Introduction

Total knee arthroplasty (TKA), known for its pain relief and joint mobility functional improvements, is considered the primary treatment for patients with end-stage knee arthritis1. Postoperative challenges, such as muscle damage, severe pain, and operated limb swelling, profoundly affect patients’ early rehabilitation exercises and psychological well-being despite the effectiveness of TKA2,3. Oxidative stress, inflammatory factors and markers of muscle injury related to sports medicine have also been widely reported4,5,6.These adverse effects often decrease physical activity and lower satisfaction levels during hospitalization7,8. Current clinical practices, such as oral nonsteroidal anti-inflammatory drug (NSAID) administration, drainage tube placement, and periarticular infiltration analgesia, provide limited relief9. However, these approaches inadequately address the resultant muscle damage, inflammation and pain, thereby limiting the progress of enhanced recovery after surgery in TKA.

Hyperbaric oxygen therapy (HBOT), a treatment involving breathing pure or high-concentration oxygen in a high-pressure environment, has demonstrated potential in addressing these postoperative difficulties. Preliminary studies indicate HBOT’s potential to influence activated endothelial cells in vitro, down-regulate inflammatory and oxidative stress genes, modulate the inflammatory system, and inhibit inflammation development10,11. Moreover, HBOT improves angiogenesis markers, such as epidermal growth factor and vascular endothelial growth factor (VEGF), correlated with Nrf-2 transcription factor activation. This improves local blood circulation and alleviates tissue edema12. Furthermore, HBOT’s role in improving stem cell recruitment accelerates tissue regeneration13. In recent years, HBOT has gained increasing attention in the clinical setting. HBOT, which was initially used for craniocerebral trauma and cerebrovascular disease, has been expanded to include a variety of clinical conditions, such as bone nonunion, femoral head necrosis, and knee injuries, with positive therapeutic outcomes10,14. HBOT significantly reduces the recovery time from injury in the context of exercise-induced muscle damage (EIMD)15.In total knee arthroplasty, muscle injuries mainly originate from traumatic injuries caused by surgical manipulation as well as ischemia-reperfusion injuries caused by the use of tourniquets. Studies have shown that direct muscle injury due to surgical manipulation is unavoidable in various current surgical approaches, including the medial parapatellar approach16. In addition, studies have shown that the degree of muscle injury is relatively low without the use of a tourniquet17. However, once a tourniquet was applied, signs of muscle damage became significant. This suggests that ischemia-reperfusion injury to the distal limb due to tourniquet use is a major contributor to muscle damage during TKA surgery. Based on this, this study hypothesized that hyperbaric oxygen therapy (HBOT) would be effective in reducing ischemia-reperfusion injury in the affected limb after TKA surgery. However, to the best of the authors’ knowledge, no clinical research has yet investigated the effectiveness of HBOT after TKA. Therefore, a prospective randomized controlled trial was conducted with the hypothesis that HBOT could attenuate ischemia-reperfusion injury in affected limb muscles and inflammatory response after TKA.

Method

Materials and ethics statement

All procedures of this study were strictly conducted under the ethical standards set by the relevant institutional and national research committees. This adherence extended to the principles of the 1964 Helsinki Declaration and its subsequent amendments, as well as other equivalent ethical standards18. The Institutional Review Board of our hospital approved this study, registered in the Clinical Trial Registry (ChiCTR2300072685). All participants provided written informed consent and research authorizations before study initiation. Furthermore, participants were explicitly informed about the intention to submit data from this study for publication purposes, and their consent for the same was obtained.

Study design

G*Power, Version 3.1.9.7 software (Franz Faul; UniKiel, Germany) was used to calculate the sample size. Our study focused on the primary outcome measure of serum CK levels to evaluate the efficacy of HBOT in reducing muscle damage after TKA. A preliminary study with 20 patients (10 per group) revealed mean CK levels of 183.6 U/L and 146.4 U/L 2 days postoperatively in the HBOT and control groups, respectively, with a standard deviation of 51.5. The calculation result of the effect size was 0.73. Based on this, we determined that 33 patients per group were necessary by setting an alpha level of 0.05 (one-tailed) with a power of 90%. However, our study enrolled 80 patients, randomizing them equally into the control group and the HBOT group, to account for potential attrition and ensure a robust sample size for final follow-up evaluation. Patients with osteoarthritis and scheduled for primary unilateral TKA at our hospital from July 2023 to December 2023 were recruited. Inclusion criteria were all patients slated for primary TKA who was diagnosed with osteoarthritis according to Kellgren-Lawrence (K-L) classification and grade 3 with surgical criteria19. The following exclusion criteria were meticulously set to ensure the study’s integrity: (1) known contraindications to HBOT; (2) severe knee deformity (varus-valgus or flexion deformity of ≥ 30°); (3) mental illnesses or neuromuscular disease history; (4) unwillingness to participate or inability to provide informed consent. Out of 98 assessed patients, 10 were ineligible and 8 declined participation, resulting in 80 enrolled patients. Two patients in the HBOT group withdrew during the course of the study, leaving 38 patients in the HBOT group and 40 in the control group (Fig. 1). Patients were randomized into the HBOT or control group in a 1:1 ratio upon admission. A computer algorithm generated random numbers, concealed in opaque envelopes. Patients selected an envelope postoperatively to determine their group. A specialized hyperbaric oxygen nurse provided pre-hyperbaric chamber education and training to the patients in the HBOT group. Moreover, nurses administred a nasal drop of 1% ephedrine hydrochloride to patients as a prophylactic measure to prevent discomfort reactions before entering the hyperbaric oxygen chamber. Surgeons, data collectors, and analysts were blinded to treatment assignments throughout the study.

Fig. 1
figure 1

Trial enrollment information.

Full size image

Patient characteristics

Baseline characteristics, including age, sex, body mass index (BMI), American Society of Anesthesiologists status (ASA), operation side, knee deformity on the coronal plane, range of motion, hospital for special surgery (HSS) scores, tourniquet time, quadriceps strength, and preoperative laboratory outcomes, demonstrated no significant differences (Table 1).

Table 1 Baseline characteristics and intraoperative demographics.
Full size table

Surgical procedures

The same primary surgeon and three specially trained orthopedic surgeons performed all surgical procedures. A controlled hypotensive anesthesia protocol (blood pressure < 100/60 mmHg) was maintained intraoperatively. The patients were positioned supine, and a medial parapatellar approach was used. Pneumatic tourniquets, inflated to > 100 mmHg of the patient’s baseline systolic pressure, were applied at the thigh base before incision. The tourniquets were gradually deflated following skin suturing and elastic bandage compressing. The surgical techniques incorporated both measured resection and soft tissue balancing. Additionally, a preoperative intravenous dose of tranexamic acid (20 mg/kg) was administered 10 min preoperatively20. Notably, no drains were used postoperatively.

Perioperative care protocol

All patients were managed perioperatively following the enhanced recovery protocol for joint surgery21. Breakthrough pain was managed with oral short-acting opioids, specifically OxyContin. Additionally, tranexamic acid (1 g) was administered intravenously at 3 and 6 h postoperatively. Prophylactic measures against deep venous thrombosis (DVT) included a combination of mechanical and pharmacological approaches. An intermittent foot pump system was used routinely to avert DVT until ambulation commenced. Enoxaparin (Clexane of 0.2 mL with 2,000 IU) was given subcutaneously in a half-dose 6 h postoperatively, followed by a full dose (0.4 mL containing 4,000 IU) daily until discharge. Transfusion decisions adhered to the National Ministry of Health guidelines, recommending transfusion for patients with hemoglobin (Hb) levels of ≤ 70 g/L, or those with Hb levels of 70–100 g/L demonstrating anemia symptoms such as dizziness, elevated heart rates, tachypnea, or reduced exercise tolerance.

Intervention measures

HBOT was incorporated into the standard treatment protocol in the intervention arm of our study. The HBOT sessions were applied once at 24 h and again at 48 h postoperatively. Each session involved an initial pressurization to 1.6 atmosphere absolute (ATA), followed by a phase of 100% oxygen inhalation. The pressurization and depressurization phases were each set to last 15 min. The oxygen inhalation phase, including 45 min at stable pressure and an additional 15 min during depressurization, totaled 1 h. A 5-min interval for air exchange was incorporated within this timeframe. Both groups were treated with normobaric oxygen therapy (oxygen inhalation by nasal cannula at normal atmospheric pressure with an oxygen flow rate of 4 L/min for 48 h) for the remaining time, except for the intervention.

Outcome measurements

Two independent researchers gathered the following data for each participant for this study: (1) basic demographic and clinical information, including age, sex, height, weight, BMI, length of stay, ASA classification, HSS score, tourniquet time and comorbid conditions; (2) preoperative and postoperative interleukin-6 (IL-6), C-reactive protein (CRP), CK, Mb, LDH, and GOT levels; (3) perioperative functional recovery metrics, such as the ROM in the knee of the affected limb, HSS score, limb circumference, knee swelling ratio, and quadriceps strength; (4) perioperative VAS scores (at rest and motion); (5) adverse event and complications. The primary outcome of the study was the detection of muscle injury biomarkers at various time points. This included measuring serum CK, Mb, LDH, and GOT levels preoperatively and 1, 3, and 14 days postoperatively22,23. Secondary outcomes encompassed changes in inflammation markers and functional recovery, assessed preoperatively and 1, 2, 3, and 14 days postoperatively24,25. Functional recovery assessments included VAS (rest and motion at knee flexion of 45°), ROM, HSS scores, quadriceps muscle strength, and knee swelling ratio. The swelling ratio was calculated by dividing the circumference of the surgical knee by that of the non-surgical knee, using measurements taken around the patella’s upper and lower poles, following the methodology used in our previous studies26. Quadriceps strength was evaluated using manual muscle testing scores (range: 0–5), with patients performing hip and knee flexion. Tertiary outcomes included postoperative adverse events and complications. Most complications associated with HBOT are minor and reversible, including barotrauma, sinus pain, oxygen toxicity, and cataract maturation (though notably, HBOT does not directly cause cataracts), whereas major adverse events, such as seizures, heart failure exacerbation, pulmonary edema, and retinal changes, though rare, were monitored. Management strategies for HBOT-related adverse effects included controlled exposure time and pressure and risk stratification. Other perioperative complications monitored included DVT, Pulmonary Embolism (PE), intramuscular vein thrombosis, nausea, vomiting, and various wound complications.

Statistical analysis

All data were analyzed using the statistical software Statistical Package for the Social Sciences version 26 (IBM, Armonk, NY, USA), with statistical significance set at a p-value of < 0.05. GraphPad Prism 9.5 (GraphPad Software, San Diego, CA) was utilized for the graphical representation of data. Quantitative data were presented as mean ± standard deviation, while qualitative data were depicted as frequencies or ratios. The Mann–Whitney U test was used for continuous data that were not normally distributed or exhibited unequal variances to evaluate significant differences between the two groups. In contrast, the independent samples t-test was used for continuous data that followed a normal distribution. The chi-squared test or Fisher’s exact test was applied for categorical data, depending on the appropriateness of the dataset. (Fig. 2)

Fig. 2
figure 2

VAS comparison.

Full size image

Results

Primary outcome

Table 2 shows the changes in Mb, CK, LDH, and GOT levels 1 day postoperatively, but with no statistical significance. However, the indicators of muscle injury 3 days postoperatively were statistically significant between the two groups (p < 0.05). No significant statistical differences in Mb, CK, LDH, and GOT levels 2 weeks postoperatively were found between the two groups (Table 2; Fig. 3).

Table 2 Postoperative muscle damage.
Full size table
Fig. 3
figure 3

Muscle danage.

Full size image

Secondary outcomes

No significant statistical differences in the changes in IL-6 and CRP levels were found between the two patient groups 1 day postoperatively. However, the HBOT group showed a significant reduction in inflammatory markers, especially CRP, 3 days postoperatively, compared to the control group (CRP: p = 0.004; IL-6: p = 0.028). No significant statistical differences in IL-6 and CRP levels were found between the two groups 2 weeks postoperatively (Fig. 4). VAS scores at rest and motion were similar between the groups 1 day postoperatively. VAS scores (rest and motion) 2 and 3 days postoperatively were significantly lower in the HBOT group (p < 0.05) (Fig. 2). The HBOT group exhibited better ROM performance than the control group 2 and 3 days postoperatively, with statistically significant differences (p < 0.05). Quadriceps strength and limb swelling ratio were better in the HBOT group 2 and 3 days postoperatively, demonstrating significant differences (p < 0.05). No significant differences in the ROM, quadriceps strength, or swelling ratio were observed 14 days postoperatively (Tables 3 and 4; Figs. 5 and 6). HSS scores differed significantly between the two patient groups 3 days postoperatively (p = 0.005). The HBOT group demonstrated higher HSS scores compared to the control group 2 weeks postoperatively, although the difference was not statistically significant. No significant differences in HSS scores were noted at 6 and 12 weeks postoperatively (Table 3).

Fig. 4
figure 4

Inflammatory markers.

Full size image
Table 3 Postoperative functional outcomes.
Full size table
Table 4 Postoperative swelling rate of knee.
Full size table
Fig. 5
figure 5

Swelling rate.

Full size image
Fig. 6
figure 6

ROM and Quadriceps strength.

Full size image

Tertiary outcomes

No significant differences in postoperative complications were observed between the groups (Table 5).

Table 5 Postoperative complication and adverse events.
Full size table

Discussion

The prevalence of TKA is increasing with the demographic shift toward an aging population. TKA significantly alleviates pain, corrects deformities, and improves functionality, thereby greatly enhancing postoperative quality of life for patients27. However, muscle injury and inflammatory response, among others, occurring in the early postoperative period hinder early knee recovery22,28. Several clinical measures have been used to address these issues, but direct and effective methods to mitigate muscle damage and inflammatory responses have been difficult to discover20,29,30. Our study investigates the use of HBOT post-TKA to alleviate these issues, potentially providing a novel pathway for improving patient outcomes in orthopedic surgery. To the best of our knowledge, this is the first study to investigate the effects of HBOT on perioperative muscle damage and the inflammatory reaction after TKA.

The popular use of inflatable tourniquets in TKA, though helpful in reducing blood loss, providing a clear surgical field, and improving prosthesis-bone fit, is associated with ischemia-reperfusion injury. This condition triggers inflammatory responses and intensifies postoperative limb pain31,32. Previous basic studies have revealed that the use of tourniquets during TKA inhibits protein kinase-B (Akt) signaling and SAPK/JNK/MAPK pathway activation, causing muscle protein degradation due to oxidative stress33,34,35. Clinical studies corroborate these basic scientific results, revealing a 20% reduction in quadriceps muscle volume, as verified by magnetic resonance imaging 1 month postoperatively, and a sustained reduction in quadriceps strength for up to 3 months36,37. However, effective ways to improve the muscle damage in the affected limbs caused by the postoperative period remain lacking. Recent studies indicate that initiating HBOT within a day of injury significantly induces inflammatory mediators, such as nitric oxide (NO), in skeletal muscle injury models38,39. HBOT may reduce hypoxia and enhance blood supply in damaged areas, thereby preserving energy homeostasis, reducing edema and damage, and enhancing muscle healing39,40. Moreover, data from studies in humans revealed the efficacy of HBOT in treating large muscle injuries due to blunt trauma41,42,43.HBOT treatment has decreased complications and stimulated muscle regeneration after muscle injury by inducing factors such as NO, Hypoxia-Inducible Factor-1α (HIF-1α), and VEGF which are crucial for muscle regeneration38,39,44.And a large number of studies from sports medicine show that HBOT can effectively reduce the muscle damage caused by exercise, and relieve the subsequent acute and chronic pain45,46,47. Through comprehensive detection and analysis of these muscle injury markers, we can objectively assess the muscle injury and recovery of patients. Therefore. we selected CK, Mb, LDH, and GOT as biomarkers for muscle damage post-TKA. Notably, the HBOT group exhibited significantly lower biomarker levels 3 days postoperatively compared to the control group. Moreover, quadriceps strength and ROM in early functional exercises were significantly better in the HBOT group. Similarly, the HSS scores 3 days postoperative were better in the HBOT group. These results align with previous basic science and clinical studies, emphasizing the efficacy of early HBOT treatment in muscle recovery post-TKA15,38,39.In conclusion, it can be concluded that in the future medical and sports industry, HBOT therapy may have good application prospects in postoperative muscle ischemia and reperfusion injury and acute and chronic muscle injury after exercise.

TKA, involving extensive bone resection and soft tissue trauma, predominantly triggers a significant inflammatory response1,22. Systemic inflammation caused by surgery decreases muscle strength and endurance, increases pain, and impedes surgical recovery2,3,20. Insights from previous studies elucidate the effectiveness of HBOT in reducing inflammatory responses10,11,38. In particular, research on spinal cord injury (SCI) revealed that HBOT markedly diminishes inflammatory cytokine levels, such as Tumor Necrosis Factor-α (TNF-α), IL-6, IL-8, and IL-10, at different post-injury intervals48. Another study of secondary SCI indicated that HBOT therapy reduced plasma Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) levels to reduce the inflammatory response and promote neurological function recovery49. These studies provide valuable perspectives on the potential of HBOT in managing postoperative inflammation. These results indicate that HBOT provided a promising approach to mitigate inflammatory reactions and improve recovery outcomes in patients undergoing TKA, considering the similarities in the inflammatory patterns in SCI and TKA. CRP is a widely recognized inflammatory marker in clinical practice, frequently used in tandem with IL-6, which exhibits similar response patterns to surgical trauma20,50. Our study revealed significant reductions in CRP and IL-6 levels in the HBOT group compared to the control group 3 days postoperatively, a statistically significant finding. This reduction in inflammatory markers in the HBOT group correlates with improved clinical outcomes, including decreased postoperative swelling ratio, lower VAS pain scores, increased ROM, and higher HSS scores. Attributing these improvements solely to inflammation control may not be feasible, but these results highlight the potential clinical significance of managing postoperative inflammation.

Pain after surgery is an undesirable consequence, frequently hindering the patient’s ability to engage in early functional exercises crucial for rehabilitation. The analgesic potential of HBOT has been explored in various models of pain, including nociceptive, inflammatory, and neuropathic pain, indicating its possible application in diverse pain conditions51. Studies have revealed that HBOT inhibits nociceptive responses in mouse pain models, potentially through mechanisms that involve nitric oxide-dependent release of opioid peptides. This indicates a central analgesic effect of HBOT, which also involves neurexin release and µ- and κ-opioid receptor activation in the spinal cord52. Additionally, the role of HBOT in attenuating post-injury inflammatory responses and consequent inflammatory pain is noteworthy. Its efficacy in reducing inflammation and mechanical hypersensitivity in rat arthritis models has been associated with aspirin53. These results emphasize the potential of HBOT not only in alleviating postoperative inflammation but also in managing TKA-associated pain.

The widespread use of HBOT in clinical practice is not only due to its remarkable efficacy, but also closely related to its economic cost. Studies showed that HBOT can effectively reduce the length of hospitalization, improve patient satisfaction during hospitalization, and reduce the cost during hospitalization54. Furthermore, data showed that from 2013 to 2022, HBOT is not as expensive to treat as described in the literature, and its cost is actually decreasing over time55. In addition, studies stated that despite the high direct costs of HBOT treatment, it significantly reduces the incidence of other serious clinical complications56. In our study center, patients received twice (approximately $100/time) of hyperbaric oxygen therapy, which resulted in postoperative pain relief and improved mobility of the affected limbs. This shows that HBOT is a cost-effective, widely accepted, and efficacious treatment option. Additionally, our study examined the postoperative effects of HBOT in TKA, considering the potential effects of tourniquet use and NSAID use on muscle damage and inflammatory markers. However, the results of the study revealed no significant differences between the groups in this regard. Most likely because tourniquet use was evenly distributed in both groups and the type and dose of NSAIDs taken perioperatively were uniform for all participants, which also ensured the accuracy of the study. Notably, the study results revealed significant differences in both muscle damage markers and inflammatory factors at multiple postoperative time points. These differences strongly indicate that the HBOT intervention, rather than the use of a tourniquet or NSAIDs, was the primary factor affecting the observed postoperative variations between the groups.

We randomly assigned each patient to which group through opaque envelopes. During the operation, the chief surgeon did not know which patient was in the hyperbaric oxygen group or the control group. Through the contents of the envelopes, we identified which patient needed hyperbaric oxygen therapy after the operation, informed the patients of the hazards and effectiveness of hyperbaric oxygen, obtained the patients’ consent and signed the informed consent form for hyperbaric oxygen therapy. Furthermore, in the final stage of choosing hyperbaric oxygen therapy, even if the patients have been grouped, they still have the right to accept or reject hyperbaric oxygen therapy to avoid psychological discomfort of the patients affecting the recovery effect.

Our study was well-designed, but some limitations persist. First, this single-center study included a small sample size, which may affect the reliability of the results, especially in terms of complications, which will limit the application of our findings. Second, this study only assessed the effect of HBOT on muscle damage and inflammatory response in the early postoperative period after TKA due to the short hospital stay of patients. Subsequent studies with larger sample sizes and longer follow-up periods will be required to evaluate the long-term effects and potential therapeutic mechanisms of HBOT after knee arthroplasty. Third, This trial confirmed that total knee arthroplasty with the use of a tourniquet has a good therapeutic effect on the affected knee. However, it remains unclear whether the absence of a tourniquet alleviates muscle injury after total knee arthroplasty. In the future, prospective randomized symptomatic trials on the simultaneous use of hyperbaric oxygen for muscle injury after total knee arthroplasty with and without tourniquets can be conducted to confirm whether there are differences between them.However, the strengths of the study include its prospective, randomized, controlled design. The baseline characteristics of the patients were consistent across both groups, and the same team uniformly conducted all surgical procedures, adhering to established anesthetic, surgical, and perioperative care protocols. Finally, a unique aspect of our study was its focus on muscle damage, an area not extensively covered in existing literature.

Conclusion

This study indicates the effectiveness of HBOT in mitigating muscle damage and inflammation post-primary TKA with the use of a tourniquet, ultimately contributing to reduced pain, decreased knee swelling ratio, and improved knee functionality for patients.