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WARM MOIST AIR FOR BURNS
1152 WARM MOIST AIR FOR BURNS SiR,-The observations reported by Dr. Barr and his associates (Jan. 27, p. 164) represent important physiological considerations in the supportive care of burned persons. Their conclusions led to review of our data on metabolic rates of extensively burned adults, with grossly different conclusions. Basal metabolic rates were determined in duplicate on several occasions in non-septic patients with burns of 22-88% body-surface area treated by exposure. No one of a pair of observations differed by more than 10% of the larger value. The 19 pairs of observations were made at temperatures of 26-31°C (79-88°F) and humidities of 45-90%, both measured near the patient. The three positive correlations with increased metabolic rates were, in decreasing order of significance, the injured body surface area, humidity, and temperature. Those data indicate that within these limits a humid environment is more beneficial in controlling evaporative heat and water loss from the burn-wound than is warmth. Dr. Barr and his associates admit that warm moist air might favourably affect the hypermetabolism of severely burned man, but suggest that the patient and staff would find it uncomfortable and that it would favour bacterial proliferation upon the burned surface. Our patients are most uncomfortable on arid " days and much less so in humid, hurricane weather. As for the staff, they should adapt to the conditions most favourable " skinned " patient or institute suitable isolation proceto the dures. Finally, the concern for bacterial growth ignores the demonstrated efficacy of certain antimicrobial solutions, such as aqueous silver nitrate (0.5%), to control surface bacterial colonisation 1-2 Indeed, metabolic rates in burned persons treated with thick gauze dressings wet with warm 0.5% 3 aqueous silver nitrate and covered with a dry cotton blanket are much lower for the extent of injury described than those reported in warm dry air by Dr. Barr and his associates. I would agree that warmth is indicated in the environment of individuals convalescing from burn injuries. However, humidity, in lieu of aridity, lightens yet another important physiological load and, when provided in the form of an effective surface antimicrobial agent, need not promote invasive "
infection. Department of Surgery, University of Miami School of Medicine, Miami, Florida 33152.
HIRAM C.
POLK, Jr.
SIDE-EFFECTS OF CYTOTOXIC DRUGS SIR,-In your annotation (April 20, p. 854) on the toxic effects of busulphan you note the increased incidence of pulmonary fibrosis, and state that " the mechanism of production of these lung changes is not known ". However, I believe it may be possible to account for these lung changes and, at the same time, predict the appearance of other unwanted sideeffects. These effects are not confined to busulphan but may be seen with other cytotoxic drugs. Furthermore, side-effects may become more important, since these drugs are now being used in non-malignant conditions such as the nephrotic syndrome. Many of these drugs are alkylating agents. They are not specific for cancer cells but are toxic to all body cells. They act directly on essential proteins and enzymes in cells. Unstable alkyl end-groups attach themselves to molecules, especially the guanine moiety of D.N.A. Abnormal cross-linkages are formed between chromosomes, and cellular growth is inhibited. In many ways the action of these drugs is similar to that of radiation. For this reason they have been called radiomimetic drugs. In the circumstances it would not be surprising to find that the toxic effects of these drugs were similar if not identical to the effects of radiation. This seems to be the case. The radiobiological effects of radiation have been closely studied lately. After irradiation latent cell damage and death 1. 2. 3.
Cason, J. S., Lowbury, E. J. L. Lancet, March 30, 1968, p. 651. Brentano, L., Moyer, C. A., Gravens, D. L., Monafo, W. W., Jr. Archs Surg. 1966, 93, 456. Polk, H. C., Jr. Ann. Surg. 1966, 164, 753.
seen until the cell later enters mitosis. At this point cells fail to divide and are lysed. Rapidly dividing cells are the first to show the effects of injury. These include epithelial cells lining the gastrointestinal tract and bone-marrow cells. Thus after fairly small single doses of whole-body radiation (25-100 rads) the first symptoms patients complain of are anorexia, nausea, and occasionally vomiting. Shortly after this they may develop leucopenia and changes in the peripheral-blood picture. Precisely the same effects are seen with antimitotic drugs. With slightly larger doses of radiation (200-300 rads) temporary epilation of the scalp occurs and ovarian function is inhibited. Again alopecia and amenorrhoea are commonly seen after cytotoxic therapy. By the same token one would also expect to find oligospermia and perhaps evidence of a protein-losing
may not be
gastroenteropathy. It is difficult to give the exact equivalent single dose of radiation required to produce pulmonary fibrosis but it is probably about 500 rads to both lung fields. This dose is close to that known to cause radiation nephritis. Hence we may shortly see reports of kidney damage after long-term cytotoxic therapy. Similar changes may also be found in other organs. Two final points are worth noting: first, it may be that many of the different effects reported with antimitotic drugs are simply due to different dose levels; secondly, it is also worth remembering that, with fractionated radiation, cellular recovery is possible after sublethal damage. Thus it would seem wise to keep careful records of dosimetry in cytotoxic therapy. In addition the total time of drug administration should be recorded. In this way it may be possible to extend the use of these drugs by judicious cyclical therapy. Northern Ireland Radiotherapy Centre, Montgomery House, Purdysburn, Belfast.
W. S. B. LOWRY.
CHROMOSOMES IN CYSTIC FIBROSIS SIR,-The letter of Dr. Peter and Dr. Whang-Peng (May 4, p. 978) describes normal karyotypes in 7 patients with cystic fibrosis of the pancreas (c..). Normal karyotypes were also found in 5 male and 2 female cases of proven C.F. examined in out laboratory since 1964. In 5 cases, we used post-mortem cultures of thymic tissue.l There was a high incidence of endoreduplication (>5%) and of polyploidy in all. This is in contrast with the rarity of these changes in our peripheral-blood cultures (< 1 %) and in post-mortem cultures in general, with the exception of cultures of splenic tissue.2 Cultures of peripheral-blood lymphocytes in 2 additional male patients were obtained through the courtesy of Dr. Carolyn Denning and Dr. Celia Ores. These also showed a high incidence of endoreduplication in one case and of both endoreduplication and polyploidy in the other. Despite a rash of reports following a letter by Aspillaga et al.,3 the factor(s) inducing endoreduplication in individual instances cannot be readily defined. Chemotherapeutic agents have been incriminated.4 It appears difficult to determine the role of a specific agent in c.F., since the patients receive several drugs and are submitted to a host of deleterious factors, such as anoxia, acidosis, and malnutrition. It may be of interest to obtain karyotypes in parents of c.F. children and determine whether heterozygotes also show a perturbance of the normal mitotic mechanisms in vitro. The karyotypes of two fathers of c.F. children were published by Bueno et aJ.5 Endoreduplication is not mentioned. These workers described particularly prominent secondary constrictions of chromoIt is, however, generally recognised that somes number 9. the secondary constrictions of some chromosomes (numbers 1, 1. Bain, A. D., Gauld, I. K. Lancet, 1963, ii, 304. 2. Bain, A. D., Gauld, I. K. ibid. 1964, i, 936. 3. Aspillaga, M. J., Neu, R. L., Gardner, L. I. ibid. p. 937. 4. Nasjleti, C. E., Walden, J. M., Spencer, H. H. New Engl. J. Med. 1965, 272, 250. 5. Bueno, M., del Amo, A., Vasquez, J. J., Hermida, F., Garcia-Merlo, S., Zaldna, B. Rev. Med. Univ. Navarra, 1965, 9, 50.
infection. Department of Surgery, University of Miami School of Medicine, Miami, Florida 33152.
HIRAM C.
POLK, Jr.
SIDE-EFFECTS OF CYTOTOXIC DRUGS SIR,-In your annotation (April 20, p. 854) on the toxic effects of busulphan you note the increased incidence of pulmonary fibrosis, and state that " the mechanism of production of these lung changes is not known ". However, I believe it may be possible to account for these lung changes and, at the same time, predict the appearance of other unwanted sideeffects. These effects are not confined to busulphan but may be seen with other cytotoxic drugs. Furthermore, side-effects may become more important, since these drugs are now being used in non-malignant conditions such as the nephrotic syndrome. Many of these drugs are alkylating agents. They are not specific for cancer cells but are toxic to all body cells. They act directly on essential proteins and enzymes in cells. Unstable alkyl end-groups attach themselves to molecules, especially the guanine moiety of D.N.A. Abnormal cross-linkages are formed between chromosomes, and cellular growth is inhibited. In many ways the action of these drugs is similar to that of radiation. For this reason they have been called radiomimetic drugs. In the circumstances it would not be surprising to find that the toxic effects of these drugs were similar if not identical to the effects of radiation. This seems to be the case. The radiobiological effects of radiation have been closely studied lately. After irradiation latent cell damage and death 1. 2. 3.
Cason, J. S., Lowbury, E. J. L. Lancet, March 30, 1968, p. 651. Brentano, L., Moyer, C. A., Gravens, D. L., Monafo, W. W., Jr. Archs Surg. 1966, 93, 456. Polk, H. C., Jr. Ann. Surg. 1966, 164, 753.
seen until the cell later enters mitosis. At this point cells fail to divide and are lysed. Rapidly dividing cells are the first to show the effects of injury. These include epithelial cells lining the gastrointestinal tract and bone-marrow cells. Thus after fairly small single doses of whole-body radiation (25-100 rads) the first symptoms patients complain of are anorexia, nausea, and occasionally vomiting. Shortly after this they may develop leucopenia and changes in the peripheral-blood picture. Precisely the same effects are seen with antimitotic drugs. With slightly larger doses of radiation (200-300 rads) temporary epilation of the scalp occurs and ovarian function is inhibited. Again alopecia and amenorrhoea are commonly seen after cytotoxic therapy. By the same token one would also expect to find oligospermia and perhaps evidence of a protein-losing
may not be
gastroenteropathy. It is difficult to give the exact equivalent single dose of radiation required to produce pulmonary fibrosis but it is probably about 500 rads to both lung fields. This dose is close to that known to cause radiation nephritis. Hence we may shortly see reports of kidney damage after long-term cytotoxic therapy. Similar changes may also be found in other organs. Two final points are worth noting: first, it may be that many of the different effects reported with antimitotic drugs are simply due to different dose levels; secondly, it is also worth remembering that, with fractionated radiation, cellular recovery is possible after sublethal damage. Thus it would seem wise to keep careful records of dosimetry in cytotoxic therapy. In addition the total time of drug administration should be recorded. In this way it may be possible to extend the use of these drugs by judicious cyclical therapy. Northern Ireland Radiotherapy Centre, Montgomery House, Purdysburn, Belfast.
W. S. B. LOWRY.
CHROMOSOMES IN CYSTIC FIBROSIS SIR,-The letter of Dr. Peter and Dr. Whang-Peng (May 4, p. 978) describes normal karyotypes in 7 patients with cystic fibrosis of the pancreas (c..). Normal karyotypes were also found in 5 male and 2 female cases of proven C.F. examined in out laboratory since 1964. In 5 cases, we used post-mortem cultures of thymic tissue.l There was a high incidence of endoreduplication (>5%) and of polyploidy in all. This is in contrast with the rarity of these changes in our peripheral-blood cultures (< 1 %) and in post-mortem cultures in general, with the exception of cultures of splenic tissue.2 Cultures of peripheral-blood lymphocytes in 2 additional male patients were obtained through the courtesy of Dr. Carolyn Denning and Dr. Celia Ores. These also showed a high incidence of endoreduplication in one case and of both endoreduplication and polyploidy in the other. Despite a rash of reports following a letter by Aspillaga et al.,3 the factor(s) inducing endoreduplication in individual instances cannot be readily defined. Chemotherapeutic agents have been incriminated.4 It appears difficult to determine the role of a specific agent in c.F., since the patients receive several drugs and are submitted to a host of deleterious factors, such as anoxia, acidosis, and malnutrition. It may be of interest to obtain karyotypes in parents of c.F. children and determine whether heterozygotes also show a perturbance of the normal mitotic mechanisms in vitro. The karyotypes of two fathers of c.F. children were published by Bueno et aJ.5 Endoreduplication is not mentioned. These workers described particularly prominent secondary constrictions of chromoIt is, however, generally recognised that somes number 9. the secondary constrictions of some chromosomes (numbers 1, 1. Bain, A. D., Gauld, I. K. Lancet, 1963, ii, 304. 2. Bain, A. D., Gauld, I. K. ibid. 1964, i, 936. 3. Aspillaga, M. J., Neu, R. L., Gardner, L. I. ibid. p. 937. 4. Nasjleti, C. E., Walden, J. M., Spencer, H. H. New Engl. J. Med. 1965, 272, 250. 5. Bueno, M., del Amo, A., Vasquez, J. J., Hermida, F., Garcia-Merlo, S., Zaldna, B. Rev. Med. Univ. Navarra, 1965, 9, 50.