D Azzopardi

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.

Cerebral metabolism within 18 hours of birth asphyxia : A proton magnetic resonance spectroscopy study

Proton magnetic resonance spectroscopy (1H MRS) was performed within 18 h of birth (median 13, range 4-18 h) on 16 term infants with clinical features of birth asphyxia. Ten infants with no evidence of birth asphyxia were studied as controls at 5-18 (median 8) h after birth. To detect delayed impairments in cerebral energy metabolism, 15 infants suspected of asphyxia underwent 31P MRS at 33-106 (median 62) h of age. Choline, creatine, and N-acetylaspartate (NAA) were detected in spectra located to the basal ganglia in all infants. Lactate was detected in 15 of the 16 infants suspected of asphyxia, but in only 4 of the 10 controls (p < 0.05, χ2). Glutamine and glutamate (Glx) was detected in 11 infants suspected of asphyxia and in three controls, but this difference was not significant at the 5% level. The spectra revealed no other significant differences between asphyxiated infants and controls. In the asphyxiated infants, there was a negative correlation between the ratio of lactate to creatine in the first 18 h of life and phosphocreatine/inorganic phosphate(PCr/Pi) at 33-106 h (p < 0.001). Five severely asphyxiated infants had PCr/Pi < 0.75 (median 0.53, range 0.14-0.65), indicating a poor neurodevelopmental prognosis, and a further infant died before PCr/Pi could be measured. Ten infants had PCr/Pi > 0.75 (1.03, 0.76-1.49). Median lactate/creatine was 1.47(range 0.67-3.81) in the six severely affected subjects, 0.38 (0-1.51) in the latter group, and 0 (0-0.6) in controls (p < 0.0005, Kruskall-Wallis). These results suggest that, after birth asphyxia, cerebral energy metabolism is abnormal during the period when 31P MRS characteristically gives normal results. 1H MRS might be of value in predicting which infants are likely to suffer a decline in cerebral high energy phosphate concentrations and subsequent neurodevelopmental impairment.

Relation between proton magnetic resonance spectroscopy within 18 hours of birth asphyxia and neurodevelopment at 1 year of age

The aim of the study was to test the hypotheses that elevated cerebral lactate, detected by proton spectroscopy performed within 18 hours of suspected birth asphyxia, is associated with adverse outcome, and that increased lactate can be used to predict adverse outcome. Thirty-one term infants suspected of having had birth asphyxia and seven control infants underwent proton magnetic resonance spectroscopy, using three-dimensional chemical shift imaging, within 18 hours of birth. Adverse outcome was defined as death or neurodevelopmental impairment at 1 year of age or more. Nine infants had an adverse outcome. The other 22 and all of the control infants remained normal. Median (range) lactate/creatine plus phosphocreatine (lactate/creatine) ratios in the abnormal, the normal, and the control group were 1.14 (0.17 to 3.81), 0.33 (0 to 1.51), and 0.05 (0 to 0.6) respectively (P=0.003). Lactate/creatine >1.0 predicted neurodevelopmental impairment at 1 year of age with sensitivity of 66% and specificity of 95%, positive and negative predictive values of 86% and 88%, and a likelihood ratio of 13.2. Elevated cerebral lactate/creatine within 18 hours of birth asphyxia predicts adverse outcome.

Cerebral intracellular lactic alkalosis persisting months after neonatal encephalopathy measured by magnetic resonance spectroscopy.

We have found that cerebral lactate can be detected later than 1 month of age after neonatal encephalopathy (NE) in infants with severe neurodevelopmental impairment at 1 y. Our hypothesis was that persisting lactate after NE is associated with alkalosis and a decreased cell phosphorylation potential. Forty-three infants with NE underwent proton and phosphorus-31 magnetic resonance spectroscopy at 0.2-56 wk postnatal age. Seventy-seven examinations were obtained: 25 aged <2 wk, 16 aged ≥ 2 to ≤ 4 wk, 25 aged >4 to ≤ 30 wk, and 11 aged >30 wk. Neurodevelopmental outcome was assessed at 1 y of age: 17 infants had a normal outcome and 26 infants had an abnormal outcome. Using univariate linear regression, we determined that increased lactate/creatine plus phosphocreatine (Cr) was associated with an alkaline intracellular pH (pHi) (p < 0.001) and increased inorganic phosphate/phosphocreatine (Pi/PCr) (p < 0.001). This relationship was significant, irrespective of outcome group or age at time of study. Between outcome groups, there were significant differences for lactate/Cr measured at <2 wk (p = 0.005) and >4 to ≤ 30 wk (p = 0.01); Pi/PCr measured at <2 wk (p < 0.001); pHi measured at <2 wk (p < 0.001), ≥ 2 to ≤ 4 wk (p = 0.02) and >4 to ≤ 30 wk (p = 0.03); and for N-acetylaspartate/Cr measured at ≥ 2 to ≤ 4 wk (p = 0.03) and >4 to ≤ 30 wk (p = 0.01). Possible mechanisms leading to this persisting cerebral lactic alkalosis are a prolonged change in redox state within neuronal cells, the presence of phagocytic cells, the proliferation of glial cells, or altered buffering mechanisms. These findings may have implications for therapeutic intervention.

Improving infant outcome with a 10 min Apgar of 0

Objective Asystole at birth and extending through 10 min is rare, with current international recommendations stating it may be appropriate to consider discontinuation of resuscitation in this clinical scenario. These recommendations are based on small case series of both term and preterm infants, where death or abnormal outcome was nearly universal. Study objective was to determine recent outcome of infants with an Apgar score of 0 at 10 min despite cardiopulmonary resuscitation, treated with therapeutic hypothermia or standard treatment, in randomised cooling studies. Design Outcome studies of infants with an Apgar of 0 at 10 min subsequently resuscitated and treated with hypothermia or standard treatment were reviewed and combined with local outcome data of infants treated with hypothermia. Results Four recent studies (n=81) and local data (n=9) yielded a total of 90 infants with an Apgar of 0 at 10 min, with 56 treated with hypothermia and 34 controls. Primary outcome of death or abnormal neurodevelopmental outcome (18–24 months) occurred in 73% cooled and 79.5% normothermic infants (p=0.61). Implications Although poor, the outcome for infants with an Apgar of 0 at 10 min of life has improved substantially in recent years. This may be related to treatment with hypothermia, enhanced resuscitation techniques and/or other supportive management. Current recommendations to consider discontinuation of resuscitation without a detectable heart rate at 10 min should consider these findings.