BRITISH JOURNAL OF ANAESTHESIA
50
A. MATHIEU
Althesin. A woman aged 63 yr with hypertension and stress incontinence was anaesthetized in October, 1974, with Althesin, diazepam and nitrous oxide in oxygen for stretching of the bladder. The anaesthetic was uneventful and after operation she had a short course of imipramine for the treatment of depression. In January, 1975, she was readmitted to hospital so that her bladder could be stretched painlessly for a prolonged period under a long-acting extradural nerve block. With the patient conscious, a lumbar extradural block was administered using 18 ml of etidocaine 1%. For 30 min after initiation of the block, there were no significant changes in heart rate, arterial pressure or ventilation and the level of the block was assessed. Owing to the patient's apprehension, a short general anaesthetic was then given for the preliminary cystoscopy. Althesin 5 ml was injected i.v. through a vein on the dorsum of the right hand. Before the onset of unconsciousness, the patient complained of nausea. This was followed by the development of bronchospasm, tachycardia, hypotension and erythematous mottling of the right forearm. Cardiac arrest occurred, but this responded to resuscitation. The patient remained unconscious for 4-5 days and recovered with some degree of mental confusion and amnesia together with a very cold right arm and a circular sloughing skin lesion at the site of injection of Althesin. The skin lesion persisted for 3-4 months. Subsequent patch-testing of the patient using etidocaine and Althesin was negative for both drugs. Thus it is now clear that the anaesthetist who has hitherto assumed that a previous uneventful response to Althesin is indicative of the safety of the drug, may be led unwittingly into dire trouble.
Boston
GEOFFREY C. STEEL
J. P. GRILLIAT
Nancy REFERENCES
Lorenz, W., Doenicke, A., Meyer, R., Reimann, H. J., Kusche, J., Barth, H., Geesing, H., Hutzel, M., and Weissenbacher, B. (1972). Histamine release in man by propanidid and thiopentone: pharmacological effects and clinical consequences. Br.J. Anaesth., 44, 355. Mandappa, J. M., Chandrasekhara, P. M., and Nelvigi, R. G. (1975). Anaphylaxis to suxamethonium: two case reports. Br. J. Anaesth., 47, 523. Moneret-Vautrin, D., and Grilliat, J. P. (1975). Les facteurs de hauts risques; in Symposium sur le risque allergique en anesthesiologie. Ann. Anesth. (Franf.) (in press).
London REFERENCES
Avery, A. F., and Evans, A. (1973). Reactions to Althesin. Br. J. Anaesth., Horton, J. N. (1973). Adverse reaction to Althesin. Anaesthesia, 28, 182. Kessell, J., and Assem, E. S. K. (1974) An adverse reaction to Althesin. Br. J. Anaesth., 46, 209. Mehta, S. (1973). Anaphylactic reaction to Althesin. Anaesthesia, 28, 669. Tweedie, D. G., and Ordish, P. M. (1974). Reactions to intravenous agents (Althesin and Pancuronium). Br. J. Anaesth., 46, 244. Watt, J. M. (1975). Anaphylactic reactions after use of CT 1341, Althesin. Br. Med.J., 3, 205.
REACTION TO ALTHESIN
Sir,—There have been recent reports of adverse reactions to the intravenous induction agent Althesin. The effects produced have included restlessness during injection, hypotension, bronchospasm and mottling of the skin at the site of the injection (Horton, 1973; Mehta, 1973; Kessell and Assem, 1974; Tweedie and Ordish, 1974). In addition, hypersensitivity reactions have been described in which patients, although reacting normally to an initial dose of Althesin, reacted adversely to a subsequent dose given 11 days to 1 month later (Avery and Evans, 1973; Watt, 1975). I should like to report the history of a patient who eveloped an adverse reaction to Althesin following an interval of 3 months between the first and second doses of
MALIGNANT HYPERTHERMIA
Sir,—In their interesting report on the effects of Althesin on malignant hyperthermia (MH) in susceptible Pietrain pigs, Luke and Lister (1975) make a reference to a similar experiment of mine, reported previously (Harrison, 1973) which I feel needs some clarification. I found that in MH-susceptible Landrace swine, the protection against MH initiation with halothane afforded by Althesin was only effective on continuous infusion of the drug. Approximately 20 min after discontinuance of Althesin infusion, MH could be induced by re-exposure of animals to halothane. From their report, Luke and Lister appear to have used, as did Hall, Trimm and Woolf (1972),
Downloaded from http://bja.oxfordjournals.org/ at University of Ulster on April 15, 2015
cells, if the test is performed soon after the drug reaction. Thus an interval of 6 weeks before testing is recommended also. Now we shall respond to Dr Fisher's qualification of "wrong and dangerous" in reference to our statement that ketamine could be used again in the child with a cutaneous anaphylactoid reaction without signs of circulatory embarrassment, for example hypotension. Again, he does not support his statement by any reference(s). Our statement was based on the following information: (1) data from a recent study show that anaphylactoid reactions are dependent to a large extent on the speed and mode of administration of the drug (i.v. or i.m.) (Moneret-Vautrin, and Grilliat, 1975); (2) histamine release from an anaphylactoid mechanism produces localized reactions most frequently (Moneret-Vautrin, and Grilliat, 1975). In this context, it was found that between 20 and 40% of anaesthetic drugs produce non-specific release of histamine of minor consequence (for example, localized hives along the site of injection). Thus, further use of these drugs administered in small increments is not prohibited. (3) In the event of a more severe reaction, that is bronchospasm, it has been reported that anti-histamines with or without corticosteroids, administered for a period of 48 hr before anaesthesia can block effectively non-specific histamine release. However, in severe reactions with circulatory collapse, from either anaphylactic or anaphylactoid mechanisms, we suggest that further use of the drug should be prohibited, if at all possible.
51
CORRESPONDENCE a single induction dose of Althesin. In my experiment, continuous infusion of Althesin failed to protect against initiation of the MH syndrome by suxamethonium as well as proving useless as a means of treatment of the established syndrome. G. G. HARRISON
Cape Town REFERENCES
Hall, L. W., Trimm, C. M., and Woolf, N. (1972). Further studies of porcine malignant hyperthermia. Br. Med. J., 2, 145. Harrison, G. G. (1973). Althesin and malignant hyperpyrexia. Br. J. Anaesth., 45, 1010. Lucke, J. N. and Lister, D. (1975). Althesin and malignant hyperthermia. Br. J. Anaesth., 7, 419.
EDWARD S. REYNOLDS
Boston REFERENCES
Carlson, G. P. (1974). Enhancement of the hepatotoxicity of trichloroethylene by inducers of drug metabolism. Res. Comm. Chem. Path. Pharmacol., 7, 637. Conney, A. H., and Burns, J. J. (1972). Metabolic interactions among environmental chemicals and drugs. Science, 178, 576. Crawford, J. S., and Davies, P. (1975). A return to trichloroethylene for obstetric anaesthesia. Br. J. Anaesth. 47, 482.
Sir,—Thank you for the opportunity of replying to Dr Reynolds' interesting letter. Whilst I am impressed by the diligence and perseverence of the authorities whose publications Dr Reynolds quotes, I am totally unimpressed by the relevance of their observations to clinical practice. I appreciate that currently members of the medical profession in the United States are being severely buffeted by successive waves of—apparently—bureaucratically and legally inspired hysteria with respect to the potential hazards of a vast range of the therapy to which their patients might be exposed. I sincerely hope that we in the United Kingdom will continue to be successful in warding off similarly directed tendencies. As far as I can gather, if investigations were to be pursued on a sufficiently wide and intensive scale, we would all, on the basis of the derived results, be urgently advised to refrain from eating, drinking or inhaling anything, and from exposing ourselves to any environmental influence in order to guard ourselves against a putative potential noxious agent. I believe that in medicine, as in many other walks of life, common sense must prevail when a balanced opinion is in the process of achievement. During the past two decades, literally several millions of labouring women (that is, subjects "pre-treated" with a whole range of substances, including all the pregnancy hormones) have inhaled trichloroethylene, in a concentration of either 0.35% or 0.5%, for a cumulative period of at least 1 hr, and I cannot believe that the hepatotoxic or carcinogenic effects of this would have gone unnoticed. I really cannot credit it to be likely that the administration of trichlorethylene in a concentration of 0-2% for approximately 1 hr to a human adult has a more than infinitesimal chance of causing catastrophic damage (that is, if the agent has not been subjected to chemical change before reaching the subject). Promotion of the importance of such an association would appear to me to be like issuing an urgent warning to all potential pedestrians to hold their breath when passing a stretch of freshly tarred roadway, lest the fumes initiate a carcinoma of the bronchus. I submit that, for the sake of the dignity of medicine, we cannot afford a repeat of the now-farcical "halothane hepatitis" series of affirmation and counter-affirmation to the nth degree (although I fear that we are unpleasantly near to it with the potential idiocy of spending vast sums on "scavenging extractors" for theatres—a matter concerning which I am in total sympathy with the views recently expressed by Walts, Forsythe and Moore (1975)). In summary, whilst I appreciate the point made by Dr Reynolds, I believe it to reflect a communal sickness from which I earnestly hope he and his countryman will soon recover, and to which I fervently pray we will not become subject.
j . SELWYN CRAWFORD
Birmingham REFERENCE
Walts, L. F., Forsythe, A. B., and Moore, G. (1975). Occupational disease among operating room personnel. Anesthesiology, 42, 609.
Downloaded from http://bja.oxfordjournals.org/ at University of Ulster on April 15, 2015
A RETURN TO TRICHLOROETHYLENE
Sir,—Crawford and Davies' recent article5 "A return to trichloroethylene for obstetric anaesthesia" (Crawford and Davies, 1975), advocates "a more general re-introduction of the drug into anaesthetic practice". Although trichloroethylene may be inexpensive, its hepatotoxic potential can be enhanced greatly by prior pretreatment with drugs or other chemicals which induce components of the liver's drug-metabolizing enzyme systems (mixed function oxidase system). Specifically, Carlson (1974) reported that pretreatment of rats with phenobarbitone or 3-methylcholanthrene exacerbated trichloroethylene-induced liver damage. We have also found acute liver injury following a 2-hr exposure to 1% trichloroethylene in animals pretreated with these and other inducers of the mixed function oxidase system including a chlorinated biphenyl (Aroclor 1254), hexachlorobenzene and a synthetic steroid (pregnenolone-16a-carbonitrile) (Moslen, Reynolds and Szabo, in preparation). Numerous drugs, food additives and environmental contaminants also have the capacity to induce these drug-metabolizing enzymes (Conney and Burns, 1972). Preliminary evaluations of the National Cancer Institute (U.S.A.) indicate that trichloroethylene may have a carcinogen potential (Seltzer, 1975) similar to that already demonstrated for its monochlorinated homologue, vinyl chloride. Metabolic activation to highly reactive epoxide intermediates could be central to the apparently similar acute and long-range hepatotoxicity of both these chloroethylenes (Reynolds et al., 1975). While it cannot be said that a single exposure to trichloroethylene during anaesthesia is harmful, sufficient benefits have not yet been demonstrated to justify its general and widespread use in anaesthetic practice.
Reynolds, E. S., Moslen, M. T., Szabo, S., Jaeger, R. J., and Murphy, S. D. (1975). Hepatotoxicity of vinyl chloride and 1,1-dichloroethylene: role of mixed function oxidase system. Am. J. Pathol. (in press). Seltzer, R. J. (1975). Reactions grow to trichloroethylene alert. Chem. Eng. News, May 19, p. 41.
50
A. MATHIEU
Althesin. A woman aged 63 yr with hypertension and stress incontinence was anaesthetized in October, 1974, with Althesin, diazepam and nitrous oxide in oxygen for stretching of the bladder. The anaesthetic was uneventful and after operation she had a short course of imipramine for the treatment of depression. In January, 1975, she was readmitted to hospital so that her bladder could be stretched painlessly for a prolonged period under a long-acting extradural nerve block. With the patient conscious, a lumbar extradural block was administered using 18 ml of etidocaine 1%. For 30 min after initiation of the block, there were no significant changes in heart rate, arterial pressure or ventilation and the level of the block was assessed. Owing to the patient's apprehension, a short general anaesthetic was then given for the preliminary cystoscopy. Althesin 5 ml was injected i.v. through a vein on the dorsum of the right hand. Before the onset of unconsciousness, the patient complained of nausea. This was followed by the development of bronchospasm, tachycardia, hypotension and erythematous mottling of the right forearm. Cardiac arrest occurred, but this responded to resuscitation. The patient remained unconscious for 4-5 days and recovered with some degree of mental confusion and amnesia together with a very cold right arm and a circular sloughing skin lesion at the site of injection of Althesin. The skin lesion persisted for 3-4 months. Subsequent patch-testing of the patient using etidocaine and Althesin was negative for both drugs. Thus it is now clear that the anaesthetist who has hitherto assumed that a previous uneventful response to Althesin is indicative of the safety of the drug, may be led unwittingly into dire trouble.
Boston
GEOFFREY C. STEEL
J. P. GRILLIAT
Nancy REFERENCES
Lorenz, W., Doenicke, A., Meyer, R., Reimann, H. J., Kusche, J., Barth, H., Geesing, H., Hutzel, M., and Weissenbacher, B. (1972). Histamine release in man by propanidid and thiopentone: pharmacological effects and clinical consequences. Br.J. Anaesth., 44, 355. Mandappa, J. M., Chandrasekhara, P. M., and Nelvigi, R. G. (1975). Anaphylaxis to suxamethonium: two case reports. Br. J. Anaesth., 47, 523. Moneret-Vautrin, D., and Grilliat, J. P. (1975). Les facteurs de hauts risques; in Symposium sur le risque allergique en anesthesiologie. Ann. Anesth. (Franf.) (in press).
London REFERENCES
Avery, A. F., and Evans, A. (1973). Reactions to Althesin. Br. J. Anaesth., Horton, J. N. (1973). Adverse reaction to Althesin. Anaesthesia, 28, 182. Kessell, J., and Assem, E. S. K. (1974) An adverse reaction to Althesin. Br. J. Anaesth., 46, 209. Mehta, S. (1973). Anaphylactic reaction to Althesin. Anaesthesia, 28, 669. Tweedie, D. G., and Ordish, P. M. (1974). Reactions to intravenous agents (Althesin and Pancuronium). Br. J. Anaesth., 46, 244. Watt, J. M. (1975). Anaphylactic reactions after use of CT 1341, Althesin. Br. Med.J., 3, 205.
REACTION TO ALTHESIN
Sir,—There have been recent reports of adverse reactions to the intravenous induction agent Althesin. The effects produced have included restlessness during injection, hypotension, bronchospasm and mottling of the skin at the site of the injection (Horton, 1973; Mehta, 1973; Kessell and Assem, 1974; Tweedie and Ordish, 1974). In addition, hypersensitivity reactions have been described in which patients, although reacting normally to an initial dose of Althesin, reacted adversely to a subsequent dose given 11 days to 1 month later (Avery and Evans, 1973; Watt, 1975). I should like to report the history of a patient who eveloped an adverse reaction to Althesin following an interval of 3 months between the first and second doses of
MALIGNANT HYPERTHERMIA
Sir,—In their interesting report on the effects of Althesin on malignant hyperthermia (MH) in susceptible Pietrain pigs, Luke and Lister (1975) make a reference to a similar experiment of mine, reported previously (Harrison, 1973) which I feel needs some clarification. I found that in MH-susceptible Landrace swine, the protection against MH initiation with halothane afforded by Althesin was only effective on continuous infusion of the drug. Approximately 20 min after discontinuance of Althesin infusion, MH could be induced by re-exposure of animals to halothane. From their report, Luke and Lister appear to have used, as did Hall, Trimm and Woolf (1972),
Downloaded from http://bja.oxfordjournals.org/ at University of Ulster on April 15, 2015
cells, if the test is performed soon after the drug reaction. Thus an interval of 6 weeks before testing is recommended also. Now we shall respond to Dr Fisher's qualification of "wrong and dangerous" in reference to our statement that ketamine could be used again in the child with a cutaneous anaphylactoid reaction without signs of circulatory embarrassment, for example hypotension. Again, he does not support his statement by any reference(s). Our statement was based on the following information: (1) data from a recent study show that anaphylactoid reactions are dependent to a large extent on the speed and mode of administration of the drug (i.v. or i.m.) (Moneret-Vautrin, and Grilliat, 1975); (2) histamine release from an anaphylactoid mechanism produces localized reactions most frequently (Moneret-Vautrin, and Grilliat, 1975). In this context, it was found that between 20 and 40% of anaesthetic drugs produce non-specific release of histamine of minor consequence (for example, localized hives along the site of injection). Thus, further use of these drugs administered in small increments is not prohibited. (3) In the event of a more severe reaction, that is bronchospasm, it has been reported that anti-histamines with or without corticosteroids, administered for a period of 48 hr before anaesthesia can block effectively non-specific histamine release. However, in severe reactions with circulatory collapse, from either anaphylactic or anaphylactoid mechanisms, we suggest that further use of the drug should be prohibited, if at all possible.
51
CORRESPONDENCE a single induction dose of Althesin. In my experiment, continuous infusion of Althesin failed to protect against initiation of the MH syndrome by suxamethonium as well as proving useless as a means of treatment of the established syndrome. G. G. HARRISON
Cape Town REFERENCES
Hall, L. W., Trimm, C. M., and Woolf, N. (1972). Further studies of porcine malignant hyperthermia. Br. Med. J., 2, 145. Harrison, G. G. (1973). Althesin and malignant hyperpyrexia. Br. J. Anaesth., 45, 1010. Lucke, J. N. and Lister, D. (1975). Althesin and malignant hyperthermia. Br. J. Anaesth., 7, 419.
EDWARD S. REYNOLDS
Boston REFERENCES
Carlson, G. P. (1974). Enhancement of the hepatotoxicity of trichloroethylene by inducers of drug metabolism. Res. Comm. Chem. Path. Pharmacol., 7, 637. Conney, A. H., and Burns, J. J. (1972). Metabolic interactions among environmental chemicals and drugs. Science, 178, 576. Crawford, J. S., and Davies, P. (1975). A return to trichloroethylene for obstetric anaesthesia. Br. J. Anaesth. 47, 482.
Sir,—Thank you for the opportunity of replying to Dr Reynolds' interesting letter. Whilst I am impressed by the diligence and perseverence of the authorities whose publications Dr Reynolds quotes, I am totally unimpressed by the relevance of their observations to clinical practice. I appreciate that currently members of the medical profession in the United States are being severely buffeted by successive waves of—apparently—bureaucratically and legally inspired hysteria with respect to the potential hazards of a vast range of the therapy to which their patients might be exposed. I sincerely hope that we in the United Kingdom will continue to be successful in warding off similarly directed tendencies. As far as I can gather, if investigations were to be pursued on a sufficiently wide and intensive scale, we would all, on the basis of the derived results, be urgently advised to refrain from eating, drinking or inhaling anything, and from exposing ourselves to any environmental influence in order to guard ourselves against a putative potential noxious agent. I believe that in medicine, as in many other walks of life, common sense must prevail when a balanced opinion is in the process of achievement. During the past two decades, literally several millions of labouring women (that is, subjects "pre-treated" with a whole range of substances, including all the pregnancy hormones) have inhaled trichloroethylene, in a concentration of either 0.35% or 0.5%, for a cumulative period of at least 1 hr, and I cannot believe that the hepatotoxic or carcinogenic effects of this would have gone unnoticed. I really cannot credit it to be likely that the administration of trichlorethylene in a concentration of 0-2% for approximately 1 hr to a human adult has a more than infinitesimal chance of causing catastrophic damage (that is, if the agent has not been subjected to chemical change before reaching the subject). Promotion of the importance of such an association would appear to me to be like issuing an urgent warning to all potential pedestrians to hold their breath when passing a stretch of freshly tarred roadway, lest the fumes initiate a carcinoma of the bronchus. I submit that, for the sake of the dignity of medicine, we cannot afford a repeat of the now-farcical "halothane hepatitis" series of affirmation and counter-affirmation to the nth degree (although I fear that we are unpleasantly near to it with the potential idiocy of spending vast sums on "scavenging extractors" for theatres—a matter concerning which I am in total sympathy with the views recently expressed by Walts, Forsythe and Moore (1975)). In summary, whilst I appreciate the point made by Dr Reynolds, I believe it to reflect a communal sickness from which I earnestly hope he and his countryman will soon recover, and to which I fervently pray we will not become subject.
j . SELWYN CRAWFORD
Birmingham REFERENCE
Walts, L. F., Forsythe, A. B., and Moore, G. (1975). Occupational disease among operating room personnel. Anesthesiology, 42, 609.
Downloaded from http://bja.oxfordjournals.org/ at University of Ulster on April 15, 2015
A RETURN TO TRICHLOROETHYLENE
Sir,—Crawford and Davies' recent article5 "A return to trichloroethylene for obstetric anaesthesia" (Crawford and Davies, 1975), advocates "a more general re-introduction of the drug into anaesthetic practice". Although trichloroethylene may be inexpensive, its hepatotoxic potential can be enhanced greatly by prior pretreatment with drugs or other chemicals which induce components of the liver's drug-metabolizing enzyme systems (mixed function oxidase system). Specifically, Carlson (1974) reported that pretreatment of rats with phenobarbitone or 3-methylcholanthrene exacerbated trichloroethylene-induced liver damage. We have also found acute liver injury following a 2-hr exposure to 1% trichloroethylene in animals pretreated with these and other inducers of the mixed function oxidase system including a chlorinated biphenyl (Aroclor 1254), hexachlorobenzene and a synthetic steroid (pregnenolone-16a-carbonitrile) (Moslen, Reynolds and Szabo, in preparation). Numerous drugs, food additives and environmental contaminants also have the capacity to induce these drug-metabolizing enzymes (Conney and Burns, 1972). Preliminary evaluations of the National Cancer Institute (U.S.A.) indicate that trichloroethylene may have a carcinogen potential (Seltzer, 1975) similar to that already demonstrated for its monochlorinated homologue, vinyl chloride. Metabolic activation to highly reactive epoxide intermediates could be central to the apparently similar acute and long-range hepatotoxicity of both these chloroethylenes (Reynolds et al., 1975). While it cannot be said that a single exposure to trichloroethylene during anaesthesia is harmful, sufficient benefits have not yet been demonstrated to justify its general and widespread use in anaesthetic practice.
Reynolds, E. S., Moslen, M. T., Szabo, S., Jaeger, R. J., and Murphy, S. D. (1975). Hepatotoxicity of vinyl chloride and 1,1-dichloroethylene: role of mixed function oxidase system. Am. J. Pathol. (in press). Seltzer, R. J. (1975). Reactions grow to trichloroethylene alert. Chem. Eng. News, May 19, p. 41.
