Closed circuit xenon delivery for 72h in neonatal piglets following hypoxic insult using an ambient pressure automated control system: Development, technical evaluation and pulmonary effects

Autoři: John Dingley aff001;  Satomi Okano aff002;  Richard Lee-Kelland aff002;  Emma Scull-Brown aff002;  Marianne Thoresen aff003;  Ela Chakkarapani aff002
Působiště autorů: Department of Anaesthetics ABM University Health Board, Swansea and College of Medicine, Swansea University, Swansea, Wales, United Kingdom aff001;  Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, England, United Kingdom aff002;  Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, England, United Kingdom aff003;  Department of Physiology, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway aff004
Vyšlo v časopise: PLoS ONE 15(1)
Kategorie: Research Article



Therapeutic hypothermia (TH) for 72h is the standard treatment following neonatal encephalopathy (NE). However, one-third do not benefit and adjunctive therapies are urgently needed. Xenon enhances neuroprotection with TH when administered at 50% concentration within 5hours of hypoxia in experimental studies. Delayed initiation (~10 hours of age) of 30% xenon for 24 hours during TH did not improve early adverse biomarkers in a clinical trial of Xenon+TH vs TH. After hypoxia-ischemia, excitotoxic injury via N-methyl-D-aspartate receptor overactivation lasts days. Since xenon partially inhibits this receptor, we hypothesised that giving 50% xenon throughout the entire 72h TH and rewarming periods would enhance neuroprotection. Xenon costs $30/litre, so a closed-circuit breathing system is desirable with automated fresh gas delivery.


Seven mechanically ventilated newborn pigs were randomized to receive 50% inhaled xenon for 72h during hypothermia (rectal-temperature 35°C) and subsequent rewarming following a global hypoxic-ischemic insult (XeHT, N = 4) or under normothermia for 72h (rectal-temperature 38.5°C) following sham insult (XeNT, N = 3). An automated fresh gas delivery system injected oxygen/air/xenon boluses into a closed-circuit based on measured gas concentrations.

Results and discussion

Median (IQR) xenon consumption was 0.31 L/h (0.18, 0.50) and 0.34L/h (0.32, 0.49) for hypothermic and normothermic groups respectively, 0.34L/h (0.25, 0.53) overall. 92% of 9626 xenon and 69% of 9635 oxygen measurements were within 20% variation from targets. For xenon concentration, the median absolute performance errors for the XeHT and XeNT groups were 6.14% and 3.84% respectively and 4.31% overall. For oxygen these values were 13.42%, 15.05% and 12.4% respectively. There were no adverse pulmonary pathophysiology findings. Clinical problems over the total period included three related to sensors, seven breathing system leaks, ten partial and one complete tracheal tube occlusion episodes.


The automated controller functioned as intended maintaining an inhaled xenon concentration close to the 50% target for 72-78h at a xenon cost of $11.1/h.

Klíčová slova:

Animal performance – Breathing – Control systems – Hypothermia – Medical hypoxia – Oxygen – Swine – Xenon


1. Thoresen M, Hobbs CE, Wood T, Chakkarapani E, Dingley J. Cooling combined with immediate or delayed xenon inhalation provides equivalent long-term neuroprotection after neonatal hypoxia-ischemia. J Cereb Blood Flow Metab 2009;29:707–14. doi: 10.1038/jcbfm.2008.163 19142190

2. Chakkarapani E, Dingley J, Liu X, Hoque N, Aquilina K, Porter H, Thoresen M. Xenon enhances hypothermic neuroprotection in asphyxiated newborn pigs. Annals of neurology 2010;68:330–41. doi: 10.1002/ana.22016 20658563

3. Liu X, Dingley J, Scull-Brown E, Thoresen M. Adding 5 h delayed xenon to delayed hypothermia treatment improves long-term function in neonatal rats surviving to adulthood. Pediatric research 2015;77:779–83. doi: 10.1038/pr.2015.49 25760545

4. Peng T, Britton GL, Kim H, Cattano D, Aronowski J, Grotta J, McPherson DD, Huang SL. Therapeutic Time Window and Dose Dependence of Xenon Delivered via Echogenic Liposomes for Neuroprotection in Stroke. CNS Neurosci Ther 2013.

5. Sheng SP, Lei B, James ML, Lascola CD, Venkatraman TN, Jung JY, Maze M, Franks NP, Pearlstein RD, Sheng H, Warner DS. Xenon neuroprotection in experimental stroke: interactions with hypothermia and intracerebral hemorrhage. Anesthesiology 2012;117:1262–75.6. doi: 10.1097/ALN.0b013e3182746b81 23143806

6. Laitio R, Hynninen M, Arola O, Virtanen S,

7. Parkkola R, Saunavaara J, Roine RO, Gronlund J, Ylikoski E, Wennervirta J, Backlund M, Silvasti P, Nukarinen E, Tiainen M, Saraste A, Pietila M, Airaksinen J, Valanne L, Martola J, Silvennoinen H, Scheinin H, Harjola VP, Niiranen J, Korpi K, Varpula M, Inkinen O, Olkkola KT, Maze M, Vahlberg T, Laitio T. Effect of Inhaled Xenon on Cerebral White Matter Damage in Comatose Survivors of Out-of-Hospital Cardiac Arrest: A Randomized Clinical Trial. JAMA 2016;315:1120–8. doi: 10.1001/jama.2016.1933 26978207

8. Fries M, Brucken A, Cizen A, Westerkamp M, Lower C, Deike-Glindemann J, Schnorrenberger NK, Rex S, Coburn M, Nolte KW, Weis J, Rossaint R, Derwall M. Combining xenon and mild therapeutic hypothermia preserves neurological function after prolonged cardiac arrest in pigs. Critical care medicine 2012;40:1297–303. doi: 10.1097/CCM.0b013e31823c8ce7 22425822

9. Veldeman Michael, Coburn Mark, Rossaint Rolf, Clusmann Hans, Nolte Kay, Kremer Benedikt and Anke Höllig. Xenon Reduces Neuronal Hippocampal Damage and Alters the Pattern of Microglial Activation after Experimental Subarachnoid Hemorrhage: A Randomized Controlled Animal Trial. Front. Neurol., 27 September 2017 |

10. Miao Yi-Feng, Peng Tao, Moody Melanie R., Klegerman Melvin E., Aronowski Jaroslaw, Grotta James, McPherson David D., Hyunggun Kim & Huang Shao-Ling. Delivery of xenon-containing echogenic liposomes inhibits early brain injury following subarachnoid hemorrhage. Sci Rep. 2018 Jan 11;8(1):450. doi: 10.1038/s41598-017-18914-6 29323183

11. Campos-Pires R, Hirnet T, Valeo F, Ong BE, Radyushkin K, Aldhoun J, Saville J, Edge CJ, Franks NP, Thal SC, Dickinson R. Xenon improves long-term cognitive function, reduces neuronal loss and chronic neuroinflammation, and improves survival after traumatic brain injury in mice. Br J Anaesth. 2019 Jul;123(1):60–73. doi: 10.1016/j.bja.2019.02.032 Epub 2019 May 21. 31122738

12. Campos-Pires R, Koziakova M, Yonis A, Pau A, Macdonald W, Harris K, Edge CJ5, Franks NP, Mahoney PF, Dickinson R. J Neurotrauma. Xenon Protects against Blast-Induced Traumatic Brain Injury in an In Vitro Model. 2018 Apr 15;35(8):1037–1044. doi: 10.1089/neu.2017.5360 Epub 2018 Feb 8. 29285980

13. Baumert JH, Hein M, Gerets C, Baltus T, Hecker KE, Rossaint R. The effect of xenon anesthesia on the size of experimental myocardial infarction. Anesthesia and analgesia 2007;105:1200–6. doi: 10.1213/01.ane.0000284697.73471.9c 17959941

14. Arola O, Saraste A, Laitio R, Airaksinen J, Hynninen M, Bäcklund M, Ylikoski E, Wennervirta J, Pietilä M, Roine RO, Harjola VP, Niiranen J, Korpi K, Varpula M, Scheinin H, Maze M, Vahlberg T, Laitio T; Xe-HYPOTHECA Study Group. Inhaled Xenon Attenuates Myocardial Damage in Comatose Survivors of Out-of-Hospital Cardiac Arrest: The Xe-Hypotheca Trial. J Am Coll Cardiol. 2017 Nov 28;70(21):2652–2660. doi: 10.1016/j.jacc.2017.09.1088 29169472

15. Li Q, Lian C, Zhou R, Li T, Xiang X, Liu B. Pretreatment with xenon protected immature rabbit heart from ischaemia/reperfusion injury by opening of the mitoKATP channel. Heart Lung Circ 2013;22:276–83. doi: 10.1016/j.hlc.2012.10.016 23261327

16. Jia P, Teng J, Zou J, Fang Y, Wu X, Liang M, Ding X. Xenon Protects Against Septic Acute Kidney Injury via miR-21 Target Signaling Pathway. Critical care medicine 2015;43:e250–9. doi: 10.1097/CCM.0000000000001001 25844699

17. Zhao H, Luo X, Zhou Z, Liu J, Tralau-Stewart C, George AJ, Ma D. Early treatment with xenon protects against the cold ischemia associated with chronic allograft nephropathy in rats. Kidney Int 2014;85:112–23. doi: 10.1038/ki.2013.334 24025645

18. Jia P, Teng J, Zou J, Fang Y, Jiang S, Yu X, Kriegel AJ, Liang M, Ding X. Intermittent exposure to xenon protects against gentamicin-induced nephrotoxicity. PloS one 2013;8:e64329. doi: 10.1371/journal.pone.0064329 23737979

19. NICE. Therapeutic hypothermia with intracorporeal temperature monitoring for hypoxic perinatal brain injury: NICEIPG347, May 2010.

20. Liu X, Jary S, Cowan F, Thoresen M. Reduced infancy and childhood epilepsy following hypothermia-treated neonatal encephalopathy. Epilepsia 2017;58:1902–11. doi: 10.1111/epi.13914 28961316

21. Thoresen M, Chakkarapani E, Dingley J. The cool xenon study, 2015.

22. Hobbs C, Thoresen M, Tucker A, Aquilina K, Chakkarapani E, Dingley J. Xenon and hypothermia combine additively, offering long-term functional and histopathologic neuroprotection after neonatal hypoxia/ischemia. Stroke; a journal of cerebral circulation 2008;39:1307–13.

23. Azzopardi D, Robertson NJ, Bainbridge A, Cady E, Charles-Edwards G, Deierl A, Fagiolo G, Franks NP, Griffiths J, Hajnal J, Juszczak E, Kapetanakis B, Linsell L, Maze M, Omar O, Strohm B, Tusor N, Edwards AD. Moderate hypothermia within 6 h of birth plus inhaled xenon versus moderate hypothermia alone after birth asphyxia (TOBY-Xe): a proof-of-concept, open-label, randomised controlled trial. Lancet neurology 2015;15:145–53. doi: 10.1016/S1474-4422(15)00347-6 26708675

24. Hagberg H, David Edwards A, Groenendaal F. Perinatal brain damage: The term infant. Neurobiology of disease 2016;92:102–12. doi: 10.1016/j.nbd.2015.09.011 26409031

25. Franks NP, Dickinson R, de Sousa SL, Hall AC, Lieb WR. How does xenon produce anaesthesia? Nature 1998;396:324. doi: 10.1038/24525 9845069

26. Dickinson R1, Peterson BK, Banks P, Simillis C, Martin JC, Valenzuela CA, Maze M, Franks NP. Competitive inhibition at the glycine site of the N-methyl-D-aspartate receptor by the anesthetics xenon and isoflurane: evidence from molecular modeling and electrophysiology. Anesthesiology. 2007 Nov;107(5):756–67. (goes with ref 19) doi: 10.1097/01.anes.0000287061.77674.71 18073551

27. Preckel B, Weber N, Molecular mechanisms transducing the anesthetic, analgesic and organ protective actions of Xenon. Anesthesiology 2006, 105:187–97. doi: 10.1097/00000542-200607000-00029 16810011

28. Gruss M, Bushell TJ, Bright DP, Lieb WR, Mathie A, Franks NP. Two-pore-domain K+ channels are a novel target for the anesthetic gases xenon, nitrous oxide, and cyclopropane. Mol Pharmacol 2004; 65: 443–452. doi: 10.1124/mol.65.2.443 14742687

29. Bantel C, Maze M, Trapp S. Neuronal preconditioning by inhalational anesthetics: evidence for the role of plasmalemmal adenosine triphosphate-sensitive potassium channels. Anesthesiology 2009; 110: 986–995. doi: 10.1097/ALN.0b013e31819dadc7 19352153

30. Thoresen M, Haaland K, Loberg E.M, Whitelaw A, Apricena F, Hanko E, Steen PA. A piglet survival model of posthypoxic encephalopathy. Pediatr Res 1996;40:738–748. (ref that defines the global HI model) doi: 10.1203/00006450-199611000-00014 8910940

31. Goto T, Suwa K, Uezono S, Ichinose F, Uchiyama M, Morita S. The blood-gas partition coefficient of xenon may be lower than generally accepted. British journal of anaesthesia 1998;80:255–6. doi: 10.1093/bja/80.2.255 9602599

32. Rawat S, Dingley J. Closed-circuit xenon delivery using a standard anesthesia workstation. Anesthesia and analgesia 2010;110:101–9. doi: 10.1213/ANE.0b013e3181be0e17 19861365

33. Chakkarapani E, Thoresen M, Hobbs CE, Aquilina K, Liu X, Dingley J. A closed-circuit neonatal xenon delivery system: a technical and practical neuroprotection feasibility study in newborn pigs. Anesthesia and analgesia 2009;109:451–60. doi: 10.1213/ane.0b013e3181aa9550 19608817

34. Dingley J, Tooley J, Liu X, Scull-Brown E, Elstad M, Chakkarapani E, Sabir H, Thoresen M. Xenon Ventilation During Therapeutic Hypothermia in Neonatal Encephalopathy: A Feasibility Study. Pediatrics 2014;133:809–18. doi: 10.1542/peds.2013-0787 24777219

35. Thoresen M, Haaland K, Loberg EM, Whitelaw A, Apricena F, Hanko E, Steen PA. A piglet survival model of posthypoxic encephalopathy. Pediatric research 1996;40:738–48. doi: 10.1203/00006450-199611000-00014 8910940

36. Chakkarapani E, Thoresen M. The newborn pig Global Hypoxic-ischemic Model of Perinatal Brain and organ Injury. In: Yager JY, ed. Animal Models of the Developmental Disabilities. 1 ed.: HUMANA PRESS/SPRINGER, 2015.

37. Dingley J, Liu X, Gill H, Smit E, Sabir H, Tooley J, Chakkarapani E, Windsor D, Thoresen M. The feasibility of using a portable xenon delivery device to permit earlier xenon ventilation with therapeutic cooling of neonates during ambulance retrieval. Anesthesia and analgesia 2015;120:1331–6. doi: 10.1213/ANE.0000000000000693 25794112

38. Pietra GG, Edwards WD, Kay JM, Rich S, Kernis J, Schloo B, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, et al. Histopathology of primary pulmonary hypertension. A qualitative and quantitative study of pulmonary blood vessels from 58 patients in the National Heart, Lung, and Blood Institute, Primary Pulmonary Hypertension Registry. Circulation 1989;80:1198–206. doi: 10.1161/01.cir.80.5.1198 2805258

39. Ngan Kee WD, Tam YH, Khaw KS, Ng FF, Critchley LA, Karmakar MK. Closed-loop feedback computer-controlled infusion of phenylephrine for maintaining blood pressure during spinal anaesthesia for caesarean section: a preliminary descriptive study. Anaesthesia 2007;62:1251–6. doi: 10.1111/j.1365-2044.2007.05257.x 17991262

40. Varvel JR, Donoho DL, Shafer SL. Measuring the predictive performance of computer-controlled infusion pumps. J Pharmacokinet Biopharm 1992;20:63–94. doi: 10.1007/bf01143186 1588504

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