PEDIATRICS Vol. 107 No. 3 March 2001, pp. 480-484

Neurodevelopmental Outcome of Infants Treated With Head Cooling and Mild Hypothermia After Perinatal Asphyxia

Malcolm R. Battin, MBChB, MRCP(UK)^*, , J. Anne Dezoete, BA, PhD^*, Tania R. Gunn, MBChB, MD^{*, , §}, Peter D. Gluckman, MBChB, DSc^§, and Alistair J. Gunn, MBChB, PhD^{, §}

From the ^* Newborn Service, National Women's Hospital, Auckland, New Zealand; and the  Department of Paediatrics and ^§ Research Centre for Developmental Medicine and Biology, University of Auckland, Auckland, New Zealand.

	ABSTRACT

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Objectives.  To determine the neurodevelopmental outcome of infants treated with head cooling with systemic hypothermia after hypoxic-ischemic encephalopathy.

Study Group.  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.

Trial Design.  Infants were allocated to either no cooling (rectal temperature = 37.0 ± 0.2°C, n = 15), or, sequentially, to head cooling accompanied by different levels of systemic hypothermia, including minimal cooling, rectal temperature 36.5°C to 36°C (n = 6), and mild cooling, to either 35.9°C to 35.5°C (n = 6), 35 ± 0.5°C (n = 6) or 34.5 ± 0.5°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.

Results.  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).

Conclusions.  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.  Key words:  hypoxic-ischemic encephalopathy, asphyxia neonatorum, induced hypothermia, neurodevelopmental outcome.

Recent studies have demonstrated that in many clinical cases, as well as in experimental perinatal hypoxia-ischemia, after resuscitation from the initial insult there can be a latent stage characterized by restoration of the cerebral energy metabolism but continued suppression of electroencephalogram activity.^1,2 However, some hours later there may be secondary deterioration in a phase that is characterized by delayed onset of edema, accumulation of cytotoxins, secondary cerebral energy failure, and frequently seizures.^1-3 As perinatal hypoxic-ischemic injury remains an important cause of both neonatal death and long-term disability,⁴ there is considerable interest in therapies that may modify this process.

Prolonged, moderate hypothermia started before the start of the secondary deterioration is a potential neuroprotective therapy that may be suitable for clinical use. As recently reviewed, it has been shown to ameliorate secondary neurologic injury in a number of experimental paradigms.¹ Selective cooling of the head with mild systemic hypothermia, produced by using a cooling cap while warming the body with radiant heat, may reduce the brain temperature to a level optimal for neuroprotection while limiting the adverse systemic effects of hypothermia.⁵

We and others have shown in pilot studies that under tightly defined conditions, hypothermia is generally safe in the short-term even in the severely asphyxiated infant.^5-7 Furthermore, the short-term outcome of hypothermia was encouraging.⁵ Although large randomized trials of hypothermia for perinatal asphyxia are now underway, there is little published data on the long-term outcome of infants with perinatal asphyxia who have been cooled in the neonatal period. The aim of this study, therefore, was to determine the neurodevelopmental outcome, at 18 months of age, in a group of term infants treated with selective head cooling or studied as controls after hypoxic-ischemic encephalopathy (HIE).

	METHODS

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Ethical approval for head cooling with mild systemic hypothermia in term infants with HIE was given by the North Health Regional Ethics Committee. Parental consent to study the individual infants was obtained in each case. During the period of January 1996 until December 1998, term infants admitted to the neonatal unit at National Women's Hospital and considered at high risk of perinatal asphyxia were prospectively evaluated for signs of HIE. The infants were either inborn at National Women's Hospital, referred from local level one hospitals, or referred from the community after home birth.

Infants were enrolled in the study based on a clinical history consistent with perinatal asphyxia and the presence of all of the following entry criteria: 1) gestational age >37 weeks; 2) 5-minute Apgar score 6 or cord/first arterial pH 7.09; 3) encephalopathy consisting of lethargy/stupor, hypotonia, abnormal reflexes including an absent or weak suck. Infants with obvious major congenital abnormalities were excluded. Metabolic diseases were screened for by routine investigations, and no cases were detected. All infants were evaluated between 2 and 5 hours after birth, and monitoring and/or cooling was started before 6 hours after birth.

After parental consent had been obtained, the infants were randomized by computer-generated numbers in sealed envelopes and allocated to either a control group (n = 13) or cooling group (n = 18). To ensure that experience could be gained at one temperature range before exposure of infants to the lower temperature range, the cooling groups were sequential. The initial cooling group were cooled to a rectal temperature of 36.5°C to 36°C (minimal cooling group; n = 6).⁵ As no adverse effects were found at this temperature, infants were then studied with mild hypothermia, at rectal temperatures of 35.9°C to 35.5°C (n = 6)⁵ and 35 ± 0.5°C (n = 6).⁷ In view of the lack of adverse reactions to hypothermia and encouraging short-term outcome of cooling in the first 3 groups, ethical permission was given to allow the final group of infants to be sequentially allocated to 34.5 ± 0.5°C (n = 7).⁷ Two additional, normothermic infants who fulfilled the study entry criteria but were not randomized because of nonavailability of the researcher were also followed. Thus, a total of 25 cooled and 15 noncooled infants were studied.

In the hypothermia group of infants, selective head cooling was accomplished by circulating cooled water through a cap placed on the infant's head, as described previously.⁵ Overhead heaters, servo-controlled to the abdominal skin, were adjusted to maintain the allocated rectal temperature. The initial 17 infants were cooled using a cap made of Silclear tubing (Degania Silicone Ltd, Degania Bet, Israel) coiled to fit around the scalp of the infant and held in place by a baby bonnet. Subsequently, a commercial device (Olympic Medical, Seattle, WA) was used. The cooling devices both worked on the same principle of a small thermostatically controlled cooling unit and a pump that circulated the water through the coil. The Olympic Medical device differed in the extra provision of monitoring and alarms as an integral part of the equipment. The temperature of the water circulated could be adjusted with a specified range. The initial water temperature was set at 10°C based on experience in previous studies with appropriate adjustments as required to maintain the allocated rectal temperature. A sham cap was not used in the control infants as there was concern that it could produce a warming effect with a potentially deleterious rise in cerebral temperature.

The rectal, fontanelle, and nasopharyngeal temperatures were continuously monitored with thermistors (IncuTemp1, Mallinckrodt Medical, St Louis, MO or YSI Precision 440, Yellow Springs Instrument Co, Yellow Springs, OH). All infants had continuous electrocardiograph monitoring and pulse oximetry. Umbilical arterial catheters for blood gas and blood pressure monitoring were inserted or maintained only if clinically indicated.

In the cooled infants, the rectal temperature was maintained within the prescribed range for 72 hours. Thereafter, slow rewarming was commenced at 0.5°C per hour until the infant was within the normal temperature range. The cooling was discontinued earlier, at 48 hours, only if the infant was normal on neurologic examination at this time. Temperature and physiologic monitoring was continued for a minimum of 4 hours after the end of cooling.

Clinical care of the study infants included an early cranial head ultrasound to exclude major intracranial bleeding or malformation. Follow-up cerebral computer tomographic scan and electroencephalogram studies were obtained 5 to 7 days after delivery when clinically possible. Blood and surface cultures were performed and the infants were treated with antibiotics until the culture results were known. Clinical seizures were treated starting with a loading dose of 20 mg/kg of phenobarbitone and, if needed, additional phenobarbitone, then 20 mg/kg of phenytoin, then paraldehyde. The study infants were all kept nil by mouth during cooling, but the rate of feeding of cooled infants after rewarming and the feeding of control infants was at the discretion of the attending clinician. Similarly, the attending clinician directed all other aspects of clinical care.

Demographic and clinical data were collected from appropriate sources and included documentation of pregnancy and labor complications, mode of delivery, Apgar scores, umbilical arterial blood gases, details of resuscitation, and any other relevant clinical details. Clinical follow-up in the outpatient clinic was performed until 18 months of age and consisted of serial neurologic examination performed by 1 of the investigators (M.R.B.). In addition, a psychologist blinded to treatment group performed formal developmental assessment using the Bayley Scales of Infant Development, Second Edition at 18 months of age.⁸ Blinding was ensured by several means. The psychologist did not see patients during their neonatal admission, and the request for assessment did not include the cooling status. Patients were asked not to discuss the treatment. All infants were referred for audiology assessment at discharge. The assessment consisted of auditory brainstem-evoked potential testing or visual reinforced audiometry as developmentally appropriate.

Data are presented as mean ± standard deviation or as median (range) as appropriate. Incidences were compared by ². The groups were compared by 2-way Mann-Whitney U test or Student's t test as appropriate. For comparison with the normothermia group, the groups with mild systemic hypothermia (35.5°C-35.9°C, 35 ± 0.5°C, and 34.5 ± 0.5°C) were grouped together.

	RESULTS

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The clinical and demographic characteristics of the individual study groups were similar (Table 1). All infants had evidence of perinatal asphyxia with depressed 5-minute Apgar scores and low cord or first arterial pH; however, the degree of encephalopathy that subsequently developed varied from mild to severe. The short-term outcome of the infants undergoing cooling has previously been reported elsewhere.^5,7 In brief, 34 of the 40 study infants survived until discharge and there was 1 subsequent death in late infancy of a control infant with severe spastic quadriparesis. Of the 6 infants that died in the neonatal period, 3 were in the normothermic group of infants, 2 were in the minimally cooled group (36°C-36.5 °C), and 1 was in the 35°C group. The deaths were from primary respiratory failure with associated persistent pulmonary hypertension and/or meconium aspiration in 4 cases, and profound multisystem or renal failure in 2 cases.

Twenty-eight of the 33 surviving infants underwent both physical examination and Bayley assessment at 18 months of age. Two infants with severe cerebral palsy and microcephaly were reviewed at this time, but in view of their severe neurologic impairment did not undergo a formal Bayley assessment. Three infants were only reviewed before 18 months of age. One minimally cooled infant (36.5°C-36 °C) underwent formal neurologic examination at 12 months of age with no neurologic abnormality or developmental delay detected, but the family then moved away and declined to return for Bayley assessment. The other 2 infants not reviewed at 18 months of age were normothermic controls who were initially seen in the first year of life but thereafter did not attend the clinic. One family was contacted by phone and stated that there were no parental concerns with development at 18 months of age, but declined to attend for formal hospital review; the other infant was lost to follow-up.

The initial Sarnat staging and outcomes of the individual infants are listed in Table 2. Adverse outcome, defined as 1 or more of the following: death, cerebral palsy, Bayley scores >2 standard deviations from the norm, blindness, or hearing impairment requiring amplification, occurred in 14 out of 40 study infants. Of the 15 normothermic infants, 4 had an adverse outcome, including 3 deaths in the neonatal period and 1 death in late infancy associated with severe cerebral palsy, microcephaly, and seizures. In addition, 1 infant had a moderately impaired mental development score of 71. The minimally cooled group (36°C-36.5°C) had an adverse outcome in 4 of the 6 infants with 2 neonatal deaths and 2 cases of severe cerebral palsy. In the remaining 19 infants treated with mild systemic hypothermia, there was 1 death, 3 cases of cerebral palsy, and 1 of isolated hypotonia and developmental delay at 18 months of age. No infant had hearing impairment requiring amplification but 3 infants with developmental delay and cerebral palsy (numbers 17, 18, and 31) were reported to have mildly increased auditory thresholds. Two other infants (numbers 5 and 39) had evidence of conductive loss as a result of middle ear effusion. Seizures beyond the neonatal period occurred in only 3 cases (numbers 13, 17, and 18) all of whom had severe spastic quadriparesis and microcephaly.

Six normothermic, 1 minimally cooled, and 4 mildly cooled infants had mild early encephalopathy (stage 1); only 1 of these infants had an adverse outcome. Among infants with early Sarnat 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%); not significant compared with normothermia, odds ratio 0.46 (0.08, 2.56).

Within the groups of infants cooled to 35°C or 34.5 ± 0.5°C, there were 2 infants (numbers 28 and 38) with a very poor initial neurologic condition, and evidence of having undergone very severe insults, who had good outcomes when compared with the anticipated course. The first infant (number 28) required resuscitation in the delivery suite and after admission to the neonatal unit still had an arterial pH of 6.7. Clinical condition was very poor and the infant required cardiac massage and repeated doses of adrenaline and sodium bicarbonate for refractory bradycardia, leading to very severe encephalopathy and a 4-week stay on the neonatal unit. In the other case (number 38) the infant was an apparent stillbirth with resuscitation abandoned at 20 minutes because of lack of response. Shortly after this, precordial activity was detected and resuscitation recommenced. The infant developed a severe encephalopathy with absent brainstem reflexes on early neurologic examination. In both cases, the clinical outcome at 18 months of age was very good with a normal neurologic examination and Bayley assessment was within the normal range.

Two infants (number 37 and 39) who developed cerebral palsy and had a poor outcome after treatment with hypothermia were born after maternal pyrexia during labor of 38.4°C and 38.7°C, respectively. In the first case, the mother had taken a hot bath while in labor, and there was no sign of prolonged rupture of membranes or maternal infection. In the second case, there was a true knot in the cord and prolonged rupture of membranes but negative blood cultures. These 2 infants had rectal temperatures of 37.7°C and 38.6°C on admission to the neonatal unit and cooling was commenced at 5.6 and 3.2 hours, respectively.

	DISCUSSION

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In this study, we report the neurodevelopmental outcome of a group of term infants with evidence of postasphyxial encephalopathy who received either head cooling with varying levels of mild systemic hypothermia or standard, normothermic care. We and others have previously reported short-term outcomes after hypothermia for perinatal asphyxia,^5-7,9 but there is little longer-term outcome data. A number of small studies were performed in the 1950s and 1960s where infants not breathing spontaneously at 5 minutes were immersed in cold water until respiration resumed. These studies were uncontrolled and follow-up was limited.^10-12

The present study was not designed to test the efficacy of cerebral cooling. The primary aim was to detect major adverse effects of hypothermia in infants exposed to perinatal asphyxia. For this reason, a stepped design was used, with increasing depths of hypothermia in successive groups of treated infants.^5,7 There was no evidence of any unexpected late adverse effects of hypothermia. The major abnormal outcomes reported were cerebral palsy, developmental delay, microcephaly, hearing impairment, and seizure disorders, consistent with the well-known effects of perinatal hypoxia-ischemia.¹³

Outcome was assessed at 18 months of age in the majority of infants. This age was chosen to allow formal examination for signs of cerebral palsy. Although 3 infants were younger than this when last reviewed, it is unlikely that this influenced the results of our study. One infant was clinically normal at 12 months of age. The other 2 infants presented with a mild encephalopathy and initial follow-up findings were reassuring. In our experience, clear signs of abnormal development, such as abnormal tone and microcephaly, were detected before 12 months of age in the infants with an adverse outcome, consistent with previous reports.¹⁴

The outcomes of perinatal encephalopathy are closely related to the severity of the encephalopathy, with normal outcomes expected among infants with mild encephalopathy.¹³ Prospective neurologic assessment as used in the present study has not been systematically studied; the classic Sarnat staging is made in retrospect, and thus it is possible that infants might have developed more severe symptoms later in their course. Also the assessment was not blinded, and was performed by >1 investigator. Nevertheless, the present series clearly suggests that the great majority of the infants with milder early encephalopathy did have a normal outcome. Among infants with moderate to severe encephalopathy, there was no suggestion of a worsening of outcome in the combined mildly cooled groups, but rather a trend to better outcome (26% adverse outcome vs 44% in controls by 18 months of age). Furthermore, although it is vital not to overinterpret individual cases, it is of some interest that within the groups cooled to 35°C or 34.5 ± 0.5°C, several infants with a very adverse initial condition and clinical courses had essentially normal outcomes at follow-up.

Formal assessment of neurodevelopment with adequate power to detect differences is required before any new or innovative procedure is adopted as accepted practice. The minimum size required for such a study of the treatment of HIE is very large. For example, assuming that hypothermia started before 6 hours of age was associated with a 30% reduction in death or disability and the incidence of adverse outcome was 50% in the control arm, then 175 infants would need to complete follow-up in each group to have an 80% power of correctly detecting such an effect.

Several aspects of the present study may be relevant to future studies. First, despite entry criteria using strict clinical data, a substantial number of cases with an abnormal pH and Apgar scores developed only a mild course.¹⁵ As a consequence of this and the stepped design with small sample sizes at each temperature, the severity of encephalopathy and associated systemic disease was variable between study groups. As recently reviewed, combinations of clinical factors at birth can be used to improve the specificity of infant selection for treatment; however, this can exclude significant numbers of infants with an adverse prognosis and many proposed factors are to some extent subjective or dependent on local practice.¹⁶ One objective technique that may improve identification of high-risk infants is the amplitude-integrated electroencephalogram. Infants with abnormal amplitude-integrated encephalogram recordings may have up to an 80% to 90% rate of adverse outcome when tested before 6 hours of age.^17,18 Such a high predictive value not only reduces the numbers of infants with a good prognosis who will be unnecessarily cooled, but it markedly reduces the number of infants needed to be recruited. This may not only enable smaller, faster trials, but potentially could make it more feasible to efficiently try different cooling strategies.

An additional major issue in the clinical use of hypothermia is that a number of factors are likely to affect the interval after birth during which hypothermia may be effective,¹ including the timing of the insult and previous pyrexia. In a previous analysis we reported evidence that just a quarter of infants with evidence of postasphyxial encephalopathy were exposed to a sentinel, catastrophic event such as uterine rupture or prolapsed cord, whereas an additional quarter had evidence of antenatal hypoxia.¹⁹ In most of the remainder, the timing of injury was unclear, but was likely to have evolved during labor. Thus, in some infants, by the time of assessment on a neonatal unit, secondary damage may already be occurring.

Another factor that may limit the window of opportunity for treatment of encephalopathy is previous exposure to pyrexia.¹ There is increasing clinical and experimental evidence that hyperthermia during and after cerebral hypoxia-ischemia is associated with earlier and more severe neurologic deterioration,^20,21 and accelerates the development of apoptosis.²² It may thus be relevant that maternal pyrexia occurred during labor in 2 infants who had a poor outcome with the development of cerebral palsy after treatment with hypothermia.

	CONCLUSION

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Cerebral hypothermia offers the exciting possibility of neuroprotection after perinatal asphyxia. However, the mixed outcome from the present study infants reinforces the point that although the short-term safety of cooling has been demonstrated, the long-term efficacy of hypothermia is not proven in any clinical context. Clinicians and investigators must remain in a state of equipoise, and cooling should be only performed as part of a trial with strict entry criteria, selection, and follow-up with audited outcomes. Several large, multicenter randomized trials with adequate power to detect the potential therapeutic benefits of this promising technique are now underway.

	ACKNOWLEDGMENTS

This research was supported by the Health Research Council of New Zealand and the New Zealand Lottery Grants Board.

	FOOTNOTES

Reprints not available.

Received for publication Aug 14, 2000; accepted Oct 3, 2000.

Address correspondence to Malcolm Battin, MBChB, MRCP, Newborn Service, National Women's Hospital, Private Bag 92189, Auckland, New Zealand. E-mail: malcolmb{at}ahsl.co.nz

	ABBREVIATIONS

HIE, hypoxic-ischemic encephalopathy.

	REFERENCES

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