Presented at the Neonatal Society 2006 Widdowson Meeting.
Tucker A, Hogan S, Dingley J, Hobbs C, Thoresen M
Department of Clinical Sciences, University of Bristol, UK
Background: Animal studies have shown that the outcome of an ischemic episode in adults is worse when body temperature is elevated above 39ºC (1). Similarly, in a model of post hypoxicischaemic seizures, preventing the accompanying hyperthermia significantly attenuated brain injury2. However, the degree and duration of hyperthermia injures the neonatal brain is unknown and long-term functional studies following hypoxia-ischaemia are lacking.
Aim: To investigate the effect of small increases in temperature on the functional and histological outcomes of hypoxic-ischaemic brain injury.
Methods: All procedures were undertaken in accordance with UK Home Office guidelines. Sixty-two 7-days old (P7) Wistar rat pups underwent ligation of the left common carotid artery under halothane anaesthesia, followed by exposure to 8% oxygen for 90min at normothermia (37ºC). Pups were randomised to recover for 5 hours at one of three temperatures; 39ºC (moderate hyperthermia), 38ºC (mild hyperthermia) or 37ºC (normothermia). A further 34 animals served as juvenile controls. From 8-11 weeks of age, fine forepaw control (motor dexterity) was assessed using the staircase test (reward pellets retrieved from descending steps). The brains were preserved by perfusion fixation under deep halothane anaesthesia. Brains were then processed for histopathology of four brain regions; cortex/white matter, basal ganglia, thalamus and hippocampus and scored on a 9 step scale (0.0 = no injury, 4.0 = complete infarction and 4.5 = death).
Results: Fifty percent of animals recovering at 39ºC did not survive the 5 hour hyperthermia period, while there was minimal mortality in all other groups. Animals exposed to HI displayed significant impairment in fine motor dexterity compared to control animals (p < 0.0001; Figure 1) with a trend towards greater impairment with increasing recovery temperature. HI produced significant brain injury in the hemisphere ipsilateral to ligation (p < 0.0001). Recovering at 38ºC or 39ºC significantly exacerbated this injury (p < 0.0001 vs recovery at 37ºC; Figure 2).
Discussion: In this model of neonatal hypoxia-ischaemia, an increase in temperature by just 1ºC, after the insult signif icantly increased brain injury. Recovery at 39ºC resulted in huge mortality, and, in those that did survive, massive brain injury and functional deficits. This shows how vulnerable the neonatal brain is to even small increases in temperature. This is the first study to show the long-term functional and histological effects of hyperthermia following neonatal HI and has major implications for neonatal care where it is still standard practice to actively heat asphyxiated newborns to avoid hypothermia.
Acknowledgements: Acknowledgements – This work is supported by The Wellcome Trust.