Objective To determine whether moderate hypothermia after hypoxic-ischaemic encephalopathy in neonates improves survival and neurological outcome at 18 months of age. Design A meta-analysis was performed using a fixed effect model. Risk ratios, risk difference, and number needed to treat, plus 95% confidence intervals, were measured. Data sources Studies were identified from the Cochrane central register of controlled trials, the Oxford database of perinatal trials, PubMed, previous reviews, and abstracts. Review methods Reports that compared whole body cooling or selective head cooling with normal care in neonates with hypoxic-ischaemic encephalopathy and that included data on death or disability and on specific neurological outcomes of interest to patients and clinicians were selected. Results We found three trials, encompassing 767 infants, that included information on death and major neurodevelopmental disability after at least 18 months’ follow-up. We also identified seven other trials with mortality information but no appropriate neurodevelopmental data. Therapeutic hypothermia significantly reduced the combined rate of death and severe disability in the three trials with 18 month outcomes (risk ratio 0.81, 95% confidence interval 0.71 to 0.93, P=0.002; risk difference −0.11, 95% CI −0.18 to −0.04), with a number needed to treat of nine (95% CI 5 to 25). Hypothermia increased survival with normal neurological function (risk ratio 1.53, 95% CI 1.22 to 1.93, P<0.001; risk difference 0.12, 95% CI 0.06 to 0.18), with a number needed to treat of eight (95% CI 5 to 17), and in survivors reduced the rates of severe disability (P=0.006), cerebral palsy (P=0.004), and mental and the psychomotor developmental index of less than 70 (P=0.01 and P=0.02, respectively). No significant interaction between severity of encephalopathy and treatment effect was detected. Mortality was significantly reduced when we assessed all 10 trials (1320 infants; relative risk 0.78, 95% CI 0.66 to 0.93, P=0.005; risk difference −0.07, 95% CI −0.12 to −0.02), with a number needed to treat of 14 (95% CI 8 to 47). Conclusions In infants with hypoxic-ischaemic encephalopathy, moderate hypothermia is associated with a consistent reduction in death and neurological impairment at 18 months.

Hypothermia has been proposed as a neuroprotective strategy. However, short-term cooling after hypoxia-ischemia is effective only if started immediately during resuscitation. The aim of this study was to determine whether prolonged head cooling, delayed into the late postinsult period, improves outcome from severe ischemia. Unanesthetized near term fetal sheep were subject to 30 min of cerebral ischemia. 90 min later they were randomized to either cooling (n = 9) or sham cooling (n = 7) for 72 h. Intrauterine cooling was induced by a coil around the fetal head, leading initially to a fall in extradural temperature of 5-10 degrees C, and a fall in esophageal temperature of 1.5-3 degrees C. Cooling was associated with mild transient systemic metabolic effects, but not with hypotension or altered fetal heart rate. Cerebral cooling reduced secondary cortical cytotoxic edema (P < 0.001). After 5 d of recovery there was greater residual electroencephalogram activity (-5.2+/-1.6 vs. -15.5+/-1.5 dB, P < 0.001) and a dramatic reduction in the extent of cortical infarction and neuronal loss in all regions assessed (e.g., 40 vs. 99% in the parasagittal cortex, P < 0.001). Selective head cooling, maintained throughout the secondary phase of injury, is noninvasive and safe and shows potential for improving neonatal outcome after perinatal asphyxia.

Aims. To determine the practicality and safety of head cooling with mild or minimal systemic hypothermia in term neonates with moderate to severe hypoxic-ischemic encephalopathy. Methods. Study group infants ≥37 weeks9 gestation, who had an umbilical artery pH ≤7.09 or Apgars ≤6 at 5 minutes, plus evidence of encephalopathy. Infants with major congenital abnormalities were excluded. Trial Design. Infants were randomized to either no cooling (controls; rectal temperature = 37.0 ± 0.2°C,n = 10) or sequentially, either minimal systemic cooling (rectal temperature = 36.3 ± 0.2°C,n = 6) or mild systemic cooling (rectal temperature = 35.7 ± 0.2°C, n = 6). Head cooling was accomplished by circulating water at 10°C through a coil of tubing wrapped around the head for up to 72 hours. All infants were warmed by servo-controlled overhead heaters to maintain the allocated rectal temperature. The rectal, fontanelle, and nasopharyngeal temperatures were continuously monitored. Results. From January 1996 to October 1997, 22 term infants were randomized from 2 to 5 hours after birth. All infants showed a metabolic acidosis at delivery, with similar umbilical artery pH in the control group (mean ± standard deviation, 6.79 ± 0.25), minimal cooling group (6.98 ± 0.21), and mild cooling group (6.93 ± 0.11), and depressed Apgar scores at 5 minutes in the control group (4.5 ± 2), minimal cooling group, (4.7 ± 2) and mild cooling group (6.0 ± 1). In the mild-cooled infants, the nasopharyngeal temperature was 34.5°C during cooling, 1.2°C lower than the rectal temperature. This gradient narrowed to 0.5°C after cooling was stopped. No adverse effects because of cooling were observed. No infants developed cardiac arrhythmias, hypotension, or bradycardia during cooling. Thrombocytopenia occurred in 2 out of 10 controls, 2 out of 6 minimal cooling infants, and 1 out of 6 mild cooling infants. Hypoglycemia (glucose <2.6 mM) was seen on at least one occasion in 2 out of 10 controls, 4 out of 6 minimal cooling infants, and 1 out of 6 mild cooling infants. Acute renal failure occurred in all infants. The metabolic acidosis present in all infants at the time of enrollment into the study progressively resolved despite cooling, even in the mild hypothermia group. Conclusions. Mild selective head cooling combined with mild systemic hypothermia in term newborn infants after perinatal asphyxia is a safe and convenient method of quickly reducing cerebral temperature with an increased gradient between the surface of the scalp and core temperature. The safety of mild hypothermia with selective head cooling is in contrast with the historical evidence of adverse effects with greater depths of whole-body hypothermia. This safety study and the strong experimental evidence for improved cerebral outcome justify a multicenter trial of selective head cooling for neonatal encephalopathy in term infants.

OBJECTIVE. The goal of this study was to evaluate the role of factors that may determine the efficacy of treatment with delayed head cooling and mild systemic hypothermia for neonatal encephalopathy.METHODS. A total of 218 term infants with moderate to severe neonatal encephalopathy plus abnormal amplitude-integrated electroencephalographic recordings, assigned randomly to head cooling for 72 hours, starting within 6 hours after birth (with the rectal temperature maintained at 34.5 ± 0.5°C), or conventional care, were studied. Death or severe disability at 18 months of age was assessed in a multicenter, randomized, controlled study (the CoolCap trial).RESULTS. Treatment, lower encephalopathy grade, lower birth weight, greater amplitude-integrated electroencephalographic amplitude, absence of seizures, and higher Apgar score, but not gender or gestational age, were associated significantly with better outcomes. In a multivariate analysis, each of the individually predictive factors except for Apgar score remained predictive. There was a significant interaction between treatment and birth weight, categorized as ≥25th or <25th percentile for term, such that larger infants showed a lower frequency of favorable outcomes in the control group but greater improvement with cooling. For larger infants, the number needed to treat was 3.8. Pyrexia (≥38°C) in control infants was associated with adverse outcomes. Although there was a small correlation with birth weight, the adverse effect of greater birth weight in control infants remained significant after adjustment for pyrexia and severity of encephalopathy.CONCLUSIONS. Outcomes after hypothermic treatment were strongly influenced by the severity of neonatal encephalopathy. The protective effect of hypothermia was greater in larger infants.

Objective. Cerebral hypothermia has been shown to reduce damage from experimental hy-poxia-ischemia if started shortly after reperfusion. However, in the newborn infant it may not be feasible to determine prognosis so soon after exposure to asphyxia. The aim of this study was to determine whether head cooling, delayed until shortly before the onset of postasphyxial seizure activity, is neuroprotective. Methods. Unanesthetized near-term fetal sheep in utero were subjected to 30 minutes of cerebral ischemia. Later, at 5.5 hours, they were randomized to either cooling (n = 7) or sham cooling (n = 10) for 72 hours. Intrauterine cooling was induced by circulating cold water through a coil around the fetal head. The water temperature was titrated to reduce fetal extradural temperature from 39.1 ± 0.1°C to between 30°C and 33°C, while maintaining esophageal temperature >37°C. Results. Cerebral cooling suppressed the secondary rise in cortical impedance (a measure of cytotoxic edema), but did not prevent delayed seizures, 8 to 30 hours after ischemia. Transient metabolic changes including increased plasma lactate and glucose levels were seen with a moderate sustained rise in blood pressure. This severe cerebral insult resulted in depressed residual parietal electroencephalographic activity after 5 days recovery (−14.2 ± 1.5 decibels), associated with a watershed distribution of neuronal loss (eg, 94 ± 4% in parasagittal cortex and 77 ± 4% in the lateral cortex). Hypothermia was associated with better recovery of electroencephalographic activity (−8.9% ± 1.8 decibels) and substantially reduced neuronal loss in the parasagittal cortex (46 ± 13%), the lateral cortex (9 ± 4%), and other regions except the cornu ammonis sectors 1 and 2 of the hippocampus. Conclusions. Delayed selective head cooling begun before the onset of postischemic seizures and continued for 3 days may have potential to significantly improve the outcome of moderate to severe hypoxic-ischemic encephalopathy.