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50% Xenon Inhalation During the Whole 78H Period of Therapeutic Hypothermia with Rewarming Reduces the Seizure Burden, Anticonvulsant and Sedative Use

Presented at the Neonatal Society 2017 Summer Meeting (programme).

Chakkarapani E1, Thoresen M1,2, Okano S1, Liu X1, Scull-Brown E1, Lee-Kelland R1, Dingley J1,3

1 University of Bristol, United Kingdom
2 University of Oslo, Norway
3 Swansea University, United Kingdom

Background: Seizures are common after severe HIE and may worsen the neurodevelopmental outcome (1). Xenon (Xe), a neuroprotective anaesthetic gas, depresses aEEG background voltage, maintains cardiovascular stability in pigs (2-4) and does not increase apoptosis in the immature brain (5). In humans, 24h of 30% Xe reduced seizures in infants with HIE cooled for 72h (6). We examined the feasibility of giving 50% xenon during the 72h-TH including 6h-rewarming and hypothesised that the seizure burden and the need for analgesics will be reduced.

Methods: With home office license approval for 96h long experiments,12 newborn pigs were randomised to 72hTH35C (3.5C core temperature reduction, TH group, n=6) or 78hXe50% +72hTH35C, (XeTH group, n=6) following a 45min global hypoxic-ischaemic insult and sedated with propofol and fentanyl during treatment. Two channel EEG and aEEG were used to record upper and lower amplitude, timing, and duration of electrical seizures and doses of any anticonvulsant as well as propofol and fentanyl. Funders: Rosetrees, SPARKS, Moulton Trust.

Results: Baseline data were comparable, but the hypoxic-ischaemic insult was more severe in XeTH group. As expected, aEEG was depressed significantly more during the 78h in the XeTH group than TH group (Median (IQR): 6.3μV (2.8,8.7) vs 11.0μV (8.2,12.6), P=0.03). The aEEG amplitude recovered from 13.2μV (5.3,21.1) at the end of Xe inhalation to 27.5μV (24.3,33.8), P=0.01, at the end of further 12h survival. XeTH compared to TH group needed significantly less hourly mean (SD) propofol 3.8mg/kg (0.8) vs 7.2mg/kg (0.9), P<0.05 and fentanyl 2.6mcg/kg (0.45) vs 5.5mcg/kg (1.09), P<0.05. Two of 6 XeTH pigs compared to all 6 TH pigs had electrical seizures. Hourly seizure burden was significantly lower in XeTH group than TH group (mean(SEM): 7.8min (3.1) vs 24.4min (6.1), P=0.01. The distribution of total duration of electrical seizures were significantly lower in the XeTH group compared to TH group (P=0.009). 50% of XeTH group did not receive anticonvulsants.

Conclusion: Xenon inhalation during the whole period of 78h of TH + rewarming as compared to TH alone reduced the seizure burden by 70%. Xenon which is an anaesthetic suppresses the background EEG per se and recovers quickly when 50%Xe inhalation stops. Xenon may provide neuroprotection by reducing seizure activity.

Corresponding author:

1. Shah DK. Arch Dis Child Fetal Neonatal Ed 2014
2. Chakkarapani E. Ann Neurol 2010
3. Sabir H. J Neuro Sci 2016
4. Chakkarapani E. Intensive Care Med 2012
5. Sabir H. Anesthesiology 2013
6. Azzopardi D. 2013

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