956 in the fluid contained within the cervical pouches supports the idea that this is the source of the increased A.F.P. in the liquor.
A.F.P.
Pædiatric Research Unit, Prince Philip Research Laboratories Guy’s Hospital Medical School London SE1 9RT
MARY J. SELLER
ÆTIOLOGY OF NECROTISING ENTEROCOLITIS
SIR,-It is generally agreed that neonatal necrotising enterocolitis (N.E.C.) is the result of ischoemic necrosis of the bowel wall, but the aetiology remains unclear.’ The earliest lesion is a coagulative necrosis of the mucosa, while thrombosis of small mesenteric vessels is probably only a terminal event secondary to disseminated intravascular coagulation seen in some cases.2 Perinatal hypoxia elicits a reflex redistribution of cardiac output at the expense of sympathetically innervated organs such as the intestine, and this has been held responsible for the disease. This would explain the association between N.E.c. and abnormal birth history or fetal disease. Of 64 cases seen in twenty years by Polin et al. 51 were premature (mean gestational age thirty-one weeks), and 5 had severe congenital heart-disease. However, the remaining eight (previously normal) infants developed N.E.C. after protracted periods of diarrhoea. The above theory does not explain such cases, nor does it account for the protective effect of breast feeding. The pathological changes of N.E.C. affect predominantly the distal colon,4 and general factors such as perinatal hypoxia, reflex circulatory changes, shock, sludging, intravascular thrombosis, or cardiac insufficiency are an inadequate or incomplete explanation for the disease. Local factors operative in the colon must be at least partly responsible. Diarrhoea in infants is associated with a very active gastrocolic reflex, with peristaltic waves which traverse the entire length of the colon. Intraluminal pressures (I.L.P.S) in the distal colon may exceed 75 mm Hg in such infants. In the dog colon I.L.P.s between 30 and 90 mm Hg specifically reduce blood-flow to the metabolically highly active mucosa and to the muscularis.6 Peristalsis produces higher I.L.P.s distally in any given segment of affected intestine, and the distal colon in infants with diarrhoea is thus subjected to an ischaemogenic influence. I suggest that this feature of the diarrhoeal state (itself poorly understood) is of primary importance in the pathogenesis of N.E.C., whatever the cause of the diarrhoea (gastroenteritis, hyperosmolar feeds, and so on). High I.L.P.S could also explain the pneumatosis. The general effects of hypoxia and so on would be additive in attaining a critical degree of mucosal ischemia. I have suggested that enterocolitis in Hirschsprung’s disease is an ischxmic lesion due to high I.L.P.S proximal to the obstruction.’ The protective effect of breast feeding and that of prophylactic kanamycin would be due to nothing more complicated than a bowel flora protective against infantile diarrhoea, and immune mechanisms need not be postulated. Guy’s Hospital, London SE1 9RT
RICHARD A. FAIRBURN
CLINICAL SIGN OF UNILATERAL PNEUMOTHORAX
SiR,—Ihave had a chance to test the physical sign for unilateral pneumothorax described by Dr Welsby (March 19, p. 653). The patient had a clinically obvious right-sided spon1. Lancet, 1977, i, 459. 2. Santulli, T. V., Schullinger, J. N., Heird, W. C., Gongaware, R. D., Wigger, J., Barlow, B., Blanc, W. A., Berdon, W. E. Pediatrics, 1975, 55, 376. 3. Polin, R. A., Pollack, P. F., Barlow, B., Wigger, H. J., Slovis, T. L., Santulli, T. V., Heird, W. C. J. Pediat. 1976, 89, 460. 4. Leonidas, J. C., Hall, R. T. ibid. p. 456. 5. Jorup, S. Acta pœdiat. 1952, 41, suppl. 85. 6. Boley, S. J., Agrawal, G. P., Warren, A. R., Veith, F. J., Levowitz, B. S. Treiber, W., Dougherty, J., Schwartz, S. S., Gliedman, M. L. Am. J. Surg. 1969, 117, 228. 7. Fairburn, R. A. Lancet, 1973, i, 697.
taneous pneumothorax, with diminished breath sounds and hyperresonance to percussion. However, percussion of each clavicle produced sounds of equal pitch and intensity on auscultation at the upper end of the sternum with the patient sitting up. The patient required an intercostal drain and was discharged from hospital. One week later he returned with another large right-sided pneumothorax. He was short of breath at rest but there was no tracheal displacement. The chest was asymmetrical with a hyperinflated poorly expanding right hemithorax, which was on auscultation. There was marked hyperthat side. Again Dr Welsby’s sign was negative. Although tapping over the clavicles and auscultating over the sternum may be useful in the diagnosis of some cases of unilateral pneumothorax, it certainly cannot be regarded as a reliable sign.
almost silent
resonance on
Whittington Hospital, London N19 5NF
DAVID M. MITCHELL
CLIOQUINOL SIR,-In your April 16 issue you printed two letters arising out of your article on subacute myelo-optic neuropathy (S.M.O.N.) and clioquinol (March 5, p. 534). They contain some inaccuracies in relation to our company’s product and policies. Sandoz does not manufacture or sell anywhere in the world clioquinol, the drug which has been related to S.M.o.N. in Japan. We do market ’Intestopan’, a combination of the bromine-containing oxyquinolines, broxyquinoline and brobenzoxaldine. Therapeutic efficacy of this drug has been demonstrated in published clinical studies in several thousand patients. These deal chiefly with the treatment of diarrhoea due to protozoal infestation (e.g., intestinal amoebiasis or giardiasis), and the work was done in countries where such diseases are common and represent the major indication for the drug; no trials of note have been done in English-speaking countries or in Scandinavia. Perhaps this is the reason why your Swedish correspondents consider that efficacy has not been proved. Nowhere do we recommend the use of intestopan for prophylaxis of "traveller’s diarrhoea", and intestopan has never been sold in Britain. Our drug was not introduced in Japan, so we do not know if it could have been related to S.M.O.N. However, it has been used extensively in many parts of the world, including several European countries, over the past fifteen years. As soon as the S.M.O.N. syndrome in Japan was associated with oxyquinoline medication, we searched our records for any such adverse effects. One case of optic atrophy after intestopan is known to us-a seven-year-old with acrodermatitis enteropathica, who was treated with high doses continuously for five years. Another case has been reported, in which a combination of one component of intestopan (broxyquinoline) with a spasmolytic agent (mepenzolate bromide) was implicated.’ In our package inserts and other written material for intestopan we pay full attention to the need for care regarding dosage and duration of treatment, as well as the awareness of the possibility of untoward effects. Pharmaceutical Division, Sandoz Ltd., Basle, Switzerland
G. BERNARD R. W. GRIFFITH
RIFAMPICIN: FOR TUBERCULOSIS ONLY?
SIR,-We agree with Professor Acocella and his colleagues p. 740) that rifampicin used for non-tuberculous conditions does not increase the likelihood that rifampicin-resistant strains of Mycobacterium tuberculosis will emerge. In
(April 2,
1.
Strandvik, B., Zetterstroem, R. Lancet, 1968, i, 922.
A.F.P.
Pædiatric Research Unit, Prince Philip Research Laboratories Guy’s Hospital Medical School London SE1 9RT
MARY J. SELLER
ÆTIOLOGY OF NECROTISING ENTEROCOLITIS
SIR,-It is generally agreed that neonatal necrotising enterocolitis (N.E.C.) is the result of ischoemic necrosis of the bowel wall, but the aetiology remains unclear.’ The earliest lesion is a coagulative necrosis of the mucosa, while thrombosis of small mesenteric vessels is probably only a terminal event secondary to disseminated intravascular coagulation seen in some cases.2 Perinatal hypoxia elicits a reflex redistribution of cardiac output at the expense of sympathetically innervated organs such as the intestine, and this has been held responsible for the disease. This would explain the association between N.E.c. and abnormal birth history or fetal disease. Of 64 cases seen in twenty years by Polin et al. 51 were premature (mean gestational age thirty-one weeks), and 5 had severe congenital heart-disease. However, the remaining eight (previously normal) infants developed N.E.C. after protracted periods of diarrhoea. The above theory does not explain such cases, nor does it account for the protective effect of breast feeding. The pathological changes of N.E.C. affect predominantly the distal colon,4 and general factors such as perinatal hypoxia, reflex circulatory changes, shock, sludging, intravascular thrombosis, or cardiac insufficiency are an inadequate or incomplete explanation for the disease. Local factors operative in the colon must be at least partly responsible. Diarrhoea in infants is associated with a very active gastrocolic reflex, with peristaltic waves which traverse the entire length of the colon. Intraluminal pressures (I.L.P.S) in the distal colon may exceed 75 mm Hg in such infants. In the dog colon I.L.P.s between 30 and 90 mm Hg specifically reduce blood-flow to the metabolically highly active mucosa and to the muscularis.6 Peristalsis produces higher I.L.P.s distally in any given segment of affected intestine, and the distal colon in infants with diarrhoea is thus subjected to an ischaemogenic influence. I suggest that this feature of the diarrhoeal state (itself poorly understood) is of primary importance in the pathogenesis of N.E.C., whatever the cause of the diarrhoea (gastroenteritis, hyperosmolar feeds, and so on). High I.L.P.S could also explain the pneumatosis. The general effects of hypoxia and so on would be additive in attaining a critical degree of mucosal ischemia. I have suggested that enterocolitis in Hirschsprung’s disease is an ischxmic lesion due to high I.L.P.S proximal to the obstruction.’ The protective effect of breast feeding and that of prophylactic kanamycin would be due to nothing more complicated than a bowel flora protective against infantile diarrhoea, and immune mechanisms need not be postulated. Guy’s Hospital, London SE1 9RT
RICHARD A. FAIRBURN
CLINICAL SIGN OF UNILATERAL PNEUMOTHORAX
SiR,—Ihave had a chance to test the physical sign for unilateral pneumothorax described by Dr Welsby (March 19, p. 653). The patient had a clinically obvious right-sided spon1. Lancet, 1977, i, 459. 2. Santulli, T. V., Schullinger, J. N., Heird, W. C., Gongaware, R. D., Wigger, J., Barlow, B., Blanc, W. A., Berdon, W. E. Pediatrics, 1975, 55, 376. 3. Polin, R. A., Pollack, P. F., Barlow, B., Wigger, H. J., Slovis, T. L., Santulli, T. V., Heird, W. C. J. Pediat. 1976, 89, 460. 4. Leonidas, J. C., Hall, R. T. ibid. p. 456. 5. Jorup, S. Acta pœdiat. 1952, 41, suppl. 85. 6. Boley, S. J., Agrawal, G. P., Warren, A. R., Veith, F. J., Levowitz, B. S. Treiber, W., Dougherty, J., Schwartz, S. S., Gliedman, M. L. Am. J. Surg. 1969, 117, 228. 7. Fairburn, R. A. Lancet, 1973, i, 697.
taneous pneumothorax, with diminished breath sounds and hyperresonance to percussion. However, percussion of each clavicle produced sounds of equal pitch and intensity on auscultation at the upper end of the sternum with the patient sitting up. The patient required an intercostal drain and was discharged from hospital. One week later he returned with another large right-sided pneumothorax. He was short of breath at rest but there was no tracheal displacement. The chest was asymmetrical with a hyperinflated poorly expanding right hemithorax, which was on auscultation. There was marked hyperthat side. Again Dr Welsby’s sign was negative. Although tapping over the clavicles and auscultating over the sternum may be useful in the diagnosis of some cases of unilateral pneumothorax, it certainly cannot be regarded as a reliable sign.
almost silent
resonance on
Whittington Hospital, London N19 5NF
DAVID M. MITCHELL
CLIOQUINOL SIR,-In your April 16 issue you printed two letters arising out of your article on subacute myelo-optic neuropathy (S.M.O.N.) and clioquinol (March 5, p. 534). They contain some inaccuracies in relation to our company’s product and policies. Sandoz does not manufacture or sell anywhere in the world clioquinol, the drug which has been related to S.M.o.N. in Japan. We do market ’Intestopan’, a combination of the bromine-containing oxyquinolines, broxyquinoline and brobenzoxaldine. Therapeutic efficacy of this drug has been demonstrated in published clinical studies in several thousand patients. These deal chiefly with the treatment of diarrhoea due to protozoal infestation (e.g., intestinal amoebiasis or giardiasis), and the work was done in countries where such diseases are common and represent the major indication for the drug; no trials of note have been done in English-speaking countries or in Scandinavia. Perhaps this is the reason why your Swedish correspondents consider that efficacy has not been proved. Nowhere do we recommend the use of intestopan for prophylaxis of "traveller’s diarrhoea", and intestopan has never been sold in Britain. Our drug was not introduced in Japan, so we do not know if it could have been related to S.M.O.N. However, it has been used extensively in many parts of the world, including several European countries, over the past fifteen years. As soon as the S.M.O.N. syndrome in Japan was associated with oxyquinoline medication, we searched our records for any such adverse effects. One case of optic atrophy after intestopan is known to us-a seven-year-old with acrodermatitis enteropathica, who was treated with high doses continuously for five years. Another case has been reported, in which a combination of one component of intestopan (broxyquinoline) with a spasmolytic agent (mepenzolate bromide) was implicated.’ In our package inserts and other written material for intestopan we pay full attention to the need for care regarding dosage and duration of treatment, as well as the awareness of the possibility of untoward effects. Pharmaceutical Division, Sandoz Ltd., Basle, Switzerland
G. BERNARD R. W. GRIFFITH
RIFAMPICIN: FOR TUBERCULOSIS ONLY?
SIR,-We agree with Professor Acocella and his colleagues p. 740) that rifampicin used for non-tuberculous conditions does not increase the likelihood that rifampicin-resistant strains of Mycobacterium tuberculosis will emerge. In
(April 2,
1.
Strandvik, B., Zetterstroem, R. Lancet, 1968, i, 922.
