Top

Trials

Published in:

Open Access 01-12-2017 | Study protocol

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

Authors: Tomoyoshi Tamura, Kei Hayashida, Motoaki Sano, Shuko Onuki, Masaru Suzuki

Published in: Trials | Issue 1/2017

Abstract

Background

Hydrogen gas inhalation (HI) improved survival and neurological outcomes in an animal model of post-cardiac arrest syndrome (PCAS). The feasibility and safety of HI for patients with PCAS was confirmed in a pilot study. The objective of this study is to evaluate the efficacy of HI for patients with PCAS.

Methods/design

The efficacy of inhaled HYdrogen on neurological outcome following BRain Ischemia During post-cardiac arrest care (HYBRID II) trial is an investigator-initiated, randomized, double-blind, placebo-controlled trial designed to enroll 360 adult comatose (Glasgow Coma Scale score < 8) patients who will be resuscitated following an out-of-hospital cardiac arrest of a presumed cardiac cause. The patients will be randomized (1:1) to either the HI or control group. Patients in the HI group will inhale 2% hydrogen with 24% to 50% oxygen, and those in the control group will inhale 24% to 50% oxygen for 18 h after admission via mechanical ventilation. Multidisciplinary post-arrest care, including targeted temperature management (TTM) between 33 °C and 36 °C, will be provided in accordance with the latest guidelines. The primary outcome of interest is the 90-day neurological outcome, as evaluated using the Cerebral Performance Categories scale (CPC). The secondary outcomes of interest are the 90-day survival rate and other neurological outcomes. This study will provide 80% power to detect a 15% change in the proportion of patients with good neurological outcomes (CPCs of 1 and 2), from 50% to 65%, with an overall significance level of 0.05.

Discussion

The first multicenter randomized trial is underway to confirm the efficacy of HI on neurological outcomes in comatose out-of-hospital cardiac arrest survivors. Our study has the potential to address HI as an appealing and innovative therapeutic strategy for PCAS in combination with TTM.

Trials registration

University Hospital Medical Information Network (UMIN), 000019820. Registered on 17 November 2015.

Available only for authorised users

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.CrossRefPubMed

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.PubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

10.

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.CrossRefPubMedPubMedCentral

11.

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.CrossRefPubMedPubMedCentral

12.

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.CrossRefPubMed

13.

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.CrossRefPubMed

14.

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.CrossRefPubMedPubMedCentral

15.

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.PubMed

16.

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.CrossRefPubMed

17.

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.CrossRefPubMed

18.

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.CrossRefPubMed

19.

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.PubMed

20.

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.CrossRefPubMed

21.

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.CrossRefPubMedPubMedCentral

22.

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.CrossRefPubMed

Title: 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
Authors: Tomoyoshi Tamura
Kei Hayashida
Motoaki Sano
Shuko Onuki
Masaru Suzuki
Publication date: 01-12-2017
Publisher: BioMed Central
Published in: Trials / Issue 1/2017
Electronic ISSN: 1745-6215
DOI: https://doi.org/10.1186/s13063-017-2246-3

At a glance: The STEP trials

Springer Medicine

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

Abstract

Background

Methods/design

Discussion

Trials registration

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods/design

Discussion

Trials registration

Please log in to get access to this content

Other articles of this Issue 1/2017

Effectiveness of topical silicone gel and pressure garment therapy for burn scar prevention and management in children: study protocol for a randomised controlled trial

A core outcomes set for clinical trials of interventions for young adults with type 1 diabetes: an international, multi-perspective Delphi consensus study

Standardising the reporting of outcomes in gastric cancer surgery trials: protocol for the development of a core outcome set and accompanying outcome measurement instrument set (the GASTROS study)

Quality of transurethral resection of bladder tumor procedure influenced a phase III trial comparing the effect of KLH and mitomycin C

Telemedical support for prehospital Emergency Medical Service (TEMS trial): study protocol for a randomized controlled trial

Effectiveness of an implementation optimisation intervention aimed at increasing parent engagement in HENRY, a childhood obesity prevention programme - the Optimising Family Engagement in HENRY (OFTEN) trial: study protocol for a randomised controlled trial