THE INFLUENCE OF DIFFERENT ANAESTHETIC AGENTS ON THE RESPONSE TO RESPIRATORY TRACT IRRITATION

Transcription

1 Brit. J. Anaesth. (1962), 34, 804 THE INLUENCE O DIERENT ANAESTHETIC AGENTS ON THE RESPONSE TO RESPIRATORY TRACT IRRITATION BY G. A. HARRISON* Department of Anaesthetics, Welsh National School of edicine, Cardiff, Wales SUARY A method is described for comparing the duration of active respiratory responses to irritation of the respiratory tract during anaesthesia with different agents. The reflex responses were more prolonged with cyclopropane and thiopentone than with nitrous oxide alone or halothane with nitrous oxide. Each agent was administered to five patients. Atropine sulphate 1.2 mg given intravenously in five cases before stimulation, failed to modify the responses during cyclopropane anaesthesia. The differences in the durations of response are unexplained. It is suggested that they are determined by the strength and duration of the stimulus, and by the effect of the anaesthetic agent on the sensitivities of the reflex arc and the respiratory centre. During anaesthesia stimuli occurring in the respiratory tract or site of operation may lead to a variety of reactions in which the laryngeal muscles are involved. Laryngeal spasm, coughing and breath-holding are the commonest sequelae of these stimuli. Over the years a clinical impression has been formed by anaesthetists that during light anaesthesia with cyclopropane or thiopentone stimulation of the respiratory tract is likely to cause marked and persistent episodes of coughing or laryngeal spasm whereas with nitrous oxide or halothane these responses are likely to be of short duration. As clinical impressions may be misleading, this investigation was undertaken to compare five commonly used agents (cyclopropane, diethyl ether, halothane, nitrous oxide alone, and thiopentone) with respect to the duration of response following irritation of the respiratory tract under controlled conditions. In addition a study was made of the effect on the response of atropine administered intravenously. ETHOD O STUDY In each subject the basic procedure was to stimulate the respiratory tract with cigarette smoke. The duration of coughing, laryngeal spasm or breath-holding following the stimulus was mea- * At present at the Department of Anesthesia, Western Reserve University, Cleveland, Ohio. sured from a graph of the patient's ventilation. By applying the stimulus at a level of anaesthesia which was approximately the same for all patients it was possible to compare the responses when different anaesthetic agents were used. The patients. The series consisted of thirty patients aged between and 50 years. Within these age groups in the conscious subject the response to stimulation of the respiratory tract is comparable (Pontoppidan and Beecher, 1960). All were free of cardiovascular and respiratory disease and did not smoke more than twenty cigarettes per day; the smoking habit of each patient was noted. Premedication. Hyoscine 0.4 mg was administered subcutaneously to each patient 1 to 2 hours pre-operatively. This drug was employed for its antisialogogue and amnesic actions while sedatives and hypnotics which might affect the laryngeal reflexes or pulmonary ventilation were not used. Anaesthetic agents. Twenty-five of the thirty patients were allotted at random to five groups, each group being anaesthetized by one of the five agents under investigation (cyclopropane, di-ethyl ether, halothane, nitrous oxide and thiopentone). A further five 804

2 RESPONSE TO RESPIRATORY TRACT IRRITATION 805 patients were anaesthetized with cyclopropane but atropine sulphate 1.2 mg was administered intravenously 2 minutes before induction. The long duration of the response to irritation during cyclopropane anaesthesia alone made it possible to assess any clinical value which atropine might possess in modifying the laryngeal reflexes. ethods of administration. Nitrous oxide and oxygen. Induction was begun with 100 per cent nitrous oxide until the patient failed to obey commands, when 25 per cent oxygen was administered. The stimulus was not applied until oxygenation was clinically satisfactory. Nitrous oxide, oxygen and halothane. Induction was commenced as above with nitrous oxide and oxygen. Halothane 0.5 per cent was then administered from a luotec vaporizer. Nitrous oxide, oxygen and ether. ollowing induction with nitrous oxide and oxygen, ether was administered from the ether bottle of a Boyle machine. The lever was gradually advanced to the fourth mark on the scale but the plunger was not depressed. Thiopentone, nitrous oxide and oxygen. 2.5 per cent thiopentone 4.7 mg/kg was injected intravenously and when the patient became unconscious 25 per cent oxygen and 75 per cent nitrous oxide were given. With each of the above techniques administration of the inhalational agents was by a facepiece attached to a non-rebreathing system with a Ruben valve. The fresh gas flow was sufficient to prevent the reservoir bag from collapsing. Cyclopropane and oxygen. Induction was begun with cyclopropane and oxygen with a facepiece attached to a Coxeter-ushin circle absorber. ive hundred millilitres per minute of each were delivered through the Rotameters. resh soda lime was used for each case. Level of anaesthesia. The stimulus was applied after the patient had lost consciousness as shown by the lack of response to the spoken word but at a depth lighter than that usually classified as surgical anaesthesia (Guedel, 1954). The presence of an active lid reflex, spontaneous limb movements or roving eyeballs was accepted as a satisfactory indication of the level of anaesthesia for the experimental conditions. The stimulus. A single puff of cigarette smoke was delivered during inspiration through a small side tube close to the facepiece. Smoke was chosen as being a transient, non-injurious stimulus which was reasonably constant for each case. easurement of the duration of response. A pneumotachometer was incorporated between the facepiece and the Ruben valve or the T- junction (when the circle absorber was used) and the respiratory flows were recorded by a pen on graph paper. The duration of response was measured from the beginning of the last normal inspiration to the end of the second expiration of normal characteristics. Expiration was chosen as the end point, as in some cases apparently normal inspirations were accompanied by grossly abnormal expiratory patterns suggesting partial laryngeal closure or coughing. It was necessary to have two consecutive normal respirations because a single breath was sometimes followed by a renewed bout of coughing, breath-holding or stridor. The tidal volume and respiratory rate were recorded immediately before stimulation. RESULTS (TABLE i) Nitrous oxide and oxygen. The durations of response were, 15,, 13 and 19 seconds respectively. Transient episodes of coughing, breath-holding or stridor occurred with this agent. Before stimulation the tidal volume was large and respiratory rate high, features which were not seen with the other agents in this series. As all the patients were well oxygenated clinically, this high minute volume could not be ascribed to anoxic stimulation of the aortic and carotid chemoreceptors. Similar observations with respect to the pulmonary ventilation during nitrous oxide and oxygen anaesthesia were made by Eckenhoff and Helrich (1958). Nitrous oxide, oxygen and halothane. The durations of response were 19, 15,, 15 and 15 seconds respectively. In figure 1 the graph obtained from Case No. 27 is shown. As with those cases receiving nitrous oxide and oxygen only, the respiration quickly returned to a normal pattern following a few coughs or a short period of breathholding or transient stridor. The tidal volume in

3 TABLE I To show the durations of responses following irritation of the respiratory tract using a transient noninjurious stimulus in patients anaesthetized as indicated. Anaesthesia Case number Age in years Sex Smoking habits Tidal volume before stimulation (ml) Respiratory rate before stimulation (per min.) Duration of response (sec.) Nitrous oxide and oxygen Nitrous oxide, oxygen and halothane Nitrous oxide, oxygen and diethyl ether Thiopentone, nitrous oxide and oxygen Cyclopropane and oxygen Cyclopropane and oxygen after receiving atropine sulphate 1.2 mg intravenously as ' IS Exp IG. 1 Change in respiratory flow pattern in Case No. 27. Patient anaesthetized with nitrous oxide, oxygen and halothane. Duration of response measured from A to B.

4 RESPONSE TO RESPIRATORY TRACT IRRITATION 807 each patient before stimulation was much lower than that with nitrous oxide. Nitrous oxide, oxygen and ether. The durations of response were 48, 33, 42, 50 and 72 seconds respectively (table I). It is doubtful if these figures for ether are comparable with those obtained with the other agents because spontaneous reactions of coughing, laryngospasm and breathholding were frequent. An increase in the inhaled concentration or a sudden deep breath by the patient were particularly likely to precipitate these responses. The tidal volume varied greatly from breath to breath and the respiratory rate from moment to moment, therefore figures for these are not included as they are for the other agents with which the tidal volume and respiratory rate became reasonably constant following induction. Thiopentone, nitrous oxide and oxygen. When induction was carried out with thiopentone the durations of response were 62,, 70, 86 and 47 seconds respectively. As the duration of response in general was longer than that with nitrous oxide or halothane the changes which occurred in the respiratory flow pattern after stimulation were better seen. In Cases Nos. 1, 8, 22 and 25 breath-holding and laryngeal spasm followed the stimulus, whereas in Case No. 15 there was breath-holding and coughing. The tidal volumes varied but were smaller than those with nitrous oxide and similar to those occurring with halothane. Cyclopropane and oxygen. In the case of cyclopropane and oxygen the durations of response were 53, 100, 114, 70 and 87 seconds (table I). However, in Cases No. 12 and 13 thiopentone was administered in a dose sufficient to abolish the response. One of these (Case No. 12) at 100 seconds still had persistent laryngospasm, and at 114 seconds the other (Case No. 13) was still coughing and breath-holding. In the remaining cases the responses were a mixture of breath-holding, laryngeal spasm and coughing. The tidal volumes before stimulation were very variable. Cyclopropane, oxygen and atropine sulphate. In those patients to whom atropine sulphate 1.2 mg was given intravenously 2 to 5 minutes before induction with cyclopropane the durations of response were 57, 105, 80, 1 and 37 seconds. As with cyclopropane, two cases (Cases No. 6 and 23) received thiopentone to abolish persistent responses (at 105 and 1 seconds respectively). The administration of atropine appeared to produce no alteration in the response to stimulation of the respiratory tract in light cyclopropane anaesthesia. DISCUSSION In this series, following irritation of the respiratory tract at a level of anaesthesia at which the reflexes are considered to be most active, a marked difference was found in the duration of laryngeal spasm, coughing and breath-holding with different anaesthetic agents (fig. 2). The period for which these responses persist depends on the strength and length of time of application of the stimulus as well as the depth and type of anaesthesia. Other authors (Dripps and Severinghaus, 1955; Evans, 1954; Galley, 1943; Guedel, 1954) have noted an apparent difference in the activity of the laryngeal reflexes with different anaesthetic agents and most anaesthetists have seen the prolonged episodes of laryngeal spasm or coughing which may occur during light cyclopropane or thiopentone anaesthesia. On the other hand, halothane has achieved a favourable reputation for the infrequent occurrence of these complications. By using a relatively constant stimulus it was possible to compare quantitatively the agents under investigation, and the results tend to substantiate the clinical impression that for a given stimulus the duration of response is longest with cyclopropane; then follow thiopentone, ether, halothane and nitrous oxide, and nitrous oxide alone, in decreasing order of duration. Atropine sulphate 1.2 mg administered intravenously to five patients did not modify the response when cyclopropane was the anaesthetic used. Burstein and Rovenstine (1938) found in cats that atropine sulphate given during artificially induced laryngeal spasm caused relaxation of the vocal cords. urtagh and Campbell (1954), however, pointed out that on anatomical grounds atropine is unlikely to prevent laryngeal spasm by a peripheral blockade of the parasympathetic postganglionic fibres and Rosen (1960) suggested that the results found by Burstein and Rovenstine

5 BRITISH JOURNAL O ANAESTHESIA might be due to a profound central depression of the reflex arc by the large doses of atropine used. The results in this series suggest that atropine in a dose (1.2 mg) commonly used during anaesthesia does not prevent laryngeal spasm. The reason for the differences in the duration of response with the anaesthetic agents studied is unknown. Table II shows some of the possible factors which may be involved. Sensitivity of the reflex arc. The afferent and efferent pathways of these reflexes in the vagus nerve are not significantly depressed by general anaesthesia (Horita and Dille, 1955). Depression or abolition of the response to stimulation of the respiratory tract appears to be caused by the action of the anaesthetic agent on more centrally placed pathways. Clinically, however, it seems that the respiratory tract is hypersensitive to stimuli during light anaesthesia especially with cyclopropane and thiopentone. If it occurs this sensitivity might be present in the peripheral afferent nerve endings in a similar fashion to that in the stretch receptors during general anaesthesia (Whitteridge and Biilbring, 1946). There appear to have been no studies of TABLE II The possible factors affecting the duration of response of the respiratory reflexes (see text) actors increasing duration of response following stimulation of the respiratory reflexes (a) A prolonged or intense stimulus (b) Peripheral or central increase in sensitivity of the reflex arc (c) Depression of the respiratory centre to carbon dioxide and afferent stimuli id) A decreased number of afferent stimuli to the respiratory centre (e) Hypoxic depression of respiratory centre actors decreasing duration of response following stimulation of the respiratory reflexes (a) A transient or mild stimulus (b) Peripheral or central depression of the reflex arc (c) Sensitivity of the respiratory centre to carbon dioxide and afferent stimuli (rf) An increased number of afferent stimuli to the respiratory centre (e) An elevated blood carbon dioxide tension NITROUS OX IOC OXYCEN NITROUS OXIDE HALOTHANE NITROUS OXIDE DIETHYL ETHER THIOPENTONE NITROUS OXIDE * ' I II? " ' "' 'in 11Vf CYCLOPROPANE lyiyi'i'.' 1 i i,,, i. 7,1 CYCLOPROPANE ATROPINE- SULPHATE IV 1 1, I h, > : : - - i 2O «O SO SO IOO DURATION O RESPONSE SECONDS IG. 2 A comparison of the observed durations of response following irritation of the respiratory tract. Each shaded rectangle represents the response of one patient.

6 RESPONSE TO RESPIRATORY TRACT IRRITATION 809 changes in the threshold of the laryngeal reflexes in light anaesthesia and this investigation gives no information on the point because of the constant nature of the stimulus. A second possible site of increased sensitivity of the reflex arc is the pathway between the afferent vagal nucleus of the solitary tract and the efferent vagal nucleus ambiguus (fig. 3). Unfortunately the exact connections between these nuclei are uncertain and the precise effect of general anaesthesia on these central relays is unknown. RESPIRATORY TRACT N "X LARYNGEAL USCLES IG. 3 A simplified diagram of the arc of the laryngeal reflexes. The influence of the respiratory centre on the laryngeal reflexes. Normally the movements of the vocal cords are closely related to the phase of respiration, some degree of abduction occurring during inspiration and some degree of adduction during expiration (Green and Neil, 1955). An increased depth of respiration increases the amount of movement of the vocal cords while a decreased depth has the opposite effect. In a conscious'subject during breathholding the vocal cords cannot be held closed voluntarily once the urge to breathe becomes strong (Pressman and Kelemen, 1955). So powerful is the influence of the respiratory centre on the laryngeal reflexes that some anaesthetists administer carbon dioxide to prevent coughing or laryngospasm during laryngoscopy and endotracheal intubation in light planes of anaesthesia. It is possible that the variable duration of laryngeal spasm, etc., with different anaesthetic agents is due to a dissimilar degree of depression of the respiratory centre with each agent. Thus, theoretically, laryngeal spasm and associated effects would be prolonged with an agent which produces depression of the respiratory centre to its normal chemical and afferent nervous stimuli, in a plane of anaesthesia in which there is little depression of the appropriate reflex arc. On the other hand, with an agent which does not depress the respiratory centre at light levels of anaesthesia, the mounting carbon dioxide tension of arterial blood would stimulate respiration and cause abduction of the vocal cords and interruption of the reflex response of laryngeal spasm, coughing, and breath-holding. In general, deepening anaesthesia is associated with a diminished ventilatory response to carbon dioxide (Bellville and Seed, 1960; Dripps and Dumke, 1943; Dripps and Severinghaus, 1955). Studies in man of the response to carbon dioxide with individual anaesthetic agents include nitrous oxide and thiopentone (Eckenhoff and Helrich, 1958), nitrous oxide, oxygen and ether (Ridley and aulconer, 1952), ether and thiopentone (Patrick and aulconer, 1952), halothane (Devine, Hamilton and Pittinger, 1958), and cyclopropane and ether (Cobb, Converse and Landmesser, 1958). It is well known that cyclopropane and thiopentone cause marked respiratory depression in deeper levels of anaesthesia but evidence from the authors mentioned suggests that in light levels of anaesthesia the response to carbon dioxide is very little altered by any of the agents investigated in this series. However, before the sensitivity of the respiratory centre can be excluded as an important factor in the variations in the duration of the laryngeal reflexes, further investigation is necessary into the activity of the centre in the level of anaesthesia where these reflexes are most active. The only constant feature of the ventilation of the patients in this series was the high minute volume in those anaesthetized with nitrous oxide. The influence of afferent stimuli on the respiratory centre and laryngeal reflexes. Anaesthetic agents may alter ventilation by actions other than their direct effect on the respiratory centre. An agent which decreased the number of stimuli to the respiratory centre from the peripheral afferent nerves might theoretically

7 810 BRITISH JOURNAL O ANAESTHESIA increase the duration of the laryngeal reflex response whereas an agent which increased the number of such stimuli would shorten the response. Some of the sites of afferent stimuli which may be affected differently by anaesthetic agents can be considered. Chemoreceptors. Normally any anoxic drive to the respiratory centre is derived from the chemoreceptors in the carotid and aortic bodies, the effect of anoxia on the centre being depressant. In animals the sensitivity of the chemoreceptors during anaesthesia has been investigated by lowering the inspired concentration of oxygen or by stimulation with lobeline or cyanide. Dripps and Dumke (1943) found that ether and cyclopropane depressed chemoreceptor activity but morphine or thiopentone did not. arshall and Rosenfield (1936) reported that the receptors were active with morphine and pentobarbitone. Schmidt (1940) also discussed the action of morphine and ether. The importance of these reflexes in man during anaesthesia is uncertain although the receptors are probably not normally very sensitive to changes in the oxygen tension of the blood (Wylie and Churchill-Davidson, 1960). If a decreased sensitivity of the receptors exists during anaesthesia with cyclopropane, the high concentration of oxygen commonly used with this agent may have some significance in the duration of the laryngeal responses although it is a clinical impression that the laryngeal spasm and coughing are most prolonged in the presence of preceding anoxia. Pulmonary stretch receptors. In the cat there is a change in the sensitivity of these receptors during anaesthesia (Whitteridge and Biilbring, 1946). However, the increased sensitivity during inflation was approximately the same with all the anaesthetic agents investigated and for the deflation receptors only ether and trichloroethylene were studied. No conclusion can be drawn as to the importance of the stretch receptors in the laryngeal reflexes. Trachea. In animals, respiratory changes initiated by pressure changes in the trachea such as might occur during coughing or laryngeal spasm have been described (Widdicombe, 1954; Dripps and Severinghaus, 1955). The latter found a difference in the effects of ether and cyclopropane on the response. The effects of other anaesthetic agents do not appear to have been investigated. uscle spindles. Nunn and Ezi-Ashi (1961) have described a rapid ventilatory compensation to inspiratory and expiratory resistance by augmentation of inspiratory effort. They suggested that the explanation for this response to respiratory obstruction might be found in the muscle spindles of the respiratory muscles. The effect of different anaesthetic agents on this reflex is uncertain but it may be of importance in influencing the duration of the laryngeal reflexes. ACKNOWLEDGENTS I wish to thank Professor William W. ushin for his encouragement and criticism during the preparation of this paper. y thanks are also due to W. W. apleson, Ph.D., for many valuable theoretical discussions, and to r. B. K. Hillard, Senior Technician to this Department, for his technical assistance and help in the preparation of the illustrations. REERENCES Bellville, J. W., and Seed, J. C. (1960). The effect of drugs on the respiratory response to carbon dioxide. Anesthesiology, 21, 727. Burstein, C. L., and Rovenstine, E. A. (1938). Respiratory action of some shorter acting barbituric acid derivatives. /. Pharmacol, exp. Ther., 63, 43. Cobb, S., Converse, J., and Landmesser, C.. (1958). Respiratory responses to carbon dioxide transients during ether and cyclopropane anesthesia. Anesthesiology, 19, 359. Devine, J. C, Hamilton, W. K., and Pittinger, C B. (1958). Respiratory studies in man during luothane anesthesia. Anesthesiology, 19, 11. Dripps, R. D., and Dumke, P. R. (1943). The effect of narcotics on the balance between central and ' chemoreceptor control of respiration. J. Pharmacol, exp. Ther., 77, 290. Severinghaus, J. W. (1955). General anesthesia and respiration. Physiol. Rev., 35, 741. Eckenhoff, J. E., and Helrich,. (1958). The effect of narcotics, thiopental and nitrous oxide upon respiration and respiratory response to hypercapnia. Anesthesiology, 19, 240. Evans.. T. (1954). odern Practice in Anaesthesia, 2nd ed., p London: Butterworth. Galley, A. H. (1943). Trichlorethylene anaesthesia by the single dose method. Proc. roy. Soc. ed., 36, 462. Green, J. H., and Neil, E. (1955). The respiratory function of the laryngeal muscles. /. Physiol, 129, 134. Guedel, A. E. (1954). Inhalational Anesthesia, 2nd ed., p. 84. New York: acmillan. Horita, A., and Diile, J.. (1955). Observations on the action of thiopental (pentothal) on the laryngeal reflex. Anesthesiology,, 848. arshall, E. K., and Rosenfield,. (1936). Depression of respiration by oxygen. J. Pharmacol, exp. Ther., 57, 437.

8 RESPONSE TO RESPIRATORY TRACT IRRITATION 811 urtagh, J. A., and Campbell, C. J. (1954). Laryngeal spasm. Laryngoscope, 64, 154. Nunn, J.., and Ezi-Ashi, T. I. (1961). The respiratory effects of resistance to breathing in anesthetized man. Anesthesiology, 22, 174. Patrick, R. T., and aulconer, A. (1952). Respiratory studies during anesthesia with ether and with Pentothal sodium. Anesthesiology, 13, 252. Pontoppidan, H., and Beecher, H. (1960). Progressive loss of protective reflexes in the airway with the advance of age. /. Amer. ed. Ass., 174, 29. Pressman, J. J.. and Kelemen, G. (1955). Physiology of the larynx. Physiol. Rev., 35, 506. Ridley, R. W., and aulconer, A. (1952). Respiratory patterns during nitrous oxide, oxygen ether anesthesia. Anesihesiology, 13, 119. Rosen,. (1960). Atropine in the treatment of laryngeal spasm. Brit. J. Anaesth., 32, 190. Schmidt, C.. (1940). The effect of carotid sinus and carotid body reflexes upon respiration. Curr. Res. Anesth., 19, 261. Whitteridge, D., and Biilbring, E. (1946). Changes in the activity of pulmonary receptors in anaesthesia and their influence on respiratory behaviour. Brit, med. Bull, 4, 85. Widdicombe, J. G. (1954). Respiratory reflexes from the trachea and bronchi of the cat. J. Physiol. (Lond.), 123, 55. Wylie, W. D., and Churchill-Davidson, H. C (1960). A Practice of Anaesthesia, p. 66. London: Lloyd- Luke. SOAIRE Une methode est decrite pour la comparaison de la duree de reponses respiratoires actives a l'irritation des voies respiratoires pendant l'anesthesie avec des substances variees. Les reponses reflexes etaient plus prolongees avec le cyclopropane et la thiopentone qu'avec le protoxyde d'azote seul ou le halothane avec du protoxyde d'azote. Chacune des substances fut administree a 5 malades. 1, 2 mg de sulfate d'atropine administres par la voie intraveineuse a 5 sujets avant la stimulation ne put modifier les reactions au cours de l'anesthesie au cyclopropane. Les differences dans les durees de reaction restent inexpliquees. On avance la suggestion qu'elles sont dues a la force et la duree du stimulus, et a l'effet de l'agent anesthesique sur la sensibilite de l'arc reflexe et le centre respiratoire. ZUSAENASSUNG Eine ethode zum Vergleich der Dauer aktiven respiratorischen Ansprechens auf Reizung der Atemwege wahrend der Narkose durch verschiedene ittel wird beschrieben. Bei Zyklopropan und Thiopenton blieb die Reftexerregbarkeit langer als bei Lachgas allein oder Halothan mit Lachgas erhalten. Jedes ittel wurde an 5 Patienten verabreicht. Atropinsulfat 1, 2 mg, das in 5 allen intravenos vor Stimulierung gegeben wurde, anderte die Erregbarkeit wahrend der Zyklopropannarkose nicht. Die Unterschiede in der Dauer der Erregbarkeit bleiben unerklart. Es wird angedeutet, dass sie durch die Starke und Dauer des Reizes bestimmt werden, ferner durch den Effekt des Narkosemittels auf die Empfindlichkeit des Reflexbogens und des Atemzentrums.