CommentaryHypothermia and perinatal asphyxia: Executive summary of the National Institute of Child Health and Human Development workshop
Section snippets
Background
There are no therapies other than supportive measures for perinatal HIE, a condition associated with high neonatal mortality rates and severe long-term neurologic morbidity. Although hypothermia was used for “asphyxia neonatorum” in 1955,1 only in the past decade have systematic studies been carried out to address the safety and efficacy of this therapy in HIE.2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16
Recently, 2 large trials have been completed providing the results of 18-month
An overview of the pathogenesis of HIE
The biochemical and molecular processes leading to brain injury after an hypoxic-ischemic (HI) insult have been studied in fetal sheep, newborn mice, rat pups, piglets, and nonhuman primates,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 21, 22 as has been reviewed elsewhere.23, 24 Despite the wide range of species and experimental paradigms used, a number of general conclusions can be drawn about this topic, as follows.
Brain injury after experimental HI insult is an evolving process. The nature and
Hypothermia and neuroprotection
Studies in fetal sheep showed that brain cooling to about 32° and 34° C beginning 90 minutes or 5.5 hours after HI injury and continuing for 48 to 72 hours diminished the extent of parasagittal neuronal damage(the effect of cooling was observed in other regions of brain as well).5, 6, 8, 12 Studies in neonatal piglet, rat, and other models also led to the conclusion that mild hypothermia was neuroprotective, even after experimental HI brain injury.2, 3, 4, 7, 9, 10, 11 Improved neurologic
Translating the results of animal studies to human trials
Many limitations had to be noted before extrapolating the potentially beneficial effects seen in animal models of HIE and hypothermia to human HIE. In human beings, “perinatal encephalopathy” is not a single disease entity, but a condition resulting from diverse causes manifesting signs of brain injury at different phases of its evolution. Despite the etiologic diversity, the clinical signs may be identical. The cause(s) of HIE is rarely obvious, and the timing, nature, or severity of the HI
Pilot Trials
In 1955 Westin et al1 showed that hypothermia was beneficial in perinatal asphyxia. However, systematic pilot studies were not done until Gunn et al,13 Azzopardi et al,14 and Thoresen and Whitelaw15 described simple approaches to cooling the head and the whole body for up to 72 hours without serious, short-term adverse effects. The findings from these studies showed that although bradycardia occurred commonly, other acute complications, such as severe hypotension, acute deterioration in
Major gaps in knowledge
In spite of rapidly accumulating clinical and laboratory data related to hypothermia as a neuroprotective strategy for HIE, the speakers and discussants at the workshop underscored numerous gaps in knowledge in this field. They noted that with only 2 completed studies providing information on follow-up for only up to 18 months of age, the longer-term impact of hypothermia for HIE remains unknown. This, they concluded, should lead to an overall measure of caution in applying the new therapy of
Implications for clinical practice
The workshop participants suggested some salient points as a framework for consideration by practicing clinicians.
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Based on the available evidence and the known gaps in knowledge, at the current time, therapeutic hypothermia should be deemed as an evolving therapy, the long-term safety and efficacy of which need to be established.
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Perinatal HIE is not a single disease from a single cause, with great diversity in the timing and magnitude of brain injury. It is therefore unreasonable to expect any
Summary and conclusions
Based on the available data and large knowledge gaps, the expert panel suggested that although hypothermia appears to be a potentially promising therapy for HIE, long-term efficacy and safety are yet to be established. Clinicians choosing to offer this treatment should therefore understand all of the limitations of the available evidence, be prepared to keep up-to-date on evidence on this topic as it evolves, and counsel parents and family about the limitations of the current evidence.
Addendum:
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Cited by (161)
New Horizons in Mild Hypoxic-ischemic Encephalopathy: A Standardized Algorithm to Move past Conundrum of Care
2022, Clinics in PerinatologyOptimal Oxygenation in Extremely Preterm Infants
2018, The Newborn Lung: Neonatology Questions and Controversies, Third EditionHypoxic-Ischemic Injury in the Term Infant
2018, Volpe's Neurology of the Newborn
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See Appendix for a complete list of speakers and discussants and their institutional affiliations, available at www.jpeds.com.