Hyperbaric oxygen in the treatment of calciphylaxis: a case series
Tiina Podymow1,
Chris Wherrett2 and
Kevin D. Burns1,
1 Division of Nephrology, Department of Medicine, Kidney Research Centre, Ottawa Health Research Institute and
2 Department of Anesthesiology, Ottawa Hospital, University of Ottawa, Ottawa, Ontario, Canada
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Abstract
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Background. Calciphylaxis, also referred to as calcific uraemic arteriolopathy, is a syndrome associated with end-stage renal disease (ESRD), and causes necrotic skin ulcers, often leading to a fatal outcome. Hyperbaric oxygen (HBO2) therapy has been used to enhance wound healing, but its role in the treatment of calciphylaxis is unclear.
Methods. We undertook a retrospective study of patients on renal replacement therapy with biopsy-proven calciphylaxis who were treated with HBO2 between March 1997 and February 2000.
Results. Five patients were treated with HBO2: three patients were on continuous ambulatory peritoneal dialysis (CAPD) and two were on chronic haemodialysis therapy. None of the patients had uncontrolled hyperparathyroidism and none underwent parathyroidectomy. The patients each received 2535 treatments of HBO2 at 2.5 atmospheres for 90 min per treatment. Two of these patients had complete resolution of extensive necrotic skin ulcers, with no adverse effects of HBO2 therapy. Both had improvement in wound area transcutaneous oxygen pressure (PtcO2) with administration of 100% oxygen when measurements were taken at normobaric and hyperbaric pressures. In the other three patients receiving HBO2, the skin lesions did not resolve. PtcO2 was measured in two of these patients, neither of whom showed improvement with 100% oxygen administered at normobaric pressure.
Conclusions. The data support a role for HBO2 in the treatment of some patients with calciphylaxis, particularly as in the absence of uncontrolled secondary hyperparathyroidism there are few therapeutic options.
Keywords: calciphylaxis; dialysis; hyperbaric oxygen; renal failure
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Introduction
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Calciphylaxis (also referred to as calcific uraemic arteriolopathy) is a syndrome of small vessel calcification of unknown aetiology causing painful violaceous skin lesions that progress to non-healing ulcers and gangrene. It is observed mainly in patients with end-stage renal disease (ESRD), with a reported prevalence of 14% of patients on chronic haemodialysis [1,2]. An increasing incidence has been noted by some centres [3,4]. Although parathyroidectomy has been advocated as a treatment for calciphylaxis in some cases [2,59], other studies have not found this to be effective [1,3,1012]. Indeed, the mortality from calciphylaxis remains between 60 and 80% [1,11], with most patients dying of sepsis from secondary infection of the calciphylaxis wounds [1,8,24].
Hyperbaric oxygen (HBO2) treatment consists of breathing 100% O2 at a pressure higher than ambient pressure (1 atmosphere absolute) while the patient is situated inside a sealed treatment chamber. HBO2 has been used with some success in the treatment of select problem wounds, defined as those that fail to respond to established medical and surgical management. Problem wounds are often severely hypoxic with transcutaneous oxygen pressure (PtcO2) of 520 mmHg compared with healthy control tissue PtcO2 of 3050 mmHg [13]. Healing is impaired when tissue O2 tension is below 20 mmHg, and restoration of tissue PO2 to normal or above normal enhances fibroblast proliferation and collagen production as well as angiogenesis. Hypoxia also hinders O2-dependent polymorphonuclear leukocyte-mediated bacterial killing of the aerobic organisms most commonly found in wound infections [14].
A beneficial effect of HBO2 in the treatment of calciphylaxis has been noted in several case reports [1517]. For example, Vassa et al. [15] reported one case of a woman on continuous ambulatory peritoneal dialysis (CAPD) suffering from lower extremity calciphylaxis who failed to improve after parathyroidectomy but then experienced healing of the skin lesions after 38 sessions of HBO2 therapy. Similarly, Dean and Werman [16] reported a case of a haemodialysis patient with lower extremity calciphylaxis who responded to 7 weeks of HBO2 treatments after parathyroidectomy and wound debridement had failed. Because of the poor prognosis of this condition, we evaluated our experience at the Ottawa Hospital in a retrospective study of five patients on renal replacement therapy who were treated with HBO2 for biopsy-proven calciphylaxis.
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Methods
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Five patients at the Ottawa Hospital on renal replacement therapy with biopsy-proven calciphylaxis were treated with HBO2 during the period of March 1997 to February 2000. These cases were retrospectively studied. The patients were identified through the Hyperbaric Unit patient database at the Ottawa Hospital. Patient characteristics (age, gender, mode of dialysis, time on dialysis, distribution of lesions of calciphylaxis, serum levels of calcium, phosphate, PTH, and albumin) were obtained, and response to management was documented. Serum intact PTH was measured by radioimmunoassay. The patients were treated with HBO2 at 2.5 atmospheres absolute for 90 min, 5 days per week for 57 consecutive weeks. At the wound site, PtcO2 was measured in four patients on both room air and on 100% O2 normobaric by non-rebreathing mask to quantitatively assess O2 availability to tissue. The skin lesions in patients treated with HBO2 were photographed at the beginning of therapy and at various stages in their course. Surgical wound debridement was performed and antibiotics were administered as indicated. No specific changes were made to the CaCO3 or vitamin D treatment regimens. Resolution of the calciphylaxis was considered as healing of necrotic areas, with presence of granulation tissue, followed by a reduction in wound size and eventual scar formation.
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Results
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The characteristics of the five patients are listed in Table 1
. The patients are numbered to group them by outcome, and not in the temporal order in which they were treated. In each of the patients, the diagnosis of calciphylaxis was made by wound biopsy, which revealed medial calcification of arterioles with thrombosis, necrosis of adipose and connective tissue, and minimal lymphocytic infiltration (Figure 1
). The mean age was 50.8 years, with four females and one male patient. Four of the five patients had either Type 1 or 2 diabetes mellitus, and four were considered to be obese. All five patients were Caucasian. The renal replacement therapy was CAPD in three patients, and haemodialysis in two. The average time on dialysis was 20.2 months. All but one patient was on CaCO3 and/or vitamin D therapy for the treatment of secondary hyperparathyroidism, and no changes were made to their treatments. Two patients (#2 and #3) were on warfarin therapy for atrial fibrillation and mitral valve replacement, respectively, and anticoagulation was continued in both.

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Fig. 1. Biopsy of calciphylaxis wound of patient #2: extensive medial calcification in small muscular arteries (arrowhead) and adjacent fat necrosis (small arrow).
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The laboratory findings are also summarized in Table 1
. The average serum PTH level was 76.8± 65.5 ng/l (reference range 10.565.0 ng/l), and no patients had uncontrolled hyperparathyroidism or elevated serum calciumxserum phosphate product. The mean serum albumin level was 2.54±0.15 g/l, with all patients demonstrating hypoalbuminaemia (a serum level <3.5 g/l). A variety of organisms were cultured from the calciphylaxis wound sites, with four of five patients demonstrating growth of Enterococcus species.
The clinical course of the patients is presented in Table 2
. Of the five patients with calciphylaxis, all received a full course of HBO2 therapy. Two of these (patients #1 and #2) had excellent responses with complete resolution of the skin ulcers (Figures 2
and 3
). Healing occurred during the period of HBO2 treatment in patient #1, and weeks after treatment was completed in patient #2. Neither patient required skin grafting. Transcutaneous oximetry was performed at the wound sites of both patients. Improved tissue oxygenation (Table 1
) was observed with HBO2 in patient #1 with PtcO2 rising from 13 mmHg on room air at 1 atm. to 327 mmHg on 100% O2 at 2.5 atm. In patient #2, PtcO2 was performed at 1 atm. only. On room air, PtcO2 was 7 mmHg, and while breathing 100% O2, PtcO2 rose to 33 mmHg.

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Fig. 2. (a) Patient #1, calciphylaxis of calf, July 1998. PtcO2 probes are seen above and below the wound. (b) Wound healing, November 1998.
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Fig. 3. (a) Patient #2, necrotic area of calciphylaxis on abdominal pannus, April 1997. (b) Granulation and healing, May 1997. (c) Area healed, November 1997.
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Three patients who received full courses of HBO2 did not experience improvement of their calciphylaxis lesions. All three patients (#3, #4, and #5) had some reduction in areas of wound necrosis with some tissue healing, but two patients (#3 and #4) ultimately requested withdrawal of care because of severe intractable pain and development of other medical complications. Measurement of PtcO2 for patient #4 revealed involved areas, which failed to achieve adequate PtcO2 levels for tissue healing (1 mmHg on room air and 18 mmHg on 100% O2 normobaric). Diabetes mellitus and severe peripheral vascular disease were comorbid conditions in both patients. Both of these patients died from the complications of sepsis. The third patient who did not respond to HBO2 (#5) had a large circumferential lesion on one calf. After the course of treatment with HBO2, the wound had not improved sufficiently, and the patient required a below-knee amputation of the affected leg. Of note, this patient was diabetic, and had poor glucose control during the course of therapy, with serum glucose levels consistently above 350 mg/dl. Furthermore, in this patient transcutaneous oximetry did not demonstrate improved tissue oxygenation at the wound sites, which remained severely hypoxic (12 mmHg) on both room air and 100% O2 normobaric.
Two patients receiving HBO2 experienced claustro phobia. However, potential complications such as barotrauma, seizures, or visual refractive changes were not observed [18].
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Discussion
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In this retrospective study, five patients with biopsy-proven calciphylaxis were treated with HBO2. Two patients had eventual complete resolution of their calciphylaxis wounds. These two patients both showed improvement in wound area PtcO2 with administration of 100% oxygen (Table 2
) with measurements taken at normobaric and hyperbaric pressures respectively. In contrast, for two of the patients who did not improve with HBO2, PtcO2 was measured and did not increase above 30 mmHg, a level associated with wound healing [14]. These measurements, however, were taken at normobaric pressures; the PtcO2 levels while these patients were in the hyperbaric chamber were not measured. Accordingly, it is uncertain whether HBO2 therapy was associated with improved tissue PtcO2 levels in these cases.
Previous studies of calciphylaxis [1,11,19] indicate an unfavorable prognosis when the location of the skin lesions is proximal (26% survival) compared to distal (75% survival). One of the patients (#1) who recovered with HBO2 therapy was in a favourable prognostic group, with only distal leg lesions, while the other (patient #2) had a large lesion of the abdominal pannus which completely healed with HBO2 therapy (Figures 2
and 3
).
Of the three patients who received HBO2 therapy but did not improve (#3, #4, and #5), all had severe peripheral vascular disease and diabetes, and two had proximal lesions. In this regard, it is possible that severe diabetic microvascular disease may limit the delivery of oxygenated blood to the wound site and impair healing. This is reflected in the poor PtcO2 levels measured in two of these patients.
In our study, calciphylaxis occurred in patients with similar characteristics to those described in previous studies. Patients with ESRD and calciphylaxis tend to be relatively young (48±16 years) [6,20], obese, female, and have low levels of serum albumin [1,3,21,22]. An increased incidence of calciphylaxis with the use of warfarin has also been noted [3]. For patients on haemodialysis, the length of time on treatment prior to development of calciphylaxis has been reported to range from 33 months [1] to 80 months [2]. Indeed, our five patients were fairly typical of patients described in the literature, with an average age of 50.8 years, and four were female, two were on warfarin therapy, all five had low serum albumin levels, and four were obese.
Elevations in serum PTH level have been noted in many cases of calciphylaxis [3,7,20]. However, the development of calciphylaxis in patients with normal levels of PTH [12,21,23,24] or after parathyroidectomy [2] is also commonly reported. In our study, none of the patients had uncontrolled hyperparathyroidism, and the majority (four of five) were being treated for secondary hyperparathyroidism with CaCO3 and/or vitamin D to lower the serum PTH to 23 times normal. The role of these medications in calciphylaxis is controversial. It has been suggested that calciphylaxis may be delayed or avoided with the prevention of secondary hyperparathyroidism through medical therapy [2]. On the other hand, CaCO3 therapy has been reported as a risk factor for developing calciphylaxis in ESRD [23,25], perhaps due to its potential to cause hypercalcaemia [7]. Vitamin D has been used to suppress PTH in the treatment of calciphylaxis [26], although there are no controlled trials to support or refute its use as an effective treatment.
Most agree that parathyroidectomy should be considered as therapy for calciphylaxis when severe hyperparathyroidism is present [2,57]. However, in the presence of mild elevations of PTH, or with normal PTH levels, no clear benefit of parathyroidectomy has been identified [8,27].
Three of our patients (#2, #3, and #5) were vulnerable to desaturation while breathing room air. It is of note that previous autopsy studies show that 60% of chronic dialysis patients, as well as those with calciphylaxis, have extensive pulmonary calcification [7,28]. It is possible that patients with calciphylaxis are more vulnerable to develop systemic hypoxia, worsening their predisposition to wound hypoxia. If HBO2 is not available or possible, it is conceivable that patients with calciphylaxis may benefit from continuous supplemental oxygen.
In conclusion, two of five patients in our study demonstrated complete healing of their calciphylaxis wounds when treated with HBO2. As in our study, most patients with calciphylaxis do not have uncontrolled hyperparathyroidism, leaving them with few therapeutic options. Our data suggest that HBO2 is safe and has a role in the treatment of calciphylaxis.
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Acknowledgments
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The authors would like to thank Dr Susan Robertson, Associate Professor, Department of Anatomic Pathology and Dr John Veinot, Associate Professor, Department of Anatomic Pathology, University of Ottawa for their assistance with histologic analysis of tissues. This study was supported by funds from the Kidney Research Centre, Ottawa Health Research Institute, University of Ottawa.
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Notes
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Correspondence and offprint requests to: Kevin D. Burns MD, FRCPC, Head, Division of Nephrology, Department of Medicine, Ottawa Hospital and University of Ottawa, 501 Smyth Road, LM-18, Ottawa, Ontario, Canada K1H 8L6. Email: kburns{at}ottawahospital.on.ca 
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Received for publication: 10. 1.01
Revision received 11. 6.01.