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

Abstract

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.

Figure 1

MRI appearances in neonatal hypoxic–ischaemic encephalopathy (A-C) T1-weighted images in the transverse plane. (A) Normal neonatal brain with linear high signal intensity representing myelin in the posterior limb of the internal capsule (arrow). (B) Moderate basal ganglia and thalamic lesions with abnormal increased signal intensity in the globus (top arrow), putamen (middle arrow), and thalamus (bottom arrow). There is no normal linear high signal intensity from the intervening posterior limb of the internal capsule. (C) Cortical lesions. There is abnormal increased signal intensity in the cortex around the central sulcus (arrow head) and along the interhemispheric fissure. Abnormal low signal intensity is seen in the adjacent subcortical white matter (arrow). (D–F) T2-weighted images in the transverse plane. (D) Mild lesions in the basal ganglia. There are small bilateral foci of abnormal low signal intensity in the lentiform nuclei (arrow). (E) Mild white matter lesions. There is diffuse and slightly increased signal intensity in the periventricular white matter (arrow). (F) Severe basal ganglia and thalamic and white matter lesions. There is mixed abnormal signal intensity throughout the basal ganglia and thalami. The intervening posterior limb of the internal capsule shows abnormal high signal intensity with no evidence of low signal intensity from myelin (arrow). The hemispheric white matter has diffuse abnormal high signal intensity throughout.

Figure 2

Study profile