Hyperbaric Oxygen Therapy for Chronic Venous Leg Ulcers: A Prospective Randomised Controlled Trial

ABSTRACT

Chronic venous leg ulcers (CVLUs) affect 1%–3% of adults. Standard compression therapy achieves healing in only 40%–70% of cases at 24 weeks. Evidence for hyperbaric oxygen (HBO) therapy remains controversial, with limited sham‐controlled trials. To evaluate whether adjunctive HBO improves healing of refractory CVLUs compared to standard care alone. Single‐centre, open‐label randomised trial of 80 adults with CVLUs that persisted > 3 months despite standard care (defined as < 30% area reduction after 4 weeks of compression therapy). All consecutive eligible patients were randomised to HBO (20 sessions at 2.4 ATA, 90 min) plus standard care (n = 40) or standard care alone (n = 40). Primary outcome: percentage ulcer area reduction at day 30. Blinded assessors measured wounds, though participants knew their treatment allocation. HBO group had greater area reduction (62.1% ± 22.1% vs. 41.7% ± 21.5%; mean difference 20.4%, 95% CI: 10.1–30.7, p < 0.001; Cohen's d = 0.95). Complete healing at 90 days occurred in 62.5% vs. 30.0% (NNT = 3). TcPO₂ increased from 26.1 ± 6.3 to 150.3 ± 45.6 mmHg in HBO group (p < 0.001). Pain decreased more with HBO (ΔVAS −5.0 vs. −1.5, p < 0.001). Three patients (7.5%) had mild ear barotrauma that resolved spontaneously. Main limitations were lack of sham control and 90‐day follow‐up. In this trial, adjunctive HBO was associated with faster short‐term healing of refractory venous ulcers < 20 cm². However, the open‐label design and single‐centre setting limit confidence in these findings. Sham‐controlled multicentre trials with longer follow‐up are needed before recommending routine use.

Highlights

• Hyperbaric oxygen therapy (HBO) significantly improved chronic venous leg ulcer healing compared to standard compression therapy alone.

• HBO group achieved 62.1% mean ulcer area reduction at day 30 versus 41.7% in controls (p ⟨0.001, Cohen's d = 1.12).

• Complete healing rates at 90 days were 62.5% in the HBO group versus 30% in controls (NNT = 3).

• HBO therapy demonstrated significant improvements in tissue oxygenation (TcPO2) and pain reduction.

• Treatment benefits were consistent across all predefined subgroups including patients with diabetes and large ulcers.

1. Introduction

Chronic venous leg ulcers (CVLUs) affect 1%–3% of adults, increasing to 5% in those over 80 years [1, 2]. These wounds represent 70%–80% of lower extremity ulcerations and cost healthcare systems billions annually [3, 4, 5].

CVLUs result from venous hypertension due to valvular incompetence or obstruction [6, 7]. This causes capillary distension, increased permeability, and fibrin cuff formation around vessels [8]. The resulting tissue hypoxia triggers chronic inflammation, with activated leukocytes releasing TNF‐α, IL‐1β and matrix metalloproteinases [9, 10]. This inflammatory cascade sustains tissue damage and impairs normal wound healing, leading to chronic non‐healing ulcers [11].

Standard treatment centres on compression therapy plus wound debridement, infection control, and moisture‐retentive dressings [12]. Multi‐component compression systems improve healing compared to no compression [13]. However, only 40%–70% of ulcers heal within 24 weeks despite optimal treatment [14, 15]. Recurrence exceeds 70% at 5 years [16]. Poor patient adherence to compression further limits effectiveness [17].

Recent evidence on HBO for venous ulcers shows mixed results. Bai et al. reported a pooled risk ratio of 1.89 (95% CI: 1.45–2.47) for complete healing in their meta‐analysis of 11 trials [18]. However, Thistlethwaite et al., the only sham‐controlled trial, found no significant difference in complete healing rates, although they did observe significant improvement in ulcer area reduction [19]. Keohane et al. noted significant protocol heterogeneity across studies [20].

Alternative treatments are being explored. The ESCHAR and EVRA trials showed that surgical venous correction accelerates healing [21, 22]. Elsharnoby et al. found similar healing rates between HBO and endovenous ablation, though surgery was faster [23]. However, not all patients are surgical candidates.

Hyperbaric oxygen therapy involves breathing 100% oxygen at pressures above 1.4 atm absolute (ATA). At 2.4 ATA, dissolved oxygen in plasma increases from 0.3 to approximately 6.0 mL/dL, delivering oxygen independent of haemoglobin [24]. This marked increase in tissue oxygenation helps correct the hypoxic environment typical of chronic wounds [25].

HBO protocols vary widely: 2.0–2.8 ATA, 60–120 min per session, 10–40 total sessions. This heterogeneity complicates evidence synthesis. Most previous trials included mixed wound types or didn't strictly define ‘refractory’ ulcers.

HBO may enhance wound healing through several mechanisms, including: (1) correction of tissue hypoxia, (2) stimulation of angiogenesis via VEGF, (3) enhanced fibroblast proliferation and collagen synthesis, (4) antimicrobial effects and (5) edema reduction [26, 27, 28].

This study evaluated whether adjunctive HBO using a standardised protocol (2.4 ATA, 90 min, 20 sessions) improves healing of strictly defined refractory venous ulcers compared to standard care alone. We hypothesised that HBO would accelerate healing and improve patient‐reported outcomes.

2. Methods

2.1. Study Design and Setting

Prospective, randomised, controlled, single‐centre, open‐label trial with blinded outcome assessment conducted at a tertiary university hospital from January 2022 to December 2024. The institutional ethics committee approved the protocol (Approval No. 121/2021, dated 15 December 2021). The trial followed the Declaration of Helsinki and Good Clinical Practice guidelines. All participants provided written informed consent. Reporting follows CONSORT guidelines [29].

2.2. Participants

All consecutive eligible patients presenting to our vascular surgery and wound care clinics were screened. Of 438 patients with venous ulcers assessed for eligibility, 127 met initial inclusion criteria, with 47 excluded (28 not meeting all criteria, 11 declined participation, 8 other reasons), leaving 80 patients randomised (40 per group).

2.2.1. Inclusion Criteria

Adults (≥ 18 years) with chronic venous leg ulcer (CEAP C6), venous aetiology confirmed by duplex ultrasound (reflux > 0.5 s and/or obstruction), ulcer duration ≥ 3 months, ‘refractory’ status defined as < 30% area reduction after 4 weeks of verified compression therapy (based on literature showing these ulcers have < 25% healing probability at 24 weeks [30, 31]), ulcer size 1–20 cm², ankle‐brachial index 0.8–1.3, TcPO₂ ≥ 20 mmHg at wound edge, ability to comply with protocol.

We restricted ulcer size to 1–20 cm². Larger ulcers (> 20 cm²) often have different healing dynamics and more extensive tissue damage, which would increase heterogeneity and reduce statistical power. Similar size limits were used in previous HBO trials, improving comparability.

2.2.2. Exclusion Criteria

Arterial insufficiency (ABI < 0.8), recent DVT (< 3 months), active infection requiring systemic antibiotics, osteomyelitis, malignancy, severe cardiac/pulmonary disease (EF < 35%, FEV1 < 50%), HBO contraindications, pregnancy, cognitive impairment, uncontrolled diabetes (HbA1c > 10%), concurrent trial participation.

2.3. Sample Size

Based on pilot data, we assumed a 20 percentage‐point difference in area reduction (SD 30%). With alpha 0.05% and 80% power, 36 patients per group were needed. We enrolled 40 per group allowing for a 10% dropout. Post hoc analysis showed only 60% power for 30‐day complete healing, suggesting secondary outcomes may be underpowered.

2.4. Randomisation

Computer‐generated 1:1 randomisation using permuted blocks of 4, stratified by diabetes and ulcer size (< 10 vs. ≥ 10 cm²). An independent statistician generated the sequence. Allocation was concealed in sequentially numbered, opaque envelopes opened after eligibility confirmation.

2.5. Blinding

Participants and treating physicians couldn't be blinded. While sham HBO using low pressure (1.1–1.3 ATA) has been successfully used in other trials [19], our multiplace chamber is configured for routine clinical pressures (2.0–3.0 ATA), with safety systems that don't allow stable operation at sham pressures. Technical modification was not available within our resources. This is a major limitation. To minimise bias, outcome assessors and statisticians remained blinded.

2.6. Interventions

2.6.1. Standard Care (Both Groups)

• Multi‐layer compression (Profore) providing 30–40 mmHg, changed weekly.

• Sharp debridement weekly when needed.

• Normal saline wound cleansing.

• Moisture‐retentive dressings based on exudate: hydrocolloid (DuoDERM) for low, foam (Mepilex) for moderate, alginate (Kaltostat) for high exudate, changed 2–3× weekly.

• Silver sulfadiazine only if clinical infection is present.

• Systemic antibiotics only for cellulitis.

• Patient education: leg elevation 30 min 4× daily, ankle exercises 20 reps 3× daily, nutrition counselling.

2.6.2. HBO Group

Additionally received 20 HBO sessions over 4 weeks (Monday–Friday). Protocol: compression to 2.4 ATA over 15 min, 90 min breathing 100% oxygen via hood with 5‐min air breaks at 30 and 60 min, decompression over 15 min. Total time 120 min.

2.7. Outcomes

2.7.1. Primary

Percentage ulcer area reduction at day 30: [(Initial area−Day 30 area)/Initial area] × 100. Measured by digital planimetry from standardised photographs.

2.7.2. Secondary

Complete healing (100% epithelialisation confirmed twice, 1 week apart), time to 50% healing, TcPO₂ changes, pain (VAS 0–10), quality of life (Wound‐QoL), adverse events.

2.8. Statistical Analysis

Intention‐to‐treat analysis. Missing data handled by multiple imputation. Continuous variables: mean ± SD or median (IQR), compared by t‐test or Mann–Whitney U. Categorical: frequencies (%), compared by chi‐square or Fisher's exact.

Primary outcome analysed by ANCOVA adjusting for baseline area and stratification factors. Secondary outcomes over time analysed by mixed‐effects models. Time‐to‐event by Kaplan–Meier and Cox regression. Pre‐specified subgroup analyses for diabetes, ulcer duration, size, and age. Significance p < 0.05. SPSS v28 used.

3. Results

3.1. Participant Flow and Baseline Characteristics

From 438 screened patients, 127 met initial eligibility criteria. After exclusions, 80 were randomised (40 per group). All received allocated treatment. Follow‐up: 100% at day 30, 95% at day 90 (Figure 1).

FIGURE 1.

CONSORT flow diagram showing participant recruitment, allocation, follow‐up and analysis. A total of 127 patients were assessed for eligibility, with 80 patients randomised to HBO therapy (n = 40) or standard care control (n = 40). All patients completed 30‐day follow‐up; 38 patients per group completed 90‐day follow‐up.

Groups were well‐balanced at baseline (Table 1). Mean age was 62.3 ± 8.5 years (HBO) vs. 61.8 ± 9.2 years (control). The majority were male (55% vs. 52.5%). Mean ulcer area was 12.4 ± 5.8 cm² (HBO) versus 12.1 ± 6.1 cm² (control). Mean ulcer duration was 8.5 ± 3.2 months (HBO) versus 8.2 ± 3.5 months (control). Diabetes was present in 30% versus 25% of participants. All had venous reflux on ultrasound.

TABLE 1.

Baseline demographic and clinical characteristics.

Characteristic	HBO group	Control group	p
	(n = 40)	(n = 40)
Demographics
Age, years	62.3 ± 8.5	61.8 ± 9.2	0.84
Male sex, n (%)	22 (55.0)	21 (52.5)	0.82
Body mass index, kg/m2	28.4 ± 4.2	27.9 ± 4.5	0.61
Ulcer characteristics
Ulcer duration, months	8.5 ± 3.2	8.2 ± 3.5	0.74
Ulcer area, cm2	12.4 ± 5.8	12.1 ± 6.1	0.85
Medial malleolar location, n (%)	24 (60.0)	23 (57.5)	0.82
Recurrent ulcer, n (%)	18 (45.0)	17 (42.5)	0.82
Clinical parameters
Ankle‐brachial index	0.95 ± 0.12	0.96 ± 0.11	0.78
TcPO2 baseline, mmHg	26.1 ± 6.3	25.8 ± 5.9	0.86
Pain score (VAS 0–10)	7.5 ± 1.2	7.3 ± 1.3	0.48
Comorbidities and risk factors
Diabetes mellitus, n (%)	12 (30.0)	10 (25.0)	0.62
Hypertension, n (%)	28 (70.0)	26 (65.0)	0.63
Current smoker, n (%)	8 (20.0)	9 (22.5)	0.79
Previous DVT, n (%)	15 (37.5)	14 (35.0)	0.82

Note: Data are presented as mean ± standard deviation or n (%). p‐values were calculated using independent t‐test for continuous variables and chi‐square test for categorical variables.

Abbreviations: DVT, deep vein thrombosis; HBO, hyperbaric oxygen therapy; TcPO₂, transcutaneous oxygen pressure; VAS, visual analogue scale.

3.2. Primary Outcome

At day 30, mean area reduction was 62.1% ± 22.1% (HBO) versus 41.7% ± 21.5% (control); difference 20.4% (95% CI: 10.1–30.7, p < 0.001). Large effect size (Cohen's d = 0.95). After adjustment for baseline area and stratification factors, difference remained significant (adjusted mean difference 19.8%, 95% CI: 9.6–30.0, p < 0.001) (Figure 2).

FIGURE 2.

Ulcer area reduction over time mean percentage ulcer area reduction in HBO and control groups at days 15, 30, 60 and 90. Error bars represent standard error of the mean. The shaded area indicates the treatment period (days 0–30). **p < 0.01, ***p < 0.001. Cohen's d effect sizes are shown at day 30 (primary endpoint) and day 90.

3.3. Secondary Outcomes

All secondary outcomes are summarised in Table 2.

TABLE 2.

Primary and secondary outcomes at different time points.

Outcome	HBO group	Control group	Difference	p	Cohen's d
	(n = 40)	(n = 40)	(95% CI)
Primary outcome
Ulcer area reduction, %
Day 15	42.3 ± 20.5	25.7 ± 18.3	16.6 (6.3 to 26.9)	0.002	0.84
Day 30 a	62.1 ± 22.1	41.7 ± 21.5	20.4 (10.1 to 30.7)	< 0.001	0.95
Day 60	78.4 ± 19.2	55.3 ± 23.8	23.1 (13.4 to 32.8)	< 0.001	1.06
Day 90	85.2 ± 16.8	63.7 ± 25.4	21.5 (11.8 to 31.2)	< 0.001	0.98
Secondary outcomes
TcPO2, mmHg
Baseline	26.1 ± 6.3	25.8 ± 5.9	0.3 (−2.4 to 3.0)	0.86	0.05
Day 15	150.3 ± 45.6	28.4 ± 11.2	121.9 (100.5 to 143.3)	< 0.001	2.65
Day 30	130.2 ± 38.7	29.6 ± 10.5	100.6 (82.2 to 119.0)	< 0.001	2.50
Pain score (VAS 0–10)
Baseline	7.5 ± 1.2	7.3 ± 1.3	0.2 (−0.4 to 0.8)	0.48	0.16
Day 15	4.8 ± 1.5	6.5 ± 1.4	−1.7 (−2.4 to −1.0)	< 0.001	1.17
Day 30	2.5 ± 1.2	5.8 ± 1.4	−3.3 (−4.2 to −2.4)	< 0.001	2.46
Wound‐QoL score b
Baseline	58.3 ± 12.1	57.8 ± 11.9	0.5 (−4.8 to 5.8)	0.85	0.04
Day 30	35.6 ± 10.3	45.7 ± 11.5	−10.1 (−15.7 to −4.5)	0.001	0.92
Complete healing, n (%)
Day 30	11 (27.5)	3 (7.5)	20.0 (5.2 to 34.8) c	0.02	—
Day 90	25 (62.5)	12 (30.0)	32.5 (12.6 to 52.4) c	0.003	—

Note: Data are presented as mean ± standard deviation or n (%).

Abbreviations: CI, confidence interval; HBO, hyperbaric oxygen therapy; TcPO₂, transcutaneous oxygen pressure; VAS, visual analogue scale. Bold values in indicate statistically significant differences (p〈0.05) between the HBO and control groups.

^a Primary endpoint.

^b Lower scores indicate better quality of life (range 0–85).

^c Risk difference (percentage points). p‐values were calculated using independent t‐test for continuous variables and chi‐square test or Fisher exact test for categorical variables. Number needed to treat (NNT) for complete healing at day 30 = 5 (95% CI: 3 to 20); at day 90 = 3 (95% CI: 2 to 8).

3.3.1. Complete Healing

Day 30: 11/40 (27.5%) HBO versus 3/40 (7.5%) control (RR 3.67, 95% CI: 1.10–12.20, p = 0.02; NNT = 5). Day 90: 25/40 (62.5%) HBO versus 12/40 (30.0%) control (RR 2.08, 95% CI: 1.21–3.58, p = 0.003; NNT = 3) (Figure 3).

FIGURE 3.

Kaplan–Meier curves for complete healing cumulative incidence of complete wound healing over 90 days. Shaded areas represent 95% confidence intervals. Numbers at risk shown below the graph. Hazard ratio 2.85 (95% CI: 1.62–5.01), log‐rank test p < 0.001. NNT, number needed to treat.

3.3.2. Time to 50% Healing

Median 18 days (IQR 14–24) HBO versus 32 days (IQR 26–42) control; HR 2.12 (95% CI: 1.43–3.14, p < 0.001) (Figure 4).

FIGURE 4.

Time to 50% ulcer area reduction Kaplan–Meier curves showing time to achieve 50% ulcer area reduction, a clinically meaningful healing milestone. Median time was 18 days in the HBO group versus 32 days in the control group (14‐day difference). Hazard ratio 2.12 (95% CI: 1.43–3.14), p < 0.001.

Individual patient trajectories showed consistent benefit across the HBO group (Figure 5).

FIGURE 5.

Individual patient trajectories individual healing trajectories for all 80 patients showing percentage ulcer area reduction over 90 days. Blue lines represent HBO group patients; red lines represent control group patients. Bold lines with markers indicate group means. The vertical dashed line marks the primary endpoint at day 30.

3.3.3. Tissue Oxygenation

TcPO₂ at wound edge increased dramatically in HBO group from baseline 26.1 ± 6.3 to 150.3 ± 45.6 mmHg immediately post‐HBO at day 15, with pre‐session values 78.5 ± 22.3 mmHg at day 30. Control group: minimal change (25.8 ± 5.9 to 29.6 ± 10.5 mmHg at day 30). Treatment‐time interaction highly significant (p < 0.001) (Figure 6).

FIGURE 6.

Transcutaneous oxygen pressure (TcPO₂) changes box plots showing TcPO₂ values at baseline, day 15, and day 30 in HBO and control groups. The green shaded area indicates normal TcPO₂ range (30–50 mmHg). Diamonds represent group means. HBO therapy achieved supranormal tissue oxygenation that persisted at day 30. NS, not significant, ***p < 0.001.

3.3.4. Pain

VAS scores decreased from 7.5 ± 1.2 to 2.5 ± 1.2 (Δ‐5.0) in HBO versus 7.3 ± 1.3 to 5.8 ± 1.4 (Δ‐1.5) in control, with significant treatment‐time interaction (p < 0.001) (Figure 7).

FIGURE 7.

Pain score changes mean pain scores (Visual Analogue Scale, 0–10) at baseline, day 15, and day 30. Background colours indicate pain severity categories: Green (mild, 0–3), yellow (moderate, 4–6), red (severe, 7–10). The dashed line indicates the minimal clinically important difference (MCID) threshold. Individual patient trajectories shown as faint lines. ***p < 0.001.

3.3.5. Quality of Life

Wound‐QoL scores improved from 58.3 ± 12.1 to 35.6 ± 10.3 at day 30 in HBO versus 57.8 ± 11.9 to 45.7 ± 11.5 in control (p < 0.001). Lower scores indicate better quality of life.

3.4. Subgroup Analysis

Treatment effects were consistent across all pre‐specified subgroups (Table 3) with no significant interactions: diabetes (p‐interaction = 0.72), ulcer duration < 12 versus ≥ 12 months (p = 0.45), ulcer size < 10 versus ≥ 10 cm² (p = 0.68), age < 65 versus ≥ 65 years (p = 0.81). Forest plot shows consistent benefit across subgroups (Figure 8).

TABLE 3.

Subgroup analysis of primary outcome (day 30 ulcer area reduction).

Subgroup	HBO group	Control group	Difference	p	p interaction
	Mean ± SD (%)	Mean ± SD (%)	(95% CI)
Overall (n = 80)	62.1 ± 22.1	41.7 ± 21.5	20.4 (10.1 to 30.7)	< 0.001	—
Diabetes status
With diabetes (n = 22)	65.3 ± 20.1	43.2 ± 19.8	22.1 (5.3 to 38.9)	0.01	0.72
Without diabetes (n = 58)	60.8 ± 22.8	41.2 ± 22.1	19.6 (7.8 to 31.4)	0.002
Ulcer duration
< 12 months (n = 52)	64.2 ± 21.3	45.8 ± 20.9	18.4 (6.7 to 30.1)	0.003	0.45
≥ 12 months (n = 28)	58.7 ± 23.4	35.6 ± 20.2	23.1 (6.2 to 40.0)	0.009
Ulcer size
< 10 cm2 (n = 35)	63.8 ± 20.9	43.7 ± 19.8	20.1 (6.3 to 33.9)	0.006	0.68
≥ 10 cm2 (n = 45)	59.8 ± 21.3	38.9 ± 22.7	20.9 (7.5 to 34.3)	0.003
Age
< 65 years (n = 46)	61.4 ± 22.7	40.8 ± 21.9	20.6 (7.3 to 33.9)	0.003	0.81
≥ 65 years (n = 34)	63.1 ± 21.6	42.9 ± 21.3	20.2 (5.7 to 34.7)	0.008

Note: Data are mean ± standard deviation. p‐values were calculated using independent t‐test for between‐group comparisons. p‐interaction values were calculated using ANOVA to test for heterogeneity of treatment effect across subgroups. All p‐interaction values > 0.05 indicate no significant heterogeneity, suggesting consistent treatment effect across all predefined subgroups. Number needed to treat (NNT) for the overall population at day 30 was 5 (95% CI: 3 to 20).

Abbreviations: CI, confidence interval; HBO, hyperbaric oxygen therapy. Bold values in indicate statistically significant differences (p〈0.05) between the HBO and control groups.

FIGURE 8.

Forest plot of subgroup analyses forest plot showing treatment effect (difference in percentage ulcer area reduction at day 30) across predefined subgroups. All p (interaction) values > 0.05, indicating consistent treatment benefit across subgroups including diabetes status, ulcer duration, ulcer size, age and previous DVT history.

3.5. Adherence and Adverse Events

3.5.1. Adherence Excellent

38/40 (95%) completed all 20 HBO sessions. Two patients missed 2–3 sessions due to scheduling conflicts. No discontinuation due to adverse events.

Adverse events summarised in Table 4. Mild ear barotrauma (TEED grade 1) in 3/40 (7.5%) HBO patients resolved spontaneously within 48–72 h. Transient myopia in 2/40 (5%) HBO patients resolved within 6 weeks. One patient experienced mild claustrophobia managed with anxiolytic. Superficial wound infections occurred in 2 HBO versus 4 control patients. No serious adverse events in either group.

TABLE 4.

Adverse events.

Event	HBO group	Control group	p
	(n = 40)	(n = 40)
Any adverse event, n (%)	6 (15.0)	2 (5.0)	0.26
HBO‐related events
Ear barotrauma (mild) a	3 (7.5)	0	0.24
Transient myopia b	2 (5.0)	0	0.49
Claustrophobia c	1 (2.5)	0	1.00
Wound‐related events
Wound infection (superficial) d	2 (5.0)	4 (10.0)	0.68
Contact dermatitis	1 (2.5)	2 (5.0)	1.00
Severity and outcomes
Serious adverse events	0	0	—
Events leading to hospitalisation	0	0	—
Events requiring medical intervention	2 (5.0) e	4 (10.0) e	0.68
Treatment discontinuation due to AE	0	0	—

Note: Data are n (%). p‐values calculated using Fisher exact test. Bold values in indicate statistically significant differences (p 〈 0.05) between the HBO and control groups.

Abbreviations: AE, adverse event; HBO, hyperbaric oxygen therapy.

^a All cases of ear barotrauma were TEED grade 1 (tympanic membrane injection only), resolved spontaneously within 24–48 h without treatment interruption.

^b Transient myopic shift (average −0.5 diopters), resolved within 6 weeks after treatment completion.

^c One patient experienced mild claustrophobia during initial session; successfully completed all subsequent sessions with anxiolytic premedication.

^d Superficial wound infections treated with topical antibiotics; all resolved within 7–10 days without systemic therapy.

^e Medical interventions included topical antibiotics for wound infections (n = 6) and topical corticosteroids for contact dermatitis (n = 3).

4. Discussion

In this randomised trial, adjunctive HBO was associated with faster short‐term healing of refractory venous ulcers. The 20% greater area reduction at 30 days and doubled complete healing rate at 90 days (NNT = 3) represent clinically meaningful benefits if confirmed in rigorous trials.

Our results are similar to the Bai et al. meta‐analysis, which reported pooled RR 1.89 for healing [18]. Thistlethwaite et al., using sham control, found significant improvement in ulcer area reduction but no significant difference in complete healing rates [19]. Key differences may explain our stronger findings: they used 2.0 ATA versus our 2.4 ATA; they included only refractory ulcers showing < 50% area reduction after a washout phase of best practice care; and their 1.2 ATA sham may have had some therapeutic effects. Most importantly, our lack of sham control likely inflates effect sizes.

Comparison with previous HBO trials is shown in Table 5.

TABLE 5.

Comparison with previous HBO trials for venous leg ulcers [32, 33, 34, 35].

Study	Year	Design	N	HBO protocol	Control	Primary outcome	Key results	Limitations
Current Study (Present study)	2024	Single‐centre RCT, open‐label	80	2.4 ATA, 90 min, 20 sessions	Standard care	% area reduction at 30 days	62.1% vs 41.7% (p < 0.001); RR 2.08 at 90 days	No sham control, single‐centre, 90 days follow‐up
Thistlethwaite et al.	2018	RCT, double‐blind	75	2.0 ATA, 90 min, 30 sessions	Sham HBO (1.2 ATA)	Healing at 12 weeks	42% vs. 48% (NS)	Lower pressure, sham may have effect
Bai et al. (Meta‐analysis)	2023	Systematic review	612 (11 RCTs)	Various (2.0–2.5 ATA)	Standard care or sham	Complete healing	Pooled RR 1.89 (95% CI: 1.45–2.47)	High heterogeneity (I 2 = 68%)
Elsharnoby et al.	2025	Comparative cohort	120	2.4 ATA, 90 min, 20 sessions	Endovenous ablation	Healing at 6 months	65% vs. 68% (NS); faster with surgery	Non‐randomised, selection bias
Keohane et al. (Review)	2023	Systematic review	8 studies	Various	Various	Various	Inconclusive due to heterogeneity	Protocol variation
Hammarlund and Sundberg	1994	RCT, single‐blind	16	2.5 ATA, 90 min, 30 sessions	Air at 2.5 ATA	% area reduction	89% vs. 42% at 6 weeks	Very small sample
Abidia et al.	2003	RCT, double‐blind	18	2.4 ATA, 90 min, 30 sessions	Air at 2.4 ATA	Healing at 6 weeks	5/8 vs. 1/8 healed	Small sample, refractory ulcers
Kranke et al. (Cochrane)	2015	Meta‐analysis	375 (12 RCTs)	Various	Various	Complete healing	RR 1.47 (95% CI: 0.85–2.54) for VLUs	Few high‐quality trials
Löndahl et al. (DFU reference)	2013	RCT	94	2.5 ATA, 85 min, 40 sessions	Air at 2.5 ATA	Healing at 1 year	52% vs. 29% (p = 0.03)	Diabetic ulcers, not venous
Kessler et al.	2003	RCT	28	2.5 ATA, 90 min, 15 sessions	Standard care	% area reduction	41% vs. 21% at 2 weeks	Short follow‐up

Note: Data presented as reported in original studies. The present study represents the largest single‐centre RCT specifically for refractory venous ulcers with strict inclusion criteria. Comparison reveals consistent benefit across non‐sham‐controlled trials, while the only sham‐controlled trial [19] showed no benefit, highlighting the critical importance of blinding in HBO research. Bold values in indicate statistically significant differences (p 〈 0.05) between the HBO and control groups.

Abbreviations: CI, confidence interval; DFU, diabetic foot ulcer; HBO, hyperbaric oxygen therapy; NS, not significant; RCT, randomised controlled trial; RR, relative risk; VLU, venous leg ulcer.

The large TcPO₂ increase (from 26 to 150 mmHg) confirms that the protocol effectively increased tissue oxygenation. Whether this translates to lasting benefit is unknown given our short follow‐up. The sustained elevation in pre‐session TcPO₂ (78 mmHg at day 30) suggests persistent microcirculatory improvement.

For context, the EVRA trial of early venous surgery reported similar NNT values [22]. Elsharnoby et al. found comparable healing rates between HBO and surgery, though surgery was faster [23]. This raises questions about HBO's place in treatment algorithms.

The 5‐point pain reduction exceeds the minimal clinically important difference (1.5–2 points). This may improve compression adherence, a critical factor in healing. The parallel improvement in quality‐of‐life scores suggests that clinical benefit isn't limited to ulcer area reduction.

4.1. Strengths and Limitations

4.1.1. Strengths

Rigorous randomisation, blinded outcome assessment, 95% retention, standardised protocols, intention‐to‐treat analysis, comprehensive outcomes including patient‐reported measures.

4.1.2. Limitations

First, the single‐centre design in one tertiary hospital limits generalizability. Results may not apply to community settings or other healthcare systems.

Second, lack of sham control is our most significant limitation. Effective blinding with low‐pressure sham (1.1–1.3 ATA) has been successfully implemented in previous HBO trials and comprehensively reviewed by Lansdorp et al. [36]. Our inability to implement sham likely inflates effect sizes, especially for subjective outcomes like pain. The contrasting results with Thistlethwaite et al. underscore this concern.

Third, excluding ulcers > 20 cm² limits applicability. Many venous ulcers exceed this size and may respond differently due to more extensive damage. Our results don't apply to these complex wounds.

Fourth, 90‐day follow‐up can't determine durability. With 70% recurrence at 5 years, we don't know if HBO provides lasting benefit or just accelerates initial healing.

Fifth, sample size was calculated for primary outcome only. Post hoc analysis showed only 60% power for 30‐day complete healing. Secondary outcomes may be underpowered.

Finally, we didn't perform cost‐effectiveness analysis. At €3000–5000 per course with NNT = 3, the cost per additional healed ulcer is €9000–15 000. Whether this represents value is unknown.

4.2. Clinical Implications

While results suggest HBO may help selected patients, several factors limit implementation:

• Patient selection criteria remain unclear.

• Optimal protocol is undefined.

• Long‐term benefit is unknown.

• Cost‐effectiveness wasn't evaluated.

• Access is limited to specialised centres.

4.3. Future Research

Future research should focus on:

• Sham‐controlled multicentre trials using validated protocols.

• Direct comparisons with surgical intervention.

• Biomarker development for patient selection.

• Long‐term follow‐up (≥ 12 months).

• Cost‐effectiveness analysis.

• Studies in larger ulcers and community settings.

5. Conclusions

In this randomised trial, adjunctive HBO therapy at 2.4 ATA for 20 sessions was associated with faster short‐term healing of chronic venous ulcers < 20 cm² that had failed standard compression therapy. The treatment appeared safe with meaningful improvements in pain and quality of life.

However, major limitations preclude recommending routine use. The lack of sham control, single‐centre design, exclusion of large ulcers, and short follow‐up limit confidence. The contrasting findings with the only sham‐controlled trial raise concerns about placebo effects.

HBO may be considered for selected patients with refractory venous ulcers in specialised centres, but routine implementation cannot be recommended without sham‐controlled multicentre validation, longer follow‐up, and economic evaluation. Until such evidence exists, HBO should remain investigational rather than standard care for venous ulcers.

Funding

The authors have nothing to report.

Ethics Statement

This study was approved by the Institutional Ethics Committee of the University Clinical Center of Vojvodina (Approval No. 121/2021, dated December 15, 2021). The trial was conducted in accordance with the Declaration of Helsinki (2013 revision) and Good Clinical Practice guidelines. Written informed consent was obtained from all participants prior to enrollment.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Data S1: CONSORT 2010 CHECKLIST.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.