Summary
Background
Inhaled molecular hydrogen gas (H2) has been shown to improve outcomes in animal models of cardiac arrest (CA). H2 inhalation is safe and feasible in patients after CA. We investigated whether inhaled H2 would improve outcomes after out-of-hospital CA (OHCA).
Methods
HYBRID II is a prospective, multicentre, randomised, double-blind, placebo-controlled trial performed at 15 hospitals in Japan, between February 1, 2017, and September 30, 2021. Patients aged 20–80 years with coma following cardiogenic OHCA were randomly assigned (1:1) using blinded gas cylinders to receive supplementary oxygen with 2% H2 or oxygen (control) for 18 h. The primary outcome was the proportion of patients with a 90-day Cerebral Performance Category (CPC) of 1 or 2 assessed in a full-analysis set. Secondary outcomes included the 90-day score on a modified Rankin scale (mRS) and survival. HYBRID II was registered with the University Hospital Medical Information Network (registration number: UMIN000019820) and re-registered with the Japan Registry for Clinical Trials (registration number: jRCTs031180352).
Findings
The trial was terminated prematurely because of the restrictions imposed on enrolment during the COVID-19 pandemic. Between February 1, 2017, and September 30, 2021, 429 patients were screened for eligibility, of whom 73 were randomly assigned to H2 (n = 39) or control (n = 34) groups. The primary outcome, i.e., a CPC of 1 or 2 at 90 days, was achieved in 22 (56%) and 13 (39%) patients in the H2 and control groups (relative risk compared with the control group, 0.72; 95% CI, 0.46–1.13; P = 0.15), respectively. Regarding the secondary outcomes, median mRS was 1 (IQR: 0–5) and 5 (1–6) in the H2 and control groups, respectively (P = 0.01). An mRS score of 0 was achieved in 18 (46%) and 7 (21%) patients in the H2 and control groups, respectively (P = 0.03). The 90-day survival rate was 85% (33/39) and 61% (20/33) in the H2 and control groups, respectively (P = 0.02).
Interpretation
The increase in participants with good neurological outcomes following post-OHCA H2 inhalation in a selected population of patients was not statistically significant. However, the secondary outcomes suggest that H2 inhalation may increase 90-day survival without neurological deficits.
Funding
Taiyo Nippon Sanso Corporation.
Translation
For the Japanese translation of the abstract see Supplementary Materials section.
Keywords: Out-of-hospital cardiac arrest, Hydrogen inhalation, Coma, Reperfusion injury
Research in context.
Evidence before this study
Prior to starting the study, we searched MEDLINE, PubMed, the Cochrane Database of Systematic Reviews, the Database of Abstracts, and Review of Effects, with no language or date restrictions, using the terms “cardiac arrest”, “hydrogen gas”, and “inhalation”. We repeated the search on November 1, 2022. Neurological injury is the main cause of death for hospitalized patients with cardiac arrest, a devastating outcome for which there are no clinical treatments or medications besides cooling the patient's body temperature. The inhalation of hydrogen in low-concentrations showed promise in improving neurological functions and survival outcomes in experimental rodent models after cardiac arrest. Moreover, hydrogen inhalation was a safe and feasible treatment among selected patients with coma after out-of-hospital cardiac arrest. However, the efficacy of hydrogen inhalation has not been evaluated in any human disease or condition in a double-blinded randomised control trial.
Added value of this study
To our knowledge, HYBRID II is the first randomised, double-blinded clinical trial to investigate the efficacy and safety of hydrogen inhalation on outcomes after cardiac arrest. This trial showed that hydrogen inhalation can be safely implemented in comatose patients after out-of-hospital cardiac arrest of cardiac cause in addition to post-arrest critical care. Hydrogen inhalation was associated with improved neurological outcomes and a survival rate 90 days after the randomisation. Most importantly, hydrogen inhalation significantly aided a true functional recovery, namely, a survival without neurological sequelae.
Implications of all the available evidence
Due to enrolment restrictions during the COVID-19 pandemic, the study was terminated before the planned number of cases was reached. Thus, hydrogen inhalation in post-arrest patients warrants a larger study. Nevertheless, hydrogen inhalation confers additional therapeutic effects in post-arrest patients treated with targeted temperature management. Moreover, hydrogen inhalation did not have any adverse effects on post-arrest patients who were in a critically ill condition. Therefore, as an adjunct to targeted temperature management, hydrogen inhalation can be a safe and promising treatment option for comatose survivors of out-of-hospital cardiac arrest. The trial also establishes a feasible methodology of hydrogen inhalation for mechanically ventilated patients that can be widely applied to other critical diseases and conditions.
Introduction
Brain injury remains the leading cause of short-term death in patients hospitalised after cardiac arrest (CA).1 In patients with coma following CA, target temperature management (TTM) is recommended to prevent brain injury.2 Despite this, CA outcomes with TTM remain poor, and feasible and innovative treatments to improve CA outcomes are lacking.
Molecular hydrogen (H2) has anti-oxidative, anti-inflammatory, and anti-apoptotic properties and mitigates ischaemia-reperfusion injuries.3 Inhaled H2 is absorbed from the lungs and diffuses via the bloodstream to the cell organelles, including those in the brain.4, 5, 6, 7 Other unique features of inhaled H2 include its effectiveness even at concentrations as low as 1% v/v4,5 and no obvious adverse effects.8,9 Therefore, H2 inhalation is a promising treatment, especially in emergency and critical care medicine.10
CA and resuscitation induce whole-body ischaemia and reperfusion injuries.11 In rodent CA models, H2 inhalation improved survival rates and neurological functions and attenuated histological neuronal damage independent of TTM.12,13 In this study, we developed an H2 inhalation system for patients that allows co-administration of 2% H2 and titrated oxygen (O2) through a ventilator; in a study of this system, we confirmed that H2 inhalation is safe and feasible for selected patients with coma following CA.14
Therefore, to assess the efficacy and safety of inhaled O2 with H2 after out-of-hospital CA (OHCA), we performed a randomised double-blinded trial, Efficacy of Inhaled Hydrogen on Neurological Outcome Following Brain Ischaemia During Post-Cardiac Arrest Care (HYBRID II). Furthermore, we hypothesized that H2 inhalation would improve neurological outcomes and survival rate 90 days after OHCA of a cardiac cause.
Methods
Study design
This is a multi-centre, double-blind, placebo-controlled randomised study performed at 15 institutions in Japan (see Appendix for a complete list of study institutions).15 In accordance with the Japanese Clinical Act, in which central review is a mandatory requirement for interventional studies, the study was approved by the certified institutional review board of Keio University. HYBRID II was registered with the University Hospital Medical Information Network (registration number: UMIN000019820) and re-registered with the Japan Registry for Clinical Trials (registration number: jRCTs031180352) because of a change in the Japanese clinical trial legislation.
Participants
We consecutively screened adults (aged 20–80 years) admitted to the hospital after OHCA with a definitive or presumed cardiac cause, irrespective of the initial rhythm, between February 1, 2017, and September 30, 2021. The inclusion criteria were the following: 1) coma (Glasgow Coma Scale [GCS] score < 8) for 20 min after return of spontaneous circulation (ROSC); 2) systolic blood pressure ≥80 mmHg with or without fluids, vasopressors, or inotropes; 3) written informed consent from the family; and 4) fewer than 6 h between ROSC and starting inhalation of trial gas. The exclusion criteria included: 1) a known pre-arrest Cerebral Performance Category (CPC) score of 3 or 4; 2) known treatment limitations; 3) a do not resuscitate order; 4) trauma-associated OHCA; and 5) O2 saturation below 94% with 50% O2 inhalation (see Appendix for complete inclusion and exclusion criteria). To ensure that the participation of patients under coma was voluntary, written informed consent was obtained from the patients’ family members who were present at the hospital. After regaining competent consciousness, participants were asked whether they wished to continue participating in the study. Patients were withdrawn from the study if they or their families withdrew consent.
Randomisation and masking
Randomisation was performed using blinded gas cylinders, as previously described (see Appendix for detailed methods).15 Two cylinders were used for each patient, and each pair of cylinders contained either H2 (4% H2 + 96% N2) or nitrogen gas (100% N2) (Appendix p 9). At each institution, each set of two patients was randomly allocated 1:1 to the H2 and control groups. Cylinders were identical, and the contents were sealed and blinded at the factory (Taiyo Nippon Sanso, Omiya, Japan). Furthermore, blinding was validated by checking the seal before and after the cylinders were used.
Procedures
The intervention was inhalation of blinded trial gas for 18 h following admission to the intensive care unit (ICU) (Appendix p 10). The H2 group inhaled 2% H2 with titrated O2, and the control group inhaled titrated O2; the gas inhalation system is described elsewhere (Appendix p 9, p 11–13).15
During the intervention, the trial gas inhalation system was used to mechanically ventilate patients with mandatory volume-control ventilation; patients were administered neuromuscular blocking agents. Treating physicians chose the optimal ventilation setting from a list of predefined combinations of the ventilator and trial gas flow rates (Appendix p 11–13) to meet the following ventilation goals: peripheral oxygen saturation (SpO2) ≥94%, or partial pressure of oxygen and carbon dioxide in the arterial blood of 85–150 mmHg and 35–45 mmHg, respectively. There was no restriction on the positive end-expiratory pressure. Trial gas inhalation was discontinued when an O2 concentration of greater than 50%, the maximum O2 concentration of the gas inhalation system, was required to maintain the ventilation goals.
After the intervention, patients were switched to an ICU ventilator. Ventilation was tailored to each patient, and the neuromuscular blocking agent was discontinued when no longer necessary.
All patients received standard post-arrest care, including TTM, according to the protocol of each institution.16 A single target temperature between 32 °C and 36 °C was selected as an institutional protocol. Best efforts were made to reach the target temperature within 8 h of ROSC using surface or intravascular temperature management devices. After reaching the target temperature, all patients were maintained at the target temperature for 24 h and then passively rewarmed to 36 °C over 48 h. For patients in whom the target temperature of 36 °C was selected, the temperature was maintained at 36 °C for 72 h after the ROSC. During the intervention, sedatives were limited to midazolam and/or propofol to avoid an additive or synergistic effect of specific sedatives.
Ninety days after randomisation, neurological outcomes were determined by board-certified neurologists who were blind to patient allocation. GCS was evaluated in all survivors. Furthermore, Mini-Mental State Examination (MMSE) was performed in patients who had CPC 1 or 2 at 90 days following randomisation.
Withdrawal of life-sustaining therapy because of perceived poor neurological prognosis (WLST-N) within 72 h of ROSC (WLST-N<72) is associated with increased, potentially avoidable mortality in patients after OHCA.17 In this trial, no cases of WLST-N<72 occurred. In addition, treatment was not escalated if patients were moribund 72 h after ROSC.
Outcomes
The primary outcome was the proportion of patients with good neurological outcomes, defined as CPC 1 or 2 (at 90 days); the poor neurological outcome was defined as CPC 3–5. Secondary outcomes included neurological outcomes assessed by a 90-day modified Rankin Scale (mRS) score, GCS, MMSE, and survival rate and time.
Prespecified adverse events (AE) and serious AEs (SAEs) (definitions and the full list of AE and SAE are provided in the Appendix, Tables S3–S5) were recorded in the case report form (CRF) at 18, 24, 48, and 72 h and 14, 30, and 90 days after initiation of trial gas inhalation. An increase of ≥2 in each Sequential Organ Failure Assessment (SOFA) subcategory was defined as a significant clinical change and an AE. An independent data and safety monitoring committee reviewed AE and SAE reports.15
Statistical analysis
We estimated that a sample size of 334 patients would provide 80% power to detect a 15% difference in the proportion of good neurological outcomes in the H2 group compared with the control group at a two-sided alpha level of 0.05. Assuming a dropout rate of 5%, the estimated total sample size was 360.15 All statistical analyses were performed using SAS version 9.3 (SAS Institute, Cary, NC, USA) by independent statisticians who were not involved in patient treatment or outcome assessment. Statisticians performed analyses according to predetermined data handling and statistical methods (see Appendix).15 Briefly, all analyses were performed in the full analysis set, which was based on the intention-to-treat principle. Demographic data were compared using descriptive analyses. A per-protocol analysis was planned to investigate the effect of receiving the assigned treatment. The primary endpoint was compared using the chi-square test. In addition, the 90-day survival rate was analysed with the chi-square test; the duration of survival, by Log-rank test and Cox proportional hazards model; mRS, GCS, and MMSE scores, with the Mann–Whitney U test.
The independent variables in the Cox proportional hazards model were sex, age, duration of CA, time from ROSC to trial gas inhalation, initial shockable rhythm, and trial gas. We made no assumptions regarding the pattern of missing data and did not perform any imputations. All tests were two-tailed, and a P value of 0.05 was considered statistically significant.
The original statistical analysis plan (see Appendix) was modified because of the premature termination of the study. The interim analysis was stopped, and the final analyses were performed with the available data according to the original plan.
Role of the funding source
The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. All authors participated in the interpretation of the data, and critical review of the manuscript. All authors read and approved the final version of the manuscript and took responsibility for the decision to submit it for publication.
Results
The decision to terminate the study was made by the principal investigator for reasons associated with the COVID-19 pandemic and this change was approved by the certified institutional review board of Keio University. During the study period, 1391 patients were screened. Of these patients, 429 matched the inclusion criteria. After excluding patients who fulfilled the exclusion criteria, 73 patients were randomised (Fig. 1). All 73 patients were included in the ITT analyses (H2 group, n = 39; control group, n = 34). One patient in the control group was excluded from the per-protocol analysis set because they were withdrawn from the study prematurely when trial gas inhalation was interrupted following the recurrence of CA. There were no missing data for the mandatory variables, such as the outcomes, inclusion and exclusion criteria, and safety variables. Data on clinical variables regarding resuscitation were missing in only one patient. Both groups had a median age of 68 years and were predominantly male (Table 1). Resuscitation characteristics showed no significant intergroup differences. The median time after ROSC to initiate the trial gas inhalation was 253 and 273 min in the H2 and control groups, respectively. All patients underwent TTM between 33 °C and 36 °C.
Fig. 1.
CONSORT flow diagram. The study included adult patients who experienced cardiogenic out-of-hospital cardiac arrest. After excluding patients who fulfilled the exclusion criteria, 73 patients were randomly assigned 1:1 to receive oxygen with 2% molecular hydrogen (H2 group) or oxygen (control group). One patient in the control group was excluded from the per-protocol analysis after trial gas inhalation was interrupted. Abbreviations: ECMO, extracorporeal membrane oxygenation; ROSC, return of spontaneous circulation.
Table 1.
Baseline characteristics of the full analysis set population.
| Characteristic | H2 (n = 39) | Control (n = 34) |
|---|---|---|
| Demographic characteristics | ||
| Age, median (range), y | 68 (22–80) | 68 (24–79) |
| Male sex, n (%) | 32 (82) | 27 (79) |
| Female sex, n (%) | 7 (18) | 7 (21) |
| Medical history, n (%) | ||
| Myocardial infarction | 4 (10) | 1 (3) |
| Angina pectoris | 1 (3) | 1 (3) |
| Arrhythmia | 4 (10) | 5 (15) |
| Hypertension | 15 (38) | 12 (31) |
| Cerebrovascular disease | 1 (3) | 7 (21) |
| Type 2 diabetes | 8 (21) | 9 (26) |
| Heart failure | 5 (13) | 3 (9) |
| Chronic lung disease | 2 (5) | 6 (18) |
| Chronic kidney disease | 3 (8) | 2 (6) |
| Malignant tumour | 2 (5) | 2 (6) |
| Characteristics of the CA | ||
| CA at public location, n (%) | 22 (56) | 16 (47) |
| Bystander-witnessed CA, n (%) | 29 (74) | 22 (65) |
| Bystander-performed CPR, n (%) | 29 (74) | 21 (62) |
| Initial cardiac rhythm | ||
| Shockable rhythm | 29 (74) | 18 (53) |
| Ventricular fibrillation | 22 (56) | 15 (44) |
| Ventricular tachycardia | 0 | 0 |
| ROSC after bystander-initiated defibrillation | 1 (3) | 3 (9) |
| Unknown rhythm, shock administered | 6 (15) | 0 |
| Non-shockable rhythm | 10 (26) | 16 (47) |
| Pulseless electrical activity | 5 (13) | 6 (18) |
| Asystole | 3 (8) | 8 (24) |
| Other | 2 (5) | 1 (3) |
| Unknown rhythm, no shock administered | 0 | 1 (3) |
| Time from CA to ROSC, mean (SD), min | 28 (15) | 26 (11) |
| Time from CA to gas inhalation, mean (SD), min | 258 (55) | 271 (60) |
| Clinical characteristics on admission | ||
| Heart rate, mean (SD), bpm | 86 (17) | 81 (18) |
| Systolic arterial pressure, median (IQR), mmHg | 139 (120–162) | 126 (112–149) |
| Diastolic arterial pressure, mean (SD), mmHg | 77 (18) | 77 (19) |
| Catecholamine used, N (%) | 13 (30) | 17 (50) |
| Arterial pH, mean (SD) | 7.343 (0.1) | 7.354 (0.1) |
| Arterial oxygen partial pressure, mean (SD), Torr | 161.5 (108) | 163.1 (94) |
| Arterial carbon dioxide partial pressure, mean (SD), Torr | 41.1 (8) | 39.9 (8) |
| Arterial bicarbonate level, mean (SD), mg/dL | 22.1 (5) | 21.7 (4) |
| Arterial base excess, mean (SD), mmol/L | −3.2 (6) | −3.5 (4) |
| Arterial lactate level, mean (SD), mmol/L | 2.92 (2.6) | 4.13 (4.4) |
| ST elevation Myocardial infarction, N (%) | 12 (31) | 13 (30) |
| SOFA score, median (IQR) | 3 (1–5.25) | 4 (2–6) |
Abbreviations: bpm, beats per minute; CA, cardiac arrest; CPR, cardiopulmonary resuscitation; IQR, interquartile range; ROSC, return of spontaneous circulation.
The median time from ROSC to reaching the target temperature was 5.4 (interquartile range [IQR]: 4.3–6.7) and 5.8 (IQR: 4.7–7.4) hours for the H2 and control groups, respectively, with no significant difference (P = 0.60). The proportion of the patients successfully reaching the target temperature within 8 h was 36/39 (92%) and 29/33 (88%) in the H2 and control groups, respectively, and there was no statistical difference (P = 0.70).
The outcome data were missing for one patient in the control group because of the withdrawal from the study following protocol violation. Good neurological outcomes were recorded in 22 (56%) and 13 (39%) patients in the H2 and control groups (relative risk compared with the control group, 0.72; 95% confidence interval [CI], 0.46–1.13; P = 0.15), respectively (Fig. 2). Based on the priori assumptions that 50% of the patients achieved good neurological outcomes in the control group, H2 inhalation achieved a 15% improvement, the two-tailed alpha level was 0.05, and the total sample size was 73, the post-hoc power was calculated as 0.21.
Fig. 2.
Cerebral Performance Category at 90 days after cardiac arrest. The figure shows the proportion of each Cerebral Performance Category (CPC) 90 days after randomisation. Neurological outcomes were determined by board-certified neurologists who were blind to treatment group assignment. Good and poor neurological outcomes were defined as a CPC of 1 or 2 and 3–5, respectively. Abbreviation: H2, molecular hydrogen.
Regarding secondary outcomes, the median (IQR) mRS score was 1 (IQR, 0–5) and 5 (IQR, 1–6) in the H2 and control groups, respectively (P = 0.01) (Fig. 3). An mRS score of 0, which indicates no symptoms at all, occurred in 18 (46%) and 7 (21%) patients in the H2 and control groups (relative risk compared with the control group, 2.18; 95% CI, 1.04–4.56; P = 0.03), respectively. GCS and MMSE, the other secondary outcomes, were not statistically different among the groups 90 days following randomisation (Table S6).
Fig. 3.
Modified Rankin scale at 90 days after cardiac arrest. The figure shows the number of patients with each modified Rankin scale (mRS) score 90 days after randomisation. Neurological outcomes were determined by board-certified neurologists who were blind to treatment group assignment. A score of 0 indicates no symptoms at all. Abbreviation: H2, molecular hydrogen.
The number of patients surviving 90 days after randomisation was 33 (85%) and 20 (61%) patients in the H2 and control groups (relative risk compared with the control group, 0.39; 95% CI, 0.17–0.91; P = 0.02), respectively. Kaplan–Meier estimates demonstrated an improved probability of survival until 90 days after randomisation with H2 inhalation (P = 0.03) (Fig. 4). The Cox proportional hazards model showed a lower adjusted hazard ratio with H2 inhalation (0.38; 95% CI, 0.12–1.19; P = 0.09); however, the difference from the control group was not statistically significant (Table S7).
Fig. 4.
Survival after out-of-hospital cardiac arrest. The figure shows Kaplan–Meier estimates of the probability of survival until 90 days after randomisation among patients assigned to receive oxygen with molecular hydrogen (H2) or oxygen alone (Control). Data are shown for the 72 patients for whom survival status was available. The event was defined as death, and data were censored at the end of each patient's study period, i.e., at 90 days.
In the 72 h after initiation of trial gas inhalation, AEs occurred in 37 (95%) and 28 patients (88%) in the H2 and control groups (Table 2), respectively; furthermore, SAEs occurred in 7 patients (18%) in the H2 group and 7 (21%) in the control group. The incidence of AEs was similar among the groups up to 90 days after the randomisation. The independent data and safety monitoring committee determined that no AE or SAE was directly attributable to the trial intervention.
Table 2.
Prespecified adverse events during the study period.
| H2 group, N (%) | Control group, N (%) | P value | |
|---|---|---|---|
| Total | 37 (95) | 28 (88) | 0.40 |
| 18 h | 10 (26) | 9 (28) | 1.00 |
| 24 h | 23 (59) | 21 (66) | 0.63 |
| 48 h | 31 (82) | 24 (75) | 0.57 |
| 72 h | 29 (78) | 22 (69) | 0.42 |
| 14 days | 16 (47) | 16 (57) | 0.46 |
| 30 days | 8 (24) | 7 (35) | 0.53 |
| 90 days | 2 (6) | 5 (25) | 0.10 |
Hours and days indicate the time from the start of the trial gas inhalation. Fisher exact test.
Abbreviation: H2, molecular hydrogen.
Among the SOFA subcategories, the respiration score improved significantly 72 h after initiation of H2 inhalation (Table S3); however, H2 did not have a significant impact on the other SOFA subcategories i.e., coagulation, liver, cardiovascular, and renal, at 18, 24, 48, and 72 h after initiation of gas inhalation (Tables S8–S11).
Discussion
We compared a mixture of O2 and 2% H2 with O2 alone in patients with coma after cardiogenic OHCA. Because of circumstances related to the COVID-19 pandemic, the study was terminated prematurely before reaching the planned number of patients. The increased proportion of patients with good neurological outcomes (i.e., CPC 1 and 2) at 90 days in the H2 group (as compared to the control group) did not reach statistical significance. However, the 90-day mRS score and survival rate were significantly higher in the H2 group, and importantly, a significantly higher proportion of patients in the H2 group had neurologically intact survival, i.e., an mRS score of 0. The occurrence of AEs and SAEs did not increase with H2 inhalation, and none of them was determined to directly result from H2 inhalation.
Even though the difference in the primary outcome was not statistically significant, a median increase of 17% in good functional outcomes with H2 inhalation represents a clinically meaningful improvement in outcomes after OHCA. With an improvement in the integrated post-arrest care, recent interventional trials after OHCA showed no additional effects on top of the standard post-arrest care including TTM.18, 19, 20 Although patient characteristics and the proportion of patients achieving good functional recovery in this trial were similar to the findings in recent TTM studies,21,22 inhaled H2 had beneficial effects.
The proportion of patients with an mRS score of 0 (i.e., functional recovery without neurological sequelae) was 21% in the control group, which is similar to the proportion (17%) observed in a recent large trial comparing the effect of hypothermic and normothermic TTM after OHCA.21 In the present study, an mRS of 0 was noted in twice as many patients in the H2 group (46%) as in the control group. Thus, although H2 decreased mortality, it did not increase the proportion of patients with a severe or moderately severe disability, suggesting a promising effect of inhaled H2 in aiding true functional recovery while reducing deaths following cardiogenic OHCA.
Improvement of outcomes with inhaled H2 assessed by the CPC scale did not achieve statistical significance. The CPC scale is widely used for reporting outcomes on resuscitation science.23 However, it is known to have limited accuracy in discriminating between mild and moderate brain injuries.24 An advisory statement from the International Liaison Committee on Resuscitation, which was published after the commencement of this trial, recommends reporting outcomes after CA with the mRS rather than the CPC scale.25 Moreover, other authors emphasize the importance of evaluating score distributions because dichotomous outcomes (i.e., good vs poor) are inadequate for measuring outcomes after CA.26 The present study corroborates the idea that analysing actual scores is more useful: The median CPC was 1 (IQR, 1–4) and 4 (IQR, 1–5) in the H2 and control groups, respectively (P = 0.03).
Some patient characteristics such as shockable rhythms and witnessed arrest were enriched in the H2 group even after randomisation. Although a skew in these characteristics was not statistically significant, they are known to be associated with favourable outcomes after CA. A sensitivity analysis among the subgroup of patients with witnessed arrest and initial shockable rhythms revealed a non-significant difference between the two groups (Table S12). In contrast, among patients with initial non-shockable rhythms, CPC of 1 or 2 was achieved in 5/10 (50%) and 2/15 (13%) patients in the H2 and control groups, respectively (P = 0.08). These results suggest that the effect of inhaled H2 was not confounded by the skew of these patient characteristics in the H2 groups that are known to be associated with favourable outcomes.
This study has several limitations. First, enrolment was terminated prematurely because the COVID-19 pandemic led to a drastic increase in the demand for ventilators and a chronic staff shortage that hampered patient enrolment (60 [45%] of the 133 eligible patients were excluded because of staff availability; Fig. 1). The small sample size may explain the lack of a significant intergroup difference in the primary outcome. The reverse fragility index (RFI) was introduced to assess the statistical robustness and vulnerability of null-result trials.27 RFI indicates the minimum number of events required to change the trial result from statistically non-significant to significant. Therefore, a lower RFI indicates greater vulnerability to move from statistical non-significance to significance based on a few events. In our trial, the RFI was 3 for the primary outcome; although an acceptable cut-off for the RFI has not been established, 3 is a small value.28 The interpretation of the RFI value depends on the sample size29; thus, the reverse fragility quotient (RFQ), which accounts for the sample size by dividing the RFI by the total sample size of the trial, is also used to gauge which trial is relatively more fragile. In our trial, the RFQ was 0.04; this indicates that the primary outcomes would have been statistically significant when they turned favourable in an additional 4% of the members of the H2 group. The RFI, RFQ, and secondary outcomes warrant large trials to further investigate the effect of inhaled H2 after OHCA. Second, as in other randomised studies on CA, the study population was different from the real-world OHCA population in that the participants were predominantly males with high bystander witness rates and high rates of bystander-performed cardiopulmonary resuscitation. Moreover, cardiogenic OHCA was chosen to test the hypothesis in a relatively uniform population. These factors limit the generalizability of the results. Third, the H2 inhalation system requires further refinement. To ensure safety, we used initial H2 at a non-flammable concentration of 4% in prefilled gas in cylinders, so the maximum O2 concentration was limited to 50%, and maximum administration for 18 h.15 In theory, up to 98% of O2 can be administered with 2% H2. Recent technological advances enable continuous generation of high-volume H2 gas by water electrolysis,6 and incorporating portable H2 generators into the inhalation system would overcome its current limitations. Fourth, as this study primarily focused on the effect of H2, the selection of the target temperature for TTM was not controlled. Therefore, future studies are required to assess the interaction between H2 and the target temperature for TTM. Fifth, the effect of H2 was evaluated in a homogenous Asian cohort. Future studies should include patients from a wide genetic background and comorbidities. Furthermore, we did not account for interinstitutional variations, because the post-arrest care practice is considered relatively uniform among the tertiary medical centres that participated in this study. We will consider these variations in our next clinical trial with a larger number of participating centres. Finally, H2 administration initiated approximately 4.5 h post-ROSC improved secondary outcomes. This unique feature of inhaled H2 makes it a promising therapeutic strategy for preventing delayed neuronal death following CA and resuscitation. However, additional studies are needed to evaluate the effects of earlier and longer H2 administration.
Furthermore, this study suggested that H2 inhalation is safe and may have the potential to improve outcomes following OHCA. In addition, these results support the global trend towards the clinical use of H2 inhalation.8,30 However, the results of this study should be interpreted cautiously due to a small sample size.
In summary, the addition of H2 inhalation to standard post-arrest care in patients who remained comatose after cardiogenic OHCA did not achieve a statistically significant improvement in terms of the primary outcome. However, the secondary outcomes suggest that H2 inhalation may improve 90-day survival without neurological sequela as compared to oxygen alone. Our findings suggest the potential of inhaled H2 as an additive therapy for OHCA and warrant further studies.
Contributors
This study was conceived by TT and MSuzuki. They worked with KH and MSano to finalise the detailed protocol. TT, MSano, and MSuzuki wrote the methodological paper. MSuzuki chaired the trial steering committee. TT and MSuzuki have accessed and verified the data. Statistical analysis was performed by an independent biostatistician according to a prespecified statistical analysis plan (Dr. Naoyuki Kamatani; StaGen Co., Ltd, Tokyo, Japan). TT wrote the first draft of the manuscript. All authors participated in the interpretation of the data, and critical review of the manuscript. All authors have read and approved the final version of the manuscript and had final responsibility for the decision to submit it for publication.
Data sharing statement
Collected data will not be available publicly because of the restriction by the ethics review board. Related documents, study protocol, and statistical analysis plan will be available in the supplementary materials. The data presented in this paper are available on request from the corresponding author.
Declaration of interests
We declare no competing interests.
Acknowledgments
The authors thank Shuko Onuki for her assistance with administrative tasks. This study was supported by a research grant from the Taiyo Nippon Sanso Corporation (no funding number applicable).
Footnotes
Supplementary data related to this article can be found at https://doi.org/10.1016/j.eclinm.2023.101907.
Contributor Information
Masaru Suzuki, Email: suzuki.a2@keio.jp.
HYBRID II Study Group:
Ryoji Iizuka, Hiromichi Narimiya, Ryosuke Tsuruta, Kotaro Kaneda, Motoki Fujita, Junichi Sasaki, Osamu Akasaka, Keisuke Sawai, Makiko Nozaki, Hiroshi Imai, Ken Ishikura, Kaoru Ikejiri, Yasuyuki Kakihana, Shuhei Niiyama, Takahiro Futatsuki, Masahiro Honda, Yasuhiro Ikeda, Hideo Oka, Hideaki Yoshihara, Hirokazu Onishi, Susumu Yamashita, Koki Shimizu, Toshihiro Sakurai, Shu Yamada, Hiroshi Fukami, Nobuaki Shime, Kei Suzuki, Yasuhiro Kuroda, Kenya Kawakita, Akio Kimura, Tatsuki Uemura, Kiyotsugu Takuma, Kunio Kanao, Youichi Yanagawa, and Ikuto Takeuchi
Appendix A. Supplementary data
References
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