1506
BRITISH MEDICAL JOURNAL
19 JUNE 1976
SHORT REPORTS Diffuse alveolitis as complication of penicillamine treatment for rheumatoid arthritis Penicillamine is as effective as gold' when used as an antirheumatic drug.2 Side effects may occur, however, the best recognised being marrow suppression, the nephrotic syndrome, abnormalities of taste, rashes, and gastrointestinal disturbances. All are usually reversible on stopping treatment. Nevertheless, deaths have occurred, and recently three fatal cases of Goodpasture's syndrome were reported in patients taking 1 to 3-5 g penicillamine daily for Wilson's disease over two to three and a half years.3 I report a further pulmonary complication of treatment with penicillamine in a patient given small doses for rheumatoid arthritis.
after stopping penicillamine the forced vital capacity (2-7 1), FEV1 (2-35 1), and total lung capacity (3-95 1) had returned to normal and the gas-transfer factor had increased to 4-8 kPa (36 mm Hg) (65 % of predicted normal), the blood gases remaining within normal limits.
Comment Though histological proof of diffuse alveolitis was not available in this case, the radiological features and abnormalities in pulmonary function were strongly suggestive. Other causes of the diffuse alveolitis cannot be completely excluded but the fact that it developed while the patient was on penicillamine and improved immediately on stopping this drug strongly suggests that it was induced by penicillamine. The ultimate test would be a repeat challenge with penicillamine, but this might be at the risk of producing an irreversible lesion. I
Case report A 48-year-old woman had had classic seropositive rheumatoid arthritis for five years. Before starting penicillamine treatment she had received
indomethacin continuously and had had two courses of sodium aurothiomalate. The first was stopped after three months because she developed a rash. This did not recur with the second course, which, however, had no therapeutic effect, and two months later she was started on peniciliamine 150 mg daily increasing at monthly intervals to 450 mg daily with considerable improvement. Twelve months after starting penicillamine she complained of increasing dyspnoea and a dry cough causing central chest discomfort. She was slightly dyspnoeic at rest, without cyanosis; pulse was 90 beats/min and blood pressure 130/90 mm Hg. The heart was not clinically enlarged and the heart sounds were normal. Fine scattered crepitations were heard over both lung bases. The urine contained no red blood cells or albumin and the blood urea was normal. Haemoglobin was 14-9 g/dl, WBC 8 x 109/1 (8000/mm3), platelet count 142 x 109/1 (142 000/ mm3), and ESR 21 mm in the first hour (Westergren). The chest x-ray picture was of a fibrosing alveolitis (see fig). Three years previously the appearances had been normal. Lung function showed a restrictive pattern with vital capacity 1-95 1 (predicted normal 2-55 1), forced expiratory volume in 1 s (FEV,) 1-5 1 (predicted normal 2-2 1), and total lung capacity 2-91 (predicted normal 4-2 1). The gas-transfer factor was 3-4 kPa (26 mm Hg) (45 % of predicted normal). Paco2 (4-8 kPa; 36 mm Hg) and Pao2 (10 9 kPa; 82 mm Hg) were normal. Penicillamine was stopped and within a week the dyspnoea was improved. A month later it had almost disappeared but the arthritis was again becoming active, and in view of this azathioprine 50 mg daily was started. Chest x-ray examination one month later showed considerable improvement with only residual shadowing at the cardiophrenic angles. Three months
2
3
Huskisson, E C, et al, Annals of the Rheumatic Diseases, 1974, 33, 532. Multicentre Trial Group, Lancet, 1973, 1, 275. Sternlieb, I, Bennett, B, and Scheinberg, I H, Annals of Internal Medicine,
1975, 82, 673.
Department of Medicine, University of Liverpool, Liverpool L69 3BX C J EASTMOND, MRCP, research fellow
Prospective randomised trial of early postoperative bathing The validity of allowing patients to bath in the early postoperative period was tested in a pilot scheme when 20 patients were allowed either a full-immersion bath or a shower from the third day after operation. Encouraged by an enthusiastic response from patients we organised a randomised prospective trial. This was designed to assess the risks of sepsis and delayed healing and discharge from hospital in patients allowed to take baths soon after operation compared with those in patients given traditional wound care. Beneficial effects from early postoperative bathing have been noted.'
Patients, methods, and results One hundred inpatients normally able to bath took part in the trial. The
Posteroanterior chest x-ray film showing appearances of fibrosing alveolitis.
presence of Redivac, tube, or corrugated drains did not preclude bathing. Patients were allocated preoperatively by random card selection to a "traditional" or "bather" group. All had the original wound dressing removed on the second day after operation and the wound sprayed with a clear plastic dressing (Hibispray 4). Patients in the bather group were then allowed either a daily shower or full-immersion bath. The enamel baths used were prepared so as to reduce flora and prevent cross-infection. They were cleaned before and after with hot water and abrasive hypochlorite powder to reduce the bacteria count, as advocated by Boycott.2 To each bath of hot water (115-1351) 30 ml hexachlorophane bath concentrate was added to eliminate staphylococci and reduce other surface bacteria.3 4 The clear plastic dressing used was made up of a resin in ethyl acetate, which is deposited as a film on evaporation of a volatile solvent and contains chlorhexidine. Wounds were classed as infected if there was: (a) confluent erythema or cellulitis around the wound, with or without bacteriological confirmation; (b) discharge of pus from the wound or sutures; or (c) release of deep-seated infected haematoma despite good initial skin healing. The 100 patients had 108 surgical wounds, which were found to be equally distributed between the two groups. In each group four wounds were infected (see table). There was no appreciable difference between the groups in the timing of removal of sutures, 83 patients having them removed by the eighth postoperative day. Primary skin healing took place in all the infected
1507
19 JUNE 1976
BRITISH MEDICAL JOURNAL
Case report
Outcome of wounds in the two groups of patients Bather group (n = 50)
Type of surgery
Healed
Biliary .11 Upper gastrointestinal tract, small bowel .7 Large bowel, appendicectomy Herniorrhaphy, groin surgery Other .2 All wounds .50
1 29
Traditional group (n = 50)
Infected
Healed
Infected
2
13
2
1* 1* 4
5 5 24 3 50
it
1 4
*Fibroliposarcoma with groin metastases.
tCaecal carcinoma, faecal fistula.
cases. Extensive bacteriological examination (phage typing etc) of the patients and staff showed the nasal carriage of a typed Staphylococcus aureus in one surgeon who had been concerned with three patients with identical infections.
Comment The main problem of communal bathing facilities in hospital is cross-infection of surgical wounds. The infections in this small series were probably introduced during operation, and no cross-infection occurred as a result of bathing. Nature's coagulum is probably the best protection against bacterial invasion in surgical wounds.) The application of a plastic spray acted as a barrier in preventing soaking of silk sutures and softening of the wound coagulum by water. Baths were disinfected and cleaned with materials available on NHS wards and known to reduce the bacteria count in the bath and bath water. The shower requires less attention, but for frail or elderly patients the vertical posture in a steamy confine is contraindicated and the more reassuring and familiar bath is recommended. The overall advantage of early postoperative bathing is the physical and emotional benefit of cleanliness without the increased risk of infection or delay in healing. We thank Mr C U Webster, Mr M H Gough, and Mr N E Dudley for allowing us to study their patients, and Dr R G Mitchell for his close bacteriological supervision. Dr L Blazewicz kindly translated the paper by Wasilewski and Stawarz.'
Wiadonmoici Lekarskie, 1973, 26, 1219. Boycott, J A, Lancet, 1956, 2, 678. s Avliffe, G A J, Alder, V G, and Gillespie, W A, Lancet, 1959, 2, 456. Gillespie, W A, et al, Lantcet, 1961, 1, 1299. Donald, I, Practical Obstetric Problems, 3rd edn, p 654. London, LloydLuke, 1966.
I
Wasilewski, M, and Stawarz, B,
2
Churchill Hospital, Oxford 0X3 7LJ IAN FRASER, FRCS, surgical registrar ALLAN ASKEW, FRCS, surgical registrar (present address: Groote Schuur Hospital, Cape Town) JILL BILES, SRN, SCM, ward sister JANE PINCHIN, SRN, ward sister
The patient was a 74-year-old woman with long-standing mitral incompetence, atrial fibrillation, and recurrent congestive cardiac failure. She was being treated with digoxin 0-125 mg/day, frusemide 160 mg/day, and spironolactone 75 mg/day and had been dependent on sodium butobarbitone (Soneryl) 300 mg nightly for nine years. She complained of pain in the back and right side of the chest and was tender over the 5th and 6th ribs. Investigation showed a serum calcium concentration of 2 0 mmol/l (8 mg/100 ml) (normal 2 1-2-6 mmol/l (8-4-10-4 mg/100 ml)), serum phosphate concentration of 0-8 mmol/l (2-5 mg/100 ml) (normal 0-8-1 4 mmol/l (2 5-4 3 mg/100 ml)), and alkaline phosphatase level of 224 IU/l (normal 30-130 IU/1), predominantly bone isoenzyme. Haemoglobin, white cell count, erythrocyte sedimentation rate, serum iron levels, and vitamin B,2 levels were normal, but she had a low serum folate concentration of 3 4 tLg/l (normal 6-21 ,ug/1). The y-glutamyltranspeptidase (GGT) concentration was 179 IU/1 (normal 5-25 IU 1). Radiographs showed rarefaction of spine, ribs, and hands but no Looser's zones or fractures. A dietary history showed a specific deficiency of vitamin D (intake 27 IU/week; recommended 100 IU/week), and folate (40 fag/week; recommended 200 /ig/week). Butobarbitone and spironolactone were discontinued. Blood samples taken at 10 am 12 hours before and 12 hours after the last dose of butobarbitone were analysed for butobarbitone by gas-layer chromatography with amylobarbitone as internal standard and gave plateau values of 28-3 frmol/l (6 01 jtg/ml) and 28 9 fimol/l (6 13 /4g/ml). A sample 24 hours later showed a concentration of 8 06 ,amol/l (1 71 iLg/ml). Twenty-three hours afterwards, when the estimated butobarbitone would have fallen to less than 2 36 fmol/l (0 5 fLg/ml), 600 mg antipyrine (phenazone BPC) was given orally. Saliva samples were collected at three, five, eight, 24, and 32 hours, using a 25-mg ascorbic acid tablet as a stimulus with tongue and cheek movements over three to five minutes. Antipyrine concentrations were estimated as described.3 Antipyrine half life was 553 + 0 24 (SD) hours (95 0,, confidence limits) compared with normal values of 17 4 ± 6-8 in elderly patients.4 Nitrazepam was substituted as a hypnotic and treatment for osteomalacia started with calcium with vitamin D BPC 1 tablet/day. Four weeks later the antipyrine half life was again estimated and had increased to 18 00 + 3 78 hours. The patient was asymptomatic and biochemical values were almost normal (see figure). She was discharged on digoxin (Wellcome) 0 25 mg/day, frusemide 250 mg/day, Sando-K (Sandoz) 3 tablets/day, calcium with vitamin D 1 tablet, day, and nitrazepam nightly.
Discussion This patient had received two enzyme-inducing agents, butobarbitone and spironolactone, for nine years. The antipyrine half life was extremely short, in the range associated with enzyme induction.4 Induction was confirmed by the threefold increase, after four weeks,
D
200
E
E
Chronic ingestion of enzyme-inducing drugs is recognised as a cause of osteomalacia in epileptics.' Their use probably contributes to the renal osteodystrophy of patients on regular haemodialysis.2 Many conditions associated with vitamin D resistance or deficiency may be aggravated by enzyme-inducing agents. Assessment of individual patients is difficult, however, because there is no clinical test of microsomal enzyme induction that is both convenient for the patient and a reliable estimate. We describe a patient with osteomalacia in whom estimation of antipyrine half life from saliva was used to show enzyme induction.
phosphatase
GGT
-
100
0
Clinical application of antipyrine half life in saliva in a patient with osteomalacia
Alkaline
300 200 100
Calcium
3 02.5 20 2 .0.
=
_
~
~
~
~ -
Inorganic phosphate
5 Z_
-OE 10 E
___
------------------------------------
o-5 18 8 19 29 20 30 9 September July August May 20 Butobarbitone Antipyrine half life 0>>'g''
Changes in alkaline phosphatase, GGT, serum calcium and phosphate concentrations, and antipyrine half life after withdrawal of butobarbitone. Horizontal dotted lines represent upper and lower limits of normal. Conversion: SI to traditional units-Calcium: 1 mmol/I 3 mg/100 ml. 4 mg/100 ml. Phosphate: 1 mmol/l
BRITISH MEDICAL JOURNAL
19 JUNE 1976
SHORT REPORTS Diffuse alveolitis as complication of penicillamine treatment for rheumatoid arthritis Penicillamine is as effective as gold' when used as an antirheumatic drug.2 Side effects may occur, however, the best recognised being marrow suppression, the nephrotic syndrome, abnormalities of taste, rashes, and gastrointestinal disturbances. All are usually reversible on stopping treatment. Nevertheless, deaths have occurred, and recently three fatal cases of Goodpasture's syndrome were reported in patients taking 1 to 3-5 g penicillamine daily for Wilson's disease over two to three and a half years.3 I report a further pulmonary complication of treatment with penicillamine in a patient given small doses for rheumatoid arthritis.
after stopping penicillamine the forced vital capacity (2-7 1), FEV1 (2-35 1), and total lung capacity (3-95 1) had returned to normal and the gas-transfer factor had increased to 4-8 kPa (36 mm Hg) (65 % of predicted normal), the blood gases remaining within normal limits.
Comment Though histological proof of diffuse alveolitis was not available in this case, the radiological features and abnormalities in pulmonary function were strongly suggestive. Other causes of the diffuse alveolitis cannot be completely excluded but the fact that it developed while the patient was on penicillamine and improved immediately on stopping this drug strongly suggests that it was induced by penicillamine. The ultimate test would be a repeat challenge with penicillamine, but this might be at the risk of producing an irreversible lesion. I
Case report A 48-year-old woman had had classic seropositive rheumatoid arthritis for five years. Before starting penicillamine treatment she had received
indomethacin continuously and had had two courses of sodium aurothiomalate. The first was stopped after three months because she developed a rash. This did not recur with the second course, which, however, had no therapeutic effect, and two months later she was started on peniciliamine 150 mg daily increasing at monthly intervals to 450 mg daily with considerable improvement. Twelve months after starting penicillamine she complained of increasing dyspnoea and a dry cough causing central chest discomfort. She was slightly dyspnoeic at rest, without cyanosis; pulse was 90 beats/min and blood pressure 130/90 mm Hg. The heart was not clinically enlarged and the heart sounds were normal. Fine scattered crepitations were heard over both lung bases. The urine contained no red blood cells or albumin and the blood urea was normal. Haemoglobin was 14-9 g/dl, WBC 8 x 109/1 (8000/mm3), platelet count 142 x 109/1 (142 000/ mm3), and ESR 21 mm in the first hour (Westergren). The chest x-ray picture was of a fibrosing alveolitis (see fig). Three years previously the appearances had been normal. Lung function showed a restrictive pattern with vital capacity 1-95 1 (predicted normal 2-55 1), forced expiratory volume in 1 s (FEV,) 1-5 1 (predicted normal 2-2 1), and total lung capacity 2-91 (predicted normal 4-2 1). The gas-transfer factor was 3-4 kPa (26 mm Hg) (45 % of predicted normal). Paco2 (4-8 kPa; 36 mm Hg) and Pao2 (10 9 kPa; 82 mm Hg) were normal. Penicillamine was stopped and within a week the dyspnoea was improved. A month later it had almost disappeared but the arthritis was again becoming active, and in view of this azathioprine 50 mg daily was started. Chest x-ray examination one month later showed considerable improvement with only residual shadowing at the cardiophrenic angles. Three months
2
3
Huskisson, E C, et al, Annals of the Rheumatic Diseases, 1974, 33, 532. Multicentre Trial Group, Lancet, 1973, 1, 275. Sternlieb, I, Bennett, B, and Scheinberg, I H, Annals of Internal Medicine,
1975, 82, 673.
Department of Medicine, University of Liverpool, Liverpool L69 3BX C J EASTMOND, MRCP, research fellow
Prospective randomised trial of early postoperative bathing The validity of allowing patients to bath in the early postoperative period was tested in a pilot scheme when 20 patients were allowed either a full-immersion bath or a shower from the third day after operation. Encouraged by an enthusiastic response from patients we organised a randomised prospective trial. This was designed to assess the risks of sepsis and delayed healing and discharge from hospital in patients allowed to take baths soon after operation compared with those in patients given traditional wound care. Beneficial effects from early postoperative bathing have been noted.'
Patients, methods, and results One hundred inpatients normally able to bath took part in the trial. The
Posteroanterior chest x-ray film showing appearances of fibrosing alveolitis.
presence of Redivac, tube, or corrugated drains did not preclude bathing. Patients were allocated preoperatively by random card selection to a "traditional" or "bather" group. All had the original wound dressing removed on the second day after operation and the wound sprayed with a clear plastic dressing (Hibispray 4). Patients in the bather group were then allowed either a daily shower or full-immersion bath. The enamel baths used were prepared so as to reduce flora and prevent cross-infection. They were cleaned before and after with hot water and abrasive hypochlorite powder to reduce the bacteria count, as advocated by Boycott.2 To each bath of hot water (115-1351) 30 ml hexachlorophane bath concentrate was added to eliminate staphylococci and reduce other surface bacteria.3 4 The clear plastic dressing used was made up of a resin in ethyl acetate, which is deposited as a film on evaporation of a volatile solvent and contains chlorhexidine. Wounds were classed as infected if there was: (a) confluent erythema or cellulitis around the wound, with or without bacteriological confirmation; (b) discharge of pus from the wound or sutures; or (c) release of deep-seated infected haematoma despite good initial skin healing. The 100 patients had 108 surgical wounds, which were found to be equally distributed between the two groups. In each group four wounds were infected (see table). There was no appreciable difference between the groups in the timing of removal of sutures, 83 patients having them removed by the eighth postoperative day. Primary skin healing took place in all the infected
1507
19 JUNE 1976
BRITISH MEDICAL JOURNAL
Case report
Outcome of wounds in the two groups of patients Bather group (n = 50)
Type of surgery
Healed
Biliary .11 Upper gastrointestinal tract, small bowel .7 Large bowel, appendicectomy Herniorrhaphy, groin surgery Other .2 All wounds .50
1 29
Traditional group (n = 50)
Infected
Healed
Infected
2
13
2
1* 1* 4
5 5 24 3 50
it
1 4
*Fibroliposarcoma with groin metastases.
tCaecal carcinoma, faecal fistula.
cases. Extensive bacteriological examination (phage typing etc) of the patients and staff showed the nasal carriage of a typed Staphylococcus aureus in one surgeon who had been concerned with three patients with identical infections.
Comment The main problem of communal bathing facilities in hospital is cross-infection of surgical wounds. The infections in this small series were probably introduced during operation, and no cross-infection occurred as a result of bathing. Nature's coagulum is probably the best protection against bacterial invasion in surgical wounds.) The application of a plastic spray acted as a barrier in preventing soaking of silk sutures and softening of the wound coagulum by water. Baths were disinfected and cleaned with materials available on NHS wards and known to reduce the bacteria count in the bath and bath water. The shower requires less attention, but for frail or elderly patients the vertical posture in a steamy confine is contraindicated and the more reassuring and familiar bath is recommended. The overall advantage of early postoperative bathing is the physical and emotional benefit of cleanliness without the increased risk of infection or delay in healing. We thank Mr C U Webster, Mr M H Gough, and Mr N E Dudley for allowing us to study their patients, and Dr R G Mitchell for his close bacteriological supervision. Dr L Blazewicz kindly translated the paper by Wasilewski and Stawarz.'
Wiadonmoici Lekarskie, 1973, 26, 1219. Boycott, J A, Lancet, 1956, 2, 678. s Avliffe, G A J, Alder, V G, and Gillespie, W A, Lancet, 1959, 2, 456. Gillespie, W A, et al, Lantcet, 1961, 1, 1299. Donald, I, Practical Obstetric Problems, 3rd edn, p 654. London, LloydLuke, 1966.
I
Wasilewski, M, and Stawarz, B,
2
Churchill Hospital, Oxford 0X3 7LJ IAN FRASER, FRCS, surgical registrar ALLAN ASKEW, FRCS, surgical registrar (present address: Groote Schuur Hospital, Cape Town) JILL BILES, SRN, SCM, ward sister JANE PINCHIN, SRN, ward sister
The patient was a 74-year-old woman with long-standing mitral incompetence, atrial fibrillation, and recurrent congestive cardiac failure. She was being treated with digoxin 0-125 mg/day, frusemide 160 mg/day, and spironolactone 75 mg/day and had been dependent on sodium butobarbitone (Soneryl) 300 mg nightly for nine years. She complained of pain in the back and right side of the chest and was tender over the 5th and 6th ribs. Investigation showed a serum calcium concentration of 2 0 mmol/l (8 mg/100 ml) (normal 2 1-2-6 mmol/l (8-4-10-4 mg/100 ml)), serum phosphate concentration of 0-8 mmol/l (2-5 mg/100 ml) (normal 0-8-1 4 mmol/l (2 5-4 3 mg/100 ml)), and alkaline phosphatase level of 224 IU/l (normal 30-130 IU/1), predominantly bone isoenzyme. Haemoglobin, white cell count, erythrocyte sedimentation rate, serum iron levels, and vitamin B,2 levels were normal, but she had a low serum folate concentration of 3 4 tLg/l (normal 6-21 ,ug/1). The y-glutamyltranspeptidase (GGT) concentration was 179 IU/1 (normal 5-25 IU 1). Radiographs showed rarefaction of spine, ribs, and hands but no Looser's zones or fractures. A dietary history showed a specific deficiency of vitamin D (intake 27 IU/week; recommended 100 IU/week), and folate (40 fag/week; recommended 200 /ig/week). Butobarbitone and spironolactone were discontinued. Blood samples taken at 10 am 12 hours before and 12 hours after the last dose of butobarbitone were analysed for butobarbitone by gas-layer chromatography with amylobarbitone as internal standard and gave plateau values of 28-3 frmol/l (6 01 jtg/ml) and 28 9 fimol/l (6 13 /4g/ml). A sample 24 hours later showed a concentration of 8 06 ,amol/l (1 71 iLg/ml). Twenty-three hours afterwards, when the estimated butobarbitone would have fallen to less than 2 36 fmol/l (0 5 fLg/ml), 600 mg antipyrine (phenazone BPC) was given orally. Saliva samples were collected at three, five, eight, 24, and 32 hours, using a 25-mg ascorbic acid tablet as a stimulus with tongue and cheek movements over three to five minutes. Antipyrine concentrations were estimated as described.3 Antipyrine half life was 553 + 0 24 (SD) hours (95 0,, confidence limits) compared with normal values of 17 4 ± 6-8 in elderly patients.4 Nitrazepam was substituted as a hypnotic and treatment for osteomalacia started with calcium with vitamin D BPC 1 tablet/day. Four weeks later the antipyrine half life was again estimated and had increased to 18 00 + 3 78 hours. The patient was asymptomatic and biochemical values were almost normal (see figure). She was discharged on digoxin (Wellcome) 0 25 mg/day, frusemide 250 mg/day, Sando-K (Sandoz) 3 tablets/day, calcium with vitamin D 1 tablet, day, and nitrazepam nightly.
Discussion This patient had received two enzyme-inducing agents, butobarbitone and spironolactone, for nine years. The antipyrine half life was extremely short, in the range associated with enzyme induction.4 Induction was confirmed by the threefold increase, after four weeks,
D
200
E
E
Chronic ingestion of enzyme-inducing drugs is recognised as a cause of osteomalacia in epileptics.' Their use probably contributes to the renal osteodystrophy of patients on regular haemodialysis.2 Many conditions associated with vitamin D resistance or deficiency may be aggravated by enzyme-inducing agents. Assessment of individual patients is difficult, however, because there is no clinical test of microsomal enzyme induction that is both convenient for the patient and a reliable estimate. We describe a patient with osteomalacia in whom estimation of antipyrine half life from saliva was used to show enzyme induction.
phosphatase
GGT
-
100
0
Clinical application of antipyrine half life in saliva in a patient with osteomalacia
Alkaline
300 200 100
Calcium
3 02.5 20 2 .0.
=
_
~
~
~
~ -
Inorganic phosphate
5 Z_
-OE 10 E
___
------------------------------------
o-5 18 8 19 29 20 30 9 September July August May 20 Butobarbitone Antipyrine half life 0>>'g''
Changes in alkaline phosphatase, GGT, serum calcium and phosphate concentrations, and antipyrine half life after withdrawal of butobarbitone. Horizontal dotted lines represent upper and lower limits of normal. Conversion: SI to traditional units-Calcium: 1 mmol/I 3 mg/100 ml. 4 mg/100 ml. Phosphate: 1 mmol/l
