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A Case of Difficult Pain in a Patient With Chronic Renal Failure and Calciphylaxis
Vol. 22 No. 1 July 2001
Journal of Pain and Symptom Management 617
Palliative Care Rounds
A Case of Difficult Pain in a Patient With Chronic Renal Failure and Calciphylaxis Alison Rich, MRCP, Austin Leach, FRCA, and John Ellershaw, FRCP Marie Curie Centre (A.R.), and Royal Liverpool University Hospital (A.L., J.E.), Liverpool, United Kingdom
Abstract A difficult pain occurred in a man with chronic renal failure as a result of the underlying condition of calciphylaxis. In this condition, calcification of small and medium-sized arteries occurs, which may result in ischemia and gangrene. In general, the prognosis is poor, with mortality rates ranging from 23–63%. Pain associated with this condition has been previously reported. In this report, the pain occurred in the lower limbs and penis, and was associated with local necrosis. The pain was observed to be significantly worse on dialysis. A multiprofessional approach to care ultimately resulted in good symptom control. J Pain Symptom Manage 2001;22:617–621 © U.S. Cancer Pain Relief Committee, 2001. Key Words Calciphylaxis, end-stage renal disease, noncancer (non-MeSH)
Introduction Calciphylaxis is a rare but recognized complication of chronic renal failure. With increasing numbers of chronic renal failure patients on hemodialysis for prolonged periods, it is likely to be more frequently observed. A patient with a challenging pain problem related to calciphylaxis is presented to highlight the condition and emphasize the important of multiprofessional teamwork to optimize symptom control. In a study of 242 hemodialysis patients, the prevalence of calciphylaxis was found to be 4.1%.1 Patients with calciphylaxis were significantly younger; had undergone hemodialysis longer; and had higher median serum calcium,
Address reprint requests to: Alison Rich, MRCP, Marie Curie Centre Liverpool, Speke Road, Woolton, Liverpool L25 8QA, United Kingdom. Accepted for publication: October 10, 2000. © U.S. Cancer Pain Relief Committee, 2001 Published by Elsevier, New York, New York
phosphate, and calcium-phosphate product. Parathyroid hormone levels were also significantly higher. Calciphylaxis is diagnosed by a combination of clinical features and histological findings. The different diagnoses include cryofibrinogenemia, inflammatory vasculitis, and dermatomyositis. The skin features include purpuric plaques, nodules, or mottled skin (livedo reticularis) progressing to necrotic ulcers, gangrene, and, potentially, amputation. Sepis and death may follow. Bullous lesions preceding the ulcerating lesions have been previously described.2 A painful proximal myopathy may antedate the skin signs,3 and appear similar to dermatomyositis.4 In 90% of patients, the lower extremities are predominantly involved.5 Lower extremity involvement is associated with a lower mortality (23%).6 Proximal locations of necrosis (thigh, buttocks, trunk) carry an unfavorable prognosis (63% mortality), compared to distal locations (calves, forearms, fingers, toes, penis).6 The etiology of the disease is 0885-3924/01/$–see front matter PII S0885-3924(01)00298-6
618
poorly understood. Calcification of small- to medium-sized arteries occurs, causing ischemic necrosis of the skin and other organ systems.7 Most of the cases reported have hyperparathyroidism, and an elevated calcium-phosphate product is thought to be a major pathogenic factor. There may, however, be no distinctive pattern of serum calcium, phosphate, and parathyroid hormone levels. Other factors suggested include iron overload,8 and functional protein C deficiency.5 Biopsy specimens show varying degrees of calcification of the media layer of blood vessel walls of subcutaneous and/or digital arteries.6
Case Report A 64-year-old man with polycystic kidney disease and insulin-dependent diabetes was admitted to the hospital with a suspected left deep venous thrombosis which was treated with warfarin. He had undergone a renal transplant in 1980, which failed 16 years later. Since then, he had been receiving thrice-weekly hemodialysis. He had developed secondary hyperparathyroidism and peripheral vascular disease. He was discharged home on warfarin and continued with regular hemodialysis. A month later he presented with pain in his right lower leg and superficial erythematous skin changes. A venogram excluded a thrombosis and he was treated with intravenous antibiotics. A radiograph of his abdomen was noted to show extensive vascular calcification. He continued to complain of pain, particularly in both calves, and commenced slow-release morphine 5 mg twice daily. Nerve conduction studies of the legs showed moderately severe mixed sensory and motor neuropathy. His pain persisted and slow-release morphine was increased to 10 mg twice daily and amitriptyline 50 mg was started as a co-analgesic. Because of his continuing bilateral leg pain, an MRI scan of the spine was performed, which showed no spinal cord or nerve root problems. He was discharged on slow-release morphine 30 mg twice daily and amitriptyline 50 mg, which gave reasonable pain relief and enabled him to be managed at home. He was subsequently readmitted a month later, feeling generally unwell, with symptoms of fluid overload. He had been diagnosed with herpes zoster on the glans penis, having pre-
Rich et al.
Vol. 22 No. 1 July 2001
sented to the dermatologists with a painful rash on the penis. There was, however, no improvement in the lesions following treatment with acyclovir and it was suspected that he could have erosive balanitis or an underlying carcinoma. A biopsy was, therefore, performed. Pain in the penis became an increasing problem and he was referred to the Hospital Palliative Care Team and the Pain Specialist Consultant. He described partial relief of the pain with immediate-release morphine sulfate and was started on a regular nonsteroidal anti-inflammatory drug (diclofenac 50 mg three times daily). His regular slow-release opioid was again increased. The pain was described as burning in nature and there was extreme hypersensitivity to any dressings or clothing. He was given topical lidocaine and commenced on clonazepam 0.5 mg, increasing to 1 mg. Over the next few weeks, the fingers of his right hand became painful, with erythematous and edematous fingertips and an ulcerating purplish rash over the dorsum of the right hand. A doppler ultrasound scan of the blood supply to the penis was reported as showing “vascular calcification at the base of the penis. No arterial flow.” His fingers were cold to the touch and dusky in appearance, with multiple painful ulcers on the fingertips. The glans penis was ulcerated and had a persistent brown discharge. Serum cryofibrinogen levels were within normal limits. Further developments included severe myalgia in his shoulders and thighs. The glan penis became necrotic (Figure 1). Increasing amounts of breakthrough analgesia in the form of immediate-release morphine were required in addition of his slow-release morphine. He became drowsy and slightly twitchy, which was felt to be partly due to accumulation of morphine metabolites. He was started on a regular short-acting opioid and his long-term opioids were discontinued. Given the necrosis of the penis, it was decided to perform a partial amputation of the penis and orchidectomy/scrotectomy. At the time of surgery, an epidural catheter was inserted (having discontinued his warfarin to normalize his coagulation profile). Initially postoperatively, his pain did seem better controlled. However, three days postoperatively, his epidural became displaced and he refused the offer of replacing it. He continued on regular doses
Vol. 22 No. 1 July 2001
Difficult Pain in Chronic Renal Failure and Calciphylaxis
Figure 1. Necrotic glans penis.
of morphine, which gave moderate relief only. His mood was extremely poor and he was very angry at the medical and nursing staff. His right leg started becoming more inflamed and swollen and a large ulcer developed on the medial aspect of the right lower leg. Ecchymosis-like patches developed into blisters and then ulcers (Figure 2). Pain was present in both calves and perineum, and appeared be worse when on dialysis. Histology of penis/scrotum/testicle showed fibrocalcific obliteration of testicular arteries with no evidence of vasculitis, confirming the team’s suspicion of a diagnosis of calciphylaxis. A subcutaneous infusion of diamorphine 20 mg and midazolam 5 mg over 24 hours was commenced in an attempt to gain better pain control. The patient was becoming increas-
619
ingly apprehensive about dialysis and the associated pain, and was, therefore, given extra subcutaneous doses of diamorphine (5 mg) and midazolam (5 mg) one hour before dialysis. There did appear to be some improvement in pain with this regimen. The possibility of parathyroidectomy was considered; it was felt that the patient was too unwell to tolerate this. The right leg ulcer was extending further, with areas of significant necrosis and purulent offensive discharge. He remained on intravenous antibiotics, although blood cultures had been negative. In addition, his perineal wound started to break down. At this time, the patient became increasingly angry and distressed, refusing any further dialysis and not wanting to stay in the hospital. The possibility of transfer to a hospice local to their home was discussed. The patient was fully aware that if he had no further dialysis he would die. His request was to be at the hospice, which would enable his family to be with him much more of the time. A multidisciplinary meeting was arranged with the patient and family members, and representatives from the palliative care team and renal teams along with ward nursing staff, to discuss the current situation and future options. Later that day, transfer to the hospice was arranged. At the hospice, he was started on ketorolac (90 mg over 24 hours) via a second subcutaneous syringe driver and continued with the diamorphine/midazolam infusion. Over the course of the next week, syringe driver medication was slowly increased to diamorphine 100 mg, midazolam 40 mg, and ketorolac 90 mg over a 24-hour period. The patient died peacefully eight days after stopping hemodialysis. No post-mortem examination was performed.
Discussion Treatment of the pain associated with calciphylaxis has not previously been described, although in most of the published case reports the necrotic lesions are described as painful. In this case, the pain was significantly worse while on dialysis. We are unable to comment on whether this is a specific feature of pain in calciphylaxis, since no references to this appear in the literature. The worsening of the pain during dialysis was postulated to result from the dialysing out of some of the opioid analgesics, or
620
Rich et al.
Vol. 22 No. 1 July 2001
Figure 2. Blisters and purpuric areas developing on lower limb.
it may be linked to ionization changes (a low calcium dialysate fluid was used). Given the lack of understanding of the etiology of calciphylaxis, it is hardly surprising that treatment is not very effective and mortality is high. It has been suggested that early treatment with lowering of calcium and phosphate levels, along with parathyroidectomy, may improve the prognosis.4 It has been concluded, however, that parathyroidectomy should be reserved for patients with very high parathyroid hormone level and calcium-phosphate product or with a rapidly progressive or proximal disease. Debridement of necrotic lesions and aggressive wound care, along with prevention and treatment of infection, are also all important aspects of management. In one study, five patients were described, all of whom had painful ulcers and underwent parathyroidectomy.9 Of the three patients who survived, there was a dramatic improvement in both their pain and their ulcers. In our case, by the time the diagnosis was clear, the patient was already too unwell to undergo a parathyroidectomy. Although excellent pain control was only achieved in the last days of life, a combined approach to care involving surgical colleagues, renal physicians, anesthetists, and palliative care physicians was essential to optimize symptom
control. Our patient’s pain was exacerbated by significant emotional and psychological distress. He had been through mutilating surgery, but was not improving. He remained very angry with the hospital staff and found it difficult to accept his condition. This type of complex case emphasizes the need for multidisciplinary team involvement to attempt to address all aspects of his physical, psychological, social, and spiritual well-being. Sometimes this cannot be adequately provided in the acute setting and patients may need to physically distance themselves from all that has happened there.
References 1. Angelis M, Wong LL, Myers SA, Wong LM. Calciphylaxis in patients in hemodialysis: a prevalence study. Surgery 1997;122:1083–1090. 2. Ivker RA, Woosey J, Briggaman RA. Calciphylaxis in three patients with end-stage renal disease. Arch Dermatol 1995;131:63–68. 3. Edelstein CL, Wickham MK, Kirby PA. Systemic calciphylaxis presenting as a painful proximal myopathy. Postgrad Med J 1992;68:209–211. 4. Flanigan KM, Bromberg MB, Gregory M, et al. Calciphylaxis mimicking dermatomyositis: ischaemic myopathy complicating renal failure. Neurology 1998; 51:1634–1640. 5. Budisavljevic MN, Cheek D, Ploth DW. Calciphy-
Vol. 22 No. 1 July 2001
Difficult Pain in Chronic Renal Failure and Calciphylaxis
laxis in chronic renal failure. J Am Soc Nephrol 1996;7:978–982. 6. Hafner J, Keusch G, Wahl C, Burg G. Calciphylaxis; a syndrome of skin necrosis and acral gangrene in chronic renal failure. Vasa 1998;27:137–143. 7. Oh DH, Eulau D, Tokugawa DA, et al. Five cases of calciphylaxis and a review of the literature. J Am Acad Dermatol 1999;40:979–987.
621
8. Rubinger D, Friedlaender MM, Silver J, et al. Progressive vascular calcification with necrosis of extremities in hemodialysis patients: a possible role of iron overload. Am J Kidney Dis 1986;7:125–129. 9. Duh QY, Lim RC, Clark OH. Calciphylaxis in secondary hyperparathryroidism. Diagnosis and parathroidectomy. Arch Surg 1991;126:1213–1219.
Journal of Pain and Symptom Management 617
Palliative Care Rounds
A Case of Difficult Pain in a Patient With Chronic Renal Failure and Calciphylaxis Alison Rich, MRCP, Austin Leach, FRCA, and John Ellershaw, FRCP Marie Curie Centre (A.R.), and Royal Liverpool University Hospital (A.L., J.E.), Liverpool, United Kingdom
Abstract A difficult pain occurred in a man with chronic renal failure as a result of the underlying condition of calciphylaxis. In this condition, calcification of small and medium-sized arteries occurs, which may result in ischemia and gangrene. In general, the prognosis is poor, with mortality rates ranging from 23–63%. Pain associated with this condition has been previously reported. In this report, the pain occurred in the lower limbs and penis, and was associated with local necrosis. The pain was observed to be significantly worse on dialysis. A multiprofessional approach to care ultimately resulted in good symptom control. J Pain Symptom Manage 2001;22:617–621 © U.S. Cancer Pain Relief Committee, 2001. Key Words Calciphylaxis, end-stage renal disease, noncancer (non-MeSH)
Introduction Calciphylaxis is a rare but recognized complication of chronic renal failure. With increasing numbers of chronic renal failure patients on hemodialysis for prolonged periods, it is likely to be more frequently observed. A patient with a challenging pain problem related to calciphylaxis is presented to highlight the condition and emphasize the important of multiprofessional teamwork to optimize symptom control. In a study of 242 hemodialysis patients, the prevalence of calciphylaxis was found to be 4.1%.1 Patients with calciphylaxis were significantly younger; had undergone hemodialysis longer; and had higher median serum calcium,
Address reprint requests to: Alison Rich, MRCP, Marie Curie Centre Liverpool, Speke Road, Woolton, Liverpool L25 8QA, United Kingdom. Accepted for publication: October 10, 2000. © U.S. Cancer Pain Relief Committee, 2001 Published by Elsevier, New York, New York
phosphate, and calcium-phosphate product. Parathyroid hormone levels were also significantly higher. Calciphylaxis is diagnosed by a combination of clinical features and histological findings. The different diagnoses include cryofibrinogenemia, inflammatory vasculitis, and dermatomyositis. The skin features include purpuric plaques, nodules, or mottled skin (livedo reticularis) progressing to necrotic ulcers, gangrene, and, potentially, amputation. Sepis and death may follow. Bullous lesions preceding the ulcerating lesions have been previously described.2 A painful proximal myopathy may antedate the skin signs,3 and appear similar to dermatomyositis.4 In 90% of patients, the lower extremities are predominantly involved.5 Lower extremity involvement is associated with a lower mortality (23%).6 Proximal locations of necrosis (thigh, buttocks, trunk) carry an unfavorable prognosis (63% mortality), compared to distal locations (calves, forearms, fingers, toes, penis).6 The etiology of the disease is 0885-3924/01/$–see front matter PII S0885-3924(01)00298-6
618
poorly understood. Calcification of small- to medium-sized arteries occurs, causing ischemic necrosis of the skin and other organ systems.7 Most of the cases reported have hyperparathyroidism, and an elevated calcium-phosphate product is thought to be a major pathogenic factor. There may, however, be no distinctive pattern of serum calcium, phosphate, and parathyroid hormone levels. Other factors suggested include iron overload,8 and functional protein C deficiency.5 Biopsy specimens show varying degrees of calcification of the media layer of blood vessel walls of subcutaneous and/or digital arteries.6
Case Report A 64-year-old man with polycystic kidney disease and insulin-dependent diabetes was admitted to the hospital with a suspected left deep venous thrombosis which was treated with warfarin. He had undergone a renal transplant in 1980, which failed 16 years later. Since then, he had been receiving thrice-weekly hemodialysis. He had developed secondary hyperparathyroidism and peripheral vascular disease. He was discharged home on warfarin and continued with regular hemodialysis. A month later he presented with pain in his right lower leg and superficial erythematous skin changes. A venogram excluded a thrombosis and he was treated with intravenous antibiotics. A radiograph of his abdomen was noted to show extensive vascular calcification. He continued to complain of pain, particularly in both calves, and commenced slow-release morphine 5 mg twice daily. Nerve conduction studies of the legs showed moderately severe mixed sensory and motor neuropathy. His pain persisted and slow-release morphine was increased to 10 mg twice daily and amitriptyline 50 mg was started as a co-analgesic. Because of his continuing bilateral leg pain, an MRI scan of the spine was performed, which showed no spinal cord or nerve root problems. He was discharged on slow-release morphine 30 mg twice daily and amitriptyline 50 mg, which gave reasonable pain relief and enabled him to be managed at home. He was subsequently readmitted a month later, feeling generally unwell, with symptoms of fluid overload. He had been diagnosed with herpes zoster on the glans penis, having pre-
Rich et al.
Vol. 22 No. 1 July 2001
sented to the dermatologists with a painful rash on the penis. There was, however, no improvement in the lesions following treatment with acyclovir and it was suspected that he could have erosive balanitis or an underlying carcinoma. A biopsy was, therefore, performed. Pain in the penis became an increasing problem and he was referred to the Hospital Palliative Care Team and the Pain Specialist Consultant. He described partial relief of the pain with immediate-release morphine sulfate and was started on a regular nonsteroidal anti-inflammatory drug (diclofenac 50 mg three times daily). His regular slow-release opioid was again increased. The pain was described as burning in nature and there was extreme hypersensitivity to any dressings or clothing. He was given topical lidocaine and commenced on clonazepam 0.5 mg, increasing to 1 mg. Over the next few weeks, the fingers of his right hand became painful, with erythematous and edematous fingertips and an ulcerating purplish rash over the dorsum of the right hand. A doppler ultrasound scan of the blood supply to the penis was reported as showing “vascular calcification at the base of the penis. No arterial flow.” His fingers were cold to the touch and dusky in appearance, with multiple painful ulcers on the fingertips. The glans penis was ulcerated and had a persistent brown discharge. Serum cryofibrinogen levels were within normal limits. Further developments included severe myalgia in his shoulders and thighs. The glan penis became necrotic (Figure 1). Increasing amounts of breakthrough analgesia in the form of immediate-release morphine were required in addition of his slow-release morphine. He became drowsy and slightly twitchy, which was felt to be partly due to accumulation of morphine metabolites. He was started on a regular short-acting opioid and his long-term opioids were discontinued. Given the necrosis of the penis, it was decided to perform a partial amputation of the penis and orchidectomy/scrotectomy. At the time of surgery, an epidural catheter was inserted (having discontinued his warfarin to normalize his coagulation profile). Initially postoperatively, his pain did seem better controlled. However, three days postoperatively, his epidural became displaced and he refused the offer of replacing it. He continued on regular doses
Vol. 22 No. 1 July 2001
Difficult Pain in Chronic Renal Failure and Calciphylaxis
Figure 1. Necrotic glans penis.
of morphine, which gave moderate relief only. His mood was extremely poor and he was very angry at the medical and nursing staff. His right leg started becoming more inflamed and swollen and a large ulcer developed on the medial aspect of the right lower leg. Ecchymosis-like patches developed into blisters and then ulcers (Figure 2). Pain was present in both calves and perineum, and appeared be worse when on dialysis. Histology of penis/scrotum/testicle showed fibrocalcific obliteration of testicular arteries with no evidence of vasculitis, confirming the team’s suspicion of a diagnosis of calciphylaxis. A subcutaneous infusion of diamorphine 20 mg and midazolam 5 mg over 24 hours was commenced in an attempt to gain better pain control. The patient was becoming increas-
619
ingly apprehensive about dialysis and the associated pain, and was, therefore, given extra subcutaneous doses of diamorphine (5 mg) and midazolam (5 mg) one hour before dialysis. There did appear to be some improvement in pain with this regimen. The possibility of parathyroidectomy was considered; it was felt that the patient was too unwell to tolerate this. The right leg ulcer was extending further, with areas of significant necrosis and purulent offensive discharge. He remained on intravenous antibiotics, although blood cultures had been negative. In addition, his perineal wound started to break down. At this time, the patient became increasingly angry and distressed, refusing any further dialysis and not wanting to stay in the hospital. The possibility of transfer to a hospice local to their home was discussed. The patient was fully aware that if he had no further dialysis he would die. His request was to be at the hospice, which would enable his family to be with him much more of the time. A multidisciplinary meeting was arranged with the patient and family members, and representatives from the palliative care team and renal teams along with ward nursing staff, to discuss the current situation and future options. Later that day, transfer to the hospice was arranged. At the hospice, he was started on ketorolac (90 mg over 24 hours) via a second subcutaneous syringe driver and continued with the diamorphine/midazolam infusion. Over the course of the next week, syringe driver medication was slowly increased to diamorphine 100 mg, midazolam 40 mg, and ketorolac 90 mg over a 24-hour period. The patient died peacefully eight days after stopping hemodialysis. No post-mortem examination was performed.
Discussion Treatment of the pain associated with calciphylaxis has not previously been described, although in most of the published case reports the necrotic lesions are described as painful. In this case, the pain was significantly worse while on dialysis. We are unable to comment on whether this is a specific feature of pain in calciphylaxis, since no references to this appear in the literature. The worsening of the pain during dialysis was postulated to result from the dialysing out of some of the opioid analgesics, or
620
Rich et al.
Vol. 22 No. 1 July 2001
Figure 2. Blisters and purpuric areas developing on lower limb.
it may be linked to ionization changes (a low calcium dialysate fluid was used). Given the lack of understanding of the etiology of calciphylaxis, it is hardly surprising that treatment is not very effective and mortality is high. It has been suggested that early treatment with lowering of calcium and phosphate levels, along with parathyroidectomy, may improve the prognosis.4 It has been concluded, however, that parathyroidectomy should be reserved for patients with very high parathyroid hormone level and calcium-phosphate product or with a rapidly progressive or proximal disease. Debridement of necrotic lesions and aggressive wound care, along with prevention and treatment of infection, are also all important aspects of management. In one study, five patients were described, all of whom had painful ulcers and underwent parathyroidectomy.9 Of the three patients who survived, there was a dramatic improvement in both their pain and their ulcers. In our case, by the time the diagnosis was clear, the patient was already too unwell to undergo a parathyroidectomy. Although excellent pain control was only achieved in the last days of life, a combined approach to care involving surgical colleagues, renal physicians, anesthetists, and palliative care physicians was essential to optimize symptom
control. Our patient’s pain was exacerbated by significant emotional and psychological distress. He had been through mutilating surgery, but was not improving. He remained very angry with the hospital staff and found it difficult to accept his condition. This type of complex case emphasizes the need for multidisciplinary team involvement to attempt to address all aspects of his physical, psychological, social, and spiritual well-being. Sometimes this cannot be adequately provided in the acute setting and patients may need to physically distance themselves from all that has happened there.
References 1. Angelis M, Wong LL, Myers SA, Wong LM. Calciphylaxis in patients in hemodialysis: a prevalence study. Surgery 1997;122:1083–1090. 2. Ivker RA, Woosey J, Briggaman RA. Calciphylaxis in three patients with end-stage renal disease. Arch Dermatol 1995;131:63–68. 3. Edelstein CL, Wickham MK, Kirby PA. Systemic calciphylaxis presenting as a painful proximal myopathy. Postgrad Med J 1992;68:209–211. 4. Flanigan KM, Bromberg MB, Gregory M, et al. Calciphylaxis mimicking dermatomyositis: ischaemic myopathy complicating renal failure. Neurology 1998; 51:1634–1640. 5. Budisavljevic MN, Cheek D, Ploth DW. Calciphy-
Vol. 22 No. 1 July 2001
Difficult Pain in Chronic Renal Failure and Calciphylaxis
laxis in chronic renal failure. J Am Soc Nephrol 1996;7:978–982. 6. Hafner J, Keusch G, Wahl C, Burg G. Calciphylaxis; a syndrome of skin necrosis and acral gangrene in chronic renal failure. Vasa 1998;27:137–143. 7. Oh DH, Eulau D, Tokugawa DA, et al. Five cases of calciphylaxis and a review of the literature. J Am Acad Dermatol 1999;40:979–987.
621
8. Rubinger D, Friedlaender MM, Silver J, et al. Progressive vascular calcification with necrosis of extremities in hemodialysis patients: a possible role of iron overload. Am J Kidney Dis 1986;7:125–129. 9. Duh QY, Lim RC, Clark OH. Calciphylaxis in secondary hyperparathryroidism. Diagnosis and parathroidectomy. Arch Surg 1991;126:1213–1219.