INTRODUCTION

Chronic wounds are nonhealing wounds, recurrent wounds, or wounds with prolonged healing due to an interruption of the wound healing cycle.1 Typical chronic wounds include diabetic foot ulcers (DFUs), diabetic-ischemic lower-extremity ulcers, pressure injuries, venous leg ulcers, and other nonhealing wounds. Common causes of chronic wounds include diabetes mellitus, chronic ischemia, prolonged immobilization, peripheral vascular disease, vasculitis, chronic osteomyelitis, sickle cell disease, and skin cancer.2–4 Multiple ulcers can occur in one individual, and older adults or those with significant health problems are at risk of multiple ulcerations. In addition, chronic wounds carry an ongoing risk of decreased quality of life, gangrene, infection, sepsis, amputation, and even death.5

Current therapies, such as negative-pressure wound therapy (NPWT) and moist wound therapy, provide a limited-oxygen environment for wound tissue, which may compromise wound healing and even cause anaerobic infections.6,7 Oxygen is an essential component in cell metabolism and energy production, cell proliferation and re-epithelization, collagen synthesis and enhanced tensile strength, enhanced fibroblast activity, angiogenesis, macrophage promotion and chemotaxis, enhanced neutrophil killing capacity, antimicrobial activity, and transduction of growth factor signals.8–16 Moreover, the imbalance between a limited oxygen environment and high demand for oxygenation during tissue recovery may lead to decreased healing and limit wound repair.17,18

There are now three different types of oxygen therapy. Hyperbaric oxygen therapy (HBOT) is the oldest; it requires patients to inhale 100% pure oxygen in a pressurized chamber to achieve supersaturated oxygen levels in the bloodstream and tissues. Topical oxygen therapy is a newer treatment that treats an area around the wound directly with slightly increased pressure. Continuous diffusion of oxygen therapy is the newest treatment, which delivers pure oxygen directly to the wound through a tube under the wound dressing at a low flow rate (3-10 mL/h).

Several randomized controlled studies have demonstrated substantial benefits of these three therapies for chronic wound healing.19–21 Further, other studies have reported benefits of oxygen therapies for chronic wounds or specific ulcer types (eg, DFU).22,23 However, there is no meta-analysis reporting the effects of oxygen-based therapies on wound closure, time to heal, amputation rates, percentage of reduced ulcer size, and transcutaneous oxygen measurement (TcPO2) in patients with chronic wounds. Accordingly, this article intends to be the first meta-analysis to quantitatively analyze these variables.

METHODS

This study used the PICO (Population, Intervention, Comparison, Outcome) framework. The study population was patients with chronic wounds. For the purposes of this review, chronic wounds are those that fail to heal after a period of standard treatment prior to the intervention, including pressure injuries and venous, ischemic, or diabetic ulcers. The interventions of interest were HBOT, topical oxygen therapy, or continuous diffusion of oxygen therapy. The authors defined HBOT as the inhalation of 100% pure oxygen in a hyperbaric chamber, typically under high pressure for 90 minutes per day, three to five times per week.24 Topical oxygen therapy was defined as placing the wound in a chamber with direct exposure to 93% pure oxygen, also typically for 90 minutes per day.8 Continuous diffusion of oxygen therapy was defined as treatment provided by the TransCu O2 system (EO2 Concepts), which delivers pure oxygen on a continuous basis directly to the wound under a moist dressing.25

This analysis compared the interventions to hyperbaric air therapy, sham treatments, NPWT, or standard of care. Hyperbaric air therapy uses the same chamber as HBOT, but patients receive hyperbaric air rather than 100% oxygen.26 Similar to hyperbaric air therapy, sham treatments use the same device as topical oxygen or continuous diffusion of oxygen therapies but without oxygen.20 In NPWT, a sealed system is used to apply negative pressure to the wound tissue.27

Study outcomes included short- and long-term wound healing rates, time to heal, amputations, percentage of reduction in ulcer size, and poststudy TcPO2. Short-term wound healing included patients who healed completely in 3 months or less. Long-term wound healing included those patients who healed completely between 3 and 6 months. Wound healing time was the median healing time to complete wound closure. TcPO2 is a useful tool to assess tissue oxygenation, with higher values indicating more oxygenation and better prognosis.28

Search Strategy and Study Selection

The authors searched PubMed, EMBASE, and CENTRAL (Cochrane Central Register of Controlled Trials) from database inception to October 2022 for relevant randomized controlled trials or controlled trials using the following search strategy: ((chronic AND (wound OR ulcer)) OR (diabet* AND (foot OR feet OR mellitus OR ulcer)) OR ((venous OR leg) AND ulcer) OR ((arterial OR pressure OR ischemic) AND ulcer)) AND (((hyperbar* OR high pressure OR high tension OR topic*) AND oxygen*) OR (oxygen* AND (therapy OR treatment))).

Returned results were imported into Endnote X9 (Clarivate), where duplicates were removed. The authors screened the article titles, abstracts, and full texts in sequence, as well as the bibliographies of eligible articles for more eligible articles. Studies that met the above criteria were included for further analysis.

Data Collection

Researchers extracted the following information from the included articles: name of the first author, year of publication, chronic wound type, mean participant age, percentage of male participants, study country, sample size, description of control and intervention, short-term wound healing rate, long-term wound healing rate, wound healing time, amputation rate, percentage of reduction in ulcer size, and poststudy TcPO2. Two authors separately screened and extracted data from the included articles and compared the results. The extracted data were stored in an Excel file (Microsoft Inc).

Risk of Bias

The authors measured risk of bias using the Cochrane Collaboration Risk of Bias Tool in Review Manager 5.4.1 (RevMan), which contains seven domains: random sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attribution bias), selective reporting (reporting bias), and other bias.29 Two authors independently measured the risk of the included studies and compared the results.

Statistical Analysis

DerSimonian and Laird’s random-effects model30 was used to synthesize the overall effects and corresponding 95% CIs. For continuous outcomes such as poststudy TcPO2, the authors opted for standardized mean differences (SMDs) to eliminate the influence of different scales. In contrast, for categorical outcomes such as wound healing rate, risk ratios (RRs) were assessed. A χ2 test with I2 was used to test for heterogeneity, and P ≤ .05 was considered significant.31 For meta-analysis of 10 or more included studies, the Begg test with funnel plot was used to assess publication bias.32 Data analysis was performed using Stata 14 (StataCorp LP).

RESULTS

A total of 2,853 publications were identified (Figure 1). The relevant titles and abstracts of 2,204 records were reviewed. The authors reviewed the full text of 40 eligible publications. Three publications were removed due to duplicate trials, five were removed due to irrelevant results, and one was removed due to lack of full text access. After screening the bibliography of eligible records, 30 additional publications were identified but duplicated the included studies. In total, 31 articles were eligible for further analysis.

Figure 1.:

FLOW DIAGRAM OF META-ANALYSISAbbreviation: RCT, randomized controlled trial.

Risk of Bias

The risk of bias was assessed for 31 trials (Figure 2). One trial was not randomized, and two did not report on randomization. The remaining 28 trials described reasonable randomization methods. Sixteen trials used sealed envelopes for randomization, but the other 15 did not report a method. Seven trials used the same chamber or device as intervention, so they had a low risk of performance bias. For the other trials, it was impossible to blind participants, so these trials were at high risk of bias. Only five trials described their methods of blinding analysts. Four trials had low follow-up rates, but all others were at low risk. All studies were at low risk of selective reporting and other sources of bias.

Figure 2.:

SUMMARY OF RISK OF BIAS

Characteristics of the Included Studies

A total of 1,823 participants were included (Table). The years of publication ranged from 1984 to 2022. Twenty trials reported on patients with DFUs; two reported on patients with diabetic ischemic lower-extremity ulcers; six reported on venous leg ulcers; and one each reported on patients with pressure injury, nonhealing ulcers, and chronic traumatic wounds. The mean age of participants ranged from 42 to 73 years. The percentage of male participants ranged from 33.33% to 80.83%. Seven trials were conducted in Europe, 11 in Asia, 8 in the US, 1 in Australia, 3 in Egypt, and 1 in multiple countries. The sample sizes of the trials ranged from 11 to 146. Four studies used hyperbaric air therapy in the control group, three combined standard of care and sham, one used NPWT, and the others were standard of care. Eighteen intervention groups received HBOT; eight, topical oxygen therapy; and five, continuous diffusion of oxygen therapy.

Table. - CHARACTERISTICS OF THE INCLUDED STUDIES Author, Country, Year Wound Type Mean Participant Age, y Male Participants, % Sample Size Control Intervention Abidia et al, UK, 200326 Diabetic ischemic lower-extremity ulcer 71 50 16 Hyperbaric air therapy HBOT Altinbas and Sahsivar, Turkey, 20223 VLU 50 76.65 64 SOC Topical oxygen therapy + SOC Anirudh et al, India, 202133 DFU 58 73.68 19 SOC Topical oxygen therapy + SOC Azimian et al, Iran, 201521 Pressure injury 70 50 100 SOC Topical oxygen therapy + SOC Bajuri and Hassan, Malaysia, 201734 DFU 56 51.67 60 SOC HBOT + SOC Chen et al, China, 201723 DFU 63 55.26 38 SOC HBOT + SOC Driver et al, USA, 201320 DFU 59 70.59 17 Sham + SOC Continuous diffusion of oxygen therapy + SOC Driver et al, USA, 201735 DFU 59 74 128 SOC Continuous diffusion of oxygen therapy + SOC Elsharnoby et al, Egypt, 202236 VLU 56 78.79 33 SOC HBOT + SOC Faglia et al, Italy, 199637 DFU 63 70.59 68 SOC HBOT + SOC Fedorko et al, Canada, 201638 DFU 62 66.99 103 Hyperbaric air therapy HBOT + SOC Frykberg et al, multiple countries, 202039 DFU 63 63 73 Sham + SOC Topical oxygen therapy + SOC Hammarlund and Sundberg, Sweden, 199440 VLU — — 16 Hyperbaric air therapy HBOT He et al, China, 202141 DFU 63 58.75 80 SOC Continuous diffusion of oxygen therapy + SOC Heng et al, USA, 198442 VLU 58 — 11 SOC HBOT + SOC Kalani et al, Sweden, 200219 DFU 60 78.95 38 SOC HBOT + SOC Kaur et al, India, 201243 Nonhealing ulcer 47 83.33 30 SOC HBOT + SOC Kessler et al, France, 200344 DFU 64 70.37 27 SOC HBOT + SOC Kumar et al, India, 202045 DFU 58 72.22 54 SOC HBOT + SOC Leslie et al, USA, 198846 DFU 49 57.14 28 SOC Topical oxygen therapy + SOC Longobardi et al, Italy, 202047 VLU 72 33.33 51 SOC HBOT + SOC Ma et al, China, 201324 DFU 60 63.89 36 SOC HBOT + SOC Niederauer et al, USA, 201525 DFU 59 78.57 42 SOC Continuous diffusion of oxygen therapy + SOC Niederauer et al, USA, 20188 DFU 56 77 146 Sham + SOC Continuous diffusion of oxygen therapy + SOC Salama et al, Egypt, 201948 DFU 56 73.33 30 SOC HBOT + SOC Santema et al, the Netherlands, 201849 Diabetic ischemic lower-extremity ulcer 68 80.83 120 SOC HBOT + SOC Serena et al, USA, 202150 DLU 63 73.79 145 SOC Topical oxygen therapy + SOC Song et al, China, 202151 Chronic traumatic wounds 42 57.14 112 NPWT Topical oxygen therapy + NPWT Thistlethwaite et al, Australia, 201852 VLU 70 50 30 Hyperbaric air therapy HBOT Wadee et al, Egypt, 202153 DFU 60 — 50 SOC HBOT + SOC Wang et al, China, 202154 DFU 73 72.41 58 SOC Topical oxygen therapy + SOC

Abbreviations: DFU, diabetic foot ulcer; HBOT, hyperbaric oxygen therapy; NPWT, negative-pressure wound therapy; SOC, standard of care; VLU, venous leg ulcer.

Study Outcomes Short-term wound healing

Twenty trials reported short-term wound healing (Figure 3A). The overall pooled RR was 1.5444 and a 95% CI from 1.199 to 1.987, indicating that oxygen-based therapy improved wound healing in the short term as more patients healed completely in 3 months or less compared with their respective controls. The I2 was 34.2% with a P value of .068, indicating low heterogeneity. Figure 3B shows no publication bias, and the P value of the Begg test was 0.559 (nonsignificant).

Figure 3.:

SHORT-TERM WOUND HEALINGA, Forest plot. B, Funnel plot.Abbreviations: ES, effect size; RR, risk ratio; s.e., standard error.

 Long-term wound healing

Seven trials reported long-term wound healing (Figure 4). The overall pooled RR was 1.227 with a 95% CI from 0.976 to 1.542, suggesting that oxygen-based therapy did not improve wound healing over the long term compared with control therapies. There was no heterogeneity among the studies (I2 = 0%; P = .740).

Figure 4.:

FOREST PLOT OF LONG-TERM WOUND HEALING RATEAbbreviation: RR, risk ratio.

 Percentage of reduction in ulcer size

Nine trials reported reductions in ulcer size as a percentage (Figure 5). The overall pooled SMD was 0.999 with 95% CI from 0.439 to 1.559, suggesting that oxygen-based therapy can lead to greater reductions in ulcer size compared with the control therapies. However, the heterogeneity among studies was very high (I2 = 82.3%; P < .001).

Figure 5.:

FOREST PLOT OF PERCENTAGE OF REDUCTION IN ULCER SIZEAbbreviation: SMD, standard mean difference

 Amputations

Twelve trials reported amputation rate (Figure 6A). The overall pooled RR was 0.529 with a 95% CI from 0.325 to 0.862, suggesting that oxygen-based interventions reduced amputations compared with control therapies. Heterogeneity was moderate (I2 = 27.7%; P = .173). Figure 6B shows no publication bias, and the P value from the Begg test was .337.

Figure 6.:

AMPUTATION RATEA, Forest plot. B, Funnel plot.Abbreviations: ES, effect size; RR, risk ratio; s.e., standard error.

 Healing duration

Five trials reported time to wound healing (Figure 7). The overall pooled SMD was −0.705 with a 95% CI from −0.908 to −0.501, suggesting that oxygen-based therapy reduced the wound healing times compared with control therapies. However, heterogeneity was very high (I2 = 83.7%; P < .001).

Figure 7.:

FOREST PLOT OF WOUND HEALING TIMEAbbreviation: SMD, standard mean difference.

 Poststudy TcPO2

Five trials reported poststudy TcPO2 (Figure 8). The overall pooled SMD was 2.128 with a 95% CI from 0.978 to 3.278, suggesting that oxygen-based therapy increased poststudy TcPO2. Once again, study heterogeneity was very high (I2 = 90.5%; P < .001).

Figure 8.:

FOREST PLOT OF TcPO 2Abbreviation: SMD, standard mean difference.

DISCUSSION

This meta-analysis of 31 trials found that oxygen therapies improved traditional chronic wound healing parameters. Pooled effects showed that patients receiving oxygen-based therapy had a better chance of short-term wound healing, higher percentage reductions in the ulcer area, fewer amputations, shorter durations of healing, and higher poststudy TcPO2 than the control groups. That said, the benefits were not statistically significant for long-term healing.

This result is similar to a previous meta-analysis, which found that HBOT increased the rate of ulcer healing among patients with DFUs at 6 weeks, but the benefits were not evident after 1-year follow-up.22 This might result from incomplete outcome data (attribution bias): four of the seven included trials had very low follow-up rates. Two of them used intention-to-treat analysis, whereas the other two used per-protocol analysis, which might lower the validity of the synthesized effect. Another reason might be that the number of trials was too small for long-term effect synthesis. If more trials are conducted, and the number of trials included for long-term effect synthesis is as large as the number for short-term effect synthesis, the results may differ.

Oxygen-based therapy significantly reduced amputations, which is consistent with several previous meta-analyses on patients with DFUs.22,55

For percentage of reduction in ulcer size, duration of wound healing, and poststudy TcPO2, although the synthesized effects are statistically significant, study heterogeneity was very high. This might be due to the various time intervals at which healing was measured in the included studies, which varied from 2 to 12 weeks. The longer the measurement interval, the larger the likely reductions in ulcer size. Some trials measured wound healing during the intervention period, whereas other trials measured it in long-term follow-up. In addition, some trials measured poststudy TcPO2 just after the first therapy session, whereas the other trials measured it after all intervention sessions were complete.

Limitations

Some of the included studies have a high risk of bias because they were not randomized, which makes the present results less reliable. Second, most of included trials did not use a sham control. The lack of sham control or double blinding makes the results more prone to bias and less reliable. Some of the included trials used hyperbaric air therapy (equivalent to 50% pure oxygen) as a control therapy, but it has been demonstrated to benefit wound healing; therefore, it is not a particularly effective control.56

CONCLUSIONS

Meta-analysis indicates that oxygen-based therapy has great benefits for patients with a chronic wound as an adjunctive therapy. Future studies should focus on the burdens of the therapy for patients (including cost-benefit analysis) to enhance patient decision-making.

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