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Clinical dermatology • Original article Hyperbaric oxygen therapy for nonhealing vasculitic ulcers S. Efrati,*† J. Bergan,* G. Fishlev,* M. Tishler,‡ A. Golik† and N. Gall* *The Institute of Hyperbaric Medicine and Wound Care Clinic, †Department of Medicine A, and Department of Medicine B, ‡Assaf Harofeh Medical Center,Zerifin, Israel (affiliated to Sackler School of Medicine, Tel Aviv University, Israel) Background. Cutaneous nonhealing ulceration is a threatening manifestation of vasculitis. Hyperbaric oxygen (HBO), frequently used as adjuvant therapy for patientswith ischaemic ulcers, exerts additional beneficial effects on the vascular inflammatoryresponse.
Aim. To evaluate the effect of HBO on vasculitis-induced nonhealing skin ulcers.
Methods. The study population comprised 35 patients aged ‡ 18 years with severe,nonhealing, vasculitis-induced ulcers that had not improved following immunosup-pressive therapy. Baseline ulcer tissue oxygenation was evaluated at room air con-centration (21% O2), at 1 atmosphere absolute (ATA) breathing 100% O2, and at 2ATA breathing 100% O2. The baseline treatment protocol consisted of a 4-week courseof 100% O2 for 90 min at 2 ATA, five times ⁄ week.
Results. The mean baseline ulcer tissue oxygenation (3.1 ± 2.4 kPa at room airconcentration), was significantly increased to 13.9 ± 11.9 kPa at 1 ATA breathing100% O2 (P < 0.001), and subsequently increased further to 59.1 ± 29.8 kPa at 2ATA breathing 100% O2 (P < 0.001). At the end of the hyperbaric therapy, 28 pa-tients (80%) demonstrated complete healing, 4 (11.4%) had partial healing and 3(8.6%) had no improvement. None of the patients had any side-effects related to theHBO therapy.
Conclusion. HBO therapy may serve as an effective safe treatment for patients withvasculitis having nonhealing skin ulcers. Further studies are needed to evaluate its roleas primary therapy for this group of patients.
an indication for systemic immunosuppressive therapy, although evidence of efficacy of the latter is based only Vasculitides are defined by the presence of leucocytes in on case reports and uncontrolled trials.2 Even though the vascular vessel wall, with reactive damage to mural vasculitis is a rare cause of nonhealing skin ulcers, its structures leading to tissue ischaemia and necrosis.
impact on comorbidity, mortality and therapy cost is Cutaneous presentation of vasculitis includes purpura, erythema, urticaria, noduli, bullae and skin infarction Hyperbaric oxygen (HBO) has been used as primary leading to ulceration. Cutaneous ulceration is usually or adjunctive therapy for a variety of medical condi- caused by vasculitis in medium to small-sized vessels.1 tions.3 Most of the benefits of HBO are explained by the Persistent or progressive ulceration due to vasculitis is simple physical relationships determining gas concen-tration, volume and pressure. By altering conditions oflocal hypoxia, HBO facilitates the wound-healing Correspondence: Dr Shai Efrati, MD, Hyperbaric Medicine and Wound Care energy-consumption processes.4 HBO has also been Clinic, Assaf Harofeh Medical Center, Zerifin, 70300, Israel.
used as an adjunct to antibiotics, debridement and revascularization in the therapy of chronic nonhealing Conflict of interest: none declared.
wounds associated with diabetes or nondiabetic vascu- Accepted for publication 7 June 2006 lar insufficiency.5 Hyperoxia has an anti-inflammatory  2006 The Author(s) Journal compilation  2006 Blackwell Publishing Ltd • Clinical and Experimental Dermatology, 32, 12–17 Hyperbaric oxygen and vasculitis ulcer • S. Efrati et al.
effect in the vascular bed.6 The aim of the current study according to the following criteria: grade 0, a pre- or was to investigate the effect of HBO therapy in patients post-ulcerative site that had healed; grade 1, superficial with vasculitis-induced nonhealing skin ulcers.
wounds through the epidermis or epidermis and dermisthat did not penetrate to tendon, capsule or bone; grade2, wounds that penetrated to tendon or capsule; and grade 3, wounds that penetrated to bone or into thejoint. Within each wound grade, the following four stages were distinguished: A, clean wounds; B, non- The study population comprised patients with vasculi- ischaemic infected wounds; C, ischaemic noninfected tis-induced severe nonhealing ulcers who were admitted wounds; and D, infected ischaemic wounds. Complete to the Institute of Hyperbaric Medicine and Wound Care healing was determined as grade 0, stage A. Partial Clinic at Assaf Harofeh Medical Center, Israel between healing was defined as improvement by at least one January 2001 and May 2005. The inclusion criteria grade and one stage. In addition to the above, wound were: histologically or serologically proven vasculitis, inflammation signs (redness, oedema, pain) were also age range ‡ 18 years and immunosuppressive treat- recorded. Ulcers were photographed before and after the ment for at least 3 months. Patients having chest HBO therapy.
pathology incompatible with pressure changes, innerear disease, or suffering from claustrophobia, were Statistical analysis excluded from the study. All patients gave writteninformed consent before starting the HBO therapy.
Statistical analysis was performed using SPSS statisticalsoftware (version 11; SPSS Inc., Chicago, IL, USA).
Parametric data were expressed as means ± standard deviations and compared by the paired sample t-test.
All participants underwent a complete physical exam- Non-parametric data were compared using the v2 test.
ination, and their medications (immunosuppressives, Differences between results yielding P values < 0.05 analgesics or antibiotics) were recorded. Baseline ulcer were considered statistically significant.
tissue oxygenation was evaluated by three measure-ments of transcutaneous O2 (TCpO2) performed using a pulse oximeter (Novametrix 840; Novametrix MedicalSystems Inc. Wallingford, Connecticut, USA). The Between January 2001 and May 2005, 41 patients with hyperbaric oxygen was given via the hyperbaric cham- vasculitis-induced severe nonhealing ulcers were re- ber at Assaf Harofeh Medical Center (Israel) and the ferred to the Institute of Hyperbaric Medicine and following protocol was applied: (i) 20 min exposure to Wound Care Clinic of Assaf Harofeh Medical Center room air oxygen concentration; (ii) 20 min exposure to (Israel). Six patients were excluded from the study: three 100% oxygen at 1 atmosphere absolute (ATA) pressure; patients did not had histolgical confirmation of vascu- and (iii) 20 min exposure to 100% oxygen at 2 ATA litis process on biopsy and did not met the diagnostic criteria of any known vasculitis disease, two had inner Baseline treatment protocol consisted of a 4-week ear disease, and one had an abnormal chest X-ray. All administration of 100% O2 for 90 min at a pressure of 2 35 patients included in the study completed the ATA, five times ⁄ week. All patients received the basal 20 protocol. None demonstrated any side-effects related to HBO treatments, following which additional treatments the hyperbaric therapy.
were added according to clinical response. Wound Baseline patient characteristics are summarized in dressings were changed according to the clinical situ- ation, but never less often than three times ⁄ week.
53.5 ± 17.8 years; 76% of the participants were women.
The most common types ⁄ causes of vasculitis werecutaneous Ulcer classification 22.8%), systemic lupus erythemathosus (7; 20%), rheu- To evaluate ulcer severity, we used the University of matoid arthritis (6; 17.1%) and inflammatory bowel Texas Wound Classification System.7 The classification disease (6; 17.1%). The mean daily prednisone dosage at uses a matrix of wound grade (depth) and wound stage (infection and ⁄ or ischaemia) to categorize wounds by 0.57 ± 0.33 mg ⁄ kg, and there were 16 patients (45.7%) severity. In brief, the wounds were graded by depth, concomitantly treated with other immunosuppressive  2006 The Author(s)Journal compilation  2006 Blackwell Publishing Ltd • Clinical and Experimental Dermatology, 32, 12–17 Hyperbaric oxygen and vasculitis ulcer • S. Efrati et al.
Table 1 Baseline patient characteristics.
Mean ± SD age (years) Males ⁄ females 9 ⁄ 26 (26 ⁄ 74%) Type of vasculitis Cutaneous leukocytoclastic vasculitis Systemic lupus erythematosus Rheumatoid arthritis Inflammatory bowel disease ranscutaneous O2 (mmHg) Mixed connective tissue disease Giant cell arteritis 100% oxygen, 1ATA 100% oxygen, 2ATA Mixed cryoglobulinaemia Concomitant diseases Figure 1 Baseline ulcer tissue oxygenation at room air concen- Diabetes mellitus tration, after 20 min exposure to 100% oxygen at 1 atmosphere absolute (1 ATA) and after 20 min exposure to 100% oxygen at 2 Chronic renal failure ATA. Note: ulcer tissue oxygenation was evaluated by transcuta- Congestive heart failure neous O2 pressure (TCpO2) measurements using a pulse oximeter.
Mean ± SD daily prednisone dose (mg ⁄ kg) *P < 0.001 when compared with any of the other two mean Concomitant immunosuppressive drug prescription† TCpO2 values.
Classification of ulcers (stage and grade)‡ Complete remission Partial remission *n¼35; †in addition to prednisone; ‡University of Texas Wound Figure 2 Clinical response to hyperbaric oxygen therapy (n ¼ 35).
drugs. The mean duration of the nonhealing ulcer from its Note: complete healing was defined as grade 0, stage A according occurrence until the start the HBO therapy was to the University of Texas Wound Classification; partial healingdefined as improvement of at least one grade and one stage.
11.8 ± 22.6 months (range 4–62).
All ulcers were moderate to severe, ranging from 1C to 3D, according to the University of Texas Wound showed partial healing. Three patients (8.6%) did not Classification, with a preponderance of class 2C (10 respond to the basal 20 HBO treatments. The results of patients, 28.6%), 2D (8; 22.9%) and 2B (7; 20%). The their clinical outcome are summarized in Fig. 2.
majority of ulcers occurred in the lower limbs (32; The examples of vasculitis ulcers before and after HBO 91%), one patient had an ulcer on the hand, and one therapy are presented in Fig. 3. Mean duration of the had an ulcer on the head at the mandibular angle.
HBO therapy was 7.08 ± 2.68 weeks (five sessions per Baseline ulcer tissue oxygenation as determined by week). At the end of the HBO therapy, there was a TCpO2 measurements was 3.1 ± 2.4 kPa at room air significant decrease in the daily prednisone dose (from concentration. It was significantly elevated in 1 ATA of 0.57 ± 0.33 to 0.22 ± 0.18 mg ⁄ kg, P ¼ 0.002).
100% O2 (13.9 ± 11.9 kPa, P < 0.001) and increased Four patients demonstrated only partial resolution of further at 2 ATA of 100% O2 (59.1 ± 29.8 kPa, the ulcer. However, by observation, despite the incom- P < 0.001). The mean changes in TCpO2 are summar- plete healing, the redness and oedema around the ulcer ized in Fig. 1.
were completely resolved. Moreover, there was signifi- At the end of the hyperbaric therapy 28 patients cant improvement in the ulcer-related pain, so that the (80%) demonstrated complete healing and 4 (11.4%) amount of painkillers used could be reduced.
 2006 The Author(s) Journal compilation  2006 Blackwell Publishing Ltd • Clinical and Experimental Dermatology, 32, 12–17 Hyperbaric oxygen and vasculitis ulcer • S. Efrati et al.
Figure 3 (a–c) Representative close-up photographs of ulcers of three patients with vasculitis-induced skin ulcers (left) at baseline and(right) at the end of the hyperbaric oxygen therapy.
One of the three patients who did not respond to the lupus erythematosus and the third had cutaneous HBO treatment had pyoderma gangrenosum due to leukocytoclastic vasculitis. Baseline characteristics of inflammatory bowel disease, the second had systemic the patients who clinically responded to HBO treatment  2006 The Author(s)Journal compilation  2006 Blackwell Publishing Ltd • Clinical and Experimental Dermatology, 32, 12–17 Hyperbaric oxygen and vasculitis ulcer • S. Efrati et al.
did not differ from those of the nonresponders. Likewise, of polymorphonuclear cells in the microcirculation of there was no significant difference between the respond- skeletal muscle,11 small bowel,12 brain,13 skin flaps14 ers and nonresponders with respect to the measure- and liver.15 Furthermore, HBO has been demonstrated ments of TCpO2 breathing room air, breathing 100% to affect polymorphonuclear–endothelial cell adhesion oxygen at 1 ATA and breathing 100% oxygen at 2 ATA via modification of CD receptors,16 thus downregulating (3.0 ± 2.5 kPa vs. 4.3 ± 3.3 kPa, 12.9 ± 11.1 kPa vs.
the functions of CD11 ⁄ 18.16 HBO has been reported to 24.9 ± 16.7 kPa and 57.3 ± 28.3 kPa vs. 75.2 ± exert beneficial effects in other inflammatory conditions, 44.2 kPa, respectively).
including experimental colitis,17 Crohn's disease,18carrageenan-induced paw oedema19 in a rat modelof systemic inflammatory response, and in a model of circulatory shock induced by intraperitoneal injection Cutaneous nonhealing ulceration is a threatening of zymosan.20 In the current study, the major process manifestation of vasculitis. The standard of medical responsible for the development of the vasculitis ulcer care includes the use of systemic immunosuppressive was inflammation in the vessel walls followed by drugs, although the evidence for this therapy is scanty.2 reactive damage of mural structures. We therefore In the present study we evaluated the effect of HBO suggest that the anti-inflammatory effect of HBO, therapy on nonhealing ulcers in 35 patients with especially in the vessel walls, could serve as an vasculitis unresponsive to immunosuppressive drugs.
additional mechanism responsible for its beneficial HBO therapy was found to be extremely effective, with outcome in the vasculitis patients.
80% of the patients experiencing complete healing and While 80% of the patients experienced complete 11% demonstrating partial healing. None of the patients healing, three patients (8.6%) did not respond to the participating in this study had any side-effects related to therapy. No significant difference of the baseline patient the HBO therapy.
characteristics or tissue oxygenation was observed HBO can be used as adjuvant therapy for patients with between the nonresponders and those having complete ischaemic ulcers.5 Using HBO, the circulating haemo- healing. Consequently, based on current knowledge we globin is fully oxygenated and the oxygen dissolves in are unable to predict who will or will not benefit from the plasma, correlating with the partial pressure of HBO therapy. Further studies are needed to elucidate oxygen. Under HBO of 2–2.5 ATA, the amount of this question.
dissolved oxygen in the plasma increases more than 10- HBO therapy is generally safe and well tolerated. Most fold, exceeding the tissue oxygen requirements.8 This side-effects are mild and reversible, although adverse primary effect of HBO generates a favourable gradient for events can occur in rare cases (reversible myopia, oxygen diffusion from functioning capillaries to ischae- symptomatic otic barotraumas, pulmonary barotrau- mic tissue sites. By altering conditions of local hypoxia, mas or pulmonary oxygen toxicity, as well as seizures HBO facilitates the wound-healing processes such as due to central nervous system oxygen toxicity).21,22 In fibroblast proliferation or angiogenesis.4 The increase in the current study, HBO treatment was found to be very tissue oxygenation, as measured by TCpO2, is the most safe. None of the vasculitis patients participating in the important predictive parameter used to identify patients current study had any side-effects related to the therapy.
who are likely to benefit from HBO therapy.9 In our The costs of the technique must be taken into consid- study there was a significant sequential increase in the eration. Marroni et al. reported that while the cost of HBO ulcer tissue oxygenation, in accordance with the is equivalent to other new treatments used for nonhealing increase in inhaled oxygen pressure. The oxygen pres- ulcers (e.g. local topic treatment of human growth factor), sure increased from 3.1 ± 2.5 kPa at room air concen- HBO therapy might prove more effective.23 Taking into tration to 59.1 ± 29.8 kPa at 2 ATA of 100% oxygen, consideration the long-term immunosuppressive therap- P < 0.001 (Fig. 1). This significant increase in tissue ies usually prescribed to subjects with vasculitis-induced oxygenation appeared to be one of the major compo- nonhealing skin ulcers, the lack of major side-effects and nents responsible for the high cure rates in our patients.
the relatively low cost of HBO make the latter extremely In addition to the physical relationships determining advantageous for this patient category.
the local gas concentration, volume and pressure, HBOhas a beneficial effect in nonischaemic ulcers.10 The effect of hyperoxia on vascular inflammatory responseshas already been studied in a considerable number of HBO treatment is an effective and safe therapy for experimental models. HBO reduces rolling and adhesion vasculitis patients suffering from nonhealing skin ulcers.
 2006 The Author(s) Journal compilation  2006 Blackwell Publishing Ltd • Clinical and Experimental Dermatology, 32, 12–17 Hyperbaric oxygen and vasculitis ulcer • S. Efrati et al.
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baric oxygen on free flaps in rats. Arch Surg 1990; 125: 2 Ryan TJ. Management issues in vasculitis. Adv Exp Med Biol 1999; 455: 327–30.
15 Chen MF, Chen HM, Ueng SW et al. Hyperbaric oxygen 3 Gill AL, Bell CN. Hyperbaric oxygen: its uses, mechanisms pretreatment attenuates hepatic reperfusion injury. Liver of action and outcomes. QJM 2004; 97: 385–95.
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