Comparative Efficacy of Four-Layer Compression Bandage Therapy With and Without Hyperbaric Oxygen Therapy in Venous Leg Ulcer Patients: A Randomized Controlled Trial

Abstract

Background

Venous leg ulcers (VLU) are a significant global health challenge, predominantly resulting from chronic venous insufficiency, requiring effective treatment to enhance healing and quality of life. This study aimed to evaluate the efficacy of hyperbaric oxygen therapy (HBOT) in conjunction with four-layer compression bandage (4LCB) therapy in VLU management.

Materials and Methods

A randomized controlled trial was conducted at a tertiary care center in northern India and included 70 patients aged >15 years with chronic venous ulcers. Patients were randomized into two groups: Group A (n = 35) received 4LCB therapy with adjunct HBOT, and Group B (n = 35) received 4LCB therapy alone. Both groups received standard medical therapy, and follow-up assessments were conducted at 2, 4, 6, and 8 weeks. The primary outcomes were reduction in ulcer size and healing time, while secondary outcomes included quality of life assessed using the EQ-5D-5L and Charing Cross questionnaires.

Results

Group A showed a significantly greater reduction in ulcer size compared with Group B (p = 0.006). Quality-of-life scores improved significantly in both groups, with Group A demonstrating better Charing Cross scores (p = 0.033). A moderate positive correlation was found between healing time and pre-therapy ulcer size in both groups.

Conclusion

VLU affects patients' lives due to pain, difficulty with locomotion, exudate, odor, and repeated hospital visits. It has been proven that multilayered compression bandages, achieving 20 to 30 mm Hg of pressure, effectively reduce venous hypertension, and lead to effective ulcer healing. HBOT has also been shown to be beneficial for VLU in retrospective single-arm studies. This randomized control trial exhibits significant ulcer size reduction and improvement in quality of life in both arms. However, the addition of HBOT to standard 4LCB therapy significantly reduces the mean post-therapy ulcer size and improves post-therapy quality of life in patients with VLU compared with 4LCB therapy alone. There is scope of further studies on the effects of various HBOT regimens on ulcer healing and the use of HBOT in combination with venous surgeries.

Keywords

chronic venous ulcers - HBOT - four-layer compression bandage - quality of life - Charing Cross score

Introduction

Hard-to-heal leg ulcers represent a serious clinical problem, adversely impacting the quality of life of patients and healthcare costs.[1] The most common etiologies of these ulcers are elevated venous pressure, turbulent flow, and inadequate venous return. To combat the elevated regional pressure, local compression is the go to therapy. A Cochrane review of 39 randomized control trials comparing different wound dressings for venous leg ulcers (VLU) concluded that compression dressings significantly speed up wound healing.[1] Compression dressings consist of a non-stick padding to protect the wound, a cotton/crepe layer for padding and absorption, an elastic compression bandage, and a cohesive, self-adherent bandage to secure the system and provide additional compression. They also found that multiple layers of compression, with one layer being elastic and achieving 20 to 30 mm Hg of pressure, effectively reduce venous hypertension, and lead to effective ulcer healing.[1] However, despite the proven efficacy of multilayer compression therapy, approximately 30% of VLUs remain still open at 6 months and 18 to 28% persist after even 1 year.[2] There is no consensus about which second- and third-line therapies are the best.

Hyperbaric oxygen therapy (HBOT) involves the administration of 100% oxygen in hyperbaric chambers (1.5–2.8 atmospheres absolute, ATA) for 60- to 120-minute per session, for a total of 15 to 30 sessions (5–6 sessions/week). Hammarlund et al and Thistlethwaite et al have showed the beneficial effect of HBOT in reducing the wound size of VLUs compared with hyperbaric air.[2] [3] Longobardi et al showed that the ulcer area reduced with HBOT.[4] Bai et al pooled the results of previous studies and published a meta-analysis showing that HBOT combined with surgery definitely reduced ulcer healing time and ulcer area.[5] But, HBOT in combination with non-surgical treatments was associated with higher ulcer percent area reduction, without a statistically significant improvement in absolute ulcer area.[5]

Thus, we planned this clinical trial to study the effect of HBOT on VLU area, with patients in one arm receiving proven multilayer compressive therapy along with conservative management (daily dressings, foot care, limb elevation, injury prevention, medications) plus HBOT, while the other arm received all interventions except HBOT.

Materials and Methods

This study was designed as a randomized controlled trial to compare the usefulness of HBOT with four-layer compression bandage therapy (4LCB) versus 4LCB in VLU patients. Ethical clearance was approved by the Institutional Ethics Committee Research Cell (XVI-PGTSC-IIA/P30). Written informed consent was taken from all participants. All patients >15 years diagnosed with VLU, in the absence of significant arterial disease (i.e., Ankle Brachial Pressure Index ≥0.8 to ≤1.3), whose ulcers did not respond to 4 weeks of conservative treatment—including antibiotics in cases of infection and supervised dressings—with a reduction in ulcer area of ≤50% were included in the study. Patients with secondary varicose veins, coagulopathy, pregnancy, immunodeficiency; severe renal and/or hepatic failure, exposed bone, tendon, or fascia, and tympanic membrane perforation were excluded. The sample size was calculated to be 35 patients in each arm. Randomization was done using computer-generated randomization charts. Allocation was done through sealed, numbered opaque envelopes to ensure concealment. The outcome assessor was blinded to reduce bias.

Ulcer size was measured using vernier calipers to determine maximum length and breadth. Both samples received standard medical therapy: oral micronized purified flavonoid fraction (1,000 mg once daily), pentoxifylline (400 mg thrice daily) and ecospirin − atorvastatin (75/10 mg once daily). In all patients, slough and necrotic tissue were surgically debrided before enrollment in the study. Daily dressings, skin care, limb elevation and injury prevention were ensured in all patients.

Patients allocated to Group A underwent an HBOT trial session at 1.5 to 2.5 ATA pressure for 15 minutes to assess tolerance. Thereafter, patients received 30 HBOT sessions (5 per week) 100% O₂ at 2.4 ATA (253.31 kPa), delivered in a sequence of three 22-minute periods, separated by 2-minute intervals of normal air. The full-fledged treatment was preceded by a 14-minute breathing period under 100% O₂ at 1.5 ATA (147.1 kPa) (compression time) and was followed by a 10-minute period under 100% O2 at 1 ATA (98.066 kPa) (decompression time). Hence, the whole session lasted around 90 minutes ([Fig. 1]). Treatment was sustained until complete ulcer healing or for 8 weeks, whichever was sooner. Final ulcer size was recorded at 8 weeks.

Fig. 1 Patient in hyperbaric oxygen chamber with 4LCB. 4LCB, four-layer compression bandage.

Group A included patients who were administered 4LCB + HBOT + all conservative management (daily dressings, foot care, limb elevation, injury prevention, medications).

Group B included patients who were administered 4LCB + all conservative management measures without HBOT (daily dressings, foot care, limb elevation, injury prevention, medications).

The primary outcome was the VLU healing. If the VLU did not heal completely, then the size at the end of the study period was noted, and the percentage reduction in size was calculated. Secondary outcomes noted were improvement in quality of life and ulcer-specific quality of life. Quality of life was assessed using the EQ-5D-5L questionnaire (minimum score is 5, maximum is 25 and higher scores indicate worse disease). The EQ-5D-5L questionnaire is a standardized instrument used to measure health-related quality of life across five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression, each with five levels of severity.[6] Ulcer-specific quality of life was assessed using the Charing Cross questionnaire (minimum score is zero, maximum score is 100 and higher scores indicate worse disease). The Charing Cross Venous Ulcer Questionnaire is a disease-specific tool designed to assess the impact of venous ulcers on quality of life, covering domains such as pain, social interaction, and daily functioning.[7]

Data were entered in Microsoft Excel and analyzed using the statistical software SPSS version 26 (SPSS Inc., Chicago, Illinois, United States). Continuous variables were evaluated as mean (standard deviation) or range, as appropriate. Dichotomous variables were presented as number and frequency and analyzed using the Chi-square. The Student's t-test was used to compare means between the two groups. A p-value of less than 0.05 was considered statistically significant. Pearson's correlation test was conducted to assess the relationship between healing time and pre-therapy ulcer size, with significance set at a 95% confidence level (p <0.05).

Results

Thirty-five patients were included in each group. The baseline characteristics of the study population indicate that the majority of participants in both groups were males aged over 60 years, with a significant proportion having a high school education or higher. The distribution of age, gender, and education levels was relatively comparable between Group A and Group B. ([Table 1]) Group A had a mean age of 48.71 ± 13.36 years, which was comparable to that of Group B (mean age 44.29 ± 14.94 years).

Table 1 Demographic and outcome characteristics

Variables		Group A (HBOT + 4LCB)	Group B (4LCB)	t-score	p-Value
Age	Mean ± SD	48.71 ± 13.36	44.29 ± 14.94	4.39	0.356
Gender	Male	94.29	97.14	0.35	0.555
	Female	5.71	2.86
Area of ulcer	Pre-therapy	25.30 ± 5.51	23.28 ± 4.68	1.66	0.102
	Post-therapy	7.22 ± 4.75	10.02 ± 3.23	−2.86	0.006
	p -Value	<0.001	<0.001
EQ- 5D-5L score	Pre-therapy	17.85 ± 5.14	17.15 ± 5.33	0.56	0.580
	Post-therapy	9.88 ± 4.26	11.06 ± 4.44	−1.10	0.274
	p -Value	<0.001	<0.001
Charring score	Pre-therapy	58.55 ± 7.64	51.71 ± 11.84	2.80	0.007
	Post-therapy	48.13 ± 8.06	42.12 ± 13.50	2.18	0.033
	p -Value	<0.001	<0.001

In both groups, a significant reduction in ulcer area was observed post-therapy, with Group A showing a greater reduction compared with Group B (p = 0.006). Healing time was comparable between the groups, with no significant difference (p = 0.441). Both groups demonstrated a statistically significant improvement in ulcer area over time (p < 0.001 for both groups) ([Table 1]; [Fig. 2]).

Fig. 2 Patient who underwent HBOT with 4LCB. Site: right lower limb lateral malleolus. (A) Pre-therapy ulcer area: 21.08 cm². (B) Post-therapy ulcer area: 7.7cm². (C) Completely healed ulcer at 8 weeks. 4LCB, four-layer compression bandage; HBOT, hyperbaric oxygen therapy.

The EQ-5D-5L scores improved significantly in both groups post-therapy, indicating an overall improvement in quality of life, though the difference between the groups was not statistically significant (p = 0.274). The Charing Cross score also showed significant improvement post-therapy compared with pre-therapy scores in both groups. In Group A, the Charing Cross score improvement was substantially more than in Group B (p = 0.033), indicating better ulcer-related quality of life in the adjunctive HBOT group ([Table 2]).

Table 2 Correlation between healing time with pre-therapy area of ulcer

Correlation of healing time with pre-therapy area of ulcer	R	p-Value
Group A (HBOT + 4LCB)	0.425	0.017
Group B (4LCB only)	0.436	0.011

Abbreviations: 4LCB, four-layer compression bandage; HBOT, hyperbaric oxygen therapy.

A moderate positive correlation was observed between healing time and pre-therapy ulcer area in both groups, with correlation coefficients of 0.425 (p = 0.017) for Group A and 0.436 (p = 0.011) for Group B. This suggests that larger ulcers tend to require longer healing times ([Table 2]).

Discussion

The socioeconomic consequences, high recurrence rates, and the widespread prevalence of VLU call for disruptive innovation in medical science.[8] The meta-analysis by O' Meara et al established beyond doubt the superiority of multilayered compression therapy in effective VLU healing.[1] Sultan and McCollum note that even after extensive research, there is no evidence to support the use of expensive dressing materials over a simple, low-cost, low-adherence dressing under multilayer compression in the management of VLU.[9]

HBOT increases the oxygen content in blood, oxygen tension, and oxygen dispersion radius, which is conducive to the entry of oxygen into the ulcer area and improves hypoxia condition. This promotes the proliferation of granulation tissue on the ulcer surface and leads to ulcer healing.[4] Diffused oxygen raises the capillary PO2 levels at the wound site and stimulates epithelialization. Also, oxygen generates reactive oxygen species at the wound site, acting as signaling substances, that increase the production of vascular endothelial growth factor. High oxygen levels are lethal to anaerobic bacteria and enhance polymorphonuclear cell function and bacterial clearance. Local neovascularization assists in the dispersion of antibiotics, such as aminoglycosides, cephalosporins, quinolones, and amphotericin.[10] All these lead to production of collagen with higher tensile strength during wound healing. This reduces scarring and the risk of recurrence.[3] Repeated treatment accelerates wound closure. HBOT can contract capillaries, reduce capillary permeability, prevent fluid infiltration, and decrease edema, thereby establishing a benign cycle between swelling reduction and improved tissue hypoxia.[11]

HBOT has demonstrated effectiveness in diabetic foot ulcers, reducing the risk of amputation. It is time for HBOT to become part of the standard care for VLU. Previous studies have suggested the beneficial effects of HBOT in VLU.[2] [3] [4] [5] [12] [13] Lalieu et al conducted a single-arm cohort study and demonstrated that wound surface area decreased significantly in all subjects of VLU subjected to HBOT and conventional treatments.[12] Aldemir and Bağlı achieved wound healing in all nine patients subjected to HBOT with compression bandage therapy.[13] Despite these favorable findings, HBOT is not routinely used in the management of VLU, as the evidence is based on retrospectively collected data or on studies involving very small patient populations. Thus, we planned our study as a randomized controlled trial with prospective treatment allocation. Further, the outcome assessor was blinded, to increase the power of our study. Our study illustrates that, although both treatments (HGOT with 4LCB with conservative management and 4LCB with conservative management) significantly reduced ulcer areas, the reduction achieved by the addition of HBOT was significantly greater.

Current HBOT protocols remain empirical. In our study HBOT was applied for 30 sessions. Lalieu et al and Aldemir and Bağlı suggest that longer treatment durations with HBOT result in better healing outcomes.[12] [13] Longobardi et al found that HBOT, when applied for longer durations but less intensively, resulted in better healing outcomes compared with shorter but more frequent sessions.[4] There is scope of further studies to standardize HBOT duration and dosing.

There is strong evidence of superior VLU healing when 4LCB is paired with venous surgery.[4] Further studies may explore the results of combining HBOT with 4LCB and venous surgery. Prudent wisdom indicates that this combination has the potential to become the gold standard treatment of VLU in the future.

VLU affects patients' lives due to pain, difficulty with locomotion, exudate, odor, and repeated hospital visits. These factors can lead to mood swings and changes in family relationships and social conviviality, thus making activities of daily living and social activities dependent on patient's physical and emotional well-being.[14] Difficulty in committing to or remaining at work, in addition to challenges in performing daily and social activities, leads to far-reaching repercussions including social isolation, lack of strength, anxiety, low self-esteem, impaired self-concept, and concerns about physical and social safety.[15] The beneficial effect of HBOT on wound area also translates to significantly better Charing Cross scores, which offers stronger validation of the intervention than wound area reduction alone.

Our study also had some limitations. The short follow-up duration of 8 weeks may not adequately capture long-term healing outcomes and recurrence rates. A study looking for long-term results will reflect the actual impact of the intervention. A larger sample size would help in analyzing the percentage of difference between the two treatment modalities. As a single center study, the results may not reflect variations in patient demographics and treatment protocols across different healthcare settings. Manual measurement of ulcer area may introduce inconsistencies. At our institute, which is a government hospital, the cost of HBOT to the patient is nil. The installation of the facility and the recurring cost of running the facility is borne by government funding. Patients seeking equivalent services at private or non-government facilities may face significant financial burdens. This underlines the need for studies to analyze the cost-benefit ratio of these interventions.

Conclusion

VLU affects patients' lives in many visible and invisible ways. It has been proven that multilayered compression bandages, achieving 20 to 30 mm Hg of pressure, effectively reduce venous hypertension, and promote ulcer healing. HBOT has also been shown to be beneficial for VLU in retrospective single-arm studies. This randomized control trial provides irrefutable evidence that the addition of HBOT to standard 4LCB therapy significantly reduces mean post-therapy ulcer size and improves post-therapy quality of life in patients with VLU as compared with 4LCB therapy alone, even though there is significant ulcer size reduction and improvement in quality of life in both arms. There is scope for further studies to evaluate the effects of various HBOT regimens on ulcer healing and to assess HBOT in combination with venous surgery.

Conflict of Interest

None declared.

Ethical Approval

The study was reviewed and approved by the Institutional Ethics Committee, King George's Medical University, Lucknow, India.

Patients' Consent

Informed consent was obtained from all the participants of the study.

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Publication History

Article published online:
15 February 2026