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CHLORAMPHENICOL TOXICITY
476
physiotherapy from the second postoperative day. discharge from hospital they attended the physical-medicine department three times weekly for a total of six weeks after operation. Effusions were found to be more common, larger, and of long duration in group B. There was no significant difference had
After
between the two groups in the circumference of the thigh six weeks after operation nor in the time taken to return to work. There was, however, a slightly increased range of movements in group B from the tenth day to the sixth week, and the suggestion is that some static exercises undertaken regularly by the patient on his own would be preferable to none at all. Physiotherapists, it seems, could be better employed than encouraging patients to do their exercises after menisectomy. These patients are often young, active, and athletic and already very keen to return to normal activities. Nevertheless, many will no doubt be disappointed if the placebo effect of the physiotherapist is removed.
CHLORAMPHENICOL TOXICITY
CHLORAMPHENICOL
probably gives rise
to two
forms
of bone-marrow toxicity.1 One is an acute change which affects most patients when blood levels rise above 25 g. per 100 ml. The white-cell count falls and the platelet and red-cell count may also be depressed. Vacuolisation and inhibition of cellular respiration occur. These changes are readily and rapidly reversed when the drug is discontinued.
Chloramphenicol
may
also
give rise
to
aplastic
anasmia, which is often associated with repeated courses of the drug and is usually fatal. It may appear several weeks after the drug has been stopped. The way in which chloramphenicol produces this effect is unknown. Dameshek2 has discussed several possible mechanisms, including the prevention of binding of polyuridic acid to ribosomes or some effect on D.N.A. metabolism. Nagao and Mauer3 have described identical twins in whom reversible aplastic ansemia developed after exposure to chloramphenicol. Bone-marrow studies, including observation of tritiated-thymidine labelling indices in one twin, suggested that the defect responsible was failure of delivery of differentiated forms from a damaged undifferentiated stem-cell. Although the underlying biochemical changes are not known, it seems very probable that a genetically determined metabolic defect was responsible for these identical reactions to chloramphenicol. Such a defect would explain the low incidence of aplastic ansemia in patients given the drug. Wallerstein et al.4 have assessed the risk of dying of this complication as 1 in 36,118 with an average dose of 4-5 g. per person, rising to 1 in 21,671 with an average dose of 7-5 g. per person. Fatal
aplastic after the
anaemia seemed to be 13 times commoner use of chloramphenicol than in the untreated
population. This report of the twins 1. 2. 3. 4.
gives further impetus
studies of enzyme activity in marrow stem cells. If it were possible to demonstrate the abnormality present in patients liable to this complication, then the population at risk might be detected. Meanwhile, the use of chloramphenicol should be restricted to patients with typhoid fever or other gram-negative infections where there is no suitable alternative antibiotic.
KIDNEYS FOR TRANSPLANTATION
Nolan1
stated that donors
selected for renal
transplantation should not have systemic or renal infection, or evidence of renal disease, hypertension, or carcinoma. The donors should be relatively young and free from degenerative arterial disease; and they should not have been subjected to hypotension or anoxia before death. Owing to the scarcity of available cadaveric kidneys, however, White et a1.2 were forced to use kidneys from apparently unsuitable donors, yet subsequent renal function was good and not significantly different from that of more suitably matched kidney transplants. The kidneys from patients with renal failure complicating liver failure would generally be considered unsuitable for transplantation purposes because of the possibility of severe ischxmic tubular necrosis after hypotension and bleeding episodes; the usual absence of any previous data regarding renal function; the danger of systemic bacterial infection; and the hazard of transmitting hepatitis to the recipient. Koppel and his colleagues3 in Los Angeles now report the transplantation of kidneys to 7 recipients from donors dying of hepatic and renal failure. In all but
one case
diuresis followed in from six
to
fourteen
days, which, in the experience of Koppel et al., was not significantly different from the oliguric periods after comparable transplants from donors without hepatic failure. 4 of the kidneys achieved stable function for six months or more, and 2 patients are alive and well with creatinine clearances of 50 ml. per min. or more fifteen months later. Dunphy4 first described the " hepato-renal syn-
jaundice, and anuria after overwhelming gram-negative septicaemia and surgical shock are probably the most likely causes. Since then many forms of liver drome " of fever, shock,
upper abdominal surgery:
failure have been described in association with renal failure, and in Koppel et al.’s series 5 of the 6 donors had alcoholic cirrhosis and the 6th had chronic active hepatitis with postnecrotic cirrhosis. All had normal renal function before the onset of terminal hepatic failure, and renal insufficiency developed in all cases before terminal hypotension. All donors became hyponatrsemic and urinary sodium excretion was low during their terminal illness, despite a high urinary specific gravity. Microscopical examination of the spun urinary deposit showed occasional polymorphs
to
1.
Lancet, 1967, ii, 297. Dameshek, W. Near Engl. J. Med. 1969, 281, 42. Nagao, T., Mauer, A. M. ibid. p. 7. Wallerstein, R. O., Condit, P. K., Kasper, C. K., Brown, J. W., Morrison, F. R. J. Am. med. Ass. 1969, 208, 2045.
2. 3. 4.
Nolan, B. in Renal Disease (edited by D. A. K. Black); chapter 19. Oxford, 1967. White, H. J. O., Evans, D. B., Calne, R. Y. Br. med. J. 1968, iv, 739. Koppel, M. H., Coburn, J. W., Mims, M. M., Goldstein, H., Boyle, J. D., Rubini, M. E. New Engl. J. Med. 1969, 280, 1367. Dunphy, J. E., Harrison, J. H., Merrill, J. P. Surg. Forum, 1951, 2, 176.
physiotherapy from the second postoperative day. discharge from hospital they attended the physical-medicine department three times weekly for a total of six weeks after operation. Effusions were found to be more common, larger, and of long duration in group B. There was no significant difference had
After
between the two groups in the circumference of the thigh six weeks after operation nor in the time taken to return to work. There was, however, a slightly increased range of movements in group B from the tenth day to the sixth week, and the suggestion is that some static exercises undertaken regularly by the patient on his own would be preferable to none at all. Physiotherapists, it seems, could be better employed than encouraging patients to do their exercises after menisectomy. These patients are often young, active, and athletic and already very keen to return to normal activities. Nevertheless, many will no doubt be disappointed if the placebo effect of the physiotherapist is removed.
CHLORAMPHENICOL TOXICITY
CHLORAMPHENICOL
probably gives rise
to two
forms
of bone-marrow toxicity.1 One is an acute change which affects most patients when blood levels rise above 25 g. per 100 ml. The white-cell count falls and the platelet and red-cell count may also be depressed. Vacuolisation and inhibition of cellular respiration occur. These changes are readily and rapidly reversed when the drug is discontinued.
Chloramphenicol
may
also
give rise
to
aplastic
anasmia, which is often associated with repeated courses of the drug and is usually fatal. It may appear several weeks after the drug has been stopped. The way in which chloramphenicol produces this effect is unknown. Dameshek2 has discussed several possible mechanisms, including the prevention of binding of polyuridic acid to ribosomes or some effect on D.N.A. metabolism. Nagao and Mauer3 have described identical twins in whom reversible aplastic ansemia developed after exposure to chloramphenicol. Bone-marrow studies, including observation of tritiated-thymidine labelling indices in one twin, suggested that the defect responsible was failure of delivery of differentiated forms from a damaged undifferentiated stem-cell. Although the underlying biochemical changes are not known, it seems very probable that a genetically determined metabolic defect was responsible for these identical reactions to chloramphenicol. Such a defect would explain the low incidence of aplastic ansemia in patients given the drug. Wallerstein et al.4 have assessed the risk of dying of this complication as 1 in 36,118 with an average dose of 4-5 g. per person, rising to 1 in 21,671 with an average dose of 7-5 g. per person. Fatal
aplastic after the
anaemia seemed to be 13 times commoner use of chloramphenicol than in the untreated
population. This report of the twins 1. 2. 3. 4.
gives further impetus
studies of enzyme activity in marrow stem cells. If it were possible to demonstrate the abnormality present in patients liable to this complication, then the population at risk might be detected. Meanwhile, the use of chloramphenicol should be restricted to patients with typhoid fever or other gram-negative infections where there is no suitable alternative antibiotic.
KIDNEYS FOR TRANSPLANTATION
Nolan1
stated that donors
selected for renal
transplantation should not have systemic or renal infection, or evidence of renal disease, hypertension, or carcinoma. The donors should be relatively young and free from degenerative arterial disease; and they should not have been subjected to hypotension or anoxia before death. Owing to the scarcity of available cadaveric kidneys, however, White et a1.2 were forced to use kidneys from apparently unsuitable donors, yet subsequent renal function was good and not significantly different from that of more suitably matched kidney transplants. The kidneys from patients with renal failure complicating liver failure would generally be considered unsuitable for transplantation purposes because of the possibility of severe ischxmic tubular necrosis after hypotension and bleeding episodes; the usual absence of any previous data regarding renal function; the danger of systemic bacterial infection; and the hazard of transmitting hepatitis to the recipient. Koppel and his colleagues3 in Los Angeles now report the transplantation of kidneys to 7 recipients from donors dying of hepatic and renal failure. In all but
one case
diuresis followed in from six
to
fourteen
days, which, in the experience of Koppel et al., was not significantly different from the oliguric periods after comparable transplants from donors without hepatic failure. 4 of the kidneys achieved stable function for six months or more, and 2 patients are alive and well with creatinine clearances of 50 ml. per min. or more fifteen months later. Dunphy4 first described the " hepato-renal syn-
jaundice, and anuria after overwhelming gram-negative septicaemia and surgical shock are probably the most likely causes. Since then many forms of liver drome " of fever, shock,
upper abdominal surgery:
failure have been described in association with renal failure, and in Koppel et al.’s series 5 of the 6 donors had alcoholic cirrhosis and the 6th had chronic active hepatitis with postnecrotic cirrhosis. All had normal renal function before the onset of terminal hepatic failure, and renal insufficiency developed in all cases before terminal hypotension. All donors became hyponatrsemic and urinary sodium excretion was low during their terminal illness, despite a high urinary specific gravity. Microscopical examination of the spun urinary deposit showed occasional polymorphs
to
1.
Lancet, 1967, ii, 297. Dameshek, W. Near Engl. J. Med. 1969, 281, 42. Nagao, T., Mauer, A. M. ibid. p. 7. Wallerstein, R. O., Condit, P. K., Kasper, C. K., Brown, J. W., Morrison, F. R. J. Am. med. Ass. 1969, 208, 2045.
2. 3. 4.
Nolan, B. in Renal Disease (edited by D. A. K. Black); chapter 19. Oxford, 1967. White, H. J. O., Evans, D. B., Calne, R. Y. Br. med. J. 1968, iv, 739. Koppel, M. H., Coburn, J. W., Mims, M. M., Goldstein, H., Boyle, J. D., Rubini, M. E. New Engl. J. Med. 1969, 280, 1367. Dunphy, J. E., Harrison, J. H., Merrill, J. P. Surg. Forum, 1951, 2, 176.