433
1/610. Furthermore, between 1975 and 1988 (the last available data) only 5,3% of graduates from the Israeli medical colleges were Arabs, despite the fact that they composed 15.5% of the population at graduation age. This means that their share among medical graduates reached not more that 34% of what it should have been if an equitable system had prevailed. This representation rate is, for example, less than that of black graduates in the USA who attained 39% of their share of the population at graduation age. It is not surprising therefore to see many Arab students pursue their education abroad. Not more than a quarter of Arab physicians graduate from Israeli universities. If the Arabs relied on acquiring education only in Israeli universities, then the ratio of physicians per head of population would have been 1/2980. As Arab physicians who graduated from foreign medical schools began to enter the labour market (in relatively large numbers) various mechanisms were established to hamper their progress. In 1987 a new law required such graduates to pass a special pre-internship examination. This is different from the licensing examination that immigrant physicians who have practised abroad have to pass. So far success rates for the former examination, which mostly Arabs sit, averages 15%, whereas for the latter, which mainly Jews sit, the rates are around 70%. No alternative is provided for those who fail the examination repeatedly. Since the Israeli economy is unable to sustain a larger health-care system, we believe that Arab graduates should be given the chance to compete on equal footing with other Israeli doctors. Much has been done to absorb Jewish immigrants. For example, in 1990 the Ministry of Health opened special workshops to help 1000 immigrant physicians to pass the examinations. Moreover, an interministerial committee prepared a plan to absorb 2000 immigrant physicians. However, nothing similar had been done to help Arab physicians who completed their studies in Eastern European countries. We believe that it is time governmental attention is paid to advancing the cause of Arab citizens who have contributed much since the establishment of the State. In Israel-ie, a state in which two groups live (Jews and Arabs)—an equitable treatment is needed to create harmonious relations, characterised by mutual understanding rather than domination. This is especially timely as Israel and its Arab neighbours are communities the ratio is
embarking on peace negotiations. Galilee Society, PO Box 92, Rama 30055, Israel
HATIM KANAANEH
Are there too many medical beds? SIR,-Malcolm Dean (Jan 18, p 170) predicts that physicians and geriatricians may not be as enthusiastic in their response to the important and valuable report from the Audit Commission’ as were the surgeons to its report on day surgery. I suggest that they might well respond equally positively to many of its recommendations, but with their characteristic caution, which would be justified on at least three grounds. First, in the experience of most geriatricians, and perhaps physicians, complaints from patients and relatives that discharge is too soon (or at all) outnumber complaints that it is unduly delayed. Second, being by nature less optimistic than surgeons, geriatricians might envisage the possibility of a finance gap in the implementation of the Commission’s recommendations, resulting in hospital down-bedding preceding, and possibly not matched by, the upgrading of community sevices. Third, the "any port in a storm" role of the district general hospital needs to be defended, because it is often very difficult to know in advance which apparently "low-tech" elderly patient with a respiratory infection or heart failure will turn into a "hi-tech" patient needing advanced
diagnostic
facilities and
access to
other
specialties.
But the
ships
have to be able to set sail for other ports when the storm subsides, so that berths become available Department of Geriatric Medicine, Addenbrookes Hospital, Cambridge CB2 2QQ, UK
to
other vessels in distress.
N. K. CONI
1. Audit Commission. Lying m wait. the use of medical beds in acute hospitals. London. HM Stationery Office, 1992.
Long reports SIR,-Whatever current or past editors may say or think about medical journals and their contents (Jan 25, p 249)-as a consumer I know what I want from The Lancet. For me, the practising physician, the hallmark of a good paper is one that changes my view of things and especially changes my practice. Every week I read two general journals and between one and three specialist journals and I feel pleased if I can identify a paper that fulfils my requirements. Every week I attend and contribute to a journal club and review a specialist journal in my field and can rarely find more than one paper per issue with a clinical message of merit to share with my
colleagues. I think the editor of The Lancet should be applauded, firstly for taking the trouble to ask the consumer what he wants (Jan 4, p 33), and secondly for publishing papers that will undoubtedly change medical practice. Length and breadth are often irrelevant to the
satisfaction that can be obtained. Department of Cardiology, Royal Hallamshire Hospital,
K. S. CHANNER
Sheffield S10 2JF, UK
Glutaraldehyde allergy in endoscopy units SIR,-We have received several complaints of symptoms from health services’ staff who use glutaraldehyde, especially those in endoscopy units. In 1991 we sent 169 questionnaires to nurses in seventeen hospitals that we visited in our area. We received 167 replies. 65% of those who replied reported symptoms and 38 % had two or more. The major complaints were eye irritation 49%, skin discoloration or irritation 41%,’ headache 36%, and cough or shortness of breath 34%The complaints were reported in all seventeen hospitals, and were not related to smoking habits, atopic status, or duration of exposure. In two hospitals, environmental measurement of glutaraldehyde in air had been done and levels were below the UK occupational exposure standard, which currently is 0-2 parts per million (10 min time-weighted average).3 In the UK the Control of Substances Hazardous to Health Regulations 1988require the users of such substances to assess health risks and to reduce exposure. Simple control measures such as chemical substitution are at present impracticable for glutaraldehyde, so other methods should be considered. Cleaning of endoscopes in vertical tubes rather than horizontal trays, the closed transfer of glutaraldehyde to cleaning units, and similar precautions for disposal should reduce the exposure considerably. I. M. CALDER L. P. WRIGHT D. GRIMSTONE
Health and Safety Executive, Luton LU1 1PP, UK 1. Fowler
JF. Allergic contact dermatitis from glutaraldehyde exposure. J Occup Med
1989; 31: 852-53. 2. Wiggins P, McCurdy PA, Zeidenberg W. Epistaxis due to glutaraldehyde exposure. J Occup Med 1989; 31: 854-56. 3. Health and Safety Executive, health and safety guidance note EH40/90: occupational exposure limits. London: HSE, 1990. 4. Control of Substances Hazardous to Health
Regulations 1988: approved code of practice control of substances hazardous to health and approved code of practice control of carcinogenic substances. London: HM Stationery Office, 1988.
Research in
developing
countries
SIR,-As a specialist in tropical diseases, Dr Patel and Dr Araya’s article (Jan 11, p 110) about the lack of research in developing countries because there are too few trained personnel struck a responsive chord. I have benefited greatly from collaboration with and the hospitality of many fine scientists in South America, the Caribbean, and African and Asian countries. Thus, when I was offered the directorship of health sciences of the Rockefeller Foundation in 1977 I was pleased that I might be able to do something about the tragic difficulties so ably described by Patel and Araya. Since its founding in 1913 the Foundation has tried many strategies to support medical research and researchers in the developing world. Training in the developed world has always been
434
the basic approach, and this was augmented in certain programmes by short-term "re-entry grants". Another strategy was the building of an infrastructure in third-world countries, from departments to major areas in universities, such as medicine and agriculture. Both approaches were bedevilled by the rapid deterioration of individual scientists bereft of information, communication, and equipment, and of the infrastructure supplied, but often not maintained. During the decade I spent at the Foundation we tried to develop ways to keep highly trained and competent individuals active after their return home. One approach, the International Clinical Epidemiology Network, which Patel and Araya mention, involved the institution in more than 30 medical schools in the developing world of mutually supportive units of around 10 researchers trained in special centres in the USA, Canada, and Australia. This approach has been reinforced by an annual international meeting involving all the units. Another was the integration of our largely America/ Europe/Australia-based "greatly neglected diseases" biomedical research units, doing state-of-the-art investigation on the major diseases of the developing world, with the best of the institutionally strengthened third-world centres of the World Health Organisation’s tropical diseases research programme. Of particular interest is the biotechnology career fellowships, which enable outstanding scientists from the developing world trained in the laboratories of countries with highly developed scientific infrastructures to maintain their expertise by returning for several months each year, indefinitely. The aim of all these programmes was and is to allow fine scientists to continue to function as investigators of international calibre wherever they may be. To do anything less is wasteful of highly trained and competent human beings, and of the invaluable fruits of their labour for the wellbeing of mankind throughout the world. Macmillan, 866 Third Avenue, New York City, New York 10022, USA
KENNETH WARREN
Euphorbia species SIR,-In their report on chromosomal translocation and oncogene activation when B lymphocytes were incubated with Epstein-Barr virus (EBV) and 4-deoxyphorbol ester, Aya et all hypothesise that this plant extract might be one factor in the development of Burkitt’s lymphoma. This theory on the origin of Burkitt’s lymphoma in central Africa hinges on the ubiquity of a species of Euphorbia, which they name Euphorbia tirucalli, near habitations where the lymphoma is endemic. The common use of a species of Euphorbia as fencing and the possible indirect consumption of its sap by natives in central Africa was noted in 1863 during Speke’s journey to discover the source of the Nile. Grant’s entry in Speke’s journal reads "E tirucalli? A dense fence of this tree-sized bush surrounds nearly all the villages of the land of the moon... ; its milk is used for poisoning fish’’,2 Grant collected several specimens that were sent to Britain for classification, and the species under discussion was named "E tirucalli?".3 E tirucalli (Linnaeus) is native to India, and Thiselton-Dyer,4in his Flora of Tropical AfricaJ states that, "The name E tirucalli has been applied to several African species, but all are distinct from the true E tirucalli, native of India. There is no evidence that this species was introduced from India to Africa and the Indian plant is perfectly distinct from all African species I have seen." The African species may be E scoparia (N. E. Brown), which is closest to the Indian E tirucalli). The question is not just of nomenclature. Burkitt’s lymphoma is common in a belt of central Africa and in Papua New Guinea, both of which locations have a high incidence of EBV virus and malaria transmission. Many other areas where both these agents are found (including India) do not have endemic Burkitt’s lymphoma. The plausible explanation for the distribution of Burkitt’s lymphoma proposed by Aya and colleagues-namely, that a third agent is required for carcinogenesis and chromosomal translocation-still leaves some issues unresolved. A euphorbia species (perhaps E scoparia) may be used medicinally in, or contaminates food in, central Africa, the agent causing the translocation in Papua New Guinea being not yet identified; another possibility is that in India
and other countries without endemic Burkitt’s lymphoma, but with malaria and EBV, there is no agent causing chromosomal translocations because the euphorbiae are neither grown near human habitations nor used medicinally; and a third possibility is that the carcinogenic phorbol ester is not found in true E tirucallibut is present in E scoparia. This is why we need to know the origin of the plants used by Aya and colleagues in their experiments and to find out whether these esters are found in the African species and if there are similar species in Papua New Guinea. Department of Haematology, St Mary’s Hospital Medical School, Imperial College of Science, Technology and Medicine,
S. H. ABDALLA
London W2 1PG, UK
1. Aya T, Kinoshita T, Imai S, et al. Chromosome translocation and c-myc activation by Epstein-Barr virus and Euphorbia tirucalli in B lymphocytes. Lancet 1991; 337; 1190. 2. Speke JH. Journal of the discovery of the source of the Nile. Edinburgh. William Blackwood, 1863: 646. 3. Oliver T. The botany of the Speke and Grant expedition. Trans Linnean Soc 1872; 29 4.
(part 3): 144. Thiselton-Dyer WT. Flora of tropical Africa: vol VI,
section
1. Ashford: L
Reeve,
1913: 557.
Inhibition of NO
synthesis in septic shock
Sm,—Dr Petros and colleagues (Dec 21/28, p 1557) report that pharmacological inhibition of nitric oxide (NO) synthesis restored blood pressure in two patients in septic shock, suggesting that increased synthesis of endogenous NO is involved in the pathogenesis of the haemodynamic complications of sepsis. Although the NO synthase inhibitor NG-monomethyl-L-arginine (NMMA) increased blood pressure in both patients, it is possible that this drug concomitantly induced adverse effects on organ perfusion and patient outcome. Indeed, the cardiovascular data indicate that one patient experienced a decrease in cardiac index from 4-5 to 2-7 litres/min per m2 after NMMA. This patient died after 2 days with adult respiratory distress syndrome (ARDS), disseminated intravascular coagulation, and exacerbation of intraperitoneal sepsis. Might the NMMA have countermanded some protective role(s) of NO in sepsis, with death being due partly to complications of drug therapy rather than solely to progression of the underlying disease? Petros et al suggest that "inhibition of NO synthase may represent a novel therapeutic option" for treatment of refractory shock in sepsis. Such a proposal seems premature to us, for the following reasons: (1) NO has an important role in regulating visceral blood flow.’ In animals, inhibition of NO synthesis potentiated the jejunal vasoconstriction produced by endotoxin and induced haemorrhage in the bowel wait Such an effect could result in translocation of bacteria and endotoxin across the bowel wall, aggravating the septic condition. And in rats injected with endotoxin, inhibition of NO synthesis caused an increase in liver injury.3 Perhaps, despite the increase in mean arterial pressure in the patients described by Petros et al, visceral blood flow was compromised. (2) Administration of NO by inhalation has been effective in causing preferential vasodilatation of ventilated regions of the lung, thereby improving gas exchange and decreasing shunting in patients with ARDS’ so inhibition of NO synthesis could worsen ARDS, which is a frequent complication in septic patients. (3) Inhibition of NO synthesis could lead to platelet aggregation, resulting in microvascular stasis, thrombosis, and disseminated intravascular coagulation.5 (4) NO is an excellent antimicrobial agent and it may be a major cellular biochemical defence mechanism against intracellular pathogens, so inhibition of its synthesis could compromise the ability of host cells to eradicate infectious agents.6 (5) Although results have not been consistent, one study showed that infusion of L-arginine, the substrate for NO synthesis, enhanced survival in a septic rat model7 (6) Although NMMA increased blood pressure in a canine model of endotoxaemia, this response was due to an increase in peripheral vascular resistance at the expense of disadvantaged cardiodynamics and a decrease in cardiac output.8 Endotoxin can directly inhibit the
1/610. Furthermore, between 1975 and 1988 (the last available data) only 5,3% of graduates from the Israeli medical colleges were Arabs, despite the fact that they composed 15.5% of the population at graduation age. This means that their share among medical graduates reached not more that 34% of what it should have been if an equitable system had prevailed. This representation rate is, for example, less than that of black graduates in the USA who attained 39% of their share of the population at graduation age. It is not surprising therefore to see many Arab students pursue their education abroad. Not more than a quarter of Arab physicians graduate from Israeli universities. If the Arabs relied on acquiring education only in Israeli universities, then the ratio of physicians per head of population would have been 1/2980. As Arab physicians who graduated from foreign medical schools began to enter the labour market (in relatively large numbers) various mechanisms were established to hamper their progress. In 1987 a new law required such graduates to pass a special pre-internship examination. This is different from the licensing examination that immigrant physicians who have practised abroad have to pass. So far success rates for the former examination, which mostly Arabs sit, averages 15%, whereas for the latter, which mainly Jews sit, the rates are around 70%. No alternative is provided for those who fail the examination repeatedly. Since the Israeli economy is unable to sustain a larger health-care system, we believe that Arab graduates should be given the chance to compete on equal footing with other Israeli doctors. Much has been done to absorb Jewish immigrants. For example, in 1990 the Ministry of Health opened special workshops to help 1000 immigrant physicians to pass the examinations. Moreover, an interministerial committee prepared a plan to absorb 2000 immigrant physicians. However, nothing similar had been done to help Arab physicians who completed their studies in Eastern European countries. We believe that it is time governmental attention is paid to advancing the cause of Arab citizens who have contributed much since the establishment of the State. In Israel-ie, a state in which two groups live (Jews and Arabs)—an equitable treatment is needed to create harmonious relations, characterised by mutual understanding rather than domination. This is especially timely as Israel and its Arab neighbours are communities the ratio is
embarking on peace negotiations. Galilee Society, PO Box 92, Rama 30055, Israel
HATIM KANAANEH
Are there too many medical beds? SIR,-Malcolm Dean (Jan 18, p 170) predicts that physicians and geriatricians may not be as enthusiastic in their response to the important and valuable report from the Audit Commission’ as were the surgeons to its report on day surgery. I suggest that they might well respond equally positively to many of its recommendations, but with their characteristic caution, which would be justified on at least three grounds. First, in the experience of most geriatricians, and perhaps physicians, complaints from patients and relatives that discharge is too soon (or at all) outnumber complaints that it is unduly delayed. Second, being by nature less optimistic than surgeons, geriatricians might envisage the possibility of a finance gap in the implementation of the Commission’s recommendations, resulting in hospital down-bedding preceding, and possibly not matched by, the upgrading of community sevices. Third, the "any port in a storm" role of the district general hospital needs to be defended, because it is often very difficult to know in advance which apparently "low-tech" elderly patient with a respiratory infection or heart failure will turn into a "hi-tech" patient needing advanced
diagnostic
facilities and
access to
other
specialties.
But the
ships
have to be able to set sail for other ports when the storm subsides, so that berths become available Department of Geriatric Medicine, Addenbrookes Hospital, Cambridge CB2 2QQ, UK
to
other vessels in distress.
N. K. CONI
1. Audit Commission. Lying m wait. the use of medical beds in acute hospitals. London. HM Stationery Office, 1992.
Long reports SIR,-Whatever current or past editors may say or think about medical journals and their contents (Jan 25, p 249)-as a consumer I know what I want from The Lancet. For me, the practising physician, the hallmark of a good paper is one that changes my view of things and especially changes my practice. Every week I read two general journals and between one and three specialist journals and I feel pleased if I can identify a paper that fulfils my requirements. Every week I attend and contribute to a journal club and review a specialist journal in my field and can rarely find more than one paper per issue with a clinical message of merit to share with my
colleagues. I think the editor of The Lancet should be applauded, firstly for taking the trouble to ask the consumer what he wants (Jan 4, p 33), and secondly for publishing papers that will undoubtedly change medical practice. Length and breadth are often irrelevant to the
satisfaction that can be obtained. Department of Cardiology, Royal Hallamshire Hospital,
K. S. CHANNER
Sheffield S10 2JF, UK
Glutaraldehyde allergy in endoscopy units SIR,-We have received several complaints of symptoms from health services’ staff who use glutaraldehyde, especially those in endoscopy units. In 1991 we sent 169 questionnaires to nurses in seventeen hospitals that we visited in our area. We received 167 replies. 65% of those who replied reported symptoms and 38 % had two or more. The major complaints were eye irritation 49%, skin discoloration or irritation 41%,’ headache 36%, and cough or shortness of breath 34%The complaints were reported in all seventeen hospitals, and were not related to smoking habits, atopic status, or duration of exposure. In two hospitals, environmental measurement of glutaraldehyde in air had been done and levels were below the UK occupational exposure standard, which currently is 0-2 parts per million (10 min time-weighted average).3 In the UK the Control of Substances Hazardous to Health Regulations 1988require the users of such substances to assess health risks and to reduce exposure. Simple control measures such as chemical substitution are at present impracticable for glutaraldehyde, so other methods should be considered. Cleaning of endoscopes in vertical tubes rather than horizontal trays, the closed transfer of glutaraldehyde to cleaning units, and similar precautions for disposal should reduce the exposure considerably. I. M. CALDER L. P. WRIGHT D. GRIMSTONE
Health and Safety Executive, Luton LU1 1PP, UK 1. Fowler
JF. Allergic contact dermatitis from glutaraldehyde exposure. J Occup Med
1989; 31: 852-53. 2. Wiggins P, McCurdy PA, Zeidenberg W. Epistaxis due to glutaraldehyde exposure. J Occup Med 1989; 31: 854-56. 3. Health and Safety Executive, health and safety guidance note EH40/90: occupational exposure limits. London: HSE, 1990. 4. Control of Substances Hazardous to Health
Regulations 1988: approved code of practice control of substances hazardous to health and approved code of practice control of carcinogenic substances. London: HM Stationery Office, 1988.
Research in
developing
countries
SIR,-As a specialist in tropical diseases, Dr Patel and Dr Araya’s article (Jan 11, p 110) about the lack of research in developing countries because there are too few trained personnel struck a responsive chord. I have benefited greatly from collaboration with and the hospitality of many fine scientists in South America, the Caribbean, and African and Asian countries. Thus, when I was offered the directorship of health sciences of the Rockefeller Foundation in 1977 I was pleased that I might be able to do something about the tragic difficulties so ably described by Patel and Araya. Since its founding in 1913 the Foundation has tried many strategies to support medical research and researchers in the developing world. Training in the developed world has always been
434
the basic approach, and this was augmented in certain programmes by short-term "re-entry grants". Another strategy was the building of an infrastructure in third-world countries, from departments to major areas in universities, such as medicine and agriculture. Both approaches were bedevilled by the rapid deterioration of individual scientists bereft of information, communication, and equipment, and of the infrastructure supplied, but often not maintained. During the decade I spent at the Foundation we tried to develop ways to keep highly trained and competent individuals active after their return home. One approach, the International Clinical Epidemiology Network, which Patel and Araya mention, involved the institution in more than 30 medical schools in the developing world of mutually supportive units of around 10 researchers trained in special centres in the USA, Canada, and Australia. This approach has been reinforced by an annual international meeting involving all the units. Another was the integration of our largely America/ Europe/Australia-based "greatly neglected diseases" biomedical research units, doing state-of-the-art investigation on the major diseases of the developing world, with the best of the institutionally strengthened third-world centres of the World Health Organisation’s tropical diseases research programme. Of particular interest is the biotechnology career fellowships, which enable outstanding scientists from the developing world trained in the laboratories of countries with highly developed scientific infrastructures to maintain their expertise by returning for several months each year, indefinitely. The aim of all these programmes was and is to allow fine scientists to continue to function as investigators of international calibre wherever they may be. To do anything less is wasteful of highly trained and competent human beings, and of the invaluable fruits of their labour for the wellbeing of mankind throughout the world. Macmillan, 866 Third Avenue, New York City, New York 10022, USA
KENNETH WARREN
Euphorbia species SIR,-In their report on chromosomal translocation and oncogene activation when B lymphocytes were incubated with Epstein-Barr virus (EBV) and 4-deoxyphorbol ester, Aya et all hypothesise that this plant extract might be one factor in the development of Burkitt’s lymphoma. This theory on the origin of Burkitt’s lymphoma in central Africa hinges on the ubiquity of a species of Euphorbia, which they name Euphorbia tirucalli, near habitations where the lymphoma is endemic. The common use of a species of Euphorbia as fencing and the possible indirect consumption of its sap by natives in central Africa was noted in 1863 during Speke’s journey to discover the source of the Nile. Grant’s entry in Speke’s journal reads "E tirucalli? A dense fence of this tree-sized bush surrounds nearly all the villages of the land of the moon... ; its milk is used for poisoning fish’’,2 Grant collected several specimens that were sent to Britain for classification, and the species under discussion was named "E tirucalli?".3 E tirucalli (Linnaeus) is native to India, and Thiselton-Dyer,4in his Flora of Tropical AfricaJ states that, "The name E tirucalli has been applied to several African species, but all are distinct from the true E tirucalli, native of India. There is no evidence that this species was introduced from India to Africa and the Indian plant is perfectly distinct from all African species I have seen." The African species may be E scoparia (N. E. Brown), which is closest to the Indian E tirucalli). The question is not just of nomenclature. Burkitt’s lymphoma is common in a belt of central Africa and in Papua New Guinea, both of which locations have a high incidence of EBV virus and malaria transmission. Many other areas where both these agents are found (including India) do not have endemic Burkitt’s lymphoma. The plausible explanation for the distribution of Burkitt’s lymphoma proposed by Aya and colleagues-namely, that a third agent is required for carcinogenesis and chromosomal translocation-still leaves some issues unresolved. A euphorbia species (perhaps E scoparia) may be used medicinally in, or contaminates food in, central Africa, the agent causing the translocation in Papua New Guinea being not yet identified; another possibility is that in India
and other countries without endemic Burkitt’s lymphoma, but with malaria and EBV, there is no agent causing chromosomal translocations because the euphorbiae are neither grown near human habitations nor used medicinally; and a third possibility is that the carcinogenic phorbol ester is not found in true E tirucallibut is present in E scoparia. This is why we need to know the origin of the plants used by Aya and colleagues in their experiments and to find out whether these esters are found in the African species and if there are similar species in Papua New Guinea. Department of Haematology, St Mary’s Hospital Medical School, Imperial College of Science, Technology and Medicine,
S. H. ABDALLA
London W2 1PG, UK
1. Aya T, Kinoshita T, Imai S, et al. Chromosome translocation and c-myc activation by Epstein-Barr virus and Euphorbia tirucalli in B lymphocytes. Lancet 1991; 337; 1190. 2. Speke JH. Journal of the discovery of the source of the Nile. Edinburgh. William Blackwood, 1863: 646. 3. Oliver T. The botany of the Speke and Grant expedition. Trans Linnean Soc 1872; 29 4.
(part 3): 144. Thiselton-Dyer WT. Flora of tropical Africa: vol VI,
section
1. Ashford: L
Reeve,
1913: 557.
Inhibition of NO
synthesis in septic shock
Sm,—Dr Petros and colleagues (Dec 21/28, p 1557) report that pharmacological inhibition of nitric oxide (NO) synthesis restored blood pressure in two patients in septic shock, suggesting that increased synthesis of endogenous NO is involved in the pathogenesis of the haemodynamic complications of sepsis. Although the NO synthase inhibitor NG-monomethyl-L-arginine (NMMA) increased blood pressure in both patients, it is possible that this drug concomitantly induced adverse effects on organ perfusion and patient outcome. Indeed, the cardiovascular data indicate that one patient experienced a decrease in cardiac index from 4-5 to 2-7 litres/min per m2 after NMMA. This patient died after 2 days with adult respiratory distress syndrome (ARDS), disseminated intravascular coagulation, and exacerbation of intraperitoneal sepsis. Might the NMMA have countermanded some protective role(s) of NO in sepsis, with death being due partly to complications of drug therapy rather than solely to progression of the underlying disease? Petros et al suggest that "inhibition of NO synthase may represent a novel therapeutic option" for treatment of refractory shock in sepsis. Such a proposal seems premature to us, for the following reasons: (1) NO has an important role in regulating visceral blood flow.’ In animals, inhibition of NO synthesis potentiated the jejunal vasoconstriction produced by endotoxin and induced haemorrhage in the bowel wait Such an effect could result in translocation of bacteria and endotoxin across the bowel wall, aggravating the septic condition. And in rats injected with endotoxin, inhibition of NO synthesis caused an increase in liver injury.3 Perhaps, despite the increase in mean arterial pressure in the patients described by Petros et al, visceral blood flow was compromised. (2) Administration of NO by inhalation has been effective in causing preferential vasodilatation of ventilated regions of the lung, thereby improving gas exchange and decreasing shunting in patients with ARDS’ so inhibition of NO synthesis could worsen ARDS, which is a frequent complication in septic patients. (3) Inhibition of NO synthesis could lead to platelet aggregation, resulting in microvascular stasis, thrombosis, and disseminated intravascular coagulation.5 (4) NO is an excellent antimicrobial agent and it may be a major cellular biochemical defence mechanism against intracellular pathogens, so inhibition of its synthesis could compromise the ability of host cells to eradicate infectious agents.6 (5) Although results have not been consistent, one study showed that infusion of L-arginine, the substrate for NO synthesis, enhanced survival in a septic rat model7 (6) Although NMMA increased blood pressure in a canine model of endotoxaemia, this response was due to an increase in peripheral vascular resistance at the expense of disadvantaged cardiodynamics and a decrease in cardiac output.8 Endotoxin can directly inhibit the
