 0.03)– Improved developmental scores

Adverse events similar in two groups– Hypotension, Plts, ICH, Coag time


Cochrane Collaboration Cochrane Collaboration Eight randomized trials reviewed– 638 term infants with moderate-severe

encephalopathy and intrapartum asphyxiaResults– Statistically significant reduction in

combined outcome of mortality or major neuro disability to 18 mo

– RR 0.76; RD -0.15, NNT 7 – Adverse events: use of inotropes,

thrombocytopenia29 Cochrane Reviews, 2008

Cochrane ConclusionsCochrane ConclusionsTherapeutic hypothermia beneficial to term infants with HIEReduces mortality without increasing major disability in survivorsBoth large neonatal HI trials showed benefitBoth large neonatal HI trials showed benefit in moderate HI encephalopathy group– Suggests that HT may not be effective if neuro

injury severe– Ability to stratify by aEEG 24h/day is likely limited

Incorporation of ongoing data needed to clarify effectiveness

30 Cochrane Reviews, 2008

Cardiac Arrest Hypothermia Cardiac Arrest Hypothermia SummarySummary

Until recently, no tx shown to be efficacious for neuroprotection and survival in humans post CAIn 2002, two adult RCTs from Europe & pAustralia of therapeutic hypothermia (TH) after VF OH CA reported improved outcome. (HACA, Bernard)

In 2005, 3 RCTs for newborns with HIE, all reported improved outcomes. (Shankaran, Gluckman, Eicher)

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SummarySummaryAHA guidelines

HT for comatose adult CA from ventricular arrhythmia shows neuroprotective benefit, but not convincing for PEA/asystole CAg y

Consideration of HT for coma survivors after pediatric CALarge RCT studies for pediatric cardiac arrest– THAPCA study: Plan for 850 enrollment in

~30 centers32

Hypothermia for other Hypothermia for other diseases?diseases?

Can the data from adults and neonates be applied to other types of brain injury (trauma)?( )

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HyHypothermia pothermia PPaediatric aediatric HHead ead IInjury njury TTrial (HyPrial (HyP--HIT)HIT)

Multi- center Randomized controlled trial of 24 hours of hypothermia therapy in Ped pts with severe traumatic brain pinjury (TBI)17 centers in Canada, UK and France225 patients enrolled

Hutchison J, et al. NEJM 2008: 358: 2447-5634

N= 108

N= 117

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HyPHyP--HIT OutcomeHIT OutcomePCPC (primary outcome)PCPC (primary outcome)

6 Months Hypothermia n (%)

Normothermian (%)

P

PCPC= 4-6 32 (31.4) 23 (22.3) 0.14

Mortality 23 (21.3) 14 (12) 0.06

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ConclusionsConclusionsModerate hypothermia (32-33OC) did not improve functional outcome after 6 moNo statistically significant difference in mortality but worrisome trendmortality but worrisome trend– Increased mortality in hypothermia therapy

(P=0.06)Increase in hypotensive episodes in hypothermia group during rewarmingNo difference in adverse events

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Explanation for lack of effect?Explanation for lack of effect?

Diverse types of brain injuryHypothermia therapy is ineffectiveBetter method to apply hypothermiaBetter method to apply hypothermia therapy– Shorter time to implement therapy?– Longer duration? (>48hr)

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Hypothermia QuestionsHypothermia Questions

How to rewarm?– Worse outcome if rewarm rapidly– Management of shivering/stress responseManagement of shivering/stress response

Which patients should be cooled?– Should cooling start in the field or at the

referring hospital?

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Hypothermia QuestionsHypothermia Questions

How to monitoring cooling?– Bladder, rectal or blood temp? Brain temp?– Frequent excessive hypothermia with

surface coolingHow should we manage shivering?– Counterwarming, buspirone, fentanyl– Use of NMB then need to monitor

continuous EEGHow to adjust medication in HT pts?

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Application of HypothermiaApplication of Hypothermia

No best method for induction of coolingInformation on hypothermia protocol at UPENN site:UPENN site:– www.med.upenn.edu/resuscitation/hypothe

rmia106 protocols currently posted

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Cooling MethodsCooling MethodsSurface Cooling– Body or regional cooling

Extracorporeal coolingEndovascular coolingEndovascular coolingCold IV infusions

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Endovascular CathetersEndovascular Catheters

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Rate of CoolingRate of Cooling

47 Hoedemaekers, CCM 2007

Maintaining HypothermiaMaintaining Hypothermia

48 Hoedemaekers, CCM 2007

Survey of Pediatric Intensivists on Survey of Pediatric Intensivists on Use of Therapeutic HypothermiaUse of Therapeutic HypothermiaSurveyed for awareness and the usage of therapeutic hypothermia (143 PICU trained)Majority of physicians surveyed aware of :– Beneficial effects

Hypothermia not widely used– Hypothermia not widely used (explicit protocols, lack of evidence)

Randomized, clinical trial of induced hypothermia in children is ethical Therapeutic hypothermia should be studied in other ischemic insults

Haque et al. Pediatr Crit Care Med. 2006



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Therapeutic Hypothermia After Therapeutic Hypothermia After Pediatric Cardiac Arrest (THAPCA) Pediatric Cardiac Arrest (THAPCA)

Trials Trials



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Life Support Life Support Instruction CourseInstruction Course

Looking for Interested ResidentsIncludes renewal of BLS and PALS and initial Instructor training resulting in AHA CertificationTime Commitment: Approximately 12-15 hours Time Commitment: Approximately 12 15 hours in 3 to 4 hour sessionsMaintaining Certification requires teaching 2 classes per year No cost to participantsAsking for commitment to teach other residents as part of QI project

Interested?Interested?

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Therapeutic Hypothermia: Disclosure - UT Health Science Center

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