Abstract
Background: We are investigating xenon(Xe) gas as an adjunct neuroprotectant to therapeutic hypothermia (TH) for
hypoxic-ischemic encephalopathy (HIE). Xe is reported to have anticonvulsant and additive neuroprotective properties
without adverse effects in rat and pig models of HIE. A clinical study with an early MRI biomarker as outcome did not
show benefit from adding 30%Xe for 24hstarting around 10h of age. Since TH lasts 72h and the brain injury cascade
continues for several days, it is important to investigate the safety of adding a therapeutic Xe dose of 50% during the
whole cooling period. We have previously shown that Xe-delivery is feasible, however Xe is an anesthetic, and it is
unknown if prolonged Xe inhalation during TH may worsen or improve the brain injury.
Objective: To compare the seizure burden and brain pathology between 3d of XeTH orTH only followed by rewarming
and 12h normothermic survival in a newborn pig global HIE model.
Design/Methods: Twelve newborn pigs that survived the 45min global hypoxic-ischaemic insult were randomised to
3d Xe50%TH35°C (XeTH) and TH35°C (TH). TH was achieved by whole body cooling followed by rewarming at
0.5°C/hour. XeTH received 50%Xe/25%O2/25%N2 using an automated closed-circuit device with concurrent TH. All
animals received propofol and fentanyl sedation. Electrical seizure duration was measured on the single or dual
channel aEEG. Pigs underwent terminal perfusion fixation under deep anaesthesia, 12h after treatment. Brains
harvested were qualitatively scored as mild, moderate and severe injury in 6 regions leading to a maximum global
score of 12. Neuronal count, myelin basic protein (MBP) and glial fibrillary acidic protein (GFAP) immunofluorescence
were assessed.
Results: Baseline characteristics were comparable between the groups. XeTH group had a shorter median (IQR)
seizure burden (0h(0,109) vs 212h(72.5,383.0), P=0.02). XeTH and TH groups had comparable qualitative brain injury
score, neuronal count, MBP and GFAP immunofluorescence (Table 1, Fig 1 and 2).
Conclusion(s): Xe inhalation throughout the TH regimen reduced seizure burden and resulted in similar degrees of
brain injury to TH only in a small sample of pigs. A larger sample with longer term outcome is necessary to identify any
definitive neuroprotective effect. This suggests that a longer duration of XeTH combination reduces seizure burden
profoundly and does not worsen brain injury, hence could be investigated in neuroprotection trials.
hypoxic-ischemic encephalopathy (HIE). Xe is reported to have anticonvulsant and additive neuroprotective properties
without adverse effects in rat and pig models of HIE. A clinical study with an early MRI biomarker as outcome did not
show benefit from adding 30%Xe for 24hstarting around 10h of age. Since TH lasts 72h and the brain injury cascade
continues for several days, it is important to investigate the safety of adding a therapeutic Xe dose of 50% during the
whole cooling period. We have previously shown that Xe-delivery is feasible, however Xe is an anesthetic, and it is
unknown if prolonged Xe inhalation during TH may worsen or improve the brain injury.
Objective: To compare the seizure burden and brain pathology between 3d of XeTH orTH only followed by rewarming
and 12h normothermic survival in a newborn pig global HIE model.
Design/Methods: Twelve newborn pigs that survived the 45min global hypoxic-ischaemic insult were randomised to
3d Xe50%TH35°C (XeTH) and TH35°C (TH). TH was achieved by whole body cooling followed by rewarming at
0.5°C/hour. XeTH received 50%Xe/25%O2/25%N2 using an automated closed-circuit device with concurrent TH. All
animals received propofol and fentanyl sedation. Electrical seizure duration was measured on the single or dual
channel aEEG. Pigs underwent terminal perfusion fixation under deep anaesthesia, 12h after treatment. Brains
harvested were qualitatively scored as mild, moderate and severe injury in 6 regions leading to a maximum global
score of 12. Neuronal count, myelin basic protein (MBP) and glial fibrillary acidic protein (GFAP) immunofluorescence
were assessed.
Results: Baseline characteristics were comparable between the groups. XeTH group had a shorter median (IQR)
seizure burden (0h(0,109) vs 212h(72.5,383.0), P=0.02). XeTH and TH groups had comparable qualitative brain injury
score, neuronal count, MBP and GFAP immunofluorescence (Table 1, Fig 1 and 2).
Conclusion(s): Xe inhalation throughout the TH regimen reduced seizure burden and resulted in similar degrees of
brain injury to TH only in a small sample of pigs. A larger sample with longer term outcome is necessary to identify any
definitive neuroprotective effect. This suggests that a longer duration of XeTH combination reduces seizure burden
profoundly and does not worsen brain injury, hence could be investigated in neuroprotection trials.
| Original language | English |
|---|---|
| Publication status | Published - May 2018 |