The Efficacy of Hyperbaric Oxygen in the Treatment of Chronic Ulcers

Background: Chronic ulcers are a significant socio-economic problem and represent a major risk factor for hospitalization, amputation, sepsis and even death. The treatment of chronic ulcers is often difficult and painful. Experimental results have shown that hyperbaric oxygen therapy (HBOT) is useful to the treatment of chronic ulcers Iatrotek key words: ulcers”, “wound healing”, chronic ulcers”, ulcers”, ulcers”. Ten randomized controlled trials, one retrospective trial and one clinical trial, Nine studies involved with ulcers, in one study patients with venous ulcers, in one study patients with diabetic and venous ulcers and in one study patients with pressure ulcers. HBOT improves the healing rate of and the of the reduces the size of the and the risk of amputation in diabetic ulcers. In venous and pressure the effectiveness of HBOT minimum number of available trials. Conclusion: There is evidence that the use of HBOT can improve healing of chronic ulcers, but the available results are inadequate to prove it clearly. Any benefit from HBOT should be further examined in unbiased randomized trials.


INTRODUCTION
Chronic ulcers are classified into diabetic, vascular (venous and arterial) and pressure ulcers (bed sores) [1]. They require significant time to heal, a fact which gradually led to a better design of conventional treatments [2][3][4]. The optimal management of ulcers includes early recognition [5]. Patients are experiencing severe biopsychosocial issues, which degrade their quality of life (QOL). An improvement of QOL will be achieved by giving special attention to the interaction between the healing process and the existence of ulcers [6]. The pathophysiological relation between diabetes and delayed healing is complicated. Only two thirds are finally cured, while a 28% might be led to amputation [7]. Furthermore, the treatment of chronic wounds is a major financial burden for both patients and health system [8,9].
Many interventions have been proposed in order to accelerate the healing process. The treatment of chronic ulcers in diabetic population has been significantly improved during the last 15 years with the development of care programs and the introduction of advanced therapies [10]. One of the most promising therapies is the hyperbaric oxygen therapy (HBOT) [11] which is achieved when the person is breathing 100% O 2 with intervals, in a hyperbaric chamber where the pressure is greater than 1 atm (standard atmosphere) [2]. The partial oxygen pressure (PO 2 ) is increased at all tissues of the body, because of the increased diffusion difference of hyperbaric oxygen [12,13]. When oxygen is administered at a higher pressure than the atmospheric pressure, it is considered as a medicine with specific mechanism of action, indications, contraindications, dosage, treatment duration and adverse effects [13].
The purpose of this review was to investigate the efficacy of hyperbaric oxygen in the treatment of chronic ulcers.

METHODOLOGY
PubMed, Cinahl and Iatrotek on-line were used for the literature search, where published articles, studies and abstracts were found on the web, using keys such as: "chronic ulcers", "wound healing", "HBOT", "HBOT in chronic ulcers","venous ulcers", "diabetic ulcers" and "pressure ulcers". Moreover, a research in Health Sciences Library's magazines and books was conducted.
The review of the literature showed 65 studies concerning the use of HBOT in patients with chronic ulcers. Studies that were published during the last twenty years were included (with the exception of a study [14] which is the only one concerning the administration of HBOT in pressure ulcers). Studies in animal models and study protocols were also excluded. After the evaluation of the studies, 6 of the studies were excluded, based on the exclusion criteria (studies in animal models and study protocols), while only 12 studies met the inclusion criteria for the review (Fig. 1).
All studies referred to the application of HBOT in patients with chronic ulcers. Subsequently, nine of these studies [6, [16][17][18][19][20][21][22]24] were related to patients with diabetic ulcers, one randomized controlled trial [23] was related to patients with venous ulcers, whereas another randomized controlled trial [15] was concerned about patients with diabetic and venous ulcers. Finally, the clinical study [14] of Rosenthal et al. studied patients with chronic pressure ulcers.
The study of Kaur et al. [15] showed that HBOT increased the wound healing rate after 6 months of treatment and that three HBOT patients (out of 30) were completely healed. It was also found that the wound size was reduced by 59% in patients that underwent HBOT, while there was an increase of Transcutaneous Oxygen Tension (TcPO 2 ) or Transcutaneous oximetry (TCOM). In the following studies: RCT [6], RCT [17], RCT [18], RCT [19], RCT [20], RCT [21], RCT [22], RCT [23], there were similar results of increasing rate of wound healing and reducing wound size.

Fig. 1. Flowchart of literature review steps
Lyon included four groups of patients in her retrospective study [24] and proved that HBOT increases the healing rate, and that the use of HBOT in combination with the use of growth factors (GFs), contributes to reducing the size of the wound. Thereafter, the clinical results of Rosenthal et al. RCT [14] showed that 58% of patients treated with HBOT were completely healed, when 13% of them showed an improvement of ulcers.
The clinical results of Wang's et al. RCT [16] showed that the use of Extra corporal Shock Wave Therapy (ESWT) has been proved to be more effective than HBOT, after a 4-6 weeks period of treatment.

Errors (bias), confounding factors and restrictions
were not systematically reported in all the above studies.

DISCUSSION
According to this literature review the majority of studies regarding the use of hyperbaric oxygen (HBO) as a treatment for chronic ulcers, mostly concerned diabetic leg ulcers, one concerned venous ulcers and another one was about pressure ulcers. The clinical results of all studies were based on the rate of wound healing, the required time for the successful completion of the treatment and the decrease of the wound size after the application of HBOT. In several studies [15,17,18,19,23], data have been presented with the number of amputations performed after treatment, whereas in two studies [6,19] the patients' quality of life was evaluated, with the use of Short Form (36) Health Survey (SF-36) questionnaires. The cost-effectiveness of HBOT was examined in one study [19] and four studies [15,19,20,21] have recorded the increased TcPO 2 after HBOT administration.
The oxygen dose, the duration and the number of HBO treatments were relatively the same in all studies, although the ulcer classification, the healing time and the reduction of the wound size varies. There were recorded information on amputation (primary and secondary) in patients with diabetic ulcers in 5 studies [15,17,18,19,23], which indicated that HBOT contributed to a reduction of amputation numbers [25], in comparison with patients who were treated with either conventional treatment, or placebo.
Moreover, four studies [15,[19][20][21] showed that TcPO 2 increases in the area around the wound after an HBOT, which is indeed an advantage for its use. TcPO 2 provides an easy, reliable, noninvasive diagnostic measurement for the evaluation of tissue oxygenation and wound perfusion [26]. It can be used for the assessment of perfusion of tissue in diabetic ulcer area and for the estimation of healing probability. TcPO 2 can also be used for the selection of the level of amputation and in selecting the suitable patients for the use of HBOT as well.
Patients with diabetic foot ulcers according to Wagner classification system with Wagner grade III, IV and V (deep ulcer with abscess, osteomyelitis, joint sepsis, local gangrene or gangrene of entire foot) [27], are considered to be the most appropriate group for the application of HBO as an adjunctive therapy [25,28,29].
In two of the studies [6,19] patients completed the questionnaire (SF-36) both before treatment with hyperbaric oxygen and after a 12-month follow-up, in order to assess the mental and physical condition and their Ηealth-Related Quality of Life (HRQL). The SF-36 was comprised of eight sections, including physical functioning, general health perceptions, bodily pain, social function, vitality and the limitations which have an important role because of the physical, emotional and mental health as well.
The results of both studies showed that the use of HBOT improves the quality of life in physical functioning, as well as the psychological and social condition.
Although this review investigated research results that mainly indicated that HBOT reduces the risk of amputation and increases the rate of wound healing, several studies had different outcomes. In the study of Wang et al. [16] where clinical results of a group of patients treated with HBOT and in a group of patients that were given an ESWT treatment were compared, the use of ESWT therapy proved to be more effective than the HBOT.
A small randomized study [23] was conducted for patients with venous ulcers and showed the reduction of the wound area by using HBOT for 6 weeks, but no complete healing. This study demonstrated that HBOT efficacy in patients with venous ulcers is unreliable, since it reduces the extent of ulceration in the short term, but after 18 weeks of HBO treatment a large proportion of relapse seems to occur (31%).
A single clinical study was included [14] which demonstrated that HBOT administration to patients with pressure ulcers showed complete healing in most patients (58%). Apart from the previously mentioned study, it was not possible to find other relevant ones, while other authors [30] have identify no other trials. HBOT efficacy in patients with pressure ulcers remains unreliable and further studies must be carried out, since there are not enough studies to prove beyond scientific doubt the beneficial effects of hyperbaric oxygen on chronic pressure ulcers [30,31].
There were side effects reported in three studies [17,20,22]. In these studies, there were two cases of ear barotraumas [22] and one patient with barotraumatic otitis who was discharged from the study group [20]. In one study [17] two cases with symptoms of hypoglycaemia and an ear barotrauma incident were recorded. Furthermore, myringotomy tubes had to be inserted in four patients, because of the pain caused by the failure to equilibrate pressure in the middle ear spaces [17]. Similar treatment complications were also referred to Löndahl's review [32].
Diabetic ulcers remain a major complication of diabetes mellitus with significant importance to morbidity and mortality. The supplementary therapeutic intervention of HBO has provided significant statistic evidence of a reduction in amputations both in clinical and experimental studies of the diabetic foot, although, as suggested by many authors [30,33,34], there should have been more randomized double "blind" studies, compared to equivalent retrospective studies.

CONCLUSION
Even though there is evidence that the use of HBO can improve the healing of chronic ulcers, it is not yet widely accepted. The number of clinical studies regarding its efficacy is not large enough, resulting in a controversial application of the treatment. There are numerous clinical aspects factors that may affect the healing of chronic ulcers. Thus there is an urgent need for the creation of large, multi-centered, prospective, randomized, controlled trials based on reliable criteria for the use of HBOT.

CONSENT
It is not applicable.

ETHICAL APPROVAL
It is not applicable.