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The allopurinol hypersensitivity syndrome
Netherlands Journal of Medicine 52 Ž1998. 107–110
Brief report
The allopurinol hypersensitivity syndrome H.J. Pluim a
a,)
, M. van Deuren b, J.F.M. Wetzels
c
Interne Geneeskunde, Canisius Wilhelmina Ziekenhuis, Postbus 9015, 6500 GS Nijmegen, Netherlands Algemeen Interne Geneeskunde, Academisch Ziekenhuis Nijmegen, 6500 HB Nijmegen, Netherlands c Nefrologie, Academisch Ziekenhuis Nijmegen, 6500 HB Nijmegen, Netherlands
b
Received 12 June 1997; revised 25 September 1997; accepted 7 October 1997
Abstract We describe a 61-year-old male patient who was treated with allopurinol and developed fever, a skin rash, eosinophilia and severe renal and liver dysfunction. We discuss the allopurinol hypersensitivity syndrome as a serious complication of the use of allopurinol, and briefly review the aetiology, prevention and treatment modalities. q 1998 Elsevier Science B.V. Keywords: Allopurinol; Oxypurinol; Side effect
1. Introduction Allopurinol is frequently used for the treatment of hyperuricaemia and gout, although its use in patients with asymptomatic hyperuricaemia is not justified. Two percent of the users develop a mild exanthema w1x. Sometimes a life-threatening reaction develops, as illustrated by the following case report.
2. Case report A 61-year-old man, with known hypertension and a slowly progressive renal insufficiency Žclinical diagnosis: nephrosclerosis; serum creatinine 210 mmolrl., was admitted to hospital because of malaise, rash and subfebrile temperature. Six weeks before admission allopurinol Ž300 mgrday. was pre-
)
Corresponding author. Tel.: q31 24 3657657; fax: q31 24 3658738.
scribed by the general practitioner because of asymptomatic hyperuricaemia. Five weeks later, the patient developed fever with a non-itching rash covering the whole body. A consultant dermatologist prescribed aciclovir Ž200 mg, t.i.d.. and triamcinolone cream on suspicion of a generalized herpes simplex infection. The patient stopped his own medication, consisting of allopurinol and lisinopril, 7 days before admission. During the following days, his temperature remained subfebrile and an oedema of his face developed. The last 2 days before admission he developed a watery diarrhoea without blood or mucus. On examination, the patient was moderately ill. His temperature was 38.48C, blood pressure 100r65 mmHg and pulse 120 b.p.m. A rash was seen covering the whole body. No petechia or purpura were found. The face was swollen. Examination of the neck, heart and lungs was normal. The liver was palpable 1 cm below the costal margin. The glans penis showed two ulcus lesions. On rectal examination a large prostate was found. No oedema was found on the extremities.
0300-2977r98r$19.00 q 1998 Elsevier Science B.V. All rights reserved. PII S 0 3 0 0 - 2 9 7 7 Ž 9 7 . 0 0 0 8 8 - 0
108
H.J. Pluim et al.r Netherlands Journal of Medicine 52 (1998) 107–110
Laboratory examination showed leucocytosis Ž18.1 = 10 9rl. with eosinophilia Ž14%.. No left shift was seen. The serum creatinine was markedly elevated Ž437 mmolrl. and liver enzymes were abnormal Žalkaline phosphatase 97 IUrl, g-glutamyl transpeptidase 262 IUrl, ALAT 115 IUrl, ASAT 57 IUrl, and LDH 584 IUrl.. There was a mild proteinuria Ž0.7 grl.. The sediment showed no red cells or red cell casts. A radiograph of the chest and ultrasound examination of the liver showed no abnormalities. The kidneys were small Ž10 cm.. No signs of postrenal obstruction were found. The combination of fever, rash, leucocytosis with eosinophilia, and liver and renal insufficiency with
recent use of allopurinol in a patient with a pre-existing renal insufficiency made the diagnosis of allopurinol hypersensitivity syndrome ŽAHS. likely. This diagnosis was supported by the finding of highly elevated plasma concentrations of the allopurinol metabolite oxypurinol Ž267 mmolrl, therapeutic level - 100 mmolrl. and the presence of erythema exsudativa multiforme in the skin biopsy. Because of the development of hypotension and renal insufficiency, the patient received fluid intravenously. One day after admission, treatment was started with ceftazidim and flucloxacilline because of high fever Ž408C. and suspected septicaemia. Despite rehydration, no improvement of renal function oc-
Fig. 1. The course of the temperature, the absolute number of eosinophils and the serum creatinine in association with the dose of corticosteroids. The closed columns refer to the dose of prednisone, while the open columns refer to the dose of methylprednisolone.
H.J. Pluim et al.r Netherlands Journal of Medicine 52 (1998) 107–110
curred. The patient developed oedema and gained 11 kg in weight in a few days. Because of threatening respiratory insufficiency, he was moved to the intensive care station. Fortunately, no artificial ventilation was needed. Four days after admission, a corticosteroid Žprednisone 50 mgrday. was started, whereafter the clinical situation improved. The rash disappeared gradually, while the kidney function improved and the leucocytosis and eosinophilia declined ŽFig. 1.. Antibiotics were stopped after 5 days when urine and blood cultures remained negative. Two weeks later, while lowering the dose of corticosteroid to 10 mgrday, our patient again developed high fever, a slight eosinophilia and deteriorating kidney function. Extensive examinations only showed the presence of a non-metastasized carcinoma of the prostate, but no signs of infections or autoimmune disease. Oxypurinol could no longer be detected in the serum. On the suspicion of a relapse of the AHS due to lowering of the dose of corticosteroids, renewed treatment with high-dose steroids, including methylprednisolone, was started, again resulting in a clinical improvement, while renal function stabilized with a creatinine of 465 mmolrl ŽFig. 1.. Six weeks after admission, the patient could be discharged.
3. Discussion The frequency of AHS is about 1 in 260 patients using allopurinol w2x. Criteria for the diagnosis are: Ž1. a clear exposure to allopurinol; Ž2. a clinical picture including Ža. at least two of the following major criteria: Ži. worsening renal function, Žii. acute hepatocellular injury, Žiii. a rash including either toxic epidermal necrolysis, erythema multiforme, or a diffuse maculopapular of exfoliative dermatitis, or Žb. one of the major criteria plus at least one of the following minor criteria: Ži. fever, Žii. eosinophilia, Žiii. leucocytosis; and Ž3. lack of exposure to another drug which may have caused a similar clinical picture w3x. AHS mostly begins within days or weeks of starting therapy with allopurinol. Mortality is about 25% w3–5x. Sepsis is the most frequent cause of mortality. Frequently, gastrointestinal bleeding occurs. Liver and renal failure are, in general, reversible w5x.
109
The risk of development of AHS is related to the level of oxypurinol, the therapeutic metabolite of allopurinol. Because oxypurinol is cleared by renal excretion, AHS occurs more frequently in patients with an impaired renal function or patients using thiazide diuretics. The exact mechanism responsible for the development of AHS is still unknown. It is assumed that accumulation of oxypurinol leads to tissue damage evoking an immunological response with development of antibodies against tissue components w4,6,7x, the formation of immune complexes and subsequent tissue damage w8x. Both granular deposits of IgM at the dermal–epidermal junction w6x, and linear deposits of g-globulin and complement along the glomerular basement membrane w7x were detected in patients with AHS. More recently, it was suggested that a T-cell-mediated immune reaction is involved in the pathogenesis of AHS w9x. There is no established therapy for AHS. Besides the cessation of allopurinol at the occurrence of the first signs of AHS, supportive therapy is important. Haemodialysis can be used to lower the level of oxypurinol w10x, but the therapeutic effect on the course of AHS has never been examined. In our patient, no oxypurinol was present at the time of the recurrence of the signs of AHS, indicating that the presence of oxypurinol is not required for persistence of AHS and arguing against the use of haemodialysis treatment. The use of corticosteroids is controversial. Because of the suspected immunological reaction as the cause of AHS, the use of corticosteroids seems justified. In our patient, we decided to start corticosteroid therapy because his clinical condition did not improve. Therapy needs to be continued for a long time to prevent relapse of the clinical syndrome w11,12x, as illustrated by our patient. However, the mortality of patients treated with corticosteroids seems to be higher compared with patients not treated with corticosteroids w4x. It is unclear if corticosteroids contribute to the increased mortality. We favour the explanation that corticosteroids are more likely used for patients with a more severe clinical syndrome, such as continuing fever, liver disturbances or worsening renal function. Obviously, the literature does not provide clinical, laboratory, or biopsy criteria that allow one to select the patients who will benefit from corticosteroid treatment. Because of the lack of therapy, prevention of
110
H.J. Pluim et al.r Netherlands Journal of Medicine 52 (1998) 107–110
Table 1 Maintenance doses of allopurinol for adults based on individual creatinine clearance measurements Žaccording to Hande w10x. Creatinine clearance Žmlrmin.
Maintenance dose
0 10 20 40 60 80 100 120 140
100 mgr3 days 100 mgr2 days 100 mgrday 150 mgrday 200 mgrday 250 mgrday 300 mgrday 350 mgrday 400 mgrday
has experienced a hypersensitivity reaction, one could consider desensitization w15x. References
AHS is of primary importance. Allopurinol should only be prescribed for the correct indication. These indications are: primary gout with tophi or uric acid stones caused by overproduction; uric acid stones or calcium oxalate stones without gout, combined with increased urinary excretion of urate; secondary renal gout with tophi; myeloproliferative diseases or other malignancies Žpreferably before the start of chemotherapy of radiotherapy.; high frequency of attacks despite the use of colchicine prophylaxis; intolerance for uricosuric agents; and Lesch–Nyhan syndrome and Von Gierke disease w13x. Asymptomatic hyperuricaemia is no indication for prescribing allopurinol, but, in practice, it appears to be the main reason for prescribing allopurinol w3,14x. Another important issue in the prescription of allopurinol is the adjustment of the dose to renal function. The usual dose of 300 mgrday is suitable for patients with a good renal function only ŽTable 1.. By prescribing allopurinol only for the correct indications in a dose adjusted to renal function, the chance of provoking this iatrogenic life-threatening complication can be strongly reduced. If treatment with allopurinol cannot be avoided and the patient
w1x Aubock ¨ J, Fritsch P. Asymptomatic hyperuricemia and allopurinol induced toxic epidermal necrolysis. Br Med J 1985;290:1969–1970. w2x McInnes GT, Lawson DH, Jick H. Acute adverse reactions attributed to allopurinol in hospitalized patients. Ann Rheum Dis 1981;40:245–249. w3x Singer JZ, Wallace SL. The allopurinol hypersensitivity syndrome. Unnecessary morbidity and mortality.. Arthritis Rheum 1986;29:82–87. w4x Arellano F, Sacristan ´ JA. Allopurinol hypersensitivity syndrome: a review. Ann Pharmacother 1993;27:337–343. w5x Lang PG. Severe hypersensitivity reactions to allopurinol. South Med J 1979;72:1361–1368. w6x Utsinger PD, Yount WJ. Allopurinol hypersensitivity. Granular deposition of IgM at the dermal–epidermal junction. Am J Med 1976;61:287–293. w7x Kantor GI. Toxic epidermal necrolysis, azotemia, and death after allopurinol therapy. J Am Med Assoc 1970;212:478– 479. w8x Young JL, Boswell RB, Nies AS. Severe allopurinol hypersensitivity. Association with thiazides and prior renal compromise. Arch Intern Med 1974;134:553–558. w9x Braden GL, Warzynski MJ, Golightly M, Ballow M. Cellmediated immunity in allopurinol-induced hypersensitivity. Clin Immunol Immunopathol 1994;70:145–151. w10x Hande KR, Noone RM, Stone WJ. Severe allopurinol toxicity. Description and guidelines for prevention in patients with renal insufficiency. Am J Med 1984;76:47–56. w11x Lupton GP, Odom RB. The allopurinol hypersensitivity syndrome. J Am Acad Dermatol 1979;1:365–374. w12x Kumar A, Edward N, White MI, Hohnston PW, Catto GRD. Allopurinol, erythema multiforme, and renal insufficiency. Br Med J 1996;312:173–174. w13x Gast LF, Cats A. Geneesmiddelen tegen jicht. Ned Tijdschr Geneeskd 1988;132:1827–1831. w14x Zell SC, Carmichael JM. Evaluation of allopurinol use in patients with gout. Am J Hosp Pharm 1989;46:1813–1836. w15x Fam AG, Lewtas J, Stein J, Paton TW. Desensitization to allopurinol in patients with gout and cutaneous reactions. Am J Med 1992;93:299–302.
Brief report
The allopurinol hypersensitivity syndrome H.J. Pluim a
a,)
, M. van Deuren b, J.F.M. Wetzels
c
Interne Geneeskunde, Canisius Wilhelmina Ziekenhuis, Postbus 9015, 6500 GS Nijmegen, Netherlands Algemeen Interne Geneeskunde, Academisch Ziekenhuis Nijmegen, 6500 HB Nijmegen, Netherlands c Nefrologie, Academisch Ziekenhuis Nijmegen, 6500 HB Nijmegen, Netherlands
b
Received 12 June 1997; revised 25 September 1997; accepted 7 October 1997
Abstract We describe a 61-year-old male patient who was treated with allopurinol and developed fever, a skin rash, eosinophilia and severe renal and liver dysfunction. We discuss the allopurinol hypersensitivity syndrome as a serious complication of the use of allopurinol, and briefly review the aetiology, prevention and treatment modalities. q 1998 Elsevier Science B.V. Keywords: Allopurinol; Oxypurinol; Side effect
1. Introduction Allopurinol is frequently used for the treatment of hyperuricaemia and gout, although its use in patients with asymptomatic hyperuricaemia is not justified. Two percent of the users develop a mild exanthema w1x. Sometimes a life-threatening reaction develops, as illustrated by the following case report.
2. Case report A 61-year-old man, with known hypertension and a slowly progressive renal insufficiency Žclinical diagnosis: nephrosclerosis; serum creatinine 210 mmolrl., was admitted to hospital because of malaise, rash and subfebrile temperature. Six weeks before admission allopurinol Ž300 mgrday. was pre-
)
Corresponding author. Tel.: q31 24 3657657; fax: q31 24 3658738.
scribed by the general practitioner because of asymptomatic hyperuricaemia. Five weeks later, the patient developed fever with a non-itching rash covering the whole body. A consultant dermatologist prescribed aciclovir Ž200 mg, t.i.d.. and triamcinolone cream on suspicion of a generalized herpes simplex infection. The patient stopped his own medication, consisting of allopurinol and lisinopril, 7 days before admission. During the following days, his temperature remained subfebrile and an oedema of his face developed. The last 2 days before admission he developed a watery diarrhoea without blood or mucus. On examination, the patient was moderately ill. His temperature was 38.48C, blood pressure 100r65 mmHg and pulse 120 b.p.m. A rash was seen covering the whole body. No petechia or purpura were found. The face was swollen. Examination of the neck, heart and lungs was normal. The liver was palpable 1 cm below the costal margin. The glans penis showed two ulcus lesions. On rectal examination a large prostate was found. No oedema was found on the extremities.
0300-2977r98r$19.00 q 1998 Elsevier Science B.V. All rights reserved. PII S 0 3 0 0 - 2 9 7 7 Ž 9 7 . 0 0 0 8 8 - 0
108
H.J. Pluim et al.r Netherlands Journal of Medicine 52 (1998) 107–110
Laboratory examination showed leucocytosis Ž18.1 = 10 9rl. with eosinophilia Ž14%.. No left shift was seen. The serum creatinine was markedly elevated Ž437 mmolrl. and liver enzymes were abnormal Žalkaline phosphatase 97 IUrl, g-glutamyl transpeptidase 262 IUrl, ALAT 115 IUrl, ASAT 57 IUrl, and LDH 584 IUrl.. There was a mild proteinuria Ž0.7 grl.. The sediment showed no red cells or red cell casts. A radiograph of the chest and ultrasound examination of the liver showed no abnormalities. The kidneys were small Ž10 cm.. No signs of postrenal obstruction were found. The combination of fever, rash, leucocytosis with eosinophilia, and liver and renal insufficiency with
recent use of allopurinol in a patient with a pre-existing renal insufficiency made the diagnosis of allopurinol hypersensitivity syndrome ŽAHS. likely. This diagnosis was supported by the finding of highly elevated plasma concentrations of the allopurinol metabolite oxypurinol Ž267 mmolrl, therapeutic level - 100 mmolrl. and the presence of erythema exsudativa multiforme in the skin biopsy. Because of the development of hypotension and renal insufficiency, the patient received fluid intravenously. One day after admission, treatment was started with ceftazidim and flucloxacilline because of high fever Ž408C. and suspected septicaemia. Despite rehydration, no improvement of renal function oc-
Fig. 1. The course of the temperature, the absolute number of eosinophils and the serum creatinine in association with the dose of corticosteroids. The closed columns refer to the dose of prednisone, while the open columns refer to the dose of methylprednisolone.
H.J. Pluim et al.r Netherlands Journal of Medicine 52 (1998) 107–110
curred. The patient developed oedema and gained 11 kg in weight in a few days. Because of threatening respiratory insufficiency, he was moved to the intensive care station. Fortunately, no artificial ventilation was needed. Four days after admission, a corticosteroid Žprednisone 50 mgrday. was started, whereafter the clinical situation improved. The rash disappeared gradually, while the kidney function improved and the leucocytosis and eosinophilia declined ŽFig. 1.. Antibiotics were stopped after 5 days when urine and blood cultures remained negative. Two weeks later, while lowering the dose of corticosteroid to 10 mgrday, our patient again developed high fever, a slight eosinophilia and deteriorating kidney function. Extensive examinations only showed the presence of a non-metastasized carcinoma of the prostate, but no signs of infections or autoimmune disease. Oxypurinol could no longer be detected in the serum. On the suspicion of a relapse of the AHS due to lowering of the dose of corticosteroids, renewed treatment with high-dose steroids, including methylprednisolone, was started, again resulting in a clinical improvement, while renal function stabilized with a creatinine of 465 mmolrl ŽFig. 1.. Six weeks after admission, the patient could be discharged.
3. Discussion The frequency of AHS is about 1 in 260 patients using allopurinol w2x. Criteria for the diagnosis are: Ž1. a clear exposure to allopurinol; Ž2. a clinical picture including Ža. at least two of the following major criteria: Ži. worsening renal function, Žii. acute hepatocellular injury, Žiii. a rash including either toxic epidermal necrolysis, erythema multiforme, or a diffuse maculopapular of exfoliative dermatitis, or Žb. one of the major criteria plus at least one of the following minor criteria: Ži. fever, Žii. eosinophilia, Žiii. leucocytosis; and Ž3. lack of exposure to another drug which may have caused a similar clinical picture w3x. AHS mostly begins within days or weeks of starting therapy with allopurinol. Mortality is about 25% w3–5x. Sepsis is the most frequent cause of mortality. Frequently, gastrointestinal bleeding occurs. Liver and renal failure are, in general, reversible w5x.
109
The risk of development of AHS is related to the level of oxypurinol, the therapeutic metabolite of allopurinol. Because oxypurinol is cleared by renal excretion, AHS occurs more frequently in patients with an impaired renal function or patients using thiazide diuretics. The exact mechanism responsible for the development of AHS is still unknown. It is assumed that accumulation of oxypurinol leads to tissue damage evoking an immunological response with development of antibodies against tissue components w4,6,7x, the formation of immune complexes and subsequent tissue damage w8x. Both granular deposits of IgM at the dermal–epidermal junction w6x, and linear deposits of g-globulin and complement along the glomerular basement membrane w7x were detected in patients with AHS. More recently, it was suggested that a T-cell-mediated immune reaction is involved in the pathogenesis of AHS w9x. There is no established therapy for AHS. Besides the cessation of allopurinol at the occurrence of the first signs of AHS, supportive therapy is important. Haemodialysis can be used to lower the level of oxypurinol w10x, but the therapeutic effect on the course of AHS has never been examined. In our patient, no oxypurinol was present at the time of the recurrence of the signs of AHS, indicating that the presence of oxypurinol is not required for persistence of AHS and arguing against the use of haemodialysis treatment. The use of corticosteroids is controversial. Because of the suspected immunological reaction as the cause of AHS, the use of corticosteroids seems justified. In our patient, we decided to start corticosteroid therapy because his clinical condition did not improve. Therapy needs to be continued for a long time to prevent relapse of the clinical syndrome w11,12x, as illustrated by our patient. However, the mortality of patients treated with corticosteroids seems to be higher compared with patients not treated with corticosteroids w4x. It is unclear if corticosteroids contribute to the increased mortality. We favour the explanation that corticosteroids are more likely used for patients with a more severe clinical syndrome, such as continuing fever, liver disturbances or worsening renal function. Obviously, the literature does not provide clinical, laboratory, or biopsy criteria that allow one to select the patients who will benefit from corticosteroid treatment. Because of the lack of therapy, prevention of
110
H.J. Pluim et al.r Netherlands Journal of Medicine 52 (1998) 107–110
Table 1 Maintenance doses of allopurinol for adults based on individual creatinine clearance measurements Žaccording to Hande w10x. Creatinine clearance Žmlrmin.
Maintenance dose
0 10 20 40 60 80 100 120 140
100 mgr3 days 100 mgr2 days 100 mgrday 150 mgrday 200 mgrday 250 mgrday 300 mgrday 350 mgrday 400 mgrday
has experienced a hypersensitivity reaction, one could consider desensitization w15x. References
AHS is of primary importance. Allopurinol should only be prescribed for the correct indication. These indications are: primary gout with tophi or uric acid stones caused by overproduction; uric acid stones or calcium oxalate stones without gout, combined with increased urinary excretion of urate; secondary renal gout with tophi; myeloproliferative diseases or other malignancies Žpreferably before the start of chemotherapy of radiotherapy.; high frequency of attacks despite the use of colchicine prophylaxis; intolerance for uricosuric agents; and Lesch–Nyhan syndrome and Von Gierke disease w13x. Asymptomatic hyperuricaemia is no indication for prescribing allopurinol, but, in practice, it appears to be the main reason for prescribing allopurinol w3,14x. Another important issue in the prescription of allopurinol is the adjustment of the dose to renal function. The usual dose of 300 mgrday is suitable for patients with a good renal function only ŽTable 1.. By prescribing allopurinol only for the correct indications in a dose adjusted to renal function, the chance of provoking this iatrogenic life-threatening complication can be strongly reduced. If treatment with allopurinol cannot be avoided and the patient
w1x Aubock ¨ J, Fritsch P. Asymptomatic hyperuricemia and allopurinol induced toxic epidermal necrolysis. Br Med J 1985;290:1969–1970. w2x McInnes GT, Lawson DH, Jick H. Acute adverse reactions attributed to allopurinol in hospitalized patients. Ann Rheum Dis 1981;40:245–249. w3x Singer JZ, Wallace SL. The allopurinol hypersensitivity syndrome. Unnecessary morbidity and mortality.. Arthritis Rheum 1986;29:82–87. w4x Arellano F, Sacristan ´ JA. Allopurinol hypersensitivity syndrome: a review. Ann Pharmacother 1993;27:337–343. w5x Lang PG. Severe hypersensitivity reactions to allopurinol. South Med J 1979;72:1361–1368. w6x Utsinger PD, Yount WJ. Allopurinol hypersensitivity. Granular deposition of IgM at the dermal–epidermal junction. Am J Med 1976;61:287–293. w7x Kantor GI. Toxic epidermal necrolysis, azotemia, and death after allopurinol therapy. J Am Med Assoc 1970;212:478– 479. w8x Young JL, Boswell RB, Nies AS. Severe allopurinol hypersensitivity. Association with thiazides and prior renal compromise. Arch Intern Med 1974;134:553–558. w9x Braden GL, Warzynski MJ, Golightly M, Ballow M. Cellmediated immunity in allopurinol-induced hypersensitivity. Clin Immunol Immunopathol 1994;70:145–151. w10x Hande KR, Noone RM, Stone WJ. Severe allopurinol toxicity. Description and guidelines for prevention in patients with renal insufficiency. Am J Med 1984;76:47–56. w11x Lupton GP, Odom RB. The allopurinol hypersensitivity syndrome. J Am Acad Dermatol 1979;1:365–374. w12x Kumar A, Edward N, White MI, Hohnston PW, Catto GRD. Allopurinol, erythema multiforme, and renal insufficiency. Br Med J 1996;312:173–174. w13x Gast LF, Cats A. Geneesmiddelen tegen jicht. Ned Tijdschr Geneeskd 1988;132:1827–1831. w14x Zell SC, Carmichael JM. Evaluation of allopurinol use in patients with gout. Am J Hosp Pharm 1989;46:1813–1836. w15x Fam AG, Lewtas J, Stein J, Paton TW. Desensitization to allopurinol in patients with gout and cutaneous reactions. Am J Med 1992;93:299–302.