Efficacy of inhaled hydrogen on neurologic outcomes after cerebral ischemia during cardiac arrestScientific Research
Efficacy of inhaled HYdrogen on neurological outcome following BRain Ischemia During post-cardiac arrest care (HYBRID II trial): study protocol for a randomized controlled trial
doi: 10.1186/s13063-017-2246-3.
Abstract
Background
Hydrogen (HI) inhalation improves survival and neurological outcomes in an animal model of post-cardiac arrest syndrome (PCAS). A pilot study confirmed the feasibility and safety of HI in PCAS patients. The purpose of this study was to evaluate the efficacy of HI in patients with PCAS.
Methods/Design
The Efficacy of Hydrogen Inhalation on Neurological Outcomes After Cerebral Ischemia Without Cardiac Care (HYBRID II) study was an investigator-initiated, randomized, double-blind, placebo-controlled study recruiting 360 comatose adults (Glasgow, IL). Coma score < 8) in patients resuscitated after out-of-hospital cardiac arrest of suspected cardiac cause. Patients will be randomly assigned (1:1) to the HI group or the control group. The patients in the HI group inhaled 2% hydrogen and 24%-50% oxygen, and the patients in the control group inhaled 24%-50% oxygen 18 hours after admission to mechanical ventilation. .Provides multidisciplinary follow-up according to the latest guidelines, including target temperature management (TTM) between 33°C and 36°C. The primary outcome of interest was the 90-day neurological outcome assessed using the Brain Performance Category (CPC) scale. Secondary outcomes of interest were 90-day survival and other neurological outcomes. This study will provide 80% power to detect a 15% change from 50% to 65% in the proportion of patients with favorable neurological outcome (CPC of 1 and 2), with an overall significance level of 0.05.
References
Moulaert VR, Verbunt JA, van Heugten CM, Wade DT. Cognitive impairments in survivors of out-of-hospital cardiac arrest: a systematic review. Resuscitation. 2009;80:297–305. doi:10.1016/j.resuscitation.2008.10.034.
Arrich J, Holzer M, Havel C, Mullner M, Herkner H. Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation. Cochrane Database Syst Rev. 2016;2:CD004128. doi:10.1002/14651858.CD004128.pub4.
Peberdy MA, Callaway CW, Neumar RW, Geocadin RG, Zimmerman JL, Donnino M, et al. Part 9: post-cardiac arrest care: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2010;122(18 Suppl 3):S768–86. doi:10.1161/CIRCULATIONAHA.110.971002. Published errata appear in Circulation. 2011;123:e237 and Circulation. 2011;124:e403.
Callaway CW, Donnino MW, Fink EL, Geocadin RG, Golan E, Kern KB, et al. Part 8: post-cardiac arrest care: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2015;132(18 Suppl 2):S465–82. doi:10.1161/CIR.0000000000000262.
Cariou A, Payen JF, Asehnoune K, Audibert G, Botte A, Brissaud O, et al. Targeted temperature management in the ICU: guidelines from a French expert panel. Ann Intensive Care. 2017;7:70. doi:10.1186/s13613-017-0294-1.
De Keyser J, Sulter G, Luiten PG. Clinical trials with neuroprotective drugs in acute ischaemic stroke: are we doing the right thing? Trends Neurosci. 1999;22:535–40.
Huang L, Applegate PM, Gatling JW, Mangus DB, Zhang J, Applegate 2nd RL. A systematic review of neuroprotective strategies after cardiac arrest: from bench to bedside (part II-comprehensive protection). Med Gas Res. 2014;4:10. doi:10.1186/2045-9912-4-10.
Ohsawa I, Ishikawa M, Takahashi K, Watanabe M, Nishimaki K, Yamagata K, et al. Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med. 2007;13:688–94. doi:10.1038/nm1577.
Iuchi K, Imoto A, Kamimura N, Nishimaki K, Ichimiya H, Yokota T, et al. Molecular hydrogen regulates gene expression by modifying the free radical chain reaction-dependent generation of oxidized phospholipid mediators. Sci Rep. 2016;6:18971. doi:10.1038/srep18971.
Ichihara M, Sobue S, Ito M, Ito M, Hirayama M, Ohno K. Beneficial biological effects and the underlying mechanisms of molecular hydrogen – comprehensive review of 321 original articles. Med Gas Res. 2015;5:12. doi:10.1186/s13618-015-0035-1.
Hayashida K, Sano M, Kamimura N, Yokota T, Suzuki M, Maekawa Y, et al. H2 gas improves functional outcome after cardiac arrest to an extent comparable to therapeutic hypothermia in a rat model. J Am Heart Assoc. 2012;1:e003459. doi:10.1161/JAHA.112.003459.
Hayashida K, Sano M, Kamimura N, Yokota T, Suzuki M, Ohta S, et al. Hydrogen inhalation during normoxic resuscitation improves neurological outcome in a rat model of cardiac arrest independently of targeted temperature management. Circulation. 2014;130:2173–80. doi:10.1161/CIRCULATIONAHA.114.011848.
Tamura T, Hayashida K, Sano M, Suzuki M, Shibusawa T, Yoshizawa J, et al. Feasibility and safety of hydrogen gas inhalation for post-cardiac arrest syndrome – first-in-human pilot study. Circ J. 2016;80:1870–3. doi:10.1253/circj.CJ-16-0127.
Becker LB, Aufderheide TP, Geocadin RG, Callaway CW, Lazar RM, Donnino MW, et al. Primary outcomes for resuscitation science studies: a consensus statement from the American Heart Association. Circulation. 2011;124:2158–77. doi:10.1161/CIR.0b013e3182340239.
Green CR, Botha JA, Tiruvoipati R. Cognitive function, quality of life and mental health in survivors of our-of-hospital cardiac arrest: a review. Anaesth Intensive Care. 2015;43:568–76.
Nichol G, Guffey D, Stiell IG, Leroux B, Cheskes S, Idris A, et al. Post-discharge outcomes after resuscitation from out-of-hospital cardiac arrest: a ROC PRIMED substudy. Resuscitation. 2015;93:74–81. doi:10.1016/j.resuscitation.2015.05.011.
Nielsen N, Wetterslev J, Cronberg T, Erlinge D, Gasche Y, Hassager C, et al. Targeted temperature management at 33 °C versus 36 °C after cardiac arrest. N Engl J Med. 2013;369:2197–206. doi:10.1056/NEJMoa1310519.
Hayashida K, Sano M, Ohsawa I, Shinmura K, Tamaki K, Kimura K, et al. Inhalation of hydrogen gas reduces infarct size in the rat model of myocardial ischemia-reperfusion injury. Biochem Biophys Res Commun. 2008;373:30–5. doi:10.1016/j.bbrc.2008.05.165.
Lafay V, Barthelemy P, Comet B, Frances Y, Jammes Y. ECG changes during the experimental human dive HYDRA 10 (71 atm/7,200 kPa). Undersea Hyperb Med. 1995;22:51–60.
Fontanari P, Badier M, Guillot C, Tomei C, Burnet H, Gardette B, et al. Changes in maximal performance of inspiratory and skeletal muscles during and after the 7.1-MPa Hydra 10 record human dive. Eur J Appl Physiol. 2000;81:325–8.
Drabek T, Kochanek PM. Improving outcomes from resuscitation: from hypertension and hemodilution to therapeutic hypothermia to H2. Circulation. 2014;130:2133–5. doi:10.1161/CIRCULATIONAHA.114.013566.
Laitio R, Hynninen M, Arola O, Virtanen S, Parkkola R, Saunavaara J, et al. 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.
Acknowledgements
The authors thank Dr. N. Kamatani for providing the statistical analysis design and assisting with preparation of the manuscript.
Funding
This trial will be funded by the Taiyo Nippon Sanso Corporation, including the provision of the gas (hydrogen or nitrogen) and the cost for cylinder delivery. Ordinary post-CA care, including TTM, will be insured by the Japanese health system. The funder of this study will not be involved in study design; data collection, management, analysis, or interpretation; the writing of the report; or the decision to submit the manuscript for publication.
Availability of data and materials
All de-identified individual participant data, study protocols, statistical analysis plans, and analytic codes will be shared with investigating members of the HYBRID Study Group. Shared data may be used for any type of analysis. Data will be available from the HYBRID Study Office at Keio University for 5 years immediately following publication
DOI: 10.1186
Published on: 23/10/2017
Efficacy of inhaled HYdrogen on neurological outcome following BRain Ischemia During post-cardiac arrest care (HYBRID II trial): study protocol for a randomized controlled trial
doi: 10.1186/s13063-017-2246-3.
Abstract
Background
Hydrogen (HI) inhalation improves survival and neurological outcomes in an animal model of post-cardiac arrest syndrome (PCAS). A pilot study confirmed the feasibility and safety of HI in PCAS patients. The purpose of this study was to evaluate the efficacy of HI in patients with PCAS.
Methods/Design
The Efficacy of Hydrogen Inhalation on Neurological Outcomes After Cerebral Ischemia Without Cardiac Care (HYBRID II) study was an investigator-initiated, randomized, double-blind, placebo-controlled study recruiting 360 comatose adults (Glasgow, IL). Coma score < 8) in patients resuscitated after out-of-hospital cardiac arrest of suspected cardiac cause. Patients will be randomly assigned (1:1) to the HI group or the control group. The patients in the HI group inhaled 2% hydrogen and 24%-50% oxygen, and the patients in the control group inhaled 24%-50% oxygen 18 hours after admission to mechanical ventilation. .Provides multidisciplinary follow-up according to the latest guidelines, including target temperature management (TTM) between 33°C and 36°C. The primary outcome of interest was the 90-day neurological outcome assessed using the Brain Performance Category (CPC) scale. Secondary outcomes of interest were 90-day survival and other neurological outcomes. This study will provide 80% power to detect a 15% change from 50% to 65% in the proportion of patients with favorable neurological outcome (CPC of 1 and 2), with an overall significance level of 0.05.
References
Moulaert VR, Verbunt JA, van Heugten CM, Wade DT. Cognitive impairments in survivors of out-of-hospital cardiac arrest: a systematic review. Resuscitation. 2009;80:297–305. doi:10.1016/j.resuscitation.2008.10.034.
Arrich J, Holzer M, Havel C, Mullner M, Herkner H. Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation. Cochrane Database Syst Rev. 2016;2:CD004128. doi:10.1002/14651858.CD004128.pub4.
Peberdy MA, Callaway CW, Neumar RW, Geocadin RG, Zimmerman JL, Donnino M, et al. Part 9: post-cardiac arrest care: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2010;122(18 Suppl 3):S768–86. doi:10.1161/CIRCULATIONAHA.110.971002. Published errata appear in Circulation. 2011;123:e237 and Circulation. 2011;124:e403.
Callaway CW, Donnino MW, Fink EL, Geocadin RG, Golan E, Kern KB, et al. Part 8: post-cardiac arrest care: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2015;132(18 Suppl 2):S465–82. doi:10.1161/CIR.0000000000000262.
Cariou A, Payen JF, Asehnoune K, Audibert G, Botte A, Brissaud O, et al. Targeted temperature management in the ICU: guidelines from a French expert panel. Ann Intensive Care. 2017;7:70. doi:10.1186/s13613-017-0294-1.
De Keyser J, Sulter G, Luiten PG. Clinical trials with neuroprotective drugs in acute ischaemic stroke: are we doing the right thing? Trends Neurosci. 1999;22:535–40.
Huang L, Applegate PM, Gatling JW, Mangus DB, Zhang J, Applegate 2nd RL. A systematic review of neuroprotective strategies after cardiac arrest: from bench to bedside (part II-comprehensive protection). Med Gas Res. 2014;4:10. doi:10.1186/2045-9912-4-10.
Ohsawa I, Ishikawa M, Takahashi K, Watanabe M, Nishimaki K, Yamagata K, et al. Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med. 2007;13:688–94. doi:10.1038/nm1577.
Iuchi K, Imoto A, Kamimura N, Nishimaki K, Ichimiya H, Yokota T, et al. Molecular hydrogen regulates gene expression by modifying the free radical chain reaction-dependent generation of oxidized phospholipid mediators. Sci Rep. 2016;6:18971. doi:10.1038/srep18971.
Ichihara M, Sobue S, Ito M, Ito M, Hirayama M, Ohno K. Beneficial biological effects and the underlying mechanisms of molecular hydrogen – comprehensive review of 321 original articles. Med Gas Res. 2015;5:12. doi:10.1186/s13618-015-0035-1.
Hayashida K, Sano M, Kamimura N, Yokota T, Suzuki M, Maekawa Y, et al. H2 gas improves functional outcome after cardiac arrest to an extent comparable to therapeutic hypothermia in a rat model. J Am Heart Assoc. 2012;1:e003459. doi:10.1161/JAHA.112.003459.
Hayashida K, Sano M, Kamimura N, Yokota T, Suzuki M, Ohta S, et al. Hydrogen inhalation during normoxic resuscitation improves neurological outcome in a rat model of cardiac arrest independently of targeted temperature management. Circulation. 2014;130:2173–80. doi:10.1161/CIRCULATIONAHA.114.011848.
Tamura T, Hayashida K, Sano M, Suzuki M, Shibusawa T, Yoshizawa J, et al. Feasibility and safety of hydrogen gas inhalation for post-cardiac arrest syndrome – first-in-human pilot study. Circ J. 2016;80:1870–3. doi:10.1253/circj.CJ-16-0127.
Becker LB, Aufderheide TP, Geocadin RG, Callaway CW, Lazar RM, Donnino MW, et al. Primary outcomes for resuscitation science studies: a consensus statement from the American Heart Association. Circulation. 2011;124:2158–77. doi:10.1161/CIR.0b013e3182340239.
Green CR, Botha JA, Tiruvoipati R. Cognitive function, quality of life and mental health in survivors of our-of-hospital cardiac arrest: a review. Anaesth Intensive Care. 2015;43:568–76.
Nichol G, Guffey D, Stiell IG, Leroux B, Cheskes S, Idris A, et al. Post-discharge outcomes after resuscitation from out-of-hospital cardiac arrest: a ROC PRIMED substudy. Resuscitation. 2015;93:74–81. doi:10.1016/j.resuscitation.2015.05.011.
Nielsen N, Wetterslev J, Cronberg T, Erlinge D, Gasche Y, Hassager C, et al. Targeted temperature management at 33 °C versus 36 °C after cardiac arrest. N Engl J Med. 2013;369:2197–206. doi:10.1056/NEJMoa1310519.
Hayashida K, Sano M, Ohsawa I, Shinmura K, Tamaki K, Kimura K, et al. Inhalation of hydrogen gas reduces infarct size in the rat model of myocardial ischemia-reperfusion injury. Biochem Biophys Res Commun. 2008;373:30–5. doi:10.1016/j.bbrc.2008.05.165.
Lafay V, Barthelemy P, Comet B, Frances Y, Jammes Y. ECG changes during the experimental human dive HYDRA 10 (71 atm/7,200 kPa). Undersea Hyperb Med. 1995;22:51–60.
Fontanari P, Badier M, Guillot C, Tomei C, Burnet H, Gardette B, et al. Changes in maximal performance of inspiratory and skeletal muscles during and after the 7.1-MPa Hydra 10 record human dive. Eur J Appl Physiol. 2000;81:325–8.
Drabek T, Kochanek PM. Improving outcomes from resuscitation: from hypertension and hemodilution to therapeutic hypothermia to H2. Circulation. 2014;130:2133–5. doi:10.1161/CIRCULATIONAHA.114.013566.
Laitio R, Hynninen M, Arola O, Virtanen S, Parkkola R, Saunavaara J, et al. 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.
Acknowledgements
The authors thank Dr. N. Kamatani for providing the statistical analysis design and assisting with preparation of the manuscript.
Funding
This trial will be funded by the Taiyo Nippon Sanso Corporation, including the provision of the gas (hydrogen or nitrogen) and the cost for cylinder delivery. Ordinary post-CA care, including TTM, will be insured by the Japanese health system. The funder of this study will not be involved in study design; data collection, management, analysis, or interpretation; the writing of the report; or the decision to submit the manuscript for publication.
Availability of data and materials
All de-identified individual participant data, study protocols, statistical analysis plans, and analytic codes will be shared with investigating members of the HYBRID Study Group. Shared data may be used for any type of analysis. Data will be available from the HYBRID Study Office at Keio University for 5 years immediately following publication
