Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Moderate hypothermia to treat perinatal asphyxial encephalopathy. Selective head cooling with mild systemic hypothermia after neonatal hypoxic-ischemic encephalopathy: a multicenter randomized controlled trial in China. Neurodevelopmental outcome of infants treated with head cooling and mild hypothermia after perinatal asphyxia. Mild hypothermia via selective head cooling as neuroprotective therapy in term neonates with perinatal asphyxia: an experience from a single neonatal intensive care unit. Selective head cooling with hypothermia suppresses the generation of platelet-activating factor in cerebrospinal fluid of newborn infants with perinatal asphyxia. Whole-body hypothermia for term and near-term newborns with hypoxic-ischemic encephalopathy: a randomized controlled trial. Systemic hypothermia after neonatal encephalopathy: outcomes of neo.nEURO.network RCT. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. Whole-body hypothermia for neonatal encephalopathy: animal observations as a basis for a randomized, controlled pilot study in term infants. Moderate hypothermia in neonatal encephalopathy: efficacy outcomes.
Cerebral hypothermia can improve outcome of experimental perinatal hypoxia-ischaemia. We did a multicentre randomised controlled trial to find out if delayed head cooling can improve neurodevelopmental outcome in babies with neonatal encephalopathy.
                234 term infants with moderate to severe neonatal encephalopathy and abnormal amplitude integrated electroencephalography (aEEG) were randomly assigned to either head cooling for 72 h, within 6 h of birth, with rectal temperature maintained at 34-35 degrees C (n=116), or conventional care (n=118). Primary outcome was death or severe disability at 18 months. Analysis was by intention to treat. We examined in two predefined subgroup analyses the effect of hypothermia in babies with the most severe aEEG changes before randomisation--ie, severe loss of background amplitude, and seizures--and those with less severe changes.
                In 16 babies, follow-up data were not available. Thus in 218 infants (93%), 73/110 (66%) allocated conventional care and 59/108 (55%) assigned head cooling died or had severe disability at 18 months (odds ratio 0.61; 95% CI 0.34-1.09, p=0.1). After adjustment for the severity of aEEG changes with a logistic regression model, the odds ratio for hypothermia treatment was 0.57 (0.32-1.01, p=0.05). No difference was noted in the frequency of clinically important complications. Predefined subgroup analysis suggested that head cooling had no effect in infants with the most severe aEEG changes (n=46, 1.8; 0.49-6.4, p=0.51), but was beneficial in infants with less severe aEEG changes (n=172, 0.42; 0.22-0.80, p=0.009).
                These data suggest that although induced head cooling is not protective in a mixed population of infants with neonatal encephalopathy, it could safely improve survival without severe neurodevelopmental disability in infants with less severe aEEG changes. Whether hypothermic therapy improves neurodevelopmental outcomes in newborn infants with asphyxial encephalopathy is uncertain.
                We performed a randomized trial of infants who were less than 6 hours of age and had a gestational age of at least 36 weeks and perinatal asphyxial encephalopathy. We compared intensive care plus cooling of the body to 33.5 degrees C for 72 hours and intensive care alone. The primary outcome was death or severe disability at 18 months of age. Prespecified secondary outcomes included 12 neurologic outcomes and 14 other adverse outcomes.
                Of 325 infants enrolled, 163 underwent intensive care with cooling, and 162 underwent intensive care alone. In the cooled group, 42 infants died and 32 survived but had severe neurodevelopmental disability, whereas in the noncooled group, 44 infants died and 42 had severe disability (relative risk for either outcome, 0.86; 95% confidence interval [CI], 0.68 to 1.07; P=0.17). Infants in the cooled group had an increased rate of survival without neurologic abnormality (relative risk, 1.57; 95% CI, 1.16 to 2.12; P=0.003). Among survivors, cooling resulted in reduced risks of cerebral palsy (relative risk, 0.67; 95% CI, 0.47 to 0.96; P=0.03) and improved scores on the Mental Developmental Index and Psychomotor Developmental Index of the Bayley Scales of Infant Development II (P=0.03 for each) and the Gross Motor Function Classification System (P=0.01). Improvements in other neurologic outcomes in the cooled group were not significant. Adverse events were mostly minor and not associated with cooling.
                Induction of moderate hypothermia for 72 hours in infants who had perinatal asphyxia did not significantly reduce the combined rate of death or severe disability but resulted in improved neurologic outcomes in survivors. (Current Controlled Trials number, ISRCTN89547571.)
                2009 Massachusetts Medical Society To investigate the efficacy and safety of selective head cooling with mild systemic hypothermia in hypoxic-ischemic encephalopathy (HIE) in newborn infants.
                Infants with HIE were randomly assigned to the selective head cooling or control group. Selective head cooling was initiated within 6 hours after birth to a nasopharyngeal temperature of 34 degrees+/-0.2 degrees C and rectal temperature of 34.5 degrees to 35.0 degrees C for 72 hours. Rectal temperature was maintained at 36.0 degrees to 37.5 degrees C in the control group. Neurodevelopmental outcome was assessed at 18 months of age. The primary outcome was a combined end point of death and severe disability.
                One hundred ninety-four infants were available for analysis (100 and 94 infants in the selective head cooling and control group, respectively). For the selective head cooling and control groups, respectively, the combined outcome of death and severe disability was 31% and 49% (OR: 0.47; 95% CI: 0.26-0.84; P=.01), the mortality rate was 20% and 29% (OR:0.62; 95% CI: 0.32-1.20; P=.16), and the severe disability rate was 14% (11/80) and 28% (19/67) (OR: 0.40; 95% CI: 0.17-0.92; P=.01).
                Selective head cooling combined with mild systemic hypothermia for 72 hours may significantly decrease the combined outcome of severe disability and death, as well as severe disability.
                Copyright (c) 2010 Mosby, Inc. All rights reserved. To determine the neurodevelopmental outcome of infants treated with head cooling with systemic hypothermia after hypoxic-ischemic encephalopathy.
                Infants >/=37 weeks' gestation, who had an umbilical artery pH </=7.09 or Apgar score </=6 at 5 minutes, plus clinical encephalopathy. Infants with major congenital abnormalities were excluded.
                Infants were allocated to either no cooling (rectal temperature = 37.0 +/- 0.2 degrees C, n = 15), or, sequentially, to head cooling accompanied by different levels of systemic hypothermia, including minimal cooling, rectal temperature 36.5 degrees C to 36 degrees C (n = 6), and mild cooling, to either 35.9 degrees C to 35.5 degrees C (n = 6), 35 +/- 0.5 degrees C (n = 6) or 34.5 +/- 0.5 degrees C (n = 7). Head cooling was accomplished by circulating cooled water through a coil of tubing wrapped around the head for up to 72 hours. Survivors were followed up with regular neurologic examination by a neonatologist until 18 months of age, then with blinded developmental testing using the revised Bayley Scales.
                A total of 40 term infants were enrolled from 2 to 5 hours after birth. The control and the cooled groups were not significantly different for gestation, birth weight, Apgar score, and initial pH. There were 6 early neonatal deaths (3 normothermic and 3 cooled), and 1 death in infancy associated with severe spastic cerebral palsy in a normothermic infant. Six normothermic, 1 minimally cooled, and 4 mildly cooled infants had early stage 1 encephalopathy; all but 1 had a good outcome. Among infants with early stage 2 or 3 encephalopathy, an adverse outcome was found in 4 of 9 normothermic infants (44%) and 4 of 5 minimally cooled infants (80%), whereas in the combined mildly cooled groups, an adverse outcome was found in 4 of 15 infants (26%, odds ratio 0.46 [0.08, 2.56] vs normothermia).
                The present study supports the safety of hypothermia, with no evidence of late adverse effects in any infant. Among infants with moderate to severe encephalopathy at enrollment, there was a tendency toward better outcome. These results emphasize the relatively wide range of outcomes using purely clinical criteria for enrollment. Therapeutic hypothermia should not be used outside of stringent, multicenter trials. The objective of this study was to determine the efficacy of mild hypothermia via selective head cooling as a neuroprotective therapy in term infants with perinatal asphyxia.
                Full-term newborns who had 5 min Apgar scores <6, first arterial blood gas pH<7.10 or BD>15 mEq/l, and with the clinical signs of encephalopathy were enrolled within 6 h after birth. Patients were randomized to receive mild hypothermia treatment via selective head cooling for a total of 72 h or receive routine treatment as a control. Brain hypoxic-ischemic injury was quantified based on the head computed tomographic scan (CT scan) at postnatal age 5-7 days and a Neonatal Behavioral Neurological Assessment (NBNA) score at 7-10 days of life.
                A total of 58 patients (30 hypothermia, 28 control) completed the study. Hypothermia was well tolerated in this study and attenuated the hypoxic-ischemic brain injury due to perinatal asphyxia. Head CT scan demonstrated moderate to severe hypoxic-ischemic changes in only 4/30 cases from the hypothermic group. In contrast, 18/28 cases in the control group showed moderate to severe hypoxic-ischemic changes (chi (2)=15.97, P<0.01). Brain hypothermia also significantly improved the NBNA score (32+/-2 in the hypothermic group vs 28+/-3 in the control group, P<0.01).
                Our results suggest that selective head cooling may be used as a neuroprotective therapy in term neonates with perinatal asphyxia. A long-term follow-up study is needed to further validate the results of this study. Hypoxic-ischemic encephalopathy (HIE) remains one of the most important neurologic complications in the newborn. Several experimental and clinical studies have shown that hypothermia is the most effective means known for protecting the brain against hypoxic-ischemic brain damage. Furthermore, recent data have suggested that platelet-activating factor (PAF) could play a pathophysiologically important role in the progression of hypoxic-ischemic brain injury. The aim of the present study was to investigate the role of head cooling combined with minimal hypothermia in short-term outcome of infants with perinatal asphyxia. In addition, we have examined the effect of head cooling combined with minimal hypothermia on PAF concentrations in cerebrospinal fluid (CSF) after hypoxic-ischemic brain injury. The group of asphyxiated infants (Group 1) consisted of 21 full-term (gestational age >37 weeks). These infants were randomized and divided into either a standard therapy group (Group 1a; n=10) or cooling group (Group 1b; n=11). Head cooling combined with minimal hypothermia (rectal temperature 36.5-36 degrees C) was started as soon as practicable after birth. The infants were cooled for 72h and then were rewarmed at 0.5 degrees C/h. The control group (Group 2) consisted of seven full-term infants and none of these infants showed any sign of asphyxia. To measure PAF concentration in CSF, CSF with lumbar puncture was collected into tubes immediately before the cooling (1-3h after birth) and again after 36h. We had no evidence of severe adverse events related to hypothermia. In Group 1a, two infants died after 72h of life; however, all newborn infants in Group 1b survived. Convulsion required treatment in three infants of standard therapy group (1a); none of the infants in Group 1b had clinical seizure activity. Abnormal EEG patterns were found in four infants of Group 1a; no EEG abnormalities were noted in Group 1b (P<0.05). On admission (before cooling), PAF concentration in CSF of asphyxiated infants was found to be significantly higher when compared with that of control (P<0.001). Mean PAF concentration before initiation of the study was similar in the two asphyxiated groups (Group 1a vs. 1b) (P>0.05). Obtained PAF level in CSF after 36h, showed a profound decline in cooling group of infants compared to Group 1a infants (P<0.01). In conclusion, the present study suggests that cerebral cooling with minimal hypothermia started soon after birth has no severe adverse effects during 72-h cooling period and that short-term outcome of infants are encouraging. Our results also support the hypothesis PAF an important mediator in hypoxic-ischemic brain injury and demonstrate that head cooling combined with minimal hypothermia reduces the normal increase in PAF following hypoxic-ischemic brain injury in full-term infants. To determine the effectiveness and safety of moderate whole-body hypothermia in newborns with hypoxic-ischemic encephalopathy born in hospitals with and without newborn intensive care facilities or complicated hypothermia equipment.
                Multicenter, international, randomized controlled trial.
                Neonatal intensive care units in Australia, New Zealand, Canada, and the United States (N = 28) from February 2001 through July 2007.
                Newborns of 35 weeks' gestation or more, with indicators of peripartum hypoxia-ischemia and moderate to severe clinical encephalopathy, randomly allocated to hypothermia (n = 110) or standard care (n = 111).
                Whole-body hypothermia to 33.5°C for 72 hours or standard care (37°C). Infants who received hypothermia were treated at ambient environmental temperature by turning off the radiant warmer and then applying refrigerated gel packs to maintain rectal temperature at 33°C to 34°C.
                Death or major sensorineural disability at 2 years of age.
                Therapeutic hypothermia reduced the risk of death or major sensorineural disability at 2 years of age: 55 of 107 infants (51.4%) in the hypothermia group and 67 of 101 infants (66.3%) in the control group died or had a major sensorineural disability at 2 years (risk ratio, 0.77 [95% confidence interval, 0.62-0.98]; P = .03). The mortality rate decreased, and the survival rate free of any sensorineural disability increased. Adverse effects of hypothermia were minimal.
                Whole-body hypothermia is effective and appears to be safe when commenced within 6 hours of birth at the hospital of birth in term and near-term newborns with hypoxic-ischemic encephalopathy. This simple method of hypothermia could be used within strict protocols with appropriate training on correct diagnosis and application of hypothermia in nontertiary neonatal settings while awaiting retrieval and transport to the regional neonatal intensive care unit.
                anzctr.org.au Identifier: ACTRN12606000036516. Mild hypothermia after perinatal hypoxic-ischemic encephalopathy (HIE) reduces neurologic sequelae without significant adverse effects, but studies are needed to determine the most-efficacious methods.
                In the neo.nEURO.network trial, term neonates with clinical and electrophysiological evidence of HIE were assigned randomly to either a control group, with a rectal temperature of 37°C (range: 36.5-37.5°C), or a hypothermia group, cooled and maintained at a rectal temperature of 33.5°C (range: 33-34°C) with a cooling blanket for 72 hours, followed by slow rewarming. All infants received morphine (0.1 mg/kg) every 4 hours or an equivalent dose of fentanyl. Neurodevelopmental outcomes were assessed at the age of 18 to 21 months. The primary outcome was death or severe disability.
                A total of 129 newborn infants were enrolled, and 111 infants were evaluated at 18 to 21 months (53 in the hypothermia group and 58 in the normothermia group). The rates of death or severe disability were 51% in the hypothermia group and 83% in the normothermia group (P=.001; odds ratio: 0.21 [95% confidence interval [CI]: 0.09-0.54]; number needed to treat: 4 [95% CI: 3-9]). Hypothermia also had a statistically significant protective effect in the group with severe HIE (n=77; P=.005; odds ratio: 0.17 [95% CI: 0.05-0.57]). Rates of adverse events during the intervention were similar in the 2 groups except for fewer clinical seizures in the hypothermia group.
                Systemic hypothermia in the neo.nEURO.network trial showed a strong neuroprotective effect and was effective in the severe HIE group. Hypothermia is protective against brain injury after asphyxiation in animal models. However, the safety and effectiveness of hypothermia in term infants with encephalopathy is uncertain.
                We conducted a randomized trial of hypothermia in infants with a gestational age of at least 36 weeks who were admitted to the hospital at or before six hours of age with either severe acidosis or perinatal complications and resuscitation at birth and who had moderate or severe encephalopathy. Infants were randomly assigned to usual care (control group) or whole-body cooling to an esophageal temperature of 33.5 degrees C for 72 hours, followed by slow rewarming (hypothermia group). Neurodevelopmental outcome was assessed at 18 to 22 months of age. The primary outcome was a combined end point of death or moderate or severe disability.
                Of 239 eligible infants, 102 were assigned to the hypothermia group and 106 to the control group. Adverse events were similar in the two groups during the 72 hours of cooling. Primary outcome data were available for 205 infants. Death or moderate or severe disability occurred in 45 of 102 infants (44 percent) in the hypothermia group and 64 of 103 infants (62 percent) in the control group (risk ratio, 0.72; 95 percent confidence interval, 0.54 to 0.95; P=0.01). Twenty-four infants (24 percent) in the hypothermia group and 38 (37 percent) in the control group died (risk ratio, 0.68; 95 percent confidence interval, 0.44 to 1.05; P=0.08). There was no increase in major disability among survivors; the rate of cerebral palsy was 15 of 77 (19 percent) in the hypothermia group as compared with 19 of 64 (30 percent) in the control group (risk ratio, 0.68; 95 percent confidence interval, 0.38 to 1.22; P=0.20).
                Whole-body hypothermia reduces the risk of death or disability in infants with moderate or severe hypoxic-ischemic encephalopathy.
                Copyright 2005 Massachusetts Medical Society. Modest reduction in brain temperature is a promising therapy to reduce brain damage after neonatal encephalopathy as a result of acute perinatal asphyxia. The efficacy of modest hypothermia may in part be dependent on the stability of the desired brain temperature. The objective of this study was 1) to evaluate in newborn animals a commercially available cooling system (Blanketrol II Hyperthermia-Hypothermia system) to control brain temperature during whole-body hypothermia and 2) to use the results of the animal experiments to perform a pilot study evaluating the feasibility of whole-body hypothermia as a neuroprotective therapy for newborns with encephalopathy at birth.
                In the animal investigation, 3 miniature swine were instrumented and ventilated, and temperature probes were placed in the esophagus and the brain (1 cm and 2 cm beneath the parietal cortical surface and the dura). Body cooling was achieved using the automatic control mode (servo) of the cooling system. In the human investigation, 19 term infants with moderate or severe encephalopathy were randomized to either normothermia (n = 10) or hypothermia (n = 9) within 6 hours of birth. Whole-body hypothermia was achieved using the hyperthermia-hypothermia cooling system with servo control of esophageal temperature to 34.5 degrees C for 72 hours followed by slow rewarming.
                In the animal investigation, body cooling with the animal lying on a single blanket resulted in rapid cooling of the body within 90 minutes. Repetitive cyclical swings in esophageal temperature of 1.7 +/- 0.2 degrees C (mean +/- standard deviation) around the set point of 33.5 degrees C were reduced to 0.7 +/- 0.2 degrees C when a second, larger blanket was attached and suspended. Esophageal temperature was a good marker of deep brain temperature (esophageal to 2-cm brain difference: 0.1 +/- 0.3 degrees C). In the human investigation, the infants were randomized at 4.1 +/- 1.3 hours (mean +/- standard deviation) after birth. Age at randomization was similar in the 2 groups. Cooling was initiated at an average age of 5.3 hours. Target temperature of 34.5 degrees C was achieved within 30 minutes and remained constant throughout the intervention period. Heart rate decreased to 108 +/- 14 beats per minute (bpm) at 60 minutes and remained between 115 and 130 bpm for the duration of cooling compared with 130 to 145 bpm in the normothermia group. Blood pressure was similar in the 2 groups. No adverse events occurred during 72 hours of cooling. The mortality rate and frequency of persistent pulmonary hypertension, renal failure, hepatic dysfunction, and need for pressor support were similar in both groups.
                Animal studies showed that a simple modification of a commercially available cooling system (2 blankets attached, subject lying on 1 and the second hanging freely) results in stable core body and brain temperature when used in the automatic control mode. The pilot study in term infants with encephalopathy using this cooling system demonstrates feasibility of initiating whole-body hypothermia at <6 hours of age to a constant esophageal temperature using servo control and provides no evidence that hypothermia involved greater hazard than benefit. Therapeutic hypothermia holds promise as a rescue neuroprotective strategy for hypoxic-ischemic injury, but the incidence of severe neurologic sequelae with hypothermia is unknown in encephalopathic neonates who present shortly after birth. This study reports a multicenter, randomized, controlled, pilot trial of moderate systemic hypothermia (33 degrees C) vs normothermia (37 degrees C) for 48 hours in neonates initiated within 6 hours of birth or hypoxic-ischemic event. The trial tested the ability to initiate systemic hypothermia in outlying hospitals and participating tertiary care centers, and determined the incidence of adverse neurologic outcomes of death and developmental scores at 12 months by Bayley II or Vineland tests between normothermic and hypothermic groups. Thirty-two hypothermic and 33 normothermic neonates were enrolled. The entry criteria selected a severely affected group of neonates, with 77% Sarnat stage III. Ten hypothermia (10/32, 31%) and 14 normothermia (14/33, 42%) patients expired. Controlling for treatment group, outborn infants were significantly more likely to die than hypoxic-ischemic infants born in participating tertiary care centers (odds ratio 10.7, 95% confidence interval 1.3-90). Severely abnormal motor scores (Psychomotor Development Index < 70) were recorded in 64% of normothermia patients and in 24% of hypothermia patients. The combined outcome of death or severe motor scores yielded fewer bad outcomes in the hypothermia group (52%) than the normothermia group (84%) (P = 0.019). Although these results need to be validated in a large clinical trial, this pilot trial provides important data for clinical trial design of hypothermia treatment in neonatal hypoxic-ischemic injury.
There is evidence from the 11 randomised controlled trials included in this systematic review (N = 1505 infants) that therapeutic hypothermia is beneficial in term and late preterm newborns with hypoxic ischaemic encephalopathy. Cooling reduces mortality without increasing major disability in survivors. The benefits of cooling on survival and neurodevelopment outweigh the short-term adverse effects. Hypothermia should be instituted in term and late preterm infants with moderate-to-severe hypoxic ischaemic encephalopathy if identified before six hours of age. Further trials to determine the appropriate techniques of cooling, including refinement of patient selection, duration of cooling and method of providing therapeutic hypothermia, will refine our understanding of this intervention.