Update of HIE & Update of HIE & treatmenttreatment

Dr varsha Atul shahDr varsha Atul shah

DefinitionDefinition

Neonatal encephalopathy due to Neonatal encephalopathy due to hypoxic-ischemic brain injuryhypoxic-ischemic brain injury.. 1-2 cases in 1000 births1-2 cases in 1000 births Many causesMany causes

Different severity levelsDifferent severity levels Moderate encephalopathy carries a 10% Moderate encephalopathy carries a 10%

mortality and 30% risk of severe mortality and 30% risk of severe disability for survivorsdisability for survivors

Severe encephalopathy carries a 60% Severe encephalopathy carries a 60% mortality with nearly 100% severe mortality with nearly 100% severe neurological morbidity in survivorsneurological morbidity in survivors

Causes of asphyxiaCauses of asphyxia

MetabolicMetabolic InfectionsInfections Structural brain anomaliesStructural brain anomalies Intracranial hemorrhageIntracranial hemorrhage Maternal toxinsMaternal toxins Interruption of umbilical circulationInterruption of umbilical circulation Inadequate placental circulationInadequate placental circulation Impaired fetal or maternal circulationImpaired fetal or maternal circulation Impaired maternal oxygenationImpaired maternal oxygenation

PathologyPathology Severity and distribution is dependent on Severity and distribution is dependent on

several factorsseveral factors Certain vulnerable areasCertain vulnerable areas

- cerebral cortex , hippocampus , basal ganglia, - cerebral cortex , hippocampus , basal ganglia, thalamus, brain stem, subcortical and periventricular thalamus, brain stem, subcortical and periventricular white matterwhite matter

In full term infants gray matter structures In full term infants gray matter structures affected and in premature infants white matteraffected and in premature infants white matter

Four basic and clinically important lesionsFour basic and clinically important lesions- Neuronal necrosis, status marmoratus, para-sagittal - Neuronal necrosis, status marmoratus, para-sagittal cerebral injury, periventricular leucomalaciacerebral injury, periventricular leucomalacia

Overview of the Overview of the pathogenesispathogenesis

Evolving processEvolving process- Brain injury after experimental HI insult is an - Brain injury after experimental HI insult is an evolving process. The nature and severity of the evolving process. The nature and severity of the injury dictates the magnitude of the initial injury dictates the magnitude of the initial damage. damage.

Latent phaseLatent phase - After the initial reperfusion period, brain - After the initial reperfusion period, brain oxidative metabolism often recovers partially or oxidative metabolism often recovers partially or completelycompletely

Delayed phase of injuryDelayed phase of injury - an ominous phase of secondary deterioration - an ominous phase of secondary deterioration following the latent phasefollowing the latent phase- during which neurons and oligodendroglia - during which neurons and oligodendroglia continue to die for longer periods.continue to die for longer periods.

The processes of cell injury and death The processes of cell injury and death during the initial HI insult appear to be a during the initial HI insult appear to be a predictable phenomenonpredictable phenomenon: : - deprivation of oxygen and nutrients leads to a - deprivation of oxygen and nutrients leads to a shift to anaerobic glycolysisshift to anaerobic glycolysis- depletion of high-energy phosphate reserves- depletion of high-energy phosphate reserves- loss of cell membrane functions,- loss of cell membrane functions,- accumulation of lactic acid, calcium, free radicals - accumulation of lactic acid, calcium, free radicals and neurotoxic, excitatory neurotransmitters such and neurotoxic, excitatory neurotransmitters such as glutamate in the extracellular milieuas glutamate in the extracellular milieu- deterioration of cell function- deterioration of cell function

If the insult is not interrupted, this cascade If the insult is not interrupted, this cascade ultimately leads to ultimately leads to acute or “primary” cell acute or “primary” cell deathdeath..

However, the However, the biochemical processesbiochemical processes involved in evolving cell death that develops involved in evolving cell death that develops after reperfusion are more complex. after reperfusion are more complex.

A series of interrelated mechanisms may be A series of interrelated mechanisms may be responsible for responsible for perpetuating the initial perpetuating the initial injuryinjury, some of which include the following:, some of which include the following:- cytosolic accumulations of calcium and exposure - cytosolic accumulations of calcium and exposure to free radicals, including formation of nitric oxide, to free radicals, including formation of nitric oxide, - injury from inflammatory mediators- injury from inflammatory mediators- mitochondrial dysfunction. - mitochondrial dysfunction.

These and other processes trigger These and other processes trigger apoptotic apoptotic pathwayspathways contributing to continued contributing to continued neuronal and oligodendroglial injury and neuronal and oligodendroglial injury and deathdeath- may evolve over hours, days, or possibly weeks - may evolve over hours, days, or possibly weeks and months after an HI injury.and months after an HI injury.

Although the sequence of evolution of the Although the sequence of evolution of the phases of energy failure and cellular phases of energy failure and cellular damage and dysfunction after HI injury are damage and dysfunction after HI injury are strikingly consistent across animal species strikingly consistent across animal species and among subjects, the and among subjects, the duration of these duration of these phasesphases (especially that of the latent and (especially that of the latent and secondary deterioration) and the secondary deterioration) and the degree of degree of continuing damagecontinuing damage can vary considerably. can vary considerably.

The factors that might affect the length of The factors that might affect the length of the reperfusion and latent phases of injury the reperfusion and latent phases of injury are not well known but likely include the are not well known but likely include the following: following: - the nature, magnitude, and the pattern or - the nature, magnitude, and the pattern or repetition of the initial HI insultrepetition of the initial HI insult- the maturational stage of the brain- the maturational stage of the brain- the subject’s general health and nutritional - the subject’s general health and nutritional statusstatus- regional cerebral blood flow and metabolic - regional cerebral blood flow and metabolic characteristicscharacteristics

HI damage caused an inciting event leads to a HI damage caused an inciting event leads to a cascade of disturbances the foremost of which cascade of disturbances the foremost of which is neuronal energy failure and loss of is neuronal energy failure and loss of endothelial integrity.endothelial integrity.

Loss of ATP dependant ion pumps leads to Loss of ATP dependant ion pumps leads to increase cellular sodium and calcium which in increase cellular sodium and calcium which in turn leads to edema and neuronal lysis.turn leads to edema and neuronal lysis.

Build up of intracellular calcium leads to Build up of intracellular calcium leads to glutamate release and neuronal excitation glutamate release and neuronal excitation which may progress to seizure activity and which may progress to seizure activity and also causes the release of lipase, proteases also causes the release of lipase, proteases and endonucleases that contribute to free and endonucleases that contribute to free radical formation and cellular death.radical formation and cellular death.

The release of nitric oxide and subsequent The release of nitric oxide and subsequent free radical formation causes lipid free radical formation causes lipid peroxidation and loss of cellular integrity. It peroxidation and loss of cellular integrity. It also cause increased release of glutamate and also cause increased release of glutamate and thereby further incites excitotoxity caused by thereby further incites excitotoxity caused by this neurotransmitter.this neurotransmitter.

Prognosis based on Prognosis based on ApgarsApgars

Score at 1, 5 minutes does not give Score at 1, 5 minutes does not give prognosis indicator prognosis indicator

The longer the score remains lower, the The longer the score remains lower, the greater its significancegreater its significance

0-3 @ 1min has mortality of 5-10%0-3 @ 1min has mortality of 5-10% may be increased to 53% if at 20min may be increased to 53% if at 20min

apgars score 0-3 apgars score 0-3 0-3 @ 5min , CP risk app. 1%0-3 @ 5min , CP risk app. 1% may be increased to 9%if for 15minmay be increased to 9%if for 15min dramatic rise to 57% CP risk if for 20mindramatic rise to 57% CP risk if for 20min

Newborn neurological Newborn neurological assessmentassessment

Staging system of Sarnat and SarnatStaging system of Sarnat and Sarnat Means of recording severity of insult Means of recording severity of insult

to brain, to initiate med management to brain, to initiate med management and to predict ultimate prognosisand to predict ultimate prognosis

Infants occasionally sustain insult to Infants occasionally sustain insult to brain arising from complication of brain arising from complication of systemic diseasesystemic disease

Seizures in 50-70%Seizures in 50-70%

Mild HIEMild HIE

Muscle tone may be increased slightly Muscle tone may be increased slightly Deep tendon reflexes may be brisk Deep tendon reflexes may be brisk

during the first few days. during the first few days. Transient behavioral abnormalities, Transient behavioral abnormalities,

such as poor feeding, irritability, or such as poor feeding, irritability, or excessive crying or sleepiness, may be excessive crying or sleepiness, may be observed. observed.

By 3-4 days of life, the CNS By 3-4 days of life, the CNS examination findings become normal.examination findings become normal.

Moderate HIEModerate HIE Lethargic, significant hypotonia Lethargic, significant hypotonia Diminished deep tendon reflexes. Diminished deep tendon reflexes. Grasp, Moro, and sucking reflexes Grasp, Moro, and sucking reflexes

may be sluggish or absent. may be sluggish or absent. Occasional periods of apnea. Occasional periods of apnea. Seizures may occur within the 1Seizures may occur within the 1stst 24 24

hours of life. hours of life. Full recovery within 1-2 weeks is Full recovery within 1-2 weeks is

possible and is associated with a possible and is associated with a better long-term outcome. better long-term outcome.

Severe HIESevere HIE Stupor or coma is typical. Stupor or coma is typical. may not respond to any physical stimulus. may not respond to any physical stimulus. Breathing may be irregular, and the infant often Breathing may be irregular, and the infant often

requires ventilatory support. requires ventilatory support. Generalized hypotonia and depressed deep tendon Generalized hypotonia and depressed deep tendon

reflexes are common. reflexes are common. Neonatal reflexes (e.g., sucking, swallowing, Neonatal reflexes (e.g., sucking, swallowing,

grasping, Moro) are absent.grasping, Moro) are absent. Disturbances of ocular motion, such as a skewed Disturbances of ocular motion, such as a skewed

deviation of the eyes, nystagmus, bobbing, and deviation of the eyes, nystagmus, bobbing, and loss of "doll's eye" (i.e., conjugate) movements may loss of "doll's eye" (i.e., conjugate) movements may be revealed by cranial nerve examination. be revealed by cranial nerve examination.

Pupils may be dilated, fixed, or poorly reactive to Pupils may be dilated, fixed, or poorly reactive to light. light.

Seizures occur early and often, may be initially Seizures occur early and often, may be initially resistant to conventional treatments. The resistant to conventional treatments. The seizures are usually generalized, and their seizures are usually generalized, and their frequency may increase during the 2-3 days frequency may increase during the 2-3 days after onset, correlating with the phase of after onset, correlating with the phase of reperfusion injury. reperfusion injury.

As the injury progresses, seizures subside and As the injury progresses, seizures subside and the EEG becomes isoelectric or shows a burst the EEG becomes isoelectric or shows a burst suppression pattern. At that time, wakefulness suppression pattern. At that time, wakefulness may deteriorate further, and the fontanel may may deteriorate further, and the fontanel may bulge, suggesting increasing cerebral edema. bulge, suggesting increasing cerebral edema.

Irregularities of heart rate and BP are common Irregularities of heart rate and BP are common during the period of reperfusion injury, as is during the period of reperfusion injury, as is death from cardiorespiratory failuredeath from cardiorespiratory failure

InterventionIntervention Brain injury begins with the hypoxic-Brain injury begins with the hypoxic-

ischemic event and evolves after ischemic event and evolves after resuscitation resuscitation interval of several hours after resuscitation interval of several hours after resuscitation

when therapies might be applied to lessen the when therapies might be applied to lessen the severity of the evolving brain damage.severity of the evolving brain damage.

HIE is a progressive syndromeHIE is a progressive syndrome Initially show transient recovery with a Initially show transient recovery with a

secondary failure of cerebral energy secondary failure of cerebral energy metabolism 6-15 hours after birth. metabolism 6-15 hours after birth.

The severity of this second deterioration is The severity of this second deterioration is highly predictive of neurodevelopmental highly predictive of neurodevelopmental outcome at 1-4 years of age.outcome at 1-4 years of age.

Therapies, to be effective, Therapies, to be effective, must be applied in this must be applied in this latent latent phase phase of the disease in order of the disease in order to modulate long term to modulate long term outcomeoutcome

ManagementManagement Prevention, prevention, prevention !!!Prevention, prevention, prevention !!! Ensure physiological oxygen & CO2 levels Ensure physiological oxygen & CO2 levels

- hyperoxia causes - hyperoxia causes ↓↓ in CBF or exacerbate free radical in CBF or exacerbate free radical damagedamage- hypercapnia causes cerebral vasodilation- hypercapnia causes cerebral vasodilation- hypocapnia can decrease CBF- hypocapnia can decrease CBF

Acid-base balanceAcid-base balance Maintain environmental temp and humidityMaintain environmental temp and humidity Correct caloric, fluid and electrolyte Correct caloric, fluid and electrolyte

disturbancesdisturbances- watch for hypoglycemia & hypocalcemia- watch for hypoglycemia & hypocalcemia

SeizuresSeizures- treated with phenobarb, phenytoin or lorazepam- treated with phenobarb, phenytoin or lorazepam

Newer modalitiesNewer modalities

Antagonists of excitotoxic Antagonists of excitotoxic neurotransmitter receptors neurotransmitter receptors

- NMDA receptor blockers- NMDA receptor blockers Free radical inhibitors / scavengersFree radical inhibitors / scavengers

- vitamin E, superoxide dismutase- vitamin E, superoxide dismutase Ca channel blockersCa channel blockers Nitric oxide synthetase inhibitorsNitric oxide synthetase inhibitors HypothermiaHypothermia

Hypothermia as a Hypothermia as a Treatment for HIETreatment for HIE

Studies have shown that hypoxic Studies have shown that hypoxic ischemic injury can be reduced by brain ischemic injury can be reduced by brain cooling.cooling.

Favorable effect on many of the pathways Favorable effect on many of the pathways contributing to brain injurycontributing to brain injury Excitatory amino acidsExcitatory amino acids Cerebral energy stateCerebral energy state Cerebral blood flow and metabolismCerebral blood flow and metabolism Nitric oxide production Nitric oxide production ApoptosisApoptosis

Mechanism of ActionMechanism of ActionHypothermia modulates all these areas in the cascade of neuronal damage and death

Hypothermia acts to:- Block NMDA

activation- Decrease

neurotransmitter release

- Limit formation and activity of nitric oxide

- Decrease depletion of ATP stores

* N-methyl-D-aspartic acid

Cooling for newborns Cooling for newborns with hypoxic ischaemic with hypoxic ischaemic

encephalopathy encephalopathy The standard search strategy of the Neonatal The standard search strategy of the Neonatal Review Group as outlined in the Cochrane Review Group as outlined in the Cochrane Library (Issue 2, 2003) was used.Library (Issue 2, 2003) was used.

Randomised controlled trials evaluating Randomised controlled trials evaluating therapeutic hypothermia in term newborns with therapeutic hypothermia in term newborns with hypoxic ischaemic encephalopathy were hypoxic ischaemic encephalopathy were identified by searching identified by searching the Oxford Database of Perinatal Trials, the Oxford Database of Perinatal Trials, the Cochrane Central Register of Controlled Trials the Cochrane Central Register of Controlled Trials

(CENTRAL, The Cochrane Library Issue Issue 2, (CENTRAL, The Cochrane Library Issue Issue 2, 2003),2003),

MEDLINE (1966 to July 2003), MEDLINE (1966 to July 2003), previous reviews including cross-references, previous reviews including cross-references,

abstracts, conferences, symposia proceedings, expert abstracts, conferences, symposia proceedings, expert informants and journal hand searching. informants and journal hand searching.

Selection criteriaSelection criteria Randomised controlled trials comparing Randomised controlled trials comparing

the use of therapeutic hypothermia with the use of therapeutic hypothermia with normothermia in encephalopathic newborn normothermia in encephalopathic newborn infants with evidence of peripartum infants with evidence of peripartum asphyxia and without recognisable major asphyxia and without recognisable major congenital anomalies were included. congenital anomalies were included.

The primary outcome measure was death The primary outcome measure was death or long-term major neurodevelopmental or long-term major neurodevelopmental disability. disability.

Other outcomes included adverse effects of Other outcomes included adverse effects of cooling and 'early' indicators of cooling and 'early' indicators of neurodevelopmental outcome. neurodevelopmental outcome.

Main resultsMain results Two randomised controlled trials were Two randomised controlled trials were

included in this review, comprising 50 term included in this review, comprising 50 term infants with moderate/ severe infants with moderate/ severe encephalopathy and evidence of intrapartum encephalopathy and evidence of intrapartum asphyxia. asphyxia.

There was no significant effect of therapeutic There was no significant effect of therapeutic hypothermia on the combined outcome of hypothermia on the combined outcome of death or major neurodevelopmental disability death or major neurodevelopmental disability in survivors followed. in survivors followed.

No adverse effects of hypothermia on short No adverse effects of hypothermia on short term medical outcomes or on some 'early' term medical outcomes or on some 'early' indicators of neurodevelopmental outcome indicators of neurodevelopmental outcome were detected.were detected.

Data collection & Data collection & analysisanalysis

Three reviewers independently selected, Three reviewers independently selected, assessed the quality of and extracted assessed the quality of and extracted data from the included studies. data from the included studies.

Authors were contacted for further Authors were contacted for further information. information.

Meta-analyses were performed using Meta-analyses were performed using relative risk and risk difference for relative risk and risk difference for dichotomous data, and weighted mean dichotomous data, and weighted mean difference for continuous data with 95% difference for continuous data with 95% confidence intervals. confidence intervals.

Reviewers' conclusionsReviewers' conclusions

Although two small randomised controlled Although two small randomised controlled trials demonstrated neither evidence of trials demonstrated neither evidence of benefit or harm, current evidence is benefit or harm, current evidence is inadequate to assess either safety or inadequate to assess either safety or efficacy of therapeutic hypothermia in efficacy of therapeutic hypothermia in newborn infants with hypoxic ischaemic newborn infants with hypoxic ischaemic encephalopathy. encephalopathy.

Therapeutic hypothermia for Therapeutic hypothermia for encephalopathic asphyxiated newborn encephalopathic asphyxiated newborn infants should be further evaluated in well infants should be further evaluated in well designed randomised controlled trials. designed randomised controlled trials.

Hypothermia and Hypothermia and perinatal perinatal asphyxia:asphyxia:

Executive summary Executive summary of the National of the National

Institute of Child Institute of Child Health and Human Health and Human

Development Development (NICHD) workshop(NICHD) workshop

Journal of Pediatrics. Vol 148 (2). Feb Journal of Pediatrics. Vol 148 (2). Feb 20062006

NICHD held a workshop on hypothermia as a NICHD held a workshop on hypothermia as a potential treatment modality for perinatal potential treatment modality for perinatal hypoxic-ischemic encephalopathy (HIE) in May hypoxic-ischemic encephalopathy (HIE) in May 2005. 2005. A panel of experts summarized the current evidence A panel of experts summarized the current evidence

on the efficacy and safety of hypothermia and on the efficacy and safety of hypothermia and reviewed knowledge gaps. reviewed knowledge gaps.

The panel concluded that The panel concluded that mild, therapeutic mild, therapeutic hypothermiahypothermia offered a potential for offered a potential for short-term short-term benefits (up to 18 months of age)benefits (up to 18 months of age) when used when used under strict experimental protocols in term under strict experimental protocols in term infants. infants. However, these findings have not been tested in However, these findings have not been tested in

preterm infants or severely growth-restricted preterm infants or severely growth-restricted infants with asphyxia. infants with asphyxia.

Many questions still remained about the optimal use Many questions still remained about the optimal use of hypothermia for HIE in term infants, including of hypothermia for HIE in term infants, including the incidence of possible rare, short-, and long-term the incidence of possible rare, short-, and long-term side effects. side effects.

The The longer-term benefitslonger-term benefits in neurodevelopmental in neurodevelopmental outcomes after hypothermia for HIE remain to outcomes after hypothermia for HIE remain to be shown. be shown. Because of these and other reasons, the panel Because of these and other reasons, the panel

concluded that at the current time, therapeutic concluded that at the current time, therapeutic hypothermia for perinatal HIE should be considered hypothermia for perinatal HIE should be considered an evolving therapy, the longer-term safety and an evolving therapy, the longer-term safety and efficacy of which are still to be established. efficacy of which are still to be established.

The panel offered a framework for patient care The panel offered a framework for patient care emphasizing the need for emphasizing the need for standardized protocolsstandardized protocols for treatment and follow-up, including school-for treatment and follow-up, including school-age outcome assessments. age outcome assessments.

Research prioritiesResearch priorities were also recommended. The were also recommended. The panel strongly urged that the ongoing panel strongly urged that the ongoing hypothermia trials should be continued to enable hypothermia trials should be continued to enable assessment of its efficacy and safety. assessment of its efficacy and safety.

It recommended the formation of It recommended the formation of national and national and international HIE registriesinternational HIE registries, so that scientific , so that scientific progress in this field can be assessed progress in this field can be assessed continuously to develop, refine, and optimize continuously to develop, refine, and optimize therapies for HIE. therapies for HIE.

Hypothermia & Hypothermia & NeuroprotectionNeuroprotection

Studies in fetal sheep, neonatal piglets, Studies in fetal sheep, neonatal piglets, rat, and other models showed that:rat, and other models showed that:- brain cooling to about 32° and 34° C - brain cooling to about 32° and 34° C beginning 90 minutes or 5.5 hours after HI injury beginning 90 minutes or 5.5 hours after HI injury - continuing for 48 to 72 hours - continuing for 48 to 72 hours - diminished the extent of parasagittal neuronal damage (the - diminished the extent of parasagittal neuronal damage (the effect of cooling was observed in other regions of brain as well).effect of cooling was observed in other regions of brain as well).

Improved neurologic outcomes were confirmed by use Improved neurologic outcomes were confirmed by use of quantitative neuropathologic methods, imaging of quantitative neuropathologic methods, imaging studies, and tests of learning and memory functions.studies, and tests of learning and memory functions.

Conclusions from the Conclusions from the animal studiesanimal studies

Brain cooling should be initiated as early as feasible Brain cooling should be initiated as early as feasible after the brain injury, preferably within 2 hours, but after the brain injury, preferably within 2 hours, but not later than 6 hoursnot later than 6 hours

Rectal temperature should be reduced to between Rectal temperature should be reduced to between 32° to 34° C for effective brain cooling with whole-32° to 34° C for effective brain cooling with whole-body hypothermiabody hypothermia

Smaller reductions in rectal temperature (34°-35° C) Smaller reductions in rectal temperature (34°-35° C) may be needed for head coolingmay be needed for head cooling

Cooling should be continued for about 48 to 72 Cooling should be continued for about 48 to 72 hourshours

Slow rewarmingSlow rewarming optimal methods for rewarming were not tested in optimal methods for rewarming were not tested in

newborn animals, adult animal studies indicated that slow newborn animals, adult animal studies indicated that slow rewarming was to be preferred.rewarming was to be preferred.

Translating the Translating the results of animal results of animal studies to human studies to human

trialstrials Many limitations had to be noted before Many limitations had to be noted before

extrapolating the potentially beneficial effects extrapolating the potentially beneficial effects seen in animal models of HIE and seen in animal models of HIE and hypothermia to human HIE. hypothermia to human HIE.

In human beings, HIE is not a single disease In human beings, HIE is not a single disease entity, but a condition resulting from diverse entity, but a condition resulting from diverse causes manifesting signs of brain injury at causes manifesting signs of brain injury at different phases of its evolution. different phases of its evolution.

The cause(s) of HIE is rarely obvious, and the The cause(s) of HIE is rarely obvious, and the timing, nature, or severity of the HI injury is timing, nature, or severity of the HI injury is almost never known.almost never known.

The The underlying status of the human brainunderlying status of the human brain, such , such as its maturity, nutritional and hormonal status, as its maturity, nutritional and hormonal status, inflammatory, and preexisting developmental inflammatory, and preexisting developmental abnormalities may alter the responses to acute abnormalities may alter the responses to acute insults.insults.

Moreover, one can only offer therapy for HIE in Moreover, one can only offer therapy for HIE in human infants at a human infants at a known postnatal ageknown postnatal age - not - not after a known interval from brain injury. after a known interval from brain injury.

However, in only about 25% of HIE cases can one However, in only about 25% of HIE cases can one discern signs of a discern signs of a sentinel eventsentinel event in the in the peripartum period indicating the time of injury. peripartum period indicating the time of injury.

There is There is considerable variabilityconsiderable variability in the neuronal in the neuronal (and other brain cellular) responses to HI injury (and other brain cellular) responses to HI injury and to hypothermia among the experimental and to hypothermia among the experimental species, and in human infants. species, and in human infants.

Thus one cannot determine with precision how Thus one cannot determine with precision how late after an ischemic injury one can provide late after an ischemic injury one can provide cooling and still expect neuroprotection.cooling and still expect neuroprotection.

Initial Pilot TrialsInitial Pilot Trials In 1955, Westin et alIn 1955, Westin et al showed that hypothermia was showed that hypothermia was

beneficial in perinatal asphyxia. beneficial in perinatal asphyxia. However, systematic pilot studies were not done However, systematic pilot studies were not done

until Gunn et al,until Gunn et al, Azzopardi et al,Azzopardi et al, and Thoresen and and Thoresen and WhitelawWhitelaw described simple approaches to cooling described simple approaches to cooling the head and the whole body for up to 72 hours the head and the whole body for up to 72 hours without serious, short-term adverse effects. without serious, short-term adverse effects. Findings from these studies showed that although Findings from these studies showed that although

bradycardia occurred commonly, other acute bradycardia occurred commonly, other acute complications, such as severe hypotension, acute complications, such as severe hypotension, acute deterioration in pulmonary function, increased rates of deterioration in pulmonary function, increased rates of infection, or imbalances in blood viscosity, electrolytes, infection, or imbalances in blood viscosity, electrolytes, and clotting did not occur with mild therapeutic and clotting did not occur with mild therapeutic hypothermia for 72 hours. hypothermia for 72 hours.

Shankaran et al also confirmed the feasibility of Shankaran et al also confirmed the feasibility of providing whole-body cooling for 72 hours without providing whole-body cooling for 72 hours without major short-term complications.major short-term complications.

In a pilot study of whole-body cooling to a In a pilot study of whole-body cooling to a rectal temperature of 33° ± 0.5° C for 48 rectal temperature of 33° ± 0.5° C for 48 hours in infants with severe HIE, Eicher et al hours in infants with severe HIE, Eicher et al reported a higher incidence of bradycardia reported a higher incidence of bradycardia and a greater use of inotropic agents during and a greater use of inotropic agents during cooling in the hypothermia group (n = 33) cooling in the hypothermia group (n = 33) compared with in the control subjects (n = compared with in the control subjects (n = 32). 32).

The hypothermia group also had longer The hypothermia group also had longer prothrombin times and lower platelet counts prothrombin times and lower platelet counts than the control subjects, but all of the than the control subjects, but all of the values were within normal range.values were within normal range.

Thus the cumulative evidence from Thus the cumulative evidence from numerous animal studies and the reassuring numerous animal studies and the reassuring conclusions about the short-term safety and conclusions about the short-term safety and feasibility of providing therapeutic feasibility of providing therapeutic hypothermia in human infants led to the hypothermia in human infants led to the development of larger randomized controlled development of larger randomized controlled trials.trials.

Hypothermia for Hypothermia for Neonates with Hypoxic-Neonates with Hypoxic-

Ischemic Ischemic EncephalopathyEncephalopathy

Whole Body Hypothermia

Versus

Selective Head Cooling

What’s the difference?What’s the difference? The brain can be cooled by cooling the body, cooling the The brain can be cooled by cooling the body, cooling the

head selectively, or cooling the head and body together. head selectively, or cooling the head and body together. The majority of studies in animals have used whole-body The majority of studies in animals have used whole-body

cooling, but some have used selective head cooling. cooling, but some have used selective head cooling. Whole-body cooling provides homogeneous cooling to all Whole-body cooling provides homogeneous cooling to all

brain structures, including peripheral and central brain brain structures, including peripheral and central brain regions. regions.

Selective head cooling provides greater cooling to the Selective head cooling provides greater cooling to the periphery of the brain than to the central brain structures periphery of the brain than to the central brain structures

Head cooling combined with some body cooling minimizes Head cooling combined with some body cooling minimizes temperature gradients across the brain and facilitates the temperature gradients across the brain and facilitates the cooling of central regions. cooling of central regions.

Given the propensity for hypoxic–ischemic injury to affect Given the propensity for hypoxic–ischemic injury to affect deep-brain structures such as the thalamus, internal deep-brain structures such as the thalamus, internal capsule, and basal ganglia in the human neonate, whole-capsule, and basal ganglia in the human neonate, whole-body cooling may achieve a consistent reduction in brain body cooling may achieve a consistent reduction in brain temperature in such structures.temperature in such structures.

Large Scale Clinical Large Scale Clinical TrialsTrials

First completed multicenter trial (CoolCap) First completed multicenter trial (CoolCap) conducted in 25 centers in New Zealand, Great conducted in 25 centers in New Zealand, Great Britain, and the United StatesBritain, and the United States

234 infants with acute perinatal HIE were enrolled234 infants with acute perinatal HIE were enrolled Criteria for entry:Criteria for entry:

>36 weeks gestation>36 weeks gestation an Apgar score <5 at 10 minutes after birth an Apgar score <5 at 10 minutes after birth oror a continued need for resuscitation at 10 minutes a continued need for resuscitation at 10 minutes

after birthafter birth oror a pH <7.0 or base deficit > 16 mmol/L in the a pH <7.0 or base deficit > 16 mmol/L in the

umbilical blood or venous blood sample within 60 umbilical blood or venous blood sample within 60 minutes of birthminutes of birth

andand a modified Sarnat score a modified Sarnat score andand amplitude-integrated EEG (aEEG) criteria amplitude-integrated EEG (aEEG) criteria

consistent with a diagnosis of moderate to severe HIEconsistent with a diagnosis of moderate to severe HIE

CoolCapCoolCap

Infants in the experimental group (n Infants in the experimental group (n = 116) received selective head = 116) received selective head cooling with mild systemic cooling with mild systemic hypothermia induced with a cooling hypothermia induced with a cooling cap device in which cold water was cap device in which cold water was circulated. circulated.

The rectal temperature was The rectal temperature was maintained between 34° to 35° C for maintained between 34° to 35° C for 72 hours, and the infants were 72 hours, and the infants were rewarmed at a rate <0.5° C per rewarmed at a rate <0.5° C per hour. hour.

Conventional intensive care with Conventional intensive care with normal body temperature was normal body temperature was provided for infants in the control provided for infants in the control group.group.

CoolCap - ResultsCoolCap - Results Children followed-up for 18 monthsChildren followed-up for 18 months 50% of cooled infants had unfavorable primary 50% of cooled infants had unfavorable primary

outcomes (death or severe neurologic disability) outcomes (death or severe neurologic disability) while 2/3 of control group had unfavorable while 2/3 of control group had unfavorable outcomes.outcomes.

Overall no statistically significant improvement Overall no statistically significant improvement between cooled group and control, however…between cooled group and control, however…

When controlling for most severely effected it was When controlling for most severely effected it was found that selective head cooling of those with found that selective head cooling of those with moderate HIE there was a significant difference moderate HIE there was a significant difference between the study group and the controls.between the study group and the controls.

The collaborative group suggested that selective The collaborative group suggested that selective head cooling of those infants with moderate HIE head cooling of those infants with moderate HIE was likely to be beneficial in the reduction of was likely to be beneficial in the reduction of neurodevelopmental disability. neurodevelopmental disability.

Second large Second large randomised randomised controlled controlled

clinical trial - clinical trial - Whole-Body Whole-Body HypothermiaHypothermiaShankaran et alShankaran et al

208 infants from 16 Neonatal Research Network 208 infants from 16 Neonatal Research Network centers randomized within 6 hours after birthcenters randomized within 6 hours after birth

Infants in hypothermia group placed on 2 cooling Infants in hypothermia group placed on 2 cooling blankets and esophageal temperatures were kept blankets and esophageal temperatures were kept at 33.5at 33.5o o C for 72 hours.C for 72 hours.

Eligibility criteria included:Eligibility criteria included: gestational age ≥ 36 weeks, gestational age ≥ 36 weeks, a pH of 7.0 or less or a base deficit of 16 mmol/L or a pH of 7.0 or less or a base deficit of 16 mmol/L or

more more in a sample of umbilical cord blood or any blood during the first in a sample of umbilical cord blood or any blood during the first

hour after birth. hour after birth. If, during this interval, pH was between 7.01 and 7.15, a If, during this interval, pH was between 7.01 and 7.15, a

base deficit was between 10 and 15.9 mmol/L, or a blood base deficit was between 10 and 15.9 mmol/L, or a blood gas level was not available, additional criteria were gas level was not available, additional criteria were required. required.

These included an acute perinatal event and either a 10-minute These included an acute perinatal event and either a 10-minute Apgar score of 5 or less or assisted ventilation initiated at birth Apgar score of 5 or less or assisted ventilation initiated at birth and continued for at least 10 minutes.and continued for at least 10 minutes.

Same eligibility criteria were used for this study Same eligibility criteria were used for this study as the as the cool cap study, however no AEEG was used. cool cap study, however no AEEG was used.

All surviving infants were followed up between All surviving infants were followed up between 18-22 months of age with developmental 18-22 months of age with developmental assessments. Growth, vision, and hearing assessments. Growth, vision, and hearing characteristics were obtained and neurologic characteristics were obtained and neurologic and developmental testing was performed. and developmental testing was performed.

Cognitive outcome was assessed with the use of Cognitive outcome was assessed with the use of Bayley scales of infantile development.Bayley scales of infantile development.

Significant differences were not found in rates Significant differences were not found in rates of mental retardation, blindness, hearing of mental retardation, blindness, hearing deficits, or cerebral palsy. This evidence deficits, or cerebral palsy. This evidence suggests that hypothermia did not cause an suggests that hypothermia did not cause an increased rate disability amongst survivors.increased rate disability amongst survivors.

Death or moderate/severe disability occurred in:Death or moderate/severe disability occurred in: 44% (45/102) of the hypothermia group 44% (45/102) of the hypothermia group 62% (64/103) of the control group 62% (64/103) of the control group

Mortality rate Mortality rate 24% in the hypothermia group 24% in the hypothermia group 37% in the control group37% in the control group

For the hypothermia group versus the control For the hypothermia group versus the control group, respectively the risk of group, respectively the risk of disabling cerebral palsy was 19.2% and 30.0%disabling cerebral palsy was 19.2% and 30.0% blindness 7% versus 14% blindness 7% versus 14% hearing impairment requiring a hearing aid was 4% hearing impairment requiring a hearing aid was 4%

and 6%and 6% The frequency of adverse event rates during The frequency of adverse event rates during

cooling was similar: cooling was similar: 19% in the hypothermia group 19% in the hypothermia group 15% in the control group15% in the control group

OTHER OTHER ONGOING ONGOING

TRIALSTRIALS TOBYTOBY ICEICE

Total Body Cooling Trial Total Body Cooling Trial (TOBY)(TOBY) EnglandEngland Infants with moderate-to-severe HIE are randomized to Infants with moderate-to-severe HIE are randomized to

receive whole-body cooling or standard intensive care. receive whole-body cooling or standard intensive care. Thus far, 206 of the planned 239 (86%) infants (as of Thus far, 206 of the planned 239 (86%) infants (as of

January 26, 2006) have been enrolled, and the study is January 26, 2006) have been enrolled, and the study is continuing. continuing.

The trial design features and the entry criteria for the The trial design features and the entry criteria for the TOBY trial are similar to those of the CoolCap trial.TOBY trial are similar to those of the CoolCap trial.

Thus, upon completion, the findings from the TOBY Thus, upon completion, the findings from the TOBY trial can be effectively compared with those of CoolCap trial can be effectively compared with those of CoolCap to assess the relative benefits from whole-body versus to assess the relative benefits from whole-body versus selective head cooling in HIE. selective head cooling in HIE.

Such comparisons would be of great value, since these Such comparisons would be of great value, since these trials will constitute 2 of the largest cohorts of infants trials will constitute 2 of the largest cohorts of infants studied under an identical enrollment protocol.studied under an identical enrollment protocol.

ICE (Infant Cooling ICE (Infant Cooling Evaluation)Evaluation)

15 participating centers in Australia, New 15 participating centers in Australia, New Zealand, and Canada in this ongoing trial. Zealand, and Canada in this ongoing trial.

The trial aims to enroll infants from a wide The trial aims to enroll infants from a wide geographic region, using simplified protocols.geographic region, using simplified protocols.

Hypothermia is achieved by turning off the Hypothermia is achieved by turning off the ambient heating systems and by applying ambient heating systems and by applying “Hot-Cold” gel packs (at 10° C) around the “Hot-Cold” gel packs (at 10° C) around the infant’s head and over the chest, so that the infant’s head and over the chest, so that the rectal temperature is reduced to 33° to 34° C. rectal temperature is reduced to 33° to 34° C.

After demonstrating the feasibility of this After demonstrating the feasibility of this approach in 17 infants, the investigators have approach in 17 infants, the investigators have enrolled 96 of the planned 276 infants fromenrolled 96 of the planned 276 infants from

Major Gaps in Major Gaps in KnowledgeKnowledge

In spite of rapidly accumulating clinical and In spite of rapidly accumulating clinical and laboratory data related to hypothermia as a laboratory data related to hypothermia as a neuroprotective strategy for HIE, the speakers neuroprotective strategy for HIE, the speakers and discussants at the workshop underscored and discussants at the workshop underscored numerous gaps in knowledge in this field. numerous gaps in knowledge in this field.

They noted that with only 2 completed studies They noted that with only 2 completed studies providing information on follow-up for only up to providing information on follow-up for only up to 18 months of age, the longer-term impact of 18 months of age, the longer-term impact of hypothermia for HIE remains unknown. This, they hypothermia for HIE remains unknown. This, they concluded, should lead to an overall measure of concluded, should lead to an overall measure of caution in applying the new therapy of caution in applying the new therapy of hypothermia indiscriminately for all cases of HIE. hypothermia indiscriminately for all cases of HIE.

Is It Safe?Is It Safe?

No significant differences in adverse No significant differences in adverse events between control and events between control and hypothermic infants in either large hypothermic infants in either large trial.trial.

More studies need to be conducted More studies need to be conducted before widespread applicability and before widespread applicability and safety can be ascertained.safety can be ascertained.

Late at night, and without permission, Reuben would often enter the nursery and perform

experiments in static electricity.

Adverse effectsAdverse effects Electrolyte & Renal DysfunctionElectrolyte & Renal Dysfunction

metabolic derangements metabolic derangements metabolic acidosis metabolic acidosis

Renal dysfunction Renal dysfunction Cardiac adverse eventsCardiac adverse events

Bradycardia Bradycardia Significantly lower mean blood pressures Significantly lower mean blood pressures Cardiac echocardiograms indicated worsening Cardiac echocardiograms indicated worsening

right ventricular function in two hypothermia right ventricular function in two hypothermia patients. patients.

Greater and longer cardiac inotropic support Greater and longer cardiac inotropic support was required in the hypothermia group was required in the hypothermia group compared with the normothermia group compared with the normothermia group

Coagulopathy & ThrombocytopeniaCoagulopathy & Thrombocytopenia required plasma and platelet transfusions required plasma and platelet transfusions

than normothermia patientsthan normothermia patients Mean lowest platelet counts were Mean lowest platelet counts were

significantly lower in the hypothermia significantly lower in the hypothermia groupgroup

The median highest prothrombin time The median highest prothrombin time values were significantly higher in the values were significantly higher in the hypothermia grouphypothermia group

However, clinical manifestations of However, clinical manifestations of coagulopathy were uncommon. coagulopathy were uncommon.

Pulmonary HypertensionPulmonary Hypertension Pulmonary vascular resistance has been Pulmonary vascular resistance has been

demonstrated to be increased with demonstrated to be increased with hypothermia, but may also be present under hypothermia, but may also be present under normothermic conditions after hypoxic-normothermic conditions after hypoxic-ischemia. ischemia.

Although pulmonary vascular resistance cannot Although pulmonary vascular resistance cannot be measured directly in neonates, nitric oxide be measured directly in neonates, nitric oxide treatment and extracorporeal membrane treatment and extracorporeal membrane oxygenation are surrogate measures of the oxygenation are surrogate measures of the severity of pulmonary hypertension severity of pulmonary hypertension

Significantly more hypothermia patients Significantly more hypothermia patients required nitric oxide than normothermia required nitric oxide than normothermia patients, but only one normothermic patient patients, but only one normothermic patient required extracorporeal membrane required extracorporeal membrane oxygenation as an adverse eventoxygenation as an adverse event

Other Significant Other Significant Adverse EventsAdverse Events

Seizures Seizures significantly more common in the hypothermia group as an significantly more common in the hypothermia group as an

adverse event than in the normothermia group adverse event than in the normothermia group For this variable, all infants who had not seized before or For this variable, all infants who had not seized before or

during enrollment were considered to have the adverse during enrollment were considered to have the adverse event of seizures, which were largely clinically identified, as event of seizures, which were largely clinically identified, as continuous electroencephalographic recording was not continuous electroencephalographic recording was not routinely performed. routinely performed.

There was also a trend toward more abnormal There was also a trend toward more abnormal electroencephalograms at 72 hours in the hypothermia electroencephalograms at 72 hours in the hypothermia groupgroup

StridorStridor more common, perhaps related to reduced ventilator more common, perhaps related to reduced ventilator

temperature of humidified air. temperature of humidified air. This condition may have increased the transient tracheal This condition may have increased the transient tracheal

swelling after extubation, but stridor was quickly dispelled swelling after extubation, but stridor was quickly dispelled with inhalation of racemic epinephrine, and no infant with inhalation of racemic epinephrine, and no infant required reintubation because of stridor.required reintubation because of stridor.

Moderate Moderate hypothermia in hypothermia in

neonatal neonatal encephalopathy: encephalopathy: Safety outcomes Safety outcomes Pediatric NeurologyPediatric Neurology, , Vol 32 (1) Vol 32 (1)

January 2005January 2005

Multicenter, randomized, controlled pilot trial of Multicenter, randomized, controlled pilot trial of moderate systemic hypothermia (33°C) vs moderate systemic hypothermia (33°C) vs normothermia (37°C) for 48 hours in infants with normothermia (37°C) for 48 hours in infants with neonatal encephalopathy instituted within 6 hours neonatal encephalopathy instituted within 6 hours of birth or hypoxic-ischemic event. of birth or hypoxic-ischemic event.

A total of 32 hypothermia and 33 normothermia A total of 32 hypothermia and 33 normothermia neonates were enrolled in seven centers. neonates were enrolled in seven centers.

Adverse events observed were significantly more Adverse events observed were significantly more commonly in the hypothermia group: commonly in the hypothermia group: more frequent bradycardia and lower heart rates during more frequent bradycardia and lower heart rates during

the period of hypothermiathe period of hypothermia longer dependence on pressorslonger dependence on pressors higher prothrombin timeshigher prothrombin times lower platelet counts with more patients requiring lower platelet counts with more patients requiring

plasma and platelet transfusions. plasma and platelet transfusions. Seizures as an adverse event were more common in the Seizures as an adverse event were more common in the

hypothermia group. hypothermia group. These observed side effects of 48 hours of These observed side effects of 48 hours of

moderate systemic hypothermia were of mild to moderate systemic hypothermia were of mild to moderate severity and manageable with minor moderate severity and manageable with minor interventions. interventions.

Unresolved Unresolved issuesissues

1. Implementing 1. Implementing hypothermia for HIEhypothermia for HIE

lackslacks long term safety and efficacy datalong term safety and efficacy data (at the present (at the present time)time) Institutions choosing to offer hypothermia should implement Institutions choosing to offer hypothermia should implement

studied and reported protocols from existing or ongoing trials, and studied and reported protocols from existing or ongoing trials, and incorporate longer-term follow up plans. incorporate longer-term follow up plans.

knowledge gaps, uncertain longer term outcomeknowledge gaps, uncertain longer term outcome parents of infants with HIE offered hypothermia should be parents of infants with HIE offered hypothermia should be

appropriately appraisedappropriately appraised National and international registriesNational and international registries

need to be organized for ongoing assessment of the global burden need to be organized for ongoing assessment of the global burden of HIE, its treatment and outcomes.of HIE, its treatment and outcomes.

International interest groupsInternational interest groups of scientists, practitioners, and others involved in public policy of scientists, practitioners, and others involved in public policy

need to be formed for continued evaluation of accumulating need to be formed for continued evaluation of accumulating evidenceevidence

Countries with limited resourcesCountries with limited resources the role of therapeutic hypothermia in HIE for children born in the role of therapeutic hypothermia in HIE for children born in

these countries needs to be studied in the context of regional these countries needs to be studied in the context of regional issues of feasibility, risks and potential benefits. issues of feasibility, risks and potential benefits.

2. Identification of 2. Identification of infants for offering infants for offering

hypothermiahypothermia Value of Value of standardized clinical examinations, scoring standardized clinical examinations, scoring

systemssystems (e.g., modified Sarnat score), and aEEG should (e.g., modified Sarnat score), and aEEG should be studied to assess eligibility for hypothermia.be studied to assess eligibility for hypothermia.

Hypothermia in Hypothermia in premature infantspremature infants, , severe IUGR infants severe IUGR infants has not been studied. has not been studied. although it has been tested in term infants and to a lesser extent although it has been tested in term infants and to a lesser extent

in late preterm, (>35 weeks gestation) infantsin late preterm, (>35 weeks gestation) infants The risk benefit ratio for these infants cannot be assessed at this The risk benefit ratio for these infants cannot be assessed at this

time due to lack of data.time due to lack of data. The The severity of HIEseverity of HIE at which the risk versus benefit ratio at which the risk versus benefit ratio

favors hypothermia remains unknown. favors hypothermia remains unknown. whether developmental outcomes are affected by the type and whether developmental outcomes are affected by the type and

timing of HI injury needs to be studied.timing of HI injury needs to be studied. ““how late is not too latehow late is not too late””

the latest postnatal age at which initiation of therapeutic the latest postnatal age at which initiation of therapeutic hypothermia might still be effective is unknown.hypothermia might still be effective is unknown.

Hypothermia Hypothermia during resuscitation and transferduring resuscitation and transfer needs to needs to be studied.be studied. potential beneficial or deleterious effectpotential beneficial or deleterious effect

3. Cooling and 3. Cooling and rewarmingrewarming

Optimal degree and duration of cooling is unknown Optimal degree and duration of cooling is unknown although it is postulated that deeper, longer, and earlier although it is postulated that deeper, longer, and earlier

therapy with hypothermia is to be preferredtherapy with hypothermia is to be preferred whether the degree and duration of therapy should be whether the degree and duration of therapy should be

based on the cause, severity, stage of brain injury, and based on the cause, severity, stage of brain injury, and the age at starting of hypothermia is unknown.the age at starting of hypothermia is unknown.

Optimal mode of cooling (whole body or selective Optimal mode of cooling (whole body or selective head) is unknownhead) is unknown, , differential protective effects on various regions of the differential protective effects on various regions of the

brain (generalized cortical versus deep brain nuclei), has brain (generalized cortical versus deep brain nuclei), has not been established. not been established.

optimal/safe pace of re-warming is unknown.optimal/safe pace of re-warming is unknown. The frequency of uncommon and rare The frequency of uncommon and rare systemic systemic

side effectsside effects, and the method of monitoring for , and the method of monitoring for these need to be studiedthese need to be studied

4. Long-term outcome4. Long-term outcome Role of Role of MRIMRI or other or other anatomic or functional anatomic or functional

imaging modalitiesimaging modalities in prognosis and during follow-up remains to be in prognosis and during follow-up remains to be

studied.studied. Assessing outcome Assessing outcome

duration of follow-up and the appropriate tests to duration of follow-up and the appropriate tests to assess outcome should be similar so that assess outcome should be similar so that outcomes under differing protocols can be outcomes under differing protocols can be compared. compared.

Longer-term follow-up of infants who Longer-term follow-up of infants who participated in the completed and ongoing participated in the completed and ongoing and future hypothermia trials should be and future hypothermia trials should be strongly supported.strongly supported.

So should we be using So should we be using it?it?

Pediatrics Vol. 117 No. 3 March Pediatrics Vol. 117 No. 3 March 20062006The Committee on Fetus and Newborn concluded that: The Committee on Fetus and Newborn concluded that:

Therapeutic hypothermia should be considered Therapeutic hypothermia should be considered investigational until the short-term safety and efficacy have investigational until the short-term safety and efficacy have been confirmed. Long-term safety and efficacy remain to be been confirmed. Long-term safety and efficacy remain to be defined. defined.

Additional trials are needed that would define the most Additional trials are needed that would define the most effective cooling strategies. effective cooling strategies.

Registries of infants with perinatal Registries of infants with perinatal encephalopathies should be established encephalopathies should be established to facilitate data collection regarding to facilitate data collection regarding diagnoses, treatments, and outcomes. diagnoses, treatments, and outcomes.

Longer-term follow-up at least through Longer-term follow-up at least through early school age is essentialearly school age is essential

Summary & ConclusionsSummary & Conclusions Based on the available data and large knowledge Based on the available data and large knowledge

gaps, hypothermia appears to be a potentially gaps, hypothermia appears to be a potentially promising therapy for HIE, long-term efficacy promising therapy for HIE, long-term efficacy and safety are yet to be established. and safety are yet to be established.

Clinicians choosing to offer this treatment Clinicians choosing to offer this treatment should therefore understand all of the should therefore understand all of the limitations of the available evidence, be limitations of the available evidence, be prepared to keep up-to-date on evidence on this prepared to keep up-to-date on evidence on this topic as it evolves, and counsel parents and topic as it evolves, and counsel parents and family about the limitations of the current family about the limitations of the current evidence.evidence.

Thank You!

Selective head Selective head cooling cooling

with mild systemic with mild systemic hypothermia hypothermia after neonatal after neonatal

encephalopathy: encephalopathy: multicentre multicentre

randomised trial randomised trial

Journal of Pediatrics Vol 147 No. 1 Journal of Pediatrics Vol 147 No. 1 July 2005July 2005

Objective Objective To determine the efficacy of selective head cooling with mild systemic To determine the efficacy of selective head cooling with mild systemic

hypothermia on survival free of severe disability at 18 months of age in hypothermia on survival free of severe disability at 18 months of age in newborn infants with moderate or severe hypoxic-ischemic encephalopathy.newborn infants with moderate or severe hypoxic-ischemic encephalopathy.

Design Design Multi-center, international, unmasked, randomized controlled trial.Multi-center, international, unmasked, randomized controlled trial. Setting Twenty-five perinatal centers in the United States, United Kingdom, Setting Twenty-five perinatal centers in the United States, United Kingdom,

New Zealand, and CanadaNew Zealand, and Canada Enrolled term newborn infants of at least 36 weeks gestation (n=234) with Enrolled term newborn infants of at least 36 weeks gestation (n=234) with

clinical evidence of moderate to severe neonatal encephalopathy (based on clinical evidence of moderate to severe neonatal encephalopathy (based on modified Sarnat criteria) and/or seizures, modified Sarnat criteria) and/or seizures, andand clinical evidence of perinatal clinical evidence of perinatal hypoxia-ischemia (Apgar score of 5 or less at 10 minutes, continued hypoxia-ischemia (Apgar score of 5 or less at 10 minutes, continued resuscitation or respiratory support at 10 minutes, or severe acidosis within resuscitation or respiratory support at 10 minutes, or severe acidosis within one hour of birth) one hour of birth) andand with moderately or severely abnormal background with moderately or severely abnormal background activity or seizures on amplitude integrated electroencephalography (aEEG).activity or seizures on amplitude integrated electroencephalography (aEEG).

InterventionsInterventions Infants were randomly assigned within 6 hours of birth to either head Infants were randomly assigned within 6 hours of birth to either head

cooling (cooling cap with water circulated at 8-12°C [Olympic Medical Cool cooling (cooling cap with water circulated at 8-12°C [Olympic Medical Cool Care System]) with concomitant mild systemic hypothermia (rectal Care System]) with concomitant mild systemic hypothermia (rectal temperature 34-35°C) for 72 hours, or to conventional care (rectal temperature 34-35°C) for 72 hours, or to conventional care (rectal temperature 36.8-37.2°C).temperature 36.8-37.2°C).

Main OutcomeMain Outcome Primary outcome was death or severe disability at 18 months of age.Primary outcome was death or severe disability at 18 months of age. Secondary outcomes consisted of potential adverse effects of cooling and Secondary outcomes consisted of potential adverse effects of cooling and

complications of hypoxia-ischemia including death, arrhythmia, complications of hypoxia-ischemia including death, arrhythmia, coagulopathy, hypotension, abnormal renal function, electrolyte disturbance, coagulopathy, hypotension, abnormal renal function, electrolyte disturbance, bone marrow depression, raised liver enzymes, and metabolic acidosis.bone marrow depression, raised liver enzymes, and metabolic acidosis.

ResultsResults Baseline clinical and aEEG characteristics were similar in the Baseline clinical and aEEG characteristics were similar in the

two groups. In the 218 (93%) infants followed to 18 months, two groups. In the 218 (93%) infants followed to 18 months, there was no significant difference in the primary outcome of there was no significant difference in the primary outcome of death or severe disability in the infants treated with hypothermia death or severe disability in the infants treated with hypothermia (unadjusted: 55% vs 66%, P=0.10, OR 0.61 [95% CI 0.34-1.09]; (unadjusted: 55% vs 66%, P=0.10, OR 0.61 [95% CI 0.34-1.09]; adjusted [for baseline aEEG amplitude, presence of seizures, and adjusted [for baseline aEEG amplitude, presence of seizures, and age at randomization]: P=0.05, OR 0.57 [95% CI 0.32-1.01]), or age at randomization]: P=0.05, OR 0.57 [95% CI 0.32-1.01]), or on any secondary outcome measures.on any secondary outcome measures.

Two predefined subgroup analyses based on pre-randomization Two predefined subgroup analyses based on pre-randomization background aEEG amplitude abnormalities demonstrated: a) no background aEEG amplitude abnormalities demonstrated: a) no apparent effect of delayed cerebral hypothermia on outcome in apparent effect of delayed cerebral hypothermia on outcome in infants with severe aEEG abnormalities (n=46: 79% vs 68%, infants with severe aEEG abnormalities (n=46: 79% vs 68%, P=0.51, OR 1.8 [95% CI 0.49-6.4]), and b) benefit in infants with P=0.51, OR 1.8 [95% CI 0.49-6.4]), and b) benefit in infants with intermediate (moderate) aEEG abnormalities (n=172: 48% vs intermediate (moderate) aEEG abnormalities (n=172: 48% vs 58%, P=0.021, OR 0.47 [95% CI 0.26-0.87]; adjusted P=0.009, 58%, P=0.021, OR 0.47 [95% CI 0.26-0.87]; adjusted P=0.009, OR 0.42 [95% CI 0.22-0.88]) and the number needed to treat was OR 0.42 [95% CI 0.22-0.88]) and the number needed to treat was six infants (95% CI 3-27).six infants (95% CI 3-27).

Conclusions Conclusions Selective head cooling with mild systemic hypothermia is a Selective head cooling with mild systemic hypothermia is a

feasible therapeutic maneuver without clear-cut evidence of feasible therapeutic maneuver without clear-cut evidence of benefit in selected infants with moderate or severe hypoxic-benefit in selected infants with moderate or severe hypoxic-ischemic encephalopathy. It may, however, improve the outcome ischemic encephalopathy. It may, however, improve the outcome for encephalopathic newborn infants with intermediate for encephalopathic newborn infants with intermediate (moderate) abnormality on aEEG background amplitude.(moderate) abnormality on aEEG background amplitude.

Treatment of Term Treatment of Term Infants With Head Infants With Head Cooling and Mild Cooling and Mild

Systemic Systemic Hypothermia Hypothermia

(35.0°C and 34.5°C) (35.0°C and 34.5°C) After Perinatal After Perinatal

Asphyxia Asphyxia

PEDIATRICS Vol. 111 No. 2 PEDIATRICS Vol. 111 No. 2 February 2003February 2003

Modest Hypothermia as a Modest Hypothermia as a Neuroprotective Strategy in Neuroprotective Strategy in

High-Risk Term Infants High-Risk Term Infants Clinics in PerinatologyClinics in Perinatology

Volume 33 • Number 1 • March 2006Volume 33 • Number 1 • March 2006

Hypothermia: A Hypothermia: A Neuroprotective Therapy for Neuroprotective Therapy for Neonatal Hypoxic-Ischemic Neonatal Hypoxic-Ischemic

Encephalopathy Encephalopathy PEDIATRICS Vol. 117 No. 3 March PEDIATRICS Vol. 117 No. 3 March

2006, pp. 942-9482006, pp. 942-948

Selective Head Selective Head Cooling in Cooling in

Newborn Infants Newborn Infants After Perinatal After Perinatal

Asphyxia: Asphyxia: A Safety StudyA Safety Study

Pediatrics Vol. 102 (4) Pediatrics Vol. 102 (4) October 1998October 1998

University of Auckland, Auckland, New University of Auckland, Auckland, New Zealand.Zealand.

Study group infants 37 weeks' gestation, who Study group infants 37 weeks' gestation, who had an umbilical artery pH 7.09 or Apgars 6 had an umbilical artery pH 7.09 or Apgars 6 at 5 minutes, plus evidence of encephalopathy. at 5 minutes, plus evidence of encephalopathy.

Infants were randomized to either:Infants were randomized to either: no cooling (controls; rectal no cooling (controls; rectal

temperature = 37.0 ± 0.2°C, temperature = 37.0 ± 0.2°C, nn = 10)  = 10) or sequentially, either minimal systemic cooling or sequentially, either minimal systemic cooling

(rectal temperature = 36.3 ± 0.2°C, (rectal temperature = 36.3 ± 0.2°C, nn = 6) = 6) or mild systemic cooling (rectal or mild systemic cooling (rectal

temperature = 35.7 ± 0.2°C, temperature = 35.7 ± 0.2°C, nn = 6). = 6). Head cooling was accomplished by circulating Head cooling was accomplished by circulating

water at 10°C through a coil of tubing wrapped water at 10°C through a coil of tubing wrapped around the head for up to 72 hours. around the head for up to 72 hours.

All infants were warmed by servo-controlled All infants were warmed by servo-controlled overhead heaters to maintain the allocated overhead heaters to maintain the allocated rectal temperature. rectal temperature.

The rectal, fontanelle, and nasopharyngeal The rectal, fontanelle, and nasopharyngeal temperatures were continuously monitored. temperatures were continuously monitored.

No adverse effects because of cooling were No adverse effects because of cooling were observed. observed.

No infants developed cardiac arrhythmias, No infants developed cardiac arrhythmias, hypotension, or bradycardia during cooling. hypotension, or bradycardia during cooling.

Thrombocytopenia occurred in 2 out of Thrombocytopenia occurred in 2 out of 10 controls, 2 out of 6 minimal cooling 10 controls, 2 out of 6 minimal cooling infants, and 1 out of 6 mild cooling infants. infants, and 1 out of 6 mild cooling infants.

Hypoglycemia (glucose <2.6 mM) was seen Hypoglycemia (glucose <2.6 mM) was seen on at least one occasion in 2 out of on at least one occasion in 2 out of 10 controls, 4 out of 6 minimal cooling 10 controls, 4 out of 6 minimal cooling infants, and 1 out of 6 mild cooling infants. infants, and 1 out of 6 mild cooling infants.

Acute renal failure occurred in all infants. Acute renal failure occurred in all infants. The metabolic acidosis present in all infants The metabolic acidosis present in all infants

at the time of enrollment into the study at the time of enrollment into the study progressively resolved despite cooling, even progressively resolved despite cooling, even in the mild hypothermia group. in the mild hypothermia group.

Moderate Moderate hypothermia in hypothermia in

neonatal neonatal encephalopathy: encephalopathy:

Efficacy Efficacy outcomesoutcomes

Pediatric Neurology Vol 32 (1) Pediatric Neurology Vol 32 (1) January 2005January 2005

Multicenter, randomized, controlled, pilot trial of Multicenter, randomized, controlled, pilot trial of moderate systemic hypothermia (33°C) vs moderate systemic hypothermia (33°C) vs normothermia (37°C) for 48 hours in neonates normothermia (37°C) for 48 hours in neonates initiated within 6 hours of birth or hypoxic-initiated within 6 hours of birth or hypoxic-ischemic event. ischemic event.

The trial tested the ability to initiate systemic The trial tested the ability to initiate systemic hypothermia in outlying hospitals and hypothermia in outlying hospitals and participating tertiary care centers, and participating tertiary care centers, and determined the incidence of adverse neurologic determined the incidence of adverse neurologic outcomes of death and developmental scores at outcomes of death and developmental scores at 12 months by Bayley II or Vineland tests between 12 months by Bayley II or Vineland tests between normothermic and hypothermic groups. normothermic and hypothermic groups.

Thirty-two hypothermic and 33 normothermic neonates Thirty-two hypothermic and 33 normothermic neonates were enrolled. were enrolled.

The entry criteria selected a severely affected group of The entry criteria selected a severely affected group of neonates, with 77% Sarnat stage IIIneonates, with 77% Sarnat stage III

Ten hypothermia (10/32, 31%) and 14 normothermia Ten hypothermia (10/32, 31%) and 14 normothermia (14/33, 42%) patients expired(14/33, 42%) patients expired

Controlling for treatment group, outborn infants were Controlling for treatment group, outborn infants were significantly more likely to die than hypoxic-ischemic significantly more likely to die than hypoxic-ischemic infants born in participating tertiary care centersinfants born in participating tertiary care centers

Severely abnormal motor scores (Psychomotor Severely abnormal motor scores (Psychomotor Development Index < 70) were recorded in 64% of Development Index < 70) were recorded in 64% of normothermia patients and in 24% of hypothermia normothermia patients and in 24% of hypothermia patients. patients.

The combined outcome of death or severe motor scores The combined outcome of death or severe motor scores yielded fewer bad outcomes in the hypothermia group yielded fewer bad outcomes in the hypothermia group (52%) than the normothermia group (84%)(52%) than the normothermia group (84%)

Although these results need to be validated in a large Although these results need to be validated in a large clinical trial, this pilot trial provides important data for clinical trial, this pilot trial provides important data for clinical trial design of hypothermia treatment in neonatal clinical trial design of hypothermia treatment in neonatal hypoxic-ischemic injury.hypoxic-ischemic injury.

Improvement in the most serious outcomes of death or Improvement in the most serious outcomes of death or severe motor scores at 12 months of age. severe motor scores at 12 months of age.

Severely abnormal motor outcomes alone were decreased Severely abnormal motor outcomes alone were decreased in the hypothermia group compared with the in the hypothermia group compared with the normothermia group, even with the predominantly Sarnat normothermia group, even with the predominantly Sarnat stage III neonates, who were expected to be less stage III neonates, who were expected to be less responsive to treatment. responsive to treatment.

Cognitive scores in this pilot trial did not seem as sensitive Cognitive scores in this pilot trial did not seem as sensitive to hypothermia treatment effects as motor scores. to hypothermia treatment effects as motor scores.

The incidence of death and severe motor scores at 12 The incidence of death and severe motor scores at 12 months in this pilot trial indicate that hypothermia may be months in this pilot trial indicate that hypothermia may be helpful even in severe neonatal hypoxic-ischemic injury. helpful even in severe neonatal hypoxic-ischemic injury.

The efficacy, optimal length of hypothermia therapy, and The efficacy, optimal length of hypothermia therapy, and an assessment of the risk-benefit of hypothermia will be an assessment of the risk-benefit of hypothermia will be determined in future clinical trials. The favorable results of determined in future clinical trials. The favorable results of this pilot trial offer important considerations for the design this pilot trial offer important considerations for the design of hypothermia trials in neonatal hypoxic-ischemic injury.of hypothermia trials in neonatal hypoxic-ischemic injury.

Whole-Body Whole-Body Hypothermia for Hypothermia for Neonates with Neonates with

Hypoxic–Ischemic Hypoxic–Ischemic Encephalopathy Encephalopathy NEJM Oct 05, Vol 353(15): NEJM Oct 05, Vol 353(15):

1574-15841574-1584

Randomized trial of hypothermia in infants with:Randomized trial of hypothermia in infants with: a gestational age of at least 36 weeks a gestational age of at least 36 weeks who were admitted to the hospital at or before six who were admitted to the hospital at or before six

hours of age hours of age with either severe acidosis or perinatal complications with either severe acidosis or perinatal complications

and resuscitation at birth and resuscitation at birth and who had moderate or severe encephalopathy.and who had moderate or severe encephalopathy.

Infants were randomly assigned to Infants were randomly assigned to usual care (control group) or usual care (control group) or whole-body cooling to an esophageal temperature of whole-body cooling to an esophageal temperature of

33.5°C for 72 hours, 33.5°C for 72 hours, followed by slow rewarming (hypothermia followed by slow rewarming (hypothermia

group).group). Neurodevelopmental outcome was assessed at Neurodevelopmental outcome was assessed at

18 to 22 months of age. 18 to 22 months of age. The primary outcome was a combined end point The primary outcome was a combined end point

of death or moderate or severe disability. of death or moderate or severe disability.

Of 239 eligible infants, 102 were assigned to Of 239 eligible infants, 102 were assigned to the hypothermia group and 106 to the control the hypothermia group and 106 to the control group. group.

Adverse events were similar in the two groups Adverse events were similar in the two groups during the 72 hours of cooling. during the 72 hours of cooling.

Primary outcome data were available for 205 Primary outcome data were available for 205 infants. infants.

Death or moderate or severe disability occurred Death or moderate or severe disability occurred in 45 of 102 infants (44%) in the hypothermia in 45 of 102 infants (44%) in the hypothermia group and 64 of 103 infants (62%) in the control group and 64 of 103 infants (62%) in the control group group

Twenty-four infants (24%) in the hypothermia Twenty-four infants (24%) in the hypothermia group and 38 (3%) in the control group died group and 38 (3%) in the control group died

There was no increase in major disability among There was no increase in major disability among survivors; the rate of cerebral palsy was 15 of survivors; the rate of cerebral palsy was 15 of 77 (19%) in the hypothermia group as compared 77 (19%) in the hypothermia group as compared with 19 of 64 (30%) in the control group with 19 of 64 (30%) in the control group

Whole-body hypothermia reduces the risk of Whole-body hypothermia reduces the risk of death or disability in infants with moderate or death or disability in infants with moderate or severe hypoxic–ischemic encephalopathy. severe hypoxic–ischemic encephalopathy.

A concern with any therapy that reduces A concern with any therapy that reduces mortality among infants at high risk of mortality among infants at high risk of death and disability is the possibility of death and disability is the possibility of an increase in the number of infants who an increase in the number of infants who survive with disabilities. survive with disabilities.

In this study, there was no evidence of In this study, there was no evidence of increased rates of moderate or severe increased rates of moderate or severe disability at 18 to 22 months of age disability at 18 to 22 months of age among infants treated with hypothermia.among infants treated with hypothermia.

The rates of disabling cerebral palsy The rates of disabling cerebral palsy were:were: 19 percent in the hypothermia group19 percent in the hypothermia group 30 percent in the control group, 30 percent in the control group,

The rates of a Mental Development Index The rates of a Mental Development Index below 70 were:below 70 were: 25 percent in the hypothermia group25 percent in the hypothermia group 39 percent in the control group, 39 percent in the control group,

NeurodevelopmentNeurodevelopmental Outcome of al Outcome of

Infants Treated Infants Treated With Head Cooling With Head Cooling

and Mild and Mild Hypothermia After Hypothermia After Perinatal Asphyxia Perinatal Asphyxia

Pediatrics Vol. 107 (3) March Pediatrics Vol. 107 (3) March 20012001

National Women's Hospital & National Women's Hospital & University of Auckland, Auckland, New University of Auckland, Auckland, New

Zealand. Zealand.

Infants 37 weeks' gestation, who had an umbilical Infants 37 weeks' gestation, who had an umbilical artery pH 7.09 or Apgar score 6 at 5 minutes, artery pH 7.09 or Apgar score 6 at 5 minutes, plus clinical encephalopathy. Infants with major plus clinical encephalopathy. Infants with major congenital abnormalities were excluded. congenital abnormalities were excluded.

Infants were allocated to either:Infants were allocated to either: no cooling (rectal temperature = 37.0 ± 0.2°C, no cooling (rectal temperature = 37.0 ± 0.2°C, nn = 15)  = 15) or, sequentially, to head cooling accompanied by or, sequentially, to head cooling accompanied by

different levels of systemic hypothermia, including different levels of systemic hypothermia, including minimal cooling, rectal temperature 36.5°C to 36°C minimal cooling, rectal temperature 36.5°C to 36°C

((nn = 6)  = 6) and mild cooling, to either and mild cooling, to either

35.9°C to 35.5°C (35.9°C to 35.5°C (nn = 6)  = 6) 35 ± 0.5°C (35 ± 0.5°C (nn = 6) or = 6) or 34.5 ± 0.5°C (34.5 ± 0.5°C (nn = 7)  = 7)

Head cooling was accomplished by circulating Head cooling was accomplished by circulating cooled water through a coil of tubing wrapped cooled water through a coil of tubing wrapped around the head for up to 72 hours. around the head for up to 72 hours.

Survivors were followed up with regular Survivors were followed up with regular neurologic examination by a neonatologist until neurologic examination by a neonatologist until 18 months of age, then with blinded 18 months of age, then with blinded developmental testing using the revised Bayley developmental testing using the revised Bayley Scales. Scales.

ResultsResults A total of 40 term infants were enrolled from 2 to A total of 40 term infants were enrolled from 2 to

5 hours after birth. The control and the cooled 5 hours after birth. The control and the cooled groups were not significantly different for groups were not significantly different for gestation, birth weight, Apgar score, and initial pH. gestation, birth weight, Apgar score, and initial pH.

There were 6 early neonatal deaths There were 6 early neonatal deaths (3 normothermic and 3 cooled), and 1 death in (3 normothermic and 3 cooled), and 1 death in infancy associated with severe spastic cerebral infancy associated with severe spastic cerebral palsy in a normothermic infant. Six normothermic, palsy in a normothermic infant. Six normothermic, 1 minimally cooled, and 4 mildly cooled infants had 1 minimally cooled, and 4 mildly cooled infants had early stage 1 encephalopathy; all but 1 had a good early stage 1 encephalopathy; all but 1 had a good outcome. outcome.

Among infants with early stage 2 or Among infants with early stage 2 or 3 encephalopathy, an adverse outcome was found 3 encephalopathy, an adverse outcome was found in 4 of 9 normothermic infants (44%) and 4 of in 4 of 9 normothermic infants (44%) and 4 of 5 minimally cooled infants (80%), whereas in the 5 minimally cooled infants (80%), whereas in the combined mildly cooled groups, an adverse combined mildly cooled groups, an adverse outcome was found in 4 of 15 infants (26%, odds outcome was found in 4 of 15 infants (26%, odds ratio 0.46 [0.08, 2.56] vs normothermia). ratio 0.46 [0.08, 2.56] vs normothermia).

ConclusionsConclusions The present study supports the safety of The present study supports the safety of

hypothermia, with no evidence of late hypothermia, with no evidence of late adverse effects in any infant. adverse effects in any infant.

Among infants with moderate to severe Among infants with moderate to severe encephalopathy at enrollment, there was encephalopathy at enrollment, there was a tendency toward better outcome. a tendency toward better outcome.

These results emphasize the relatively These results emphasize the relatively wide range of outcomes using purely wide range of outcomes using purely clinical criteria for enrollment. clinical criteria for enrollment.

Therapeutic hypothermia should not be Therapeutic hypothermia should not be used outside of stringent, multicenter used outside of stringent, multicenter trials. trials.