A systematic review of cooling for neuroprotection in neonates with hypoxic ischemic encephalopathy - are we there yet?
Topic: Hyperthermia

The objective of this study was to systematically review randomized trials assessing therapeutic hypothermia as a treatment for term neonates with hypoxic ischemic encephalopathy.

PICO
Population: Term neonates with hypoxic ischemic encephalopathy
Intervention: Therapeutic hypothermia
Comparison: Standard care or placebo
Outcomes: Assessment of neuroprotection and treatment efficacy

Included studies:
title: Moderate hypothermia in neonatal encephalopathy: efficacy outcomes.
abstract: 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.
title: Composite outcomes in randomized trials: greater precision but with greater uncertainty?
abstract: Composite outcomes, in which multiple end points are combined, are frequently used as primary outcome measures in randomized trials and are often associated with increased statistical efficiency. However, such measures may prove challenging for the interpretation of results. In this article, we examine the use of composite outcomes in major clinical trials, assess the arguments for and against them, and provide guidance on their application and reporting. To assess incidence and quality of reporting, we systematically reviewed the use of composite end points in clinical trials in Annals of Internal Medicine, BMJ, Circulation, Clinical Infectious Diseases, Journal of the American College of Cardiology, JAMA, Lancet, New England Journal of Medicine, and Stroke from 1997 through 2001 using a sensitive search strategy. We selected for review 167 original reports of randomized trials (with a total of 300 276 patients) that included a composite primary outcome that incorporated all-cause mortality. Sixty-three trials (38%) were neutral both for the primary end point and the mortality component. Sixty trials (36%) reported significant results for the primary outcome measure but not for the mortality component. Only 6 trials (4%) were significant for the mortality component but not for the primary composite outcome, whereas 19 trials (11%) were significant for both. Twenty-two trials (13%) were inadequately reported. Our review suggests that reporting of composite outcomes is generally inadequate, implying that the results apply to the individual components of the composite outcome rather than only to the overall composite. Current guidelines for the undertaking and reporting of clinical trials could be revised to reflect the common use of composite outcomes in clinical trials.
title: Treatment of term infants with head cooling and mild systemic hypothermia (35.0 degrees C and 34.5 degrees C) after perinatal asphyxia.
abstract: To assess the safety of selective head cooling in birth-asphyxiated term newborn infants while maintaining the rectal temperature at 35.0 degrees C or 34.5 degrees C.
title: Determinants of outcomes after head cooling for neonatal encephalopathy.
abstract: 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.
title: Selective head cooling with hypothermia suppresses the generation of platelet-activating factor in cerebrospinal fluid of newborn infants with perinatal asphyxia.
abstract: 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.
title: School performance of survivors of neonatal encephalopathy associated with birth asphyxia at term.
abstract: School performance testing was completed at 8 years of age on 145 children who had had neonatal encephalopathy associated with birth asphyxia as term infants and on a comparison peer group of 155 children. The prospectively identified clinical categories of encephalopathy for the neonates were 56 mild (hyperalertness, hyperexcitability), 84 moderate (lethargy, hypotonia, suppressed primitive reflexes), and 5 severe (stupor, flaccidity, absent primitive reflexes). The mortality rate to 8 years of age was 13%. The incidence of impairment, which included cerebral palsy, blindness, cognitive delay, convulsive disorder, and severe hearing loss, was 16% among those assessed at 8 years (75% of survivors). Intellectual, visual-motor integration, and receptive vocabulary scores, as well as reading, spelling, and arithmetic grade levels for those with moderate or severe encephalopathy, were significantly below (p less than 0.01) those in the mild encephalopathy or peer comparison groups. Predictors of reading performance for the study group included category of encephalopathy, birth weight for gestational age, native language, and mother's educational level (multiple R = 0.58). Nonimpaired survivors of moderate encephalopathy were more likely to be more than one grade level delayed than were children from the peer group (reading 35% vs 15%, spelling 18% vs 8%, arithmetic 20% vs 12%, p less than 0.01). Thus children who had moderate and severe neonatal encephalopathy are at risk for physical and mental impairment and reduced school performance. Children with mild encephalopathy had school performance scores similar to those of their peers.
title: Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial.
abstract: 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.
title: Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy.
abstract: 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.
title: Selective head cooling in newborn infants after perinatal asphyxia: a safety study.
abstract: 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.
title: Moderate hypothermia in neonatal encephalopathy: safety outcomes.
abstract: Hypoxic-ischemic injury may cause multisystem organ damage with significant aberrations in clotting, renal, and cardiac functions. Systemic hypothermia may aggravate these medical conditions, such as bradycardia and increased clotting times, and very little safety data in neonatal hypoxic-ischemic injury is available. 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 infants with neonatal encephalopathy instituted within 6 hours of birth or hypoxic-ischemic event. The best outcome measures of safety were determined, comparing rates of adverse events between normothermia and hypothermia groups. A total of 32 hypothermia and 33 normothermia neonates were enrolled in seven centers. Adverse events and serious adverse effects were collected by the study team during the hospital admission, monitored by an independent study monitor, and reported to Institutional Review Boards and the Data and Safety Monitoring Committee. The following adverse events were observed significantly more commonly in the hypothermia group: more frequent bradycardia and lower heart rates during the period of hypothermia, longer dependence on pressors, higher prothrombin times, and lower platelet counts with more patients requiring plasma and platelet transfusions. Seizures as an adverse event were more common in the hypothermia group. These observed side effects of 48 hours of moderate systemic hypothermia were of mild to moderate severity and manageable with minor interventions.
title: Hypoxic-ischemic encephalopathy in term neonates: perinatal factors and outcome.
abstract: Ninety-five infants of 37 weeks' gestation or greater with evidence of hypoxic-ischemic encephalopathy following perinatal asphyxia were prospectively identified in the neonatal period. The degree of encephalopathy was graded the staging system of Sarnat and Sarnat. Six infants died, 78 infants were sequentially followed in the Neonatal Follow-up Clinic, and in five additional infants, follow-up information was available. The mean duration of follow-up was 19.3 months. Fifty-eight (65%) of the 89 infants followed were normal or mildly handicapped, six (7%) died, and the remainder had significant handicap. There was no significant relationship between any of over 100 obstetrical antepartum or intrapartum variables and outcome. Infants with five-minute Apgar scores of 0 to 3, seizures within the first day of life, Stage II or III encephalopathy, or a suppressed electroencephalogram had a significantly greater incidence of severe handicap or death. In addition, although there were fewer females, they had a significantly greater incidence of handicap. There appeared to be an improved outcome in the last two years (1977-1978) compared to the first two years (1975-1976), suggesting that improved recognition and neonatal management may lead to a decrease in significant sequelae.
title: Neurodevelopmental outcome of infants treated with head cooling and mild hypothermia after perinatal asphyxia.
abstract: To determine the neurodevelopmental outcome of infants treated with head cooling with systemic hypothermia after hypoxic-ischemic encephalopathy.
title: [Effects of hypothermia on cardiac function in neonates with asphyxia].
abstract: To study the effects of hypothermia on cardiac function in neonates after birth asphyxia.
title: Dramatic neuronal rescue with prolonged selective head cooling after ischemia in fetal lambs.
abstract: 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.
title: Whole-body hypothermia for neonatal encephalopathy: animal observations as a basis for a randomized, controlled pilot study in term infants.
abstract: 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.
title: Mild hypothermia via selective head cooling as neuroprotective therapy in term neonates with perinatal asphyxia: an experience from a single neonatal intensive care unit.
abstract: 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.