Surgical Management of Pain or Infection Secondary to Calciphylaxis: A Wound Center’s Experience and Algorithmic Multidisciplinary Approach

Calciphylaxis is a rare, life-threatening cutaneous vascular disease. Formerly known as calcific uremic arteriolopathy, calciphylaxis was historically believed to primarily affect patients with ESRD; however, nonuremic cases have since been documented.^1,2 The estimated incidence of calciphylaxis among patients receiving hemodialysis in the United States is 35 cases per 10 000 patients.² Often seen as a herald of end-of-life care, calciphylaxis is associated with 1-year mortality rates as high as 40% to 80%, with sepsis secondary to wound infection comprising the most common cause of mortality.^3,4 

Pathophysiologically, calciphylaxis involves progressive vascular calcification. Subsequent microvessel occlusion ultimately manifests as chronic and intensely painful violaceous skin lesions, which involve indurated blisters and ulcers that can develop an overlying eschar.^2,5,6 Nonhealing wounds or painful subcutaneous nodules may necessitate serial surgical debridement, primary excision, or amputation to minimize pain and infection risks.^7,8 Because calciphylaxis is an end-stage disease, surgical management is not typically indicated; however, it is occasionally warranted to manage intractable pain or infection. Concurrently, medical therapy is indicated for the management of associated endocrine disorders such as hyperparathyroidism and subsequent dysregulation in calcium and phosphate.^2,9,10 While previous studies have demonstrated that both medical and surgical measures are associated with prolonged patient survival, the role of surgery in patients with pain or infection secondary to calciphylaxis remains largely understudied.^2,3,11,12 

The current paucity of literature is partially a consequence of the rarity of calciphylaxis, which precludes large, prospective investigational studies. Nonetheless, prior observational reports and small case series provide valuable data regarding presenting symptoms and diagnostic techniques.^13,14 Thus, the authors of the current study sought to build upon prior studies by reporting a case series that is further contextualized by an institutional algorithmic approach to the multidisciplinary management of pain and infection secondary to calciphylaxis at a tertiary care wound center.

Following institutional review board approval (MGUH study number 00005805), a retrospective review of all adult patients with calciphylaxis treated at the MGUH tertiary wound care center in Washington, DC between January 2010 and November 2022 was performed. Patients were identified by submitting a query for ICD-9 and ICD-10 codes 275.49 and E83.50, respectively, that is, “Unspecified disorder of calcium metabolism.” Patients were screened for eligibility and were included if they met the following criteria: (1) aged 18 years or older, (2) had a confirmatory biopsy reflective of a calciphylaxis diagnosis (eg, medial calcification, internal hypertrophy, local inflammation, epidermal necrosis) documented in the EMR, and (3) had undergone surgery directly related to their calciphylaxis.¹³ Patients with calciphylaxis who did not undergo surgery and those with other disorders of calcium metabolism without concurrent biopsy-confirmed calciphylaxis (ie, primary hyperparathyroidism, hypocalcemia, hypercalcemia, or Paget disease) were excluded. All surgical management was performed by the senior authors (J.S.S., K.K.E, and C.E.A). Primary outcomes of interest included surgical approach, total number of debridements, and postoperative complications. Secondary outcomes of interest included rates of ambulation and mortality. 

Preoperative patient and calciphylaxis characteristics

The EMR was reviewed to collect data pertaining to patient demographics and comorbidities; calciphylaxis characteristics; medical, vascular, and surgical management details; postoperative complications; and long-term outcomes. The CCI, a validated scale used to quantify mortality risk based on comorbidity burden, was calculated for each patient.¹⁵ Rates of related pathologies such as ESRD and associated duration of hemodialysis, hyperparathyroidism, hypercoagulable traits, and renal transplantation were recorded. Medical management encompassed HBOT history in addition to medication regimen at the time of presentation, including phosphate binders and sodium thiosulfate. Preoperative vascular management included venous or arterial Doppler or duplex ultrasonography, ankle-brachial index measurements, or angiography performed by the senior vascular surgeon (C.M.A.). 

Surgical details

Surgical details included indication for surgery as recorded by the surgeon, wound characteristics, laterality, details regarding the debridement, and means of wound closure, or, if the wound was left open, postoperative wound management. Wound characteristics consisted of wound location and size, presence of infection, and wound depth along with identification of any exposed structures or hardware. Debridement details included level of debridement, microbiological culture results, and the number of cumulative debridements over the course of the hospitalization. The type of debridement performed was surgical unless otherwise noted. Postoperatively, wounds were either left open and dressed, or closed. Dressings consisted of either multilayer compression wrapping or NPWT. If applicable, closure methods included primary or secondary closure with or without autologous skin grafts, acellular dermal matrices, and local flaps. 

Postoperative monitoring, complications, and outcomes

Postoperatively, a multidisciplinary team of plastic and reconstructive, podiatric, and vascular surgeons, wound certified nurses, nephrologists, and infectious diseases specialists managed the patients to optimize their medical conditions and ensure that the appropriate antibiotic regimen was used based on the post-initial debridement culture results and sensitivities. In addition, nurses at the MGUH wound care center are certified to treat complex wounds. By providing patient education about wound management, dressing changes, and pain control, the nurses help patients attain their individual wound treatment goals. 

Postoperative complication rates were assessed globally and included dehiscence, hematoma, seroma, infection, re-ulceration, and return to the operating room within 30 days of the final surgical procedure (ie, the operation after which no further surgical intervention was indicated). Outcomes included follow-up duration at the time of analysis, ambulation status, changes in pain medication regimen, and all-cause mortality. Pain medication regimens were assessed at 3 time points: (1) at the time of preoperative consultation or presentation, (2) at the time of discharge, and (3) the time of healing, defined as the earliest postoperative visit whereby the wounds were described as “healing” in the EMR. 

Statistical analysis

Descriptive statistics were calculated for all patient data. Shapiro-Wilk testing of normality was performed to assess the distribution of continuous variables. Continuous variables normally distributed were expressed as mean ± SD, and nonnormally distributed variables were reported using median (IQR). Frequencies and percentages were used to represent categorical variables. Data were collected and tabulated in Excel (Microsoft). 

Patient demographics

Of the 554 patients issued the ICD-9 and ICD-10 codes for “Unspecified disorder of calcium metabolism” within the study period, a total of 11 patients with biopsy-proven calciphylaxis underwent surgical management for infected or painful calciphylaxis. Patient demographics and comorbidities are presented in Table 1. The average age and body mass index were 50.9 years ± 15.8 SD and 26.5 ± 3.8, respectively. The majority of patients were female (n = 7 [63.6%]) and identified as Black (n = 9 [81.8%]). The average CCI score was 5.7 ± 2.3, signifying a substantial comorbidity burden. Ten patients (90.9%) had a history of ESRD, with an average hemodialysis duration of 12.5 years ± 6.7. In the patient without ESRD, calciphylaxis was purportedly secondary to long-standing exposure to warfarin. Other relevant comorbidities present in the study population included peripheral arterial disease (n = 6 [54.5%]), prior history of deep vein thrombosis or pulmonary embolism (n = 5 [45.5%]), hyperparathyroidism (n = 2 [18.2%]), and prior renal transplant (n = 2 [18.2%]).

At presentation, home medical management of calciphylaxis included phosphate binders (n = 10 [90.9%]), sodium thiosulfate (n = 9 [81.8%]), systemic steroids (n = 6 [54.5%]), immunosuppressive therapy (n = 4 [36.4%]), and HBOT (n = 3 [27.3%]). Seven patients (63.6%) were on home anticoagulation therapy, and 3 were on home antiplatelet therapy. Two patients (18.2%) had a prior history of lower extremity amputation on the ipsilateral or contralateral side in relation to the location of the presenting wound, and 1 patient (9.1%) had previously undergone an open lower extremity vascular intervention (ie, femoropopliteal bypass) (Table 1). 

Preoperative characteristics

Indications for surgical management included sepsis secondary to an infected wound (n = 6 [54.5%]) and/or intractable pain (n = 11 [100%]). Several wounds were unilateral (n = 5 [45.5%]), and most frequently located on the thigh (n = 6 [54.5%]), followed by the forefoot (n = 3 [27.3%]), sacrum/gluteal region (n = 2 [18.2%]), lower leg (n = 1 [9.1%]), ankle (n = 1 [9.1%]), and midfoot (n = 1 [9.1%]). Wounds most often extended to the level of the bone (n = 4 [36.4%]) or subcutaneous tissue (n = 4 [36.4%]), followed by fascia (n = 3 [27.3%]) and muscle (n = 2 [18.2%]). At presentation, gangrene was present in 6 patients (54.5%) and osteomyelitis in 2 patients (18.2%) (Table 2). Preoperative laboratory results revealed a mean hemoglobin level of 8.3 g/dL ± 1.4, a mean prealbumin level of 15.8 mg/dL ± 2.5, and a mean albumin level of 2.8 g/dL ± 1.1. Additional relevant laboratory values are listed in Table 3. 

The average ankle-brachial index measurement across the study population was 1.4 ± 0.1. Calcified vessels of the lower extremity were visualized on arterial duplex ultrasonography in 9 patients (81.8%), with the posterior tibial (n = 3 [27.3%]) and dorsalis pedis (n = 3 [27.3%]) arteries being most frequently reported, followed by the anterior tibial (n = 2 [18.2%]), peroneal (n = 2 [18.2%]), popliteal (n = 2 [18.2%]), femoral (n = 2 [18.2%]), and iliac arteries (n = 1 [9.1%]). Six patients underwent lower extremity diagnostic or therapeutic angiography (54.5%). Three patients (27.3%) received preoperative vascular intervention during their hospital stay, with 2 patients (18.2%) undergoing angioplasty and 1 (9.1%) undergoing femoropopliteal bypass (Table 3). 

Operative course and postoperative outcomes

The operative course for each of the 11 patients is listed in Table 4. Patients underwent an average of 2.9 excisional debridements during their hospital course. Post-debridement cultures were positive in 7 cases (63.6%); these cultures were most commonly polymicrobial (n = 4/11 [36.4%]), consisting of various combinations of pathogens such as Escherichia coli (n = 3/11 [27.3%]), methicillin-sensitive Staphylococcus aureus (n = 3 [17.6%]), vancomycin-resistant Enterococci (n = 2/11 [18.2%]), Pseudomonas aeruginosa (n = 2/11 [18.2%]), Proteus mirabilis (n = 1/11 [9.1%]), and Stenotrophomonas maltophilia (n = 1/11 [9.1%]). Among the monomicrobial infections, pathogens included Enterococcus faecalis (n = 1 [9.1%]), methicillin-resistant S aureus (n = 1 [9.1%]), and P aeruginosa (n = 1 [9.1%]). Following pathogen identification, antibiotic regimens were tailored accordingly by infectious diseases specialists; these regimens are listed in Table 4. 

Among the 8 patients who underwent multiple surgical debridements, NPWT was applied between debridements in 7 cases (7/8, 87.5%). Following the final debridement, wounds were left open in 5 cases (5/11, 45.5%) and closed primarily in 4 cases (4/11, 36.4%), and local flaps were used in 3 cases (3/11, 27.3%). PriMatrix dermal scaffolding (Integra LifeSciences) was applied in 3 cases (27.3%). Dressing types used following final debridement included standard nonadhesive dressing (n = 6 [54.5%]), 25% strength acetic acid-soaked gauze (n = 3 [27.3%]), and multilayer compression consisting of either Mepitel (Mölnlycke Health Care AB) soft silicone dressing, Webril (Covidien, Cardinal Health) undercast padding, and bandaging (n = 4 [36.4%]), or Profore (Smith & Nephew) 4-layer compression dressing (n = 2 [18.2%]). The median length of stay was 35.5 days (IQR 30 days) across the study population. 

Postoperatively, of the 7 patients who underwent primary closure or received a local flap, the average time to wound healing was 57.4 days ± 12.6. Recorded complications included dehiscence (n = 1 [9.1%]), and progression to cellulitis (n = 2 [18.2%]), osteomyelitis (n = 1 [9.1%]), and lower extremity amputation (n = 2 [18.2%]). By an average follow-up of 26.4 months ± 34.1, 7 patients (63.6%) were deceased, with an average time to mortality of 4.8 months ± 6.7. Of the 4 remaining patients, 3 (75.0%) were ambulatory by their most recent follow-up visit (Table 5). 

Pain medication regimens across the 3 time points of interest are listed in Table 6. Although all 11 patients were taking narcotics either at the time of consultation or at the time of discharge, 5 of the 6 remaining patients (83.3%) were no longer taking narcotic medications at the time of healing. Of the 5 deceased patients, 2 (2/5, 40.0%) required an increase in their pain medication regimen from the time of presentation to the time of discharge. 

Although rare, calciphylaxis carries a high risk of morbidity and mortality, which likely is exacerbated by its inclination to affect patients with a substantial comorbidity burden at baseline.^3,11,16 Associated morbidity includes chronic, severe pain secondary to subcutaneous nodules or open wounds, which have the potential to severely affect quality of life. In this case series of 11 patients with calciphylaxis treated at a tertiary care wound center, the authors demonstrated that surgical excision is an effective tool to decrease this intractable pain, as evidenced by the fact that 5 of the 6 surviving patients were no longer taking narcotic medications at the time of healing. These findings emphasize that while calciphylaxis is an end-stage disease, surgery can have an effective role in tempering the severe pain or infection that substantially affects quality of life. 

Given the progressive nature of calciphylaxis, which involves nonhealing wounds that frequently harbor infections, affected patients often require serial debridements and excisions, thereby contributing to a prolonged hospital LOS and increased risk of nosocomial infection.^3,4,17 This was reflected in the cohort in the current case series, with most patients undergoing multiple debridements and experiencing prolonged hospital stays, with a median LOS of 35.5 days (IQR: 30 days). The risks of infection and prolonged nosocomial exposure must be balanced against the benefits of surgical debridement, as demonstrated by a 2007 study in which surgical debridement was associated with a 34.2% difference in 1-year survival in patients with calciphylaxis who underwent debridement compared with those who did not undergo debridement (61.6% and 27.4%, respectively).¹⁸ However, a review of the literature revealed only 14 published studies examining the role of surgical management in calciphylaxis through clinical evidence (Table 7).^{3,4,11,16-23,25-27} Of these studies, only 4 explicitly discuss the ability of a multidisciplinary approach to positively influence the disease course and possibly prolong survival.^3,4,11,26 Through a combination of this previous evidence and the senior authors’ experiences, MGUH has developed an algorithmic approach to determine the optimal strategy for management of calciphylaxis (Figure). 

Across the patient cohort discussed in the current study, clinical presentations reflected those reported in previous studies,^3,4 including, in the current study, intense pain refractory to analgesics (n = 11 [100%]), chronic wounds (n = 8 [72.7%]), muscle weakness (n = 7 [63.6%]), and sepsis (n = 6 [54.5%]). Upon presentation to the authors’ institution, patients are assessed for the presence of any open wounds. If open wounds are not present and the pain is localized to subcutaneous nodules that are adequately controlled with analgesics, nonsurgical modalities alone (eg, sodium thiosulfate, phosphate binders, regular dialysis, HBOT) are preferred; based on the findings of previous studies,^24,28-30 such care typically is managed by a medical multidisciplinary team of nephrologists, dermatologists, and endocrinologists. As evidenced by the average parathyroid hormone level of 207.4 pg/mL in the current cohort, medical therapies are essential for adequate management of secondary hyperparathyroidism and associated dysregulation of calcium and phosphate in this patient population.

When a wound or wounds are present but are not associated with clinical symptoms of infection (eg, erythema, induration, purulent drainage, pyrexia, leukocytosis) and are progressing toward healing, standard wound care and close outpatient follow-up with the wound center team are recommended. Conversely, in cases in which lesions cause severe pain refractory to conservative management, do not progress toward healing over time, or present with clinical signs of infection, patients are assessed for surgical candidacy through evaluation of their medical and nutritional status. In the setting of a substantial comorbidity burden, patients with calciphylaxis are at risk of presenting with nutritional deficiencies,^2,31 as demonstrated by the cohort discussed in this study, who presented with an average albumin level and prealbumin level of 2.8 g/dL ± 1.1 and 15.8 mg/dL ± 2.5, respectively. These results highlight the importance of assessing nutritional status to determine whether nutritional optimization is necessary prior to declaring the patient a candidate for surgical management. Similarly, in cases of extremity wounds, a vascular surgeon should be consulted to perform noninvasive vascular imaging to visualize vessel characteristics, course, and patency status throughout the affected limb to better inform reconstructive decision-making.³² However, it is important to note that such screening measures may not always be possible in urgent settings of rapidly progressive infection or sepsis. 

For a wound that is deemed to be infected, serial surgical debridement with removal of all grossly infected and nonviable, necrotic tissue is indicated, along with intraoperative soft tissue and bone cultures.^2,4 In the current case series, 7 primary post-debridement cultures were positive (63.6%), with polymicrobial cultures being most common (n = 4). Given the intricacies involved in managing polymicrobial infections in comorbid patients, collaboration with infectious diseases specialists is vital to ensure that an adequately tailored antibiotic regimen is provided.³³ Between debridements, wound dressings included either diluted acetic acid-soaked gauze or NPWT, as supported by prior evidence demonstrating the efficacy of NPWT as part of a multimodal approach to the management of infected wounds.^25,34,35 Once the infection is cleared, as evidenced by negative results of cultures and a clinically healthy-appearing wound bed, closure via a number of means (eg, primary, local flap, skin graft, artificial dermal scaffolding) may be considered.^4,22 In such cases, the specific approach to closure used will depend on the size and depth of the defect, in addition to vascular status.

In noninfectious cases, primary excision of severely painful wounds or subcutaneous nodules may be performed. The current study authors’ analysis of pain medication regimens reflects the ability of surgical management to substantially decrease the intense pain experienced by many patients with calciphylaxis. However, in patients who died during hospital admission or shortly thereafter, this improvement was not appreciated, which suggests that the pain-relieving benefits of surgery may be confounded in severely ill patients by several confounding factors; however, surgery should be considered on an individual basis.

Following primary excision, immediate closure may be accomplished by primary closure, local flaps, skin grafting, or dermal scaffolding.^21,27 Although Tsolakidis et al²¹ argued that local flap techniques showed no benefit and instead advocated for skin grafting in the setting of an appropriate wound bed, all 3 local flaps used in the current series were successful, with no episodes of flap necrosis or failure. This divergence may be owing to differences in regional perfusion surrounding the wound or each patient’s individual medical stability; however, the reason for this divergence is difficult to discern because neither vascular or laboratory findings were reported by Tsolakidis et al.²¹ Ultimately, if attempted, closure must be achieved with minimal tension to reduce the risk of further necrosis and, subsequently, disease progression.^23,25 

Postoperatively, the most common complications observed in the current study included delayed wound healing, cellulitis, and progression to amputation. The surgical decision to continue limb salvage attempts versus progressing to amputation is often difficult; thus, continuous collaboration between the aforementioned medical and surgical multidisciplinary teams is necessary to determine the optimal individualized approach. Consultation with urologic surgeons also may be indicated, depending on the lesion location.^16,19,20 In a 2019 case series, Dado et al²⁶ suggested that highly specialized institutions such as burn centers may be particularly equipped to manage the complex, multimodal care required by patients with calciphylaxis. Similarly, wound centers are staffed by a variety of medical and surgical specialists with experience in treating chronic wounds such as those that affect patients with calciphylaxis.^36,37 Continued investigations are therefore warranted to better understand the ways in which such centers can further contribute to the optimization of care in this patient population. Additionally, although the findings of the current study support the use of surgical intervention to reduce pain and improve quality of life in patients with calciphylaxis, future studies examining the role of surgery in the palliative management of patients with calciphylaxis are indicated to better inform end-of-life care for this population.

This study has several limitations, including its retrospective nature, which is dependent on the quality of EMR reporting. Additionally, the small sample size precluded any comparative analysis; thus, additional studies are needed to further characterize the effect of each treatment approach on patient outcomes. Nonetheless, when combined with findings from previous studies, the results from the current study not only reflect the substantial morbidity and mortality associated with calciphylaxis, but also enabled the establishment of an algorithmic approach to multidisciplinary management of patients with calciphylaxis. 

In this case series of 11 patients with calciphylaxis with intractable pain or infected wounds, patients often required serial debridement and careful wound care during frequently prolonged hospital stays. While calciphylaxis continues to carry a substantial morbidity and mortality burden, as demonstrated by a 2-year mortality rate of 63.6%, 5 of the 6 patients alive at the recorded time of healing were no longer taking narcotic medications, which reflects the ability of surgery to effectively reduce the intractable pain associated with calciphylaxis lesions. Wound care centers are uniquely equipped with medical and surgical specialists with experience in treating chronic wounds, affording the establishment of an algorithmic approach to a multidisciplinary care model for patients with calciphylaxis.