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Randomized Controlled Trial
. 2024 Oct 1;52(10):1567-1576.
doi: 10.1097/CCM.0000000000006395. Epub 2024 Aug 12.

Combination of Hydrogen Inhalation and Hypothermic Temperature Control After Out-of-Hospital Cardiac Arrest: A Post hoc Analysis of the Efficacy of Inhaled Hydrogen on Neurologic Outcome Following Brain Ischemia During PostCardiac Arrest Care II Trial

Tomoyoshi Tamura  1   2 , Hiromichi Narumiya  3 , Koichiro Homma  1   2 , Masaru Suzuki  4 ; Efficacy of Inhaled Hydrogen on Neurologic Outcome Following Brain Ischemia During PostCardiac Arrest Care (HYBRID II) Study Group
Collaborators, Affiliations
Randomized Controlled Trial

Combination of Hydrogen Inhalation and Hypothermic Temperature Control After Out-of-Hospital Cardiac Arrest: A Post hoc Analysis of the Efficacy of Inhaled Hydrogen on Neurologic Outcome Following Brain Ischemia During PostCardiac Arrest Care II Trial

Tomoyoshi Tamura et al. Crit Care Med. .

Abstract

Objective: The Efficacy of Inhaled Hydrogen on Neurologic Outcome Following Brain Ischemia During Post-Cardiac Arrest Care (HYBRID) II trial (jRCTs031180352) suggested that hydrogen inhalation may reduce post-cardiac arrest brain injury (PCABI). However, the combination of hypothermic target temperature management (TTM) and hydrogen inhalation on outcomes is unclear. The aim of this study was to investigate the combined effect of hydrogen inhalation and hypothermic TTM on outcomes after out-of-hospital cardiac arrest (OHCA).

Design: Post hoc analysis of a multicenter, randomized, controlled trial.

Setting: Fifteen Japanese ICUs.

Patients: Cardiogenic OHCA enrolled in the HYBRID II trial.

Interventions: Hydrogen mixed oxygen (hydrogen group) versus oxygen alone (control group).

Measurements and main results: TTM was performed at a target temperature of 32-34°C (TTM32-TTM34) or 35-36°C (TTM35-TTM36) per the institutional protocol. The association between hydrogen + TTM32-TTM34 and 90-day good neurologic outcomes was analyzed using generalized estimating equations. The 90-day survival was compared between the hydrogen and control groups under TTM32-TTM34 and TTM35-TTM36, respectively. The analysis included 72 patients (hydrogen [ n = 39] and control [ n = 33] groups) with outcome data. TTM32-TTM34 was implemented in 25 (64%) and 24 (73%) patients in the hydrogen and control groups, respectively ( p = 0.46). Under TTM32-TTM34, 17 (68%) and 9 (38%) patients achieved good neurologic outcomes in the hydrogen and control groups, respectively (relative risk: 1.81 [95% CI, 1.05-3.66], p < 0.05). Hydrogen + TTM32-TTM34 was independently associated with good neurologic outcomes (adjusted odds ratio 16.10 [95% CI, 1.88-138.17], p = 0.01). However, hydrogen + TTM32-TTM34 did not improve survival compared with TTM32-TTM34 alone (adjusted hazard ratio: 0.22 [95% CI, 0.05-1.06], p = 0.06).

Conclusions: Hydrogen + TTM32-TTM34 was associated with improved neurologic outcomes after cardiogenic OHCA compared with TTM32-TTM34 monotherapy. Hydrogen inhalation is a promising treatment option for reducing PCABI when combined with TTM32-TTM34.

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Conflict of interest statement

Dr. Tamura’s institution received funding from the Taiyo Nippon Sanso Corporation, the Japanese Society for Promotion of Science, and the Marumo Memorial Foundation Grant for Emergency Medicine Research. Drs. Tamura and Suzuki disclosed off-label use of hydrogen gas. Dr. Narumiya disclosed work for hire. Dr. Homma has disclosed that he does not have any potential conflicts of interest.

Figures

Figure 1.
Figure 1.
Selection of a target temperature. A, Target temperature management (TTM) at 32 and 34°C (TTM32–TTM34) was predominantly selected in the hydrogen (H2) and control gas (CTL) groups, respectively. TTM32–TTM34 and TTM at a target temperature between 35 and 36°C (TTM35–36) were similarly selected in the H2 group and the CTL group (p = 0.46). B, Respective number of patients in the H2 and CTL group who were treated under TTM32–TTM34 or TTM35–TTM36 are shown in each institution. The majority of institutions selected TTM32–TTM34 as default in the institutional protocol.
Figure 2.
Figure 2.
Combination therapy of hydrogen gas (H2) inhalation and target temperature management (TTM)32–TTM34 was associated with improved 90-day neurologic outcomes (neuro). Good and poor neurologic outcomes were defined as a Cerebral Performance Category (CPC) of 1 or 2 and 3–5 at 90 d after randomization, respectively. A, The number of patients achieving good or poor neurologic outcomes with each gas under TTM32–TTM34 is shown. Under TTM32–TTM34, H2 inhalation significantly increased the proportion of patients achieving good neurologic outcomes compared with that with the control gas inhalation (p < 0.05). B, The number of patients achieving good or poor neurologic outcomes with each gas under TTM35–TTM36 is shown. Under TTM35–TTM36, H2 inhalation did not improve neurologic outcomes (p = 0.99). Good and poor denote good and poor neurologic outcomes, respectively. CTL = control gas, neuro = neurologic outcomes.
Figure 3.
Figure 3.
Combination therapy of H2 inhalation and target temperature management (TTM)32–TTM34 was associated with improved 90-d survival. Kaplan-Meier estimates of the probability of survival are depicted for the hydrogen (H2) and control gas (CTL) under TTM32–TTM34 (A) and TTM35–TTM36 (B). The event was defined as death, and data were censored at the end of each patient’s study period, that is, at 90 days.
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