Calciphylaxis (also termed calcific uremic arteriolopathy) is a rare and serious medical condition characterized by abnormal, excessive calcification in the underlying vascular system of the subcutaneous fat and dermal tissues.1 This calcification leads to clinically significant manifestations such as painful ischemic sores, often with associated tactile hyperesthesia.1 Whereas calciphylaxis is most commonly associated with uremia and end-stage renal disease (ESRD), other characteristics and comorbid conditions have been postulated to be related, including female sex, White race, obesity, diabetes, protein undernourishment, coagulopathy, use of a vitamin K inhibitor such as warfarin, and endocrine or metabolic derangements such as hyperparathyroidism and hypercalcemia.1–5 Most patients with non-nephrogenic calciphylaxis have more than one of these conditions.6 In the US, the incidence of calciphylaxis in patients with ESRD requiring hemodialysis has been reported at 35 cases per 10,000 persons.7 Diagnosis carries a 6-month survival rate of 57%.3
The resultant clinical effects of calciphylaxis create perioperative treatment challenges. Skin ulcerations can predispose to infection with the potential for spread to deeper sites, and death from sepsis is a common finding in calciphylaxis vasculopathy.2 A particularly debilitating feature of this disease is pain. The pain associated with ischemic calciphylaxis lesions is described as excruciating and unrelenting and often leads to a decline in patients’ functional status and to repeated hospitalizations.8 For patients with severe cases without adequate pain control, poor quality of life is expected. Surgical debridement of necrotic ulcers is often necessary to preserve surrounding tissue, and patients may require repeated surgical procedures after diagnosis and near the end of life.3,4,9
Currently, no standard treatment protocol exists for calciphylaxis nor are comprehensive guidelines available for perioperative care of patients with calciphylaxis. The purpose of this review was to evaluate existing literature in order to offer guidance on treating patients with this challenging disease through the perioperative period.
We conducted a narrative review of OVID Medline and EMBASE databases from January 2000 to May 2021 for English-language–only articles by using the search terms “calciphylaxis,” “calcific uremic arteriolopathy,” “anesthesia,” “anesthesiology,” “perioperative,” “acute pain,” “pain management,” and “postoperative pain.” Additional sources were also identified from cited references in the articles initially returned by the search.
The articles were organized according to 4 categories: 1) case reports/case series with an emphasis on surgical/procedural treatment, 2) case reports/case series with an emphasis on pain-control measures, 3) case reports/case series with an emphasis on medical management, and 4) retrospective analyses and reviews evaluating risk factors, treatment outcomes, and general recommendations (Tables 1-5). For each identified case, data for patient age, sex, and comorbid conditions were collected and summarized along with author recommendations for management (if available). For each identified retrospective analysis or review article with general conclusions for disease and management recommendations, the level of supporting evidence was evaluated and a descriptive summary of each was generated.
The database search identified 300 potentially relevant articles. A total of 29 case reports from 32 sources met criteria for inclusion (Figure). As described in Methods, Tables 1 through 5 summarize the reports by subject area: surgical/procedural treatment; pain control measures; medical management; relevant retrospective analyses and recommendations relevant to perioperative management; and risk factors, treatment outcomes, and general recommendations.
Although a standard protocol does not exist for treating calciphylaxis, the literature search identified several common therapies being used including intravenous sodium thiosulfate,3,6,36,37 parathyroidectomy,3,9,13 surgical debridement,2,4,9,14 bisophosphonate,35 cinacalcet,5 and hyperbaric oxygen therapy.3,5,21 However, the reports conflicted regarding the efficacy of each, which will be described in detail in the Discussion. There are also no comprehensive guidelines for perioperative management of patients with calciphylaxis. A retrospective analysis of cases of 5 patients treated with parathyroidectomy reported no specific additional risks of surgery.13 Several reports showed that ultrasound-guided neurolytic therapy with cryoneurolysis15 or phenol injection16,17 was effective for pain relief. Interestingly, one report documented a case of postoperative calciphylaxis in a patient with ESRD who was exposed to multiple calciphylaxis-associated risk factors perioperatively.11 Thus, it may be prudent to identify at-risk patients undergoing surgery and control risk factor exposure to minimize development of calciphylaxis postoperatively.
Recommendations for Perioperative Management
Based on the literature review and case reports, we recommend the following perioperative management for patients with calciphylaxis (Supplemental Table).
Preoperative evaluation should assess for common comorbid conditions including ESRD, diabetes, obesity, and hyperparathyroidism and/or hypercalcemia.1–5 A thorough history and physical examination should be conducted before surgery with special consideration to baseline pain scores and functional activity because of the debilitating effects of calciphylaxis on patient pain and functional capacity.32 For these assessments, structured questionnaires have been reported as more accurate than subjective assessments.38 For patients taking long-acting opioids for pain management, we recommend having them take their extended-release medication the morning of surgery. Given the large proportion of patients with calciphylaxis who are dialysis dependent, timing dialysis must be considered when scheduling surgery—optimally 24 hours after dialysis to minimize the impact on volume status and electrolyte balance (level II).18 Laboratory studies should be obtained to assess for relevant parameters including estimated glomerular filtration rate, electrolyte imbalances, serum glucose, and anemia. ESRD, diabetes, and obesity are associated with increased perioperative risk for cardiovascular events. The following validated models may be useful for predicting cardiac complications: revised cardiac risk index39 and American College of Surgeons surgical risk calculator.40
To our knowledge, no intraoperative issues specific to calciphylaxis require special consideration. A retrospective analysis of 5 patients with calciphylaxis undergoing parathyroidectomy showed no additional surgical risks.13 However, given the cutaneous involvement of the disease, care should be taken when positioning the patient to avoid exacerbating existing wounds. As with other patients with ESRD, fluid and electrolyte status need to be monitored preoperatively and intraoperatively to avoid complications such as pulmonary edema, anesthesia-induced hypotension, and arrhythmias attributable to hyperkalemia or hypocalcemia (level II).41 For patients undergoing parathyroidectomy to treat hyperparathyroidism, parathyroid hormone assays should be considered to monitor any decrease in parathyroid hormone levels during surgery.42
Pain control should be aggressively pursued using a multimodal approach. Because of the prevalence of renal impairment in patients with calciphylaxis, medications such as nonsteroidal anti-inflammatory drugs (which impair renal autoregulation) or morphine (risk of metabolite accumulation) may be contraindicated.43 Therapies used successfully preoperatively should be continued perioperatively, eg, fentanyl/fentanyl analogs, benzodiazepines, local anesthetics such as lidocaine, and neuropathic pain agents such as anticonvulsants or ketamine (level IV).18 Low-dose ketamine infusions have been used in opioid-tolerant patients for acute pain control without adverse effects or need for dose modification due to renal impairment and therefore may be an adjunctive therapy for achieving pain control (level IV).44 Intraoperative ketamine at lower rates (0.1-0.5 mg/kg/h) has been used for perioperative pain management of burn patients with similarly complex wounds.38
Calciphylaxis may be triggered or exacerbated by corticosteroids and blood transfusions. Therefore, systemic corticosteroid use should be avoided, and steps should be taken to minimize perioperative blood transfusions (eg, reversing anemia associated with chronic kidney disease through iron and/or erythropoietin supplementation before surgery and careful fluid management and repletion during surgery). A patient with calciphylaxis and POEMS syndrome who received dexamethasone every 2 weeks had remission of both POEMS syndrome and the calciphylaxis skin lesions.37 Dexamethasone may still be an option for postoperative nausea and vomiting prophylaxis.
If complications due to peripheral ischemia (based on location of calciphylaxis lesions) are a concern, laser Doppler blood flowmetry monitoring may be used to maintain peripheral blood flow in conjunction with vasodilators such as prostaglandin E1 analogs (level IV).12
If a patient has diabetes, intraoperative glycemic control is important.
For this study, we identified 3 areas of interest that should be considered in postoperative care.
First, risk factors and triggers need to be avoided. For example, vitamin K antagonists such as warfarin may trigger or exacerbate calciphylaxis.18 Therefore, we recommend giving a direct anticoagulant to patients who require postoperative anticoagulation therapy. A retrospective study of 20 patients with ESRD and calciphylaxis showed that apixaban was a safe and effective alternative to warfarin.29 Other potential calciphylaxis triggers include corticosteroids19,31 and blood transfusions.11
Second, poor wound healing is another postsurgical issue. A retrospective study of 71 patients with calciphylaxis undergoing sodium thiosulfate treatment showed that cerium nitrate-silver sulfadiazine therapy might be useful for vascular decalcification and infection prevention.28 A study evaluating a biofilm of purified collagen matrix with polyhexamethylene biguanide showed complete ulcer healing and re-epithelization in a patient with calciphylaxis.23 Use of the novel therapy SNF472, an intravenous formulation of myoinositol hexaphosphate, to inhibit hydroxyapatite crystal formation and prevent vascular calcification has shown potential therapeutic benefit.26 Hyperbaric oxygen therapy and referral to a burn center are options for managing recalcitrant wounds8,21; however, this therapy—like others for calciphylaxis—has not been validated by adequately powered prospective studies.45
Finally, adequate pain control is notoriously difficult to achieve for patients with calciphylaxis, requiring a multifactorial approach. Reported successful strategies include a combination of fentanyl/fentanyl analogs with benzodiazepines and neuropathic agents such as ketamine (level IV).18,44 Success has also been reported for neurolytic nerve blocks using phenol16,17 or cryoneurolysis.15 Diagnostic nerve blocks using fast-acting agents such as lidocaine or benzocaine may be useful for determining efficacy for individual patients. Given the high rates of morbidity and mortality associated with calciphylaxis, discussing palliative care options with patients early in the treatment process may be useful to maximize quality of life (level V).27,32
Calciphylaxis is a complex disorder affecting those with liver disease, diabetes, obesity, or, more commonly, uremia and ESRD. The formation of calcified microvascular deposits leads to microthrombosis, ischemia, and painful cutaneous manifestations. For these patients, preoperative and intraoperative disease management involves monitoring and optimizing comorbid conditions, taking into account any electrolyte imbalance. In postoperative management, the challenges involve potential triggers of calciphylaxis such as warfarin and corticosteroids. Moreover, poor wound healing and difficult pain control are frequent issues. A multifactorial approach that includes nerve blocks, renal-sparing opioids, benzodiazepines, and/or ketamine is recommended to optimize postoperative pain.
Marianne Mallia, ELS, MWC, senior scientific/medical editor, Mayo Clinic, substantively edited the manuscript. The Scientific Publications staff at Mayo Clinic provided proofreading, administrative, and clerical support.
All authors made substantial contributions to the analysis and interpretation of data for this manuscript. The drafting of the manuscript was performed evenly by all authors, and all authors are accountable for the accuracy and integrity of the work.
Declaration of Competing Interests
The Authors declare that there are not conflicting interests.
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.