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
435
synthesis and/or release of NO from cultured vascular endothelial cells.9 Endotoxin and its endogenous mediators can inhibit coronary vasodilator responses to agents that depend on increased synthesis of endothelium-derived NO; hence, the use of NO synthase inhibitors in this setting could induce coronary vasoconstriction and nominally restrict myocardial perfusion at best or provoke myocardial ischaemia at worst."’ This might explain the fall in cardiac index in one of Petros and colleagues patients.1 Although The Lancet editorial accompanying the paper by Petros et al implies that NO synthase inhibitors produced "beneficial cardiovascular effects" in the two patients, a fall in cardiac index would not be beneficial during sepsis, especially if accompanied by (or due to) an increase in peripheral vascular resistance and its attendant increase in cardiac workload. In view of the complex pharmacodynamic spectrum of drugs that inhibit NO synthase, we do not support further clinical trials in sepsis until animal studies have been done to disclose any adverse actions of these agents on perfusion of the coronary vasculature and other vital oxidative tissues. Departments of Anesthesiology and Internal Medicine, Washington University School of Medicine
RICHARD S. HOTCHKISS IRENE E. KARL
Department of Physiology, University of Missouri
JANET L. PARKER
Department of Veterinary Biomedical Sciences,
University of Missouri, Columbia, Missouri 65211, USA
H. RICHARD ADAMS
1. Moncada S, Higgs EA. Endogenous nitric oxide: physiology, pathology, and clinical relevance. Eur J Clin Invest 1991; 21: 361-74. 2. Hutcheson IR, Whittle B Jr, Boughton-Smith NK. Role of nitric oxide in maintaining vascular integrity in endotoxin-induced intestinal damage in the rat. Br J Pharmacol 1990; 101: 815-20. 3. Billiar TR, Curran RD, Harbrecht BG, Stuehr DJ, Demetris AJ, Simmons RL. Modulation of nitrogen oxide synthesis in vivo: NG-monomethyl-L-arginine inhibits endotoxin-induced nitrite/nitrate biosynthesis while promoting hepatic damage. J Leukoc Biol 1990; 48: 565-69 4. Faule KJ, Rossaint R, Keitel M, et al. Successful treatment of severe adult respiratory distress syndrome with nitric oxide: the first three patients. Presented at Second International Meeting on the Biology of Nitric Oxide (London, October, 1991). 5. Durante W, Schini VB, Scott-Burden T, et al Platelet inhibition by an L-arginine derived substance released by IL-I&bgr;-trcared vascular smooth muscle cells. Am J Physiol 1991; 261: H2024-H2030. 6. Nathan CF, Hibbs JB. Role of nitric oxide synthesis in macrophage antimicrobial activity. Curr Opin Immunol 1991; 3:65-70. 7 Madden HP, Breslin RJ, Wasserkrug HL, Efron BAG, Barbul A Stimulation of T cell immunity by arginine enhances survival in peritonitis. J Surg Res 1988; 44: 658-63. 8. Klabunde RE, Ritger RC. NG-monomethyl-L-arginine (NMMA) restores arterial blood pressure but reduces cardiac output in a canine model of endotoxic shock. Biochem Biophys Res Comm 1991; 178: 1135-40 9. Myers PR, Wright TF, Tanner MA, Adams HR. Endothelium-derived relaxing factor and nitric oxide production in cultured endothelial cells: direct inhibition by E coli endotoxin. Am J Physiol (in press) 10 Parker JL, Keller RS, DeFily DV, Laughlin MH, Novotny MJ, Adams HR. Coronary vascular smooth muscle function in E coli endotoxemia in dogs. Am J Physiol 1991; 260 (Heart Circ Physiol 29): H832-H841.
SIR,—To add to the two patients described by Dr Petros and colleagues, we would like to report a case of septic shock in a patient with severe hypotension and multiple organ failure who was successfully treated with 700 mg NG-monomethyl-L-arginine (NMMA). Less than 3 min after intravenous injection ofNMMA the blood pressure was normal and a continuous infusion of noradrenaline 25 pg/min could be stopped. A 29-year-old man was admitted to intensive care with necrotising pancreatitis. From admission the patient was on ventilatory support. Eleven abdominal surgical interventions were necessary and a splenic abscess was treated by splenectomy. The patient was on haemofiltration for 54 days and episodes of septicaemia were treated with antibiotics. From day 90 he improved. Haemofiltration was stopped on that day, and renal function returned to normal. The patient was still artificially ventilated but he could communicate again and started to exercise. On day 109 Pseudomonas aerugirwsa infection was diagnosed; this could be controlled with antibiotics. On day 119 the patient went into severe septic shock with hypotension due to septicaemia with a multiresistant coagulase-negative staphylococcus. He became anuric and haemofiltration had to be reintroduced. From day 119,
catecholamines had to be given in doses up to 25 ug/min noradrenaline, 400 ug/min dopamine, and 800 ug/min dobutamine to maintain the blood pressure. Despite antimicrobial treatment and massive volume substitution leading to a positive liquid balance of 32 litres in the previous 11 days, the patient deteriorated on day 123. Again, extensive volume substitution was necessary to maintain a systolic blood pressure around 100 mm Hg and a fatal outcome seemed likely. In this desperate setting, and knowing that NMMA had been approved for use in healthy volunteers, we decided to administer this agent, and the father of the unconscious patient
agreed. 700 mg NMMA (Sigma Chemicals) corresponding to 7 mg/kg body weight was given in 3 min by intravenous injection. Immediately after the injection the infusion of noradrenaline could be stopped and the blood pressure remained stable for about 25 min. His mean blood pressure then fell again below 85 mm Hg and noradrenaline had to be readminstered, at a dose of 14 ug/min. Subsequently, the dose of noradrenaline could be gradually reduced and 24 h after NMMA was given, it was stopped. Heart rate
(110-117/min) and central venous pressure were stable before, during, and after NMMA treatment. No side-effects of NMMA recorded. For 12 days thereafter, he was haemodynamically stable without catecholamines or haemofiltration being required. Further haemodynamic data are not available because a pulmonary catheter could not be inserted due to central venous obstruction as a consequence of the long stay in the intensive care unit and the number of catheters that had previously been inserted and removed. This experience strongly supports that of Petros et al and shows that the NO-synthase inhibitor, NMMA, may be successful in the treatment of severe hypotension in septic shock. were
STEPHANOS GEROULANOS
JULIAN SCHILLING METIN CAKMAKCI University Hospital Zurich,
HANS H. JUNG
CH-8091 Zurich, Switzerland
FELIX LARGIADER
Dissection of vertebral artery after cervical trauma
SIR,-Dissection of the vertebral artery has been described after trauma received during chiropractic manipulations,’ seizures,2 attempted strangulation,3playing softball, heavy lifting,4 yoga, bowhunting, neck hyperextension, atlantoaxial dislocation, sudden head turning, and fitness exercises.s Symptoms can arise immediately after trauma, but commonly are delayed from several hours to a few days.6 We report an unusual cause of vertebral artery cervical
dissection. A 33-year-old woman had abrupt onset of headache. Computed tomography of the head was normal and she was treated with analgesics. She awoke the next day with dysequilibrium, nausea, dysphagia, and slurred speech. Magnetic resonance imaging (MRI) of the head showed infarction of the left superior cerebellum and small infarctions of the left medial inferior temporal lobe and deep white matter of the right occipital lobe. She was admitted and left-sided ataxia, slight flattening of the left nasolabial fold, and dysarthria were noted. Cerebral angiography showed occlusion of the left vertebral artery; all other extracranial and intracranial vessels were normal. MRI angiography confirmed the total occlusion of the vertebral artery from C5 to the basilar artery. These findings were most consistent with dissection of the vertebral artery. Echocardiography and transoesophageal echocardiography were
normal,
as
were
laboratory
tests,
including erythrocyte
sedimentation rate, antinuclear antibodies, rheumatoid factor, complement levels, lupus anticoagulant, and antiphospholipid antibodies, and lumbar puncture results. On further questioning, the patient stated that four days before onset of headache she attended a fair where she rode an amusement ride called "the scrambler". This ride inflicted spinning motions as well as violent changes in direction on the participants. Her head was shaken in several linear and torsional directions. On completion of the ride, she felt disoriented and was asked by the attendent whether she was all right. She had generalised neck pain for several days afterwards.
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
435
synthesis and/or release of NO from cultured vascular endothelial cells.9 Endotoxin and its endogenous mediators can inhibit coronary vasodilator responses to agents that depend on increased synthesis of endothelium-derived NO; hence, the use of NO synthase inhibitors in this setting could induce coronary vasoconstriction and nominally restrict myocardial perfusion at best or provoke myocardial ischaemia at worst."’ This might explain the fall in cardiac index in one of Petros and colleagues patients.1 Although The Lancet editorial accompanying the paper by Petros et al implies that NO synthase inhibitors produced "beneficial cardiovascular effects" in the two patients, a fall in cardiac index would not be beneficial during sepsis, especially if accompanied by (or due to) an increase in peripheral vascular resistance and its attendant increase in cardiac workload. In view of the complex pharmacodynamic spectrum of drugs that inhibit NO synthase, we do not support further clinical trials in sepsis until animal studies have been done to disclose any adverse actions of these agents on perfusion of the coronary vasculature and other vital oxidative tissues. Departments of Anesthesiology and Internal Medicine, Washington University School of Medicine
RICHARD S. HOTCHKISS IRENE E. KARL
Department of Physiology, University of Missouri
JANET L. PARKER
Department of Veterinary Biomedical Sciences,
University of Missouri, Columbia, Missouri 65211, USA
H. RICHARD ADAMS
1. Moncada S, Higgs EA. Endogenous nitric oxide: physiology, pathology, and clinical relevance. Eur J Clin Invest 1991; 21: 361-74. 2. Hutcheson IR, Whittle B Jr, Boughton-Smith NK. Role of nitric oxide in maintaining vascular integrity in endotoxin-induced intestinal damage in the rat. Br J Pharmacol 1990; 101: 815-20. 3. Billiar TR, Curran RD, Harbrecht BG, Stuehr DJ, Demetris AJ, Simmons RL. Modulation of nitrogen oxide synthesis in vivo: NG-monomethyl-L-arginine inhibits endotoxin-induced nitrite/nitrate biosynthesis while promoting hepatic damage. J Leukoc Biol 1990; 48: 565-69 4. Faule KJ, Rossaint R, Keitel M, et al. Successful treatment of severe adult respiratory distress syndrome with nitric oxide: the first three patients. Presented at Second International Meeting on the Biology of Nitric Oxide (London, October, 1991). 5. Durante W, Schini VB, Scott-Burden T, et al Platelet inhibition by an L-arginine derived substance released by IL-I&bgr;-trcared vascular smooth muscle cells. Am J Physiol 1991; 261: H2024-H2030. 6. Nathan CF, Hibbs JB. Role of nitric oxide synthesis in macrophage antimicrobial activity. Curr Opin Immunol 1991; 3:65-70. 7 Madden HP, Breslin RJ, Wasserkrug HL, Efron BAG, Barbul A Stimulation of T cell immunity by arginine enhances survival in peritonitis. J Surg Res 1988; 44: 658-63. 8. Klabunde RE, Ritger RC. NG-monomethyl-L-arginine (NMMA) restores arterial blood pressure but reduces cardiac output in a canine model of endotoxic shock. Biochem Biophys Res Comm 1991; 178: 1135-40 9. Myers PR, Wright TF, Tanner MA, Adams HR. Endothelium-derived relaxing factor and nitric oxide production in cultured endothelial cells: direct inhibition by E coli endotoxin. Am J Physiol (in press) 10 Parker JL, Keller RS, DeFily DV, Laughlin MH, Novotny MJ, Adams HR. Coronary vascular smooth muscle function in E coli endotoxemia in dogs. Am J Physiol 1991; 260 (Heart Circ Physiol 29): H832-H841.
SIR,—To add to the two patients described by Dr Petros and colleagues, we would like to report a case of septic shock in a patient with severe hypotension and multiple organ failure who was successfully treated with 700 mg NG-monomethyl-L-arginine (NMMA). Less than 3 min after intravenous injection ofNMMA the blood pressure was normal and a continuous infusion of noradrenaline 25 pg/min could be stopped. A 29-year-old man was admitted to intensive care with necrotising pancreatitis. From admission the patient was on ventilatory support. Eleven abdominal surgical interventions were necessary and a splenic abscess was treated by splenectomy. The patient was on haemofiltration for 54 days and episodes of septicaemia were treated with antibiotics. From day 90 he improved. Haemofiltration was stopped on that day, and renal function returned to normal. The patient was still artificially ventilated but he could communicate again and started to exercise. On day 109 Pseudomonas aerugirwsa infection was diagnosed; this could be controlled with antibiotics. On day 119 the patient went into severe septic shock with hypotension due to septicaemia with a multiresistant coagulase-negative staphylococcus. He became anuric and haemofiltration had to be reintroduced. From day 119,
catecholamines had to be given in doses up to 25 ug/min noradrenaline, 400 ug/min dopamine, and 800 ug/min dobutamine to maintain the blood pressure. Despite antimicrobial treatment and massive volume substitution leading to a positive liquid balance of 32 litres in the previous 11 days, the patient deteriorated on day 123. Again, extensive volume substitution was necessary to maintain a systolic blood pressure around 100 mm Hg and a fatal outcome seemed likely. In this desperate setting, and knowing that NMMA had been approved for use in healthy volunteers, we decided to administer this agent, and the father of the unconscious patient
agreed. 700 mg NMMA (Sigma Chemicals) corresponding to 7 mg/kg body weight was given in 3 min by intravenous injection. Immediately after the injection the infusion of noradrenaline could be stopped and the blood pressure remained stable for about 25 min. His mean blood pressure then fell again below 85 mm Hg and noradrenaline had to be readminstered, at a dose of 14 ug/min. Subsequently, the dose of noradrenaline could be gradually reduced and 24 h after NMMA was given, it was stopped. Heart rate
(110-117/min) and central venous pressure were stable before, during, and after NMMA treatment. No side-effects of NMMA recorded. For 12 days thereafter, he was haemodynamically stable without catecholamines or haemofiltration being required. Further haemodynamic data are not available because a pulmonary catheter could not be inserted due to central venous obstruction as a consequence of the long stay in the intensive care unit and the number of catheters that had previously been inserted and removed. This experience strongly supports that of Petros et al and shows that the NO-synthase inhibitor, NMMA, may be successful in the treatment of severe hypotension in septic shock. were
STEPHANOS GEROULANOS
JULIAN SCHILLING METIN CAKMAKCI University Hospital Zurich,
HANS H. JUNG
CH-8091 Zurich, Switzerland
FELIX LARGIADER
Dissection of vertebral artery after cervical trauma
SIR,-Dissection of the vertebral artery has been described after trauma received during chiropractic manipulations,’ seizures,2 attempted strangulation,3playing softball, heavy lifting,4 yoga, bowhunting, neck hyperextension, atlantoaxial dislocation, sudden head turning, and fitness exercises.s Symptoms can arise immediately after trauma, but commonly are delayed from several hours to a few days.6 We report an unusual cause of vertebral artery cervical
dissection. A 33-year-old woman had abrupt onset of headache. Computed tomography of the head was normal and she was treated with analgesics. She awoke the next day with dysequilibrium, nausea, dysphagia, and slurred speech. Magnetic resonance imaging (MRI) of the head showed infarction of the left superior cerebellum and small infarctions of the left medial inferior temporal lobe and deep white matter of the right occipital lobe. She was admitted and left-sided ataxia, slight flattening of the left nasolabial fold, and dysarthria were noted. Cerebral angiography showed occlusion of the left vertebral artery; all other extracranial and intracranial vessels were normal. MRI angiography confirmed the total occlusion of the vertebral artery from C5 to the basilar artery. These findings were most consistent with dissection of the vertebral artery. Echocardiography and transoesophageal echocardiography were
normal,
as
were
laboratory
tests,
including erythrocyte
sedimentation rate, antinuclear antibodies, rheumatoid factor, complement levels, lupus anticoagulant, and antiphospholipid antibodies, and lumbar puncture results. On further questioning, the patient stated that four days before onset of headache she attended a fair where she rode an amusement ride called "the scrambler". This ride inflicted spinning motions as well as violent changes in direction on the participants. Her head was shaken in several linear and torsional directions. On completion of the ride, she felt disoriented and was asked by the attendent whether she was all right. She had generalised neck pain for several days afterwards.
