Henry L. Halliday

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.

European Consensus Guidelines on the Management of Neonatal Respiratory Distress Syndrome in Preterm Infants – 2010 Update

Despite recent advances in the perinatal management of neonatal respiratory distress syndrome (RDS), controversies still exist. We report the updated recommendations of a European panel of expert neonatologists who had developed consensus guidelines after critical examination of the most up-to-date evidence in 2007. These updated guidelines are based upon published evidence up to the end of 2009. Strong evidence exists for the role of a single course of antenatal steroids in RDS prevention, but the potential benefit and long-term safety of repeated courses are unclear. Many practices involved in preterm neonatal stabilisation at birth are not evidence-based, including oxygen administration and positive pressure lung inflation, and they may at times be harmful. Surfactant replacement therapy is crucial in the management of RDS, but the best preparation, optimal dose and timing of administration at different gestations is not always clear. Respiratory support in the form of mechanical ventilation may also be lifesaving, but can cause lung injury, and protocols should be directed at avoiding mechanical ventilation where possible by using nasal continuous positive airways pressure or nasal ventilation. For babies with RDS to have best outcomes, it is essential that they have optimal supportive care, including maintenance of a normal body temperature, proper fluid management, good nutritional support, management of the ductus arteriosus and support of the circulation to maintain adequate tissue perfusion.

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.

The pathophysiology of HOX genes and their role in cancer

The HOM‐C clustered prototype homeobox genes of Drosophila, and their counterparts, the HOX genes in humans, are highly conserved at the genomic level. These master regulators of development continue to be expressed throughout adulthood in various tissues and organs. The physiological and patho‐physiological functions of this network of genes are being avidly pursued within the scientific community, but defined roles for them remain elusive. The order of expression of HOX genes within a cluster is co‐ordinated during development, so that the 3′ genes are expressed more anteriorly and earlier than the 5′ genes. Mutations in HOXA13 and HOXD13 are associated with disorders of limb formation such as hand–foot–genital syndrome (HFGS), synpolydactyly (SPD), and brachydactyly. Haematopoietic progenitors express HOX genes in a pattern characteristic of the lineage and stage of differentiation of the cells. In leukaemia, dysregulated HOX gene expression can occur due to chromosomal translocations involving upstream regulators such as the MLL gene, or the fusion of a HOX gene to another gene such as the nucleoporin, NUP98. Recent investigations of HOX gene expression in leukaemia are providing important insights into disease classification and prediction of clinical outcome. Whereas the oncogenic potential of certain HOX genes in leukaemia has already been defined, their role in other neoplasms is currently being studied. Progress has been hampered by the experimental approach used in many studies in which the expression of small subsets of HOX genes was analysed, and complicated by the functional redundancy implicit in the HOX gene system. Attempts to elucidate the function of HOX genes in malignant transformation will be enhanced by a better understanding of their upstream regulators and downstream target genes. Copyright

Assessment of brain tissue injury after moderate hypothermia in neonates with hypoxic-ischaemic encephalopathy : a nested study 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.

Randomised controlled trial of an aggressive nutritional regimen in sick very low birthweight infants

AIMS To improve energy intake in sick very low birthweight (VLBW) infants; to decrease growth problems, lessen pulmonary morbidity, shorten hospital stay, and avoid possible feeding related morbidity. Morbidity in VLBW infants thought to be associated with parenteral and enteral feeding includes bronchopulmonary dysplasia, necrotising enterocolitis, septicaemia, cholestasis and osteopenia of prematurity. METHODS A prospective randomised controlled trial (RCT) comparing two types of nutritional intervention was performed involving 125 sick VLBW infants in the setting of a regional neonatal intensive care unit. Babies were randomly allocated to either an aggressive nutritional regimen (group A) or a control group (group B). Babies in group B received a conservative nutritional regimen while group A received a package of more aggressive parenteral and enteral nutrition. Statistical analysis was done using Student’st test, the Mann-Whitney U test, the χ2 test and logistic regression. RESULTS There was an excess of sicker babies in group A, as measured by initial disease severity (P <0.01), but mean total energy intakes were significantly higher (P <0.001) in group A at days 3 to 42 while receiving total or partial parenteral nutrition. Survival and the incidences of bronchopulmonary dysplasia, septicaemia, cholestasis, osteopenia and necrotising enterocolitis were similar in both groups. Growth in early life and at discharge from hospital was significantly better in babies in group A. There were no decreases in pulmonary morbidity or hospital stay. CONCLUSION Nutritional intake in sick VLBW infants can be improved without increasing the risk of adverse clinical or metabolic sequelae. Improved nutritional intake resulted in better growth, both in the early neonatal period and at hospital discharge, but did not decrease pulmonary morbidity or shorten hospital stay.

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 childrens 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. (Funded by the United Kingdom Medical Research Council and others; TOBY ClinicalTrials.gov number, NCT01092637.).

Impact of Postnatal Systemic Corticosteroids on Mortality and Cerebral Palsy in Preterm Infants: Effect Modification by Risk for Chronic Lung Disease

Objective. In preterm infants, chronic lung disease (CLD) is associated with an increased risk for cerebral palsy (CP). However, systemic postnatal corticosteroid therapy to prevent or treat CLD, although effective in improving lung function, may cause CP. The objective of this study was to determine the effect of systemic postnatal corticosteroid treatment on death and CP and to assess any modification of effect arising from risk for CLD. Methods. Randomized, controlled trials of postnatal corticosteroid therapy for prevention or treatment of CLD in preterm infants that reported rates of both mortality and CP were reviewed and their data were synthesized. Twenty studies with data on 1721 randomized infants met eligibility criteria. The relationship between the corticosteroid effect on the combined outcome, death or CP, and the risk for CLD in control groups was analyzed by weighted meta-regression. Results. Among all infants who were randomized, a significantly higher rate of CP after corticosteroid treatment (typical risk difference [RD]: 0.05; 95% confidence interval [CI]: 0.02, 0.08) was partly offset by a nonsignificant reduction in mortality (typical RD: −0.02; 95% CI: −0.06 to 0.02). Consequently, there was no significant effect of corticosteroid treatment on the combined rate of mortality or CP (typical RD: 0.03; 95% CI: −0.01 to 0.08). However, on meta-regression, there was a significant negative relationship between the treatment effect on death or CP and the risk for CLD in control groups. With risks for CLD below 35%, corticosteroid treatment significantly increased the chance of death or CP, whereas with risks for CLD exceeding 65%, it reduced this chance. Conclusions. The effect of postnatal corticosteroids on the combined outcome of death or CP varies with the level of risk for CLD.

Surfactants: past, present and future.

In 1929 Kurt von Neergaard performed experiments suggesting the presence of pulmonary surfactant and its relevance to the newborns first breath. Almost 25 years later, Richard Pattle, John Clements and Chris Macklin, each working on the effects of nerve gases on the lungs, contributed to the understanding of the physiology of pulmonary surfactant. About 5 years later Mary Ellen Avery and Jere Mead published convincing evidence that preterm neonates dying of hyaline membrane disease (respiratory distress syndrome, RDS) had a deficiency of pulmonary surfactant. The first trials of nebulized synthetic (protein-free) surfactant to prevent RDS were published soon after Patrick Bouvier Kennedy (son of President John F Kennedy) died of this disorder after treatment in Boston. These trials were unsuccessful; however, Goran Enhorning and Bengt Robertson in the early 1970s demonstrated that natural surfactants (containing proteins) were effective in an immature rabbit model of RDS. Soon after this Forrest Adams showed that a natural surfactant was also effective in an immature lamb model. Working with him was Tetsuro Fujiwara who 2 years later, after returning to Japan, published the seminal article reporting the responses of 10 preterm infants with RDS to a bolus of modified bovine surfactant. During the 1980s there were numerous randomized controlled trials of many different natural and synthetic surfactants, demonstrating reductions in pulmonary air leaks and neonatal mortality. Subsequently natural surfactants were shown to be superior to the protein-free synthetic products. Recently there have been a number of randomized trials comparing different natural surfactant preparations. Commercially available bovine surfactants may have similar efficacy but there is some evidence that a porcine surfactant used to treat RDS with an initial dose of 200 mg per kg is more effective than a bovine surfactant used in an initial dose of 100 mg per kg. Bovine and porcine surfactants have not been compared in trials of prophylaxis. Very recently a new synthetic surfactant with a surfactant protein mimic has been compared with other commercially available natural and synthetic surfactants in two trials. The new surfactant may be superior to one of the older protein-free synthetic surfactants but there is no evidence of its superiority over established natural products and it is currently not approved for clinical use. A number of other new synthetic surfactants have been tested in animal models or in treatment of adults with ARDS, but so far there have been no reports of treatment of neonatal RDS. Natural surfactants work best if given by a rapid bolus into the lungs but less invasive methods such as a laryngeal mask, pharyngeal deposition or rapid extubation to CPAP have showed promise. Unfortunately, delivery of surfactant by nebulization has so far been ineffective. Surfactant treatment has been tried in a number of other neonatal respiratory disorders but only infants with meconium aspiration seem to benefit although larger and more frequent doses are probably needed to demonstrate improved lung function. A surfactant protocol based upon early treatment and CPAP is suggested for very preterm infants. Earlier treatment may improve survival rates for these infants; however, there is a risk of increasing the prevalence of milder forms of chronic lung disease. Nevertheless, surfactant therapy has been a major contribution to care of the preterm newborn during the past 25 years.