Hyperbaric oxygen therapy for the management of chronic wounds

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Introduction

Wound healing is actually a complex, precisely coor-dinated interaction between inflammatory cells and mediators, establishing significant overlap between the phases of wound healing (1). The last several decades have seen an explosion of knowledge related to normal wound healing. Healing is understood to be a sequence of hundreds of individual steps from wound formation to closure (2).

Cutaneous wound healing is divided into three major phases: (i) inflammatory phase, (ii) proliferative phase (angiogenesis, granulation, re-epithelialization) and (iii) remodeling phase (extracellular matrix remodel-ing). Chronic wounds are defined as wounds that do not follow the well-defined stepwise process of physiologic healing. Instead, they are trapped in an uncoordinated and self-sustaining phase of inflammation that impairs the restoration of anatomic and functional integrity in the normal period of time (3).

The true incidence and economic impact of chronic wounds are difficult to assess because of the wide range of causative diseases and available treatment options (4). Wound management techniques are continuously devel-oped. Strategies include treatment of the underlying pathology (e.g. optimal diabetes care with blood glucose control, vein surgery, arterial reconstruction), systemic treatment aimed at improving the local wound environ-ment (e.g. nutrition supplements, pentoxifylline, aspirin, flavonoids, thromboxane alpha-2 agonists, suledoxide and local treatment aimed at improving the wound envi-ronment (e.g. dressings, negative local pressure, pressure relieving mattresses, ultrasound, application of growth factors, skin-grafting) (5).

There are many other treatment options but, despite multiple simultaneous and sequential therapeutic approaches, chronic wounds are highly resistant to treatment and are often indolent or even slowly progressive (4).

RevIew ARtIcle

Hyperbaric oxygen therapy for the management of chronic wounds

Ferdi Öztürk1, Aylin Türel Ermertcan2, and Işıl İnanır2

1Department of Dermatology, Bursa State Hospital, Bursa, Turkey and 2Department of Dermatology, Celal Bayar University, Faculty of Medicine, Manisa, Turkey

AbstractWound healing is actually a complex, precisely coordinated interaction between inflammatory cells and mediators, establishing significant overlap between the phases of wound healing. Chronic wounds are defined as wounds that do not follow the well-defined stepwise process of physiologic healing. The true incidence and economic impact of chronic wounds are difficult to assess because of the wide range of causative diseases and available treatment options. Despite multiple simultaneous and sequential therapeutic approaches, chronic wounds are highly resistant to treatment and are often indolent or even slowly progressive. Hyperbaric oxygen therapy (HBOT) has been explored as a treatment modality for chronic wounds because of its potential to promote healing and reduce bioburden in the wound bed. Multiple potential beneficial effects for wound healing have been demonstrated in various laboratory studies and experimental animal models. In this manuscript, HBOT, its mechanism of action, adverse effects and usage in diabetic and nondiabetic chronic wounds have been reviewed.Keywords: Hyperbaric oxygen, wound healing, chronic wounds

Address for Correspondence: Prof. Dr. Aylin Türel Ermertcan, Department of Dermatology, Celal Bayar University, Faculty of Medicine, 45010, Manisa, Turkey. Tel: +905322243384. E-mail: [email protected]

(Received 21 May 2012; revised 05 June 2012; accepted 18 June 2012)

Cutaneous and Ocular Toxicology, 2013; 32(1): 72–77© 2013 Informa Healthcare USA, Inc.ISSN 1556-9527 print/ISSN 1556-9535 onlineDOI: 10.3109/15569527.2012.705407

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Hyperbaric oxygen in chronic wounds

F. Öztürk et al.

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Hyperbaric oxygen in chronic wounds 73


Hyperbaric oxygen therapy (HBOT) is useful for the treatment of infection and for the healing of chronic wounds. Hyperbaric medicine is based on the premise that the delivery of supraphysiological concentrations of oxygen to diseased tissues will result in beneficial physiological changes (6). HBOT has been explored as a treatment modality for chronic wounds because of its potential to promote healing and reduce bioburden in the wound bed. Multiple potential beneficial effects for wound healing have been demonstrated in various laboratory studies and experimental animal models. The principal benefit is HBOT’s ability to increase oxygen ten-sion in the blood stream and local tissues. HBOT exerts a bacteriostatic effect on the wound bed by increasing the generation of oxygen free radicals that damage bacterial membranes DNA strands. Raising tissue oxygenation also enhances leukocyte activity in the wound bed and improves the transport of some antimicrobial agents across the wall of the individual bacterium (7).

HBOT-induced hyperoxia enhances wound healing by increasing the growth of new capillaries, collagen synthe-sis and maturation, and fibroblast replication. HBOT also regulates microcirculation and improves the survival of compromised flaps (8).

Hyperbaric oxygen therapy

Hyperbaric oxygen therapy (HBOT) is one method of sup-plemental oxygen delivery and is used mainly for chronic wounds (9). HBOT involves the intermittent exposure of the body to 100% oxygen at a pressure greater than 1 atmosphere absolute (ATA) and its use is supported in the treatment of chronic nonhealing wounds (10).

Treatment involves increasing the pressure up to 1.5–3.0 ATA, for a time frame of between 60 and 120 min at least once a day, but sometimes there are multiple treatment periods. However, oxygen in high doses is toxic to normally perfused tissue, particularly in the brain and lungs and therefore regular HBOT sessions should not last longer than one to two hours. The period of treatment may range from less than one week to several months, the average being two to four weeks. A typical course might involve 15–30 such treatments (11).

HBOT can be administered in either a single-person or multiperson chamber. Monoplace (singleperson) chambers are pressurized with oxygen, whereas multi-place (multiperson) chambers are pressurized with air, and oxygen is provided via mask, tent, or endotracheal tube. The pressure increase in the chamber must be systematic. The first phase, compression, increases the atmospheric pressure within the chamber. This might cause the recipient to experience pressure on the ears and sinuses that may be relieved by decongestants, yawning, or the Valsalva maneuver. The second phase consists of the prescribed constant pressure followed by decompression in which the atmospheric pressure returns to normal (12).

HBOT is a US Food and Drug Administration (FDA)-approved treatment with some established indications. These include chronic, nonhealing wounds, necrotiz-ing soft tissue infections, clostridial gas gangrene, crush injuries, thermal burns, graft preparation, refractory mycoses, refractory osteomyelitis, osteoradionecrosis, intracranial abscess, blood loss anemia, carbon mon-oxide poisoning, cyanide poisoning, air embolism, and decompression sickness (9).

The beneficial effects of HBOT include intermit-tent correction of wound hypoxia, reduction of tissue edema, enhanced host immune response, improved wound metabolism, prevention of reperfusion injury, and induction of cytokine and cytokine receptors. Since tissue hypoxia is the key feature in many patients with non-healing wounds, the marked increase in tissue oxy-gen gradient from blood to ischemic tissue under hyper-baric oxygen conditions is the main mechanism whereby HBOT can improve cellular oxygenation (13).

The pO2 in chronic wounds has been measured using

invasive oxygen electrodes, and has been found to lie in the range ~0.67–2.67 kPa (compared with typical values of ~4.0–6.67 kPa in healthy tissue). This prolonged hypoxia impairs several processes involved in wound healing, including collagen synthesis and deposition, epitheli-alization, and phagocytic activity. Additionally, chronic wounds are typically colonized by numerous species of bacteria, particularly opportunistic pathogens, as the hypoxic environment allows the growth of anaerobic bacteria. Breathing HBO forces high levels of oxygen to dissolve in the patient’s plasma, which increases oxygen delivery to hypoxic wound tissue, where large intercapil-lary distances limit the diffusion of hemoglobin-bound oxygen. Oxygen dissolved in the plasma can diffuse fur-ther into the hypoxic tissue, raising wound oxygen levels from 0.67–2.67 kPa to 133.3–226.6 kPa (14).

HBOT has been shown to improve wound healing and reduce amputation rates of diabetic patients with lower extremity wounds refractory to standard manage-ment (15).

History of hyperbaric oxygen therapy

Therapeutic administration of HBO was first mentioned in 1873 when miners were treated for decompression sickness (16). In 1960, Dutch Professor Ita Boerema, a cardiac surgeon, and colleagues published a land-mark article entitled “Life without blood,” in which they described unanesthetized pigs being sustained without injury by breathing hyperbaric oxygen in the absence of circulating hemoglobin (hemoglobin 0.5%). The dem-onstration that a dramatic increase in plasma-dissolved oxygen (only possible if the body is exposed to an increased atmospheric pressure) could meet metabolic requirements explained their successful use of hyper-baric oxygen therapy during pediatric atrial septal repair before the advent of cardiac bypass. Boerema also used

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74 F. Öztürk et al.


hyperbaric oxygen therapy for necrotizing infections and ischemic leg ulcers (17).

Since the 1970s, more scientifically sound guidelines for the use of HBOT have been formulated, based on prospective randomized controlled clinical trials and well-executed basic science studies. The benefits of hyperbaric medicine were subsequently observed for split-thickness skin graft take, flap survival and salvage, acute thermal burns, necrotizing fasciitis infections, chronic wound healing including diabetic ulcers (if adequate vascular inflow is present), hypoxic wounds and radiation injuries (18).

It was not until the late twentieth century that the role of growth factors in regulating and controlling the healing process was elucidated. Despite increased understanding of the mechanisms of healing, a com-mon debilitating problem such as the diabetic foot ulcer remains unsolved (17).

Mechanism of action

To understand the role of oxygen in wound healing, it is helpful to understand the central role oxygen plays in cellular activity. One of the most significant cellular pro-cesses oxygen is involved in is oxidative phosphorylation in mitochondria. This results in adenosine triphosphate (ATP) production. Oxygen homeostasis is necessary to produce and maintain ATP levels in cells, providing energy critical for proper cellular function and protein synthesis (9).

Many chronic wounds fail to heal because of local tis-sue ischemia or ischemia-reperfusion injury. Hyperbaric oxygen is used as it is reported to be effective in increas-ing oxygen availability and enhancing healing. Oxygen availability at the tissue level is critical for wound heal-ing. It has been theorized that, during HBO therapy, cellular oxygen concentrations in the plasma and tissue increase (17). HBOT has turned out to be an effective tool to increase pO

2 values in wound tissue, and the effects of

HBOT on chronic wound healing have been described by a mathematical model (19,20).

Animal trials have documented wound healing ben-efits of HBO. The basis for its efficacy continues to be investigated and appears to be a combination of sys-temic events as well as local alterations within the wound margin. Neovascularization occurs by two processes: Regional angiogenic stimuli influence the efficiency of new blood vessel growth by local endothelial cells (termed angiogenesis) and they stimulate the recruitment and differentiation of circulating stem/progenitor cells (SPCs) to form vessels de novo in a process termed vas-culogenesis. HBO has effects on both of these processes (21). SPCs mobilization due to HBOT was demonstrated in healthy humans and in patients undergoing treatment for radiation necrosis. HBOT mobilizes SPCs by stimulat-ing parenchymal bone marrow cell nitric oxide synthase (type 3 or endothelial NOS [eNOS]). Activity of eNOS is controlled by regulatory protein–protein interactions,

protein phosphorylation, and by dynamic subcellular targeting. The synthesis and function of eNOS is often impaired in diabetes due to mechanisms linked to hyper-glycemia, insulin resistance, and augmented superoxide production by mitochondria and NADPH oxidase (15).

In addition, recent studies have suggested that reac-tive oxygen species (ROS), such as H

2O

2 and superoxide

(O2−), may have an important role in wound healing. ROS at low concentrations are thought to act as cellular messengers to stimulate key processes associated with wound healing, including cell motility, cytokine action (including PDGF signal transduction), and angiogen-esis. More specifically, it has been shown that hypoxia induces hypoxia-inducible transcription factor 1a (HIF-1a). HIF-1a is the regulated part of the transcription factor heterodimer HIF-1a/b, which complexes inside cells with another endogenous form of HIF. Together, they act as a transcription factor and enter the cell nucleus. There, under hypoxic conditions, HIF-1a binds to hypoxia response elements in gene promoter regions. HIF-1a upregulates genes involved in glucose metabo-lism, erythropoiesis, iron transport, control of vessel tone, and angiogenesis. Therefore, HIF-1a also regulates oxygen homeostasis in the wound (9).

Separate from its effect on SPCs mobilization, HBO-mediated oxidative stress at sites of neovascularization will stimulate SPCs growth factor production. This is due at least in part to augmented synthesis and stabilization of hypoxia inducible factors (HIF). Vascular endothelial growth factor (VEGF) and angiopoietin, as well as stro-mal derived factor (SDF-1) influence SPCs homing to wounds and SPCs differentiation to endothelial cells. Synthesis of VEGF has been shown to be increased in wounds by HBO, and it is the most specific growth factor for neovascularization. HBO also stimulates synthesis of basic fibroblast growth factor (bFGF) and transforming growth factor β1 by human dermal fibroblasts, angiopoi-etin-2 by human umbilical vein endothelial cells, bFGF and hepatocyte growth factor in ischemic limbs, and it upregulates platelet derived growth factor (PDGF) recep-tor in wounds (21).

Sheikh et al. (22) demonstrated increased VEGF expression in rats treated with HBOT, and Hopf et al. (23) showed a stimulation of neovascularization in hypoxic tissue after HBOT. Moreover, oxygen adminis-tration has been shown to increase VEGF mRNA levels in endothelial cells and macrophages and VEGF protein expression in wound fluids in vivo. Knighton et al. (24) reported accelerated vessel growth following supple-mental oxygen administration. The transcutaneous pO

2

in wound surrounding tissue measured during HBOT correlated directly with the improvement in wound healing of chronic wounds (11). Thus, there is a strong scientific underpinning for the efficacy of hyperbaric oxygen therapy in impaired wound healing due to pathologic inflammation/impaired inflammation (dia-betes, radiation injury, ischemia-reperfusion injury) and ischemia (17).

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contraindications and adverse effects

There are only a few absolute contraindications for HBOT. Absolute contraindications to HBO therapy include untreated pneumothorax (danger of becoming a tension pneumothorax), restrictive airway disease (air becomes trapped with decompression and can lead to alveolar rupture with the gas expansion), and concomitant che-motherapy (has associated morbidity) (12).

Relative contraindications include respiratory infec-tion (might cause sinus and middle ear barotraumas), severe asthma/chronic obstructive pulmonary disease (might cause pneumothorax), high fever (might aggra-vate the risk of oxygen toxicity), and steroid treatment (aggravates the risk for oxygen toxicity). Other relative contraindications are seizure disorders, pregnancy, not approved implanted pacemaker, history of optic neuritis, and claustrophobia (18).

Hyperbaric oxygen therapy is considered safe if the therapy does not exceed 2 h and the pressure does not exceed 3 atm. Myopia is a reversible adverse effect. Other adverse effects include otic, sinus, or pulmonary baro-traumas; neurological oxygen toxicity (seen most often with HBO therapy of 4 ATA) and claustrophobia (12). Development of nuclear cataracts has been reported with excessive treatments that exceed a total of 150–200 h, and the change does not spontaneously reverse (25).

Researches supporting HBOt in the treatment of diabetic wounds

Diabetic wounds are associated with peripheral neu-ropathy, vascular disease and impaired local immunity. Chemotaxis, phagocytosis, bacterial killing and lympho-cytic function are reduced, impairing inflammation and healing. Morbidity and mortality are high, and improved healing and limb salvage have been shown with HBOT (26). The risk for limb loss is greater for more complex lesions that require surgical intervention and hence have a higher Wagner grade. Wagner grade scale provides a framework for surgical decision making for diabetic foot ulcers. There are 5 categories: (I) superficial ulcer; (II) deep ulcer to tendon, capsule, or bone; (III) deep ulcer with abscess, osteomyelitis, or septic arthritis; (IV) gan-grene of toe, toes, forefoot, or heel; (V) generalized gan-grene, entire foot. Patients with Wagner I and II wounds are usually treated as outpatients; those with Wagner III, IV, and V wounds present for hospital admission for sur-gical debridement, parenteral antibiotics, revasculariza-tion, or amputation (27,28).

Faglia et al. conducted a prospective, randomized, controlled study (7 weeks) without blinding: 70 consecu-tively hospitalized Wagner II-IV patients were considered, 36 randomized to HBOT and 34 to control regimen. Two patients dropped out at this analysis (1 control, 1 HBOT). They contributed 59% of the patients in this analysis. There was a significantly greater increase in transcutane-ous oxygen tension following HBOT. Consistently, skin

microcirculation transcutaneous oxygen measurement (TCOM) for the HBOT cohort (discharge vs admission) increased 14 ± 11 mmHg, but increased only slightly in the non-HBOT group 5 ± 5 mmHg (p = 0.004). There was a significant reduction in amputation rate with the application of HBOT (the RR of major amputation with HBOT was 0.31, 95% CI = 0.13–0.71, p = 0.006), and het-erogeneity did not account for a significant proportion of the variability between studies (I2 = 0). This result was not sensitive to the allocation of dropouts (best case RR of amputation 0.28, 95% CI = 0.12–0.64, p = 0.002, worst case 0.41, 95% CI = 0.19–0.86, p = 0.02) (29). Abidia et al. con-ducted a prospective, randomized, controlled, double-blind study of 16 patients with diabetic food ulcer that were not infected but had reached the fascia, tendon, or joint capsule (Wagner II, n = 15; Wagner I, n = 1). Data were analyzed on an “intent to treat” basis. These wounds had been present for 6–9 months and ranged from 1 to 10 cm2 in area. These patients had mild peripheral arte-rial disease (arterial brachial index = 0.8) and were not candidates for revascularization. All patients underwent a comprehensive program of wound care. There was a significant increase in the proportion of ulcers healed following HBOT (the RR of failing to heal with sham treatment was 2.3, 95% CI = 1.1–4.7, p = 0.03). However this result was sensitive to the allocation of dropouts. Best case risk of failing to heal with sham is 3.0, 95% CI = 1.2–7.6, p = 0.02, worst case RR 2.0, 95% CI = 0.9–4.3, p = 0.08). At 1 year, the number healed for the HBOT group was 5 (62%); the control group was 0% (p = 0.027). There was no difference in major amputations between groups (n = 1 in each group), after a 1-year observation (30).

Kesser et al. conducted a prospective study of 27 patients with Wagner I–III diabetic foot ulcers. Wounds averaged 2.5 cm2 for both groups. At the end of 2 weeks of twice-daily HBOT, HBOT wounds were significantly smaller than the controls. However, within an addi-tional 2 weeks, control wounds “caught up” in terms of area reduction. At 4 weeks, the final recorded point of observation, 2 wounds in the HBOT group had healed and it was 0 in the control group. It should be noted that the observation period of 4 weeks is short relative to the 12–16 weeks expected for healing to occur. However, the good initial response of the HBOT group was consistent with excellent response to oxygen challenge on initial HBOT evaluation (31).

Oxygen tension in the area near the nonhealing wound can be measured using a polarographic electrode in an ionic solution separated from the epidermis by an oxygen-permeable membrane. Oxygen diffusing from the capillary bed beneath the electrode is reduced at the cathode to produce a measurable current correspond-ing to the oxygen concentration. Transcutaneous oxygen concentration (Tcpo2) measured in this manner provides an objective parameter that can be used with modest pre-dictive ability in the initial and subsequent evaluation of the patient (32). In a retrospective study, Fife et al. mea-sured Tcpo2 and used hyperbaric oxygen therapy only in

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those patients with periwound hypoxia. Consistent with this patient selection, there was a dose-response effect noted, with response rates diminishing as the Wagner classification increased from grade I to grade V. The over-all response rate for treated patients with Wagner grade III wounds was 77%; for Wagner grade IV, 64%; and for Wagner grade V, 30%. The healing rate for patients with Wagner grade I and II wounds was 83% (19).

Doctor et al. reported significantly fewer amputa-tions in an HBOT treated group. From the descriptions, patients primarily meet the criteria of Wagner III or IV (according to wound descriptions; Wagner grade is not explicitly stated). Patients enrolled (n = 30) had diabe-tes with foot ulcers. There were 7 major amputations in the control group, and 2 in the HBOT group (p = 0.05) (33). Although concerns with this study include unusual HBOT dosing schedule and incomplete disclosure of study details (including nondisclosure of per group, sub-ject attrition, and randomization details). These quality concerns lower strength of evidence to moderate (24). In the study by Kalani et al. 76% of patients treated with hyperbaric oxygen therapy had intact skin at the 3-year follow-up, compared with 48% of control patients. In addition, there was a 20% reduction of amputation in the treated group (34).

Zamboni et al. have examined the effect of HBOT on chronic nonhealing wounds in patients with insulin-dependent diabetes in a nonrandomized, blinded, and controlled prospective study with a sample size of 10. The control group consisted of 5 patients who were either claustrophobic or lived too far from the treatment facil-ity. All patients received standard wound care. Patients treated with HBOT showed significantly greater reduc-tions in wound size throughout the 7 weeks of the study (p = 0.05). All patients were monitored for up to 6 months following the completion of the study. Four of 5 (80%) of the control group continued to have nonhealing wounds, whereas 4 of 5 (80%) of the treatment group had sponta-neous healing of their wounds. No subject in either group underwent an amputation. Although the sample size was too small to allow generalization of the results, the study suggests that adjunctive HBOT may reduce wound size and may be efficacious in the healing of chronic foot wounds in persons with diabetes (35).

Baroni et al. conducted a prospective cohort study comparing patients with diabetes and gangrenous foot ulcers or “perforating ulcers” (interpreted to be Wagner II-IV). Twenty-eight patients were considered for HBOT: 10 refused or were not appropriate and became the “control” cohort. HBOT was effective, 16 (89%) of sub-jects in the HBOT group healed their wounds. In con-trast, for the non-HBOT group, only 1 healed (p = 0.001). Additionally, 4 wounds worsened, eventually leading to major amputations, in contrast to 2 major amputations in the HBOT group. Despite the positive effect, wounds healed faster than would be expected if there were an arterial component, and there was incomplete disclo-sure of arterial disease (36).

The numerous clinical parameters that may affect wound healing in the diabetic lower extremity ulcer make large, multicenter, prospective, randomized, controlled trials imperative to establish reliable selection criteria for use of adjunctive hyperbaric oxygen therapy (32).

HBOt in the treatment of non-diabetic wounds

• There is a moderate level of evidence that HBOT promotes healing of arterial ulcers as part of an inter-disciplinary program. Consensus on a definition of “arterial ulcer” is an essential step in advancing the evidence base.

• Calciphylactic and refractory vasculitic ulcers are unusual and particularly catastrophic. There is a moderate level of evidence that HBOT promotes wound healing. Further observational work will help clarify effect.

• There is a low to moderate level of evidence, tech-niquespecific, that HBOT promotes uncomplicated healing after ablative or reconstructive surgery, and promotes salvage of compromised flaps or grafts.

• There is a moderate level of evidence that HBOT, in combination with a comprehensive program of sur-gery and antibiotics, promotes remission of refrac-tory osteomyelitis (27).

Hyperbaric oxygen is a well-accepted adjuvant treat-ment for hypoxic wounds and is recommended by differ-ent medical societies, health organizations and healthcare agencies. Patient selection for HBOT should be executed carefully and according to accepted guidelines. HBOT should be considered in cases of hypoxic wound (due to ischemia) that demonstrate reversibility of tissue hypoxia under hyperbaric oxygen conditions (18).

HBOT appears to have benefit in the treatment of ulcers in diabetic patients, and may help to avoid the trauma of amputation. Amputation as an end point of nonhealing wound is particularly debilitating and can end careers and restrict social life and independence that mobility affords. HBOT is an adjunct to standard wound care. The use of HBOT should not preclude other treat-ment methodologies, including vascular interventions, metabolic control, off-loading techniques, and scrupu-lous ulcer care (37).

Declaration of interest

The authors declare no conflicts of interest.

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Hyperbaric oxygen therapy for the management of chronic wounds