Hypothermia For Neonatal Hypoxic-ischemic Encephalopathy Research Articles

Therapeutic Hypothermia for Neonatal Hypoxic-Ischemic Encephalopathy: Reducing Variability in Practice through a Collaborative Telemedicine Initiative.

This study aimed to assess the viability of implementing a tele-educational training program in neurocritical care for newborns diagnosed with hypoxic-ischemic encephalopathy (HIE) and treated with therapeutic hypothermia (TH), with the goal of reducing practice variation. Prospective study including newborns with HIE treated with TH from 12 neonatal intensive care units in Brazil conducted from February 2021 to February 2022. An educational intervention consisting of 12 biweekly, 1-hour, live videoconferences was implemented during a 6-month period in all centers. Half of the centers had the assistance of a remote neuromonitoring team. The primary outcome was the rate of deviations from TH protocol, and it was evaluated during a 3-month period before and after the intervention. Logistic regression via generalized estimating equations was performed to compare the primary and secondary outcomes. Protocol deviations were defined as practices not in compliance with the TH protocol provided. A subanalysis evaluated the differences in protocol deviations and clinical variables between centers with and without neuromonitoring. Sixty-six (39.5%) newborns with HIE were treated with TH during the preintervention period, 69 (41.3%) during the intervention period and 32 (19.1%) after intervention. There was not a significant reduction in protocol deviations between the pre- and postintervention periods (37.8 vs. 25%, p = 0.23); however, a decrease in the rates of missing Sarnat examinations within 6 hours after birth was seen between the preintervention (n = 5, 7.6%) and postintervention (n = 2, 6.3%) periods (adjusted odds ratio [aOR]: 0.36 [0.25-0.52], p < 0.001). Centers with remote neuromonitoring support had significantly lower rates of seizures (27.6 vs. 57.5%; aOR: 0.26 [0.12-0.55], p < 0.001) and significant less seizure medication (27.6 vs. 68.7%; aOR: 0.17 [0.07-0.4], p < 0.001). This study shows that implementing a tele-educational program in neonatal neurocritical care is feasible and may decrease variability in the delivery of care to patients with HIE treated with TH. · Neurocritical care strategies vary widely in low- and middle-income countries.. · Heterogeneity of care may lead to suboptimal efficacy of neuroprotective strategies.. · Tele-education and international collaboration can decrease the variability of neurocritical care provided to infants with HIE..

A biochemical feedback signal for hypothermia treatment for neonatal hypoxic-ischemic encephalopathy: focusing on central nervous system proteins in biofluids.

Hypothermia has been widely used to treat moderate to severe neonatal hypoxic-ischemic encephalopathy (HIE), yet evaluating the effects of hypothermia relies on clinical neurology, neuroimaging, amplitude-integrated electroencephalography, and follow-up data on patient outcomes. Biomarkers of brain injury have been considered for estimating the effects of hypothermia. Proteins specific to the central nervous system (CNS) are components of nervous tissue, and once the CNS is damaged, these proteins are released into biofluids (cerebrospinal fluid, blood, urine, tears, saliva), and they can be used as markers of brain damage. Clinical reports have shown that CNS-specific marker proteins (CNSPs) were early expressed in biofluids after brain damage and formed unique biochemical profiles. As a result, these markers may serve as an indicator for screening brain injury in infants, monitoring disease progression, identifying damage region of brain, and assessing the efficacy of neuroprotective measures. In clinical work, we have found that there are few reports on using CNSPs as biological signals in hypothermia for neonatal HIE. The aim of this article is to review the classification, origin, biochemical composition, and physiological function of CNSPs with changes in their expression levels after hypothermia for neonatal HIE. Hopefully, this review will improve the awareness of CNSPs among pediatricians, and encourage future studies exploring the mechanisms behind the effects of hypothermia on these CNSPs, in order to reduce the adverse outcome of neonatal HIE.

Neurological and Visual Outcomes in Infants and Toddlers Following Therapeutic Hypothermia for Neonatal Hypoxic-Ischemic Encephalopathy

BackgroundThe majority of studies have investigated neurodevelopmental outcomes, whereas visual impairment is less explored in children with a history of neonatal (hypoxic-ischemic) encephalopathy. Our aim was to perform a detailed neurological and visual assessment and also to investigate the presence of cerebral visual impairment in infants and toddlers with neonatal encephalopathy. MethodsThirty participants with a history of neonatal encephalopathy, who had been hospitalized for therapeutic hypothermia, underwent a detailed neurological examination at age five to 36 months. Age-matched, 30 healthy children were also enrolled as a control group. All children in the study and control groups received neurological and a comprehensive ophthalmologic examination, including visual field and visual acuity. Presence of cerebral visual impairment was also evaluated clinically. ResultsRates of cerebral palsy, severe motor impairment, cognitive impairment, epilepsy, and cerebral visual impairment were found to be 20%, 10%, 15.3%, 10%, and 20%, respectively. When compared with healthy controls, oculomotor functions, pupillary light response, refractive parameters, anterior/posterior segment examinations, ocular visual impairment rates, and last, visual acuities were found similar. However, we found a statistically significant increase in visual field defects in our study group. ConclusionsIt could be better to perform a comprehensive ophthalmologic examination including visual field, visual acuity, and oculomotor functions by a pediatric ophthalmologist to accurately diagnose neurovisual deficits in infants following therapeutic hypothermia. Early identification and rehabilitation of the visual deficits might improve the neurodevelopment in these children.

Timing Neonatal Hypoxic-Ischemic Encephalopathy

Therapeutic hypothermia for neonatal hypoxic-ischemic encephalopathy initiated within six hours after birth effectively prevents neurodevelopmental impairments in some but not all infants. In part, this may be related to the timing of hypoxia before birth relative to the initiation of cooling. Metabolic acidosis at birth (suggesting acute hypoxia-ischemia) is required for treatment with hypothermia. However, placental evidence suggests that some infants also have chronic hypoxemia or poor perfusion before birth. Furthermore, although fetal distress is often noted during labor, timing the inciting event is difficult without a discrete sentinel event (such as umbilical cord prolapse). Another potential method of timing the onset of fetal hypoxia is through the evaluation of neonatal nucleated red blood cell counts. Fetal hypoxia induces production of erythropoietin and then nucleated red blood cells. These cells first appear in the blood at 24-36 hours after administration of darbepoetin in newborn infants,1Christensen R.D. Lambert D.K. Richards D.S. Estimating the nucleated red blood cell ‘emergence time’ in neonates.J Perinatol. 2014; 34: 116-119https://doi.org/10.1038/jp.2013.113Crossref PubMed Scopus (20) Google Scholar suggesting that elevated counts at birth reflect hypoxic events at least 24 hours earlier. In this volume of The Journal of Pediatrics, Bahr et al. report that infants with sentinel events during labor did not have elevated nucleated red cell counts at birth (>95% for age) and that normal counts were associated with somewhat better neurodevelopmental outcomes. Further work in this area, perhaps combined with biomarker studies and placental evaluations, may help researchers identify infants with a longer duration of fetal hypoxia who may not respond to therapeutic hypothermia alone. Research on new therapies could then be targeted to those who are most likely to benefit. Article page 12

Case series of therapeutic hypothermia for neonatal hypoxic-ischemic encephalopathy during extracorporeal life support

Therapeutic hypothermia initiated within 6 hours of birth is currently the standard of care for the management of neonates with hypoxic-ischemic encephalopathy. Neonates undergoing therapeutic hypothermia for hypoxic-ischemic encephalopathy are also at risk for severe respiratory failure and need for extracorporeal life support. The risks and benefits of therapeutic hypothermia for hypoxic-ischemic encephalopathy during extracorporeal life support are still not well defined. We report our experience of a case series of six neonates who underwent therapeutic hypothermia for hypoxic-ischemic encephalopathy during extracorporeal life support. We also report long-term neurodevelopmental follow-up from 6 to 24 months and add to the current body of evidence regarding feasibility, clinical experience, and short-term complications.

Parental participation during therapeutic hypothermia for neonatal hypoxic-ischemic encephalopathy

ObjectivesTo examine parental participation in the care of newborn infants receiving therapeutic hypothermia, and to explore the possible impact of in-born vs out-born status, and location of hospital accommodation. Study designRetrospective, quantitative and descriptive design. Main outcome measuresInfants medical charts were reviewed for defined aspects of parental participation (infant holding, tube feeding, and diaper change), and related to their in-born vs out-born status, and whether the parents were accommodated in the NICU or elsewhere. All infants have been cared for at the University Hospital Neonatal Intensive Care Unit, serving as a regional referral center for hypothermia treatment. This study is a part of a population-based regional cohort of asphyxiated newborn infants (n = 112) that received therapeutic hypothermia in 2007–2015. ResultsParents engaged in holding (60/112, 54%) or tube feeding (59/112, 53%) their infant. Parents of in-born infants (24/112, 21%) were more likely to check the placement of the feeding tube (11/24, 46% vs 15/88, 17%; p < 0.01) and change diapers (9/24, 38% vs 14/88, 16%; p < 0.05) than parents of out-born infants (88/112, 79%). A similar pattern of more extensive involvement was observed for both mothers and fathers who stayed at the neonatal intensive care compared to those accommodated elsewhere (p < 0.05). ConclusionsActive parental participation is feasible at the NICU even during therapeutic hypothermia. Timely postnatal transfer of parents of out-born/transported infants, and the provision of on-site accommodation may influence the quality of parental involvement.

Therapeutic hypothermia for neonatal hypoxic-ischemic encephalopathy: magnetic resonance imaging findings and neurological outcomes in a Brazilian cohort

Objective: To determine the neurodevelopment outcomes after therapeutic hypothermia for neonatal hypoxic-ischemic encephalopathy (HIE) and identify the neonatal magnetic resonance imaging (MRI) findings associated with neurological outcome in a middle-income country.Study design: All infants born after 35 completed weeks’ gestation with signs of moderate to severe encephalopathy and evidence of perinatal asphyxia before 6 hours of life were submitted to whole-body hypothermia and were imaged at 18 ± 8.4 days of life (range 7–33 days) after birth. Surviving infants had the neurodevelopment outcome assessed at 12 to 18 months of age by trained professional masked to MRI findings.Results: Forty-eight infants included, MRI scans were obtained from 34 infants; 14 (29.1%) patients died during hospitalization before MRI was performed. Nine (64.3%) of 14 patients were classified as severe encephalopathy presented Posterior Limb Internal Capsule (PLIC) sign at the MRI, 10 (71.4%) thalamus and basal ganglia (TBG) lesion, 9 (64.3%) white matter (WM) lesion, and 7 (50.0%) cortical lesion. Severe encephalopathy was associated with the motor delay at 12–18 months by Bayley III, Alberta Infant Motor Scale (AIMS), and Gross Motor Function Classification System (GMFCS) scores (p = .020, p = .048, p = .033, respectively), but not for the cognitive (p = .167) or language skills (p = .309). Lower BSID-III motor, cognitive, and language composite scores were associated with PLIC sign (p = .047; p = .006 and p = .003, respectively). TBG lesion (p = .051) and cortical lesion (p = .030) were associated with lower language composite score. Motor delay by AIMS and the presence of PLIC sign, TBG lesion, WM lesion, and Cortical lesion on MRI were observed (p < .001; p = .002; p = .001 and p = .027, respectively); as well as higher GMFCS score were associated with the presence of PLIC sign, TBG lesion, WM lesion, and Cortical lesion on MRI (p < .001; p = .001; p = .001, and p = .011, respectively).Conclusions: Brain MRI in neonates with HIE after therapeutic hypothermia is a valuable tool for diagnosis of encephalopathy cerebral abnormalities and is an early predictor of outcome in infants treated with whole body hypothermia for HIE in the Brazilian experience.

36. Bilateral loss of cortical SEPs predict severe MRI lesions in neonatal hypoxic ischemic encephalopathy treated with hypothermia

The introduction of therapeutic hypothermia for neonatal hypoxic-ischemic encephalopathy call for reevaluation of the prognostic role of SEPs. This study aimed to test the prognostic value of SEPs using as outcome measure MRI severity and patterns of injury. Neonates eligible for hypothermia were recruited from four Italian Centers if they performed SEP and MRI at 4–15 days of life. SEPs were scored as: normal (bilaterally recorded/unilaterally absent N20) or altered (bilaterally absent N20). The severity of brain injury was measured using a validated MRI scoring system for acute and sub-acute signal abnormalities. 58 neonates were included in the analysis. Bilaterally absent N20 was observed in 10/58 (17%); all had moderate/severe MRI abnormalities. Furthermore, 37 infants (62%) had normal MRI all with normal N20. The positive predictive value of SEP on MRI outcome was of 100%, while the negative predictive value 72%, sensitivity 43%, specificity 100%, with an accuracy of 78% (p < .001). Bilateral absence of cortical SEPs is associated with a moderate/severe MRI pattern of injury, as previously reported in non-cooled infants. The prognostic value of SEPs is not (or minimally) affected by hypothermia.

Therapeutic hypothermia for neonatal hypoxic-ischemic encephalopathy: temperature control during transport

This study aims to assess the adequacy of temperature control during transport of patients referred for therapeutic hypothermia at our centre and to evaluate the occurrence of complications when temperature control is not adequate. Transport data of patients (n = 37) referred during a period of 30 months was reviewed retrospectively, as well as our prospectively collected database of infants treated with hypothermia. We evaluated duration of transport, incidence of excessive cooling on admission and associated complications. Distance from the referring hospital and duration of the transport were not associated with excessive cooling. We then divided patients into two groups according to adequacy of temperature control during transport depending on the presence or absence of regular temperature recordings and compared study variables between the groups. A significant correlation was found between the lack of adequate temperature records during transport (n = 19) and excessive hypothermia on admission (42% vs. 11% for the group with adequate temperature monitoring). There was a trend towards increased incidence of coagulation problems for infants who had admission temperatures below 32.0°C. Passive cooling is simple and effective to ensure early achievement of neuroprotective temperature, but continuous temperature monitoring during transportation is mandatory in order to avoid excessive cooling.

Temporal Relationship between Serum Levels of Interleukin-6 and C-Reactive Protein in Therapeutic Hypothermia for Neonatal Hypoxic-Ischemic Encephalopathy.

Objective C-reactive protein (CRP) is a useful marker of neonatal infection. Recent studies have shown that neonatal therapeutic hypothermia delays an elevation of CRP in infants with hypoxic-ischemic encephalopathy (HIE). This study investigated the time difference of peak levels of serum CRP and other inflammatory responses during therapeutic hypothermia. Study design We prospectively studied the serial serum data of CRP, interleukin-6 (IL-6), procalcitonin (PCT), and complete blood counts during the first week of life in HIE infants receiving therapeutic hypothermia. Results We identified 22 infants who received therapeutic hypothermia between August 2013 and July 2015. No infants developed clinically overt infections. The peak of serum levels of IL-6, PCT, and CRP were postnatal days 1, 2, and 4, respectively. White blood cells, neutrophils, and platelet counts gradually decreased from days 1 to 7. Early postnatal serum levels of IL-6 correlated with CRP on day 4 (IL-6 on day 2; r = 0.78, p < 0.001). Conclusion The peak value of CRP on day 4 might reflect the early production and secretion of IL-6 rather than an actual infection. Serial measurement of IL-6 might help avoid invasive sepsis workup and unnecessary change of antibiotics in infants.

Are 2-Year Old Children Who Underwent Therapeutic Hypothermia for Neonatal Hypoxic-Ischemic Encephalopathy at Risk for Behavioral Problems?

Are 2-Year Old Children Who Underwent Therapeutic Hypothermia for Neonatal Hypoxic-Ischemic Encephalopathy at Risk for Behavioral Problems?

Neonatal Magnetic Resonance Imaging Pattern of Brain Injury as a Biomarker of Childhood Outcomes following a Trial of Hypothermia for Neonatal Hypoxic-Ischemic Encephalopathy

To examine the ability of magnetic resonance imaging (MRI) patterns of neonatal brain injury defined by the National Institute of Child Health and Human Development Neonatal Research Network to predict death or IQ at 6-7 years of age following hypothermia for neonatal encephalopathy. Out of 208 participants, 124 had MRI and primary outcome (death or IQ <70) data. The relationship between injury pattern and outcome was assessed. Death or IQ <70 occurred in 4 of 50 (8%) of children with pattern 0 (normal MRI), 1 of 6 (17%) with 1A (minimal cerebral lesions), 1 of 4 (25%) with 1B (extensive cerebral lesions), 3 of 8 (38%) with 2A (basal ganglia thalamic, anterior or posterior limb of internal capsule, or watershed infarction), 32 of 49 (65%) with 2B (2A with cerebral lesions), and 7 of 7 (100%) with pattern 3 (hemispheric devastation), P < .001; this association was also seen within hypothermia and control subgroups. IQ was 90 ± 13 among the 46 children with a normal MRI and 69 ± 25 among the 50 children with an abnormal MRI. In childhood, for a normal outcome, a normal neonatal MRI had a sensitivity of 61%, specificity of 92%, a positive predictive value of 92%, and a negative predictive value of 59%; for death or IQ <70, the 2B and 3 pattern combined had a sensitivity of 81%, specificity of 78%, positive predictive value of 70%, and a negative predictive value of 87%. The Neonatal Research Network MRI pattern of neonatal brain injury is a biomarker of neurodevelopmental outcome at 6-7 years of age. ClinicalTrials.gov: NCT00005772.

Therapeutic Hypothermia for Neonatal Hypoxic-Ischemic Encephalopathy - Where to from Here?

Hypoxia–ischemia before or around the time of birth occurs in approximately 2/1000 live births and is associated with a high risk of death or lifelong disability. Therapeutic hypothermia is now well established as standard treatment for infants with moderate to severe hypoxic–ischemic encephalopathy but is only partially effective. There is compelling preclinical and clinical evidence that hypothermia is most protective when it is started as early as possible after hypoxia–ischemia. Further improvements in outcome from therapeutic hypothermia are very likely to arise from strategies to reduce the delay before starting treatment of affected infants. In this review, we examine evidence that current protocols are reasonably close to the optimal depth and duration of cooling, but that the optimal rate of rewarming after hypothermia is unclear. The potential for combination treatments to augment hypothermic neuroprotection has considerable promise, particularly with endogenous targets such as melatonin and erythropoietin, and noble gases such as xenon. We dissect the critical importance of preclinical studies using realistic delays in treatment and clinically relevant cooling protocols when examining combination treatment, and that for many strategies overlapping mechanisms of action can substantially attenuate any effects.

Serum Cytokines in a Clinical Trial of Hypothermia for Neonatal Hypoxic-Ischemic Encephalopathy

Inflammatory cytokines may mediate hypoxic-ischemic (HI) injury and offer insights into the severity of injury and the timing of recovery. In our randomized, multicenter trial of hypothermia, we analyzed the temporal relationship of serum cytokine levels in neonates with hypoxic-ischemic encephalopathy (HIE) with neurodevelopmental outcome at 12 months. Serum cytokines were measured every 12 hours for 4 days in 28 hypothermic (H) and 22 normothermic (N) neonates with HIE. Monocyte chemotactic protein-1 (MCP-1) and interleukins (IL)-6, IL-8, and IL-10 were significantly higher in the H group. Elevated IL-6 and MCP-1 within 9 hours after birth and low macrophage inflammatory protein 1a (MIP-1a) at 60 to 70 hours of age were associated with death or severely abnormal neurodevelopment at 12 months of age. However, IL-6, IL-8, and MCP-1 showed a biphasic pattern in the H group, with early and delayed peaks. In H neonates with better outcomes, uniform down modulation of IL-6, IL-8, and IL-10 from their peak levels at 24 hours to their nadir at 36 hours was observed. Modulation of serum cytokines after HI injury may be another mechanism of improved outcomes in neonates treated with induced hypothermia.

Hypothermia for neonatal hypoxic-ischemic encephalopathy: may an early amplitude-integrated EEG improve the selection of candidates for cooling?

Objective: To report our experience in the selection of newborns candidate to therapeutic hypothermia. Methods: Retrospective study involving 47 newborns suffering from perinatal asphyxia from January 2008 to September 2011. Results: Thirty-five of 47 newborns admitted to our hospital fulfilled metabolic and neurological criteria for recruitment and were cooled. aEEG was carried out in 26 of them and resulted always abnormal. In three of the 12 newborns with only metabolic criteria, aEEG was moderately abnormal. They were cooled and their outcome (evaluated by General Movements and Griffiths Mental Development Scales for children aged 0–2 years) is good. Three additional newborns who only met the metabolic criterion reached our hospital after the therapeutic window for hypothermia and exhibited seizures; their outcome is poor. Conclusions: In our experience, the inclusion of aEEG in the entry criteria would not have precluded newborns with neurological criteria from cooling. On the contrary, without an early aEEG, we would have excluded from hypothermia infants with moderate hypoxic-ischemic encephalopathy without precocious neurological signs who exhibited only the metabolic criterion, but with abnormal aEEG. If further studies will confirm that early aEEG might identify newborns suitable for cooling even in the absence of clinical signs, a revision of the entry criteria should be considered.

Evolution of Encephalopathy during Whole Body Hypothermia for Neonatal Hypoxic-Ischemic Encephalopathy

To examine the predictive ability of stage of hypoxic-ischemic encephalopathy (HIE) for death or moderate/severe disability at 18 months among neonates undergoing hypothermia. Stage of encephalopathy was evaluated at <6 hours of age, during study intervention, and at discharge among 204 participants in the National Institute of Child Health and Human Development Neonatal Research Network Trial of whole body hypothermia for HIE. HIE was examined as a predictor of outcome by regression models. Moderate and severe HIE occurred at <6 hours of age among 68% and 32% of 101 hypothermia group infants and 60% and 40% of 103 control group infants, respectively. At 24 and 48 hours of study intervention, infants in the hypothermia group had less severe HIE than infants in the control group. Persistence of severe HIE at 72 hours increased the risk of death or disability after controlling for treatment group. The discharge exam improved the predictive value of stage of HIE at <6 hours for death/disability. On serial neurologic examinations, improvement in stage of HIE was associated with cooling. Persistence of severe HIE at 72 hours and an abnormal neurologic exam at discharge were associated with a greater risk of death or disability.

Induced Hypothermia for Neonatal Hypoxic-Ischemic Encephalopathy: Pathophysiology, Current Treatment, and Nursing Considerations

Hypoxic-ischemic encephalopathy (HIE) can lead to devastating neurodevelopmental consequences such as cerebral palsy, seizure disorders, and significant developmental delays. HIE in the newborn is often the result of a hypoxic event, such as uterine rupture, placental abruption, or cord prolapse. Biphasic brain injury occurs in HIE. The first phase involves activation of the sympathetic nervous system as a compensatory mechanism. The second phase, known as reperfusion brain injury, occurs hours later. Induced hypothermia, a neuroprotective strategy for treating HIE, targets the second phase to prevent reperfusion injury. NICU nurses are in a unique position to detect patient instability and to maintain the therapeutic interventions that contribute to the healing process. This article highlights the significant role nurses play in the management of infants diagnosed with HIE who are treated with induced hypothermia.

Hypocarbia and Adverse Outcome in Neonatal Hypoxic-Ischemic Encephalopathy

To evaluate the association between early hypocarbia and 18- to 22-month outcome among neonates with hypoxic-ischemic encephalopathy. Data from the National Institute of Child Health and Human Development Neonatal Research Network randomized, controlled trial of whole-body hypothermia for neonatal hypoxic-ischemic encephalopathy were used for this secondary observational study. Infants (n = 204) had multiple blood gases recorded from birth to 12 hours of study intervention (hypothermia versus intensive care alone). The relationship between hypocarbia and outcome (death/disability at 18 to 22 months) was evaluated by unadjusted and adjusted analyses examining minimum PCO(2) and cumulative exposure to PCO(2) <35 mm Hg. The relationship between cumulative PCO(2) <35 mm Hg (calculated as the difference between 35 mm Hg and the sampled PCO(2) multiplied by the duration of time spent <35 mm Hg) and outcome was evaluated by level of exposure (none-high) using a multiple logistic regression analysis with adjustments for pH, level of encephalopathy, treatment group (± hypothermia), and time to spontaneous respiration and ventilator days; results were expressed as odds ratios and 95% confidence intervals. Alternative models of CO(2) concentration were explored to account for fluctuations in CO(2). Both minimum PCO(2) and cumulative PCO(2) <35 mm Hg were associated with poor outcome (P < .05). Moreover, death/disability increased with greater cumulative exposure to PCO(2) <35 mm Hg. Hypocarbia is associated with poor outcome after hypoxic-ischemic encephalopathy.

Outcomes of Safety and Effectiveness in a Multicenter Randomized, Controlled Trial of Whole-Body Hypothermia for Neonatal Hypoxic-Ischemic Encephalopathy

Whole-body hypothermia reduced the frequency of death or moderate/severe disabilities in neonates with hypoxic-ischemic encephalopathy in a randomized, controlled multicenter trial. Our goal was to evaluate outcomes of safety and effectiveness of hypothermia in infants up to 18 to 22 months of age. A priori outcomes were evaluated between hypothermia (n = 102) and control (n = 106) groups. Encephalopathy attributable to causes other than hypoxia-ischemia at birth was not noted. Inotropic support (hypothermia, 59% of infants; control, 56% of infants) was similar during the 72-hour study intervention period in both groups. Need for blood transfusions (hypothermia, 24%; control, 24%), platelet transfusions (hypothermia, 20%; control, 12%), and volume expanders (hypothermia, 54%; control, 49%) was similar in the 2 groups. Among infants with persistent pulmonary hypertension (hypothermia, 25%; control, 22%), nitric-oxide use (hypothermia, 68%; control, 57%) and placement on extracorporeal membrane oxygenation (hypothermia, 4%; control, 9%) was similar between the 2 groups. Non-central nervous system organ dysfunctions occurred with similar frequency in the hypothermia (74%) and control (73%) groups. Rehospitalization occurred among 27% of the infants in the hypothermia group and 42% of infants in the control group. At 18 months, the hypothermia group had 24 deaths, 19 severe disabilities, and 2 moderate disabilities, whereas the control group had 38 deaths, 25 severe disabilities, and 1 moderate disability. Growth parameters were similar between survivors. No adverse outcomes were noted among infants receiving hypothermia with transient reduction of temperature below a target of 33.5 degrees C at initiation of cooling. There was a trend in reduction of frequency of all outcomes in the hypothermia group compared with the control group in both moderate and severe encephalopathy categories. Although not powered to test these secondary outcomes, whole-body hypothermia in infants with encephalopathy was safe and was associated with a consistent trend for decreasing frequency of each of the components of disability.

Time to Adopt Cooling for Neonatal Hypoxic-Ischemic Encephalopathy: Response to a Previous Commentary

On the basis of opinions of problematic evidence, Kirpalani et al1 stated that the “standard of care” criteria for adopting hypothermia for neonatal hypoxic-ischemic encephalopathy (HIE) had not been met. They argued for a “conservative approach.” Clinicians who are “impressed” by their evidence are not mandated to offer cooling and can ethically continue to randomly assign patients “into ongoing, or new trials.” Yet, the authors considered the evidence to be “certainly” sufficiently strong for cautious use of this treatment by clinicians who are “impressed with the results.” These apparently conflicting statements are reinforced by previous confusing statements by co-author Barks2: “Many of us, including this author and the lead author [Dr Shankaran] of the Network trial,[3] who caution against uncontrolled adoption of cooling, have lost equipoise, and we are now cooling babies who meet the eligibility criteria of our original trials,” and the semantically elusive, “In a small number of experienced centers, it is a novel therapy that has become ‘standard care’ (without randomization), but it is not yet the ‘standard of care’ (emphasis in the original). Evolution in this field has outdated this conservative approach. One cooling trial (Infant Cooling Evaluation [ICE])4 was stopped prematurely, the research protocol of another has been altered,5 a third trial (Trial of Whole Body Hypothermia for Perinatal Asphyxia [TOBY])6 was stopped at the end of the funding period before achieving its revised sample size, and 3 independent systematic reviews4,7,8 have confirmed the efficacy and safety of cooling. Today's question is whether it is acceptable for individual hospitals or physicians to withhold from parents … Address correspondence to Max Perlman, MB, BS, FRCPC, FRCP, 1711/175 Cumberland St, Toronto, Ontario, Canada M5R 3M9. E-mail: max.perlman{at}sympatico.ca