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Breathing During Pentothal Anesthesia1
BREATHING DURING PENTOTHAL ANESTHESIA1 C. A. MOYER
AND
H. K. BEECHER
From Harvard University, Boston, Mass.
The convenience of intravenous anesthesia has led to the general use of pentothal sodium in spite of the fact that the anesthesia induced by it is less controllable than that induced by the volatile and gaseous agents. The use of pentothal sodium is not without danger, as attested by the deaths that have occurred during its administration. Its well known depressant effect on breathing appears to be the most dangerous immediate action of the drug. Knowledge concerning the manner by which it effects respiratory depression is a fundamental prerequisite in determining the indications for the use of pentothal and in selecting physiologically appropriate methods for dealing with severe respiratory depression when it does occur. In an attempt to provide the prerequisite knowledge, ·the action of pentothal upon the central chemical and peripheral reflex chemical control mechanisms of breathing has been studied on dogs. The effectiveness ·of the central chemical mechanism was determined by the repetitive subjection of the animal to a fixed increase in the carbon dioxide of the inspired air. Some of the stimulation of breathing that attended such a procedure may have been in part due to reflex stimulation but it is probable that the greater part of it, if not all, was the result of the action of carbon dioxide upon the respiratory center itself. The effectiveness of the peripheral chemical reflex mechanisms was determined by repetitively subjecting the animals to a fixed degree of oxygen deficiency in the inspired air. Normally, a large part of the regulation and maintenance of breathing depends upon the integrated functioning of the central chemical mechanism (regulation of breathing by carbon-dioxide) and t~e peripheral reflex chemical mechanisms (regulation of breathing by oxygen need). The central chemical seems to be the least variable and the most important of the two in both the normal dog and the normal man at low altitudes. Therefore, one of the most desirable attributes that an anesthetic could have, would be the property of producing the state of surgical anesthesia (stage III-Guedel) without seriously depressing the respiratory regulatory action of carbon dioxide. Pentothal sodium does not possess this attribute. Approximately 25 per cent (4 of 11) of the animals were found to have lost their sensitivity to carbon dioxide by the time the depth of anesthesia had reached the end of plane 22 of stage III, (the 1 Read before annual meeting, North Central Section, American Urological Association, Ann Arbor, Mich., October 25, 1941. 2 For convenience the third stage of pentothal anesthesia has been divided int o planes. These planes are not comparable to the planes of the third stage of ether anesthesia. Plane 2 designates very light "surgical" anesthesia; the corneal, lid, and tendon reflexes are very active, and the incising of the skin and the retracting of a muscle are followed by an intense respiratory stimulation. Plane 2 designates a moderate depth of anesthesia; the reflexes (lid, corneal, and t endon) are active though diminished and the respiratory stimulation that follows trauma is relatively slight. Plane 3 designates deep barbiturate anesthesia. The corneal and lid reflexes are usually absent, the tendon reflexes are present but they are very much diminished, respiratory minute volume is decreased and expiratory pauses are usually present, and surgical procedures are attended by a very little or no respiratory stimulation. 222
BREATHING DURING PENTOTHAL ANESTHESIA
223
depth of anesthesia at which a large part of major surgery is performed). The breathing of 2 animals that showed a 300 and a 600 per cent increase in minute volume of breathing when subjected to 12 per cent carbon dioxide during plane l (light anesthesia) was actually depressed by it during plane 2. Those animals that did not lose their sensitivity to carbon dioxide showed nervertheless great reductions in their reaction to carbon dioxide, but the respiratory stimulation that attended carbon dioxide inhalation was relatively satisfactory. The administration of oxygen to those animals that had lost their sensitivity to carbon dioxide produced serious depressions of breathing that were attended by a rapid rise in the carbon dioxide content of the arterial blood. This indicates, as pointed out by others for deep anesthetic states produced by other barbiturates, that breathing under pentothal anesthesia, (plane 2 or deeper) is frequently maintained by the peripheral reflex chemical control mechanisms, the aortic and carotid bodies. The effectiveness of these mechanisms was not regularly depressed by pentothal in this series of experiments. In fact, in 9 animals of the eleven, a given oxygen deficiency induced a greater percentile increase in minute volume of breathing during plane 2 than during plane l. However, since these mechanisms vary greatly in effectiveness when compared with the central chemical mechanism of the unanesthetised animal, and since they depend upon a degree of oxygen unsaturation of arterial blood for sustained action, they cannot be considered to be as physiologically adequate as the central chemical mechanism in regulating breathing at low altitudes. The frequent occurrence of cyanosis in man under pentothal anesthesia, contrasted with its infrequent occurrence during comparable depths of anesthesia induced by ether, supports this belief as cyanosis indicates anoxia, the dangers of which, are well known, to obviate this danger, oxygen is recommended. This expedient, although it relieves the cyanosis, is not without possible danger. If breathing slows appreciably when oxygen is breathed, as is to be expected when cyanosis is present, carbon dioxide will probably pile up in the body. (Derra and Korth; Beecher and Moyer.) This alone increases the respiratory depressant action of pentothal and tends to decrease cellular oxidations. This depressant effect of carbon dioxide on oxidations might well be as deleterious to the individual as the anoxia that was present when room air was breathed. Furthermore, since the well known anesthetic property of carbon dioxide is not, as far as can be determined, depressed by pentothal, the rise in carbon dioxide that occurs during the breathing of oxygen might well produce a rapidly fatal increase in depth of anesthesia without administering more pentothal. This has been noted not infrequently in experimental work (Marshall and Rosenfeld; Beecher and Moyer). It is therefore obvious that from the standpoint of respiration, pentothal sodium is not nearly as safe an agent as one that is capable of inducing surgical anesthesia without obliterating the regulatory action of carbon dioxide. Ether and- cyclopropane have this property for, as is common knowledge, carbon dioxide stimulates breathing appreciably even after complete intercostal paralysis has occurred (plane 4) when these agents are employed. These findings regarding the effects of pentothal sodium on breathing emphasize the clinical
224
C. A, MOYER AND H. K, BEECHER
limitations that should be placed upon this agent. These have been described previously (Moyer). When respiratory failure occurs during pentothal anesthesia, the administration of carbon dioxide in excess of 5 per cent and of oxygen above 40 per cent are contraindicated. Coramine, metrazol and alpha lobeline are not capable of stimulating breathing when it has failed during deep pentothal anesthesia (Mousel and Essex). The measures recommended for treating respiratory failure produced by pentothal are as follows: 1. Artificial respiration preferably by a prone pressure method. 2. The administration of 40 per cent oxygen, and 5 per cent carbon dioxide (to prevent acapnia, not to stimulate breathing) during the artificial respiration. 3. If blood pressure is low or falls rapidly during the period of artificial ventilation, epinephrin, 2-3 mins., intravenously (repeat as necessary) in order to provide a more adequate flow to the brain. Because of the serious and dangerous depressant action of pentothal sodium upon the central chemical control of breathing that becomes apparent during anesthesia of a nature roughly comparable to stage III plane 2 of ether anesthesia, it is felt that the use of pentothal in major surgery should be very restricted since there are other agents that are far safer from the standpoint of respiration. However, the dangers that attend surgical anesthesia are not present during the stage of analgesia (Beecher and Moyer). The induction of analgesia as described by Nesbit might well prove, within a short time, to be pentothal's major claim to usefulness in the armamentarium of the anesthetist. SUMMARY
Pentothal sodium seriously depresses the respiratory stimulating power of carbon dioxide and frequently completely obliterates it at a stage of anesthesia comparable to stage III, later plane 2 of ether anesthesia. As a consequence, the regulation of breathing rests upon the peripheral reflex chemical control mechanisms of breathing. The disadvantages of this state are discussed. Because of the untoward effects of pentothal upon breathing when it is given in sufficient quantity to produce anesthesia deep enough for major surgery it is felt that its use should be greatly restricted in this field; especially since agents are available that do not have the effect on breathing that pentothal has. However, its use to induce analgesia (stage I) is not attended by the dangers that attend surgical anesthesia. Its use in this field might well constitute its major usefulness in the future. REFERENCES BEECHER, H.K. AND MOYER, C. A.: J. Olin. Investigation, 20: 549, 1941. DERRA, E. AND KoRTH, J . : Deutsche Ztschr. f. Chir., 263: 381, 1940. , GuEDEL, A. E.: Anes. and Analg., 16: 1, 1936. MARSHALL, E. K., JR. AND RosENFELD, M. J . : Pharmacol and Exper . Therapy, 67: 437, 1930. MousEL, H. AND EssEx, H. E.: Anesthesiol., 2: 272, 1941. MoYER, 0.: J. Thoracic Surgery. (In press.) NESBIT,R.: J. Urol., 47: 000, 1942. ScHMIDT, C. F.: Macleod's Physiology in Modern Medicine, St. Louis: C. V. Mosby Co., 1941, ed. 9.
AND
H. K. BEECHER
From Harvard University, Boston, Mass.
The convenience of intravenous anesthesia has led to the general use of pentothal sodium in spite of the fact that the anesthesia induced by it is less controllable than that induced by the volatile and gaseous agents. The use of pentothal sodium is not without danger, as attested by the deaths that have occurred during its administration. Its well known depressant effect on breathing appears to be the most dangerous immediate action of the drug. Knowledge concerning the manner by which it effects respiratory depression is a fundamental prerequisite in determining the indications for the use of pentothal and in selecting physiologically appropriate methods for dealing with severe respiratory depression when it does occur. In an attempt to provide the prerequisite knowledge, ·the action of pentothal upon the central chemical and peripheral reflex chemical control mechanisms of breathing has been studied on dogs. The effectiveness ·of the central chemical mechanism was determined by the repetitive subjection of the animal to a fixed increase in the carbon dioxide of the inspired air. Some of the stimulation of breathing that attended such a procedure may have been in part due to reflex stimulation but it is probable that the greater part of it, if not all, was the result of the action of carbon dioxide upon the respiratory center itself. The effectiveness of the peripheral chemical reflex mechanisms was determined by repetitively subjecting the animals to a fixed degree of oxygen deficiency in the inspired air. Normally, a large part of the regulation and maintenance of breathing depends upon the integrated functioning of the central chemical mechanism (regulation of breathing by carbon-dioxide) and t~e peripheral reflex chemical mechanisms (regulation of breathing by oxygen need). The central chemical seems to be the least variable and the most important of the two in both the normal dog and the normal man at low altitudes. Therefore, one of the most desirable attributes that an anesthetic could have, would be the property of producing the state of surgical anesthesia (stage III-Guedel) without seriously depressing the respiratory regulatory action of carbon dioxide. Pentothal sodium does not possess this attribute. Approximately 25 per cent (4 of 11) of the animals were found to have lost their sensitivity to carbon dioxide by the time the depth of anesthesia had reached the end of plane 22 of stage III, (the 1 Read before annual meeting, North Central Section, American Urological Association, Ann Arbor, Mich., October 25, 1941. 2 For convenience the third stage of pentothal anesthesia has been divided int o planes. These planes are not comparable to the planes of the third stage of ether anesthesia. Plane 2 designates very light "surgical" anesthesia; the corneal, lid, and tendon reflexes are very active, and the incising of the skin and the retracting of a muscle are followed by an intense respiratory stimulation. Plane 2 designates a moderate depth of anesthesia; the reflexes (lid, corneal, and t endon) are active though diminished and the respiratory stimulation that follows trauma is relatively slight. Plane 3 designates deep barbiturate anesthesia. The corneal and lid reflexes are usually absent, the tendon reflexes are present but they are very much diminished, respiratory minute volume is decreased and expiratory pauses are usually present, and surgical procedures are attended by a very little or no respiratory stimulation. 222
BREATHING DURING PENTOTHAL ANESTHESIA
223
depth of anesthesia at which a large part of major surgery is performed). The breathing of 2 animals that showed a 300 and a 600 per cent increase in minute volume of breathing when subjected to 12 per cent carbon dioxide during plane l (light anesthesia) was actually depressed by it during plane 2. Those animals that did not lose their sensitivity to carbon dioxide showed nervertheless great reductions in their reaction to carbon dioxide, but the respiratory stimulation that attended carbon dioxide inhalation was relatively satisfactory. The administration of oxygen to those animals that had lost their sensitivity to carbon dioxide produced serious depressions of breathing that were attended by a rapid rise in the carbon dioxide content of the arterial blood. This indicates, as pointed out by others for deep anesthetic states produced by other barbiturates, that breathing under pentothal anesthesia, (plane 2 or deeper) is frequently maintained by the peripheral reflex chemical control mechanisms, the aortic and carotid bodies. The effectiveness of these mechanisms was not regularly depressed by pentothal in this series of experiments. In fact, in 9 animals of the eleven, a given oxygen deficiency induced a greater percentile increase in minute volume of breathing during plane 2 than during plane l. However, since these mechanisms vary greatly in effectiveness when compared with the central chemical mechanism of the unanesthetised animal, and since they depend upon a degree of oxygen unsaturation of arterial blood for sustained action, they cannot be considered to be as physiologically adequate as the central chemical mechanism in regulating breathing at low altitudes. The frequent occurrence of cyanosis in man under pentothal anesthesia, contrasted with its infrequent occurrence during comparable depths of anesthesia induced by ether, supports this belief as cyanosis indicates anoxia, the dangers of which, are well known, to obviate this danger, oxygen is recommended. This expedient, although it relieves the cyanosis, is not without possible danger. If breathing slows appreciably when oxygen is breathed, as is to be expected when cyanosis is present, carbon dioxide will probably pile up in the body. (Derra and Korth; Beecher and Moyer.) This alone increases the respiratory depressant action of pentothal and tends to decrease cellular oxidations. This depressant effect of carbon dioxide on oxidations might well be as deleterious to the individual as the anoxia that was present when room air was breathed. Furthermore, since the well known anesthetic property of carbon dioxide is not, as far as can be determined, depressed by pentothal, the rise in carbon dioxide that occurs during the breathing of oxygen might well produce a rapidly fatal increase in depth of anesthesia without administering more pentothal. This has been noted not infrequently in experimental work (Marshall and Rosenfeld; Beecher and Moyer). It is therefore obvious that from the standpoint of respiration, pentothal sodium is not nearly as safe an agent as one that is capable of inducing surgical anesthesia without obliterating the regulatory action of carbon dioxide. Ether and- cyclopropane have this property for, as is common knowledge, carbon dioxide stimulates breathing appreciably even after complete intercostal paralysis has occurred (plane 4) when these agents are employed. These findings regarding the effects of pentothal sodium on breathing emphasize the clinical
224
C. A, MOYER AND H. K, BEECHER
limitations that should be placed upon this agent. These have been described previously (Moyer). When respiratory failure occurs during pentothal anesthesia, the administration of carbon dioxide in excess of 5 per cent and of oxygen above 40 per cent are contraindicated. Coramine, metrazol and alpha lobeline are not capable of stimulating breathing when it has failed during deep pentothal anesthesia (Mousel and Essex). The measures recommended for treating respiratory failure produced by pentothal are as follows: 1. Artificial respiration preferably by a prone pressure method. 2. The administration of 40 per cent oxygen, and 5 per cent carbon dioxide (to prevent acapnia, not to stimulate breathing) during the artificial respiration. 3. If blood pressure is low or falls rapidly during the period of artificial ventilation, epinephrin, 2-3 mins., intravenously (repeat as necessary) in order to provide a more adequate flow to the brain. Because of the serious and dangerous depressant action of pentothal sodium upon the central chemical control of breathing that becomes apparent during anesthesia of a nature roughly comparable to stage III plane 2 of ether anesthesia, it is felt that the use of pentothal in major surgery should be very restricted since there are other agents that are far safer from the standpoint of respiration. However, the dangers that attend surgical anesthesia are not present during the stage of analgesia (Beecher and Moyer). The induction of analgesia as described by Nesbit might well prove, within a short time, to be pentothal's major claim to usefulness in the armamentarium of the anesthetist. SUMMARY
Pentothal sodium seriously depresses the respiratory stimulating power of carbon dioxide and frequently completely obliterates it at a stage of anesthesia comparable to stage III, later plane 2 of ether anesthesia. As a consequence, the regulation of breathing rests upon the peripheral reflex chemical control mechanisms of breathing. The disadvantages of this state are discussed. Because of the untoward effects of pentothal upon breathing when it is given in sufficient quantity to produce anesthesia deep enough for major surgery it is felt that its use should be greatly restricted in this field; especially since agents are available that do not have the effect on breathing that pentothal has. However, its use to induce analgesia (stage I) is not attended by the dangers that attend surgical anesthesia. Its use in this field might well constitute its major usefulness in the future. REFERENCES BEECHER, H.K. AND MOYER, C. A.: J. Olin. Investigation, 20: 549, 1941. DERRA, E. AND KoRTH, J . : Deutsche Ztschr. f. Chir., 263: 381, 1940. , GuEDEL, A. E.: Anes. and Analg., 16: 1, 1936. MARSHALL, E. K., JR. AND RosENFELD, M. J . : Pharmacol and Exper . Therapy, 67: 437, 1930. MousEL, H. AND EssEx, H. E.: Anesthesiol., 2: 272, 1941. MoYER, 0.: J. Thoracic Surgery. (In press.) NESBIT,R.: J. Urol., 47: 000, 1942. ScHMIDT, C. F.: Macleod's Physiology in Modern Medicine, St. Louis: C. V. Mosby Co., 1941, ed. 9.