Effect of Inhalation of Hydrogen Gas on Postoperative Recovery After Hepatectomy: A Randomized, Double-Blind, Placebo-Controlled Trial

Abstract

Hydrogen has antioxidant and anti-inflammatory properties that may attenuate perioperative stress responses. However, its clinical impact on postoperative recovery remains unclear. This randomized, double-blind, placebo-controlled trial evaluated whether perioperative hydrogen inhalation improves early recovery after hepatectomy. Sixty-eight patients undergoing elective hepatectomy were randomized (1:1) to receive 5% hydrogen gas or placebo air via nasal cannula from postoperative day (POD) 1 to POD7. The primary endpoint was the total Quality of Recovery-40 (QoR-40) score on POD3, analyzed at α = 0.2 with 80% confidence intervals in accordance with the pre-specified statistical analysis plan. Secondary and exploratory outcomes, analyzed at α = 0.05, included postoperative liver function, oxidative stress markers, and QoR-40 subdomain scores. Analyses were performed in the modified intention-to-treat population using the Mann–Whitney U test. Sixty-four patients (hydrogen, n = 31; placebo, n = 33) were analyzed. At POD3, the median QoR-40 score was 192.0 (184.0–198.0) vs. 163.0 (140.0–190.0) (p < 0.001), indicating significantly better early recovery in the hydrogen group. As supportive findings, prothrombin activity was higher with hydrogen (85.0% vs. 76.2%, p = 0.005), and QoR-40 subdomain analysis showed significantly higher emotions and physical independence scores, whereas comfort, pain, and patient support domains showed no difference. No other between-group differences were observed in biochemical parameters or urinary 8-OHdG levels. Perioperative hydrogen inhalation significantly improved early postoperative recovery after hepatectomy, primarily through psychophysical domains of well-being. These findings suggest that hydrogen may selectively enhance emotional stability and functional independence during the early recovery phase.

1. Introduction

Hepatectomy inevitably induces oxidative stress due to hepatic ischemia–reperfusion (I/R) injury, which contributes to postoperative inflammation, hepatocellular damage, and delayed functional recovery [1,2,3]. Excess reactive oxygen species (ROS) generated during I/R play a central role in this process. Molecular hydrogen has attracted growing interest as a potential medical gas because it selectively scavenges the highly cytotoxic hydroxyl radical and peroxynitrite, thereby attenuating oxidative stress at the molecular level [4]. Beyond its antioxidant properties, hydrogen has been shown to modulate inflammatory cytokine production, stabilize mitochondrial function, and improve microvascular perfusion in various organ systems. These cytoprotective mechanisms are supported by extensive preclinical work demonstrating that inhaled hydrogen reduces infarct size, mitigates I/R injury, and preserves organ function in rodent and porcine models [4,5,6]. Furthermore, early-phase human studies in post-cardiac arrest syndrome have shown that hydrogen inhalation is feasible, safe, and capable of reducing biochemical markers of oxidative stress [7,8]. Together, these findings indicate that hydrogen—despite its limited aqueous solubility—rapidly diffuses into tissues and exerts biologically meaningful antioxidant and anti-inflammatory effects.

These mechanisms provide a biologically plausible rationale for investigating hydrogen therapy in hepatectomy, where oxidative stress and transient hepatocellular injury are unavoidable. Although hydrogen has limited aqueous solubility, previous studies have confirmed that inhaled hydrogen rapidly diffuses into tissues and exerts organ-protective effects in both animal models and early human studies [4,5,6,7,8].

Despite improvements in perioperative care, many patients—particularly older individuals—experience substantial fatigue and delayed recovery following liver resection. Previous studies have shown that postoperative quality of recovery (QoR) often remains impaired during the early postoperative period, highlighting the need for interventions that enhance patient-centered recovery trajectories [9,10,11,12].

Given the mechanistic promise of hydrogen and the ongoing clinical need to enhance early recovery, hydrogen inhalation represents a rational and potentially feasible perioperative intervention [4,5,6,7,8]. We therefore conducted a randomized, double-blind, placebo-controlled trial to evaluate whether perioperative hydrogen inhalation initiated in the immediate postoperative period could attenuate excessive oxidative stress and improve early postoperative recovery. The primary endpoint was the total Quality of Recovery score on postoperative day 3 (POD3) using the validated QoR-40 instrument [13,14,15,16]. Secondary endpoints included safety and postoperative clinical outcomes, and exploratory analyses assessed oxidative stress using urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG) and related biomarkers.

2. Materials and Methods

2.1. Study Design and Oversight

This was a single-center, randomized, double-blind, placebo-controlled superiority trial conducted under the Japanese Clinical Trials Act. The trial followed a prespecified, peer-reviewed protocol and prospective registration; full methodological details (eligibility, interventions, endpoints, sample-size justification, and the statistical analysis plan) are reported in the protocol paper [17]. Smoking history, alcohol consumption, and BMI were recorded as part of the baseline characteristics because these factors may influence postoperative recovery; however, they were not applied as exclusion criteria unless associated with severe organ dysfunction or unstable medical conditions. The study was reviewed and approved by the Certified Review Board: Niigata University Central Review Board of Clinical Research (CRB3180025).

2.2. Participants

Adults (≥20 years) scheduled for elective hepatectomy for hepatobiliary malignancy or benign disease were screened. Key exclusion conditions (e.g., severe hepatic/renal dysfunction, uncontrolled infection, pregnancy/lactation, concurrent investigational therapy) and the consent process were as specified in the protocol. Written informed consent was obtained from all participants.

2.3. Randomization and Masking

Participants were assigned 1:1 to hydrogen gas or placebo air using a web-based minimization algorithm with stratification by surgical approach (laparoscopic vs. open), extent of resection (≥sectionectomy vs. ≤segmentectomy), and diagnosis (HCC vs. non-HCC). Randomization and allocation concealment were centrally implemented and maintained by Medical Research Support Co., Ltd. (Osaka, Japan) as the independent data center. Participants, care providers, outcome assessors, and data analysts were blinded to treatment.

2.4. Interventions

Participants randomized to the hydrogen group received 5% hydrogen gas via nasal cannula from postoperative day (POD) 1 through POD7, at least 1 h per session, three times daily (daily total ≤ 8 h). The placebo group received room air on an identical schedule. When supplemental oxygen was clinically required, an oxygen mask was placed over the cannula without altering group assignment or schedule. The median daily inhalation time was 3.0 h/day (IQR 2.3–3.7) in the hydrogen group and 2.7 h/day (IQR 2.0–3.6) in the placebo group, indicating excellent adherence in both groups.

2.5. Outcomes

The primary endpoint was early postoperative recovery on postoperative day 3 (POD3) measured by the QoR-40 total score. The QoR-40 total score ranges from 40 to 200, with higher scores indicating better recovery [13,14,15,16]. Secondary endpoints included safety and postoperative outcomes (e.g., complications by Clavien–Dindo, graded per CTCAE v5.0, pain by NRS, dietary intake, length of stay) together with inflammatory and liver function indices. Pain was assessed using an NRS on a 0–10 scale. Exploratory analyses assessed oxidative stress via urinary 8-OHdG, collected as 24 h urine at baseline (preoperative) and on POD3; values were expressed as ng/mg creatinine, and Δ8-OHdG was defined as POD3 minus baseline.

2.6. Sample Size and Statistical Analysis

The sample size was prespecified in the published protocol. Based on the protocol assumptions, 31 participants per group (total n = 62) were required for the planned comparison. The primary analysis compared POD3 QoR-40 between groups using two-sided tests at α = 0.2 with 80% confidence intervals in the modified intention-to-treat (mITT) population. Given the exploratory design of this pilot study, an alpha level of 0.2 (80% CI) was prespecified to detect a potential signal of benefit while minimizing the risk of Type II error. Continuous outcomes were analyzed with t test or the Mann–Whitney U test, and categorical outcomes with χ² or Fisher’s exact tests, as appropriate. Secondary and exploratory endpoints were analyzed without multiplicity adjustment and interpreted as supportive. Preplanned subgroup analyses (e.g., by extent of resection) were treated as exploratory. In accordance with CONSORT recommendations, no statistical testing was performed for baseline characteristics; values are presented descriptively by randomized group. All statistical analyses were performed using IBM SPSS Statistics for Windows, version 22.0 (IBM Japan Ltd., Tokyo, Japan).

3. Results

3.1. Participant Flow and Baseline Characteristics

Participant flow is shown in Figure 1. Sixty-eight patients were randomized; four did not initiate the assigned intervention (patient decision, n = 3; postoperative condition, n = 1). The modified intention-to-treat/safety population therefore comprised 64 patients (hydrogen, n = 31; placebo, n = 33).

Baseline characteristics were descriptively similar between groups across demographics, diagnoses, and laboratory measures. No meaningful differences were evident, and stratification factors (surgical approach, extent of resection, diagnosis) were balanced by design. Detailed descriptive values are shown in

Table 1. Baseline characteristics of patients in the hydrogen and placebo cohorts.

Parameters	n (%) or Median (IQR)
	Hydrogen Gas n = 31	Placebo Air n = 33
Age	74.0 (67.0–79.0)	71.0 (61.0–77.0)
Gender, male	17 (54.8)	21 (63.6)
Body mass index, kg/m2	23.6 (19.9–25.3)	23.6 (21.4–26.7)
Smoking status, yes	5 (16.1)	6 (18.2)
Alcohol consumption, none/occasional/habitual	24/1/6 (77.4/3.2/19.4)	25/4/4 (75.8/12.1/12.1)
Diagnosis: HCC/CRLM/ICC/Others	16/7/5/3 (51.6/22.6/16.1/9.7)	17/8/4/4 (51.5/12.1/24.2/12.1)
WBC counts (×102/µL)	50.0 (42.0–62.0)	52.0 (46.5–67.0)
Hemoglobin (g/dL)	12.7 (11.9–14.2)	13.1 (11.4–14.0)
Platelet count (×104/µL)	18.1 (16.0–21.4)	19.0 (15.1–21.6)
Albumin (g/dL)	4.2 (3.8–4.4)	4.2 (3.7–4.6)
Total bilirubin (mg/dL)	0.6 (0.5–0.8)	0.7 (0.6–0.9)
AST, U/L	26.0 (20.0–33.0)	24.0 (20.0–37.0)
ALT, U/L	22.0 (14.0–35.0)	19.0 (14.0–40.5)
ALP, U/L	84.0 (66.0–96.0)	79.0 (69.0–108.5)
GGT, U/L	35.0 (16.0–72.0)	48.0 (31.5–86.0)
CRP, mg/dL	0.11 (0.03–0.34)	0.08 (0.05–0.22)
PT activity, %	102.7 (95.2–112.1)	100.6 (89.3–107.5)
ALBI index	−2.87 (−3.07–−2.53)	−2.99 (−3.22–−2.42)
Surgical approach: laparoscopic/open	23/8 (74.2/25.8)	23/10 (69.7/30.3)
Liver resection extent: ≥section/≤segment	12/19 (38.7/61.3)	15/18 (45.5/54.5)
Diagnosis: HCC/non-HCC	16/15 (51.6/48.4)	17/16 (51.5/48.5)

Values are presented descriptively as median (IQR) or n (%) by randomized group. In accordance with CONSORT, no hypothesis testing was performed for baseline characteristics. Stratification factors were balanced by design via web-based minimization. Others includes benign hepatobiliary diseases such as intrahepatic lithiasis (n = 2), hepatic hemangioma (n = 3), and multiple hepatic cysts (n = 2). Among patients with malignant tumors, no meaningful imbalance in disease stage was observed between groups. IQR, interquartile range; HCC, hepatocellular carcinoma; CRLM, colorectal liver metastasis; ICC, intrahepatic cholangiocarcinoma; WBC, white blood cell; AST, aspartate aminotransferase; ALT, alanine aminotransferase; ALP, alkaline phosphatase; GGT, gamma-glutamyl transferase CRP, C-reactive protein; PT, prothrombin time; ALBI, albumin–bilirubin.

.

3.2. Perioperative Course

Perioperative metrics relevant to hepatectomy—including operative time, intraoperative blood loss, cumulative Pringle time, serious postoperative complications (Clavien–Dindo grade ≥ IIIa), and length of stay—were comparable between groups, with no clinically meaningful differences (

Table 2. Perioperative outcomes.

Parameters	n (%) or Median (IQR)		p Value
	Hydrogen Gas n = 31	Placebo Air n = 33
Operative time, min	311.0 (240.0–374.0)	325.0 (256.0–362.0)	0.712
Blood loss, mL	357.0 (56.0–598.0)	326.0 (107.0–658.0)	0.920
Pringle maneuver time, min	60.0 (0.0–86.0)	61.0 (30.5–88.5)	0.716
Clavien-Dindo score, IIIa and more	4 (12.9)	3 (9.1)	0.704
Postoperative hospital stay, days	13.0 (11.0–20.0)	13.0 (11.0–17.0)	0.746

These intraoperative variables were recorded before initiation of the study gas. Values are median (IQR) or n (%). Continuous variables were compared using the Mann–Whitney U test; categorical variables using the χ² test or Fisher’s exact test. IQR, interquartile range.

). No hydrogen-related or other device-related adverse events were observed in either group throughout the study period.

3.3. Early Postoperative Outcomes (Postoperative Day 3)

Clinical and laboratory outcomes at postoperative day 3 (POD3) are summarized in

Table 3. Clinical and laboratory outcomes at POD3.

Parameters	n (%) or Median (IQR)		p Value
	Hydrogen Gas n = 31	Placebo Air n = 33
Body temperature, °C	36.8 (36.5–36.9)	36.8 (36.6–37.2)	0.418
Maximum NRS, 0–10	0.0 (0.0–2.0)	2.0 (0.0–3.0)	0.151
Food intake, %	70.0 (50.0–100.0)	70.0 (40.0–80.0)	0.349
Steps per day	243.0 (42.0–1307.0)	87.5 (30.3–806.0)	0.165
Urine volume, L	2.7 (1.7–3.2)	2.9 (1.9–3.1)	0.788
Body weight, kg	63.6 (55.2–72.6)	66.7 (53.7–77.2)	0.724
WBC counts (×102/µL)	74.0 (66.0–86.0)	86.0 (67.0–100.0)	0.136
Hemoglobin (g/dL)	11.1 (9.1–12.7)	10.9 (10.0–11.6)	0.856
Platelet count (×104/µL)	12.2 (9.8–14.8)	12.1 (8.6–14.9)	0.573
Albumin (g/dL)	2.9 (2.6–3.2)	3.0 (2.5–3.3)	0.962
Total bilirubin (mg/dL)	0.8 (0.6–1.1)	0.9 (0.7–1.2)	0.200
AST, U/L	146.0 (97.0–187.0)	150.0 (93.5–280.5)	0.472
ALT, U/L	238.0 (161.0–329.0)	262.0 (160.5–503.5)	0.307
ALP, U/L	74.0 (56.0–85.0)	82.0 (51.5–109.0)	0.279
GGT, U/L	35.0 (22.0–63.0)	51.0 (27.0–83.0)	0.110
CRP, mg/dL	7.4 (4.1–14.9)	8.8 (4.7–11.8)	0.930
PT activity, %	85.0 (77.7–95.3)	76.2 (67.8–86.1)	0.005
ALBI index	−1.71 (−1.97–−1.51)	−1.79 (−1.98–−1.41)	0.788
QoR-40 score	192.0 (184.0–198.0)	163.0 (140.0–190.0)	<0.001
ΔQoR-40 score	−2.0 (−9.0–0.0)	−19.0 (−41.0–−0.5)	0.022
Urinary 8-OHdG	7.6 (5.1–10.4)	5.7 (3.7–9.0)	0.382
Δ Urinary 8-OHdG	−0.5 (−2.6–1.6)	−2.3 (−4.4–1.8)	0.322

Values are expressed as median (IQR) or n (%). Group comparisons were performed using the Mann–Whitney U test for continuous variables and the χ² test or Fisher’s exact test for categorical variables, unless otherwise specified. Urine samples were collected over a 24 h period. Urinary 8-OHdG is expressed as ng/mg creatinine; Δ8-OHdG = POD3 − baseline. IQR, interquartile range; WBC, white blood cell; AST, aspartate aminotransferase; ALT, alanine aminotransferase; ALP, alkaline phosphatase; GGT, gamma-glutamyl transferase; CRP, C-reactive protein; PT, prothrombin time; ALBI, albumin–bilirubin; QoR-40, Quality of Recovery-40; 8-OHdG, 8-hydroxy-2′-deoxyguanosine; NRS, Numerical Rating Scale.

. For clinical measures (hydrogen vs. placebo), body temperature and pain were comparable between groups: temperature 36.8 °C (36.5–36.9) vs. 36.8 °C (36.6–37.2), p = 0.418; maximum NRS 0.0 (0.0–2.0) vs. 2.0 (0.0–3.0), p = 0.151. Food intake was similar (70% (50–100) vs. 70% (40–80)). Steps per day were also similar between groups. Across hematologic and hepatic panels (WBC, neutrophils, lymphocytes, platelets; total bilirubin, AST, ALT, ALP, GGT; CRP, NLR, ALBI), no consistent between-group differences were observed at POD3. As a supportive finding, PT% at POD3 was higher in the hydrogen group (85.0 vs. 76.2, p = 0.005). Urinary 8-OHdG showed no significant between-group difference for either the POD3 level (p = 0.382) or Δ8-OHdG (POD3 − baseline) (p = 0.322). Regarding the primary endpoint, the QoR-40 total score at POD3 was higher in the hydrogen group, indicating better early recovery: mean 186.2 vs. 160.7 (80% CI for the difference, −22.8 to −17.0; p < 0.001 by t-test) and median 192.0 (IQR 184.0–198.0) vs. 163.0 (144.0–190.0), p = 0.001 by Wilcoxon test. The change from baseline (ΔQoR-40) also favored hydrogen: −2.0 (−9.0–0.0) vs. −19 (−41.0–−0.5), p = 0.022.

3.4. QoR-40 at Postoperative Day 3 and Subsequent Time Course

Time course over the first postoperative week is displayed in Figure 2. QoR-40 declined from baseline to POD3 in both groups, with higher median scores in the hydrogen group at POD3 (the only time point with a statistically significant difference). By POD7 and at discharge, scores improved in both arms, and no significant between-group differences were observed, indicating that the early advantage with hydrogen attenuated as recovery progressed. In parallel, Figure 3 details the five QoR-40 dimensions—comfort, emotions, physical independence, patient support, and pain. At POD3, the hydrogen group showed significantly higher scores in the emotions and physical independence domains, whereas comfort, patient support, and pain did not differ significantly; by POD7 and toward discharge, subdomain scores improved in both groups and between-group gaps narrowed, mirroring the total score pattern. Taken together, these results suggest that perioperative hydrogen inhalation facilitated early functional and emotional recovery after hepatectomy without altering biochemical or oxidative stress parameters.

4. Discussion

In this randomized, double-blind, placebo-controlled trial, perioperative hydrogen inhalation significantly improved early postoperative recovery after hepatectomy, as reflected by higher total QoR-40 scores at postoperative day 3 (POD3). Moreover, subdomain analysis revealed significantly higher emotions and physical independence scores in the hydrogen group, suggesting that hydrogen selectively enhanced specific aspects of recovery rather than exerting uniform effects across all dimensions. These findings indicate that hydrogen inhalation may preferentially preserve psychophysical components of early recovery—emotional stability and functional independence—rather than directly influencing comfort or pain perception.

Although the between-group difference did not persist to POD7 or discharge, this may reflect accelerated early recovery rather than the absence of a biological effect. POD3 represents the period of greatest postoperative discomfort, and improvement at this time point is clinically meaningful. By POD7, most patients approach their preoperative functional status, producing a ceiling effect that narrows detectable differences.

Despite the exploratory alpha level of 0.2, the improvement in the QoR-40 score on POD3 still met the conventional significance threshold of p < 0.05, reducing concern about an inflated Type I error and supporting the robustness of this preliminary finding.

The mechanisms underlying these domain-specific benefits are likely multifactorial. Hydrogen’s well-documented antioxidant and anti-inflammatory properties may attenuate systemic stress responses, neuroinflammation, and sympathetic overactivation, thereby alleviating postoperative fatigue, anxiety, and mood disturbance. In addition, improved microcirculatory function and mitigation of hepatic ischemia–reperfusion injury may contribute to better physical performance and earlier mobilization, consistent with previous preclinical studies in cardiac and cerebral ischemia–reperfusion models [4,5,6]. As a supportive clinical finding, the hydrogen group exhibited higher prothrombin activity at POD3 (85.0% vs. 76.2%, p = 0.005), which may reflect earlier recovery of hepatic synthetic and coagulative function. Mechanistically, molecular hydrogen may bridge our psychophysical findings through convergent biological pathways. H₂ downregulates redox-sensitive inflammatory signaling (e.g., NF-κB), lowers pro-inflammatory cytokines (TNF-α, IL-6), and preserves mitochondrial function with downstream anti-apoptotic effects [18,19]. These actions plausibly translate into clinical benefits because systemic inflammation is linked with anxiety and mood disturbance [20]. In parallel, autonomic balance indexed by heart-rate variability relates to emotional regulation, offering an additional pathway by which dampened inflammation and improved cellular energetics could yield higher “emotions” and “physical independence” scores during early recovery [21]. In the present study, HRV was assessed as an exploratory autonomic marker; however, no significant between-group differences were observed. Because HRV is highly sensitive to postoperative influences such as fluid balance, hemodynamic fluctuations, pain, and medications, detecting stable differences in the early postoperative period may require a larger sample size or more standardized monitoring conditions. Thus, while improvements in emotional and physical independence domains raise the possibility of psychophysiological effects, the current findings do not provide direct evidence of autonomic modulation by hydrogen. Future studies incorporating more intensive HRV monitoring and complementary autonomic biomarkers will be needed to clarify these mechanisms.

In contrast, the comfort, patient support, and pain domains of the QoR-40 did not differ significantly between groups. These components are more strongly influenced by analgesic management, nursing care, and environmental factors, which are unlikely to be modulated by hydrogen therapy. Similarly, urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG), a marker of oxidative DNA damage, showed no significant differences between groups at POD3. Because 8-OHdG represents systemic DNA repair turnover, its urinary excretion depends on renal handling and sampling timing [22,23]. Given that the peak of oxidative stress after hepatectomy may occur within the first 24 h postoperatively, the POD3 measurement likely reflected a post-peak decline rather than peak oxidative injury [24]. Moreover, the physiological effects of hydrogen may occur primarily in local tissues—such as the liver or neural circuits regulating stress and emotion—rather than in systemic compartments, making global urinary markers less sensitive to such localized changes.

Taken together, these results suggest that hydrogen inhalation primarily supports psychophysical recovery in the immediate postoperative phase, with benefits that diminish as recovery progresses. Such effects align well with perioperative care strategies emphasizing early ambulation, rehabilitation, and anxiety reduction in the increasingly elderly surgical population. While exploratory and hypothesis-generating, these findings provide a clinical correlate to experimental evidence of hydrogen’s cytoprotective actions.

5. Limitations

This study has several limitations. First, the sample size was moderate, reflecting the exploratory, pilot nature of this randomized trial, which may limit statistical power. The subdomain analyses were exploratory and not adjusted for multiplicity, and the primary analysis used an exploratory significance threshold (α = 0.2), which is less stringent than conventional thresholds and may increase the risk of type I error; therefore, the findings should be interpreted as hypothesis-generating rather than confirmatory. Second, because no prior evidence exists to define the optimal dose, duration, or timing of perioperative hydrogen administration, the inhalation protocol was determined primarily based on feasibility within routine postoperative care. Earlier initiation or prolonged exposure may yield greater therapeutic benefit and should be evaluated in future studies. Third, oxidative stress was assessed solely by urinary 8-OHdG measured on POD3. As oxidative stress after major surgery may fluctuate dynamically during the early postoperative phase, this single sampling point may not have captured peak perioperative changes. Future investigations should incorporate earlier or serial sampling and additional biomarkers, such as 4-HNE or F2-isoprostanes, for a more comprehensive assessment. Finally, this was a single-center study conducted in Japan, which may limit generalizability to other ethnic populations or healthcare settings. In addition, residual confounding and the possibility of response bias cannot be fully excluded, as QoR-40 is a patient-reported outcome.

6. Conclusions

Perioperative hydrogen inhalation improved early postoperative recovery after hepatectomy, particularly emotional stability and physical independence, without affecting biochemical or oxidative stress parameters. These findings suggest that hydrogen therapy may facilitate psychophysical aspects of recovery during the vulnerable immediate postoperative period. Further multicenter studies with earlier biomarker assessments are warranted to clarify its mechanisms and clinical utility in perioperative care.