Published online Jun 18, 2026. doi: 10.5312/wjo.v17.i6.121358
Revised: April 18, 2026
Accepted: May 13, 2026
Published online: June 18, 2026
Processing time: 86 Days and 20.1 Hours
Molecular hydrogen, with antioxidant and anti-inflammatory properties, has shown therapeutic potential in knee osteoarthritis (KOA). However, optimal inha
To evaluate the effect of different durations of hydrogen inhalation on KOA sym
In this 12-week pilot study, elderly KOA patients were assigned to either a long-term (LT) or short-term (ST) hydrogen inhalation group based on the median cumulative inhalation duration. Primary outcomes were the changes in the Western Ontario and McMaster Universities Osteoarthritis Index (ΔWOMAC) total and subscale scores. Secondary outcomes included changes in 36-item Short-Form Health Survey scores (ΔSF-36), dose-response analysis between cumulative inhalation duration and ΔWOMAC, and adverse events. Assessments were conducted at baseline and week 12.
A total of 49 patients (mean age 80.1 ± 5.8 years; 77.6% female) were enrolled. At week 12, the LT group showed significantly greater symptom improvement in the ΔWOMAC total score (LT: 28.2 ± 7.0 vs ST: 11.2 ± 4.6, P < 0.001). Multivariable regression confirmed a positive association between cumulative inhalation duration and ΔWOMAC total score (β = 15.176, 95%CI: 12.177-18.176, P < 0.001). ΔSF-36 scores did not differ significantly. Dose-response analysis revealed a logarithmic relationship between inhalation duration and symptom improvement, plateauing after approximately 114 cumulative hours.
Our pilot study indicated that LT hydrogen inhalation may provide greater symptom relief in elderly KOA pati
Core Tip: This pilot study is the first to demonstrate a dose-response relationship between cumulative hydrogen inhalation duration and symptom relief in elderly patients with knee osteoarthritis. Long-term inhalation (over 30 cumulative hours) provided significantly greater improvements in pain, stiffness, and physical function than short-term inhalation. The therapeutic benefit followed a logarithmic curve, plateauing after approximately 114 cumulative hours, suggesting a potential saturation point for clinical efficacy.
- Citation: Wang CH, Li YR, Han L, Wang HQ, Jia SF, Liu XC, Wu H, Wu F, Wang BG. Effects of hydrogen inhalation duration on symptom relief in elderly patients with knee osteoarthritis: A pilot study. World J Orthop 2026; 17(6): 121358
- URL: https://www.wjgnet.com/2218-5836/full/v17/i6/121358.htm
- DOI: https://dx.doi.org/10.5312/wjo.v17.i6.121358
Knee osteoarthritis (KOA), the most prevalent chronic pain condition among the elderly, exerts effects that extend beyond joint-related symptoms[1]. It is associated with elevated risks of cardiovascular events, hip fractures, and lower extremity deep vein thrombosis, contributing to adverse outcomes such as disability and diminished quality of life[2,3]. As population aging accelerates, the number of individuals aged 65 and older in China is projected to reach 365 million by 2050[4]. This demographic shift is expected to significantly increase the prevalence of KOA, further exacerbating the socio-economic burden[5].
Oxidative stress and inflammation are critical drivers in the progression of KOA, making them key therapeutic targets[6,7]. Molecular hydrogen, known for its antioxidant and anti-inflammatory properties, has demonstrated promising therapeutic potential in KOA management[8]. Preclinical studies have shown that hydrogen can inhibit the c-Jun N-terminal kinase signaling pathway and suppress the expression of apoptosis-related proteins such as cysteinyl aspartate-specific proteinase (caspase)[9]. Additionally, it downregulates the expression of cyclooxygenase-2 and inducible nitric oxide synthase, thereby mitigating extracellular matrix degradation, reducing inflammation, and slowing articular cartilage degeneration[10]. Despite these promising findings, the clinical application of hydrogen therapy in KOA remains in its early stages, and its efficacy in elderly KOA patients has yet to be clearly established. Moreover, although hydrogen inhalation therapy has been investigated in various clinical contexts, the optimal duration of inhalation remains inconsistent across studies. Reported inhalation times range from as short as 0.5 hours per day—primarily for the adjunctive treatment of postherpetic neuralgia—to as long as 7 hours per day, as used for symptom recovery in patients infected with the Omicron variant of coronavirus disease of 2019 (COVID-19)[11,12]. Clinical evidence suggests that 0.5 hours of daily hydrogen inhalation combined with gabapentin significantly alleviates neuropathic pain and improves sleep quality in patients with postherpetic neuralgia, compared to gabapentin alone[11]. In contrast, 7 hours of daily hydrogen inhalation has been shown to accelerate viral clearance, reduce inflammation levels, and lower the risk of severe cases of COVID-19 when compared to oxygen therapy[12]. However, in the context of KOA, no consensus has been reached regarding the optimal inhalation parameters, and no comprehensive studies have yet explored the dose-response relationship between hydrogen inhalation duration and symptomatic relief in KOA patients.
Therefore, this study aims to investigate the effects of varying hydrogen inhalation durations on symptom relief in patients with KOA and to analyze the dose-response relationship between inhalation duration and therapeutic efficacy.
This pilot study was conducted in Taikang Yanyuan Continuing Care Retirement Community in China from January 2024 to September 2024. This study has been approved by Ethics Committee of Sanbo Brain Hospital, Capital Medical University (No. SBNK-YJ-2024-009-01). All the subjects and their legal representatives fully understood the purpose, content, protocol and assessment methods of the study and provided informed consent before the start of the study.
Participants were eligible for inclusion if they met the following criteria: (1) Aged 65 years or older; (2) Diagnosed with KOA according to Taikang healthcare medical records; (3) Classified as Kellgren-Lawrence (KL) grade 2 or 3[13]; and (4) Had a KOA duration of at least 6 months without having undergone joint replacement or arthroscopic surgery. Exclusion criteria included: (1) Presence of mental disorders; (2) Cognitive impairment; (3) Severe systemic conditions such as advanced cardiopulmonary disease or multi-organ failure; (4) Current receipt of other KOA treatments, including platelet-rich plasma or stem cell injections; (5) Intolerance to inhalation therapy; and (6) Participation in other clinical trials within the preceding three months.
This study conducted a three-month follow-up of all enrolled KOA patients who underwent hydrogen inhalation therapy. The therapy was administered via nasal catheter using a hydrogen-oxygen nebulizer (AMS-H-01, Shanghai Asclepius Meditec Co., Ltd., China), delivering hydrogen at a concentration of 66.7% and a flow rate of 3 L/minute[14]. The recommended inhalation duration was 1 hour to 3 hours per day, with the actual daily inhalation time self-determined by each patient. At the end of the study, researchers inspected the hydrogen-oxygen nebulizers and recorded the cumulative hydrogen inhalation time for each participant (in hours). The study endpoint was defined as 12 weeks following the initiation of hydrogen therapy. Participants who experienced worsening knee pain during the study and received additional interventions to relieve KOA symptoms—such as increased use of oral analgesics, application of topical analgesic agents, or intra-articular injection therapy—were excluded from the final analysis.
Based on the median cumulative duration of hydrogen inhalation among the included participants, subjects were categorized into two groups: The long-term (LT) hydrogen inhalation group and the short-term (ST) hydrogen inhalation group. This grouping was conducted as a post-hoc stratification for exploratory analysis rather than a pre-specified or randomized assignment.
The primary outcome of the study was the change in the Western Ontario and McMaster Universities Osteoarthritis Index (ΔWOMAC)[15]. The WOMAC scale is a widely used self-assessment tool for evaluating KOA symptoms in clinical practice, comprising three dimensions: Joint pain, joint stiffness, and physical function. It includes 24 items, each scored using a visual analog scale, where 0 indicates no symptoms and 10 represents severe, unbearable symptoms. Participants responded to each item based on their actual condition. The pain dimension consists of 5 items with a maximum score of 50, the stiffness dimension includes 2 items with a maximum score of 20, and the physical function dimension comprises 17 items with a maximum score of 170. The total WOMAC score is calculated by summing the scores of all three dimensions, with higher scores indicating more severe symptoms[16]. The ΔWOMAC total score and the changes in each dimension (ΔWOMAC subscale score) were defined as the differences between baseline and week 12, reflecting changes in symptom severity over the study period.
The secondary outcome of the study was quality of life, assessed using the 36-item Short-Form Health Survey (SF-36)[17]. This instrument evaluates eight health dimensions: Physical function (PF), body pain (BP), role limitations due to physical health problems (RP), role limitations due to emotional problems (RE), general mental health (MH), social functioning (SF), vitality (VIT), and general health perceptions (GH). Higher scores correspond to better health status[18]. Changes in SF-36 scores (ΔSF-36) for each dimension were calculated as the difference between the scores at week 12 and baseline, reflecting improvements or declines in quality of life over the study period.
Additionally, the study analyzed the relationship between ΔWOMAC scores and varying cumulative durations of hydrogen inhalation. Any adverse events occurring during the hydrogen inhalation therapy were also documented.
Upon enrollment, demographic and KOA-related data were collected. Demographic information included age, gender, body mass index (BMI), educational attainment, smoking history, alcohol consumption, and comorbidities. KOA-specific data encompassed the affected knee(s), KL grade, disease duration, and analgesic medication usage. Participants were scheduled for assessment at baseline and week 12 post-enrollment, during which the WOMAC and SF-36 scales were administered to evaluate symptom severity and quality of life.
The normality of quantitative variables was assessed using the Kolmogorov-Smirnov test. Continuous data were expressed as medians and interquartile ranges or as mean and SD, depending on their distribution. Categorical data were presented as n (%). Analysis of differences was performed using the Mann-Whitney U test, Student’s t-test, or χ2 test, based on the data type and distribution. Multiple linear regression analysis was employed to adjust for potential confounding factors, including age, affected knee side, and baseline total WOMAC score, in evaluating the outcome measures. For secondary outcomes, including the eight domains of the SF-36, multiple comparisons were addressed by controlling the false discovery rate (FDR) using the Benjamini–Hochberg method. A scatter plot was created with cumulative hydrogen inhalation time as the independent variable (X-axis) and ΔWOMAC as the dependent variable (Y-axis). The least squares method was then applied to fit the trend line, thereby constructing the dose-response curve illustrating the relationship between hydrogen inhalation duration and KOA symptom relief.
All statistical analyses were conducted using SPSS (version 26.0, IBM, United States) and Origin Pro (version 2021, OriginLab Corporation, United States). Two-sided statistical tests were employed, and statistical significance was established at a value of P < 0.05.
A total of 89 subjects were initially screened for this study. Following rigorous evaluation against the inclusion and exclusion criteria, 32 individuals were excluded—14 declined participation during the informed consent process, and 18 did not meet the eligibility requirements. Consequently, 57 subjects commenced hydrogen inhalation therapy. During the study, 6 participants were excluded due to worsening knee pain following intra-articular injection treatment, and 2 were lost to follow-up. Ultimately, 49 subjects completed the study and were included in the final analysis. Based on the median cumulative hydrogen inhalation time of 30 hours, participants were divided into two groups: The LT group, comprising 24 subjects with inhalation times exceeding 30 hours, and the ST group, consisting of 25 subjects with inhalation times below 30 hours (Figure 1).
The average age of the included subjects was 80.1 ± 5.8 years, with females comprising 77.6% (38/49) of the cohort, and the mean BMI was 23.5 ± 2.9 kg/m2. Unilateral KOA was predominant, affecting 61.2% (30/49) of participants, while KL grade 2 was the most frequent classification, observed in 51.0% (25/49) of subjects. The median duration of KOA was 20 years (range: 6-29 years). Notably, the prevalence of bilateral KOA was significantly higher in the LT group compared to the ST group (LT: 79.2%, 19/24 vs ST: 44.0%, 11/25, P = 0.012). No other demographic differences between the groups reached statistical significance (Table 1).
| Variables | Total (n = 49) | LT group (n = 24) | ST group (n = 25) | P value |
| Age, years, mean (SD) | 80.1 (5.8) | 80.5 (5.6) | 79.6 (6.1) | 0.594 |
| Sex, female | 38 (77.6) | 19 (79.2) | 19 (76.0) | 0.791 |
| BMI, kg/m2, mean (SD) | 23.5 (2.9) | 23.3 (2.9) | 23.8 (2.9) | 0.507 |
| Affected side | 0.012 | |||
| Unilateral | 30 (61.2) | 5 (20.8) | 14 (56.0) | |
| Bilateral | 19 (38.8) | 19 (79.2) | 11 (44.0) | |
| KL grade | 0.477 | |||
| 2 | 25 (51.0) | 11 (45.8) | 14 (56.0) | |
| 3 | 24 (49.0) | 13 (52.4) | 11 (44.0) | |
| Duration of KOA, years, median (IQR) | 20 (6, 29) | 20 (6.3, 30) | 20 (6, 20) | 0.389 |
| Education level | 0.428 | |||
| High school education or less | 8 (16.3) | 3 (12.5) | 5 (20.0) | |
| College degree | 15 (30.4) | 6 (25.0) | 9 (36.0) | |
| Bachelor degree or above | 26 (53.1) | 15 (62.5) | 11 (44.0) | |
| Cigarette smoking | 2 (4.1) | 0 (0) | 2 (8.0) | - |
| Alcohol drinking | 4 (8.2) | 1 (4.2) | 3 (12.0) | 0.609 |
| Medical history | ||||
| Respiratory disease | 13 (26.5) | 4 (16.7) | 9 (36.0) | 0.125 |
| Hypertension | 35 (71.4) | 18 (75.0) | 17 (68.0) | 0.588 |
| Coronary heart disease | 19 (38.8) | 7 (29.2) | 12 (48.0) | 0.176 |
| Gastrointestinal disease | 11 (22.4) | 5 (20.8) | 6 (24.0) | 0.791 |
| Diabetes mellitus | 13 (26.5) | 7 (29.2) | 6 (24.0) | 0.682 |
| Chronic kidney disease | 1 (2.0) | 1 (4.2) | 0 (0) | - |
| Cancer | 4 (8.2) | 2 (8.3) | 2 (8.3) | 1.000 |
| Cerebrovascular disease | 11 (22.4) | 4 (16.7) | 7 (28.0) | 0.342 |
| Analgesics taken | 73 (60.3) | 39 (63.9) | 34 (56.7) | 0.414 |
| Types of analgesics taken | 32 (65.3) | 14 (58.3) | 18 (72.0) | 0.315 |
At baseline, the LT group exhibited a significantly higher WOMAC total score than the ST group (LT: 100.3 ± 22.3 vs ST: 84.9 ± 17.8, P = 0.010). While there were no significant differences in WOMAC pain score and WOMAC stiffness score between the two groups, the LT group scored notably higher in WOMAC function score (LT: 71.9 ± 19.5 vs ST: 57.7 ± 14.4, P = 0.005). Quality of life assessments via the SF-36 questionnaire revealed no significant differences across PF, RE, SF, RP, MH, GH, BP, and VIT between the two groups (Table 2).
| Variables | LT group (n = 24) | ST group (n = 25) | P value |
| WOMAC, mean (SD) | |||
| WOMAC total score | 100.3 (22.3) | 84.9 (17.8) | 0.010 |
| WOMAC pain score | 19.0 (5.5) | 18.2 (5.3) | 0.625 |
| WOMAC stiffness score | 9.3 (4.1) | 9.0 (3.2) | 0.722 |
| WOMAC function score | 71.9 (19.5) | 57.7 (14.4) | 0.005 |
| SF-36, mean (SD) | |||
| Physical function | 51.0 (12.5) | 58.2 (17.4) | 0.105 |
| Physical role | 52.1 (40.3) | 45.0 (40.2) | 0.541 |
| Social function | 79.2 (15.5) | 79.5 (13.9) | 0.937 |
| Emotion role | 66.7 (40.5) | 64.0 (40.7) | 0.820 |
| Body pain | 42.3 (13.3) | 43.3 (10.0) | 0.759 |
| Vitality | 68.1 (12.2) | 65.0 (15.7) | 0.443 |
| General health | 44.9 (14.6) | 46.2 (17.6) | 0.776 |
| Mental health | 69.7 (12.0) | 65.6 (15.7) | 0.315 |
At week 12, the LT group demonstrated a significantly greater improvement in ΔWOMAC total score compared to the ST group (LT: 28.2 ± 7.0 vs ST: 11.2 ± 4.6, P < 0.001). After adjusting for confounders including age, affected KOA side, and baseline WOMAC total score, multiple linear regression analysis confirmed that longer hydrogen inhalation duration remained significantly positively associated with ΔWOMAC total score (β = 15.176, 95%CI: 12.177-18.176, P < 0.001). Regarding WOMAC subscales, the LT group showed significantly higher improvements in ΔWOMAC pain score (LT: 8.2 ± 4.3 vs ST: 3.6 ± 3.4, P < 0.001), ΔWOMAC stiffness score (LT: 2.4 ± 2.5 vs ST: 0.5 ± 1.2, P = 0.002), and ΔWOMAC function score (LT: 17.6 ± 6.3 vs ST: 7.4 ± 4.5, P < 0.001) compared to the ST group. Adjusted regression analyses demonstrated that extended hydrogen inhalation time was significantly positively correlated with improvements in ΔWOMAC pain score (β = 3.006, 95%CI: 0.645-5.367, P = 0.014), ΔWOMAC stiffness score (β = 2.048, 95%CI: 0.771-3.326, P = 0.002), and ΔWOMAC function score (β = 9.962, 95%CI: 6.745-13.179, P < 0.001) (Table 3, Figure 2).
| Variables | LT group (n = 24) | ST group (n = 25) | P value |
| ΔWOMAC total score | 28.2 (7.0) | 11.2 (4.6) | < 0.001 |
| ΔWOMAC pain score | 8.2 (4.3) | 3.6 (3.4) | < 0.001 |
| ΔWOMAC stiffness score | 2.4 (2.5) | 0.5 (1.2) | 0.002 |
| ΔWOMAC function score | 17.6 (6.3) | 7.4 (4.5) | < 0.001 |
At week 12, the LT group showed significantly greater improvements in the SF-36 subscales of ΔPF (LT: 26.7 ± 11.2 vs ST: 16.3 ± 12.4, P = 0.003) and ΔGH (LT: 12.0 ± 11.9 vs ST: 4.1 ± 10.9, P = 0.019) compared to the ST group. However, no significant differences were observed between the two groups in the remaining subscales, including ΔRP, ΔSF, ΔRE, ΔBP, ΔVIT, and ΔMH. After FDR adjustment, only the difference in the ΔPF domain (LT: 26.7 ± 11.2 vs ST: 16.3 ± 12.4, adjust P = 0.024) remained statistically significant, while the other domains did not retain significance. After adjusting for confounding factors such as age, the affected side of KOA, and baseline WOMAC scores, multiple linear regression analysis indicated that prolonged hydrogen inhalation time was not significantly associated with improvements in the SF-36 subscales of ΔPF (β = 6.570, 95%CI: -1.000 to14.141, P = 0.087) or ΔGH (β = 7.345, 95%CI: -0.308 to 14.998, P = 0.060). Furthermore, after adjusting for the same confounding variables, prolonged hydrogen inhalation time showed no significant correlations with changes in other SF-36 domains, including ΔRP (β = -11.232, 95%CI: -34.222 to 11.757, P = 0.330), ΔSF (β = 3.802, 95%CI: -5.222 to 12.826, P = 0.400), ΔRE (β = -13.873, 95%CI: -39.036 to 11.290, P = 0.273), ΔBP (β = 4.983, 95%CI: -2.262 to 12.588, P = 0.194), ΔVIT (β = -2.501, 95%CI: -11.566 to 6.546, P = 0.581), and ΔMH (β = -2.281, 95%CI: -11.580 to 7.019, P = 0.624) (Table 4, Figure 3).
| Variables | LT group (n = 24) | ST group (n = 25) | P value | Adjust P value |
| Δ Physical function | 26.7 (11.2) | 16.3 (12.4) | 0.003 | 0.024 |
| Δ Physical role | 39.0 (37.4) | 34.9 (37.7) | 0.704 | 0.996 |
| Δ Social function | 23.9 (15.2) | 17.5 (12.5) | 0.110 | 0.220 |
| Δ Emotion role | 21.6 (40.6) | 21.5 (39.6) | 0.996 | 0.996 |
| Δ Body pain | 27.4 (12.3) | 20.9 (10.6) | 0.057 | 0.152 |
| Δ Vitality | 12.7 (13.5) | 12.1 (14.4) | 0.890 | 0.996 |
| Δ General health | 12.0 (11.9) | 4.1 (10.9) | 0.019 | 0.076 |
| Δ Mental health | 13.4 (12.7) | 14.6 (15.1) | 0.755 | 0.996 |
The relationship between cumulative hydrogen inhalation duration and improvements in WOMAC scores was analyzed using scatter plots and least squares fitting, with fitted curves accompanied by 95% confidence and prediction intervals. Overall, the ΔWOMAC total score (Figure 4A) showed a logarithmic improvement trend (adjusted R2 = 0.66), which began to plateau after about 114 hours. Similar logarithmic trends were observed for ΔWOMAC pain score (Figure 4B, adjusted R2 = 0.25) and ΔWOMAC function score (Figure 4C, adjusted R2 = 0.46), with plateau points around 119 hours and 97 hours, respectively. In contrast, ΔWOMAC stiffness score (Figure 4D, adjusted R2 = 0.29) exhibited a linear improvement without a clear plateau within the observed range.
A total of 2 (4.1%) adverse events were observed in this study. One case of headache occurred in the LT group, and one case of profuse sweating was reported in the ST group. There was no statistically significant difference in the incidence of adverse events (LT: 4.2%, 1/24 vs ST: 4.0%, 1/25, P = 1.000) between the two groups. Both symptoms resolved spontaneously after discontinuation of hydrogen inhalation. No severe adverse events were reported during the study.
This study analyzed data from 49 patients with KOA who received hydrogen inhalation therapy. Participants were divided into long-duration and short-duration groups based on the median cumulative inhalation duration. Differences in ΔWOMAC and ΔSF-36 scores between the two groups were evaluated. The results demonstrated that LT hydrogen inhalation seemed to be more effective in alleviating KOA symptoms in elderly patients compared to ST inhalation. Furthermore, symptom improvement was positively associated with cumulative inhalation duration. However, this effect tended to plateau when the cumulative inhalation duration reached approximately 114 hours.
Regarding the comparison between LT and ST duration of hydrogen inhalation, Wang[11] was the first to conduct a randomized controlled trial investigating the use of hydrogen inhalation for the treatment of herpes zoster–related neuralgia. The study primarily compared the effects of 1-hour vs 0.5-hour daily hydrogen inhalation on pain intensity and inflammatory markers in patients with zoster-related neuralgia. The results demonstrated that patients who inhaled hydrogen for 1 hour per day experienced significantly greater reductions in neuropathic pain, improved sleep quality, and more pronounced decreases in inflammatory markers such as interleukin-6 and tumour necrosis factor alpha, as well as oxidative stress markers like malondialdehyde[11]. Additionally, there was a significant increase in antioxidant enzymes such as superoxide dismutase. These findings suggest that prolonging the duration of hydrogen inhalation confers greater benefits in pain relief and sleep improvement, potentially through mechanisms involving reduced oxi
Although no studies have specifically investigated the relationship between cumulative hydrogen inhalation time and symptom relief in KOA, evidence from other disease models demonstrates a clear dose-response effect of inhalation duration on therapeutic outcomes. For instance, in acute lung injury models, ST inhalation of high-concentration hydrogen (67%) for 1 hour daily significantly inhibits inflammatory pathways (nuclear factor kappa B, p38 MAPK) and reduces pro-inflammatory mediators[25,26], while extending inhalation to 4 hours further decreases oxidative stress markers and improves survival rates[27]. Similarly, clinical trials in non-alcoholic fatty liver disease show that continuous hydrogen inhalation for 13 weeks (4 hours per day) results in substantial reductions in hepatic fat and improvements in liver function, whereas shorter interventions provide limited benefits[28]. In myocardial infarction models, prolonged daily inhalation of low-concentration hydrogen (2%) over 28 days markedly enhances cardiac function and reduces fibrosis, with LT exposure required to reverse cardiomyocyte apoptosis and restore mitochondrial function[29]. Collectively, these findings underscore a robust dose-dependent relationship between hydrogen inhalation duration and therapeutic efficacy across multiple conditions, with extended inhalation time more effectively alleviating oxidative stress and inflammation and promoting functional recovery[30].
However, it remains unclear whether a plateau effect exists for hydrogen inhalation duration. To explore this, our study initially constructed a dose-response curve correlating cumulative hydrogen inhalation time with symptom relief in KOA, based on changes in WOMAC scores. The curve suggests that after approximately 114 hours of cumulative inhalation, the improvement in KOA symptoms plateaus, indicating a possible plateau effect for hydrogen’s therapeutic benefit. This observation aligns with findings from Wu et al[31], who investigated perioperative hydrogen inhalation in patients undergoing glioma resection. Their study showed that postoperative brain edema volume decreased following a logarithmic decline as hydrogen inhalation time increased, with the smallest edema volume occurring at an average of 5 hours per day. Beyond this duration, no further edema reduction was observed. Based on these results, we speculate that the plateau effect observed in KOA treatment may be due to biological saturation of hydrogen within the local joint after about 114 cumulative hours. Consequently, extending inhalation time beyond this point may not enhance therapeutic effects since local hydrogen levels no longer increase. This hypothesis is supported by the study of Yamamoto et al[32], which demonstrated that continuous inhalation of 3% hydrogen in rats led to a gradual, logarithmic increase in hydrogen concentration across different organs until saturation was reached. Notably, muscle tissue required the longest time—20.2 minutes—to reach saturation, compared to 6.3 minutes to 9.4 minutes for other organs. Therefore, when local hydrogen concentration reaches its peak, the maximum therapeutic effect maybe also achieved.
There are several strengths and limitations to this study. This study is the first to reveal the impact of different hydrogen inhalation durations on symptom relief in patients with KOA by establishing dose-response curves, thereby providing a theoretical foundation for selecting optimal time parameters in future hydrogen therapy research. However, several limitations should be acknowledged. First, this was an exploratory pilot study with a relatively small sample size of only 49 patients. Larger-scale randomized controlled trials are necessary to validate these findings. Second, as an observational study, patients were categorized into short-duration and long-duration groups based on their cumulative hydrogen inhalation time, without randomization. The non-randomized and post-hoc grouping design introduces potential selection bias. Notably, baseline WOMAC total and function scores were higher in the LT group, which may have contributed to greater observed improvements due to regression to the mean. Therefore, the magnitude of the treatment effect should be interpreted with caution. Third, absence of a control group made it difficult to distinguish whether the improvement of KOA symptoms was attributable solely to hydrogen inhalation or partially due to placebo effects or natural fluctuation over time. As a result, the internal validity of the study is constrained, and causal inferences cannot be established. This design introduces potential selection bias and limits the generalizability of the results, which requires further confirmation in large-scale, double-blind, randomized controlled trials.
Long-term hydrogen inhalation may be associated with greater symptom improvement compared to shorter exposure in elderly KOA patients. A potential dose-response relationship was observed, with therapeutic benefits suggesting a potential plateau trend around 114 cumulative hours. However, these findings are exploratory and require confirmation in well-designed randomized controlled trials.
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