Recent Advances in General Anesthesia

Recent Advances in General Anesthesia E. M. PAPPER, M.D.*

THE last few years have witnessed renewed emphasis upon the use of general anesthesia in the United States and in many European countries. The reasons for the increased interest in general anesthesia at the expense of regional methods are several. The widespread practice of pleasant inductions with barbiturates; the superb surgical fields created with the aid of muscle relaxants; the extension of operative treatment to the heart and great vessels in which only general anesthesia can be applied, and the increasing numbers of operations of long duration are among the explanations for this trend. These facts in no way imply that regional anesthesia is unsatisfactory or unsafe. They are cited only to explain why general anesthesia appears to be increasing in popularity. Research efforts directed toward understanding the physiological derangements of the anesthetized state have aided in providing a more secure foundation for safer clinical practices. Even the study of newer agents and drugs has conformed, to an increasing degree, to the basic endeavor to measure quantitatively and to understand more completely. Of course, much remains to be learned. This essay will be concerned with some of the more significant aspects of recent and current studies designed to acquire fundamental and applied knowledge in the field of general anesthesia. These studies in the recent development of general anesthesia may be conveniently considered in several classifications.

PREMEDICATION AND PREOPERATIVE PREPARATION

Many clinicians have always taught that preanesthetic medication must be individualized for the needs of each patient, taking into account "medical" illnesses, the personality of the patient, the surgical procedure to be performed, and the anesthesia to be selected. Nobody quarreled with this point of view and yet adherence to the principle of individual evaluation was not and is not complete. Progress has beea made toward this goal, however, and today in many institutions, pa-

* Director of Anesthesiology Service, Presbuteriam H ospiial; Executive Officer and Professor of Anesthesiology, College of Phueiciane and Surqeons, Columbia University, New York, N. Y. 289

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tients are seen regularly before operation, their problems evaluated, discussed with the surgeon and other physicians who may be involved in' the care of the patient when such discussion is necessary and appropriate, and preanesthetic medication is prescribed accordingly rather than in a routine manner. STUDIES OF PHYSIOLOGICAL DISTURBANCES IN THE ANESTHETIZED STATE

Ventilation

Interest in respiration always occupied a prominent place in understanding general anesthesia. For a long time attention was centered7 upon the problem of oxygenation. One can never minimize the importance of adequate oxygenation during anesthesia. However, this is not the entire story. There has been a renewed awareness of the serious problem of proper elimination of carbon dioxide. It was taught from the earliest days of carbon dioxide absorption technique that tachypnea, hypertension and tachycardia were pathognomonic signs of carbon dioxide retention. This complication was viewed almost as an isolated phenomenon without realizing completely the implications of hypoventilation and subsequent respiratory acidosis resulting in other disturbances 0 f clinical importance. Recent studies indicate that the diagnosis of carbon dioxide retention is not a simple matter. In fact, the "pathognomonic" signs of respiratory acidosis are more frequently absent than present, creating a diagnostic problem of real difficulty for the anesthesiologist. One of the major areas of study in recent years in this connection has been the observance by many groups of workers of the progressive respiratory acidosis during thoracic operations because of alveolar hypoventilation. It was shown by Holaday and his associates' that this respiratory acidosis itself could induce a consequent metabolic derangement consisting of gain of fixed acid or loss of fixed base. The mechanism for this effect is not clear and its importance is still undetermined. The maintenance of "adequate" total ventilation during anesthesia with the open chest is not enough to prevent retention of carbon dioxide. Stead, Martin and Jensen" showed there was an excellent correlation between the changes in pH and alveolar ventilation in contrast to total ventilation during these procedures. Circulation

There are many streams of evidence which suggest that acidosis during general anesthesia must be considered serious and responsible for important complications both during and after anesthesia. From the observations of Dripps" and of Buckley and his associates," it is clear that sharp falls in blood pressure may be the consequence of recovery from

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respiratory acidosis in the immediate postoperative period. If retention of carbon dioxide is avoided, falls in blood pressure do not occur at the end of anesthesia. Altschule and Sulzbach" observed that the inhalation of carbon dioxide in oxygen with reduction of the arterial pH to 6.90 produced electrocardiographic evidences indicating myocardial injury in unanesthetized psychotic patients. There was evidence of nodal rhythm in some cases. In the experiments of Whitehead and Draper," electrocardiographic tracings showed a progressive rise in the amplitude of Rand T waves with premature ventricular contractions during progressive respiratory acidosis. The interesting experiments of Brown and Miller? and their associates showed that there was an increased amplitude of T waves, ectopic beats and a depression of the ST segment during the inhalation of carbon dioxide in the dog. Upon sudden withdrawal of carbon dioxide and the substitution of room air or oxygen, a variety of important changes occurred which suggested that heart block and increased myocardial irritability developed. The large majority of dogs suffered from ventricular fibrillation under these circumstances and died. So impressive were these data that the authors suggested that a "patient after a prolonged and severe siege of respiratory acidosis, hovers on the brink of disaster if suddenly ventilated with a mixture low in carbon dioxide concentration." It is important, therefore, to avoid both the accumulation of carbon dioxide and its rapid correction if these experiments have clinical significance. It has also been observed that the response of the heart to direct or reflex vagal stimulation may be increased during respiratory acidosis. 8 These experimental findings suggest that patients may be more vulnerable to reflex vagal stimulation during anesthesia if they have acidosis and In ay explain the catastrophic effects of "vagovagal" reflexes occasionally seen during endotracheal manipulation or pulmonary hilar dissection. These serious consequences of hypoventilation have stimulated much interest in methods designed to prevent insufficient gas exchange at the alveolar membrane. The reliability and efficiency of the commonly practiced method of assisting or controlling ventilation by rhythmic manual pressure on the rebreathing bag have been questioned. Artificial Ventilators

Because of the inadequacies of manual methods of assisting breathing there is a resurgence of interest in the use of mechanical ventilators or respirators to insure efficient and uninterrupted gas exchange during general anesthesia. If the proper type of instrument could be found, a more satisfactory ventilation pattern than is possible even in the most skillful of hands could be insured. There is, at present, no ventilator which can accomplish the desired goals in all cases. Many machines work

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well in most patients but not in the most difficult respiratory or circulatory problems where the need is greatest. The problem of imposing excessive peak pressures in a mechanical ventilator appears to have been solved to a degree by using machines which use positive-negative pressure changes so that the net mean pressure will be modest, indeed. Of the many pieces of apparatus thus far developed, one which has gained much popularity is the positive-negative Jefferson respirator introduced by Allbritten and his associates. 9 Other methods of using mechanical ventilation have been reported or are in the process of development. One of the more interesting in this connection is the apparatus developed by Frumin and Lee 10 which employs apneic techniques with a nonrebreathing valve. Ventilation is maintained automatically in a system which is an electrochemical analogue of that found normally in the body in the control of respiration. A servo-mechanism which is sensitive to CO 2 from the end of exhalation (approximating alveolar air) governs the movement of the ventilator and, thus controls tidal ventilation. This machine is not yet ready for general clinical use, but is most useful as a research tool. However, it has been employed successfully for anesthesia during clinical surgery for some 75 patients. It is quite clear that efficient respiration is necessary to prevent and treat respiratory acidosis during general anesthesia in order to avoid the serious complications which are associated with acidosis or which acidosis makes possible. The methods of combating acidosis are improved ventilation by a variety of means. It is probable that this purpose will be served by the proper type of mechanical ventilator developed for this purpose. Developmental progress appears to be promising. In connection with the problem of acid base balance, relatively little was mentioned about the increasing use of controlled or assisted spontaneous respiration. It is not possible to document factually, but it seems as though the methods employed in general anesthesia have changed from permitting full spontaneous breathing to the use of assisted or controlled breathing. The trend may be due to the increased use of muscle relaxants. Controlled respiration has been practiced with increasing frequency even in nonthoracic procedures in recent years. Much can be said for this method and something against it. In the patient who is not a respiratory cripple or who is not deficient in blood volume, the practice of controlled respiration when efficiently and effectively performed, appears to be useful, safe and without damage to patients. When there is a problem of deficient circulating blood volume or pulmonary emphysema, to mention only two clinical problems, there appear to be disadvantages of importance in the use of controlled respiration. Maloney and his associates" have shown that there is rapid circulatory deterioration when positive pressure controlled ventilation is

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imposed upon patients with hemorrhage or those who have a circulatory disturbance from the establishment of high spinal anesthesia. Less is known about the precise circulatory derangement in patients who have pulmonary emphysema or other respiratory difficulties. More knowledge must be acquired about the beneficial effects of negative pressures during exhalation in these situations. Controlled respiration also limits the type of agents which may be used with impunity. If a patient is made apneic, the use of potent anesthetic agents with controlled respiration becomes a potential hazard. This is less true of cyclopropane than of ether. It is a possible explanation of the increased mortality associated with the use of d-Tubocurare and ether as reported by Beecher and Todd." Perhaps the relaxant is the lesser culprit under these circumstances than the increased ease of administering large doses of ether to a defenseless patient. The alleged greatest safety provided by ether is at once negated by the use of this method of controlled respiration. These thoughts are not designed to suggest that controlled respiration must never be employed with potent agents. It is necessary, however, to pose the serious problems associated with the use of potent agents, especially ether, with controlled respiration. Nonpotent agents do not share this difficulty. Providing there is an adequate tension of oxygen in the inhaled atmosphere, it is impossible to overdose a patient with nitrous oxide or with ethylene by practicing controlled respiration. This is, unfortunately, not true with ether or cyclopropane. Another facet of the problem of ventilation has been the increased interest in the use of nonrebreathing methods in anesthesiology. Nonrebreathing Techniques

It is difficult to know the reason for the sudden spurt of renewed interest in nonrebreathing methods but it is probably associated with the increasing desire to eliminate the dead space of certain types of closed methods and to eliminate the increased temperatures of the inhaled atmosphere with closed methods for children. In any event, the recent interest in these methods was established in pediatric practice by Leigh and Belton," by Stephen and Slater,'! and subsequently by Fink." The nonrebreathing principle involves the elimination of absorbing material, the use of higher gas flows and the complete separation of inhalation and exhalation in the patient's ventilatory cycle. Mechanical modifications of various valves or devices have been reported, the three most recent ones by Fink" in this country and Ruben" and Rattenborg" in Denmark. Further study is certainly in order since this technique offers several possible advantages. Agents like trichlorethylene cannot be used with absorption materials because toxic decomposition products are liberated if contact is made with soda lime or Baralyme,

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The tendency to accumulate heat and carbon dioxide in any system of closed general anesthesia is reduced. The two problems posed by this method are first, the large consumption of gases and subsequent expense, and secondly, the inconvenience of using potent agents by this method. Potent agents are usually given as reinforcing vapors for the nonpotent agents when the method is applied to children. THE RELAXANTS

Drugs which have been used to suppress muscle power during anesthesia and, therefore, provide muscular relaxation were introduced in 1942 by Griffith and Johnson.'? Early after the introduction of Intocostrin, the practice of producing skeletal muscular relaxation with the relaxants became well established. From what has appeared in the literature related to anesthesiology and from what one sees in observing anesthesia in many parts of this country, the muscle relaxants have enjoyed increasingly large usage in the last five years. This has occurred despite some controversy about the safety of relaxants. There has been a very gradual abandonment of the use of relaxants with potent agents particularly ether and a much more widespread use of relaxants with the nonpotent agents. Obviously this type of generalization is not susceptible of proof nor is it totally accurate, but it is probable that this is the trend. When one, in today's practice, sees d-Tubocurare used with ether anesthesia, the use of the word "anesthesia" becomes a courtesy since the depth of anesthesia is so light as to justify the word "analgesia." Only light anesthesia is possible when the nonpotent gases are employed. In analyzing the conflicting evidence which has appeared about the muscle relaxants one should take a responsible stand. It seems to this observer that these agents are of great clinical value, that they have made the administration of general anesthesia much more comfortable for the surgeon and, therefore, safer for the patient, since the surgeon can do his work more efficiently and with less trauma. They have also permitted the use of light anesthesia with nonpotent agents and adequate oxygen, minimizing the "toxic" effects of profound anesthesia and the harmful effects of the potent anesthetics. The fact that relaxants present problems is not a serious criticism. One must be aware of these and deal with them. It is necessary, as pointed out previously, to insure effective ventilation for the patient who receives a relaxant since his ventilation is usually diminished and may be completely suppressed. It does not seem appropriate to summarize in detail the extensive pharmacological information which has been collected about, the relaxants. The drug most commonly used in clinical practice is succinylcholine if one can judge by word of mouth reports, clinical observations

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and the orders placed by purchasing agents in hospitals. The duration of action of this agent is short, permitting its use for brief procedures including endotracheal intubation. It is also given by continuous intravenous drip which allows for more flexibility in its administration. Succinylcholine may be given intravenously as a single dose of 40 to 100 mg. in adult patients for a period of relaxation of some ten minutes. For sustained relaxation, the doses can be repeated or the drug administered as a continuous infusion in 0.9 per cent saline or 5 per cent dextrose in water as a 0.1 or 0.2 or even 0.5 per cent solution. The most commonly used concentration is 0.2 per cent because this insures flexibility of drug dosage as well as volume of infusate. The degree of relaxation can be adjusted by the rate of infusion. Succinylcholine has proved most satisfactory for clinical purposes but has given rise to two important unsolved problems. There is hypertension occasionally, the cause of which is not clear, and there is an occasional and serious instance of prolonged postanesthetic respiratory depression. This phenomenon is thought by Foldes" to be due to a relative overdosage. Foldes believes that the only safe way of administering succinylcholine infusion from this standpoint is to insure that respiration is spontaneous and assisted by the anesthesiologist. "If apnea does not occur prolonged apnea cannot occur." Many anesthesiologists, however, employ this agent with apneic technique and stop the rate of infusion from time to time to insure the return of spontaneous respiration. This appears to be safe for most purposes. Antagonists of the Relaxants

A word or two must be added about the pharmacological antagonists of the relaxants. On face value, it would appear desirable to have a drug which reverses the action of the muscle relaxants so as to minimize the danger of depression of respiration. An antagonist for succinylcholine has not as yet been reported. The most commonly used antagonist, Tensilon, opposes the action of d-Tubocurare. Its exact mechanism of action is not completely understood. There is evidence that suggests that its action is primarily due to its anticholinesterase activity and there is also evidence that this compound has a direct excitatory effect on unstimulated muscles similar to that of acetylcholine and, therefore, acts by competing with curare for position on the motor end plate. It seems that the use of the antagonists at the present time is not warranted without many reservations. The primary difficulty experienced by patients given relaxants, once the postoperative period is reached, is depression of breathing. It is dangerous to use presently available antagonists without adequate supervision of patients because respiratory depression from a drug like d-Tubocurare can recur even

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after the use of Tensilon. It is safer to support ventilation with assisted breathing and oxygen until spontaneous respiration is fully adequate than it is to rely upon the antagonists of the relaxants. THE MECHANISM OF ANESTHESIA

The precise neurophysiological disturbance which brings about the anesthetized state is still imperfectly understood despite many years of effort. The systematic studies of Magoun, French and their associates" on the physiology of the reticular activating system of the brain stem and the effects of depressant drugs on its activity help in understanding the state of wakefulness and that of anesthesia. It was observed in several species of mammals that excitation of the cephalic portion of the brain stem and its central area caused arousal. Destruction of this area produced a state of chronic unresponsiveness. They concluded that the brain stem activating system appears to exert a desynchronizing influence on the cortex and diencephalon during the state of wakefulness. During anesthesia with pentobarbital and ether this area was selectively depressed whereas the area in the lateral direct sensory pathways and the primary sensory cortex was unaltered. The anesthetics apparently block synaptic transmission long before fiber conduction iseffected. Transmission in the reticular activating system is mediated by units of many neurones. These findings indicate that depression of activity in this area and in the intraneuronal system of the cortex participated to an important degree in the production of anesthesia. The electroencephalographic observations during anesthesia reported by Faulconer and his associates" are consistent with these experimental findings. These workers were able to correlate electroencephalographic patterns with different levels of thiopental, ether and cyclopropane anesthesia. Deepening of the anesthesia tended to suppress the voltage and the frequency of electrical spikes until there was no longer evidence of electroencephalographic activity in very deep anesthesia. The energy obtained from the electroencephalogram was used also to regulate the rate of administration of anesthetics through a servo-mechanism. The studies of electrical activity of the brain are not only of intrinsic interest but appear promising in providing further information to the clinical anesthesiologist. However, all the information obtained thus far is not as clear-cut as one might immediately suppose. Preliminary studies by Frumin and Schweiss" indicate that the electroencephalogram of patients obviously unconscious during nitrous oxide oxygen anesthesia, and made apneic by the administration of succinylcholine, is altered very little from the normal if controlled respiration is efficiently performed. The patient certainly has no memory, can tolerate surgical procedures, and has all the apparent clinical signs of anesthesia, and yet the elec-

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trical activity of the brain is that of normal waking or, at the most, of normal sleep. The meaning of these changes needs considerably more study. INTRAVENOUS ANESTHETICS

Drugs which produce anesthesia when injected into a vein produce general anesthesia just as effectively as if they were inhaled or given by rectum. Many drugs have been used to achieve general anesthesia by vein. The most commonly employed ones for the last 25 years and in current practice are the barbiturates. In the course of studies in the last few years, Brodie, Papper and their co-workers'" demonstrated that the anesthetic barbiturates are not truly ultra short-acting. It was shown that the concentration of thiopental (Pentothal) in the plasma decreased as the concentration in the body fat increased. The initial fall of plasma levels is due to redistribution into body fat and to a lesser extent to other tissues. The actual rate of drug degradation is only 10 to 15 per cent per hour. Thiopental is almost entirely metabolized within the body by the three possible routes of oxidation of the side chain, enzymatic removal of the sulfur and splitting of the malonyl urea ring.": 26 The last possibility is not actually supported by direct evidence. Two other short-acting thiobarbiturates were introduced into clinical practice recently, Surital and Kemithal. Quantitative study of these compounds indicates that they are treated by the body in a manner similar to thiopental and that their advantages and shortcomings are similar to those of thiopental. The same can also be said of some of the n-alkyl thiobarbiturates. From all these studies an important clinical practice was confirmed and extended. The intravenous barbiturates should be employed as basal hypnotic agents and combined with the nonpotent gases, usually nitrous oxide with oxygen, to avoid central depression of breathing, circulatory depression and the postanesthetic somnolence and respiratory obstruction which are associated with large doses of the barbiturates when used alone. Other materials have been used for intravenous anesthesia. Recently (June 1955) a steroid anesthetic was reported by Murphy and his associates" at the meeting of the American Medical Association. This material was tried on a relatively small number of patients and was found to produce a satisfactory state of anesthesia, particularly when supplemented with nitrous oxide and oxygen. Too little experience has accumulated to know what place this or related compounds will occupy in general anesthesia but the idea of employing a steroid for the production of anesthesia is an interesting one. Studies on the behavior of this compound in the body and its action on patients are in progress.

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ANESTHESIA DURING INDUCED HYPOTENSION

To assist the surgeon in his constant effort to secure hemostasis, artificial reduction of arterial blood pressure has been practiced in recent years to a larger extent than previously. Among the methods are arteriotomy, high spinal anesthesia, and ganglionic blocking agents. In current practice the most commonly used compound in the United States is the ganglionic blocking drug, Arfonad. The drug is administered in either a 0.1 or 0.2 per cent solution dissolved in 5 per cent dextrose in water. The rate of infusion is determined by the level of arterial pressure desired. For most purposes a level of between 70 and 80 mm. Hg systolic is considered both sufficient and safe. A diastolic pressure of 50 to 60 mm. Hg is considered reasonable for the same purpose. There appears to be little question that artificial reduction in blood pressure does accomplish its desired end for surgical purposes. However, the artificial reduction of blood pressure represents a "physiological trespass." Whether or not the danger from hypotension outweighs the clinical advantages has been the subject of some controversy. The possible dangers are cerebral anoxia, renal damage, vascular thrombosis and reactionary hemorrhage. The dangers appear to be increased in patients with arteriosclerosis and vascular diseases. Unfortunately the survey reported by Hampton and Little'" does not answer all of the important questions. Their data indicated, however, that the major causes of death from induced hypotension are cerebral anoxia or thrombosis, kidney failure, coronary thrombosis and cardiac arrest. The mortality was 1 in 500. Hampton and Little pointed out that cardiovascular and renal diseases and reduced blood volume are definite contraindications to the use of induced hypotension. They also maintained that the method was relatively safe if the systolic pressure were kept near 80 mm. Hg. and if the amount of blood lost was scrupulously replaced during the period of induced hypotension. The method should be reserved for surgical situations where the ability to perform an important surgical task would be greatly compromised unless hypotension is established as an essential aid to hemostasis. SUMMARY

A discussion of some of the current investigations and clinical practices in the field of general anesthesia has been presented, These areas of progress are concerned with better preanesthetic preparation, increased knowledge of the physiological disturbances incident to general anesthesia, a better evaluation of drugs including the relaxants, intravenous anesthetics, and ganglionic blocking agents, and the application of this newer knowledge to clinical practices.

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REFERENCES 1. Holaday, D. A., Ma, D. and Papper, E. M.: Dynamic Changes in Acid Base

Balance During Anesthesia. Bull. New York Acad. Med. 28: 543, (Aug.) 1952. 2. Stead, W. W., Martin,F. E. and Jensen, N.I\:.: Physiologic Studies Following Thoracic Surgery. IV. Mechanism of Development of Acidosis During Anesthesia. J. Thoracic Surge 25: 435-447, 1953. 3. Dripps, R. D.: Immediate Decrease in Blood Pressure Seen at Conclusion of Cyclopropane Anesthesia: "Cyclopropane Shock." Anesthesiology 8: 15-35, 1947. 4. Buckley.vl. J., Van Bergen, F. H., Dobkin, A. B., Brown, E. B. Jr., Miller, F. A. and Varco, R. L.: Postanesthetic Hypotension Following Cyclopropane: Its Relationship to Hypercapnia. Anesthesiology 14: 226-237, 1953. 5. Altschule, M. D. and Sulzbach, W. M.: Tolerance of Human Heart to Acidosis: Reversible Changes in RS-T Interval During Severe Acidosis Caused by Administration of Carbon Dioxide. Am. Heart J. 33: 458-463, 1947. 6. Whitehead, R. W., Spencer, J. N., Parry, T. M. and Draper, W. B.: Studies on Diffusion Respiration. IV. Oxygen and Carbon Dioxide Content and Hydrogen-ion Concentration of Arterial and Venous Abdominal Blood of Dogs During Diffusion Respiration. Anesthesiology 10: 54-60, 1949. 7. Brown, E. B. Jr. and Miller, F.: Ventricular Fibrillation Following Rapid Fall in Alveolar Carbon Dioxide Concentration. Am. J. Physiol.169: 56-60,1952. 8. Young, W. G. Jr., Sealy, W. C., Harris, J. and Botwin, A.: Effects of Hypercapnia and Hypoxia on Response of Heart to Vagal Stimulation. Surge Gynec. & Obst. 93: 51-55, 1951. 9. Allbritten, F. F. Jr., Haupt, G. J. and Amadeo, J. H.: The Change in Pulmonary Alveolar Ventilation achieved by Aiding the Deflation Phase of Respiration During Anesthesia for Surgical Operations. Ann. Surge 140: 569-582 (Oct.) 1954. 10. Frumin, M. J.: The Automatic Maintenance of Anesthesia. J.A.l\1.A. 157: 1536 (April 23) 1955. 11. Maloney, J. V. Jr., Elam, J. 0., Handford, S. W., Balla, G. A.., Eastwood, D. W., Brown, E. S. and Tenpas, R. H.: Importance of Negative Pressure Phase in Mechanical Respirators. J.A.M.A. 152: 212-216, 1953. 12. Beecher, H. K. and Todd, D. P.: A Study of the Deaths Associated with Anesthesia and Surgery. Ann. Surge 140: 2-34 (July) 1954. 13. Leigh, M. D. and Belton, M. K.: Pediatric Anesthesia. New York, The Macmillan Co., 1949. 14. Stephen, C. R. and Slater, H. M.: A Nonresisting Nonrebreathing Valve. Anesthesiology 9: 550, 1948. 15. Fink, B. R.: Nonrebreathing Systems in Pediatric Anesthesia. New York State J. Med. 54: 2189-2194 (Aug.) 1954. 16. Fink, B. R.: A Nonrebreathing Valve of New Design. Anesthesiology 15: 471-474 (Sept.) 1954. 17. Ruben, H.: A New Nonrebreathing Valve. Anesthesiology (in press). 18. Rattenborg, C.: A N onreturn Valve, designed to Ventilate Polio Patients with Respiratory Paralysis by Manual Positive Pressure Ventilation. Acta med. Scandinav. 147: fasc. V-VI, 1954. 19. Griffith, H. R. and Johnson, G. E.: Use of Curare in General Anesthesia. Anesthesiology 3: 418-420, 1942. 20. Foldes, F. F.: Address to Anesthesiology Staff, The Presbyterian Hospital, New York, N. Y., January 20,1955. 21. French, J. D., Verzeano, M. and Magoun, H. W.: Neural Basis of Anesthetic State. Arch. Neurol. & Psychiat. 69: 519-529, 1953. 22. Soltero, D. E., Faulconer, A. Jr. and Bickford, R. G.: Clinical Application of Automatic Anesthesia. Anesthesiology 12: 574-582, 1951. 23. Frumin, M. J. and Schweiss, J. F. Unpublished data. 24. Brodie, B. B., Burns, J. J., Lief, P. A. and Papper, E. M.: Intravenous Anes-

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thetics-New Concepts. 1. Experimental Aspects. Anesth. & Analg. 31: 145-147, 1952. Brodie, B. B., Mark, L. C., Papper, E. M., Lief, P. A., Bernstein, E. and Rovenstine, E. A.: Fate of Thiopental in Man and Method for Its Estimation in Biological Material. J. Pharmacol. & Exper. Therap. 98: 85-96, 1950. Taylor, J. D., Richards, R. K. and Tabern, D. L.: Metabolism of S35 Thiopental (Pentothal); Chemical and Paper Chromatographic Studies of S35 Excretion by Rat and Monkey. J. Pharmacol. & Exper. Therap. 104: 93-102, 1952. Murphy, F. J., Guadagni, N. P., and De Bon, F.: Use of Steroid Anesthesia in Surgery, J.A.M.A., 158: 1412-1414, Aug. 20, 1955. Hampton, L. J. and Little, D. M. Jr.: Complications Associated with Use of "Controlled Hypotension" in Anesthesia. Arch. Surge 67: 549-556, 1953.

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