Pharmac. 1"her. B, Vol. 2, pp. 463-469, 1976. Pergamon Press.
Printed in Great Britain
Specialist Subject Editor: J. WIDDICOMBE
H. GAUTIER and J. VINCENT Laboratoire de Physiologie, Facult~ de M~decine Saint -Antoine, 75012 Paris, France
1. INTRODUCTION Muscle relaxants, especially paralyzing agents, are used extensively in anesthesiology in order to provide convenient muscular relaxation during surgical procedures by blocking neuromuscular transmission (see Foldes, 1957; Feldman, 1973). Without the help of such paralyzing drugs, very deep anesthesia would be required to obtain the same relaxation. Other non-paralyzing muscle relaxants are commonly given to depress the generalized muscle hyperactivity of rigidity and spasticity or to reduce localized contractions and muscle spasms. These substances, which do not normally affect motor end-plate transmission, may act at several sites of the motor pathway, i.e. on supra-spinal structures, spinal neurons or interneurons, 3,-motoneuron system or muscle spindle activity. They are often called central m u s c l e r e l a x a n t s as opposed to the peripheral action of the paralyzing agents. The paralyzing muscle relaxants may obviously interfere with the contraction of the respiratory muscles and gas exchanges whereas central muscle relaxants are normally devoid of any effect on breathing when given at normal dosages. Nowadays, controlled or assisted ventilation is commonly used or is at hand during surgical procedures when paralyzing drugs are employed, but this was not the case when curare-like agents were originally used during anesthesia in man (Griffith and Johnson, 1942). This review will deal mainly with the effects of muscle relaxants, especially paralyzing agents, on breathing. In addition, possible ventilatory effects of muscle relaxants which do not normally act on the motor end-plate will be briefly described. Finally, the use of several muscle relaxants in respiratory physiology will be described as they have helped investigators in the understanding of some particular problems. 2. EFFECTS OF M U S C L E RELAXANTS ON RESPIRATORY AND NON-RESPIRATORY MUSCLES When a drug which interferes with neuromuscular transmission is used, muscles of limbs, neck and trunk are involved before intercostal muscles, and ultimately the diaphragm is paralyzed. Recovery of muscle activity usually occurs in the reverse order to that of their paralysis so that the diaphragm is ordinarily the first to regain function (Goodman and Gilman, 1970). This observation is very important when one considers the use of relaxants during anesthesia since the ideal blocking agent, when given in a convenient dosage, would act selectively on non-respiratory muscles but would relatively spare respiratory muscles. This would allow muscle relaxation to be produced without large impairment of spontaneous ventilation. The purpose of several studies was to evaluate precisely the effects of muscle relaxants on respiratory and non-respiratory muscles. In 1951, Paton and Zaimis demonstrated that, in the anesthetized cat, decamethonium depressed limb muscle activity before that of respiratory muscles. Several authors have compared the effects of paralyzing drugs on respiratory and non-respiratory muscle activity in awake man. The effects of the blocking agents were assessed from the study of several respiratory variables such as vital capacity (Unna and Pelikan, 1951; Bodman, 1952; Foldes et al., 1961; Foldes, 1967; Rigg et al., 1970), respiratory airflows and pressures (Bodman, 1952; Johansen et al., 1964) or ventilation and alveolar carbon dioxide tension when the 463
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subject breathed air or mixtures containing carbon dioxide (Bellville et al., 1964; Asmussen et al., 1965; Rigg et ai., 1970). The activity of the non-respiratory muscles was assessed from the study of voluntary hand-grip strength. In addition, Johansen et al. (1964) measured the strength of head lift, because it is often stated empirically by anesthesiologists that the ability to lift the head owing to the recovery from paralysis of the neck muscles indicated that the subject had regained enough muscle power to maintain adequate ventilation after anesthesia. In any case, following major operations the patient is placed in a recovery room to record his vital signs including respiratory ones. All the above reports are in agreement and show that hand-grip strength is more depressed than respiratory variables by paralyzing agents. Thus, when the hand-grip strength was decreased by 80-90 per cent, the respiratory values were decreased only by 30-50 per cent. The same conclusion can be drawn from a review by Grob (1967) on motor end-plate blocking agents. In addition, for a given dose of a curarizing drug, the power in head-lift was always more affected than the hand-grip strength (Johansen et al., 1964). When the hand-grip strength was reduced by 55-94 per cent and the vital capacity was reduced by only 14-34 per cent, the ventilatory response to increasing concentrations of carbon dioxide was very little affected (Bellville et al., 1964; Rigg et al., 1970). On the other hand, as will be described below, with a partial curarization in man with a resulting reduction of hand-grip strength by 30-40 per cent, the ventilatory response to exercise is not reduced; it is even significantly increased (Asmussen et al., 1965). The reason for this increase will be described below. These converging results indicate that relaxation of non-respiratory muscles can be achieved when the respiratory activity is only slightly affected. However, it should be mentioned that the foregoing experiments were carried out in awake subjects and the differences observed between respiratory and non-respiratory muscles may not be so apparent when the subject is under anesthesia during which the possible depressant effect of many anesthetic drugs is added to the depressant effect of the paralyzing agent on respiratory function. This interaction of drugs may be increased furthermore by the possible potentiation of the paralyzing action of the muscle relaxant by anesthetics such as halothane or even narcotic agents used extensively in anesthesia such as demerol or phenoperidine (see below). It has to be shown therefore whether the ventilatory functions or the response to carbon dioxide of the anesthetized subject remain the same after slight curarization. It also has to be confirmed that the doses of blocking agents used to provoke a decrease in hand-grip strength are sufficient to provide the muscular relaxation needed in surgical procedures. Finally, it should be noticed whether the effects of blocking agents have been investigated in nerve-muscle preparations. According to Ellis et al. (1952), using high doses of blocking agents, a failure in the diaphragmatic twitch response to stimulation of the phrenic nerve was seen, corresponding in every respect to the failure of the twitch response of the gastrocnemius to stimulation of the sciatic nerve. Conversely, Waud and Waud (1972), using similar preparations, concluded that the diaphragm recovers before the tibialis anterior. The differences observed in responses towards blocking agents of respiratory and non-respiratory muscles remain to be explained. Several hypotheses concerning differences in blood flow, temperature and innervation have been put forward by Johansen et al. (1964). On the other hand, Paton and Zaimis (1951) suggested different histological structures in the two groups of muscles. One has also to consider all the chemical and electrical events which take place in neuromuscular transmission and which may differ in these two groups of muscles. 3. EFFECTS OF MUSCLE RELAXANTS ON PULMONARY MECHANICS Many studies have been devoted to the effects of general anesthesia on respiratory mechanics and, in several studies, the subsequent effects of muscle relaxation have been investigated.
Muscle relaxants and breathing
A decrease of functional residual capacity is a common feature during general anesthesia using various anesthetic agents in combination with muscle relaxants (Laws, 1968; Hickey et al., 1973; Rehder et al., 1974). Several hypotheses have been put forward to explain this modification of pulmonary mechanics: gas trapping (Don et al., 1972; Rehder et al., 1974), shift to the right of the pressure-volume curve of the chest wall (Westbrook et al., 1973) and/or decrease in total compliance, the latter being due to a decrease in lung compliance without any change in chest wall compliance. Actually, the role of muscle relaxants appears negligible in the decrease of the functional residual capacity in the above studies because it has been shown that normal subjects anesthetized with thiopentone already have a decrease in functional residual capacity. The subsequent injection of muscle relaxants such as succinylcholine does not provoke any significant additional change in functional residual capacity and lung elastic properties (Westbrook et al., 1973). Likewise, the muscle relaxants do not affect the distribution of ventilation as tested by nitrogen clearance in anesthetized and paralyzed subjects (Rehder et al., 1971) nor the (zA/Q distribution (Marsh et al., 1973). It has been reported several times that curare can provoke the liberation of histamine or histamine-like substances from skeletal muscles (West, 1934; Alam et al., 1939; Comroe and Dripps, 1946; Landmesser et al., 1952) and consequently may cause an increase in airways resistance. However, the occurrence of bronchoconstriction caused by d-tubocurarine is still a matter of controversy. For instance, Westgate et al. (1962), using d-tubocurarine, observed an increase of airways resistance in only seven out of twenty-three patients free of any cardiopulmonary disease. On the other hand, Crago et al. (1972) observed a significant increase in resistance in all subjects studied. The increase was small and without clinical consequences in subjects free of bronchopulmonary disease but was quite large in patients with lung disease. In addition, Gerbershagen and Bergman (1967) did not find any modification of airways resistance in patients free of allergic disease. Nana et al. (1972), using pancuronium, did not observe any bronchoconstriction in asthmatic patients even when an acetylcholine provocation test demonstrated marked bronchial sensitivity. Furthermore, Crago et al. (1972) observed a decrease of resistance in two asthmatic patients and concluded that curare should be avoided in patients with significant airway obstruction and suggested that pancuronium is the agent of choice in this case. However, Heath (1973) reported the case of an intense bronchospasm occurring after administration of pancuronium in one asthmatic patient and questioned the harmlessness of this drug as far as the effect on airway resistances is concerned.
4. MODIFICATIONS OF THE ACTION OF M U S C L E RELAXANTS Many factors which may modify and especially enhance the neuromuscular blocking effect of muscle relaxants have been described. These factors may therefore change the duration of recovery from paralysis during which assisted ventilation will be maintained. Only a few factors will be reviewed, as they are related to the physiological state of the patient undergoing surgery, whereas other factors are related to interaction of the relaxant with other drugs or anesthetics used during surgery. 4.1. PHYSIOLOGICAL STATE OF THE PATIENT When the body temperature decreases, the paralysis produced by depolarizing agents increases, but the effects of curare or other non-depolarizing agents are antagonized by hypothermia (Feldman, 1973). Although this effect has been observed in the phrenic nerve-diaphragm preparation of the rat, and confirmed in human volunteers, its consequences are probably of little importance in the clinical use of muscle relaxants. There is a general agreement that changes in acid-base balance can modify the neuromuscular blockade caused by paralyzing agents (Payne, 1960; Katz and Wolf, 1964). Recently, Hughes (1970), recording the contraction of the gastrocnemius muscle of the cat in response to supramaximal stimulation of the sciatic nerve, observed that
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blockade by tubocurarine was significantly increased by respiratory and metabolic acidosis and was slightly reduced by respiratory and metabolic alkalosis. Corresponding disturbances in acid-base balance had opposite effects on paralysis by gallamine or suxamethonium. These different effects of pH on depolarizing and non-depolarizing agents have not been explained although it is known that alterations in pH modify the ability of plasma proteins to take up certain drugs and can also change ionization at the level of the receptors (Hughes, 1970). Although the effects of changes in pH on the action of paralyzing agents may be important in patients with acid-base disturbances such as respiratory insufficiency undergoing surgery, large changes in pH are often necessary to modify the action of relaxants and the extent of these effects, within the clinical pH range expected during normal surgery, is probably relatively small. In some pathological states, it has been reported that paralysis by relaxants may be altered; for example, patients with liver disease are sometimes resistant to curare-like drugs. Conversely, patients with kidney disease with an impairment of renal excretion of gallamine may present a prolonged paralysis (see Feldman, 1973). 4.2. INTERACTIONS WITH ANESTHETICS Several reports have indicated that non-depolarizing muscle relaxants are potentiated by volatile anesthetics such as nitrous oxide or halothane. Thus, it has been shown that when force of thumb adduction is recorded with a force-displacement transducer in response to stimulation of the ulnar nerve, smaller doses of d-tubocurarine are needed for adequate relaxation with high concentration of halothane (Miller et al., 1972). In addition, it is well known that some anesthetics like ether possess neuromuscular blocking properties of their own. Other anesthetics like thiopentone potentiate also the action of non-depolarizing blocking agents. 4.3. INTERACTIONS WITH OTHER DRUGS In addition to the obvious effects of anticholinesterases on the effects of muscle relaxants, some drugs have the property of prolonging the duration of neuromuscular block caused by relaxants. Such is the case for diazepam (see below) and antibiotics which may potentiate the effects of non-depolarizing agents. These antibiotics include streptomycin, kanamycin and neomycin (Feldman, 1973) and their effects can be antagonized by calcium (Grob, 1967). It has been reported that prolonged apnea or hypopnea can be observed following administration of paralyzing agents during surgery. In certain cases, interactions with the physiological state of the patient have been recognized but, in other cases, the mechanism of this phenomenon remains unknown. It is interesting to note that tracheal stimulation is sometimes sufficient to initiate spontaneous breathing (Utting, 1963). 5. EFFECTS OF MUSCLE RELAXANTS ON THE CENTRAL NERVOUS SYSTEM As was described previously, breathing can be affected by an action of paralyzing drugs on the respiratory muscle motor end-plates. Breathing can also be affected by drugs acting at several levels of the peripheral, spinal or supra-spinal nervous system. It has been claimed in several papers that paralyzing drugs may have, in addition to their action on the motor end-plate, a possible action on the central nervous system. These effects consist in changes in the electroencephalogram in cats which suggest an indirect hypnotic action of the drug (Feldman, 1973), although cuneate neurons are strongly excited by local application of gallamine (Galindo et al., 1968). On the other hand, rats which are conditioned lost their ability to respond after they have received a small dose of decamethonium (Feldman, 1960). It has also been shown that d-tubocurarine when injected into the carotid artery consistently changed phrenic nerve discharge in cats (Hougs, 1964). It seems therefore that muscle blocking agents may exhibit some action at various sites in the central nervous system. However,
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because of the very low permeability of the blood-brain barrier to these drugs (Cohen, 1963), high doses are needed to cross the barrier and, when these drugs are administered in ordinary clinical doses, they are virtually devoid of any central effect resulting in a depression of breathing (Feldman, 1973). Many drugs, especially the central nervous depressants, when used in relatively high doses, may cause muscle relaxation with possible respiratory impairment associated with sedative effects by an action on spinal or supra-spinal structures. This is especially the case with drugs used to diminish muscle tone such as mephenesin, diazepam and meprobamate. In an extensive review on non-paralyzing muscle relaxants it was mentioned that, when high doses are used, respiratory failure may be observed (Smith, 1965). However, with ordinary clinical dosages which produce muscular relaxation, no modification of breathing was observed with mephenesin (Berger and Bradley, 1947) or diazepam (Steen et al., 1966). On the other hand, when diazepam is used, for example in anesthesiology in association with blocking agents, it may potentiate the effect of a peripheral muscle relaxant such as the paralyzing agents.
6. USE OF MUSCLE RELAXANTS IN RESPIRATORY PHYSIOLOGY Curare has been used in studying the mechanism of the breaking point of breath holding (Campbell et al., 1967). It has been shown that prevention of contraction of the respiratory muscles by d-tubocurarine suppresses the distressing sensation associated with breath holding allowing the subject to tolerate apnea for a longer duration. This observation suggests that it is the contraction of the respiratory muscles when respiratory movements are impeded which gives rise to the unpleasant sensation associated with breath holding and forces the subject to resume breathing. The interesting observation concerning the lower sensitivity of respiratory muscles to curare and curare-like agents as opposed to non-respiratory muscles (see above) was used in man to study the regulation of breathing during muscular exercise (Asmussen et al., 1965). Tubocurarine was injected i.v. in subjects exercising on a bicycle ergometer. The doses chosen provoked a decrease in muscular contraction evaluated by repeated hand-grip strength measurements of 30-40 per cent with no changes in resting ventilation or oxygen consumption. Compared with values for control experiments performed without curarization, oxygen intake remained the same during exercise but the ventilation was increased by up to 50 per cent. By adding carbon dioxide to the inspired air, the alveolar carbon dioxide tension was maintained at its normal control level. It is therefore assumed that the known humoral factors controlling ventilation in exercise must have been normal. The greatly increased ventilation must consequently have been caused by some nervous factors although the origin of these factors, whether central or peripheral, remains unknown. The possible role of the peripheral factor will be discussed below. Several curare-like agents, especially succinylcholine and, to a lesser extent, decamethonium, when used in sub-paralytic doses can stimulate afferent activity from muscle spindles of the limbs in the cat (Granit et al., 1953). When succinylcholine is given by injections in small doses into the abdominal aorta of anesthetized cats, it immediately provokes an increase in ventilation which disappears after section of the muscular nerves or of the spinal cord at the lumbar level (Gautier et al., 1969). This reflex increase in ventilation is considered to be caused by the stimulation of afferent activity from the muscle spindles of the hindlimbs. This observation suggests that the natural stimulation of the muscle spindles during muscular exercise may account for a portion of the increase in ventilation observed during exercise, especially the abrupt augmentation noticed at the onset of exercise. This hypothesis is confirmed by observations made in dogs which received injections of another muscle relaxant 2,4di(diethylamino)-6-(2-phenylacetylhydrazino)-l,3,5-triazine (CIBA 28882-Ba), which depresses the muscle spindle activity (Bein and Fehr, 1962). The reflex hyperventilation
H. GAUTIER and J. VINCENT
c a u s e d b y p a s s i v e m o t i o n o f t h e l e g s is c o n s i d e r a b l y r e d u c e d a f t e r i n j e c t i o n o f t h i s m u s c l e r e l a x a n t ( F l a n d r o i s et al., 1967). Other effects on ventilation resulting from injection of succinylcholine are also p o s s i b l e b e c a u s e it h a s b e e n s h o w n t h a t s u c c i n y l c h o l i n e , w h e n i n j e c t e d i n t r a - a r t e r i a l l y in small doses, can stimulate the chemoreceptors o f t h e c a r o t i d b o d y ( L a n d g r e n et al., 1952).
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