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Toxicity of Anesthetics
BRITISH JOURNAL OF ANAESTHESIA
46 EFFETS CIRCULATOIRES DE L'ATROPINE CHEZ DES PATIENTS ANESTHESIES AVEC LE TRIETHIODIDE DE GALLAMINE ET LE PROTOXYDE D'AZOTE
ATROPINWIRKUNGEN AUF DEN KREISLAUF VON PATIENTEN UNTER GALLAMINTRIATHYLJODID- UND STICKOXYDULNARKOSE
SOMMAIRE
Bei zehn mit Stickoxydul, Sauerstoff und Gallamintriathyljodid anasthesierten und kiinstlich beatmeten Patienten wurden die nach intravenoser Injektion von akzelerierenden Dosen Atropinsulfat von seiten des Krcislaufs eintretenden Reaktionen untersucht. Kleine aber bedeutsame Erhohungen in der Herzfrequenz und der vom Herzen ausgetriebenen Blutmenge konnten zusammen mit einer Herabsetzung des gesatnten peripheren Widerstandes und der Zirkulationszeit bsobachtet werden. Die arteriellen Druckwerte, Schlagvolumina und Schlagarbeit blieten unverandert. Die initial gemessenen Herzfrequenz- und Druckwerte waren aufgrund der Gallaminapplikation hoch, und es ist anzunehmen, dafi auch die Kontrollwerte fiir die vom Hsrzen geforderte Blutmenge hoch waren. Dies wiirde die kleineren Abweichungen von den in friiheren B2richten beschriebsnen Atropinwirkungen bei kiinstlich mit Tubokurarin beatmeten Patienten gegenuber dsn spontan atmenden Patienten bei Zufuhr von Stickoxydul, Sauerstoff und Halothan erklaren.
ZUSAMMENFASSUNG
BOOK REVIEW Toxicity of Anesthetics. Edited by B. R. Fink. Published by Williams and Wilkins Co., Baltimore (1968). Pp. 332; indexed; illustrated; 47 contributors. Price £7 7s. 6d. This book, expensive, weighty, and beautifully produced, contains the proceedings (26 papers, with brief discussions) of a Research Symposium held in Seattle in May 1967. The hitherto arbitrary, perhaps imaginary, boundary separating toxicity from pharmacology will at once impress the reader, and so will a reminder from Claude Bernard that "molecular events underlying narcosis are not confined to neural tissue and that anaesthesia is, to a degree, merely a local expression in the nervous system of a much more widespread phenomenon". The first of the book's four main sections concerns some actions of inhalation anaesthetics on cell models (cultures of tissue or of disaggregated cells); of the five chapters the first two provide an outline of carbohydrate metabolism and its control mechanisms, and discuss the influences of glucose and oxygen tension on cell growth. Two actions of halothane are then described: first, it affects mitochondria, shown for example by a reduction in their uptake of oxygen in the presence of ADP; second, there is depression of growth in cell cultures at halothane concentrations above 0.4 per cent, an effect which is more pronounced in mouse sarcoma. Lastly in this section, minimal changes in human liver cells are shown to result from perfusion with halogenated anaesthetics for three days, provided the right amino-acids are present (with glucose in the case of chloroform). Section 2, headed "Regional cellular effects", deals first with detoxification of anaesthetics, touching on their probable metabolism in the cell membranes of
liver and kidney where they are bound to cytochrome; because of their mere presence, they may therefore inhibit the metabolism of other drugs. In a discussion of toxic impurities and breakdown products of anaesthetics it is a fair question whether biological testing should supplement gas chromatography in the routine screening of established agents by manufacturers. The subject of fluorocarbon toxicity and biological action is next presented comprehensively and in detail in the space of 26 pages; here, there is a mass of information about both accepted and unacceptable anaesthetic agents. That prolonged inhalation of nitrous oxide causes leucopoenia has been known for some time, and in the next paper the effect is demonstrated with several other gases; on the same lines, associated with prolonged inhalation of 70 per cent nitrous oxide there is a fall in the DNA content of rat bone marrow and thymus, suggesting decreased mitotic activity. But in the following paper a similar effect of halothane is considered to involve other processes. Here there emerge faint resemblances between features of amino-acid deficiency, antibiotics, and anaesthetics, and there are thoughts expressed about possible treatment of virus infections with anaesthetics. There is then an abrupt and curiously irrelevant change to a paper on the effect of barbiturates on catecholamine-activated lipid metabolism. The concluding chapter of Section 2 deals with electro-physiological changes in cardiac muscle incident to anaesthetics, and questions the possible role of membrane permeability to calcium. "Effects on organ function" is the title of Section 3, which begins with a quite outstanding review, in 16 pages, of mechanisms of toxic and drug-induced [continued on p. 53
Downloaded from http://bja.oxfordjournals.org/ at Monash University on June 15, 2015
Les reactions circulatoires a l'injection intraveineuse de doses accelerantes de sulphate d' atropine ont ete etudiees chez 10 patients anesthesies au protoxyde d'azote, oxygene et triethiodide de gallamine, sous ventilation artificielle. Des augmentations peu importantes mais significatives de la frequence et du debit du coeur etaient accompagnees d'une reduction de la resistance peripherique totale et du temps de circulation. La pression arterielle, le volume pulsatoire et l'effort pulsatoire demeuraient inchanges. Les frequences cardiaques et les pressions initiales etaient elevees, suite a l'emploi de gallamine, et on suppose que les taux de controle du debit cardiaque etaient egalement eleves. Ceci expliquerait pourquoi les modifications etaient moins grandes que celles observees anterieurement sous l'effet d'atropine chez des patients ventiles artificiellement sous tubocurarine, et chez ceux avec respiration spontanee sous protoxyde d'azote, oxygene et halothane.
REBREATHING IN A DOUBLE T-PIECE SYSTEM REFERENCES
Ayre, T. P. (1937). Anaesthesia for intracranial operations. Lancet, 1, 561. Mapleson, W. (1954). The elimination of rebreathing in various semiclosed systems. Brit. J. Anaesth., 26, 323. Nightingale, D., Richards, C , and Glass, A. (1965). An evaluation of rebreathing in a modified Tpiece system during controlled ventilation of anaesthetized children. Brit. J. Anaesth., 37, 762. Rees, G. J. (1950). Anaesthesia in the newborn. Brit, med. J., 2, 1419. Waters, D. J., and Mapleson, W. (1961). Rebreathing during controlled respiration with various semiclosed anaesthetic systems. Brit. J. Anaesth., 33, 374.
SOMMAIRE
Un systeme pediatrique ayec piece en double T est decrit. Au cows de la respiration spontanee, le systeme agit comme un systeme Magill, si le flux de gaz frais arrive par la partie distale du T; la partie proximale servira a l'echappement. Au cours de la ventilation controlee, l'appareil agit comme un systeme Rees,
BOOK REVIEW—continued from p. 46 hepatic injury; this is lucid and of direct and immediate import to all clinicians, even if every anaesthetist might not agree with the stringent recommendations for the use of halothane. Interesting it is, also, to ponder that slow desensitization may be responsible for the rarity (or is it only apparent?) of liver damage among anaesthetists, dentists, and surgeons exposed to halothane over long periods. The next two chapters, on the isolated calf liver perfused with anaesthetics, and on spermidine levels as a response to liver injury, have a few rough edges and less than certain conclusions; but there is the pertinent comment that no-one has yet produced a drug sensitivity (liver) reaction in any animal, including primates. When the term "Indirect periodicity analysis" appears the reader should not be deterred from discovering that mortality from halothane in mice depends on the time of day at which they are exposed (the cause of death is not specified, and is presumably circulatory arrest). The effect of cyclopropane on catecholamine biotransformation is next discussed and related to its pharmacological action, but quite unconvincingly to this reviewer. It is then shown that the uptake of glucose by red cells, which is stimulated by carbon dioxide and is not insulin-dependent, is depressed by halothane. It is difficult to assess the claims of the next paper, that radiosensitivity of tumours is increased by locally-injected hydrogen peroxide; but it is of interest that intra-carotid injection causes temporary hemiparesis not infrequently. The final chapter in Section 3 describes "anaesthetic" actions of helium, nitrogen, and hydrogen at high pressure, findings of relevance more to under-sea exploration than to anaesthesia.
sil'arrivee du gaz frais se fait par la piece proximale du T ; la piece distale sert alors comme echappement de controle. Evalue suivant le degre de reinspiration, le flux a arrivee distale est plus efficace que l'arrivee proximale durant la respiration spontanee. L'efficacite du flux a arrivee distale est egale a celle du flux a arrivee proximale au cours de l'hyperventilation controlee.
NARKOSE IN EINEM "DOPPELTEN T-STOCKSYSTEM" ZUSAMMENFASSUNG
Ein in der Padiatrie verwendetes, "doppeltes T-StuckSystem" wird beschrieben. Wahrend der spontanen Atmung arbeitet das System wie ein Magill-System, sofern der Zuflufi frischen Narkosegases tiber das distale T-Stiick erfolgt; das proximale T-Stiick dient als Auslafi. Bei kontrollierter Ventilation arbeitet das Grat wie ein Rees-System, wenn der Einstrom des frischen Gases iiber das proximale T-Stiick erfolgt; dann dient das distale T-Stiick als Ablafiventil. Bei einer Beurteilung nach dem Grad der Wiederverwendung des Narkosegases erweist sich wahrend spontaner Atmung der distale Zuflufi als leistungsfahiger, wahrend bei kontrollierter Hyperventilation distale und proximale Gaszufuhr von gleicher Wirksamkeit sind.
Section 4, "Teratogenic effects", starts with problems of testing drugs, and there is the sinister deduction that the major sensitivity to foetal abnormabilities may occur 15-30 days after conception (i.e. sometimes before pregnancy is detected in the human). The chick embryo is the preparation used in the next three studies. First, diethyl ether, acting perhaps to cause cell death in a population whose individual susceptibility varies, causes peak teratogenesis at a dose level near the LD50. Then, 6 hours of 20 per cent cyclopropane reduces the mitotic index (the fraction of cells in division in a homogeneous population at a given time), and produces an increased number of abnormal embryos; less dramatic effects are caused by nitrous oxide and halothane. Finally, foetal lesions become common when pregnant rats are exposed to nitrous oxide for periods exceeding 24 hours. The above is but a brief summary of many notes taken during study of this impressive publication. As the reader will judge, the studies are "far out"; the editor, whose name appears on three papers, writes that the participants found this symposium exhilarating; so is this book, in which research endeavour is shown at full stretch toward goals mostly far removed from everyday activity in the operating-room—in fact, the kind of effort which should proceed in parallel with clinical research in an academic department. To forecast the future in a many-faceted specialty like anaesthesia is probably impossible, but it is a safe wager that this book contains a core of findings of critical importance to future research. Farsightedness (which disregards the inherently sterile, and often frankly malicious, accusation of "lack of immediate clinical relevance") has characterized the work of many contributors to this most important publication, and particularly that of the editor. This is an outstanding book which deserves wide reading and study. R. A. Millar
Downloaded from http://bja.oxfordjournals.org/ at Monash University on June 15, 2015
REINSPIRATION AVEC UN SYSTEME A PIECE EN DOUBLE T
53
46 EFFETS CIRCULATOIRES DE L'ATROPINE CHEZ DES PATIENTS ANESTHESIES AVEC LE TRIETHIODIDE DE GALLAMINE ET LE PROTOXYDE D'AZOTE
ATROPINWIRKUNGEN AUF DEN KREISLAUF VON PATIENTEN UNTER GALLAMINTRIATHYLJODID- UND STICKOXYDULNARKOSE
SOMMAIRE
Bei zehn mit Stickoxydul, Sauerstoff und Gallamintriathyljodid anasthesierten und kiinstlich beatmeten Patienten wurden die nach intravenoser Injektion von akzelerierenden Dosen Atropinsulfat von seiten des Krcislaufs eintretenden Reaktionen untersucht. Kleine aber bedeutsame Erhohungen in der Herzfrequenz und der vom Herzen ausgetriebenen Blutmenge konnten zusammen mit einer Herabsetzung des gesatnten peripheren Widerstandes und der Zirkulationszeit bsobachtet werden. Die arteriellen Druckwerte, Schlagvolumina und Schlagarbeit blieten unverandert. Die initial gemessenen Herzfrequenz- und Druckwerte waren aufgrund der Gallaminapplikation hoch, und es ist anzunehmen, dafi auch die Kontrollwerte fiir die vom Hsrzen geforderte Blutmenge hoch waren. Dies wiirde die kleineren Abweichungen von den in friiheren B2richten beschriebsnen Atropinwirkungen bei kiinstlich mit Tubokurarin beatmeten Patienten gegenuber dsn spontan atmenden Patienten bei Zufuhr von Stickoxydul, Sauerstoff und Halothan erklaren.
ZUSAMMENFASSUNG
BOOK REVIEW Toxicity of Anesthetics. Edited by B. R. Fink. Published by Williams and Wilkins Co., Baltimore (1968). Pp. 332; indexed; illustrated; 47 contributors. Price £7 7s. 6d. This book, expensive, weighty, and beautifully produced, contains the proceedings (26 papers, with brief discussions) of a Research Symposium held in Seattle in May 1967. The hitherto arbitrary, perhaps imaginary, boundary separating toxicity from pharmacology will at once impress the reader, and so will a reminder from Claude Bernard that "molecular events underlying narcosis are not confined to neural tissue and that anaesthesia is, to a degree, merely a local expression in the nervous system of a much more widespread phenomenon". The first of the book's four main sections concerns some actions of inhalation anaesthetics on cell models (cultures of tissue or of disaggregated cells); of the five chapters the first two provide an outline of carbohydrate metabolism and its control mechanisms, and discuss the influences of glucose and oxygen tension on cell growth. Two actions of halothane are then described: first, it affects mitochondria, shown for example by a reduction in their uptake of oxygen in the presence of ADP; second, there is depression of growth in cell cultures at halothane concentrations above 0.4 per cent, an effect which is more pronounced in mouse sarcoma. Lastly in this section, minimal changes in human liver cells are shown to result from perfusion with halogenated anaesthetics for three days, provided the right amino-acids are present (with glucose in the case of chloroform). Section 2, headed "Regional cellular effects", deals first with detoxification of anaesthetics, touching on their probable metabolism in the cell membranes of
liver and kidney where they are bound to cytochrome; because of their mere presence, they may therefore inhibit the metabolism of other drugs. In a discussion of toxic impurities and breakdown products of anaesthetics it is a fair question whether biological testing should supplement gas chromatography in the routine screening of established agents by manufacturers. The subject of fluorocarbon toxicity and biological action is next presented comprehensively and in detail in the space of 26 pages; here, there is a mass of information about both accepted and unacceptable anaesthetic agents. That prolonged inhalation of nitrous oxide causes leucopoenia has been known for some time, and in the next paper the effect is demonstrated with several other gases; on the same lines, associated with prolonged inhalation of 70 per cent nitrous oxide there is a fall in the DNA content of rat bone marrow and thymus, suggesting decreased mitotic activity. But in the following paper a similar effect of halothane is considered to involve other processes. Here there emerge faint resemblances between features of amino-acid deficiency, antibiotics, and anaesthetics, and there are thoughts expressed about possible treatment of virus infections with anaesthetics. There is then an abrupt and curiously irrelevant change to a paper on the effect of barbiturates on catecholamine-activated lipid metabolism. The concluding chapter of Section 2 deals with electro-physiological changes in cardiac muscle incident to anaesthetics, and questions the possible role of membrane permeability to calcium. "Effects on organ function" is the title of Section 3, which begins with a quite outstanding review, in 16 pages, of mechanisms of toxic and drug-induced [continued on p. 53
Downloaded from http://bja.oxfordjournals.org/ at Monash University on June 15, 2015
Les reactions circulatoires a l'injection intraveineuse de doses accelerantes de sulphate d' atropine ont ete etudiees chez 10 patients anesthesies au protoxyde d'azote, oxygene et triethiodide de gallamine, sous ventilation artificielle. Des augmentations peu importantes mais significatives de la frequence et du debit du coeur etaient accompagnees d'une reduction de la resistance peripherique totale et du temps de circulation. La pression arterielle, le volume pulsatoire et l'effort pulsatoire demeuraient inchanges. Les frequences cardiaques et les pressions initiales etaient elevees, suite a l'emploi de gallamine, et on suppose que les taux de controle du debit cardiaque etaient egalement eleves. Ceci expliquerait pourquoi les modifications etaient moins grandes que celles observees anterieurement sous l'effet d'atropine chez des patients ventiles artificiellement sous tubocurarine, et chez ceux avec respiration spontanee sous protoxyde d'azote, oxygene et halothane.
REBREATHING IN A DOUBLE T-PIECE SYSTEM REFERENCES
Ayre, T. P. (1937). Anaesthesia for intracranial operations. Lancet, 1, 561. Mapleson, W. (1954). The elimination of rebreathing in various semiclosed systems. Brit. J. Anaesth., 26, 323. Nightingale, D., Richards, C , and Glass, A. (1965). An evaluation of rebreathing in a modified Tpiece system during controlled ventilation of anaesthetized children. Brit. J. Anaesth., 37, 762. Rees, G. J. (1950). Anaesthesia in the newborn. Brit, med. J., 2, 1419. Waters, D. J., and Mapleson, W. (1961). Rebreathing during controlled respiration with various semiclosed anaesthetic systems. Brit. J. Anaesth., 33, 374.
SOMMAIRE
Un systeme pediatrique ayec piece en double T est decrit. Au cows de la respiration spontanee, le systeme agit comme un systeme Magill, si le flux de gaz frais arrive par la partie distale du T; la partie proximale servira a l'echappement. Au cours de la ventilation controlee, l'appareil agit comme un systeme Rees,
BOOK REVIEW—continued from p. 46 hepatic injury; this is lucid and of direct and immediate import to all clinicians, even if every anaesthetist might not agree with the stringent recommendations for the use of halothane. Interesting it is, also, to ponder that slow desensitization may be responsible for the rarity (or is it only apparent?) of liver damage among anaesthetists, dentists, and surgeons exposed to halothane over long periods. The next two chapters, on the isolated calf liver perfused with anaesthetics, and on spermidine levels as a response to liver injury, have a few rough edges and less than certain conclusions; but there is the pertinent comment that no-one has yet produced a drug sensitivity (liver) reaction in any animal, including primates. When the term "Indirect periodicity analysis" appears the reader should not be deterred from discovering that mortality from halothane in mice depends on the time of day at which they are exposed (the cause of death is not specified, and is presumably circulatory arrest). The effect of cyclopropane on catecholamine biotransformation is next discussed and related to its pharmacological action, but quite unconvincingly to this reviewer. It is then shown that the uptake of glucose by red cells, which is stimulated by carbon dioxide and is not insulin-dependent, is depressed by halothane. It is difficult to assess the claims of the next paper, that radiosensitivity of tumours is increased by locally-injected hydrogen peroxide; but it is of interest that intra-carotid injection causes temporary hemiparesis not infrequently. The final chapter in Section 3 describes "anaesthetic" actions of helium, nitrogen, and hydrogen at high pressure, findings of relevance more to under-sea exploration than to anaesthesia.
sil'arrivee du gaz frais se fait par la piece proximale du T ; la piece distale sert alors comme echappement de controle. Evalue suivant le degre de reinspiration, le flux a arrivee distale est plus efficace que l'arrivee proximale durant la respiration spontanee. L'efficacite du flux a arrivee distale est egale a celle du flux a arrivee proximale au cours de l'hyperventilation controlee.
NARKOSE IN EINEM "DOPPELTEN T-STOCKSYSTEM" ZUSAMMENFASSUNG
Ein in der Padiatrie verwendetes, "doppeltes T-StuckSystem" wird beschrieben. Wahrend der spontanen Atmung arbeitet das System wie ein Magill-System, sofern der Zuflufi frischen Narkosegases tiber das distale T-Stiick erfolgt; das proximale T-Stiick dient als Auslafi. Bei kontrollierter Ventilation arbeitet das Grat wie ein Rees-System, wenn der Einstrom des frischen Gases iiber das proximale T-Stiick erfolgt; dann dient das distale T-Stiick als Ablafiventil. Bei einer Beurteilung nach dem Grad der Wiederverwendung des Narkosegases erweist sich wahrend spontaner Atmung der distale Zuflufi als leistungsfahiger, wahrend bei kontrollierter Hyperventilation distale und proximale Gaszufuhr von gleicher Wirksamkeit sind.
Section 4, "Teratogenic effects", starts with problems of testing drugs, and there is the sinister deduction that the major sensitivity to foetal abnormabilities may occur 15-30 days after conception (i.e. sometimes before pregnancy is detected in the human). The chick embryo is the preparation used in the next three studies. First, diethyl ether, acting perhaps to cause cell death in a population whose individual susceptibility varies, causes peak teratogenesis at a dose level near the LD50. Then, 6 hours of 20 per cent cyclopropane reduces the mitotic index (the fraction of cells in division in a homogeneous population at a given time), and produces an increased number of abnormal embryos; less dramatic effects are caused by nitrous oxide and halothane. Finally, foetal lesions become common when pregnant rats are exposed to nitrous oxide for periods exceeding 24 hours. The above is but a brief summary of many notes taken during study of this impressive publication. As the reader will judge, the studies are "far out"; the editor, whose name appears on three papers, writes that the participants found this symposium exhilarating; so is this book, in which research endeavour is shown at full stretch toward goals mostly far removed from everyday activity in the operating-room—in fact, the kind of effort which should proceed in parallel with clinical research in an academic department. To forecast the future in a many-faceted specialty like anaesthesia is probably impossible, but it is a safe wager that this book contains a core of findings of critical importance to future research. Farsightedness (which disregards the inherently sterile, and often frankly malicious, accusation of "lack of immediate clinical relevance") has characterized the work of many contributors to this most important publication, and particularly that of the editor. This is an outstanding book which deserves wide reading and study. R. A. Millar
Downloaded from http://bja.oxfordjournals.org/ at Monash University on June 15, 2015
REINSPIRATION AVEC UN SYSTEME A PIECE EN DOUBLE T
53