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CYANIDE RELEASE FROM NITROPRUSSIDE
CORRESPONDENCE ADVERSE RESPONSES TO I V ANAESTHETICS
survive but, because of the underlying pathology, even a mild reaction resulted in a fatal outcome. Althesin is frequently chosen as an induction agent in poor-risk patients, (Dundee and Clarke, 1980). However, these are the very patients who may be least able to withstand even a minor adverse reaction. E. E. M. THOMPSON S. G. GREENHOUGH
Manchester REFERENCES
Dundee, J. W., and Clarke, R. S J. (1980). Non-inhalanonal anaesthetics; m Gtneral Anaesthesia (Eds T. G. Gray, J. F. Nunn and J. E. Utting), 4th edn, vol. 1, p. 244. London: Burterworth. Mehta, S. (1981). Adverse responses to i.v. anaesthesia. Br. J.
AnaesA.,&, 1005. Watkins, J. (1979). Anaphylactoid reaction to i.v. substances. Br.J. Anaesth., 51, 51. Thornton, J. A., and Clarke, R. S. J. (1979). Adverse reactions to i.v. agents. Br. J. Anaesth., 51, 469
CYANIDE RELEASE FROM NITROPRUSSIDE
Sir,—We hasten to take issue with the recent report by Bisset and others (1981) before some innocent patient is placed m jeopardy by a physician who accepts it at face value. They suggest that there is "no unambiguous evidence that cyanide is released from nitroprusside tn vivo". Workers too numerous to cite exhaustively here have contributed positive finding* in patients and in laboratory animal* to the contrary. In the interests of conserving space I will review only our personal experience (Smith and Kruszyna, 1974). Mice and rats given acute lethal doses of nitroprusside exhibit classic signs of cyanide poisoning, have lethal concentrations of cyanide in their blood at death, and are protected against death by two cyanide antagonists with independent mechanisms of action, namely nitrite and thiosulphate. If Bisset and his colleagues (1981) are correct, there are two possible interpretations of these results First, the solutions of nitroprusside, freshly prepared before injection, had already undergone complete photolytic decomposition to cyanide before they were even administered. A critical observation suggests that that was not the case. Animals injected with cyanide as such invariably die in less than 5 min, whereas in animals given nitroprusside, death was delayed for an average of 30 min, indicating a critical time-dependent phenomenon was required in vivo for conversion of nitroprusside to cyanide. We reiterate our conviction that this phenomenon involves a direct chemical redox reaction between nitroprusside and haemoglobin. The alternative explanation which Bisset would have us accept is that the blood cyanide measured was generated artefactually during the analytical procedure. If such was the case, it is difficult to rationalize how or why the ammnl« died and how or why cyanide antagonists protected them against death. Quite aside from cyanide analyses, we have demonstrated spectrophotometricaUy (Smith and Kruszyna, 1974) a direct chemical reaction between nitroprusside and haemoglobin both aerobically and anaerobically, in which the product is cyanmethaemoglobin. Obviously, such a product can only arise by
Downloaded from http://bja.oxfordjournals.org/ at University of Winnipeg on August 12, 2015
Sir,—Shortly after reading Dr Mehta's letter (1981) we had the following unfortunate experience. A 67-year-old male was scheduled for right thoracotomy for recurrent pleura] effusion, which was thought hkely to be of malignant origin. He had had a bronchotcopy 4 weeks previously (which showed no abnormality), for which he was anaesthetized uneventfully with Althesin S mis, diluted to 10 ml with water, and suxamethonium. At the preoperative visit he was in moderate health. The e.c.g. showed left ventricular hypertrophy and slight S - T depression. However, there was no history of any previous illnwre His arterial pressure was 140/90 mm HG and his heart rate 120 beat min" 1 . He was given lorazepam 3.5 mg 2 h before operation. After pre-oxygenatkra, anaesthesia was induced with Althesin 2.5ml diluted to 5ml with water and given slowly, droperidol 20 mg, fentanyl 500 fig and pancuronium 6 mg. After 2 mm ventilation with 50% nitrous oxide in oxygen, a slight generalized flush was noted. Bronchoscopy was commenced, ventilation being maintained with a Sanders injector. However, the patient soon became cyanosed and hypotensive and developed a severe bradycardia. Bronchoscopy was abandoned and resuscitarive measures commenced. The lungs were easily inflated with no sign of bronchospasm but, in spite of rapid fluid replacement, drug treatment and external cardiac massage, the circulation remained inadequate. Left thoracotomy was performed and internal cardiac mamiagf commenced with an improvement in oxygenaQon, but not in the size of the pupils, which remained fixed and dilated. At this time it was noted that the left ventricle in particular remained atonic. Internal cardiac massage and supportive measures were continued for 1 h, to no avail. At postmortem the findings showed a massive left ventricular myocardial infarction, considerable evidence of previous myocardial ischaemia, and severe narrowing of all coronary vessels. Two blood samples were taken, one into EDTA and one into heparin, 40 min after induction, and sent to Dr J. Watkins at the Supraregional Protein Reference Unit at the Royal Hallamshire Hospital, Sheffield (Watkins, Thornton and Clarke, 1979). These indicated an identical degree of complement C3 conversion around 90% of total, involving excessive activation of the alternative pathway. In the absence of a sequence of samples it was quite impossible to determine whether or not this activation proceeded via an immune-mediated event, that is alternative pathway activation occurring as an enhancement of classical complement activation. However, the previous apparently uneventful exposure to Althesin 4 weeks earlier might well suggest the acquisition of immunological memory to this drug by the patient. Irrespective of the true initiating mechanism, immune or non-immune, this pattern of C3 conversion is consistent with an Althesin reaction (Watkins, 1979) and the degree of conversion would be expected to initiate, through hintamine release, a marked degree of hypotension. However, even with this degree of C3 activation, most patients recover rapidly with few side-effects following aggressive therapy. The evidence points to an Althesm-mitiated reaction, involving complement, m contrast to pancuronium, which would have been expected to liberate histaminr directly We feel that this report is important for the following reasons: this is a proven reaction to Althesin in spite of the fact that the drug was diluted, that only a small dose was used and that it was given slowly. The case also underlines the dangers of repeated exposure to the same anaesthetic drug and particularly to the Cremophor - containing drug formulations when these are repeatedly administered at intervals of only a few weeks. In the majority of instances the patient would have been expected to
1145
BRITISH JOURNAL OF ANAESTHESIA
1146
Surgeons of Australasia in Hobart, I presented a short paper entitled "Huntington's Chorea—Is there an Anaesthetic Problem?" Arising from this paper, two points of significance emerged. First, with the advent of CAT Scanning it is dear that a number of patients with Huntington's Chorea may have considerable hydrocephalus. This may account for dose-dependent depression of cerebral metabolism leading torespiratorydepression. Second Whirtaker (1980), in her recent article indicated that patients with Huntington's disease could have a greater frequency of the rare Ei' gene; thus the anaesthetist simply requesting a dibucaine number guarding against the possibility of apnoea, may overlook the presence of the other variant. Browne and Cross did, in fact, perform the fluoride estimation. Third, using a peripheral nerve stimulator m a small number of patients, I have been able to obtain a satisfactory train-of-four together with fade and tetanus. A. S. M.
LAMONT
Hobart, Tasmania REFERENCES
Browne, M. G., and Cross, R. (1981). Huntington's Chorea. Br. J. Anaesth., 53,1367. Davies, D. D. (1966). Abnormal response to anaesthesia in a case of Huntington's Chorea. Br. J. Anaesth , 38, 490. Farina, J., and Rauscher, L. A. (1977). Anaesthesia and Huntington's Chorea. A report of two cases. Br. J. Anaesth., 49, 1167. Gualandi, W., and Bonfanti, G. (1968). A case of prolonged apnoea in Huntington's Chorea. Aeta Anaathesiol. (Padova), 19, (Suppl. 6), 235. Lamont, A. S. M. (1979). Anaesthesia and Huntington's Chorea. Anaesth. Intens. Care, 7, 189. Whittaker, M. (1980). Plasma cholinesterasc variants and the anaesthetist. Anaesthesia, 35, 174.
R. P. SMITH H. KRUSZYNA R. KRUSZYNA
Hanover, New Hampshire, U.S.A. EXTRADURAL BUPRENORPHINE REFERENCES
Bisset, W. I. K., Butler, A. R., Glidewell, C , and Reglinski, J. (1981) Sodium nitroprusside and cyanide release: Reasons for re-appraisal. Br. J. Anaath., 53, 1015. Smith, R. P., and Kruszyna, H. (1974). Nitroprusside produces cyanide poisoning via a reaction with hemoglobin. / . Pharmacol. Exp. Ther., 191, 557.
HUNTING-TON'S CHOREA
Sir,—I was interested to read the letter from Drs Browne and Cross (1981) on Huntington's Chorea. In earlier years, Tasmania was regarded as having the greatest frequency (seven per 100 000) in the world. I discussed (Lamont, 1979) the previous case reports by Davies (1966), Fanna and Rauscher (1977), Gualandi and Bonfanti (1968) and concluded by asking ifrelaxantsof either the depolarizing or the non-depolarizing types be used "carte blanche". Subsequently, at a meeting of the Royal College of
Sir,—We would like to comment on a letter from Chnstensen and Andersen (1982) regarding extradural buprenorphine which, unfortunately, leaves some misinterpretations of the literature, including our own. Buprenorhphine is a new narcotic analgesic acting as a partial agonist. Contrary to the opinion of Christensen and Andersen, the opiate agonist-antagonist group is known to be associated with respiratory depression similar to that produced by morphine when given in therapeutic doses i.m. or l.v. The carbon dioxide response curve is depressed by 42% with morphine (Weil et al., 1975), by 46% with pentazoane (Mahschewski, Sybrecht and Fabel, 1980) and by 27% with buprenorphine (Klose, Ehrhart and Jung, 1982). The time-course of respiratory depression shows a more prolonged displacement of the carbon dioxide response curve with buprenorphine compared with morphine (Orwin, Orwin and Price, 1976). In an unpublished investigation on the respiratory depressant effects of extradural buprenorphine we have seen carbon dioxide response curves similar to those in an earlier study on extradural morphine. It is important to mention that all these studies were performed on pain-free patients. We suggest that, in clinical practice, when a narcotic analgesic is given for example to abolish upper abdominal pain, there is even an increase inrespiratoryfunction. This was demon-
Downloaded from http://bja.oxfordjournals.org/ at University of Winnipeg on August 12, 2015
oxidation of the ferrous haem groups of haemoglobin We have postulated a direct exchange of electrons from nitroprusside to ferrous haem groups by analogy with the well-known reaction between ferricyanide and haemoglobin. If dithionite is also present, the product is nitnc oxide haemoglobin. We have found large differences in the rates of cyanide release when nitroprusside was incubated with red cells from various laboratory species, differences in the rates of cyanide release between red cell suspensions and lysates, and difference* in rates of cyanide release between red cell suspensions, suspensions of their membranes (ghosts) and solutions of glutathione. These differences were found in experiments which were all conducted under identical conditions of ambient illumination. If cyanide release were a result only of photolytic decomposition of nitroprusside during the analytical procedure, no such differences should have been found. We are at a loss to explain the failure of Bisset and his colleagues (1981) to confirm these results which have, at least in part, been confirmed many rimes over by others. We have, of course, tested nitroprusside as such in our analytical procedure for cyanide and obtained values comparable to those found with saline. A possible explanation for one of their experiments occurs to us, namely the failure of blood to accelerate cyanide release from nitroprusside in solutions at pH4.0. Depending cm ionic strength and buffer capacity, solutions of such acid pH would be expected to lyse red cells, denature haemoglobin and generate methaemoglobin or acid harmarin. Methaemoglobin is not reactive toward nitroprusside, which is in accord with our hypothetical mechanism (Smith and Kruszyna, 1974). Bisset and colleagues (1981) have performed a service in reminding us that, under some conditions, nitroprusside may undergo photolytic decomposition so that precautions to protect solutions against ambient illumination are only prudent To suggest, however, that "it may well be safe to infuse quantities (. . of nitroprusside . .) larger than those currently recommended" is to invite disaster.
survive but, because of the underlying pathology, even a mild reaction resulted in a fatal outcome. Althesin is frequently chosen as an induction agent in poor-risk patients, (Dundee and Clarke, 1980). However, these are the very patients who may be least able to withstand even a minor adverse reaction. E. E. M. THOMPSON S. G. GREENHOUGH
Manchester REFERENCES
Dundee, J. W., and Clarke, R. S J. (1980). Non-inhalanonal anaesthetics; m Gtneral Anaesthesia (Eds T. G. Gray, J. F. Nunn and J. E. Utting), 4th edn, vol. 1, p. 244. London: Burterworth. Mehta, S. (1981). Adverse responses to i.v. anaesthesia. Br. J.
AnaesA.,&, 1005. Watkins, J. (1979). Anaphylactoid reaction to i.v. substances. Br.J. Anaesth., 51, 51. Thornton, J. A., and Clarke, R. S. J. (1979). Adverse reactions to i.v. agents. Br. J. Anaesth., 51, 469
CYANIDE RELEASE FROM NITROPRUSSIDE
Sir,—We hasten to take issue with the recent report by Bisset and others (1981) before some innocent patient is placed m jeopardy by a physician who accepts it at face value. They suggest that there is "no unambiguous evidence that cyanide is released from nitroprusside tn vivo". Workers too numerous to cite exhaustively here have contributed positive finding* in patients and in laboratory animal* to the contrary. In the interests of conserving space I will review only our personal experience (Smith and Kruszyna, 1974). Mice and rats given acute lethal doses of nitroprusside exhibit classic signs of cyanide poisoning, have lethal concentrations of cyanide in their blood at death, and are protected against death by two cyanide antagonists with independent mechanisms of action, namely nitrite and thiosulphate. If Bisset and his colleagues (1981) are correct, there are two possible interpretations of these results First, the solutions of nitroprusside, freshly prepared before injection, had already undergone complete photolytic decomposition to cyanide before they were even administered. A critical observation suggests that that was not the case. Animals injected with cyanide as such invariably die in less than 5 min, whereas in animals given nitroprusside, death was delayed for an average of 30 min, indicating a critical time-dependent phenomenon was required in vivo for conversion of nitroprusside to cyanide. We reiterate our conviction that this phenomenon involves a direct chemical redox reaction between nitroprusside and haemoglobin. The alternative explanation which Bisset would have us accept is that the blood cyanide measured was generated artefactually during the analytical procedure. If such was the case, it is difficult to rationalize how or why the ammnl« died and how or why cyanide antagonists protected them against death. Quite aside from cyanide analyses, we have demonstrated spectrophotometricaUy (Smith and Kruszyna, 1974) a direct chemical reaction between nitroprusside and haemoglobin both aerobically and anaerobically, in which the product is cyanmethaemoglobin. Obviously, such a product can only arise by
Downloaded from http://bja.oxfordjournals.org/ at University of Winnipeg on August 12, 2015
Sir,—Shortly after reading Dr Mehta's letter (1981) we had the following unfortunate experience. A 67-year-old male was scheduled for right thoracotomy for recurrent pleura] effusion, which was thought hkely to be of malignant origin. He had had a bronchotcopy 4 weeks previously (which showed no abnormality), for which he was anaesthetized uneventfully with Althesin S mis, diluted to 10 ml with water, and suxamethonium. At the preoperative visit he was in moderate health. The e.c.g. showed left ventricular hypertrophy and slight S - T depression. However, there was no history of any previous illnwre His arterial pressure was 140/90 mm HG and his heart rate 120 beat min" 1 . He was given lorazepam 3.5 mg 2 h before operation. After pre-oxygenatkra, anaesthesia was induced with Althesin 2.5ml diluted to 5ml with water and given slowly, droperidol 20 mg, fentanyl 500 fig and pancuronium 6 mg. After 2 mm ventilation with 50% nitrous oxide in oxygen, a slight generalized flush was noted. Bronchoscopy was commenced, ventilation being maintained with a Sanders injector. However, the patient soon became cyanosed and hypotensive and developed a severe bradycardia. Bronchoscopy was abandoned and resuscitarive measures commenced. The lungs were easily inflated with no sign of bronchospasm but, in spite of rapid fluid replacement, drug treatment and external cardiac massage, the circulation remained inadequate. Left thoracotomy was performed and internal cardiac mamiagf commenced with an improvement in oxygenaQon, but not in the size of the pupils, which remained fixed and dilated. At this time it was noted that the left ventricle in particular remained atonic. Internal cardiac massage and supportive measures were continued for 1 h, to no avail. At postmortem the findings showed a massive left ventricular myocardial infarction, considerable evidence of previous myocardial ischaemia, and severe narrowing of all coronary vessels. Two blood samples were taken, one into EDTA and one into heparin, 40 min after induction, and sent to Dr J. Watkins at the Supraregional Protein Reference Unit at the Royal Hallamshire Hospital, Sheffield (Watkins, Thornton and Clarke, 1979). These indicated an identical degree of complement C3 conversion around 90% of total, involving excessive activation of the alternative pathway. In the absence of a sequence of samples it was quite impossible to determine whether or not this activation proceeded via an immune-mediated event, that is alternative pathway activation occurring as an enhancement of classical complement activation. However, the previous apparently uneventful exposure to Althesin 4 weeks earlier might well suggest the acquisition of immunological memory to this drug by the patient. Irrespective of the true initiating mechanism, immune or non-immune, this pattern of C3 conversion is consistent with an Althesin reaction (Watkins, 1979) and the degree of conversion would be expected to initiate, through hintamine release, a marked degree of hypotension. However, even with this degree of C3 activation, most patients recover rapidly with few side-effects following aggressive therapy. The evidence points to an Althesm-mitiated reaction, involving complement, m contrast to pancuronium, which would have been expected to liberate histaminr directly We feel that this report is important for the following reasons: this is a proven reaction to Althesin in spite of the fact that the drug was diluted, that only a small dose was used and that it was given slowly. The case also underlines the dangers of repeated exposure to the same anaesthetic drug and particularly to the Cremophor - containing drug formulations when these are repeatedly administered at intervals of only a few weeks. In the majority of instances the patient would have been expected to
1145
BRITISH JOURNAL OF ANAESTHESIA
1146
Surgeons of Australasia in Hobart, I presented a short paper entitled "Huntington's Chorea—Is there an Anaesthetic Problem?" Arising from this paper, two points of significance emerged. First, with the advent of CAT Scanning it is dear that a number of patients with Huntington's Chorea may have considerable hydrocephalus. This may account for dose-dependent depression of cerebral metabolism leading torespiratorydepression. Second Whirtaker (1980), in her recent article indicated that patients with Huntington's disease could have a greater frequency of the rare Ei' gene; thus the anaesthetist simply requesting a dibucaine number guarding against the possibility of apnoea, may overlook the presence of the other variant. Browne and Cross did, in fact, perform the fluoride estimation. Third, using a peripheral nerve stimulator m a small number of patients, I have been able to obtain a satisfactory train-of-four together with fade and tetanus. A. S. M.
LAMONT
Hobart, Tasmania REFERENCES
Browne, M. G., and Cross, R. (1981). Huntington's Chorea. Br. J. Anaesth., 53,1367. Davies, D. D. (1966). Abnormal response to anaesthesia in a case of Huntington's Chorea. Br. J. Anaesth , 38, 490. Farina, J., and Rauscher, L. A. (1977). Anaesthesia and Huntington's Chorea. A report of two cases. Br. J. Anaesth., 49, 1167. Gualandi, W., and Bonfanti, G. (1968). A case of prolonged apnoea in Huntington's Chorea. Aeta Anaathesiol. (Padova), 19, (Suppl. 6), 235. Lamont, A. S. M. (1979). Anaesthesia and Huntington's Chorea. Anaesth. Intens. Care, 7, 189. Whittaker, M. (1980). Plasma cholinesterasc variants and the anaesthetist. Anaesthesia, 35, 174.
R. P. SMITH H. KRUSZYNA R. KRUSZYNA
Hanover, New Hampshire, U.S.A. EXTRADURAL BUPRENORPHINE REFERENCES
Bisset, W. I. K., Butler, A. R., Glidewell, C , and Reglinski, J. (1981) Sodium nitroprusside and cyanide release: Reasons for re-appraisal. Br. J. Anaath., 53, 1015. Smith, R. P., and Kruszyna, H. (1974). Nitroprusside produces cyanide poisoning via a reaction with hemoglobin. / . Pharmacol. Exp. Ther., 191, 557.
HUNTING-TON'S CHOREA
Sir,—I was interested to read the letter from Drs Browne and Cross (1981) on Huntington's Chorea. In earlier years, Tasmania was regarded as having the greatest frequency (seven per 100 000) in the world. I discussed (Lamont, 1979) the previous case reports by Davies (1966), Fanna and Rauscher (1977), Gualandi and Bonfanti (1968) and concluded by asking ifrelaxantsof either the depolarizing or the non-depolarizing types be used "carte blanche". Subsequently, at a meeting of the Royal College of
Sir,—We would like to comment on a letter from Chnstensen and Andersen (1982) regarding extradural buprenorphine which, unfortunately, leaves some misinterpretations of the literature, including our own. Buprenorhphine is a new narcotic analgesic acting as a partial agonist. Contrary to the opinion of Christensen and Andersen, the opiate agonist-antagonist group is known to be associated with respiratory depression similar to that produced by morphine when given in therapeutic doses i.m. or l.v. The carbon dioxide response curve is depressed by 42% with morphine (Weil et al., 1975), by 46% with pentazoane (Mahschewski, Sybrecht and Fabel, 1980) and by 27% with buprenorphine (Klose, Ehrhart and Jung, 1982). The time-course of respiratory depression shows a more prolonged displacement of the carbon dioxide response curve with buprenorphine compared with morphine (Orwin, Orwin and Price, 1976). In an unpublished investigation on the respiratory depressant effects of extradural buprenorphine we have seen carbon dioxide response curves similar to those in an earlier study on extradural morphine. It is important to mention that all these studies were performed on pain-free patients. We suggest that, in clinical practice, when a narcotic analgesic is given for example to abolish upper abdominal pain, there is even an increase inrespiratoryfunction. This was demon-
Downloaded from http://bja.oxfordjournals.org/ at University of Winnipeg on August 12, 2015
oxidation of the ferrous haem groups of haemoglobin We have postulated a direct exchange of electrons from nitroprusside to ferrous haem groups by analogy with the well-known reaction between ferricyanide and haemoglobin. If dithionite is also present, the product is nitnc oxide haemoglobin. We have found large differences in the rates of cyanide release when nitroprusside was incubated with red cells from various laboratory species, differences in the rates of cyanide release between red cell suspensions and lysates, and difference* in rates of cyanide release between red cell suspensions, suspensions of their membranes (ghosts) and solutions of glutathione. These differences were found in experiments which were all conducted under identical conditions of ambient illumination. If cyanide release were a result only of photolytic decomposition of nitroprusside during the analytical procedure, no such differences should have been found. We are at a loss to explain the failure of Bisset and his colleagues (1981) to confirm these results which have, at least in part, been confirmed many rimes over by others. We have, of course, tested nitroprusside as such in our analytical procedure for cyanide and obtained values comparable to those found with saline. A possible explanation for one of their experiments occurs to us, namely the failure of blood to accelerate cyanide release from nitroprusside in solutions at pH4.0. Depending cm ionic strength and buffer capacity, solutions of such acid pH would be expected to lyse red cells, denature haemoglobin and generate methaemoglobin or acid harmarin. Methaemoglobin is not reactive toward nitroprusside, which is in accord with our hypothetical mechanism (Smith and Kruszyna, 1974). Bisset and colleagues (1981) have performed a service in reminding us that, under some conditions, nitroprusside may undergo photolytic decomposition so that precautions to protect solutions against ambient illumination are only prudent To suggest, however, that "it may well be safe to infuse quantities (. . of nitroprusside . .) larger than those currently recommended" is to invite disaster.