Published online March 1, 2006
PEDIATRICS Vol. 117 No. 3 March 2006, pp. 942-948 (doi:10.1542/10.1542/peds.2005-2950)
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COMMENTARY

Hypothermia: A Neuroprotective Therapy for Neonatal Hypoxic-Ischemic Encephalopathy

Lillian R. Blackmon, MDa, Ann R. Stark, MDb and the Committee on Fetus and Newborn, American Academy of Pediatrics

a Department of Pediatrics, Division of Neonatology, University of Maryland School of Medicine, Baltimore, Maryland
b Department of Pediatrics, Section of Neonatology, Baylor College of Medicine, Houston, Texas

Abbreviations: NICHD, National Institute of Child Health and Human Development • HIE, hypoxic-ischemic encephalopathy • RCT, randomized, controlled trial • NRN, Neonatal Research Network

In May, 2005, the National Institute of Child Health and Human Development (NICHD) convened a workshop to evaluate the status of knowledge regarding the safety and efficacy of hypothermia as a neuroprotective therapy for neonatal hypoxic-ischemic encephalopathy (HIE).1 Participants, including the current and past chairs of the American Academy of Pediatrics Committee on Fetus and Newborn, reviewed current evidence and identified gaps in knowledge and clinical implications. They agreed that current evidence supports the conclusion that mild to moderate hypothermia holds promise for the amelioration of neural injury after a perinatal hypoxic-ischemic insult.


   OBJECTIVES
TOP
 OBJECTIVES
BACKGROUND
 DISCUSSION
 RECOMMENDATIONS
 CONCLUSIONS
 Committee on Fetus and...
 LIAISONS
 STAFF
 REFERENCES
 
The objectives of this commentary are to review briefly the background and current knowledge regarding the therapeutic efficacy and safety of sustained mild to moderate hypothermia to prevent death and severe disability in neonates who have experienced a significant hypoxic-ischemic insult and to urge caution and restraint in the immediate implementation of this therapy before more corroborating evidence has been published.


   BACKGROUND
TOP
 OBJECTIVES
 BACKGROUND
DISCUSSION
 RECOMMENDATIONS
 CONCLUSIONS
 Committee on Fetus and...
 LIAISONS
 STAFF
 REFERENCES
 
The lack of a definitive therapeutic approach for HIE remains one of the unresolved clinical frustrations of contemporary neonatal medicine. The dismal prognosis for infants who sustain a severe asphyxial insult in the perinatal period has altered little despite advances in the application of diagnostic and multiorgan life-support techniques to newborns.2–5 In part because the principal etiologies differ, therapeutic advances in the management of encephalopathy in older children and adults have not proved to be applicable to neonates.6 In addition, unlike older patients, the etiology, onset, and duration of perinatal hypoxic-ischemic injury are varied and often unknown.

Early Studies
In the 1950s and 1960s, Miller and Westin7,8 studied the physiologic basis for the neuroprotective role of hypothermia in the treatment of "asphyxia neonatorum," first in newborn animals and then in human newborns. They and others demonstrated improved survival without cerebral palsy or mental retardation of apneic newborns who were cooled rapidly to 23 to 32°C after delivery when conventional resuscitation techniques failed.9–13 Despite their results, hypothermia did not become an accepted therapy in neonatal care, in part because it was never evaluated by randomized, controlled trials (RCTs).

Hypothermia During Cardiac Surgery
Hypothermic circulatory arrest (core temperature of 18–20°C) was introduced in the 1960s to facilitate repair of complex congenital heart disease.14 This technique allowed earlier definitive repair of complex defects and thus less cardiac morbidity in infancy and early childhood. It was widely adopted, although the duration of ischemia that could be sustained without incurring permanent central nervous system injury was not established. The heterogeneity of lesions and lack of uniformity of the operative procedures and duration of circulatory arrest made it difficult to draw conclusions about safety. Some case series reported poor neurologic outcomes linked to longer duration of arrest, although the role of depth of cooling is uncertain.15–17 The Boston Circulatory Arrest Trial compared deep hypothermia with either circulatory arrest or low-flow cardiopulmonary bypass in infants with a single lesion. In this study, all groups have had more neurodevelopmental problems than expected for their age peers, and more functional deficits that may impact educational achievement have been revealed as the children have grown older.18–20

Contemporary Studies
Several groups have demonstrated recently that either selective or whole-body mild to moderate hypothermia (33–34°C), applied within hours of an acute asphyxial event, is neuroprotective in various animal models.21–26 In addition, the pathogenesis of neural injury from a hypoxic-ischemic insult has been defined better,27,28 and technically applicable mechanisms for cooling neonates have been developed.29,30

After pilot studies to identify technical and safety issues (~104 infants subjected to various regimens of hypothermia),29–35 RCTs were initiated to test hypothermia in near-term and term human neonates (≥35–36 weeks' gestation) with HIE. To date, only 3 trials have been reported, with a total of 250 hypothermia-treated infants and 257 routine-thermal-support controls. These trials include those by Eicher et al,36,37 who used whole-body cooling with surface ice packs and cooling blankets, Gluckman et al,38 who used an experimental head-cooling device (Cool Cap), and the Neonatal Research Network (NRN) (Shankaran et al39), who used whole-body cooling with cooling blankets. These trials assessed the primary composite outcome of death or neurodevelopmental disability at 12 months37 or 18 months38,39 of age. Characteristics of the trials and the various outcomes are summarized in Tables 1 and 2. The 3 reported studies differ considerably in methodology, entry criteria, and follow-up evaluation. Three additional RCTs—the TOBY trial,40 the Infant Cooling Evaluation trial,41 and a trial by Simbruner and the neo.nEuro.network42—are underway and share some similarities to the published reports in entry criteria, methodology, and outcomes that may make meta-analysis possible.


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  		TABLE 1 Comparison of Study Methodology of RCTs

 

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  		TABLE 2 Comparison of Severity and Outcomes of RCTs

 

   DISCUSSION
TOP
 OBJECTIVES
 BACKGROUND
 DISCUSSION
RECOMMENDATIONS
 CONCLUSIONS
 Committee on Fetus and...
 LIAISONS
 STAFF
 REFERENCES
 
The question of sufficient efficacy has not been answered adequately. Because the trials vary in methodology and results, comparisons are difficult. The improvement in the composite primary outcome of death or moderate and severe disability at 18 months of age was statistically significant in only 1 trial (NRN).39 In that trial, blood gas entry criteria were less stringent than in the others, and the primary outcome included moderate as well as severe disability. Neither survival nor survival without disability was independently significantly improved. The influence of the initial severity of clinical status on the ultimate outcome is uncertain, because none of the studies were designed to demonstrate a relationship between clinical severity at entry and the final outcomes. Infants with less severe manifestations of HIE may be at lower risk for a severe outcome. However, including moderate disability as a component of the primary study outcome could decrease the likelihood of showing a significant difference between treatment and control groups.

Safety was addressed in both the initial pilot trials and the RCTs, although more comprehensively in some.29–39 Cold-injury syndrome, a potential complication of therapeutic hypothermia, can result in sclerema, multisystem organ damage (especially pulmonary hemorrhage, renal failure, and disseminated intravascular coagulopathy), hypovolemia, glucose instability, and pulmonary hypertension.43,44 However, no serious adverse safety issues have been reported to date, although all 3 RCTs noted reversible cardiovascular effects, specifically sinus bradycardia and hypotension. Thoresen and Whitelaw45 reported that some concurrent medications exacerbated adverse cardiovascular effects during both cooling and rewarming in an early pilot study. Gluckman et al38 reported elevated liver enzymes and Eicher et al36 noted an increase in late coagulopathy (several days after rewarming) and more persistent pulmonary hypertension that required inhaled nitric-oxide treatment in the hypothermia-treated infants. Reported causes of death included multiorgan failure; however, it is uncertain whether this resulted from the initial hypoxic-ischemic insult or from that resulting from the hypothermia treatment.37–39 Excessive warming after a hypoxic-ischemic insult may be deleterious and magnify any difference in outcome between treatment groups.46,47 In the NRN trial, 41 infants in the control group experienced hyperthermia (core temperatures of >38°C) at least once during the study period.39 Eicher et al36 reported elevated core temperatures during both the study period and later in the first week in treated and control infants.

The NICHD conference identified many significant questions that remain to be answered before universal implementation can be encouraged. These questions include:

  1. What is the most effective technique—head cooling with or without deep body cooling or deep body cooling?
  2. What is the most effective and safest duration of cooling—48 hours, 72 hours, or longer?
  3. What is the most appropriate target temperature—33, 33.5, 34, or 34.5°C or another temperature?
  4. What is the most important central nervous system anatomic target—superficial cortical or deep cortical/brainstem?
  5. Which infants are most likely to benefit, and what is the best way to identify them—gestational age, predisposing history, or clinical criteria or objective measures such as electroencephalography or diagnostic imaging?
  6. What is the optimal age from birth to institute hypothermia, and how late is too late?
  7. What is the safest timing and method of rewarming?
  8. How does the incidence and spectrum of adverse neurodevelopmental outcomes change at 4 years of age, 8 years of age, and beyond?


   RECOMMENDATIONS
TOP
 OBJECTIVES
 BACKGROUND
 DISCUSSION
 RECOMMENDATIONS
CONCLUSIONS
 Committee on Fetus and...
 LIAISONS
 STAFF
 REFERENCES
 
NICHD workshop participants concluded that therapeutic hypothermia, at present, should be considered an evolving therapy for which long-term safety and efficacy have not been established.1 They noted that given the heterogeneity of etiology and pathogenesis of HIE, no single intervention is likely to result in a favorable outcome in all infants treated.

Based on a review of the 3 published RCTs,37–40 the Committee on Fetus and Newborn concludes that:

  1. Therapeutic hypothermia is a promising therapy that should be considered investigational until the short-term safety and efficacy have been confirmed in the additional human trials underway. Long-term safety and efficacy remain to be defined.
  2. Completion of the 3 large RCTs in progress41–43 should be supported so that projected enrollment is accomplished.
  3. Additional trials are needed that would define the most effective cooling strategies.
  4. Registries of infants with perinatal encephalopathies should be established to facilitate data collection regarding diagnoses, treatments, and outcomes.
  5. If therapeutic hypothermia is to be implemented outside of an RCT, clinicians should follow published protocols, ensure systematic follow-up of survivors validated neurodevelopmental tests, and submit patient data to national or international registries as they are established. Parents should be informed of the current status of hypothermia therapy and consent for the procedure obtained.
  6. Longer-term follow-up at least through early school age is essential


   CONCLUSIONS
TOP
 OBJECTIVES
 BACKGROUND
 DISCUSSION
 RECOMMENDATIONS
 CONCLUSIONS
Committee on Fetus and...
 LIAISONS
 STAFF
 REFERENCES
 
Substantial uncertainties exist regarding mild to moderate hypothermia as a safe and effective neuroprotective intervention for newborns who have sustained a perinatal hypoxic-ischemic insult resulting in encephalopathy. Completion of ongoing trials and long-term follow-up of survivors is essential. Thus, widespread implementation outside the limits of controlled trials is premature.


   Committee on Fetus and Newborn, 2005–2006
TOP
 OBJECTIVES
 BACKGROUND
 DISCUSSION
 RECOMMENDATIONS
 CONCLUSIONS
 Committee on Fetus and...
LIAISONS
 STAFF
 REFERENCES
 
Ann R. Stark, MD, Chairperson

David H. Adamkin, MD

Daniel G. Batton, MD

Edward F. Bell, MD

Susan E. Denson, MD

William A. Engle, MD

Gilbert I. Martin, MD

Lillian R. Blackmon, MD, Immediate Past Chairperson

Vinod K. Bhutani, MD


   LIAISONS
TOP
 OBJECTIVES
 BACKGROUND
 DISCUSSION
 RECOMMENDATIONS
 CONCLUSIONS
 Committee on Fetus and...
 LIAISONS
STAFF
 REFERENCES
 
Keith J. Barrington, MD

Canadian Paediatric Society, Committee on Fetus and Newborn Chairman

Gary Hankins, MD

American College of Obstetricians and Gynecologists, Committee on Obstetric Practice Chairman

Kay M. Tomashek, MD, MPH

Centers for Disease Control and Prevention

Carol Wallman, MSN, RNC, NNP

National Association of Neonatal Nurses, Association of Women's Health, Obstetric and Neonatal Nurses

Tonse N. K. Raju, MD, DCH

Pregnancy and Perinatology Branch, National Institutes of Child Health and Human Development


   STAFF
TOP
 OBJECTIVES
 BACKGROUND
 DISCUSSION
 RECOMMENDATIONS
 CONCLUSIONS
 Committee on Fetus and...
 LIAISONS
 STAFF
REFERENCES
 
James Couto, MA


   FOOTNOTES
 
Accepted Dec 14, 2005.

Address correspondence to Lillian R. Blackmon, MD, University of Maryland School of Medicine, Room N5W68, 22 S Greene St, Baltimore, MD 21201. E-mail: lblackmon{at}peds.umaryland.edu

The authors have indicated they have no financial relationships relevant to this article to disclose.


   REFERENCES
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 BACKGROUND
 DISCUSSION
 RECOMMENDATIONS
 CONCLUSIONS
 Committee on Fetus and...
 LIAISONS
 STAFF
 REFERENCES
 

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