EDITORIAL How May Neuromuscular Blocking Drugs Affect the State of General Anesthesia? M ANY of us have probably noted the following
development during abdominal surgery under light general anesthesia supplemented with muscle relaxants: The patient suddenly, and unexpectedly, becomes “tight” and at the same time seems too lightly anesthetized. Are these two circumstances simply coincidental, or are they related in any way? The traditionalists among us might explain the matter just as inadequate maintenance of anesthesia. Certainly, few clinicians would blame the apparent lightening of the patient’s state of consciousness on inadequate maintenance of dosage of a neuromuscular blocking drug. The paper by Forbes, Cohen, and Eger’ in this issue of Anesthesia and Analgesia, however, does suggest that at least one neuromuscular blocker (pancuronium) may supplement the anesthetic state (MAC). In this study, 17 halothane-anesthetized patients received pancuronium (0.1mg/kg) while 18 did not. Pancuronium was excluded from three extremities by pneumatic tourniquets, and was injected intravenously into one arm. MAC was determined in standard fashion by observation of movement of the isolated extremities in response to surgical incision. Pancuronium was found to lower halothane MAC from 0.73% to 0.55%. This appears to be a welldocumented demonstration in man of an interaction between the general anesthetics and the neuromuscular blockers on sensory pathways, whether or not the sensory routes in question are affected peripherally or centrally. Until the past decade, classic peripheral cholinergic pharmacology involved the interaction of acetylcholine and its inhibitors (including neuromuscular blocking agents) at nicotinic receptors (neuromuscular junction and autonomic ganglia), at muscarinic receptors at postganglionic parasympathetic neuroeffector
junctions, and at esteratic receptors (on the active sites of the enzymes acetylcholinesterase and the nonspecific plasma cholinesterase). The subject, however, has become more complicated. Now, additional nicotinic and muscarinic cholinergic receptors modulating catecholamine release at peripheral adrenergic nerve terminals are well-known? Furthermore, two different types of cholinergic receptors are now postulated to be involved with transmission in sympathetic ganglia, one (the so-called Mereceptor) promoting slow depolarization of ganglion cells (a facilitatory pathway) and one (the Mi receptor) subserving transmission within an inhibitory p a t h ~ a y .Both ~ pancuronium and gallamine are now known to produce their side effects (tachycardia and increased blood pressure) by not only inhibiting muscarinic receptors in the sinus node of the heart4. (the “vagolytic” effect), but also by inhibiting the Mi receptors3 and the muscarinic receptors on adrenergic neuron terminals described above?. The latter actions in effect “facilitate” sympathetic nervous system activity and increase catecholamine release. The preceding remarks highlight only a few of many new facets of the currently broadening pharmacology of neuromuscular blockers, including pancuronium. Note especially that all of pancuronium’s effects in the peripheral autonomic nervous system involve blockade of muscarinic receptors. It is true that the neuromuscular junction is classified as a nicotinic site, and that, indeed, pancuronium is a potent neuromuscular blocker; but its effects at other nicotinic sites (such as ganglia) are minimal.5 It is, therefore, not a classic nicotinic blocker like d-tubocurarine. In contrast, the latter drug, and its derivative, metocurine, produce their autonomic effects by blockade of nicotinic receptors (the ganglion-blocking action)? They have very little effect on muscarinic receptors. NonANESTHESIA AND ANALGESIA VOI 58, NO6. NOV-DW1979
449
EDITORIAL
&polarizing neuromuscular blockers, therefore, fall into two classes according to their preponderance of either nicotinic or muscarinic side effects in the peripheral autonomic nervous system. In fact, the cholinergic receptors at the neuromuscular junction should probably not be labeled "nicotinic," but should receive separate classification. What about the central nervous system (CNS)? Certainly many cholinergic pathways, subserving a variety of behavioral functions such as memory and learning, temperature control, appetite, aggression, and, especially pertinent to this discussion, sleep, have been described within the brain.'. Both nicotinic and muscarinic pathways probably do exist." Therefore, neuromuscular blocking drugs might affect some of these circuits provided that they could enter the CNS in great enough concentration. Pancuronium, since it has been shown to inhibit muscarinic receptors at several sites within the peripheral autonomic nervous system, might presumably act on this type receptor within the CNS. Matteo's work". l2 certainly shows that relatively low concentrations of d-tubocurarine can be detected within the spinal fluid of man after ordinary clinical doses given intravenously. Although not yet demonstrated, the same might be true for pancuronium. Therefore, we might assume that enough pancuronium might reach cholinergic receptors in the brain to exert a measurable influence on certain behavioral patterns subserved by cholinergic pathways, including sleep. Sleep, of course, is not anesthesia; and general anesthetics have a global influence on the brain, do not act specifically on any receptor type, and, therefore, do not preferentially affect any cerebral function, although some evidence does suggest that one important action of general anesthetics may be an inhibition of the ascending reticular formation, an area responsible for maintenance of wakefulness.l3*'' However, agents promoting sleep, such as thiopental and diazepam, are commonly used to supplement general anesthetics. If pancuronium blocks muscarinic receptors in the CNS, then, in order to lower MAC as suggested by Forbes et all it might act on muscarinic receptors in the ascending reticular activating system, which involves cholinergic path~ays.'~-''This system, when activated, produces an arousal response mimicked by cholinergic antagonists and by anticholinesterases." Inhibition of this pathway by a specific antagonist (pancuronium?) might lead to supplementation of a sleep-influence and in turn a lowering of MAC. The foregoing discussion is admittedly grossly
450
ANESTHESIA AND ANALGESIA Vol 58, No 6, Nov-Dec 1979
oversimplified. There are many cholinergic pathways within the brain, and probably many different cholinergic receptor types modulating transmission along a variety of other routes (eg., adrenergic, gabaminergic, etc.). It is difficult to imagine that a muscarinic antagonist such as pancuronium might lower MAC by an action on only one pathway. Rather, the end-result probably represents a complex algebraic sum of inhibitory effects of pancuronium on many muscarinic receptors in a large number of cerebral circuits. The observation that a neuromuscular blocking drug which blocks muscarinic receptors may augment general anesthesia is novel but does seem plausible and, of course, needs further substantiation. The novelty of the subject raises several questions. For example, will other neuromuscular blockers have the same effect on MAC as pancuronium? Gallamine, another muscarinic inhibitor, might indeed have a similar effect; but the nicotinic blockers, d-tubocurarine and metocurine, and the nicotinic and muscarinic stimulant, succinylcholine, might interact in an entirely different fashion. If pancuronium lowers MAC, why do neuromuscular blockers, when injected directly intraventricularly, cause convulsions? Do the observations of Forbes et all have any clinical significance? Answers to these questions may not be apparent for several years, but it is possible that an improved knowledge of the CNS effects of neuromuscular blockers may lead to a better understanding of the state of general anesthesia and to an improvement of our clinical practice. John J. Savarese, MD Associate Professor of Anesthesia Harvard Medical School at Massachusetts Genera1 Hospital Boston, Massachusetts 02114 REFERENCES 1. Forbes AR, Cohen NH, Eger El 11: Pancuronium reduces halo-
thane requirement in man. Anesth Analg 58497-499, 1979 2. Langer SA: Presynaptic regulation of catecholamine release.
Biochem Pharmacol231793-1800,1974. 3. Gardier RW, Tsevdos EJ, JacksonDB: Effects of gallamine and pancuronium on inhibitory transmission in cat sympathetic ganglia. J Pharmacol Exp Ther 20446-53,1978 4. Saxena PR,Bonta IL: Mechanism of selective cardiac vagolytic action of pancuronium bromide: specific blockade of cardiac muscarinic receptors. Eur J Pharmacol 11:332-336, 1970 5. Hughes R, Chapple D: Effects of non-depolarizing neuromuscular blocking agents on peripheral autonomic mechanisms in cats. Br J Anaesth 4859-67, 1976 6. Vercruysse P,Hanegreefs G, Vanhoutte PM: Influence of skeletal muscle relaxants on the prejunctional effects of acetylcholine in adrenergically-innervated blood vessels. Arch Int Pharmacodyn Ther 232350-355, 1978
EDITORIAL 7. Savarese J J The autonomic margin of safety of metocurhe and
d-tubocurarine in the cat. Anesthesiology 50:40-%,19!79 8. Jouvet M: Cholinergic mechanisms and sleep, in Cholinergic Mechanisms. Edited by PG Waser. New York, Raven Press,
tubocurarine concentration to neuromuxular blockade in man. Anesthesiology 41:440-443,1974 13. Brazier MAB: Some effects of anesthesia on the brain. Br J
10. Domino EF, Yamamoto K,Dren AT: Role of choliner@cmech-
Anaesth 33A94-u)4,1%1 14. Magoun HW:Brain mechankms for wakefulness. Br J Anaesth 33163-193,1961 15. Shute CCD, Lewis PR: Cholinesterase containing systems of the brain of the rat. Nature 19ik1160-1161,1963 16. Shute CCD, Lewis PR:Cholinergic and monoaminergicsystems
anisms in states of wakefulness and sleep. Prog Brain Res 28: 113-133,1968 11. Matteo RS, Pua EK, Khambatta HJ,et ak Cerebrospinal fluid levels of d-tubocurarine in man. Anesthesiology 46:396-399,
17. Shute CCD, Lewis PR: The ascending choliergic reticular system: newortical, olfactoq and subcortical projections. Brain 90:497-520,1%7
1975 9. Karczmar AG: Cholinergic influences on behavior, in Cholin-
ergic Mechanisms. Edited by PG Waser. New York, Raven
Press,1975
1977
12. Matteo RS, Spector 5, Horowik
PE: Relation of serum d-
of the brain. Nature 212:7lO-n1,1%6
IS. Morgane 0 Chemical mapping of hypnogenic and arousal systems in the brain. Psychophysiology 6219-225,1969
Prqxrative Pulmonary Preparation A group of 157 patients with chronic obstructive pulmonary disease who were treated before surgery, using a standardized pulmonary preparation, underwent physiologic assessment both before and after the prophylactic program. The postoperative course of each patient also was evaluated to assess the incidence of respiratory morbidity and mortality. Although many physiologic values were statisticallyimproved after the pulmonary preparation, most of the changes are of doubtful functional significance. It is difficult to detennine which patients will develop pulmonary complications not requiring mechanical ventilation. However, the group requiring this type of support appears to be predictable on the basis of the severity of their pulmonary functional impairment and their lack of response to the standard pulmonary preparation used. The single most reliable test for this purpose was the mean forced expiratory flow during the middle half of the forced vital capacity. The frequency of postoperative respiratory complications was related to the type of operation, with the highest incidence occurring in the group that had extensive surgery of the upper abdomen. While the occurrence of these complications was significantly reduced in patients undergoing a standard preoperative pulmonary preparation, the explanation for the beneficial effect of this procedure is not apparent. (Gracey OR, Divertie MB, Didier ER- Preoperativepulmonary preparation ofpatients with chronic obstructive pulmonary disease: a prospective study. Chest 76:IW-129,1979)
ANESTHESIA AND ANALQESIA VOI 58, NO 6, NW-Dec 1979
451
development during abdominal surgery under light general anesthesia supplemented with muscle relaxants: The patient suddenly, and unexpectedly, becomes “tight” and at the same time seems too lightly anesthetized. Are these two circumstances simply coincidental, or are they related in any way? The traditionalists among us might explain the matter just as inadequate maintenance of anesthesia. Certainly, few clinicians would blame the apparent lightening of the patient’s state of consciousness on inadequate maintenance of dosage of a neuromuscular blocking drug. The paper by Forbes, Cohen, and Eger’ in this issue of Anesthesia and Analgesia, however, does suggest that at least one neuromuscular blocker (pancuronium) may supplement the anesthetic state (MAC). In this study, 17 halothane-anesthetized patients received pancuronium (0.1mg/kg) while 18 did not. Pancuronium was excluded from three extremities by pneumatic tourniquets, and was injected intravenously into one arm. MAC was determined in standard fashion by observation of movement of the isolated extremities in response to surgical incision. Pancuronium was found to lower halothane MAC from 0.73% to 0.55%. This appears to be a welldocumented demonstration in man of an interaction between the general anesthetics and the neuromuscular blockers on sensory pathways, whether or not the sensory routes in question are affected peripherally or centrally. Until the past decade, classic peripheral cholinergic pharmacology involved the interaction of acetylcholine and its inhibitors (including neuromuscular blocking agents) at nicotinic receptors (neuromuscular junction and autonomic ganglia), at muscarinic receptors at postganglionic parasympathetic neuroeffector
junctions, and at esteratic receptors (on the active sites of the enzymes acetylcholinesterase and the nonspecific plasma cholinesterase). The subject, however, has become more complicated. Now, additional nicotinic and muscarinic cholinergic receptors modulating catecholamine release at peripheral adrenergic nerve terminals are well-known? Furthermore, two different types of cholinergic receptors are now postulated to be involved with transmission in sympathetic ganglia, one (the so-called Mereceptor) promoting slow depolarization of ganglion cells (a facilitatory pathway) and one (the Mi receptor) subserving transmission within an inhibitory p a t h ~ a y .Both ~ pancuronium and gallamine are now known to produce their side effects (tachycardia and increased blood pressure) by not only inhibiting muscarinic receptors in the sinus node of the heart4. (the “vagolytic” effect), but also by inhibiting the Mi receptors3 and the muscarinic receptors on adrenergic neuron terminals described above?. The latter actions in effect “facilitate” sympathetic nervous system activity and increase catecholamine release. The preceding remarks highlight only a few of many new facets of the currently broadening pharmacology of neuromuscular blockers, including pancuronium. Note especially that all of pancuronium’s effects in the peripheral autonomic nervous system involve blockade of muscarinic receptors. It is true that the neuromuscular junction is classified as a nicotinic site, and that, indeed, pancuronium is a potent neuromuscular blocker; but its effects at other nicotinic sites (such as ganglia) are minimal.5 It is, therefore, not a classic nicotinic blocker like d-tubocurarine. In contrast, the latter drug, and its derivative, metocurine, produce their autonomic effects by blockade of nicotinic receptors (the ganglion-blocking action)? They have very little effect on muscarinic receptors. NonANESTHESIA AND ANALGESIA VOI 58, NO6. NOV-DW1979
449
EDITORIAL
&polarizing neuromuscular blockers, therefore, fall into two classes according to their preponderance of either nicotinic or muscarinic side effects in the peripheral autonomic nervous system. In fact, the cholinergic receptors at the neuromuscular junction should probably not be labeled "nicotinic," but should receive separate classification. What about the central nervous system (CNS)? Certainly many cholinergic pathways, subserving a variety of behavioral functions such as memory and learning, temperature control, appetite, aggression, and, especially pertinent to this discussion, sleep, have been described within the brain.'. Both nicotinic and muscarinic pathways probably do exist." Therefore, neuromuscular blocking drugs might affect some of these circuits provided that they could enter the CNS in great enough concentration. Pancuronium, since it has been shown to inhibit muscarinic receptors at several sites within the peripheral autonomic nervous system, might presumably act on this type receptor within the CNS. Matteo's work". l2 certainly shows that relatively low concentrations of d-tubocurarine can be detected within the spinal fluid of man after ordinary clinical doses given intravenously. Although not yet demonstrated, the same might be true for pancuronium. Therefore, we might assume that enough pancuronium might reach cholinergic receptors in the brain to exert a measurable influence on certain behavioral patterns subserved by cholinergic pathways, including sleep. Sleep, of course, is not anesthesia; and general anesthetics have a global influence on the brain, do not act specifically on any receptor type, and, therefore, do not preferentially affect any cerebral function, although some evidence does suggest that one important action of general anesthetics may be an inhibition of the ascending reticular formation, an area responsible for maintenance of wakefulness.l3*'' However, agents promoting sleep, such as thiopental and diazepam, are commonly used to supplement general anesthetics. If pancuronium blocks muscarinic receptors in the CNS, then, in order to lower MAC as suggested by Forbes et all it might act on muscarinic receptors in the ascending reticular activating system, which involves cholinergic path~ays.'~-''This system, when activated, produces an arousal response mimicked by cholinergic antagonists and by anticholinesterases." Inhibition of this pathway by a specific antagonist (pancuronium?) might lead to supplementation of a sleep-influence and in turn a lowering of MAC. The foregoing discussion is admittedly grossly
450
ANESTHESIA AND ANALGESIA Vol 58, No 6, Nov-Dec 1979
oversimplified. There are many cholinergic pathways within the brain, and probably many different cholinergic receptor types modulating transmission along a variety of other routes (eg., adrenergic, gabaminergic, etc.). It is difficult to imagine that a muscarinic antagonist such as pancuronium might lower MAC by an action on only one pathway. Rather, the end-result probably represents a complex algebraic sum of inhibitory effects of pancuronium on many muscarinic receptors in a large number of cerebral circuits. The observation that a neuromuscular blocking drug which blocks muscarinic receptors may augment general anesthesia is novel but does seem plausible and, of course, needs further substantiation. The novelty of the subject raises several questions. For example, will other neuromuscular blockers have the same effect on MAC as pancuronium? Gallamine, another muscarinic inhibitor, might indeed have a similar effect; but the nicotinic blockers, d-tubocurarine and metocurine, and the nicotinic and muscarinic stimulant, succinylcholine, might interact in an entirely different fashion. If pancuronium lowers MAC, why do neuromuscular blockers, when injected directly intraventricularly, cause convulsions? Do the observations of Forbes et all have any clinical significance? Answers to these questions may not be apparent for several years, but it is possible that an improved knowledge of the CNS effects of neuromuscular blockers may lead to a better understanding of the state of general anesthesia and to an improvement of our clinical practice. John J. Savarese, MD Associate Professor of Anesthesia Harvard Medical School at Massachusetts Genera1 Hospital Boston, Massachusetts 02114 REFERENCES 1. Forbes AR, Cohen NH, Eger El 11: Pancuronium reduces halo-
thane requirement in man. Anesth Analg 58497-499, 1979 2. Langer SA: Presynaptic regulation of catecholamine release.
Biochem Pharmacol231793-1800,1974. 3. Gardier RW, Tsevdos EJ, JacksonDB: Effects of gallamine and pancuronium on inhibitory transmission in cat sympathetic ganglia. J Pharmacol Exp Ther 20446-53,1978 4. Saxena PR,Bonta IL: Mechanism of selective cardiac vagolytic action of pancuronium bromide: specific blockade of cardiac muscarinic receptors. Eur J Pharmacol 11:332-336, 1970 5. Hughes R, Chapple D: Effects of non-depolarizing neuromuscular blocking agents on peripheral autonomic mechanisms in cats. Br J Anaesth 4859-67, 1976 6. Vercruysse P,Hanegreefs G, Vanhoutte PM: Influence of skeletal muscle relaxants on the prejunctional effects of acetylcholine in adrenergically-innervated blood vessels. Arch Int Pharmacodyn Ther 232350-355, 1978
EDITORIAL 7. Savarese J J The autonomic margin of safety of metocurhe and
d-tubocurarine in the cat. Anesthesiology 50:40-%,19!79 8. Jouvet M: Cholinergic mechanisms and sleep, in Cholinergic Mechanisms. Edited by PG Waser. New York, Raven Press,
tubocurarine concentration to neuromuxular blockade in man. Anesthesiology 41:440-443,1974 13. Brazier MAB: Some effects of anesthesia on the brain. Br J
10. Domino EF, Yamamoto K,Dren AT: Role of choliner@cmech-
Anaesth 33A94-u)4,1%1 14. Magoun HW:Brain mechankms for wakefulness. Br J Anaesth 33163-193,1961 15. Shute CCD, Lewis PR: Cholinesterase containing systems of the brain of the rat. Nature 19ik1160-1161,1963 16. Shute CCD, Lewis PR:Cholinergic and monoaminergicsystems
anisms in states of wakefulness and sleep. Prog Brain Res 28: 113-133,1968 11. Matteo RS, Pua EK, Khambatta HJ,et ak Cerebrospinal fluid levels of d-tubocurarine in man. Anesthesiology 46:396-399,
17. Shute CCD, Lewis PR: The ascending choliergic reticular system: newortical, olfactoq and subcortical projections. Brain 90:497-520,1%7
1975 9. Karczmar AG: Cholinergic influences on behavior, in Cholin-
ergic Mechanisms. Edited by PG Waser. New York, Raven
Press,1975
1977
12. Matteo RS, Spector 5, Horowik
PE: Relation of serum d-
of the brain. Nature 212:7lO-n1,1%6
IS. Morgane 0 Chemical mapping of hypnogenic and arousal systems in the brain. Psychophysiology 6219-225,1969
Prqxrative Pulmonary Preparation A group of 157 patients with chronic obstructive pulmonary disease who were treated before surgery, using a standardized pulmonary preparation, underwent physiologic assessment both before and after the prophylactic program. The postoperative course of each patient also was evaluated to assess the incidence of respiratory morbidity and mortality. Although many physiologic values were statisticallyimproved after the pulmonary preparation, most of the changes are of doubtful functional significance. It is difficult to detennine which patients will develop pulmonary complications not requiring mechanical ventilation. However, the group requiring this type of support appears to be predictable on the basis of the severity of their pulmonary functional impairment and their lack of response to the standard pulmonary preparation used. The single most reliable test for this purpose was the mean forced expiratory flow during the middle half of the forced vital capacity. The frequency of postoperative respiratory complications was related to the type of operation, with the highest incidence occurring in the group that had extensive surgery of the upper abdomen. While the occurrence of these complications was significantly reduced in patients undergoing a standard preoperative pulmonary preparation, the explanation for the beneficial effect of this procedure is not apparent. (Gracey OR, Divertie MB, Didier ER- Preoperativepulmonary preparation ofpatients with chronic obstructive pulmonary disease: a prospective study. Chest 76:IW-129,1979)
ANESTHESIA AND ANALQESIA VOI 58, NO 6, NW-Dec 1979
451
