Treatment of Term Infants With Head Cooling and Mild Systemic Hypothermia (35.0°C and 34.5°C) After Perinatal Asphyxia
* Newborn Service, National Women’s Hospital, Auckland, New Zealand
Department of Paediatrics and Liggins Institute, University of Auckland, Auckland, New Zealand
Chelsea and Westminster Hospital, London, United Kingdom
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ABSTRACT |
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Objective. To assess the safety of selective head cooling in birth-asphyxiated term newborn infants while maintaining the rectal temperature at 35.0°C or 34.5°C.
Methods. Twenty-six term infants with Apgar 
6 at 5 minutes or cord/first arterial pH <7.1, plus evidence of encephalopathy, were studied. After parental consent had been obtained, 13 infants received selective head cooling with the rectal temperature maintained at 35.0°C in 6 infants and at 34.5°C in 7 infants. The remaining 13 infants were normothermic. Cooling was achieved by circulating water at 10°C through a cap placed around the head. Rectal, fontanelle, and nasopharyngeal temperatures were monitored.
Results. One cooled infant died 2 days after rewarming, and 3 control infants died. Seizures occurred in 9 (69%)of 13 cooled infants and 5 (38%) of 13 control infants. Respiratory support within the first 72 hours of life was required in 10 of 13 infants in both the cooled and control groups. Three cooled infants and 1 control infant received nitric oxide for persistent pulmonary hypertension. During the same interval, 6 of the cooled infants and 4 of the control infants had episodes in which their blood pressure fell to <40 mm Hg; in 2 infants in each group, the lowest blood pressure was below 35 mm Hg. No requirement for volume expansion or increased inotropic support was seen in any infant during stepwise rewarming. All of the cooled infants demonstrated a fall in heart rate during cooling, but the rate was <80/min in only 2 cases and no infant had a rate <70/min. No infant demonstrated an abnormal rhythm or was clinically compromised by the change in heart rate. One infant cooled to a rectal temperature of 34.5°C had a prolonged QT interval of 570 ms associated with a heart rate of 85/min on electrocardiogram aged 34 hours. This returned to normal after rewarming. Platelet counts below 150 x 109/L, hypoglycemia below 2.6 mmol/L, and highest creatinine were not statistically different between cooled and control infants. Positive precooling blood cultures were found in 1 cooled and 1 control infant. The mean cap water input temperature used during cooling was 10 ± 1°C. During active cooling, the mean difference between rectal and nasopharyngeal temperature was 1.4°C in the infants who were not receiving respiratory support, but this gradient could not be measured in those who were receiving respiratory support that involved delivery of warmed gases to the nasopharynx.
Conclusions. This study suggests that selective head cooling combined with mild systemic hypothermia of 34.4°C or 35.0°C is a stable, well-tolerated method of reducing cerebral temperature in term newborn infants after perinatal asphyxia.
Key Words: asphyxia neonatorum • induced hypothermia • controlled trial • term neonate • hypoxic-ischemic encephalopathy
Abbreviations: BP, blood pressure • HIE, hypoxic-ischemic encephalopathy • CT, computer tomographic • EEG, electroencephalographic • ECG, electrocardiogram • PPHN, persistent pulmonary hypertension
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INTRODUCTION |
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Hypothermia has been proposed as a therapeutic intervention to reduce secondary neuronal injury after severe perinatal hypoxia ischemia.1 Animal studies have shown that a reduction in core temperature of 2°C to 5°C can reduce both histologic evidence of brain damage2–6 and delayed cerebral energy failure,7 with an improvement in behavioral outcome after hypoxia-ischemia.8 However, there are no definitive data confirming that resuscitative hypothermia is neuroprotective in humans. Furthermore, hypothermia has a significant profile of potential adverse effects, including metabolic, cardiovascular, pulmonary, coagulation, and immunologic complications.9,10 These problems generally seem to be proportional to the degree of cooling, with most clinically significant problems occurring at temperatures well below 34°C.9 However, experimentally, neuroprotection has typically been found to require brain temperatures of 34°C or lower.1 Thus, ideally, for providing adequate neuroprotection with minimal risk of systemic adverse effects, only the brain would be cooled. Although this has been demonstrated experimentally using cardiac bypass procedures,11 it is clearly impractical for routine practice. More pragmatically, partially selective cerebral cooling can be obtained using a cooling cap applied to the scalp, while the body is warmed by some method such as an overhead heater to limit the degree of systemic hypothermia,.12,13 This approach has recently been confirmed by studies in the piglet to be associated with a substantial decrease in the deep intracerebral temperature compared with the rectal temperature.14
We have previously demonstrated in a preliminary randomized, controlled study that selective cerebral cooling with mild systemic hypothermia is a safe and convenient method of reducing cerebral temperature. However, these studies were part of a cautious stepwise evaluation of the effects of lower temperature. It is highly likely that a lower rectal temperature, of approximately 34°C to 35°C, is needed to protect deeper brain structures.1 For this reason, subsequent small pilot series of infants have examined the effects of both whole-body cooling and partially selective head cooling using target temperatures of 33°C to 34°C or 34 ± 0.5°C, respectively. Azzopardi et al15 suggested that moderate whole-body cooling was associated with some metabolic changes, including mild hypokalemia and metabolic acidosis. Similarly, a case series from Thoresen and Whitelaw16 raised several issues regarding the treatment of infants during "selective" head cooling, including the suggestion that rewarming or a sudden increase in overhead heater activity could cause a fall in the infant’s blood pressure (BP), temperature instability in relation to drug administration, and increased inspired oxygen requirements during induction of hypothermia. None of these problems was sufficiently severe to compromise the infants but were of concern. However, it is difficult to evaluate the significance of these concerns in the absence of appropriate controls. The aim of the current study, therefore, was to assess the safety of selective head cooling in birth-asphyxiated newborn infants while maintaining the rectal temperature at 35.0°C or 34.5°C, a temperature range that from animal data may be expected to provide cerebroprotection, in comparison with normothermic infants.
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METHODS |
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Ethical approval to perform selective head cooling in term infants with hypoxic-ischemic encephalopathy (HIE) was given by the North Health Regional Ethics Committee. Written parental consent to study the individual infants was obtained in each case. During the study period, November 1997 until December 1998, term infants with a history suggestive of perinatal asphyxia were evaluated prospectively for signs of HIE after admission to the neonatal unit at National Women’s Hospital. Infants were enrolled in the study on the basis of a clinical history consistent with perinatal asphyxia and the presence of the following clinical entry criteria: 1) gestational age >37 weeks; 2) 5-minute Apgar score below 6 or cord/first arterial pH <7.1; and 3) encephalopathy consisting of lethargy/stupor, hypotonia, and abnormal reflexes, including an absent or weak suck. Infants with obvious major congenital abnormalities or those who presented to National Women’s Hospital neonatal unit after 6 hours of age were excluded.
After parental consent had been obtained, the infants were randomized by sealed envelopes to either a control group or the cooling group. So that experience would be gained at 1 temperature range before exposure of infants to the lower temperature range, the 2 cooling groups were sequential. Six infants were randomized to be cooled to 35 ± 0.5°C, and 3 infants were randomized to be controls. In view of the lack of adverse reactions to hypothermia and encouraging short-term outcome of cooling in the first group, ethical permission was then given to allow the final group of infants to be allocated to 34.5 ± 0.5°C (n = 7). As this study followed a previous study using the same enrollment criteria for the period 1996 to 1997, data were used from an additional 10 infants who were randomized as controls in the previous study period.12 Thus, in total, data were available from 13 infants who were treated with hypothermia and 13 control infants.
Selective cerebral hypothermia was achieved via a cooling cap as previously described.12,17 The initial 5 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 bonnet.12 The remaining 8 infants were cooled using a commercially made device (Olympic Medical, Seattle, WA). The devices both consisted of a small thermostatically controlled cooling unit and a pump that circulated the water through the coil. In addition, the Olympic Medical device incorporated the facility for monitoring, had temperature alarms, and allowed the temperature of the circulating water to be adjusted within a specified range. The initial water temperature was set at 10°C as based on experience from the previous studies, with minor subsequent adjustments during each study.
The rectal, fontanelle, and nasopharyngeal temperatures were monitored continuously with thermistors (IncuTemp1, Mallinckrodt Medical, St Louis, MO; or YSI Precision 440, Yellow Springs Instrument Co, Yellow Springs, OH). In addition, all infants had continuous electrocardiograph monitoring and pulse oximetry, but umbilical arterial catheters for blood gas and BP were inserted only when clinically indicated.
The rectal temperature was maintained within the prescribed range (34.5 ± 0.5°C, 35 ± 0.5°C, or normothermic) for 72 hours. Thereafter, the cooled infants were slowly rewarmed at 0.5°C per hour until their temperature was within the normal temperature range. The cooling was discontinued earlier at 48 hours only when the infant was judged by the attending clinician to have significantly recovered on a neurologic examination at this time. Temperature and physiologic monitoring were continued for a minimum of 4 hours after the end of cooling. Sham caps were not used on the control infants because these might cause a rise in cerebral temperature with deleterious consequences, without meaningfully masking the treatment.
Early cranial ultrasound was performed in both groups of infants to exclude major intracranial bleeding or malformation. Follow-up cerebral computer tomographic (CT) scan and electroencephalographic (EEG) 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. Seizures were diagnosed clinically and managed as previously reported12 using a loading dose of 20 mg/kg phenobarbitone and, if needed, additional phenobarbitone, 20 mg/kg phenytoin or paraldehyde. When heart rate fell to <80 beats per minute during the cooling run an ECG was performed to allow study of QT interval. 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 who directed all other aspects of clinical care. After discharge, the infants had a neurodevelopmental assessment in the follow-up clinic by the pediatrician and assessment at 18 months by a developmental psychologist using the Bayley Scale as previously reported.17
Data are presented as mean ± standard deviation if normally distributed or as median (range) as appropriate. Incidences were compared by Fisher exact test or by 
2. The groups were compared by 2-way Mann Whitney U test or Student t test as appropriate. Because of the small sample size and minor difference in temperature between the 2 cooling groups (35°C, n = 6; 34.5°C, n = 7), the groups were combined for comparison with the control group. Thus, results are given for the cooling group as a whole, ie, all 13 cooled infants, unless otherwise stated. Blood gases were analyzed at 37°C in all infants then corrected for rectal temperature.12 When results of blood gases are given for the whole group, values closest to 1, 2, 3, 6, 12, 24, 48, 72, and 76 hours were analyzed to reduce the effect of disproportionate sampling of the sickest infants.
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RESULTS |
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Twenty-six infants (15 girls and 11 boys) were enrolled in the study after a clinical evaluation. Thirteen of the 26 infants received selective head cooling, 12 infants for 72 hours and 1 infant for 48 hours. Cooling commenced at a mean of 4.9 ± 1.3 hours after birth. The mean age of initiation of cooling was 4.8 ± 1 hours for inborn (n = 4) and 5.2 ± 0.9 hours for outborn (n = 9) infants. There were no significant differences in gestational age, birth weight, initial pH, or Apgar scores at 5 minutes for the individual groups (Table 1).
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No infant died while undergoing cooling. However, 1 cooled infant and 3 control infants died. The cooled infant, who was postterm and growth restricted, had severe persistent pulmonary hypertension (PPHN) as a result of meconium aspiration and grade 3 HIE. Although the infant was very sick, with an oxygenation index of 30 to 35, there was no significant clinical change or deterioration in oxygenation during either induction of cooling or rewarming, and died 48 hours after rewarming. There were 3 deaths in control infants. Two of these deaths occurred in the first 24 hours. One infant was a home birth with severe respiratory failure, and another had multisystem failure including hypotension and PPHN that failed to respond to intensive care. The third death occurred in a profoundly handicapped infant with microcephaly and spastic quadriparesis who was discharged from the hospital for terminal care. Thus, 12 of the cooled and 10 of the control infants were discharged from the hospital on full sucking feeds. There was no significant difference between the groups in age at discharge of survivors with the cooled infants discharged at a mean ± standard deviation of 12.4 ± 5.3 days and the controls at 13 ± 12 days.
A summary of the respiratory and cardiovascular support required by the study infants during the first 72 hours is given in Table 2. No infants required rewarming for clinical instability during cooling. Although respiratory support was required in 10 of the 13 cooled infants, the inspired oxygen requirements did not increase or decrease significantly during the first 6 hours of cooling. Positive pressure ventilation for >72 hours after birth was required in 4 cooled and 1 control infants. Three of the 4 cooled infants and the control infant demonstrated clinical and echocardiographic evidence of persistent PPHN in the first 24 hours after admission and were treated with nitric oxide (not significant). The infant with meconium aspiration syndrome and PPHN noted above required high-frequency ventilation, nitric oxide, and inotropic support from admission with no change in the level of respiratory supported required during cooling. The fifth infant ventilated beyond 72 hours of age was cooled to 34.5°C and required support primarily for neurologic reasons. Pulmonary hemorrhage occurred in 2 of the cooled infants with PPHN and none of the controls. In 1 case, it developed after the start of cooling, at 9 hours of age, whereas in the other case, it occurred at 3 hours, before initiation of cooling.
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The changes in heart rate and mean arterial pressure for the study group throughout the cooling period are shown in Fig 1. There were no significant differences in the incidence of hypotension or use of volume and inotropic support between the cooled and control infants (Table 2). Six of the cooled infants and 4 of the control infants demonstrated hypotension defined as a BP <40 mm Hg during the first 72 hours (not significant). Severe hypotension, <35 mm Hg despite volume and inotropic support, occurred in 2 cooled and 2 control infants. Volume was used in the initial resuscitation of 2 cooled infants and 4 control infants (P = .64). During the next 72 hours, additional volume support was given to 3 cooled infants and no control infants. Inotropes were used to maintain BP in 3 cooled and 2 control infants during the first 72 hours (not significant). In 2 of the cooled infants, this was started before cooling and no adjustment was required during induction of cooling. No infant required volume expansion or a change in inotropic support during the phase of stepped, elective rewarming.
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) and cooled infants (•). There is a significant fall in heart rate during hypothermia but no significant change in mean arterial pressure. Data are mean ± standard deviation.All of the cooled infants demonstrated a fall in heart rate during cooling (Fig 1). In 2 cases, the rate dropped below 80/min. However, no infant had a rate <70/min, and none demonstrated an abnormal rhythm or seemed to be clinically compromised by the change in heart rate. One infant had a bradycardia of <80/min before cooling. One infant who was cooled to a rectal temperature of 34.5°C had a prolonged QT interval of 570 ms associated with a heart rate of 85/min on ECG at 34 hours of age as previously reported.18 The QT returned to normal after rewarming. Five other cooled and 2 noncooled infants who exhibited heart rates of 90 beats per minute or less had an ECG performed during cooling or the first 3 days of life. The lead V5 QT intervals in these infants were not prolonged (Table 3).19
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Thrombocytopenia defined as platelets <150 x 109/L occurred in 4 (31%) cooled and 4 (31%) control infants. In the infants without thrombocytopenia, no excessive bleeding was observed from venipuncture sites or mucus membranes in either study or control group. The minimum values during the first 3 days of life were 16, 45, 61, and 111 x 109/L in the cooled and 73, 106, 134, and 136 x 109/L in the control infants. In this subgroup, formal clotting studies were performed in 2 cooled and 4 control infants for clinical indications. The results were abnormal in 2 cases with an International Normalized Ratio of 2.4 in a cooled infant who died and 4.5 in a control infant who died; all other results were within normal limits.
Hypoglycemia, defined as blood sugar <2.6 mmol/L, occurred in 3 cooled and 4 control infants and resolved in all cases during the first 24 hours despite the use of restricted fluids. All infants had clinical or biochemical evidence of renal impairment, which resolved in all surviving infants. There was no significant difference between creatinine levels in the cooled group (0.145 ± .068 mmol/L) and that of the control group (0.146 ± .060 mmol/L). The median (interquartile range) for serum potassium in nonhemolyzed samples taken in the first 72 hours was 4.6 mmol/L (4.2–5.1 mmol/L) in cooled infants and 3.5 mmol/L (3.2–4.5 mmol/L; not significant) in the control infants; similar numbers of infants in both groups had hypokalemia. The mean sampled pH for the cooled group during cooling was 7.33 ± 0.1 and 7.36 ± 0.2 in the control infants during the first 72 hours (not significant). No infant had clinical evidence of hepatic or gastrointestinal complications, although a transient rise in liver enzymes was seen in both groups.
All infants received prophylactic antibiotics for 48 hours until the results of admission blood cultures were available. Infection with Bacteroides fragilis and group B streptococcus were documented in 1 cooled infant and 1 control respectively; no infections were documented after recruitment. The cooled infant was neutropenic at birth, and it is likely that infection was at least in part responsible for the initial clinical presentation.
For the cooled infants, the mean cap temperature used during the cooling process was 10.0 ± 1°C (range: 8–12°C). The minimum cap temperatures used were 8.0°C in a 5-kg infant with seizures and 8.3°C in another 3.5-kg infant who presented after maternal pyrexia and developed early, intense clinical seizures. In both infants, the cap temperature was able to be increased once seizures were controlled, suggesting that seizures were associated with a considerable increase in cerebral heat production. This is illustrated by the case shown in Fig 2, which demonstrates transient falls in temperature requiring adjustment of the cap temperature after seizure control in an infant in whom the temperature was previously stable. Finally, on removal of the cap, 2 infants demonstrated some scalp edema that resolved during the subsequent 24 to 36 hours.
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After rewarming, 4 of the cooled infants had mild overshoot in temperature above 37.3°C to a maximum of 37.7°C rectal. Once cooling had been achieved, the mean difference between rectal and nasopharyngeal temperature was 1.4°C in the infants who were not receiving respiratory support. However, this gradient could not be measured in those who were receiving warmed gases via the nasal passages either as nasopharyngeal continuous positive airway pressure or as nasal ventilation.
Cranial CT scan was performed in 12 of the cooled and 9 of the control infants at a median of 8 days (interquartile range: 7–10). One cooled infant and 2 control infants died before the CT could be performed. In the cooled group, CT appearances were within normal limits in 6 cases, demonstrated mild white matter abnormalities in 3 cases, and demonstrated overt major abnormality in 3 cases. In addition, 1 infant with mild changes demonstrated a previously undiagnosed small migration abnormality that was confirmed on magnetic resonance imaging. The control infants had CT appearances that were within normal limits in 8 cases and that revealed overt major abnormality in 1 case. In each case, the abnormalities were considered consistent with asphyxia.
Seizures, treated with anticonvulsants, were common in both groups of infants, occurring in 9 (69%) of 13 cooled infants and 5 (38%) of 13 control infants. Although there was a trend toward more frequent seizures in the cooled group, this was not significant (P = .1) and the mean age at onset was similar with cooled infants starting at 9.3 ± 7 and control infants at 12 ± 11 hours, respectively. Follow-up EEG at 1 week was performed in 19 of the 26 infants. At that time, 4 infants had died and 3 infants (1 cooled and 2 control infants) did not have an EEG performed. In cooled infants, the result was within normal limits in 6 cases and in the remaining 5 infants demonstrated either persisting abnormalities of background or excessive sharp waves. In the control infants, the follow-up EEG was within normal limits in 7 cases and abnormal with an excess of sharp wave and spike activity in 1.
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DISCUSSION |
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Perinatal asphyxia is 1 of the most damaging of neurologic processes and remains an important cause of both neonatal death and long-term disability.20 Few therapeutic interventions are available for clinical use, and the care of infants with HIE is largely limited to supportive measures and anticonvulsants.21 This study demonstrated that the innovative technique of selective head cooling with systemic hypothermia of 34.5°C or 35.0°C may be practically and safely performed, for up to 72 hours, in a population of term infants with HIE and a variety of other multisystem effects of perinatal asphyxia. We have previously reported the generally safe use of this technique with much milder cooling.12 The present study reports safety within the temperature range likely to be required for clinical trials of neuroprotection.
The potential adverse side effects of hypothermia are widely recognized in both preterm and term infants.22–25 Changes in cardiorespiratory status during cooling are of particular importance given the frequency of systemic sequelae in infants with HIE,26 and experimental data demonstrating that hypothermia of 34°C to 35°C decreases left ventricular contractility and neonatal cardiac output.27,28 In this study, 20 of the 26 infants required respiratory support within the first 72 hours of life. Although a small effect cannot be excluded, the cooled infants did not have an increased requirement for respiratory support compared with control infants and support was often able to be weaned during continued cooling, suggesting that the process was well-tolerated. Furthermore and in contrast with 1 previous case series,16 the majority of cooled infants did not demonstrate any change in oxygen requirement during the initial cooling phase.
PPHN is a frequent association with perinatal asphyxia; at the same time, experimentally, moderate to deep hypothermia (31 ± 0.4°C) has been reported to lead to a significant increase in pulmonary vascular resistance.29 Clinically, a previous case series suggested that hypothermia was associated with a modest but consistent increase in fraction of inspired oxygen.16 In the present study, 3 cooled infants had echocardiographic evidence of PPHN, which was treated with nitric oxide. These infants had clinical evidence of PPHN before initiation of cooling, but echocardiographic assessment of pulmonary artery pressure was not able to be performed before the initiation of cooling because of time constraints. However, there was no apparent change in their oxygen or ventilatory requirements during induction of hypothermia or rewarming, suggesting that mild hypothermia as used in the present study does not significantly affect the development of PPHN.
In the present study, no clinically significant change in BP was seen during either the initiation of cooling or rewarming. Other studies, however, have raised the possibility that peripheral vasodilatation and resultant hypotension may occur during rapid rewarming.16 Our experience may differ as a result of 2 factors. First, we endeavored to keep a stable balance by keeping the overhead heater usually on maximum during the cooling, thus minimizing the contribution of changes in endogenous heat production.30 Second, no infant in our group was rewarmed for clinical instability; hence, we were able to perform rewarming slowly in all cases. Following this regimen, no infant demonstrated a requirement for volume or increased inotropic support during rewarming. Although a fluid bolus during rewarming is likely not to be harmful and may be helpful in infants with a rapid redistribution of blood flow, the present experience suggests that this is not a routine need.
In keeping with the known electrophysiological effects of hypothermia and previous experience, all infants demonstrated a decrease in heart rate during cooling.12 In the cooled group, the mean decrease in heart rate during the cooling run was approximately 30/min. The electrographic finding of prolongation of the QT interval occurred in 1 infant who was cooled to 34.5°C. It is known that hypothermia decreases heart rate,9 and both of these effects are linked with an increase in QT interval.19 No other infant had bradycardia <70/min, and no arrhythmia occurred. However, as previously reported, continuous close cardiac monitoring during hypothermia is mandatory and formal ECG may be helpful to quantify the degree of QT interval prolongation if heart rate is below 70/min.18
Hypokalemia has been found in animal models during deep hypothermia but corrects spontaneously during rewarming, suggesting that this change is attributable to intracellular redistribution.31 Consistent with this, a mild fall in serum potassium was reported in the series of infants who were cooled to between 33°C and 34°C.15 In the current study, the median serum potassium was not significantly different between the 2 groups, and similar numbers of low measurements were seen in both cooled and control infants. It is likely that this difference reflects the higher core temperatures in the present study. Maintenance potassium during cooling must be used cautiously, because correction of hypokalemia during hypothermia may lead to rebound hyperkalemia on rewarming both clinically32 and experimentally.31 Indeed, the clinical significance of mild hypokalemia during hypothermia is not clear; there is evidence, for example, that it may help to protect against potassium cardiotoxicity.33
Although previous reports of hypothermia used in infants with HIE have not noted an excess of overt hemorrhage during cooling,12,13,17 hypothermia has widely known effects on coagulation.10,34 Azzopardi et al15 reported 3 infants with unusual findings on magnetic resonance imaging, including transverse sinus thrombosis, probable straight sinus thrombosis, and hemorrhagic cerebral infarction, after whole-body cooling. Four infants in that study had abnormal coagulation requiring treatment with fresh-frozen plasma. It is notable that in the patient with the hemorrhagic infarction, coagulation was abnormal even after rewarming, suggesting that hypothermia was not a major contributing factor. In contrast, in the present study, we found no difference in the rates of thrombocytopenia, clinical hemorrhage, or abnormal coagulation tests in the subgroup that was tested for clinical indications. Furthermore, no cases with sinus thrombosis were seen on follow-up imaging with CT scan, and there was no difference in the rate of (minor) intracranial hemorrhage. Nevertheless, CT scanning may not be sufficiently sensitive to detect minor changes, and the infants studied by Azzopardi et al were treated at significantly lower core temperatures. As only small numbers of infants have so far undergone either selective or whole-body cooling, this issue requires close ongoing monitoring.
In addition to the potential effects of hypothermia on the infant, there is still much to be learned regarding the clinical use of hypothermia. In our protocol, we use a servocontrolled overhead heater that provides near maximal skin warming and thus minimizes the potential for rapid changes in temperature. As previously reported, close observation is needed during the key phases of cooling and rewarming to avoid overshoot cooling or rebound hyperthermia, respectively.16 Minor adjustment may also be needed during management changes that affect the infants’ temperature balance. In the present study, such changes both were generally predictable and occurred over many hours. A very common example was ventilation changes that involved the institution or discontinuation of warmed gases. Similarly, drugs such as sedatives, anticonvulsants, and antipyretics all have the potential to reduce endogenous heat production16 and thus exaggerate the fall in temperature during active cooling as illustrated by Fig 2, whereas the onset of seizures may cause spontaneous rewarming and thus require a reduction in cap temperature.
On theoretical grounds, there must be potential for local pressure effects related to prolonged use of a cap. For this reason, our practice was that objects (eg, an EEG monitoring lead) were never placed underneath the cap, and the cap was removed briefly each day to check the scalp condition. No scalp damage occurred in any infant in the present study; however, mild scalp edema was noted in several cooled infants. Although this resolved spontaneously over 24 hours in all cases, it is important to warn parents of this possibility.
This study further supports the general safety of selective hypothermia even in sick asphyxiated infants, but this data should not be overinterpreted. This study uses a control group as many of the potential adverse effects of cooling are also common in HIE. However, this study was not designed to and is too small to test the efficacy of treatment or to detect uncommon adverse events. This is now being addressed in a multicenter trial with adequate power to assess long-term outcome. Until definitive evidence of clinical benefit is shown, cooling must continue to be confined to such clinical trials.
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ACKNOWLEDGMENTS |
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This research was supported by the Health Research Council of New Zealand, New Zealand Lottery Grants Board, and the Auckland Medical Research Foundation.
Olympic Technology (Seattle, WA) supplied the cooling device and caps that were used for the later cooling groups.
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FOOTNOTES |
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Received for publication Feb 13, 2002; Accepted Jun 18, 2002.
Address correspondence to Malcolm Battin, MBChB, MRCP(UK), Newborn Service, National Women’s Hospital, Private Bag 92189, Auckland, New Zealand. E-mail: malcolmb{at}adhb.govt.nz
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