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Nitric oxide in liver failure
1590
LETTERS to the EDITOR
Nitric oxide in liver failure SIR,-Nitric oxide (NO) is a very short-lived free radical generated by the vasculature. It acts as a potent vasodilator and has
important role in the regulation of vascular tone.1 It has been suggested that generation of NO by circulating endotoxin accounts for the severe intractable hypotension associated with septic shock and decompensated liver failure.2 Here we describe the use of methylene blue, an antagonist of the actions of nitric oxide, in a patient with severe hypotension and liver failure. A 45-year-old man with biopsy-proven alcoholic cirrhosis was admitted to our intensive therapy unit with bleeding oesophageal varices and multiple organ failure. He had encephalopathy, severe jaundice, tachypnoea, and hypotension (100/38 mm Hg), with ascites and anuria. Laboratory investigations revealed renal failure (urea 36-4 mmol/1, creatinine 1192 )Jmol/l), liver failure (bilirubin 368 umol/1), and metabolic acidosis (H 90-11 nmol/1, PaOz 17-9 kPa, PaCOz 1-85 kPa). After intubation and ventilation, he was resuscitated with blood products and 50% dextrose, underwent haemofiltration, and had successful injection sclerotherapy of oesophageal varices. Thereafter, arterial pressure and systemic vascular resistance (SVR) fell gradually, and 20 h later (arterial pressure and SVR 80/23 mm Hg and 194 dyne s/cm5 [normal 800-1200], respectively) intravenous noradrenaline infusion was started. Despite large doses (0-75 ug/kg per min) diastolic pressure an
and SVR remained low. At this stage, it was clear that the patient was resistant to standard pressor therapy and his clinical condition was poor. With the consent of the patient’s wife, bolus intravenous methylene blue (3 mg/kg) was tried during continued noradrenaline infusion. Immediately before methylene blue his blood pressure was 147/57 mm Hg, and had been fairly stable for several hours (figure), and the SVR was 400 dyne stems, cardiac output 10-6 1/min, and central venous pressure 16 mm Hg (point A, figure). After the administration of methylene blue, his blood pressure increased steadily to a peak after about 40 min (195/66 mm Hg), when SVR was 493 dyne stems, cardiac output 1281/min, and central venous pressure 12 mm Hg (point B). Blood pressure then subsided towards earlier levels over a further 60 min. Despite this temporary
cardiovascular effect, and in keeping with the very poor prognosis, the patient died. NO activates guanylate cyclase to produce increased levels of the second messenger cyclic GMP in vascular smooth muscle, leading to vasorelaxation.l3 Atrial natriuretic peptide (ANP) is the only other major stimulus for activation of guanylate cyclase, but plasma ANP concentrations are not increased in cirrhosis,4 so this is unlikely to be relevant in this patient. Methylene blue is an oxidising agent that blocks the action of NO through inhibition of guanylate cyclase.’ This agent also has minor effects on prostaglandin synthesis and sympathetic function, though neither of these are likely to explain the haemodynamic changes in our patient. Hence, the finding that methylene blue increased blood pressure in a patient who was resistant to high dose noradrenaline provides the first clinical evidence in support of the hypothesis that increased generation of NO is responsible for the hypotension of liver function. It remains unclear why an increase in cardiac output, as well as systemic vascular resistance, was observed. Confirmation of our findings may come from studies with substrate analogue inhibitors of NO synthase, the enzyme responsible for generating NO. In view of the evidence that NO plays a part in several important physiological processes,’1 and may act as a neurotransmitter, it remains to be seen whether antagonism of NO will provide clinical benefit for patients with liver failure. Intensive Therapy Unit and University Department of Medicine, Western General Hospital, Edinburgh EH4 2XU, UK
SUSAN MIDGLEY IAN S. GRANT WILLIAM G. HAYNES DAVID J. WEBB
1. Collier J, Vallance P. Physiological importance of nitric oxide: an endogenous nitrovasodilator. Br Med J 1991; 302: 1289-90 2. Vallance P, Moncada S. Hyperdynamic circulation in cirrhosis: a role for nitric oxide?
Lancet 1991; 337: 776-78. S, Palmer RMJ, Higgs EA. Biosynthesis of nitric oxide from L-arginine: a pathway for the regulation of cell function and communication. Biochem Pharmacol
3. Moncada
1989, 38: 1709-15. Miyase S, Fujiyama S, Chikazawa H, Sato T. Atrial natriuretic peptide m liver cirrhosis with mild ascites. Gastroenterol Jpn 1990; 25: 356-62. 5. Martin W, Villani GM, Jothianandan D, Furchgott RF. Selective blockage of endothelium-dependent and glyceryl trinitrate-induced relaxation by hemoglobin and by methylene blue m the rabbit aorta. J Pharmacol Exp Ther 1984; 232: 708-16.
4.
Unusual pattern of influenza mortality in
1989/90 SIR,-The winter of 1989/90 saw the first major influenza epidemic in Britain for 15 years. It was unusual in that excess mortality was concentrated in the over-65s. Among younger adults (40-64), in whom significant excess mortality had been observed previously, there was a negligible net effect. However, the influenza epidemic did seem to advance death by a few weeks in this age group and in some of the elderly. Total mortality associated with influenza epidemics has to be estimated indirectly because influenza is seldom coded as the cause of death. A method of estimating the excess mortality, based on multiple regression and developed for data from England and Wales,’ has been updated2and used to study deaths by age group
Effect of intravenous methylene blue failure.
on
blood pressure in liver
and certified cause3 for the winters 1968/69 to 1978/79. All epidemics in this period followed an antigenic shift or substantial drift in the influenza A virus. The vaccines used at the time were unlikely to have been very protective. No such shift or drift in influenza A virus preceded the 1989-90 outbreak and the resulting epidemic had several unusual features. The regression model’ has been applied to all winters up to 1989/90. 4-weekly deaths were studied over 28-week periods from
LETTERS to the EDITOR
Nitric oxide in liver failure SIR,-Nitric oxide (NO) is a very short-lived free radical generated by the vasculature. It acts as a potent vasodilator and has
important role in the regulation of vascular tone.1 It has been suggested that generation of NO by circulating endotoxin accounts for the severe intractable hypotension associated with septic shock and decompensated liver failure.2 Here we describe the use of methylene blue, an antagonist of the actions of nitric oxide, in a patient with severe hypotension and liver failure. A 45-year-old man with biopsy-proven alcoholic cirrhosis was admitted to our intensive therapy unit with bleeding oesophageal varices and multiple organ failure. He had encephalopathy, severe jaundice, tachypnoea, and hypotension (100/38 mm Hg), with ascites and anuria. Laboratory investigations revealed renal failure (urea 36-4 mmol/1, creatinine 1192 )Jmol/l), liver failure (bilirubin 368 umol/1), and metabolic acidosis (H 90-11 nmol/1, PaOz 17-9 kPa, PaCOz 1-85 kPa). After intubation and ventilation, he was resuscitated with blood products and 50% dextrose, underwent haemofiltration, and had successful injection sclerotherapy of oesophageal varices. Thereafter, arterial pressure and systemic vascular resistance (SVR) fell gradually, and 20 h later (arterial pressure and SVR 80/23 mm Hg and 194 dyne s/cm5 [normal 800-1200], respectively) intravenous noradrenaline infusion was started. Despite large doses (0-75 ug/kg per min) diastolic pressure an
and SVR remained low. At this stage, it was clear that the patient was resistant to standard pressor therapy and his clinical condition was poor. With the consent of the patient’s wife, bolus intravenous methylene blue (3 mg/kg) was tried during continued noradrenaline infusion. Immediately before methylene blue his blood pressure was 147/57 mm Hg, and had been fairly stable for several hours (figure), and the SVR was 400 dyne stems, cardiac output 10-6 1/min, and central venous pressure 16 mm Hg (point A, figure). After the administration of methylene blue, his blood pressure increased steadily to a peak after about 40 min (195/66 mm Hg), when SVR was 493 dyne stems, cardiac output 1281/min, and central venous pressure 12 mm Hg (point B). Blood pressure then subsided towards earlier levels over a further 60 min. Despite this temporary
cardiovascular effect, and in keeping with the very poor prognosis, the patient died. NO activates guanylate cyclase to produce increased levels of the second messenger cyclic GMP in vascular smooth muscle, leading to vasorelaxation.l3 Atrial natriuretic peptide (ANP) is the only other major stimulus for activation of guanylate cyclase, but plasma ANP concentrations are not increased in cirrhosis,4 so this is unlikely to be relevant in this patient. Methylene blue is an oxidising agent that blocks the action of NO through inhibition of guanylate cyclase.’ This agent also has minor effects on prostaglandin synthesis and sympathetic function, though neither of these are likely to explain the haemodynamic changes in our patient. Hence, the finding that methylene blue increased blood pressure in a patient who was resistant to high dose noradrenaline provides the first clinical evidence in support of the hypothesis that increased generation of NO is responsible for the hypotension of liver function. It remains unclear why an increase in cardiac output, as well as systemic vascular resistance, was observed. Confirmation of our findings may come from studies with substrate analogue inhibitors of NO synthase, the enzyme responsible for generating NO. In view of the evidence that NO plays a part in several important physiological processes,’1 and may act as a neurotransmitter, it remains to be seen whether antagonism of NO will provide clinical benefit for patients with liver failure. Intensive Therapy Unit and University Department of Medicine, Western General Hospital, Edinburgh EH4 2XU, UK
SUSAN MIDGLEY IAN S. GRANT WILLIAM G. HAYNES DAVID J. WEBB
1. Collier J, Vallance P. Physiological importance of nitric oxide: an endogenous nitrovasodilator. Br Med J 1991; 302: 1289-90 2. Vallance P, Moncada S. Hyperdynamic circulation in cirrhosis: a role for nitric oxide?
Lancet 1991; 337: 776-78. S, Palmer RMJ, Higgs EA. Biosynthesis of nitric oxide from L-arginine: a pathway for the regulation of cell function and communication. Biochem Pharmacol
3. Moncada
1989, 38: 1709-15. Miyase S, Fujiyama S, Chikazawa H, Sato T. Atrial natriuretic peptide m liver cirrhosis with mild ascites. Gastroenterol Jpn 1990; 25: 356-62. 5. Martin W, Villani GM, Jothianandan D, Furchgott RF. Selective blockage of endothelium-dependent and glyceryl trinitrate-induced relaxation by hemoglobin and by methylene blue m the rabbit aorta. J Pharmacol Exp Ther 1984; 232: 708-16.
4.
Unusual pattern of influenza mortality in
1989/90 SIR,-The winter of 1989/90 saw the first major influenza epidemic in Britain for 15 years. It was unusual in that excess mortality was concentrated in the over-65s. Among younger adults (40-64), in whom significant excess mortality had been observed previously, there was a negligible net effect. However, the influenza epidemic did seem to advance death by a few weeks in this age group and in some of the elderly. Total mortality associated with influenza epidemics has to be estimated indirectly because influenza is seldom coded as the cause of death. A method of estimating the excess mortality, based on multiple regression and developed for data from England and Wales,’ has been updated2and used to study deaths by age group
Effect of intravenous methylene blue failure.
on
blood pressure in liver
and certified cause3 for the winters 1968/69 to 1978/79. All epidemics in this period followed an antigenic shift or substantial drift in the influenza A virus. The vaccines used at the time were unlikely to have been very protective. No such shift or drift in influenza A virus preceded the 1989-90 outbreak and the resulting epidemic had several unusual features. The regression model’ has been applied to all winters up to 1989/90. 4-weekly deaths were studied over 28-week periods from