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TOXICITY CAUSED BY LOCAL ANAESTHETIC DRUGS
" / would have everie man write what he knowes and no
BRITISH
JOURNAL
OF
more."—MONTAIGNE
ANAESTHESIA
VOLUME 53, No. 6
JUNE 1981
Whilst every effort is made by the publishers and editorial committee to see that no inaccurate or misleading data, opinion or statement ippears in this Journal, they wish to make it clear that the data and opinions appearing in the articles and advertisements herein are the responsibility of the contributor or advertiser concerned! Accordingly, the publishers and the editorial committee and their respective employees, officers and agents accept no Itabihty whatsoever for the consequences of any such inaccurate or misleading data, opuuon or statement. Whilst every effort is made to ensure that drug doses and other quannues are presented accurately, readen are advised that new methods and techniques involving drug usage, and described within this Journal, should only be followed in conjunction with die drug manufacturer'i own published literature.
TOXICITY CAUSED BY LOCAL ANAESTHETIC DRUGS
Systemic toxicity from local anaesthetic drugs is a rare but unpleasant complication of regional anaesthesia when moderate to high dosage is used. In the main it occurs when the injection is made accidentally into a blood vessel. Signs and symptoms such as numbness of the tongue, lightheadedness, visual disturbance and muscular twitching give warning of the more serious events which may follow, namely convulsions, coma, respiratory arrest and cardiovascular depression, There is good evidence that, with drugs such as lignocaine, there is a wide margin between central nervous system toxicity and cardiovascular depression. Indeed, because the former causes apnoea, cardiovascular depression is often secondary to hypoxia rather than a primary effect of the drug. The minimum lethal dose of lignocaine in dogs may be increased four-fold if the lungs are ventilated rather than allowed to remain apnoeic (Woods and Haggart, 1957). Recently this separation of central nervous system and cardiovascular toxicity has been questioned in regard to the longer acting drugs bupivacaine and etidocaine (Albright, 1979). Case reports have appeared suggesting that severe cardiac depression, often leading to cardiac arrest, may occur soon after the appearance of convulsions. Experimentally, cats have been shown to suffer from cardiac arrhythmia during the infusion of bupivacaine (de Jong and DeRosa, 1981), an odd reaction in view of the anti-arrhythmic activity of local anaesthetics and one which does not appear to occur in dogs (Jorfeldt et'al., 1968) and, perhaps more pertinently, in primates (Munson, Paul and Embro, 1977).
Before accepting that cardiovascular depression is a direct effect of the injected drug, other factors must be considered. It is not sufficiently realized how quickly hypoxia can occur in a convulsing patient. During a grand mal attack effective ventilation ceases and oxygen is used at a very fast rate, certainly many times that of the resting subject. While there is little evidence of a significant increase in cerebral oxygen consumption during convulsions, cerebral and myocardial oxygen supply will deteriorate rapidly as the contracting muscles use up the meagre oxygen reserves. This highlights the urgent necessity of stopping convulsions and giving oxygen, the two most important procedures in treating toxicity. The rapidity with which hypoxia and acidosis may occur has been illustrated recently (Moore, Crawford and Scurlock, 1980), and central nervous system toxicity from local anaesthetics is greatly enhanced by acidosis and hypercapnia (Engelsson and Matousek, 1975). The treatment of convulsions has been an item of controversy for some years. Classically, thiopentone was the agent of choice and there is little doubt of its ability to stop convulsions quickly in moderate doses (150-300 mg). More recently, diazepam has achieved popularity as it has been shown in animals to be effective in both prevention and treatment of local anaesthetic-induced convulsions (de Jong, 1978). However, its stated advantages over thiopentone in regard to cardiovascular depression ignore two important points.First, it is much slower in effect, taking as long as 2-3 min to control convulsions (Moore, Balfour and Fitzgibbons, 1979), therefore making assess-
Downloaded from http://bja.oxfordjournals.org/ at Simon Fraser University on June 3, 2015
EDITORIAL
554
EDITORIAL Until better evidence is presented we should continue to believe that local anaesthetic drugs in clinical use cause central nervous system toxicity at smaller plasma concentrations than those which cause significant cardiovascular depression. Treatment must be directed to the rapid control of convulsions and the administration of oxygen. If cardiovascular depression is apparent, the circulation must be supported by the appropriate use of inotropes and vasopressors. D. B. Scott
REFERENCES
Albright, G. A. (1979). Cardiac arrest following regional anesthesia with etidocaine or bupivacaine. Anesthesiology, 51, 285. Engelsson, S., and Matousek, M. (1975). Central nervous gystem effects of local anaesthetic agents. Br.J. Anaesth., 47, 241. de Jong, R. H. (1978). Toxicity effects of local anesthetics. J.A.MA.,21% 1166. • DeRosa,R'. A. (1981). Proceedings of 6th Annual Meeting of American Society of Regional Anesthesia. Jordan, C , Lehane, J. R., and Jones, J. G. (1980). Respiratory depression following diazepam. Anesthesiology, 53, 293. Jorfeldt, L., Lofstrom, B., Pernow, B., Person, B., Wahren, J., and Widman, B, (1968). The effect of local anaesthetics on the central circulation and respiration in man and dog. Acta Anqusthesiol. Scand., 12, 153. Moore, D. C , Balfour, R. I., and Fitzgibbons, D. (1979). Convulsive arterial plasma levels of bupivacaine and the response to diazepam therapy. Anesthesiology, 50, 454. Crawford, R. D., and Scurlock, J. E. (1980). Severe hypoxia and acidosis following local anesthetic-induced convulsions. Anesthesiology, 53, 259. Munson, E. S., Paul, V - L-. "°d Embro, B. S. (1977). Centralnervous-system toxicity of local anesthetic mixtures in monkeys. Anesthesiology, 46, 179. Prentiss, J. E. (1979). Cardiac arrest following caudal anesthesia. Anesthesiology, 50, 51. Woods, L. A., and Haggart, J. (1957). Apneic and hypotensive effects of local anesthetic drugs in dogs and mice under general anesthesia. Anesthesiology, 18, 831.
Downloaded from http://bja.oxfordjournals.org/ at Simon Fraser University on June 3, 2015
ment of dosage problematical. Second, it is a powerful respiratory depressant (Jordan, Lehane and Jones, 1980) with a long half-life. Not least in importance in choosing between thiopentone and diazepam is the fact that the former is much more readily available in the average operating area, and all anaesthetists are fully familiar with its use. Suxamethonium will rapidly stop convulsions (though not the excessive cerebral activity associated with them) and facilitate the rapid administration of oxygen. It does not reverse the prime cause of the convulsions and should not be used by those unskilled in tracheal intubation. Another important aspect in the management of these cases is the superimposition of modern methods of cardiopulmonary resuscitation. In one reported case (Prentiss, 1979) of cardiac arrest following etidocaine, the arrest team promptly gave i.v. lignocaine, procainamide and diphenylhydantoin. While these are admirable drugs in the treatment of many types of cardiac arrest, they seem less than desirable in local anaesthetic overdosage. In general, prevention is better than cure, and to exclude intravascular (and subarachnoid) placement of an extradural catheter, a test dose is commonly used. However, the dose used by many anaesthetists is too small to detect i.v. injection unless adrenaline has been added to the test dose. More practical is the slow injection of the main dose while closely observing and questioning the patient. The early signs and symptoms of toxicity should be easily apparent before a convulsant dose is reached. The negative test dose too frequently gives a false sense of security and the main injection is made too rapidly. No great reliance should be placed upon an oral dose of say 10 mg of diazepam as a premedication in regard to preventing toxicity.
BRITISH
JOURNAL
OF
more."—MONTAIGNE
ANAESTHESIA
VOLUME 53, No. 6
JUNE 1981
Whilst every effort is made by the publishers and editorial committee to see that no inaccurate or misleading data, opinion or statement ippears in this Journal, they wish to make it clear that the data and opinions appearing in the articles and advertisements herein are the responsibility of the contributor or advertiser concerned! Accordingly, the publishers and the editorial committee and their respective employees, officers and agents accept no Itabihty whatsoever for the consequences of any such inaccurate or misleading data, opuuon or statement. Whilst every effort is made to ensure that drug doses and other quannues are presented accurately, readen are advised that new methods and techniques involving drug usage, and described within this Journal, should only be followed in conjunction with die drug manufacturer'i own published literature.
TOXICITY CAUSED BY LOCAL ANAESTHETIC DRUGS
Systemic toxicity from local anaesthetic drugs is a rare but unpleasant complication of regional anaesthesia when moderate to high dosage is used. In the main it occurs when the injection is made accidentally into a blood vessel. Signs and symptoms such as numbness of the tongue, lightheadedness, visual disturbance and muscular twitching give warning of the more serious events which may follow, namely convulsions, coma, respiratory arrest and cardiovascular depression, There is good evidence that, with drugs such as lignocaine, there is a wide margin between central nervous system toxicity and cardiovascular depression. Indeed, because the former causes apnoea, cardiovascular depression is often secondary to hypoxia rather than a primary effect of the drug. The minimum lethal dose of lignocaine in dogs may be increased four-fold if the lungs are ventilated rather than allowed to remain apnoeic (Woods and Haggart, 1957). Recently this separation of central nervous system and cardiovascular toxicity has been questioned in regard to the longer acting drugs bupivacaine and etidocaine (Albright, 1979). Case reports have appeared suggesting that severe cardiac depression, often leading to cardiac arrest, may occur soon after the appearance of convulsions. Experimentally, cats have been shown to suffer from cardiac arrhythmia during the infusion of bupivacaine (de Jong and DeRosa, 1981), an odd reaction in view of the anti-arrhythmic activity of local anaesthetics and one which does not appear to occur in dogs (Jorfeldt et'al., 1968) and, perhaps more pertinently, in primates (Munson, Paul and Embro, 1977).
Before accepting that cardiovascular depression is a direct effect of the injected drug, other factors must be considered. It is not sufficiently realized how quickly hypoxia can occur in a convulsing patient. During a grand mal attack effective ventilation ceases and oxygen is used at a very fast rate, certainly many times that of the resting subject. While there is little evidence of a significant increase in cerebral oxygen consumption during convulsions, cerebral and myocardial oxygen supply will deteriorate rapidly as the contracting muscles use up the meagre oxygen reserves. This highlights the urgent necessity of stopping convulsions and giving oxygen, the two most important procedures in treating toxicity. The rapidity with which hypoxia and acidosis may occur has been illustrated recently (Moore, Crawford and Scurlock, 1980), and central nervous system toxicity from local anaesthetics is greatly enhanced by acidosis and hypercapnia (Engelsson and Matousek, 1975). The treatment of convulsions has been an item of controversy for some years. Classically, thiopentone was the agent of choice and there is little doubt of its ability to stop convulsions quickly in moderate doses (150-300 mg). More recently, diazepam has achieved popularity as it has been shown in animals to be effective in both prevention and treatment of local anaesthetic-induced convulsions (de Jong, 1978). However, its stated advantages over thiopentone in regard to cardiovascular depression ignore two important points.First, it is much slower in effect, taking as long as 2-3 min to control convulsions (Moore, Balfour and Fitzgibbons, 1979), therefore making assess-
Downloaded from http://bja.oxfordjournals.org/ at Simon Fraser University on June 3, 2015
EDITORIAL
554
EDITORIAL Until better evidence is presented we should continue to believe that local anaesthetic drugs in clinical use cause central nervous system toxicity at smaller plasma concentrations than those which cause significant cardiovascular depression. Treatment must be directed to the rapid control of convulsions and the administration of oxygen. If cardiovascular depression is apparent, the circulation must be supported by the appropriate use of inotropes and vasopressors. D. B. Scott
REFERENCES
Albright, G. A. (1979). Cardiac arrest following regional anesthesia with etidocaine or bupivacaine. Anesthesiology, 51, 285. Engelsson, S., and Matousek, M. (1975). Central nervous gystem effects of local anaesthetic agents. Br.J. Anaesth., 47, 241. de Jong, R. H. (1978). Toxicity effects of local anesthetics. J.A.MA.,21% 1166. • DeRosa,R'. A. (1981). Proceedings of 6th Annual Meeting of American Society of Regional Anesthesia. Jordan, C , Lehane, J. R., and Jones, J. G. (1980). Respiratory depression following diazepam. Anesthesiology, 53, 293. Jorfeldt, L., Lofstrom, B., Pernow, B., Person, B., Wahren, J., and Widman, B, (1968). The effect of local anaesthetics on the central circulation and respiration in man and dog. Acta Anqusthesiol. Scand., 12, 153. Moore, D. C , Balfour, R. I., and Fitzgibbons, D. (1979). Convulsive arterial plasma levels of bupivacaine and the response to diazepam therapy. Anesthesiology, 50, 454. Crawford, R. D., and Scurlock, J. E. (1980). Severe hypoxia and acidosis following local anesthetic-induced convulsions. Anesthesiology, 53, 259. Munson, E. S., Paul, V - L-. "°d Embro, B. S. (1977). Centralnervous-system toxicity of local anesthetic mixtures in monkeys. Anesthesiology, 46, 179. Prentiss, J. E. (1979). Cardiac arrest following caudal anesthesia. Anesthesiology, 50, 51. Woods, L. A., and Haggart, J. (1957). Apneic and hypotensive effects of local anesthetic drugs in dogs and mice under general anesthesia. Anesthesiology, 18, 831.
Downloaded from http://bja.oxfordjournals.org/ at Simon Fraser University on June 3, 2015
ment of dosage problematical. Second, it is a powerful respiratory depressant (Jordan, Lehane and Jones, 1980) with a long half-life. Not least in importance in choosing between thiopentone and diazepam is the fact that the former is much more readily available in the average operating area, and all anaesthetists are fully familiar with its use. Suxamethonium will rapidly stop convulsions (though not the excessive cerebral activity associated with them) and facilitate the rapid administration of oxygen. It does not reverse the prime cause of the convulsions and should not be used by those unskilled in tracheal intubation. Another important aspect in the management of these cases is the superimposition of modern methods of cardiopulmonary resuscitation. In one reported case (Prentiss, 1979) of cardiac arrest following etidocaine, the arrest team promptly gave i.v. lignocaine, procainamide and diphenylhydantoin. While these are admirable drugs in the treatment of many types of cardiac arrest, they seem less than desirable in local anaesthetic overdosage. In general, prevention is better than cure, and to exclude intravascular (and subarachnoid) placement of an extradural catheter, a test dose is commonly used. However, the dose used by many anaesthetists is too small to detect i.v. injection unless adrenaline has been added to the test dose. More practical is the slow injection of the main dose while closely observing and questioning the patient. The early signs and symptoms of toxicity should be easily apparent before a convulsant dose is reached. The negative test dose too frequently gives a false sense of security and the main injection is made too rapidly. No great reliance should be placed upon an oral dose of say 10 mg of diazepam as a premedication in regard to preventing toxicity.