Denis Azzopardi

Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial

BACKGROUND 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. METHODS 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. FINDINGS 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). INTERPRETATION 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.

Moderate Hypothermia to Treat Perinatal Asphyxial Encephalopathy

BACKGROUND Whether hypothermic therapy improves neurodevelopmental outcomes in newborn infants with asphyxial encephalopathy is uncertain. METHODS 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. RESULTS 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. CONCLUSIONS 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.)

Neurological outcomes at 18 months of age after moderate hypothermia for perinatal hypoxic ischaemic encephalopathy: synthesis and meta-analysis of trial data

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

Assessment of neonatal encephalopathy by amplitude-integrated electroencephalography

Objective. To define normal and abnormal patterns, test interobserver variability, and the prognostic accuracy of amplitude-integrated electroencephalography (aEEG) soon after the onset of neonatal encephalopathy. Methods. Consecutive cases of neonatal encephalopathy (n = 56; gestation median, 40; range, 35–42 weeks) and healthy infants (n = 14; gestation median, 40; range, 39–40 weeks) were studied. aEEG was recorded using a cerebral function monitor, at median, 0, range, 0–21 days of age. Of the infants, 24 of the 56 with encephalopathy and all of the normal infants were studied within 12 hours of birth (median, 5; range, 3–12 hours). Forty infants were suspected of having suffered birth asphyxia. Criteria for normal and abnormal patterns were defined and the interobserver variability of these classifications determined. Results were compared with neurodevelopmental outcome assessed at 18 to 24 months of age. aEEG also was compared with a standard EEG and with magnetic resonance imaging. Results. The median upper margin of the widest band of aEEG activity in the control infants was 37.5 μV (range, 30–48 μV), and median lower margin was 8 μV (range, 6.5–11 μV). We classified the aEEG background activity as normal amplitude, the upper margin of band of aEEG activity >10 μV and the lower margin >5 μV; moderately abnormal amplitude, the upper margin of band of aEEG activity >10 μV and the lower margin ≤5 μV; and suppressed amplitude, the upper margin of the band of aEEG activity <10 μV and lower margin <5 μV. Recordings were analyzed further for the presence of seizures, defined as periods of sudden increase in voltage accompanied by a narrowing of the band of aEEG activity. Tests of interobserver variability showed excellent agreement both for assessment of amplitude (κ statistic = 0.85) and for identification of seizures (κ statistic = 0.76) There was a close relationship between the aEEG and subsequent outcome: 19 of 21 infants with a normal aEEG finding were normal on follow-up at 18 to 24 months of age, whereas 27 of 35 infants with a moderately abnormal or suppressed aEEG and/or seizures died or developed neurologic abnormalities. Thus, aEEG predicted outcome with a sensitivity of 0.93, a specificity of 0.70, positive predictive value of 0.77, negative predictive value of 0.90, and the likelihood ratio of a positive result of 3.1 and a negative result of 0.06. For the 24 infants studied within 12 hours of birth, the corresponding results were sensitivity, 1.0; specificity, 0.82; positive predictive value, 0.85; negative predictive value, 1; likelihood ratio of a positive result, 5.5; and likelihood ratio of a negative result, 0.18. Conclusion. The aEEG is a simple but accurate and reproducible clinical tool that could be useful in the assessment of infants with encephalopathy.

Assessment of brain tissue injury after moderate hypothermia in neonates with hypoxic–ischaemic encephalopathy: a nested substudy of a randomised controlled trial

Summary Background Moderate hypothermia in neonates with hypoxic–ischaemic encephalopathy might improve survival and neurological outcomes at up to 18 months of age, although complete neurological assessment at this age is difficult. To ascertain more precisely the effect of therapeutic hypothermia on neonatal cerebral injury, we assessed cerebral lesions on MRI scans of infants who participated in the Total Body Hypothermia for Neonatal Encephalopathy (TOBY) trial. Methods In the TOBY trial hypoxic–ischaemic encephalopathy was graded clinically according to the changes seen on amplitude integrated EEG, and infants were randomly assigned to intensive care with or without cooling by central telephone randomisation. The relation between allocation to hypothermia or normothermia and cerebral lesions was assessed by logistic regression with perinatal factors as covariates, and adjusted odds ratios (ORs) were calculated. The TOBY trial is registered, number ISRCTN 89547571. Findings 325 infants were recruited in the TOBY trial between 2002 and 2006. Images were available for analysis from 131 infants. Therapeutic hypothermia was associated with a reduction in lesions in the basal ganglia or thalamus (OR 0·36, 95% CI 0·15–0·84; p=0·02), white matter (0·30, 0·12–0·77; p=0·01), and abnormal posterior limb of the internal capsule (0·38, 0·17–0·85; p=0·02). Compared with non-cooled infants, cooled infants had fewer scans that were predictive of later neuromotor abnormalities (0·41, 0·18–0·91; p=0·03) and were more likely to have normal scans (2·81, 1·13–6·93; p=0·03). The accuracy of prediction by MRI of death or disability to 18 months of age was 0·84 (0·74–0·94) in the cooled group and 0·81 (0·71–0·91) in the non-cooled group. Interpretation Therapeutic hypothermia decreases brain tissue injury in infants with hypoxic–ischaemic encephalopathy. The predictive value of MRI for subsequent neurological impairment is not affected by therapeutic hypothermia. Funding UK Medical Research Council; UK Department of Health.

Comparison of findings on cranial ultrasound and magnetic resonance imaging in preterm infants

Objective. To compare findings on hard copies of cranial ultrasound (US) and magnetic resonance imaging (MRI) obtained between birth and term in a group of preterm infants. Participants and Methods. Infants born at or below a gestational age of 30 weeks who underwent cranial US scan and MRI on the same day were eligible for this study. Infants underwent, whenever possible, 3 scans between birth and term. We calculated the predictive probability (PP) of US findings as a predictor of findings on MRI. Results. Sixty-two paired MRI and US studies were performed between birth and term in 32 infants born at a median gestational age of 27 (range: 23–30) weeks and a median birth weight of 918 (530–1710) grams. US predicted some MRI findings accurately: germinal layer hemorrhage (GLH) on US had a PP of 0.8 with a 95% confidence interval of (0.70–0.90) for the presence of GLH on MRI, intraventricular hemorrhage (IVH) on US had a PP of 0.85 (0.76–0.94) for the presence of IVH on MRI, and severe white matter (WM) echogenicity on US had a PP of 0.96 (0.92–1.0) for the presence of WM hemorrhagic parenchymal infarction on MRI. Other MRI changes were less well-predicted: mild or no WM echogenicity on US had a PP of 0.54 (0.41–0.66) for the presence of normal WM signal intensity on MRI, and moderate or severe WM echogenicity on US had a PP of 0.54 (0.42–0.66) for the presence of small petechial WM hemorrhage and/or diffuse excessive high-signal intensity (DEHSI) in the WM on T2-weighted images on MRI. However, mild/moderate or severe WM echogenicity on US scans performed at ≥7 days after birth had a PP of 0.72 (0.58–0.87) for the presence of WM hemorrhage and/or DEHSI on MRI. There were no cases of cystic periventricular leukomalacia. Conclusion. US accurately predicted the presence of GLH, IVH, and hemorrhagic parenchymal infarction on MRI. However, its ability to predict the presence of DEHSI and small petechial hemorrhages in the WM on T2 weighted images is not as good, but improves on scans performed at ≥7 days after birth. In addition, normal WM echogenicity on US is not a good predictor of normal WM signal intensity on MRI.

Prognosis of newborn infants with hypoxic-ischemic brain injury assessed by phosphorus magnetic resonance spectroscopy.

ABSTRACT: To investigate the prognostic significance of abnormalities of oxidative phosphorylation, the brains of 61 newborn infants born at 27-42 wk of gestation and suspected of hypoxic-ischemic brain injury were examined by surface-coil phosphorus magnetic resonance spectroscopy. Of these infants, 23 died, and the neurodevelopmental status of the 38 survivors was assessed at 1 y of age. Of the 28 infants whose phosphocreatine/inorganic orthophosphate (PCr/Pi) ratios fell below 95% confidence limits for normal infants, 19 died, and of the nine survivors, seven had serious multiple impairments (sensitivity 74%, specificity 92%, positive predictive value for unfavorable outcome 93%). Of the 12 infants with ATP/total phosphorus ratios below 95% confidence limits 11 died (sensitivity 47%, specificity 97%, positive predictive value 91%). Among the 46 infants with increased cerebral echodensities, PCr/Pi was more likely to be low, and prognosis poor, in infants whose echodensities were diffuse or indicated intraparenchymal hemorrhage than in infants whose echodensities were consistent with periventricular leukomalacia. We conclude that when reduced values for PCr/Pi indicating severely impaired oxidative phosphorylation are found in the brains of infants suspected of hypoxicischemic injury, the prognosis for survival without serious multiple impairments is very poor, and that when ATP/ total phosphorus is reduced, death is almost inevitable.

Early prognostic indicators of outcome in infants with neonatal cerebral infarction : A clinical, electroencephalogram, and magnetic resonance imaging study

Objective. The aim of this study was to identify prognostic factors in newborns with cerebral infarction. Design. Antenatal and perinatal factors and early clinical, electroencephalogram (EEG), and magnetic resonance imaging (MRI) findings were compared with neurodevelopmental outcome in 24 children with evidence of cerebral infarction on neonatal MRI. Results. Out of 24 infants, 19 had an infarction in the territory of a major cerebral vessel and 5 in the borderzone between cerebral arteries. Neuromotor outcome was normal in 17 and abnormal in 7 infants. Of these 7 infants, 5 infants showed a definite hemiplegia, whereas the other 2 showed some asymmetry of tone or function but no definite hemiplegia. None of the adverse antenatal or perinatal factors was significantly associated with abnormal outcome. Neonatal clinical examination was also not always predictive of the outcome. The extent of the lesion on MRI was a better predictor. In particular, it was the concomitant involvement of hemisphere, internal capsule and basal ganglia that was always associated with an abnormal outcome whereas the involvement of only one or two of the three tended to be associated with a normal outcome. EEG was also very helpful. Abnormal background activity either unilateral or bilateral was found in 6 infants and 5 out of 6 developed hemiplegia. In contrast, the presence of seizure activity in presence of a normal background was not related to abnormal outcome. Conclusions. Early MRI and EEG can help to identify the infants with cerebral infarction who are likely to develop hemiplegia.

Pilot Study of Treatment With Whole Body Hypothermia for Neonatal Encephalopathy

Background. There is extensive experimental evidence to support the investigation of treatment with mild hypothermia after birth asphyxia. However, clinical studies have been delayed by the difficulty in predicting long-term outcome very soon after birth and by concern about adverse effects of hypothermia. Objectives. The objectives of this study were to determine whether it is feasible to select infants with a bad neurological prognosis and to begin hypothermic therapy within 6 hours of birth, and to observe the effect of this therapy on relevant physiologic variables. Methods. Sixteen newborn infants with clinical features of birth asphyxia (median cord blood pH: 6.74; range: 6.58–7.08) were assessed by amplitude integrated electroencephalography (aEEG), and mild whole body hypothermia was instituted within 6 hours of birth in the 10 infants with an aEEG prognostic of a bad outcome. Rectal temperature was maintained at 33.2 ± (standard deviation) .6°C for 48 hours. Rectal and tympanic membrane temperature, blood pressure, heart rate, blood gases, blood lactate, full blood count, blood electrolytes, high and low shear rate viscosity, and coagulation studies were monitored during and after cooling. A preliminary assessment of neurological outcome was made by repeated magnetic resonance imaging (MRI) and neurological examination. Results. All infants selected to receive hypothermia developed convulsions and a severe encephalopathy. During 48 hours of hypothermia infants had prolonged metabolic acidosis (median pH: 7.30; base excess: −6.3 mmol · L− 1, a high blood lactate (median lactate: 5.3 mmol · L− 1) and low blood potassium levels (median value: 3.9 mmol · L− 1). Hypothermia was associated with lower heart rate and higher mean blood pressure. However, these changes did not seem to be clinically relevant and no significant complication of hypothermia was encountered. Blood viscosity and coagulation studies were similar during and after cooling. Unusual MRI findings were noted in 3 infants: transverse sinus thrombosis with subsequent small cerebellar infarct; probable thrombosis in the straight sinus; and hemorrhagic cerebral infarction. Six of the 10 cooled infants had minor abnormalities only or normal follow-up neurological examination; 3 infants died and 1 had major abnormalities. None of the 6 infants with a normal aEEG developed severe neonatal encephalopathy or neurological sequel. Conclusions. After birth asphyxia infants can be objectively selected by aEEG and hypothermia started within 6 hours of birth in infants at high risk of developing severe neonatal encephalopathy. Prolonged mild hypothermia to 33°C to 34°C is associated with minor physiologic abnormalities. Further studies of both the safety and efficacy of mild hypothermia, including further neuroimaging studies, are warranted.

Determinants of outcomes after head cooling for neonatal encephalopathy

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