THE YOUNG INVESTIGATOR'S PRIZE LECTURE 2011
Presented at the Neonatal Society 2011 Summer Meeting (programme).
Ela Chakkarapani, Southmead Hospital, University of Bristol
'Cool Xenon': Effects on neuroprotection and haemodynamics in post-asphyxial encephalopathy
Despite Therapeutic Hypothermia (HT), 44-48% of infants with perinatal asphyxial encephalopathy develop unfavourable outcome of death or severe disability (1-3). Xenon (Xe), a scarce and expensive anaesthetic, offers neuroprotection through competitive inhibition of glycine site of N-methyl-D-aspartate (NMDA) receptor (4) and inhibition of apoptosis (5). Xenon additively enhances neuroprotection with HT in small animal model (6). In order to translate this finding to human, we designed a closed circuit breathing system and investigated in our global hypoxic-ischaemic encephalopathy newborn pig model 1) the technical and physiologic feasibility of the system to deliver 16h of Xe50%, 2) the effects of 18h Xe50% in combination with HT on neuroprotection, cardiovascular and cerebral haemodynamics.
Newborn pigs subjected to 45min of global hypoxic-ischaemic insult and randomised to normothermia (rectal temperature (Trec 38.5șC)), Xe50% for 18h, HT (Trec 33.5șC) for 12 or 24h or combined with 18h Xe50% and survived for 72h were studied for the effects of Xe and HT on neuroprotection, cardiovascular and cerebral haemodynamics. Global neuropathology was averaged from regional neuropathology scores from 6 brain regions (cortex grey matter, white matter, basal ganglia, thalamus, hippocampus and cerebellum). Cardiovascular haemodynamics was assessed with arterial blood pressure (ABP), heart rate and need for inotropic support. Cerebrovascular haemodynamics was assessed with cerebrovascular pressure reactivity (PRx). All experiments were conducted under UK Home Office licence.
Xenon is scarce and costs $30/L. When Xe was delivered at normothermia or HT through the closed circuit breathing system to asphyxiated pigs ventilated with cuffed endotracheal tube, Xe usage was significantly reduced; and ABP, oxygen saturation, and arterial carbon dioxide tension were maintained within physiological limits without increase in the duration of ventilation (7).
Xenon50% for 18h, 12h or 24h HT offered significant histological global and regional neuroprotection. Xenon HT combination improved the clinical neurology at 72h of age. While 24hHT offered 48% neuroprotection, combining 18h of Xe50% with HT additively increased the neuroprotection to 75% with significant uniform regional brain protection and improved outcome in the severely brain-injured group. There was a duration-dependent neuroprotective of HT, as 24h HT was significantly more neuroprotective than 12h HT (8).
Xenon significantly improved the ABP both during and after Xe administration, and decreased the duration of inotropic support, independent of induced HT and intravenous anaesthetics. Xenon during rewarming maintained higher ABP and ameliorated the late fall in ABP in males. Hypothermia did not affect the ABP compared to normothermia. While Xe did not affect the heart rate, HT reduced the heart rate by 10bpm/șC but this reduction was less during inotropic support. Xenon when combined with HT cleared blood lactate faster.
Cerebrovascular pressure reactivity (PRx), a key element of cerebral autoregulation, was impaired during the hypoxic-ischaemic insult and peaked from the baseline. During recovery, there was a secondary PRx peak and persistently impaired PRx in pigs with poor outcome of normothermia and HT. Secondary PRx peak occurred earlier in severe brain injury. Xenon on its own and in combination with HT preserved PRx.
Xenon in combination with hypothermia maintained stable blood pressure, preserved cerebrovascular pressure reactivity, doubled neuroprotection offered by hypothermia and can be safely delivered without wastage through the closed circuit delivery system. This has led us to successfully complete the feasibility study of 'Cool Xenon' in encephalopathic newborn babies.
I am grateful to my supervisors Prof Thoresen and Dr J Dingley for their direction in this work. I would like to acknowledge Dr X Liu, Dr N Hoque, Mr K Aquilina, Dr C Hobbs, other research colleagues and my family for their invaluable help in completing this work. I am thankful to SPARKS for funding this study.
1. Gluckman PD, et al. Lancet. 2005;365:663-70
2. Shankaran S, et al. The New England Journal of Medicine. 2005;353:1574-84
3. Azzopardi DV, et al. The New England Journal of Medicine. 2009;361:1349-58
4. Banks P, et al. Anesthesiology. 2010;112:614-22
5. Ma D, et al. Annals of Neurology. 2005;58:182-93
6. Hobbs C, et al. Stroke. 2008;39:1307-13
7. Chakkarapani E, et al. Anesthesia and Analgesia. 2009;109:451-60
8. Chakkarapani E, et al. Annals of Neurology. 2010;68:330-41.