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

Effects of Hypothermia for Perinatal Asphyxia on Childhood Outcomes

BACKGROUND: In the Total Body Hypothermia for Neonatal Encephalopathy Trial (TOBY), newborns with asphyxial encephalopathy who received hypothermic therapy had improved neurologic outcomes at 18 months of age, but it is uncertain whether such therapy results in longer-term neurocognitive benefits. METHODS: We randomly assigned 325 newborns with asphyxial encephalopathy who were born at a gestational age of 36 weeks or more to receive standard care alone (control) or standard care with hypothermia to a rectal temperature of 33 to 34°C for 72 hours within 6 hours after birth. We evaluated the neurocognitive function of these children at 6 to 7 years of age. The primary outcome of this analysis was the frequency of survival with an IQ score of 85 or higher. RESULTS: A total of 75 of 145 children (52%) in the hypothermia group versus 52 of 132 (39%) in the control group survived with an IQ score of 85 or more (relative risk, 1.31; P=0.04). The proportions of children who died were similar in the hypothermia group and the control group (29% and 30%, respectively). More children in the hypothermia group than in the control group survived without neurologic abnormalities (65 of 145 [45%] vs. 37 of 132 [28%]; relative risk, 1.60; 95% confidence interval, 1.15 to 2.22). Among survivors, children in the hypothermia group, as compared with those in the control group, had significant reductions in the risk of cerebral palsy (21% vs. 36%, P=0.03) and the risk of moderate or severe disability (22% vs. 37%, P=0.03); they also had significantly better motor-function scores. There was no significant between-group difference in parental assessments of children's health status and in results on 10 of 11 psychometric tests. CONCLUSIONS: Moderate hypothermia after perinatal asphyxia resulted in improved neurocognitive outcomes in middle childhood. Copyright © 2014 Massachusetts Medical Society

Moderate hypothermia within 6 h of birth plus inhaled xenon versus moderate hypothermia alone after birth asphyxia (TOBY-Xe):a proof-of-concept, open-label, randomised controlled trial

SummaryBackgroundModerate cooling after birth asphyxia is associated with substantial reductions in death and disability, but additional therapies might provide further benefit. We assessed whether the addition of xenon gas, a promising novel therapy, after the initiation of hypothermia for birth asphyxia would result in further improvement.MethodsTotal Body hypothermia plus Xenon (TOBY-Xe) was a proof-of-concept, randomised, open-label, parallel-group trial done at four intensive-care neonatal units in the UK. Eligible infants were 36–43 weeks of gestational age, had signs of moderate to severe encephalopathy and moderately or severely abnormal background activity for at least 30 min or seizures as shown by amplitude-integrated EEG (aEEG), and had one of the following: Apgar score of 5 or less 10 min after birth, continued need for resuscitation 10 min after birth, or acidosis within 1 h of birth. Participants were allocated in a 1:1 ratio by use of a secure web-based computer-generated randomisation sequence within 12 h of birth to cooling to a rectal temperature of 33·5°C for 72 h (standard treatment) or to cooling in combination with 30% inhaled xenon for 24 h started immediately after randomisation. The primary outcomes were reduction in lactate to N-acetyl aspartate ratio in the thalamus and in preserved fractional anisotropy in the posterior limb of the internal capsule, measured with magnetic resonance spectroscopy and MRI, respectively, within 15 days of birth. The investigator assessing these outcomes was masked to allocation. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00934700, and with ISRCTN, as ISRCTN08886155.FindingsThe study was done from Jan 31, 2012, to Sept 30, 2014. We enrolled 92 infants, 46 of whom were randomly assigned to cooling only and 46 to xenon plus cooling. 37 infants in the cooling only group and 41 in the cooling plus xenon group underwent magnetic resonance assessments and were included in the analysis of the primary outcomes. We noted no significant differences in lactate to N-acetyl aspartate ratio in the thalamus (geometric mean ratio 1·09, 95% CI 0·90 to 1·32) or fractional anisotropy (mean difference −0·01, 95% CI −0·03 to 0·02) in the posterior limb of the internal capsule between the two groups. Nine infants died in the cooling group and 11 in the xenon group. Two adverse events were reported in the xenon group: subcutaneous fat necrosis and transient desaturation during the MRI. No serious adverse events were recorded.InterpretationAdministration of xenon within the delayed timeframe used in this trial is feasible and apparently safe, but is unlikely to enhance the neuroprotective effect of cooling after birth asphyxia.FundingUK Medical Research Council

Implementation and Conduct of Therapeutic Hypothermia for Perinatal Asphyxial Encephalopathy in the UK – Analysis of National Data

BACKGROUND: Delay in implementing new treatments into clinical practice results in considerable health and economic opportunity costs. Data from the UK TOBY Cooling Register provides the opportunity to examine how one new effective therapy for newborn infants suspected of suffering asphyxial encephalopathy--therapeutic hypothermia- was implemented in the UK. METHODOLOGY/PRINCIPAL FINDINGS: We analysed returned data forms from inception of the Register in December 2006 to the end of July 2011. Data forms were received for 1384 (67%) of the 2069 infants registered. The monthly rate of notifications increased from median {IQR} 18 {15-31} to 33 {30-39} after the announcement of the results of the recent TOBY trial, and to 50 {36-55} after their publication. This rate further increased to 70 {64-83} following official endorsement of the therapy, and is now close to the expected numbers of eligible infants. Cooling was started at 3.3 {1.5-5.5} hours after birth and the time taken to achieve the target 33-34 °C rectal temperature was 1 {0-3} hours. The rectal temperature was in the target range in 83% of measurements. From 2006 to 2011 there was evidence of extension of treatment to slightly less severely affected infants. 278 of 1362 (20%) infants died at 2.9 {1.4-4.1} days of age. The rates of death fell slightly over the period of the Register and, at two years of age cerebral palsy was diagnosed in 22% of infants; half of these were spastic bilateral. Factors independently associated with adverse outcome were clinical seizures prior to cooling (p<0.001) and severely abnormal amplitude integrated EEG (p<0.001). CONCLUSIONS/SIGNIFICANCE: Therapeutic hypothermia was implemented appropriately within the UK, with significant benefit to patients and the health economy. This may be due in part to participation by neonatal units in clinical trials, the establishment of the national Register, and its endorsement by advisory bodies

Hypothermia for perinatal asphyxia: trial-based resource use and costs at 6textendash7 years

Objective: To assess the impact of hypothermic neural rescue for perinatal asphyxia at birth on healthcare costs of survivors aged 6 to 7 years, and to quantify the relationship between costs and overall disability levels. Design: Six to 7-year follow-up of surviving children from the Total Body Hypothermia for Neonatal Encephalopathy (TOBY) Trial. Setting: Community study including a single parental questionnaire to collect information on children’s healthcare resource use. Patients: 130 UK children (63 in the control group, 67 in the hypothermia group) whose parents consented and returned the questionnaire. Interventions: Intensive care with cooling of the body to 33.5°C for 72 hours or intensive care alone. Main outcome measures: Healthcare resource usage and costs over the preceding six months. Results: At 6 to 7 years, mean (standard error) healthcare costs per child were £1,543 (£361) in the hypothermia group and £2,549 (£812) in the control group, giving a saving of -£1,005 (95% CI -£2,734 to £724). Greater levels of overall disability were associated with progressively higher costs, and more parents in the hypothermia group were employed (65% v 50%). Results were sensitive to outlying observations. Conclusions: Cost results although not significant favoured moderate hypothermia and so complement the clinical results of the TOBY Children study. Estimates were however sensitive to the care requirements of two seriously ill children in the control group. A quantification of the relationship between costs and levels of disability experienced will be useful to healthcare professionals, policy makers, and health economists contemplating the longer-term economic consequences of perinatal asphyxia and hypothermic neural rescue

Hypothermia for perinatal asphyxia:Trial-based quality of life at 6-7 years

Objective: To assess the impact of hypothermic neural rescue at birth on health-related quality of life (HRQL) in middle childhood. Design: Six-year to 7-year follow-up of surviving children from the Total Body Hypothermia for Neonatal Encephalopathy (TOBY) Trial. Setting: Community study including a single parental questionnaire to collect information on children’s HRQL. Patients: 145 children (70 in the control group, 75 in the hypothermia group) whose parents consented and returned the questionnaire. Interventions: Intensive care with cooling of the body to 33.5°C for 72 hours or intensive care alone. Main outcome measures: HRQL attributes and utility scores using the Health Utilities Index (HUI). Results: At 6–7 years, speech appeared disproportionately affected when compared with other aspects of HRQL but levels of normal emotional functioning were similar in both groups. The mean (SE) HUI3 HRQL scores were 0.73 (0.05) in the hypothermia group and 0.62 (0.06) in the control group; mean difference (95% CI) 0.11 (−0.04 to 0.26). Conclusions: Findings of non-significant differences were not unexpected; the study used data from long-term survivors in a neonatal trial and was underpowered. However, results favoured moderate hypothermia and so complement the clinical results of the TOBY Children study. The work provides further insight into the long-term HRQL impact of perinatal asphyxial encephalopathy and provides previously unavailable utility data with which to contemplate the longer term cost-effectiveness of hypothermic neural rescue

Effects of Hypothermia for Perinatal Asphyxia on Childhood Outcomes

Background In the Total Body Hypothermia for Neonatal Encephalopathy Trial (TOBY), newborns with asphyxial encephalopathy who received hypothermic therapy had improved neurologic outcomes at 18 months of age, but it is uncertain whether such therapy results in longer-term neurocognitive benef its. Methods We randomly assigned 325 newborns with asphyxial encephalopathy who were born at a gestational age of 36 weeks or more to receive standard care alone (control) or standard care with hypothermia to a rectal temperature of 33 to 34°C for 72 hours within 6 hours after birth. We evaluated the neurocognitive function of these children at 6 to 7 years of age. The primary outcome of this analysis was the frequency of survival with an IQ score of 85 or higher Results A total of 75 of 145 children (52%) in the hypothermia group versus 52 of 132 (39%) in the control group survived with an IQ score of 85 or more (relative risk, 1.31; P = 0.04). The proportions of children who died were similar in the hypothermia group and the control group (29% and 30%, respectively). More children in the hypothermia group than in the control group survived without neurologic abnormalities (65 of 145 [45%] vs. 37 of 132 [28%]; relative risk, 1.60; 95% confidence interval, 1.15 to 2.22). Among survivors, children in the hypothermia group, as compared with those in the control group, had significant reductions in the risk of cerebral palsy (21% vs. 36%, P = 0.03) and the risk of moderate or severe disability (22% vs. 37%, P = 0.03); they also had significantly better motor-function scores. There was no significant between-group difference in parental assessments of children’s health status and in results on 10 of 11 psychometric tests. Conclusions Moderate hypothermia after perinatal asphyxia resulted in improved neurocognitive outcomes in middle childhood.</p

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

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 EEC, 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

Adverse events on days 1–4 after birth reported to the UK TOBY Cooling Register (Number of forms with completed data: 1384).

<p>Definitions:</p><p>Sepsis: Any evidence of infection requiring antibiotic therapy which is confirmed on culture.</p><p>Hypoglycaemia: Blood glucose below 2.6 mmol/litre.</p><p>Hypotension: Persistent mean blood pressure of <40 mmHg.</p><p>Coagulopathy: Any disorder requiring treatment in order to maintain or recover normal haemostasis.</p><p>Arrhythmia: Sinus bradycardia below 80 beats per minute and other arrhythmias identified on the electrocardiogram.</p

Distribution of cooling centres in the UK.

<p>Three centres from Eire contributed data from 35 cases and these are included in this report.</p