| | Calciphylaxis and nonhealing wounds: The role of the vascular surgeon in a multidisciplinary treatment☆☆☆★★★Received 6 May 2002; accepted 20 August 2002. Abstract Objective: Calciphylaxis, a disorder of calcium-phosphate metabolism that can result in arterial calcification, skin and solid organ calcium deposits, and nonhealing ulcerations, is associated with significant morbidity and mortality. Although its most common cause is secondary hyperparathyroidism in patients with renal failure, vascular surgeons are frequently called on to evaluate these nonhealing extremity wounds. We reviewed our experience of a multidisciplinary approach in treating patients with calciphylaxis and nonhealing ulcers. Patients and Methods: Over a 14-month period at a tertiary center, five patients were seen with calciphylaxis and nonhealing leg wounds. Demographics, disease characteristics, surgical treatment, and outcomes were analyzed. Results: All five patients were black women aged 40 ± 8.9 years with hypertensive renal failure undergoing long-term hemodialysis (80 ± 43 months). They had large, painful lower extremity wounds or necrotic ulcers (mean size, 135 cm2) that had developed over 2 to 4 months. Three patients had palpable pedal pulses, one patient had Doppler pedal signals, and one patient had absent pedal flow. Arteriogram was performed in the latter two patients, and one patient underwent lower extremity revascularization because of superficial femoral artery stenosis with symptomatic improvement. Four patients underwent aggressive debridement by the vascular surgical service, and two needed plastic surgeon-performed skin grafting. All patients had elevated parathyroid hormone levels (mean, 1735 pg/mL; > 25× normal level); mean preoperative calcium levels were normal (10 mg/dL). After either subtotal (n = 4) or total (n = 1) parathyroidectomy by an experienced endocrine surgeon, a significant reduction in parathyroid hormone and calcium levels was seen (122 pg/mL and 7.9 mg/dL, respectively; P < .05). There were no postoperative complications or amputations; one patient died 12 months after parathyroidectomy of severe preexisting cardiopulmonary disease. Complete wound healing was observed by 4.8 ± 2 months. During a mean follow-up period of 9 months (range, 1 to 18 months), all wounds remained healed without ulcer recurrence. Conclusion: The diagnosis of calciphylaxis should be considered in patients with end-stage renal disease with atypical tissue necrosis or subcutaneous nodules. Early recognition of calciphylaxis and multidisciplinary treatment, including diligent wound care, frequent debridement, parathyroidectomy, and appropriate skin grafting or revascularization, can result in improved wound healing and limb salvage. (J Vasc Surg 2003;37:501-7.)
Calciphylaxis is characterized by excessive calcium deposition in skin, arteries, and other organs that develops as a complication of secondary hyperparathyroidism, which most commonly occurs in patients with end-stage renal disease (ESRD). Up to 4% of patients for renal dialysis may show signs of calciphylaxis,1 which range from painful subcutaneous nodules to nonhealing extremity ulcers and gangrene. Although the pathogenesis of such extensive calcium deposition is unknown,2 the reported natural history is one of progression to poor wound healing, limb loss, and even death in a large number of patients.3, 4
The recognition of calciphylaxis relies on heightened clinical awareness of the presence of atypical skin nodules or ulcers that occur in patients with hemodialysis dependence. On encountering a patient with ESRD with such skin lesions, additional biochemical evaluations are critical to confirm the state of hyperparathyroidism and thus establish the diagnosis of calciphylaxis. Although serum levels of calcium, phosphate, alkaline phosphatase, and parathyroid hormone (PTH) are important diagnostic considerations, no one abnormality is pathognomonic for calciphylaxis.5 Vascular surgeons are usually the first physicians called on to evaluate such patients on the basis of a nonhealing extremity wound and a presumption of underlying peripheral arterial occlusive disease.3, 4 The prevalence of peripheral vascular disease requiring surgical intervention among patients with calciphylaxis is difficult to determine from limited case reports.3, 4, 6 Early management of calciphylaxis has traditionally consisted of local wound care, aggressive dialysis regimens, and calcium-lowering and phosphate-lowering medications. The importance of surgical interventions, such as arterial revascularization and especially parathyroidectomy, has likewise been emphasized although not routinely recommended to all patients.6, 7
We reviewed our recent experience with this rare condition in the context of multidisciplinary treatment provided to these patients at our institution. Our aim was to characterize features of calciphylaxis or components of treatment that may lead to improved outcome.
Patients and methods  During a 14-month interval from June 2000 to August 2001, five patients were seen consecutively at the vascular surgery center at a tertiary referral hospital (Emory University Hospital) with calciphylaxis and nonhealing leg wounds. Patients characteristics (age, gender, race, diagnosis of underlying kidney disease, duration of hemodialysis) and clinical variables (serum calcium, phosphate, intact PTH, alkaline phosphatase) were obtained initially and at subsequent examinations. The mean calcium phosphate product (calcium × phosphate; mg2/dL2) was calculated for each patient. The duration and extent of symptoms of calciphylaxis, responses to medical management of hyperparathyroidism, prior kidney transplantation, and prior parathyroidectomy were noted. History of peripheral vascular disease and interventions and clinical vascular examination results were recorded for each patient. Operative and postoperative data were accumulated from chart review for revascularization procedures, wound debridement, and parathyroidectomy. Wound care was performed by the Wound, Ostomy, and Continence (WOC) nurses on a weekly basis both before and after surgery, and extremity ulcers were measured and photographed until fully healed. Local wound care consisted of daily application of a hydrogel (Curasol, Healthpoint, Fort Worth, Tex) with normal saline moist gauze dressing for clean wounds or for wounds with tissue slough. Transparent adhesive dressings (OpSite, Smith & Nephew, Largo, Fla) were used for wounds with eschar to encourage autolytic debridement. Exudative wounds were covered with calcium alginates (Kaltostat, Convatec, Princeton, NJ) and a hydrocolloid wafer dressing (Duoderm CGF, Convatec). The patients and their families continued daily wound care by themselves at home between clinic visits. WOC nurses performed detailed wound care teaching in clinic until the patients were comfortable with the procedure. None of the patients needed a visiting home nurse. Family members assisted with dressing changes to large wounds on the posterior of legs or areas difficult to reach. Amputation, postoperative wound infections or medical complication, and mortality rates were determined during the follow-up interval. The late status of patients was established with office visit and follow-up patient interview. Statistical analysis of the data was performed with the use of Student t test for paired variables, denoting a P value of less than .05 as statistically significant. Results All five patients were black women who were hemodialysis dependent with a mean age of 40 ± 8.9 years. The cause of the renal failure was hypertension; two of the five patients also had insulin-dependent diabetes mellitus. The mean duration of hemodialysis was nearly 7 years (80 ± 43 months). Three of the five patients had received kidney transplantation 3 to 5 years before the current presentation and had resumed hemodialysis after kidney graft failure for at least 1 year before development of extremity wounds. All except one patient were aware of the underlying diagnosis of hyperparathyroidism. Other comorbid conditions identified in this group of patients included cardiac disease (2/5), asthma (3/5), peripheral vascular disease (1/5), gastrointestinal problems (3/5), and chronic cigarette smoking (2/5). All patients fit the criteria for a clinical diagnosis of calciphylaxis. Lower extremity wounds were present in all five patients. The mean initial size of the wounds was 135 ± 165 cm2, typically consisting of a contiguous skin defect of approximately 10 × 10 cm (Fig 1).
The largest wounds affected a 52-year-old woman with three separate patches of ulceration (14 × 9 cm, 18 × 3.5 cm, 13.5 × 5 cm) distributed circumferentially around the left lower leg. Notable wound characteristics among the patients included ulceration with thick eschar (4/5), blistering (1/5), severe local tissue pain and bony aches (3/5), pruritus (2/5), painful subcutaneous nodules (1/5), and location limited to proximal thigh and buttocks (2/5) or distal lower leg (3/5). None of the patients showed signs of local wound infection, such as cellulitis, or signs of systemic sepsis. Three of the five patients reported similar but smaller wound problems in the past that had resolved spontaneously. The current wounds developed over a period of 2 to 4 months. Tissue biopsy of one wound was obtained by a referring physician but did not reveal vascular calcifications; none of the other four patients had tissue biopsy for diagnostic purposes. The patients were symptomatic for an average of 3 ± 0.8 months before referral for initial surgical evaluation to a vascular surgeon. Hyperparathyroidism was confirmed in all five patients with elevation of PTH levels, which ranged from 538 to 3515 pg/mL (mean, 1735 ± 1190 pg/mL; normal range, 10 to 65 pg/mL). Mean preoperative calcium measurements were normal (10 ± 0.9 mg/dL), but phosphorus (4.9 ± 0.6 mg/dL) and alkaline phosphatase (778 ± 1193 mg/dL) levels were high. All patients had been treated chronically with intensified dialysis regimens and phosphate-lowering medications (sevelamar [Renagel, Genzyme Corp, Cambridge, Mass], calcium acetate [Phoslo, Braintree Laboratories, Braintree, Mass]). The calcium-phosphate product, thought to be suggestive of calciphylaxis if greater than 70 mg2/dL2,1, 5 was 50 ± 10 mg2/dL2 before surgery. One of the five patients had a prior subtotal (3
½ gland) parathyroidectomy; the presenting PTH value was 1000 pg/mL, indicating recurrent renal hyperparathyroidism. Two patients had significant osteoporosis as determined with abnormal bone density. Clinical vascular history was unremarkable, and palpable pedal pulses were detected in three of the five patients. Ankle-brachial index measurements were not obtainable because of severe pain from application of the pressure cuff and large wounds in the area. One patient had Doppler pedal signals but no prior known vascular problems, and one patient had absent pedal flow. Arteriogram was performed in these two patients, and results were abnormal in only the last patient. This was a 52-year-old woman with painful necrotic ulcers circumferentially around the left lower leg and extensive history of peripheral vascular disease, including right common femoral endarterectomy and later right femoral-popliteal bypass. The patient underwent left lower extremity revascularization for superficial femoral artery stenosis (Fig 2) with reversed saphenous vein graft femoral-popliteal bypass as the initial treatment on diagnosis with calciphylaxis.
At 18-month follow-up, this patient remained ambulatory with completely healed wounds and palpable dorsalis pedis pulses in both feet. Treatment of these five patients required the coordinated efforts of a team of surgeons (vascular, endocrine, plastic), nephrologists, and WOC nurses. Four patients underwent aggressive debridement of wounds in the operating room by the vascular surgical service. Two patients needed plastic surgeon-performed skin grafts. All five patients received subtotal (n =4) or total (n = 1) parathyroidectomy by an experienced endocrine surgeon. Evaluation by endocrine surgery was obtained within a week of initial presentation to a vascular surgeon, and parathyroidectomy and wound debridement were accomplished during the same hospital stay. WOC nurses performed daily wound care during inpatient hospitalization and monitored healing weekly during clinic follow-up visits. There were no postoperative complications or amputations. One patient died 12 months after parathyroidectomy from severe preexisting cardiopulmonary disease. After parathyroidectomy, there was a significant reduction (P< .05) in levels of PTH (122 ± 48 pg/mL), calcium (7.9 ± 1.6 mg/dL), calcium-phosphate product (36 ± 8 mg2/dL2), and alkaline phosphatase (560 ± 819 mg/dL). The radical extent of parathyroidectomy should be noted (Fig 3) because this is crucial to interrupting the abnormal pathophysiology driving hyperparathyroidism and calciphylaxis and decreases chances of persistent and recurrent hyperparathyroidism in the future.1, 7
Total parathyroidectomy without implantation of parathyroid tissue was performed in one patient with recurrent secondary hyperparathyroidism. All four parathyroid glands were enlarged in the remaining patients, and total parathyroid volume per patient averaged 1883 ± 858 mm 3. A remnant measuring only 74.2 ± 47 mm 3 was left in the neck as the sole parathyroid tissue. This is roughly equivalent to two normal parathyroids. Intraoperative PTH measurement, with final goal of PTH 100 to 200 pg/mL, and parathyroid tissue cryopreservation allow such radical removal of tissue without rendering the patient hypocalcemic. The most vital outcome was that complete healing of these large wounds was observed by 4.8 ± 2 months (Fig 4).
The rate of wound healing was proportional to the size of the tissue defect. Two patients whose extremity wounds measured 18.3 and 35 cm 2 achieved full reepithelialization in 3 months, whereas larger wounds, 257 and 364 cm 2 in size and circumferential, needed skin grafting and ultimately fully healed by 7 months. Resolution of pain and bony aches occurred faster, with improvement noted by patients even during initial hospitalization. This was manifested in an obvious manner, for example, by the improved ability of patients to tolerate touching of the extremity and dressing changes. During a mean follow-up period of 9 months (range, 1 to 18 months), all wounds remained healed without ulcer recurrence. Discussion Calciphylaxis is a relatively rare and disabling condition that presents both diagnostic and treatment challenges. A precise etiology of calciphylaxis remains undefined, although as early as 1962, Selye8 recognized this as a systematic condition of rapid calcium deposition and was able to use sensitizing agents (PTH) and challenging agents (egg whites) to produce calcification in the skin of experimental rats. Histologic examination in human tissues most often reveals small vessel involvement with medial calcification, intimal proliferation, microthrombi, and extravascular calcium deposits.9, 10 The clinical syndrome in patients associates ESRD, secondary hyperparathyroidism, and painful cutaneous lesions; these are the components critical to entertaining a diagnosis of calciphylaxis. Failure to understand better the pathophysiology linking these three conditions contributes to the delay in diagnosis and administration of currently available treatments. Our data present a group of patients with the representative combination of clinical features of calciphylaxis. Diagnosis is usually achieved because of heightened clinical suspicion, rather than the presence of any pathognomonic findings. The most important of serum blood tests are measurements of PTH, calcium, and phosphate because these establish the diagnosis of secondary hyperparathyroidism and can be followed as markers of adequate medical management and dialysis for parathyroid hyperplasia. Although the female preponderance in our series is also typical of previously reported calciphylaxis cases, factors contributing to such an epidemiologic predilection remain less clear.7, 11 Neither skin biopsies nor radiologic studies are specific for calciphylaxis,2 although they may be supportive of the diagnosis.4, 10 Only one of our patients had skin biopsy performed before referral, and this revealed dermal and epidermal changes of stasis dermatitis without vascular calcifications. With calciphylaxis, one might expect to find calcium deposits in subcutaneous tissue and arterial calcifications obliterating small blood vessels; calcium concentrated in the media of vessel walls has been described.10, 12 Similarly, roentgenograms of legs and feet may disclose an outline of arterial calcifications.9, 12 None of these manifestations are observed consistently enough to be reliable diagnostic tools. There is no diagnostic threshold level for PTH, calcium, or phosphate elevations,6 although these remain essential components of any evaluation of calciphylaxis. Preoperative PTH levels in this group of patients with calciphylaxis were, in fact, comparable with those reported in literature for renal hyperparathyroidism in general, which range from 619 to 4160 pg/mL.13, 14 There is no evidence that the degree of PTH elevation alone is related to severity of parathyroid disease or other consequences of hyperparathyroidism, such as calciphylaxis ulcers. Some surgeons advocate consideration of parathyroidectomy for all patients with dialysis-dependent renal disease when PTH levels exceed 500 pg/mL.15, 16 The experience nationally is that only about 2.5% of patients with ESRD will eventually undergo parathyroidectomy.13 This is lower even than the estimated prevalence rate (4%) of calciphylaxis in the ESRD population.1 Such statistics are a reminder that most patients with ESRD receive medical management for control of parathyroid hypersecretion. Aggressive dialysis, prevention of phosphate retention and hyperphosphatemia, maintenance of normal calcium levels, and use of calcitriol (1, 25-dihydroxyvitamin D) have been traditional components of medical therapy.13, 17 All of our patients had optimal medical management that, nevertheless, was insufficient to control the hyperparathyroidism. A recent review highlights the observation that although medical treatment is an important first intervention, this has not altered the course of hyperparathyroidism despite better medical regimens over the last 10 years; a constant number of patients will need parathyroidectomy and, like ours, be referred for this procedure late in the disease process.13 Elevated calcium-phosphate product greater than 70 mg2/dL2 has been suggested as supportive of calciphylaxis.1, 5 Although the mean value of this product in our group of patients initially was only 50 mg2/dL2, it did decrease significantly (36 mg2/dL2; P < .05) after parathyroidectomy. It is important to recognize that the calcium-phosphate product has not been advocated as a definitive diagnostic finding of calciphylaxis, even in literature reporting higher values in patients with calciphylaxis.1 Elevated calcium-phosphate product has been suggested as partially responsible for the disease process of soft tissue calcifications, although the pathophysiologic mechanism has still not been elucidated.18 Series of patients with calciphylaxis have reported both high1, 9 and normal to slightly elevated calcium-phosphate products.3, 7, 16 Until this disease process is better understood, the role of the calcium-phosphate product can best be described as supportive of calciphylaxis, if elevated, but not excluding calciphylaxis if lower than anticipated. The role of the vascular surgeon is pivotal in our multidisciplinary experience with this disease. Our institutional experience has been that vascular surgeons are typically the first to consider and confirm the diagnosis of calciphylaxis because these patients are initially referred to them out of concern for peripheral vascular disease. Because of the high incidence rate of atherosclerotic vascular disease in patients with ESRD, the distinction between calciphylaxis wounds and ischemic ulcers is important. It is essential to exclude underlying vascular disease with clinical examination and angiography if appropriate. Ulcers located more proximally on the extremity, preserved peripheral pulses, absence of neuropathy, associated subcutaneous nodules, and symptoms of extreme pain are more likely with calciphylaxis wounds. It is difficult to assess accurately the prevalence of true peripheral vascular disease in patients with calciphylaxis. The prevalence rate of peripheral vascular disease is known to be as high as 34% among patients with ESRD.20 Among 55 cases of calciphylaxis, including ours, that were recently described,1, 3, 4, 6, 7, 12, 21, 22, 23 arteriography was reported for only six patients,4, 23 three of whom went on to have lower extremity revascularization4 with a 67% postoperative complication rate. On the basis of this small group of patients, firm recommendations regarding revascularization in patients with calciphylaxis would be unfounded. It seems reasonable to suggest that surgical correction of underlying obstructive arterial disease may have an appropriate role, but such treatment should be individualized with respect to the overall medical condition of the patient and the timing of other needed interventions, such as parathyroidectomy. Remarkably, in this series of five patients with extensive calciphylaxis wounds, there were no amputations and no postoperative cardiac complications. Complete wound healing and pain relief was attained within a few months after initial wound debridement and parathyroidectomy. Only one patient died at 1 year of follow-up of reasons unrelated to calciphylaxis. These results are encouraging but atypical in comparison with morbidity and mortality rates reportedly as high as or higher than 75% in other calciphylaxis series.4, 7 The explanation is undoubtedly multifactorial and may involve all of the following elements: prompt diagnosis of calciphylaxis, aggressive multidisciplinary care, early and radical parathyroidectomy with significant reduction of PTH levels, diligent wound care, younger or less chronically ill patients, and elimination of inflammatory mediators that may be produced by the parathyroid glands.24 Like the mechanism of calciphylaxis itself, the mechanism of this healing process needs to be better understood. The observation remains, however, that even as drastic and debilitating as the calciphylaxis wounds appear, they do seem to heal. Early recognition of calciphylaxis and multidisciplinary treatment, including wound debridement, parathyroidectomy, and appropriate arterial revascularization, can lead to improved wound healing and limb salvage. The number of patients in our report is admittedly small, which undoubtedly limits recommendations on the basis of our clinical experience. However, until more is understood about this disorder, we recommend the multidisciplinary approach as outlined in Fig 5.
In our setting, the respective roles of the vascular, endocrine, and plastic surgeons were determined by preexisting referral patterns and surgical traditions in caring for certain disease states. Just as it is important to exclude a surgically correctable vascular lesion, it is even more important to consider calciphylaxis in the differential diagnosis. This allows thorough diagnostic evaluation of the patient and recruitment of appropriate specialists, whose roles may vary between institutions and include a mixture of general surgeons or other specialists. The diagnosis of calciphylaxis should be considered early by all physicians who encounter patients with ESRD and atypical painful extremity wounds. The goals of treatment should be improvement of wound healing and preservation of functional limbs, reduction of pain, and correction of the underlying hyperparathyroidism. References 1.
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Proceedings, International Surgical Week. 2001;. Cleveland, Ohio; Tallahassee, Fla; Houston, Tex; Webster, NY; and Atlanta, Ga From the Department of General Surgery, Cleveland Clinic Foundationa; The Cardiac and Vascular Centerb; the Department of Vascular Surgery, Baylor College of Medicinec; Certified Wound, Ostomy, and Continence, Visiting Nurse Serviced; Plastic Surgery, Piedmont Hospitale; the Department of Surgery, Emory University School of Medicine.f ☆ Competition of interest: none. ☆☆ Reprint requests: Thomas F. Dodson, MD, Division of Vascular Surgery, Emory University Hospital Department of Surgery, 1364 Clifton Rd, NE, Atlanta, GA 30322 (e-mail: thomas_dodson@emoryhealthcare.org). ★ Published online Jan 15, 2003. ★★ 0741-5214/2003/$30.00 + 0 PII: S0741-5214(02)75211-7 doi:10.1067/mva.2003.70 © 2003 Society for Vascular Surgery and The American Association for Vascular Surgery. Published by Elsevier Inc. All rights reserved. | |
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