Use of Hyperbaric Oxygen Therapy in Cutaneous Injury Repair

Abstract

Background

Hyperbaric oxygen therapy uses high pressure 100 percent oxygen to increase arterial and tissue oxygen levels. Adjunctive hyperbaric oxygen has been used in the treatment of air or gas embolism, decompression sickness, crush injuries, compartment syndrome, and acute peripheral ischemia. It has also been utilized as adjunctive therapy to enhance wound healing. Some physicians, however, believe wound healing depends only on proper debridement and appropriate choice of antibiotics. Evidence concerning the efficacy of hyperbaric oxygen therapy for wound healing is inconclusive. Thus, the role of hyperbaric oxygen therapy in the repair and healing of cutaneous wounds remains controversial.

Hypothesis

Adjunctive hyperbaric oxygen therapy enhances wound repair of cutaneous injury, decreases the duration of healing, and reduces postinjury complications.

Methods

Primary peer-reviewed articles relating to the use of hyperbaric oxygen therapy on diabetic foot ulcers, thermal damages, necrotizing fasciitis, and free skin flaps, were identified and selected from the PubMed database.

Results

Hyperbaric oxygen therapy showed positive results in chronic diabetic foot ulcers, which reduced the risk of amputation. It improved sepsis control in burn patients, increased the oxygen level in compromised myocutaneous flaps but did not result in better survival of the flaps.

Conclusion

Adjunctive hyperbaric oxygen therapy can be beneficial in the treatment of chronic diabetic foot ulcers and burn injuries. Based on the current data, adjunctive therapy showed improvement in the healing rate of ulcers, post-surgery sepsis control, and post-therapy health-related quality of life.

Keywords: Hyperbaric Oxygen Therapy, Diabetic foot ulcers, Burns, Free tissue flaps, Necrotizing fasciitis, Treatment outcome, Wound healing, Wounds, and injuries.

Ultra-mini abstract

Hyperbaric oxygen therapy uses high atmospheric pressure oxygen to deliver 100 percent oxygen to the blood vessels and tissues. Studies were reviewed to analyze the physiological and therapeutic effects of hyperbaric oxygen therapy as an adjunctive treatment in the management of cutaneous wounds.

Table of Contents

Hypothesis

Methods

Results

Conclusion

Ultra-mini abstract

Introduction

Hyperbaric Oxygen Therapy

Methods

Results

Adjunctive HBOT in diabetic foot ulcer

Adjunctive HBOT in thermal injuries

Adjunctive HBOT in free flap transplantation

Adjunctive HBOT in necrotizing fasciitis

Discussion

HBOT in wounds repair

Limitation and future direction

Conclusion

References

Introduction

Hyperbaric Oxygen Therapy

Hyperbaric oxygen therapy (HBOT) applies 100% oxygen at a high pressure to increase arterial and tissue oxygen levels. Pure oxygen is delivered to the patient in a pressurized chamber. It was introduced by British physician Nathaniel Henshaw in 1622 and was primarily used in the treatment of decompression sickness due to scuba diving. It was also used to treat tuberculosis, cholera, deafness, anemia, and hemorrhage (Andrade, & Vieira Santos, 2016). In past decades, HBOT was found to improve tissue hypoxia, increase perfusion, reduce edema, down-regulate inflammatory cytokines, proliferate fibroblasts, produce collagen, enhance angiogenesis, and eradicate infections (Andrade, & Vieira Santos, 2016). Some researchers and clinicians recommend its use in diabetic foot ulcer, osteomyelitis, radiation injury, acute ischemia (arterial thrombosis, reperfusion and compromised myocutaneous flaps), carbon monoxide poisoning, soft tissue infections (necrotizing fasciitis), air embolism, occlusion of central retinal artery, and burns (Andrade, & Vieira Santos, 2016).

The mechanisms of HBOT on tissue repair and wound healing are not fully understood. Studies conducted by Boykins Jr & Baylis (2007) and Vishwanah (2011) found that by increasing the tissue-cellular diffusion gradient, the cellular oxygen level is increased, and the resulting hyperoxia is effective in enhancing collagen deposition and angiogenesis. HBOT modulates cytokine release, hastens microbial oxidative destruction by neutrophils, reduces apoptosis, and inhibits leukocyte adhesion. It also affects intravascular platelet aggregation by regulating platelet-derived growth factor (PDGF) receptor mRNA, thereby maintaining microvascular homeostasis and preventing abnormal vascular permeability after ischemia-reperfusion damage (Boykin Jr, & Baylis, 2007; Vishwanath, 2011, Zhang, & Gould, 2013).

Research by Chong, Kan, Song, Soh, and Lu (2013) found that hyperoxia inhibits the activation of intracellular adhesion molecule-1, thus preventing leukocyte adhesion, and reducing the formation of microthrombi. Therefore, it maintains the integrity of microcirculation and prevents reperfusion injury (Chong et al., 2013). Other researchers discovered that HBOT decreases expression of numerous matrix metalloproteinase (MMP) while simultaneously increasing tissue inhibitor of MMP (tissue inhibitor of metalloproteinase 2), indicating it acts through reactive oxygen species/mitogen-activated protein kinase/matrix metalloproteinase (ROS/MAPK/MMP) signaling pathway to reduce tissue damage and improve wound healing (Zhang & Gould, 2013).  Wound healing is associated with increased epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) with reduced plasma tumor necrosis factor alpha (TNF- ) and Interleukin-6 (IL-6) (Nasole et al. 2014). HBOT was found to mediate increased nitric oxide (NO) production as a major factor in promoting local tissue repair by increasing granulation tissue deposition, hastening epidermal migration, and wound closure. The significant increase in NO level in the wound after HBOT is, however, only a local and not systemic process (Boykin Jr, & Baylis, 2007). These studies suggest some potential mechanisms which HBOT acts to improve wound healing.

Numerous wounds with cutaneous damage, such as diabetic ulcers, burn injuries, and necrotizing fasciitis, are comorbid with poor healing, infections, and high mortality despite applying proper standard treatments. Researchers have been experimenting with add-on therapies in order to improve the current gold standards.

Adjunctive HBOT has been proposed in many circumstances, however, the evidence is controversial. It was hypothesized that adjunctive HBOT enhances wound repair of cutaneous injury, decreases the duration of healing, and reduces postinjury complications.

Methods

A literature search was conducted using PubMed databases with Medical Subject Headings (MeSH) terms: (“Hyperbaric Oxygenation/methods”[Mesh] OR “Hyperbaric Oxygenation/therapeutic use”[Mesh] OR “Hyperbaric Oxygenation/therapy”[Mesh]) AND (Clinical Trial[ptyp] OR Controlled Clinical Trial[ptyp] OR Randomized Controlled Trial[ptyp]) AND ((Clinical Trial[ptyp] OR Controlled Clinical Trial[ptyp] OR Randomized Controlled Trial[ptyp]) AND “humans”[MeSH Terms]). Five literature articles were obtained through the search. Six additional primary literature articles were obtained via citation tracing that met the criteria.

Inclusion criteria: Humans, contained novel research, received ethics approval from an accredited institution, received informed consent for procedures

Exclusion criteria: Review Articles, Animal studies.

Results

Articles were selected based on their focus on HBOT and a variety of cutaneous injuries. This section will present research on adjunctive HBOT in addition to the gold standard treatments with their outline protocols, procedures, and results. Studies on adjunctive HBOT in diabetic foot ulcers will be presented, followed by HBOT in thermal injuries, free flaps transplantation, and lastly in necrotizing fasciitis.

Adjunctive HBOT in diabetic foot ulcer

Löndahl, Katzman, Hammarlund, Nilsson, and Landin-Olsson (2011) conducted a randomized, double-blind, placebo-controlled HBOT in diabetic patients with chronic foot ulcers. The study included 75 individuals who completed at least 36 out of 40 scheduled HBOT/placebo sessions. Patients’ baseline transcutaneous oximetry (TcPO2), toe blood pressure (TBP) and ankle-brachial index (ABI) were measured. The ulcer healing rate was examined at the 9-month follow-up visit. The ulcers that were completely epithelialized and remained so at 12 months were considered healed. The TcPO2 levels were measured on the dorsum of the foot, two centimeters proximal to the base of the third toe, at one atmosphere absolute (ATA) and in the supine position after 20 minutes of rest. A HBOT session consisted of 5 minutes of air compression, followed by a period at 2.5 ATA with 100% oxygen for 85 minutes and 5 minutes of decompression (Löndahl, Landin-Olsson, & Katzman, 2011). Researchers did not specify the protocols for measuring the TBP and ABI. Statistical comparisons were tested with the Mann-Whitney U test. Correlations were tested with Pearson’s test and differences were analyzed with Fisher’s extract test.

Among a total of 75 patients, 38 were randomized to the HBOT group while 37 were in the placebo. There were significant correlations between TBP and ABI (r2 = 0.42, p = 0.0003, n = 68), and between basal and stimulated TcPO2 (r2 = 0.52, p < 0.000001, n = 75). No significant correlation was seen between TBP or ABI and TcPO2. In the HBOT group, basal and stimulated TcPO2 were significantly lower for patients with non-healing ulcers than those whose ulcers healed (p < 0.01). A significant increased healing frequency was seen at higher TcPO2 levels (TcPO2 / healing rate: < 25 mmHg/0%; 26-50 mmHg/50%; 51-75 mmHg/73%; and > 75 mmHg/100%). No significant relationship was observed between the TBO or ABI levels and the healing frequency (Löndahl et al., 2011).

Löndahl et al. (2011) conducted a prospective, randomized, placebo-controlled, double-blind study using the SF-36 questionnaire regarding complications and quality of life after using adjunctive HBOT for diabetic foot ulcer. The SF-36 questionnaire measures eight domains, including physical functioning, body pain, general health perception, vitality, social functioning and role limitation due to physical, emotional and mental health. Comparisons were tested with Wilcoxon’s matched pair test or Mann-Whitney U-test. Differences in frequency were analyzed with a contingency table, chi-square, or Fischer’s exact test.

Among a total of 75 patients, 38 were randomized to the HBOT group while 37 were in the placebo. Two patients died during the first year of follow-up and two patients did not fill out the SF-36 at the 12-month follow-up due to medical conditions. These four patients were excluded from the evaluation. The ulcer healing rate at the 12-month follow-up was 61% in the HBOT group and 27% in the placebo group (p = 0.009). There was a significant difference between pre- and post-treatment responses to the mental summary score (p < 0.05) and two of the eight SF-36 domains (role limitation due to physical emotional; p < 0.01) in the HBOT group. No significant improvement was seen in the placebo group. Overall, the post-treatment level for social functioning (p < 0.05) and role limitation due to physical and emotional health (p < 0.01; p < 0.05) were significantly higher in patients with healed ulcers than the non-healers (Löndahl et al., 2011).

Chen et al. (2017) conducted a prospective, randomized, open-label, controlled study on adjunctive HBOT for the healing of chronic diabetic foot ulcers (DFU). Besides the standard treatment for DFU, HBOT was provided to the intervention group five days per week for four weeks for a total of 20 sessions. The patients were placed in the hyperbaric chamber under 2.5 absolute atmospheric pressure for 120 minutes. To measure the outcomes, wounds were assessed based on the Wagner classification system from 0 (percutaneous) to 5 (amputation required). Serum erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were measured to evaluate the inflammation level. Microbiology lab techniques were used to evaluate infections. Blood flow perfusion scans were used to evaluate tissue survival rate with PeriScan PIM II Laser Doppler Perfusion Imaging. Glycated hemoglobin (HbA1C) was measured to assess glycemic control and medical outcomes were measured by SF-36. Data were collected at four stages: pre-treatment (T1), during treatment (at the 10th administration of HBOT; T2), posttreatment (at 20th administration of HBOT; T3), and at follow-up (two weeks after the last treatment; T4). Data were analyzed by SPSS software program. More specifically, categorical data were evaluated using chi-square (χ2) test, differences in measurements were evaluated using the Mann-Whitney U test and the changes between the two groups before and after the HBOT were analyzed using Kruskal-Wallis H test. The SF-36 questionnaire was analyzed using the generalized estimating equation (GEE).

Among 42 patients, 22 were randomized to the HBOT group and 20 to control group. 38 patients completed the study, with 20 in the HBOT group and 28 in the control group. There were no significant differences in baseline wound severity (χ2= 1.643, p = 0.200). Wound-healing scores differed significantly between the two groups at T3 (Z = -4.205, p = 0.038, Mann-Whitney U test). Assessments at T4 showed that three patients in the HBOT group had Wagner grade 1 wound, seven had grade 2, four received skin grafts, five healed, and one underwent amputation. In contrast, nine patients had Wagner grade 3 wounds, three had grade 2, one had grade 1, two received skin grafts, one healed, and two underwent amputation in the control group. The difference was statistically significant (χ2=15.204, p = 0.010). The Kruskal-Wallis H tests revealed a significant decrease between the SR values at T4 versus T1 in the HBOT group (Z = -3.291, p < 0.001) but no significant differences were seen in the control group (Z = -1.743, p > 0.05). The ESR levels were significantly lower in the HBOT group than the control group at T4 (Z = -4.096, p < 0.05). The CRP values were significantly lower in the HBOT group at T4 versus T1 (Z = -3.920, p < 0.05). Patients in the HBOT group had significantly lower CRP levels at T4 compared to the control group (Z = -3.480, p < 0.001). The HbA1C levels were significantly lower in the HBOT group at T4 (Z = -3.826, p < 0.001), but not in the control group. Doppler blood flow in the limb significantly increased at T2 and maintained at that level in the HBOT group (Z = -2.221, p < 0.05), while there was no significant change in blood flow seen in the control group. SF-36 showed improvement after T3 and persisted at T4. Improvement was noted on both the physical and mental component summaries in the HBOT group (F = 24.297, p < 0.001; F = 11.195, p < 0.001) compared to the control group (F = 1.661, p = 0.171; F = 2.491, p – 0.052) (Chen et al., 2017).

Adjunctive HBOT in thermal injuries

Chong et al. (2013) conducted a non-blinded, prospective randomized trial comparing adjunctive HBOT given in the first 48 hours post burn with the standard wound treatment. The HBOT was performed with two sessions completed within 22 hours of admission. Each session included a 90-minute period at 243 kPa with 100% oxygen at room temperature of 22-30C. The minimum interval between the two sessions was 120 minutes. Blood samples were collected before and after HBOT for laboratory analyses, including white blood cell (WBC) count and differential, serum interleukin (IL)- 1, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, interferon-gamma (IFN-) and TNF- . Burn depth was measured by Laser Doppler imaging before and after the HBOT. A biopsy was done for each patient at 48 hours post-burn and classified into five anatomical layers: epidermis (1), upper one-third of the dermis (2), middle third of the dermis (3), deepest third of the dermis (4), and subcutaneous fat (5). Burn artifacts (distortion of cell contour) and separation of the epidermis from the dermis (subepidermal blistering) were evaluated. Immunohistochemistry was done with anti-CD11a, anti-CD68, and anti-vascular endothelial growth factor (VEGF) antibodies. Microbiology culture and histological identification of infection were done to determine the gold standard treatments. Differences between the control and HBOT groups were compared using the Mann-Whitney U test. One-sample Student’s t-test was used to compare the burn levels against the normal physiological level. Pearson chi-square test was used to compare the incidences of positive microbiological tissue cultures.

Among a total of 17 patients, eight were randomized to the HBOT group and nine to the control group. The WBC count was significantly increased after a burn compared to the normal physiological maximum (14  5 vs. 10 x 109 L-1, p = 0.011), but there was no significant increase in neutrophils (76  12% vs. 75%, p = 0.73). No significant changes in WBC count were observed between the control and HBOT groups at either assessment times. Serum 1, IL-4, IL-6, IL-10, and IFN- levels were elevated significantly afterburn, but there were no differences between the two groups. There were no significant changes in burn depth between the first and second assessments in either the control (pre: 251 vs. post: 271 PU, p = 0.522) or the HBOT (pre: 238 vs. post: 244 PU, p = 0.949) groups. No significant differences were observed between the two groups at either assessment (pre: p = 0.475, post: p = 0.253). Fifteen patients required skin excision surgery while two did not. No significant differences were observed between the two groups through immunohistochemistry. Four patients from the control group had positive bacterial cultures while there were two in the HBOT group (Chong et al., 2013).

Chiang et al. (2017) conducted a retrospective study on adjunctive HBOT and burn wounds. Serum procalcitonin (PCT) was used as a biomarker to guide the antibacterial therapy until it reached normal levels (< 0.5 g/L). The decision to receive HBOT or not was based on the judgment of the surgeon who was responsible for the patient. The HBOT protocol includes 90 minutes of 100% oxygen at 2.5 ATA inside the chamber for five days a week except on the day of the operation or when the patient is hemodynamically unstable. Statistical analyses were done using SPSS. Chi-square test was used for treatment efficacy. However, when the expected frequency was < 1 or when 20% of expecting frequencies were  5, Fisher’s exact test was used instead.

Thirty-eight patients received adjunctive HBOT and fifteen patients received routine burn care. The HBOT and the control groups did not have a significant difference in the percentage of patients receiving tracheostomy (HBOT vs. control: 2.63% vs. 20%, p = 0.064) or hemodialysis (5.26% vs. 13.33%, p = 0.568). There was no difference in skin graft (HBOT vs. control: 25.91  3.14% vs. 22.38  6.54%, p = 0.587), skin re-graft (4.50  1.18% vs. 5.87  3.13%, p = 0.616), and number of operations (4.36  0.67 vs. 3.87  1.12 times, p = 0.710). The time spent in intense care unit (18.11  4.41 vs. 33.33  12.13 days, p = 0.318) and length of hospital stays (77.92  6.61 vs. 70.21  16.23 days, p = 0.318) did not differ significantly. The number of days required to normalize the PCT levels was significantly shorter in the HBOT group ( 83.63  6.72 vs. 136.25  23.01 days, p = 0.007). The relationship between HBOT and the time required to normalize the PCT level was examined by two-stage stepwise regression. It was shown that the time required for normalization of the PCT level significantly increased with the percentage of TBSA of skin re-graft (p < 0.001) and significantly decreased with adjunctive HBOT (p = 0.017) (Chiang et al., 2017).

Adjunctive HBOT in free flap transplantation

Vishwanath (2011) conducted a prospective randomized study on adjunctive HBOT in patients requiring free tissue transplantation. The HBOT subjected patients to 100% oxygen at 2.5 ATA for an hour for seven days. The patients were observed for any flap loss, flap edema, venous congestion, and period of postoperative recovery. However, the researcher did not specify the procedures for evaluations. The recovery was defined as complete epithelialization and cessation of all discharge.

A total of eight patients were randomized to either the adjunctive HBOT (n = 4) or the control group (n = 4). There was no significant difference in terms of flap survival as well as no significant differences observed between the two groups in regards to the duration of resolution of edema (HBOT vs. control: 2 vs. 2.5 days), venous congestion (0.25 vs. 0.5 days), and duration to postoperative recovery (8.5 days vs. 8.75 days) (Vishwanath, 2011).

Gehmert et al. (2011) conducted a prospective study on the role of adjunctive HBOT in patients requiring tissue transplantation to cover the defect of the lower limb caused by trauma. The HBOT protocol consisted of a 90-minute period with 100% oxygen at 240 kPa. Transcutaneous oxygen partial pressure (ptcO2) was measured before, at 30, 60, and 120 minutes after HBOT with Luminescence Lifetime Imaging (LLI).

The average ptcO2 value for all six patients before HBOT was 42.59  1.11 Torr. Overall ptcO2 values increased significantly after adjunctive HBOT over the entire flap area (t = 0 min, 81.14  5.9, p < 0.001; t = 30 min, 81.9  8.2, p < 0.001; t = 60 min, 87.2  11.2; t = 120 min, 83.5  13.8, p < 0.006) (Gehmert et al., 2011).

Larson et al. (2013) conducted a retrospective study on patients who underwent HBOT for failing post-reconstructive flap. Out of a total of ninety-one patients who received HBOT, 15 patients were qualified for this study. Basic information including all past medical and surgical histories, smoking status, alcohol status, indication for HBOT, and pretreatment transcutaneous oxygen measurements (TCOMs) was collected from their medical records. Management and outcome data were also collected, such as the number of treatments per day, depth pressurization, duration at full depth per treatment, treatment response and resultant complications. SPSS software was used for statistical analyses. For categorical variable comparisons, Fisher’s exact test was used while the Chi-square analysis was used when more than two categories. For continuous variable comparison, Mann-Whitney U test was used and the Pearson’s Correlation Coefficient was used for linear correlations.

All patients were treated with HBOT which contained 90 minutes 100% oxygen at 2.4 ATA, with two five-minute breaks. Treatments were once daily for 14 patients, with one patient receiving twice daily. A total of 11 patients (73.3%) responded to the treatment while four patients healed, and seven patients had shown marked improvement. Treatment demonstrated a statistically significant association with the response to HBOT. Data suggested a higher rate of treatment failure among smokers vs. non-smokers (p = 0.011). Patients who completed the treatments had a significantly higher response than those who did not complete the treatments (p = 0.022). A statistically significant relationship was seen between pretreatment TCOMs and resulting flap salvage. Higher TCOMs values indicated a larger extent of flap recovery (p = 0.05) (Larson et al., 2013).

Adjunctive HBOT in necrotizing fasciitis

George et al. (2009) analyzed clinical data retrospectively for patients with necrotizing soft tissue infection (NSTI) and its relationship with adjunctive HBOT. The HBOT protocol was 100% oxygen at three atm for 90 minutes three times in the first 24 hours, followed by twice-daily until the infection was controlled. For statistical analysis, Wilcoxon two-sample test for continuous variables and the Fisher exact test for categorical variables were used.

A total of 78 patients with complete medical records were enrolled. 30 patients were in the control group while 48 received HBOT. Only two significant differences were observed between the control and HBOT groups. First, more patients in the control group had undergone a solid organ transplant before developing NSTI (control vs. HBOT: 5 vs. 1, p = 0.03). Second, the mean admission WBC count was higher in the HBOT group (control vs. HBOT: 10.9 x 109/L vs. 15.5 x 109 /L, p = 0.01) despite the similar number of patients with leukocytosis or leukopenia (67% VS. 71%, p = 0.80). With regards to microbiology cultures, four patients developed fungal infections in the control group compared to zero patients in the HBOT group (p = 0.02). The duration of antibiotic treatments did not differ significantly between the two groups (p = 0.97). The median number of surgical debridements was high in the HBOT group (p = 0.003). There were no significant differences in outcomes [length of stay in the ICU (p = 0.95), hospital (p = 0.15), and mortality rate (p = 0.48)] between the groups. For risk analysis, patients who died were more likely to be immunosuppressed (p = 0.0038). The estimated 95% confidence interval (CI) for the odds ratio showed that immunosuppression increased the odds of death at least 2.99 times, and hypertension at least 1.14 times. The proportion of survivors treated with HBOT did not significantly differ from those receiving standard treatment (37% vs. 50%, p = 0.58) (George et al., 2009).

Hassan et al. (2010) retrospectively reviewed patients with NF to compare the outcome of adjunctive HBOT versus non-HBOT. HBOT was routine practice for NF patients in their research center. Patients were withdrawn from HBOT if they had certain medical conditions such as claustrophobia, were hemodynamically unstable, or they refused a myringotomy while suffering from an earache. The medical records were reviewed for variables including age, sex, race, etiology of NF, smoking and alcohol statuses, complications, and pre-existing medical conditions. The number of surgical debridements, length of hospital stay, days of ventilator required, and amputations required were also compared between the two groups. Statistical analyses were done using chi-square, ANOVA, and multiple variable linear regression.

Among a total of 67 patients, 29 patients received HBOT and 38 patients were treated with standard care. The two groups were statistically comparable in terms of age (p = 0.75), sex (p = 0.44), race (p = 0.31), smoking (p = 0.56) and alcohol status (p = 0.80), and NF-predisposed risk factor (p = 0.47). No significant difference between the control and HBOT groups in mortality [10 (26%) vs. 5 (17%), p = 0.37]; length of hospital stay (29.93 vs. 28.45 days, p = 0.30); mean number of ventilator-free days ( 21 vs. 22.8 days, p = 0.89); and number of amputations (6 vs. 1, p = 0.09) was observed. The mean number of surgical debridements between the control and HBOT groups (2.65  1.84 vs. 4.15  2.68, p = 0.03) was statistically significant. Further analyses showed patients who needed a ventilator, their days on the ventilator (p < 0.05), were using HBOT (p = 0.008), infected with MRSA or group A streptococcus (p = 0.038), and had associated trunk involvement (p = 0.021) were associated with increased number of surgical debridements. The control group had a significant number of Pseudomonas infection compared to the HBOT group (p < 0.01), and the overall number of infections caused by gram-negative organisms were significantly higher in the control group compared to the HBOT group (p < 0.01). However, the infections did not increase the chance of death or amputation nor the mean number of surgical debridements (Hassan et al., 2010).

Andrade and Vieira Santos (2016) conducted a cross-sectional study to determine the role of HBOT in wound care. The prevalence of health outcome or health determinants were measured. A total of 200 patients’ data were collected, containing sex, origin, profession, smoking status, associated diseases, type of wound, the indication of HBOT, number of sessions, and results. The data were analyzed by the statistical software programme SPSS.

Patients with HBOT indication were mainly suffering from venous ulcer (21%) and traumatic injury (21%), followed by diabetic foot (17%). The average amount of sessions were 29.7 sessions, a median of 30 sessions, and a standard deviation of 14.6 sessions. A significant statistical difference between the HBOT and non-HBOT groups was observed for wound healing or improvement at the end of the treatments (HBOT vs. control: 119 vs. 73, p = 0.001) (Andrade & Vieira Santos, 2016).

Discussion

This paper compiles studies on the relationships between adjunctive HBOT and wound healing, including diabetic foot ulcers, burns, free flaps transplantation for injuries, and necrotizing fasciitis.

HBOT in wounds repair

Löndahl et al. (2011) suggested that TcPO2 in contrast to ABI and TBP correlates to ulcer healing following HBOT and that HBOT is a feasible adjunctive treatment in selected patients with chronic non-healing ulcers when the basal level of TcPO2 at the dorsum of the foot is above 25 mmHg. Further studies by Löndahl et al. (2011) showed adjunctive HBOT improves mental health summary scale after diabetic foot ulcer healing. The improvements in health-related quality of life in patients with chronic ulcers after the HBOT were likely attributed to better ulcer healing. Chen et al. (2017) suggested that combined standard treatments with HBOT helped alleviate inflammation that patients suffered from non-healing diabetic foot ulcers. Specifically, the improvements were seen after 10 HBOT treatments (T2), while wounds with standard treatments began to deteriorate. The changes in ESR and serum CRP levels in patients with diabetic foot ulcer are critical for prognosis indication. The significant decrease in the ESR and serum CRP in the HBOT group suggested a reduction in inflammation and indicated better wound healing. The study showed improved HbA1c level after HBOT, however, further studies are required to determine the relationship between HBOT and glycemic control. The effect of HBOT on microorganism growth was observed at two weeks after the treatment (T4), showing less S. aureus colonies found in HBOT patients. Chen et al. (2017) hypothesized that HBOT suppressed the growth of anaerobic bacteria and possibly impaired the activation of bacterial endotoxin. The study also showed improvement in the quality of life following HBOT for the treatment of DFUs. It was concluded that HBOT promotes DFU healing by increasing oxygen dispersion to damaged tissue, alleviating inflammation, and suppressing the growth of anaerobic bacteria. In addition, it reduces the risk for amputation and improves health-related quality of life.

Chong et al. (2013) did not observe significant differences in biochemical and hematological indices and inflammatory cytokine markers between standard burn treatments and adjunctive HBOT. No significant benefit was suggested by HBOT in the study, due to the limited number of subjects resulting in low study power. However, a lower proportion of patients had a positive culture after HBOT, suggesting that HBOT might have a broad-spectrum antimicrobial action which requires further studies to determine the significance of this effect. Furthermore, Chiang et al. (2017) found no significant differences between the standard burn treatment and the adjunctive HBOT group in the percentage of TBSA of skin grafts, the percentage of TBSA of skin re-graft, and the length of hospital stay. However, a higher survival rate of skin grafts was observed in the HBOT group. Burn patients are especially susceptible to infection by antibiotic-resistant organisms due to the widespread use of antibiotics and it was shown that serum PCT level is useful for diagnosis of sepsis in burn patients. The serum PCT level was monitored and used as a guide for antibiotic treatments. Chiang et al. (2017) showed that fewer days were required for the normalization of the serum PCT level in the HBOT group. The time required to normalize the PCT levels increased with an increase in the percentage of TBSA of skin grafts and decreased with the use of HBOT. Although adjunctive HBOT improves sepsis control and shortens antibiotic treatment, PCT levels do not return to normal until most of the infection is cleared. It was concluded that along with multidisciplinary burn care, adjunctive HBOT improves sepsis and reduces the risk of antibiotic resistance in burn patients.

Vishwanath (2011) failed to establish any significant benefit to free flaps using HBOT. No benefit was found from the use of HBOT in cases of free tissue transfer in flap survival, resolution of edema, venous congestion, or period of postoperative recovery. It was suggested that HBOT is not indicated in patients undergoing free tissue transfer. Further study by Gehmert et al. (2011) demonstrated a significant increase of oxygen supply over the entire flap after HBOT. Since oxygen is an important factor for tissues, HBOT could potentially benefit the repair and maintenance of the flap through increased arterial oxygen pressure and improved microvasculature. Further valuation is needed to determine how increased skin oxygenation benefits clinically. Larson et al. (2013) demonstrated a 68.3% HBOT success rate in compromised flaps. Smoking status appeared to be significantly associated with treatment failure, suggesting that it plays a detrimental role in the outcome of HBOT for compromised flaps. It was hypothesized that smokers exhibit a lower response to HBOT due to a chronically injured endothelium from carbon monoxide, hydrogen cyanide and other toxins from smoking. Authors also indicated that baseline TCOMS value greater than or equal to 25 mmHg are more likely to benefit from HBOT than those below 25 mmHg supporting the importance of peripheral oxygenation in tissue repair. Finally, the completion of the treatment is significantly associated with the response to HBOT. However, patients who were more compliant and finished the treatment that resulted in a better outcome might not be attributed to the effect of HBOT, therefore further studies are required to fully delineate the relationship.

George et al. (2009) suggested that adjunctive HBOT to standard treatment for NSTIs did not confer a significant outcome benefit. Mortality rate, number of debridements, duration of antibiotic use, ICU length of stay, and hospital length of stay were not significantly reduced with HBOT. Furthermore, Hassan et al. (2010) did not find any significant improvements in the outcome in NF patients who underwent adjunctive HBOT compare to standard treatments. The higher number of debridements observed in the HBOT group might be contributed by more amputations in the non-HBOT group. However, no significance in outcome in terms of mortality, amputation, and length of hospital stay were observed. More gram-negative infections, especially Pseudomonas, were seen in the non-HBOT group. Although the difference was not significant, there is a trend in clinical outcomes which shows that HBOT has the potential to decrease infection and risk of amputation.

The cross-sectional study conducted by Andrade and Vieira Santos (2016) included a large number of patients with a wide range of injuries, suggesting adjunctive HBOT can be important for treating patients with chronic wounds.

Limitation and future direction

There are many limitations in the studies discussed above. One of the challenges is that the measurement of oxygen level in the tissue can be limited by factors such as electrode location, skin thickness, and ointments used. Many studies found no statistical significance in the data due to the low statistical power of the studies. The main reason for the low power is the low number of patients included in the research. Patients are excluded from HBOT due to their past medical histories such as claustrophobia or being hemodynamically unstable or other reasons that were described. Many authors suggested that if the sample size was bigger, statistically significant clinical benefits might be obtained. In addition, retrospective studies are highly dependent on the validity of the medical records so only brief correlations can be made but not used to predict relative risk. Given the nature of HBOT, getting a sufficient number of participants for the studies is a crucial factor in attaining stronger power for the study. To further examine the relationship between HBOT and wound healing, large prospective, randomized controlled trials are needed to provide significant evidence. Further studies should focus on a variety of aspects of the hyper oxygen therapy, for example, the ideal pressure and duration of the therapy for different types of wounds, the number of treatments required for observable improvement, the indication of the therapy in different injuries, and the mechanisms of HBOT on sustaining and repairing tissues.

Conclusion

Based on current evidence, adjunctive HBOT shows improvements in the treatment of chronic diabetic foot ulcer, reducing the risk for amputation of the affected limbs but requiring at least 10 sessions of HBOT to be effective. HBOT improves sepsis control in burn patients, increases the oxygen level in compromised myocutaneous flaps but does not result in better survival of the flaps. Although adjunctive HBOT showed some effects on antimicrobial function, it was not beneficial in patients with necrotizing fasciitis. Therefore, HBOT should be recommended for patients with chronic diabetic foot ulcers and patients with burn injuries for post-operation sepsis control. By improving the clinical outcomes and reducing complications, patients will also have improved health-related quality of life. Further research is needed to prove its clinical role in wounds with burns, free flaps, and necrotizing fasciitis.

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