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

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.

KEY POINTS.

Question: Is the combination of target temperature management (TTM) and hydrogen inhalation associated with improved outcomes following cardiogenic out-of-hospital cardiac arrest (OHCA)?

Findings: In this post hoc analysis of a randomized controlled trial, the combination therapy of hydrogen inhalation and TTM at 32 to 34°C (TTM32–TTM34) was associated with improved 90-day neurologically intact survival compared with TTM32–TTM34 monotherapy. Hydrogen inhalation did not improve outcomes under TTM35–TTM36.

Meaning: A combination therapy of hydrogen inhalation and TTM32–TTM34 was associated with improved outcomes after cardiogenic OHCA.

The annual incidence of out-of-hospital cardiac arrest (OHCA) is approximately 40–100 individuals per 100,000 in the United States, Europe, Asia, and Oceania (1). Despite the advances in prehospital and critical care of cardiac arrest (CA) patients, survival to hospital discharge and 30-day survival for OHCA ranges from 5% to 16%. Post-cardiac arrest brain injury (PCABI) is the leading cause of morbidity and mortality among CA survivors (2).

Current neuroprotective therapies applied after achieving the return of spontaneous circulation (ROSC) are limited to supportive interventions and target temperature management (TTM) (3, 4). Considering the unsatisfactory outcomes after CA with current postarrest care, a novel neuroprotective intervention for PCABI is urgently required.

Hydrogen is a mild antioxidant that selectively reduces cytotoxic hydroxyl radicals (5). Hydrogen has antioxidative, anti-inflammatory, and anti-apoptotic properties and mitigates ischemia-reperfusion injuries (6). We previously reported that hydrogen inhalation improved neurologic function and survival in an experimental model of CA (7), in which 2% hydrogen inhalation under normothermic-TTM (TTM35–TTM36) and hypothermic-TTM (TTM32–TTM34) alone yielded similar neuroprotection. Furthermore, the combination of hydrogen inhalation and TTM32–TTM34 showed a synergistic effect in improving neurologic function and survival. A recent randomized trial, the Efficacy of Inhaled Hydrogen on Neurologic Outcome Following Brain Ischemia During Post-Cardiac Arrest Care (HYBRID) II trial, evaluated the efficacy of hydrogen inhalation for improving neurologic outcomes after OHCA (8). The study was incomplete, and the primary endpoint did not reach statistical significance. However, secondary outcomes suggested hydrogen may increase neurologically intact survival after OHCA. In the HYBRID II trial, the temperature was controlled between 32 and 36°C, but the target temperature was not randomized and selected per the institutional protocol. Therefore, the impact of combination therapy of target temperature and hydrogen inhalation on outcomes remains unclear.

We hypothesized that a combination of hydrogen inhalation and TTM32–TTM34 (hydrogen + TTM32–TTM34) has a synergistic effect in improving outcomes compared with TTM32–TTM34 monotherapy after OHCA. Recent randomized trials have questioned many aspects of temperature control after CA, including the optimal target temperature (9, 10). Considering the substantial heterogeneity of the patients resuscitated after CA, TTM32–TTM34 may confer better neuroprotection in some subpopulations (11, 12). Furthermore, based on the preclinical observations, neuroprotection may be suboptimal with TTM32–TTM34 alone, and hydrogen + TTM32–TTM34 may exert additional neuroprotection (7). To test our hypothesis, we conducted a secondary analysis of the HYBRID II trial data and evaluated the impact of the hydrogen + TTM32–TTM34 on outcomes after OHCA.

METHODS

This study was a post hoc analysis of the HYBRID II trial (registered at University Hospital Medical Information Network [UMIN000019820] and Japan Registry for Clinical Trials [jRCTs031180352]) was a multicenter double-blind trial conducted in 15 institutions in Japan between February 1, 2017, and September 30, 2021 that randomized 73 patients with a 90-day follow-up (8). The HYBRID II trial was approved by the certified institutional review board of Keio University (HYBRID II; approval date: November 17, 2015) and was conducted in accordance with the Helsinki Declaration of 1975. According to the HYBRID II trial protocol (13), patients were randomized to hydrogen (39 patients inhaled 2% hydrogen mixed oxygen) and control (34 patients inhaled oxygen alone) groups (Fig. S1, http://links.lww.com/CCM/H572). This study was performed according to the Strengthening the Reporting of Observational Studies in Epidemiology reporting guidelines (14).

PATIENTS

The HYBRID II trial included comatose adult patients after cardiogenic OHCA. The main exclusion criteria were a known prearrest severe neuroglial impairment requiring assistance in daily life, trauma-associated OHCA, and oxygen saturation of less than 94% with 50% oxygen inhalation (8). A total of 72 participants in the HYBRID II trial were included in the current analysis after excluding one withdrawn patient who lacked outcome data.

Research Gas Inhalation

The intervention was inhalation of blinded study gas for 18 hours following admission to the ICU (Fig. S1, http://links.lww.com/CCM/H572). The hydrogen group inhaled 2% hydrogen with titrated oxygen, and the control group inhaled titrated oxygen. During the intervention, the study gas inhalation system (Fig. S2A, http://links.lww.com/CCM/H572) was used to mechanically ventilate patients with mandatory volume-controlled ventilation. Treating physicians selected the optimal ventilation setting from a list of predefined combinations of ventilator and study gas flow rates (Fig. S2D, http://links.lww.com/CCM/H572) to achieve the following ventilation goals: peripheral oxygen saturation greater than or equal to 94% or arterial oxygen and carbon dioxide partial pressures of 85–150 Torr and 35–45 Torr, respectively. Positive end-expiratory pressure was not restricted. Trial gas inhalation was discontinued when an oxygen concentration of greater than 50% was required to maintain the ventilatory goals. Patients were disconnected from the study gas inhalation system and connected to an ICU ventilator for tailored ventilation, including pressure-controlled ventilation, after completion of the study intervention.

TTM Protocol

In the HYBRID II trial, all patients were treated with TTM and complied with the guidelines (4). A target temperature between 32 and 36°C was selected per the institutional protocol. Surface or endovascular temperature feedback devices were used to reach the target temperature as quickly as possible, preferably within 8 hours of ROSC. The target temperature was maintained for 24 hours and passively rewarmed to 36°C over 48 hours. For patients treated at 36°C, the temperature was maintained at 36°C for 72 hours after the ROSC. Therapeutic mild hypothermia is commonly defined as a target temperature below 35°C (15). Therefore, we defined TTM32–TTM34 and TTM35–TTM36 as a target temperature of less than 35°C and 35–36°C, respectively.

Neurologic Outcomes

Two board-certified neurologists, blinded to the group allocations, assessed the neurologic outcomes 90 days after CA. A good neurologic outcome was defined as a Cerebral Performance Category score of 1 or 2 (for details, see Supplemental Methods, http://links.lww.com/CCM/H572).

Outcome Measures

The primary outcome was good neurologic outcomes 90 days after CA, and the secondary outcome was survival until 90 days after CA.

Statistical Analysis

Descriptive statistics are presented as mean with sd, median with interquartile range, or number with percentage. Frequencies were compared between the two and four groups using the Fisher exact test and analysis of variance test with Tukey multiple comparisons, respectively. Multivariable logistic regression analysis fitted with generalized estimating equations was performed to adjust for patient characteristics (age and sex), CA and resuscitation information (witness status, bystander cardiopulmonary resuscitation [CPR] implementation, initial shockable rhythm, duration of CA, and time from the ROSC to the start of gas inhalation) and account for within-institution clustering. The Log-rank test and Cox proportional hazards regression analysis compared survival between the two groups. The above patient demographics, CA characteristics, and resuscitation information were adjusted in the Cox proportional hazards model. The methods for sensitivity analysis are provided in the supplementary materials (http://links.lww.com/CCM/H572). All analyses were conducted as two-sided tests, and statistical significance was set at p < 0.05. All statistical analyses were performed using SPSS (IBM Statistics, version 29.0; IBM Corp., Armonk, NY).

RESULTS

TTM32–TTM34 was implemented in 25 (64%) and 24 (73%) patients in the hydrogen and control groups, respectively (p = 0.46; Fig. 1A). Among the 15 participating institutions, 11 (73%) institutions implemented TTM32–TTM34 as the default in the institutional protocol during this trial (Fig. 1B). Additionally, 34°C was the most selected target temperature among patients treated under TTM32–TTM34 (47 patients [96%]; Fig. S3, http://links.lww.com/CCM/H572). Therefore, despite the rapid spread of TTM35–TTM36, comparatively fewer patients (23 [32%] patients) were treated under TTM35–TTM36 in a fraction of institutions (4 [27%] institutions) in this trial. Furthermore, each group noted no biased surface or endovascular device selection (Table S1, http://links.lww.com/CCM/H572).

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.

The characteristics of patients were balanced among each group (Table S2, http://links.lww.com/CCM/H572). However, there were relatively fewer cases of witnessed arrests and bystander CPR implementation in the control gas group treated under TTM35–TTM36 compared with other groups. Additionally, the lactate levels and sequential organ failure assessment scores before the gas inhalation were higher among the patients in the control gas + TTM32–TTM34 group compared with other groups. Nevertheless, the catecholamine index, hemodynamic parameters, and arterial gas analysis result indicated that patients in the control gas + TTM32–TTM34 group required only a minimal dosage of catecholamines and maintained stable hemodynamics. The time from ROSC to reaching the target temperature tended to be longer among patients treated under TTM35–TTM36 than those treated under TTM32–TTM34 (Table S2, http://links.lww.com/CCM/H572). The multivariable methods accounted for these minor imbalances of characteristics among the treatment groups.

Comatose postarrest patients are in critical condition, and they are at risk of developing adverse events (AE), including death, irrespective of interventions. Since there is no standardized definition of AE or serious AE for postarrest clinical trials, we defined AE using a verifiable measure by the Common Terminology Criteria for AE, version 4.0 (see Supplemental Methods and Tables S3–S5, http://links.lww.com/CCM/H572) (8). Although several AE were observed in the participating patients, there was no significant difference in the occurrence rate of AE among the hydrogen and control groups under TTM32–TTM34 or TTM35–TTM36 (Table 1; and Tables S6–S9, http://links.lww.com/CCM/H572).

TABLE 1.

Prespecified Adverse Events During the Study Period

Time	H2 + TTM32–TTM34, n (%)	CTL + TTM32–TTM34, n (%)	H2 + TTM35–36, n (%)	CTL + TTM35–TTM36, n (%)	p
18 hr	4 (16)	5 (21)	6 (43)	4 (44)	0.15
24 hr	13 (52)	16 (70)	10 (42)	5 (56)	0.53
48 hr	21 (84)	17 (74)	10 (77)	7 (78)	0.87
72 hr	21 (84)	16 (70)	8 (67)	6 (67)	0.52
14 d	8 (35)	11 (58)	8 (73)	5 (71)	0.12
30 d	4 (17)	6 (35)	4 (36)	2 (29)	0.54
90 d	1 (4)	3 (23)	1 (9)	2 (29)	0.17

CTL = control gas; H₂, hydrogen, TTM = target temperature management.

Hours and days indicate the time from the start of the trial gas inhalation. Fisher exact test.

Under TTM32–TTM34, 17 (68%) and 9 (38%) patients achieved good neurologic outcomes at 90 days in the hydrogen and control groups, respectively (relative risk: 1.81 [95% CI, 1.05–3.66], p < 0.05; Fig. 2A). In contrast, under TTM35–TTM36, good neurologic outcomes were achieved in 5 (36%) and 4 (44%) patients in the hydrogen and control groups, respectively (relative risk: 0.80 [95% CI, 0.30–2.27], p > 0.99) (Fig. 2B). As the selection of the target temperature was not randomized in the HYBRID II trial, we sought to analyze whether hydrogen + TTM32–TTM34 was associated with good neurologic outcomes. The adjusted analysis using the generalized estimating equations model showed that a combination of hydrogen and TTM32–TTM34 was associated with a higher rate of good neurologic outcomes at 90 days (adjusted OR 16.10 [95% CI, 1.88–138.17], p = 0.01; Table 2). A sensitivity analysis using a multivariable logistic regression analysis demonstrated that the combination of hydrogen + TTM32–TTM34 was independently associated with good neurologic outcomes at 90 days (Table S10, http://links.lww.com/CCM/H572).

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.

TABLE 2.

Hydrogen + Target Temperature Management 32-Target Temperature Management 34 is Associated With Good Neurologic Outcomes at 90 Days

Variables	Adjusted OR (95% CI)	p
Age, yr	0.94 (0.88–1.00)	0.04
Male sex	2.87 (0.42–19.61)	0.28
Arrest at a public location	6.45 (0.78–52.63)	0.09
Witnessed arrest	1.32 (0.29–6.05)	0.72
Bystander cardiopulmonary resuscitation was performed	3.29 (0.60–18.09)	0.17
Shockable rhythm	0.17 (0.03–0.94)	0.04
Duration of cardiac arrest, min	0.87 (0.78–0.98)	0.02
Time from the return of spontaneous circulation to gas inhalation, min	0.98 (0.97–1.00)	0.03
Sequential Organ Failure Assessment score on day 0	0.56 (0.33–0.94)	0.03
Hydrogen + TTM32–TTM34	16.10 (1.88–138.17)	0.01

OR = odds ratio, TTM = target temperature management.

Subsequently, we evaluated the impact of the target temperature selection and the hydrogen inhalation on survival. Under TTM32–TTM34, the number of patients who survived 90 days after randomization was 22 (88%) and 13 (54%) in the hydrogen and control groups, respectively (relative risk: 0.62 [95% CI, 0.39–0.88], p = 0.01). Kaplan-Meier estimates demonstrated an improved probability of survival until 90 days after randomization with hydrogen + TTM32–TTM34 compared with TTM32–TTM34 alone (p = 0.01; Fig. 3A). Cox proportional hazards regression analysis showed a trend toward a lower adjusted hazard ratio with a combination of hydrogen + TTM32–TTM34 (adjusted hazard ratio: 0.22 [95% CI, 0.05–1.06], p = 0.06) (Table S11, http://links.lww.com/CCM/H572). Conversely, under TTM35–TTM36, the number of patients that survived 90 days after the randomization was 11 (79%) and 7 (78%) in the hydrogen and control groups, respectively (p > 0.99). The Kaplan-Meier estimates showed no significant improvement in the probability of survival until 90 days with hydrogen + TTM35–36 (p = 0.93) (Fig. 3B).

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.

DISCUSSION

In the HYBRID II trial, TTM32–TTM34 was predominantly selected irrespective of the allocated gas. Although the selection of a target temperature was not randomized in this trial, TTM32–TTM34 was similarly selected in both treatment groups. Hydrogen + TTM32–TTM34 was associated with improved neurologic outcomes 90 days after the randomization. Hydrogen + TTM32–TTM34 was independently associated with good neurologic outcomes after accounting for patient, resuscitation, and inter-institutional heterogeneity. Conversely, under TTM35–TTM36, hydrogen inhalation did not show neuroprotective or survival benefits.

Numerous publications have reported the efficacy of inhaled hydrogen for treating and preventing diseases from preclinical models to patients with COVID-19 (6, 16, 17), with no reported adverse effects specifically attributed to hydrogen use. We found no increase of any AE associated with hydrogen inhalation in postarrest patients (8). Similarly, no specific AE was identified in the present analysis associated with hydrogen + TTM32–TTM34 (Table 1). Critical AE associated with hydrogen inhalation include suffocation and explosion. Hydrogen is a flammable gas in concentrations between 4% and 75% at ambient temperature and pressure. To eliminate the risk of explosion in our hydrogen inhalation system, we used hydrogen gas prediluted below the lowest combustible threshold of 4% hydrogen in nitrogen.

Inhaled hydrogen mitigates lung injury in various animal models, such as hemorrhagic shock (18), ventilator-induced lung injury (19), and radiation-induced lung injury (20). However, hydrogen + TTM32–TTM34 was not associated with improved oxygenation. This study excluded patients with severe respiratory distress; therefore, the safety of hydrogen inhalation in post-CA patients with severe hypoxemia has not been established. Likewise, hydrogen did not affect hemodynamic parameters following OHCA (8). This finding aligns with results from preclinical models of CA (7, 21). Notably, research in preclinical models suggested that inhaled hydrogen could have bidirectional hemodynamic effects. For example, hydrogen inhalation showed an antihypertensive effect by augmenting parasympathetic nerve activity (22) and a pressor effect via attenuation of hyperpermeability (23). Therefore, inhaled hydrogen may exert hemodynamic effects through different mechanisms, but current evidence suggests that hydrogen inhalation does not impact acute hemodynamics after CA.

TTM32–TTM34 is believed to exert neuroprotective effects through reduced cerebral oxygen consumption and multifactorial chemical and physical mechanisms (15). However, the results of recent large clinical trials have suggested that TTM35–36 or even fever prevention provides similar neuroprotection as TTM32–TTM34 in a selected group of patients after CA (9, 10). Despite this, whether a single target temperature fits all patients remains unclear. Patients who are presumed to have sustained moderate to severe PCABI may merit TTM32–TTM34 (11, 12). Therefore, current expert opinion recognizes that some populations of patients with PCABI may benefit from temperature control at temperatures between 33 and 36°C (3, 24). Our results show that the neurologic outcomes were similar between hydrogen + TTM35–TTM36 and control gas + TTM32–TTM34, suggesting that monotherapy with hydrogen or TTM32–TTM34 might not have provided sufficient neuroprotection to improve outcomes. Conversely, a combination of hydrogen + TTM32–TTM34 exerted additive neuroprotective effects and was associated with improved outcomes. Despite being a preliminary study, our results may explain the statistical insignificance when analyzed irrespective of the target temperature (8). This is reminiscent of our previous results in a rat model of CA, in which TTM32–TTM34 alone and hydrogen + TTM35–36 exerted similar neuroprotective effects (7). Notably, in this experimental model of CA, hydrogen inhalation attenuated the rise of interleukin-6, which was not evident with TTM32–TTM34 alone, while the combination of hydrogen + TTM32–TTM34 further provided synergistic effects in improving neurologic function and survival.

Hydrogen was initially introduced as a selective scavenger of cytotoxic oxidants (5). However, in the HYBRID II trial, hydrogen inhalation started after the burst of oxidative stress that peaked minutes after the reperfusion (25). This implies that hydrogen mitigates PCABI through different mechanisms. The exact mechanisms by which hydrogen attenuates neurologic injury after CA have not been fully elucidated. A brief cellular ischemia-reperfusion injury leads to activation of inflammatory pathways and activation of downstream immune responses. Accumulating evidence suggests the role of immune-mediated cellular injury after CA (26, 27). Immune cells and their responses as a potential target of hydrogen warrant investigation (28, 29). Another role of hydrogen in neuroprotection after CA may involve inhibition of ferroptosis. Ferroptosis is a form of cell death that results from iron accumulation and lipid peroxidation. Hydrogen replaces the hydroxyl group of oxidized porphyrin to form the hydride Fe³⁺-porphyrin (30). This hydride acts as a scavenger for alkyl radicals and inhibits the chain reaction of lipid peroxidation and subsequent ferroptosis. The delayed onset of ferroptosis can explain why the delayed hydrogen inhalation confers neuroprotection. A recent study reported that hydrogen inhalation attenuated neuronal ferroptosis and inhibited neuroinflammation after subarachnoid hemorrhage (31).

Direct comparisons between TTM32–TTM34 and hydrogen + TTM32–TTM34 demonstrated that hydrogen + TTM32–TTM34 showed a higher cerebral blood volume and lower cerebral hemoglobin oxygen saturation than TTM32–TTM34 (32). The lower cerebral hemoglobin oxygen saturation level indicates a higher oxygen demand or consumption in the brain, suggesting improved neuroactivity. We did not directly measure cerebral blood flow or cerebral metabolic rate of oxygen in our patients; however, these preclinical results imply that the addition of hydrogen attenuated the detrimental suppression of the cardiovascular system associated with TTM32–TTM34 and improved cerebral microcirculation and oxygen utilization. Hydrogen is reported to improve oxygen utilization by maintaining mitochondrial structure and function (33).

Furthermore, hypothermia delays the peak of inflammatory cytokine production in peripheral blood mononuclear cells (34). Thus, TTM32–TTM34 may have fewer disadvantages associated with the delay in starting hydrogen inhalation, partly through attenuating the inflammatory response. Based on these facts, we speculated that hydrogen and TTM32–TTM34 mutually negated the disadvantages and thus resulted in better neuroprotection.

Our findings are in line with those of previous studies that showed a synergistic effect between pharmacologic agents and TTM32–TTM34 (25, 35). Furthermore, multi-drug cocktail therapy has recently been proposed to attenuate PCABI by simultaneously targeting multiple pathways (36). This concept aligns well with our results and highlights the importance of the multifaceted approach against PCABI. Hydrogen inhalation can easily be combined with other neuroprotective cocktails and TTM.

Patient demographics were balanced between the two groups that inhaled control gas (Table 1), and the proportion of patients achieving a good neurologic outcome was similar (Fig. 2, A and B). Therefore, the reason for the difference in survival between these two groups is unclear (Fig. 3, A and B). We could not analyze the within-institution comparison of temperatures on outcomes because mostly one target temperature was chosen per institution in this trial. Future two-factorial randomization designs of gas and target temperature would address this point.

One of this study’s unexpected findings was that the TTM35–TTM36 group took longer than the TTM32–TTM34 group to attain the desired temperature. One explanation for this may be that, in comparison to the TTM32–TTM34 group, the device’s cooling effort may have been relatively mild owing to the smaller difference in the body temperature and the target temperature, resulting in a temperature fluctuation between 36.1 and 36.5°C for a longer duration.

We acknowledge several limitations of the study. First, because this is a post hoc analysis of a study with a small sample size, the results must be interpreted with caution. Although the results were statistically robust after various adjustments of confounding factors, future investigations involving the selection of a target temperature will confirm our results. Second, it is unclear how hydrogen + TTM32–TTM34 contributed to improved outcomes. Subsequent analysis of oxidative stress markers and cytokines may support the current findings. Third, the two target temperatures did not have a clear separation. This was because the guidelines at the time of the study recommended selecting a target temperature between 32 and 36°C (4). Future studies taking target temperatures into account will confirm our results. Despite these limitations, hydrogen has several unique features that make it promising in the field of emergency and critical care medicine (37). First, inhaled hydrogen diffuses from the lungs through the bloodstream to the cell organelles, including those in the brain (5, 38–40). Second, hydrogen concentration saturates within minutes after the initiation of inhalation (39). Third, hydrogen mediates effects at concentrations as low as 1% v/v (5, 38). Fourth, hydrogen has no obvious adverse effects (16, 41). Future studies addressing the above limitations will confirm our analysis results.

CONCLUSIONS

In the HYBRID II trial, hydrogen + TTM32–TTM34 was associated with increased neurologically intact survival after cardiogenic OHCA. However, hydrogen + TTM35–TTM36 did not significantly improve neurologic outcomes or survival compared with TTM35–TTM36 mono. Hydrogen inhalation is a promising treatment option in the multifaceted approach, including TTM32–TTM34 to mitigate PCABI.

Supplementary Material

ccm-52-1567-s001.docx ^{(8.2MB, docx)}