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Xenon inhalation with therapeutic hypothermia offers greater neuroprotection after hypoxic schaemic encephalopathy in newborn pigs

Presented at the Neonatal Society 2009 Summer Meeting (programme).

Chakkarapani E1, Liu X1, Hoque N1, Porter H2, Aquilina K1, Dingley J3, Thoresen M1

1 CSSB, University of Bristol, Bristol, UK
2 Histopathology, Leicester Royal Infirmary, UK
3 Anaesthetics, Morriston Hospital, Swansea, Wales, UK

Background: Therapeutic hypothermia (HT) benefits one in 7 infants after neonatal hypoxic ischaemic encephalopathy (HIE) (1). This necessitates the development of combination neuroprotective therapy. Xenon (Xe), an inert gas, is a scarce and expensive inhalational anaesthetic; and offer long-term neuroprotection in a rat cerebral hypoxic-ischaemia (HI) model (2). Before translating to clinical trial in babies, Xes systemic and neuroprotective effects need to be assessed in a large global HIE animal model closely simulating the clinical situation, with different severity of HI insults using minimal amount of gas delivered through a system that can be used in babies (4).

Aim: To determine the neuroprotective effect of Xe, HT and the combined therapy compared to Normothermia (NT) in an established global HIE pig model.

Methods: The study was performed in accordance with UK home office regulations. 95 newborn pigs (mean (sd): age 16.7(7) h, weight 1667(258)g) underwent 45 min of global HI insult, during which FiO2 and blood pressure were reduced until aEEG fell below 7μv (3). The animals were randomised immediately to NT (rectal temperature (Trec 38.5C), n = 18), XeNT (18h 50%Xe, 30%O2, 20%N2 with 72h NT, n =12), 12hHT (12h Trec33.5C + 6h rewarming + 60h NT, n=18), Xe12hHT (18h 50%Xe, 30%O2, 20%N2 with 12h Trec33.5C + 6h rewarming + 60h NT, n=19), 24hHT (24h Trec33.5C + 10h rewarming + 38h NT, n=15) and Xe24hHT (18h 50%Xe, 30%O2, 20%N2 with 24h Trec33.5C + 10h rewarming + 38h NT, n=13). There was no difference in the insult severity between different groups. All animals were ventilated and given intravenous anaesthetics after the HI insult. On average, a net volume of only 180ml/hour of Xe through a closed circuit delivery system (4) was used. At 72h, pigs underwent terminal perfusion fixation of the brain and full autopsy under deep anaesthesia. Neuropathology was assessed by H.P.using a 9 point scale and blinded to the randomisation (3). Multiple linear regression (SPSSv15) was used to assess the treatment effects and anova to assess interactions (p < 0.05 was considered significant).

Results: 18h Xe, HT duration, lactate at the end of HI and the number of anticonvulsants used were the significant independent predictors of global neuropathology (Table 1). Fig1 shows the mean and estimated global neuropathology scores (0.5 step scale 0=no injury, 2.0=50% injury (5)) of all 6 groups. The effect of Xe and HT was additive, there was no significant interactions p=0.54).

Table 1: Multiple linear regression model with global neuropathology as dependent variable and 18hXe, HT duration, sex, weight, inotrope duration, no.of inotropes & anticonvulsants, presence of seizures, lactate, arterial pH, base excess at the end of insult and 1hr after insult as independent variables. The predictor model (R 2 0.33)shows the independent significant predictors.

Figure 1: Mean (black bar) and estimated global neuropathology (corrected for lactate at the end of insult & number of anticonvulsants).

Conclusion: Combining 18h 50%Xe with 24h therapeutic HT provided 73% reduction in brain injury.


1. Jacob S, et al. Cochrane database of systematic reviews, 2007.
2. Hobbs C, Thoresen M, et al. Stroke 2008; 39:1307-1313.
3. Thoresen M, et al. Pediatr Res 1995; 37:667-670.
4. Chakkarapani E, et al. A closed-circuit neonatal xenon delivery system: technical and practical neurprotection feasibility study in newborn pigs. Anesth Analg 2009 (in press June).
5. Thoresen M, et al. A piglet survival model of posthypoxic encephalopathy. Pediatr Res; 40:738-748.

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