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NEUROLEPT ANALGESIA AND ANESTHESIA FOR OPEN-HEART SURGERY
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VOLUME 49 JUNE 1965 NUMBER 6
Thoracic and Cardiovascular Surgery
ja Original
Communications
NEUROLEPT ANALGESIA A N D ANESTHESIA FOR OPEN-HEART SURGERY Pharmacologic Rationale and Clinical Experience Guenter Corssen, M.D., Peter Chodoff, M.D., Edward F. Domino, and Donald R. Kahn, M.D., Ann Arbor,
M.D.,
Mich.
T
wo major problems confront the anesthesiologist in his management of pa tients undergoing surgery for the correction of congenital and acquired heart defects. First is the limited physiologic reserve of these patients. Second, and possibly more important, are the pathophysiologic changes during bypass, which have been shown to be similar to those observed in low perfusion shock even though high flow rates are employed. Anesthetic agents and techniques are required which will afford protection against disturbances in homeostasis and at the same time provide smooth and rapid induction of anesthesia, with minuteto-minute control and prompt reversibility when needed. Agents at our disposal have met such requirements only in part. For exam ple, nonexplosive inhalation anesthetics, such as halothane and methoxyflurane, exert undesirable depressant effects on the myocardium. With "balanced" anes thesia, involving intravenous barbiturates, similar cardiac depression can occur. Cyclopropane is highly flammable and explosive. There is a vital need for agents which will counteract undesirable vascular reactions which may occur during cardiac bypass and which may simulate shock. A thorough understanding of the various pathophysiologic mechanisms that are activated during the extracorporeal phase is, of course, essential to proper and effective therapy. Lillehei 1 was the first to draw attention to the From the Departments of Anesthesiology, Pharmacology and Surgery, Division of Thoracic Surgery, The University of Michigan Medical Center, Ann Arbor, Mich. Received for. publication Nov. 23, 1964. 901
902
COESSEN E T AL.
J. Thoracic and Cardiovas. Surg.
pernicious effects of some vasoactive amines released during cardiopulmonary bypass and to present evidence of the beneficial effects obtained from alpha adrenergic blockade with phenoxybenzamine (Dibenzyline) to counteract exces sive vasoconstriction. From these observations it became apparent that patients exposed to cardiopulmonary bypass present a unique situation for the prophy lactic use of alpha adrenergic blockade. While Dibenzyline seems to be an ex cellent adrenergic blocking agent, its prolonged duration of action is a disad vantage because of the difficulty of controlling its powerful blocking action. Janssen and his associates2 introduced a group of butyrophenones among which dehydrobenzperidol appears to be particularly suitable for use in anes thesia. In the absence of any measurable toxic effects on vital organs, the drug mimics chlorpromazine in its pharmacologic actions, including powerful tranquilizing, antiemetic, antifibrillatory, and, what they have called, its alpha adrenergic blocking properties. When drugs of this type are used in conjunction with short-acting narcotic analgesics, such as phentanyl, a new and potent meperidine-like agent, 3 the result is "neuroleptanalgesia." 4 When the agents are used in conjunction with nitrous oxide-oxygen mixtures, an anesthetic state can be produced which is adequate for any minor or major surgical procedure. This relatively new anesthetic technique appears to exert few side effects. It has re cently been reported to be of particular value in the anesthetic management of patients who are poor surgical risks because of advanced age or for some other reason. 5 The absence of appreciable cardiac depression when these two drugs are used, along with the fact that the adrenergic blocking effects are limited, prompted us to study the application of this technique in anesthetic procedures for open cardiac surgery. It was decided to carry out simultaneous laboratory investigations of the pharmacologic rationale for employing the two drugs mentioned above, dehydro benzperidol and phentanyl. The results presented below provide a theoretical as well as practical basis for the suitability of this new anesthetic approach in the management of patients undergoing open-heart surgery with the aid of cardio pulmonary bypass. E X P E R I M E N T A L STUDY
Methods.—For the study of the cardiovascular effects of various alpha adrenergic blockers, including Dibenzyline, chlorpromazine, and dehydrobenz peridol, 30 adult mongrel dogs of both sexes were used. The animals were anes thetized with pentobarbital (30 mg./Kg., intravenously). An endotracheal tube was placed and artificial ventilation was maintained at 300 ml./air/Kg./min. Blood pressure recordings were obtained through the cannulated femoral artery by means of a mercury manometer with a lever writing on a smoked kymograph. The femoral vein was cannulated for the injection of the test drugs. Epinephrine and norepinephrine wei*e injected intravenously in a dose of 2 fig per kilogram. Increasing doses of Dibenzyline, chlorpromazine, and de hydrobenzperidol, calculated as base, were administered every 15 minutes and the per cent change in blood pressure over control levels was recorded for each
Vol. 49, No. 6 June, 1965
NETJROLEPT ANALGESIA AND ANESTHESIA
903
administration of epinephrine and norepinephrine. After each injection, the venous cannula was flushed with 5 ml. of normal saline. The study of the tranquilizing effects of Dibenzyline, ehlorpromazine, and dehydrobenzperidol was carried out in 60 male Holtzmann rats that weighed between 150 and 400 grams. The modification of the Cook and Weidley 6 con ditioned avoidance pole-jump technique was used. Each rat was given 100 train ing trials before the drug studies. The conditioned stimulus (CS) consisted of a 6-volt buzzer sound lasting 5 seconds, followed by a 5-second unconditioned stimulus (US) consisting of a scrambled electric shock through the grid floor. The parameters of electric stimulation were 60 c.p.s. sine waves at 1 Ma. The CS overlapped the US. Prior to drug testing, the rats were required to meet a criteria of 19 out of 20 successful avoidances. To avoid possible cumulative effects, at least 5 days lapsed between the administration of the drugs. The narcotic analgesics, morphine sulfate and phentanyl, were given only once to each animal, in order to avoid tolerance development. Dose-response curves for all agents were obtained, in addition to an index of duration of action. All data were subjected to statistical analysis, including regression analysis performed according to Snedecor.7 Correlation coefficients for each line were obtained according to Croxton.8 Results.—As expected, increasing doses of Dibenzyline, ehlorpromazine,
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Fig. 1.—Modification of mean per cent increase in blood pressure response to epinephrine by various adrenergic blocking agents in the pentobarbital-anesthetized dog. To facilitate calcu lation the logarithm of the dose X 100 was used and expressed in the equations of the regres sion lines in this and subsequent figures.
CORSSEN ET AL.
904
J. Thoracic and Cardiovas. Surg.
and dehydrobenzperidol progressively decreased the mean arterial pressor re sponse to intravenous epinephrine. This is illustrated in Fig. 1. In this and the following graphic presentations, each point represents the average response of 3 to 6 animals given cumulative doses of each of the adrenergic blocking agents. Estimates of the potency of the drugs in reducing the pressor response to epi nephrine, calculated from the regression equations and expressed as ED 50 , were 0.16 mg. per kilogram for Dibenzyline, 0.37 mg. per kilogram for chlorpromazine, and 0.36 mg. per kilogram for dehydrobenzperidol. Dibenzyline was the most potent. Chlorpromazine and dehydrobenzperidol were less so; there was no difference between the two. All three agents showed a plateau-like effect when doses larger than 2 mg. per kilogram were used. The effect of higher doses of the three drugs in causing epinephrine reversal is illustrated in Fig. 2. Dibenzyline again was the most potent, while chlor promazine and dehydrobenzperidol were similar but less effective. The alteration of the norepinephrine pressor response by these drugs is 62.555 50 -
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NEITROLEPT ANALGESIA AND A N E S T H E S I A
Vol. 49, No. June, 1965
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graphically shown in Fig. 3. Dibenzyline produced a progressive block of the norepinephrine pressor response. The marked variability observed with chlorpromazine and dehydrobenzperidol may be explained by the fact that both drugs can reduce as well as enhance the pressor effects of norepinephrine. The over-all values indicated that the regression lines of both drugs did not sig nificantly differ from zero correlation (p > 0.4). An index of the tranquilizing action of the. three drugs is their ability to block conditioned avoidance in rats. As illustrated in Fig. 4, the ED 5 0 for de hydrobenzperidol was 0.06 mg. per kilogram and 1.56 mg. per kilogram for chlorpromazine. Thus, dehydrobenzperidol proved in this test to be 26 times as potent in its tranquilizing effect as chlorpromazine. In contrast, Dibenzyline had no effect on conditioned avoidance behavior in rats in doses ranging from 1 mg. to 32 mg. per kilogram. After 8 hours, rats given chlorpromazine still had not recovered, while rats given dehydrobenzperidol were back to normal, indicating that the latter drug has a shorter duration of action.
COESSEN ET AL.
906 100-
J. Thoracic and Cardiovas. Surg.
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Fig. 4.—Modification of conditioned pole-jumping by various alpha adrenergic blocking agents. The per cent blocked avoidance and escape responses are plotted on the Y-axis. The drugs were given subcutaneously and the animals tested before and 60 minutes later.
Narcotic analgesics like morphine sulfate and phentanyl can also block conditioned avoidance behavior (Fig. 5). Phentanyl proved to be over 100 times as potent as morphine sulfate in this regard; its ED 5 0 was 0.04 mg. per kilo gram as compared to 4.58 mg. per kilogram for the latter. It was also noted that phentanyl had a much quicker onset of action followed by a more rapid recovery. CLINICAL STUDY
The series of clinical cases studied included 47 male and 54 female patients ranging in age from 3 weeks to 60 years. Preanesthetic Medication.—In infants and children, preanesthetic medica tion consisted of pentobarbital, 1 to 2 mg. per pound of body weight, combined with seopolamine, 0.1 to 0.2 mg. Adults received a total of 100 to 150 mg. of pentobarbital together with 0.4 mg. of seopolamine. The drugs were given sub cutaneously 90 minutes before induction of anesthesia. No opiates were admin istered as preanesthetic medication in this series of patients.
Vol.49, No. 6 June, 1965
NEUBOLEPT ANALGESIA AND ANESTHESIA
907
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F i g . 5.—Blockade of conditioned p o l e - j u m p i n g of r a t s b y p h e n t a n y l a n d m o r p h i n e s u l f a t e . T h e d r u g s w e r e given s u b c u t a n e o u s ! y a n d t h e a n i m a l s t e s t e d before a n d 30 m i n u t e s l a t e r .
Induction.—Anesthesia was induced by 0.1 to 0.2 ml. per pound of body weight of the fixed mixture containing dehydrobenzperidol 1 mg./l ml. com bined with phentanyl 0.02 mg. per kilogram (50:1)* administered intravenously over a period of approximately 30 to 60 seconds. During the earlier phase of the study, patients received a 100:1 ratio of dehydrobenzperidol to phentanyl (1 mg. of dehydrobenzperidol combined with 0.01 mg. of phentanyl). The in jection was followed by inhalation of 50 per cent to 75 per cent nitrous oxide in oxygen. Intravenous sueeinyleholine (20 to 60 mg.) was given 1 to 2 minutes after starting the administration of nitrous oxide-oxygen to facilitate the place ment of the endotracheal tube. Maintenance.—Anesthesia was maintained with 50 per cent to 75 per cent nitrous oxide in oxygen. Eespiration was controlled by manual pressure on a • I n n o v a r , McNeil L a b o r a t o r i e s , F o r t W a s h i n g t o n , P a .
908
CORSSEN ET AL.
J. Thoracic and Cardiovas. Surg.
breathing bag connected to a semi-closed carbon dioxide absorption system. Small doses of phentanyl (0.025 mg. to 0.1 mg.) were administered intrave nously when signs of surgical stimulation (sudden rise in blood pressure, in crease in pulse rate) indicated the need for elevating the pain threshold. For adequate control of diaphragmatic activity, intravenous increments of 10 to 20 mg. of succinylcholine were administered intermittently, preceded by a single dose (20 to 40 mg.) of hexafluorenium given at the start of surgery to prolong the succinylcholine effect, as proposed by Foldes and his associates.9 Some adult patients received intermittent doses of nondepolarizing muscle relaxants such as d-tubocurarine (3 to 6 mg.) or gallamine (20 to 40 mg.). During bypass, ad ditional small increments of succinylcholine or d-tubocurarine or gallamine were injected into the pump oxygenator to control diaphragmatic movements. Continuous electroencephalographic recordings (left frontal-parietal) and electrocardiographs recordings (Lead II) were obtained in all patients. Pres sures from the femoral artery and femoral vein were also continuously recorded and transmitted to a Grass multichannel recorder. During bypass the lungs were kept inflated with a 50 per cent mixture of nitrous oxide and oxygen. The pump oxygenator consisted of a rotating disc oxygenator with five roller pumps. Venous blood was returned to the pump by gravity and oxy genated blood was returned to the femoral artery. Oxygenation of the blood was achieved with 98 per cent oxygen and 2 per cent carbon dioxide. The blood temperature was controlled by circulation through a heat exchanger. As a rule, the blood temperature during bypass was kept in a range of 30° to 32° C. The superior and inferior venae cavae were cannulated through the right atrial appendage. In aortic valve replacements, coronary perfusion was instituted by inserting catheters into the right and left coronary ostia. The control series included 50 consecutive patients who had recently under gone open-heart surgery under anesthesia induced by halothane-nitrous oxideoxygen. In this group of patients, maintenance concentrations of halothane ranged from 0.5 to 1.0 per cent (Fluotec vaporizer). During the bypass, halo thane was administered via the pump oxygenator, in 0.5 to 1.0 per cent con centrations; after bypass, the anesthesia usually involved nitrous oxide-oxygen mixtures only. Fifty polygraph and perfusion records available from these pa tients were compared with those of 50 consecutive patients in the study series. Systolic and diastolic blood pressures before and after bypass were compared as a nonindependent pair of samples while the perfusion pressures and the ages were analyzed by group comparison.8 Results.—Following intravenous administration of dehydrobenzperidol and phentanyl, all patients lapsed within 1 to 3 minutes into a semiconscious state in which they lay resting and unresistant but were able to follow verbal commands such as "take a deep breath," "open your mouth," etc. However, spontaneous respiration usually ceased. With the inhalation of nitrous oxide-oxygen mix tures, consciousness was lost within 30 to 60 seconds. Frequently at this point pulmonary compliance decreased markedly, making passive inflation of the lungs difficult. Intravenous administration of succinylcholine (20 to 40 mg.) resulted
Vol. 49, No. 6 June, 1965
N E U R O L E P T ANALGESIA AND A N E S T H E S I A TABLE
TYPE OF CARDIAC DEFECT
909
I.*
| NO. OF PATIENTS |
TYPE OF SURGERY
Ventricular septal defect 41 Closure of defect (2 repeat) Closure of defect (1 repeat) 13 Atrial septal defect Repair of stenosis 9 Pulmonic stenosis (valvular and/or infundibular) Mitral valvuloplasty (12 patients) 19 Acquired mitral valve disease (mitral Mitral valve replacement (7 patients) valve stenosis and/or insufficiency) Aortic valvuloplasty (6 patients) 11 Congenital or acquired aortic valve Aortic valve replacement (5 patients) disease (aortic valve stenosis and/or insufficiency) Total correction 4 Tetralogy of Fallot Closure of defect 2 Ostium primum Creation of atrial septum defect 1 Transposition of great vessels Repair of atrioventricularis communis 1 Atrioventricularis communis Total 101 •Types of cardiac defects and surgical repairs carried out under neurolept anesthesia in 101 patients.
invariably in immediate restoration of adequate pulmonary compliance. The endotracheal tube was then placed and the patient was ready for surgery. During the course of surgery the patient could be awakened at any time by simply shutting off the nitrous oxide flow and washing out the breathing bag with oxygen. The patient was able to follow commands, such as to open the eyes or turn the head, and could answer questions readily by nodding the head. Al though some patients were kept awake for prolonged periods, none remembered the episodes of wakefulness when later asked about memory of this event. The types of cardiac effects and surgical procedures involved in operations under neurolept analgesia and anesthesia are summarized in Table I. The average duration of surgery was 3 hours and 10 minutes. In the longest operation, which lasted 8 hours and 30 minutes, the patient was a 43year-old women with mitral and tricuspid stenosis and insufficiency. The short est procedure, lasting 2 hours, was for repair of pulmonic stenosis in a 7-yearold boy. The average duration of cardiopulmonary bypass was 1 hour and 6 minutes. The longest period, 3 hours and 55 minutes, was recorded during replacement of a mitral valve in a 40-year-old woman. The shortest bypass, 18 minutes, was carried out in a 14-year-old boy for repair of a pulmonic stenosis. Spontaneous cardiac activity was maintained throughout the bypass in 90 patients. In the remaining 11, ventricular fibrillation occurred following inter mittent cross-clamping of the aorta, and in 9 of these the sinus rhythm was re stored with a single electroshock from an internal defibrillator (150 v., 1.5 amps., 15 sec. duration). In 1 patient, the heart converted spontaneously to sinus rhythm at the end of the surgical repair (closure of ventricular septal defect). In another patient, a 53-year-old man in a terminal stage of aortic valve disease, fibrillation occurred shortly after the aorta was cross-clamped. The heart con verted to spontaneous rhythm with the sixth defibrillating electroshock. Multiple air emboli found in the coronary system appeared to have contributed to this development.
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Fig. 7.—Polygraph record of a 4-year-old white girl, 29 pounds, with tetralogy of Fallot, physical state 3 (moderate cyanosis, several episodes of congestive heart failure, digitalized). Surgery: complete repair of tetralogy of Fallot; patient received dehydrobenzperidol 6 mg„ and phentanyl 0.06 mg. (ratio 100:1). Note: Ventricular fibrillation occurred 2 minutes after clamping of the aorta. Spontaneous conversion from ventricular fibrillation to sinus rhythm shortly before completion of repair of the defect.
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Fig. 10.—Anesthesia r e c o r d of 5 % - y e a r - o l d w h i t e b o y w h o u n d e r w e n t s u r g e r y for c l o s u r e of v e n t r i c u l a r s e p t a l defect a t t h e a g e of 5 % y e a r s ( F l u o t h a n e - n i t r o u s oxide a n e s t h e s i a , p r o c e d u r e I, dark shadowed area). P a t i e n t r e t u r n e d for r e p e a t of closure of v e n t r i c u l a r s e p t a l defect a t t h e a g e of 7 y e a r s ( n e u r o l e p t a n e s t h e s i a , p r o c e d u r e I I , longitudinal bars). Note: H y p o t e n s i v e episodes before, d u r i n g , a n d a f t e r completion of b y p a s s w i t h F l u o t h a n e - n i t r o u s o x i d e a n e s t h e s i a a s c o m p a r e d t o a d e q u a t e s u s t a i n e d systolic a n d d i a s t o l i c blood p r e s s u r e r e c o r d e d w i t h neurolept anesthesia.
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I
G.B. 963865 WHITE BOY 5 1/2 Year old, 50 lt». SURGERY CLOSURE I.V.S.D. ANESTHESIA: INDUCTION CYCLOPROPANE MAINTENANCE: FLUOTHANE - N 2 0 - 0 2 , SEMI CLOSEO, CIRCLE ABSORPTION
Vol. 49, No. 6 June, 1965
N E U R O L E P T ANALGESIA AND A N E S T H E S I A TABLE
Neurolept anesthesia Systolic blood pressure Diastolie blood pressure Halothane anesthesia Systolic blood pressure Diastolie blood pressure
915
II.*
MEAN PREPERFUSION PRESSURE
MEAN POSTPERFUSION PRESSURE
SIGNIFICANCE t
113.3 69.6
121.0 73.2
p < 0.05 N. S.
100.2 61.1
93.2 61.2
p < 0.05 N. S.
NEUROLEPT
HALOTHANE
SIGNIFICANCE}
p < 0.001 89.0 98.5 Perfusion pressure 18.2 Age N, S. 23.25 •Mean systolic and diastolie blood pressures recorded before and after cardiopulmonary bypass and average perfusion pressure in 50 consecutive patients anesthetized with neurolept anesthesia and halothane-nitrous oxide anesthesia. Note: Mean systolic blood pressure in the post-perfusion period and average perfusion pressure are increased with neurolept anesthesia and decreased -with halothane-nitrous oxide anesthesia. Both values are statistically significant. tPaired comparison. JGroup comparison.
TABLE I I I . * RECOVERY STATUS
Awake on operating table Awake at return to recovery room Awakening within one hour after return to recovery room No recovery 1 died on table 1 cerebral embolism (?) 1 heart failure Total ♦Postoperative recovery in 101 patients following neurolept anesthesia.
NO. OF PATIENTS
81 10 7
101
Figs. 6, 7, 8, and 9 represent polygraph records of 4 patients undergoing closure of interatrial septal defect, complete repair of tetralogy of Pallot, mitral valve replacement, and aortic valve replacement, respectively. Fig. 10 represents the anesthesia record of a 514-year-old boy who had undergone repair of a ventricular septal defect under halothane-nitrous oxideoxygen anesthesia (procedure I, dark shadow). Eighteen months later the pro cedure was repeated, this time under neurolept anesthesia (procedure II, parallel bars). In Table II are listed mean systolic and diastolie blood pressures before and after cardiopulmonary bypass, as well as the average perfusion pressures, in a total of 100 consecutive patients (50 with neurolept anesthesia and 50 with fluothane-nitrous oxide-oxygen). Table I I I summarizes the various states of recovery following surgery. In this series a patient was considered awake as soon as he responded to questioning and was oriented as to person, time, and place. Postoperative Analgesia.—Most patients were pain-free when awakening on the operating table or arriving in the recovery room. In general, they did not need pain-relieving drugs for the first 6 to 8 hours postoperatively. During the first and second postoperative day, not more than 1 to 2 mg. of morphine
916
CORSSEN ET AL.
J. Thoracic and Cardiovas. Surg.
sulfate, given intramuscularly at 4 to 8 hour intervals, was necessary to keep patients comfortable. Usually on the third postoperative day the administration of narcotic analgesics could be discontinued. In infants and children, intramuscular injections of morphine sulfate at dosages of 0.25 to 0.5 mg. were usually given for pain relief on the first post operative day and repeated at 4 to 8 hour intervals. In a few cases the dose had to be increased to 1 mg. to achieve adequate pain control. It should be noted that patients undergoing neurolept anesthesia should not be given the usual doses of narcotic analgesics postoperatively because of the marked potentiation of action and the possibility of severe respiratory depression. Operative Complications.—At operation, complications attributable to the anesthetic management were few. In 2 infants, arterial perfusion pressures recorded during bypass were below 80 mm. Hg in spite of optimal flow rates produced by the pump oxygenator. After completion of the extracorporeal phase and restoration of effective heart action, arterial pressures were adequate in both patients. In 3 adult patients, the arterial perfusion pressures during bypass rose to values above 120 mm. Hg; the highest value was recorded in 1 patient at 150 mm. Hg. In 2 of these patients the administration of dehydrobenzperidol (10 mg.) into the pump oxygenator resulted in immediate return of the perfusion pressures to normal values which ranged from 100 to 110 mm. Hg. Decreased pulmonary compliance, usually occurring shortly after the completion of the intravenous injection of the dehydrobenzperidol-phentanyl mixture, was observed in the majority of patients in this series. Phentanylinduced muscle rigidity appeared to be the cause of this phenomenon. Intra venous administration of small amounts of suecinylcholine resulted invariably in immediate restoration of adequate pulmonary compliance. Postoperative Complications.—Circulatory: Hypotension, requiring treat ment with vasopressor agents, occurred soon after the operation in 12 cases. In all instances, this complication appeared to be related to the severity of the defect repaired and the ability of the heart to adjust to the altered hemodynamics. Respiratory: Three patients who had received d-tubocurarine during the operation showed signs of inadequate respiratory exchange on awakening, apparently due to the curare effect which was still partially present. All 3 patients responded promptly to conversion with the use of intravenous atropine sulfate and neostigmine methyl sulfate. Inability or unwillingness to cough was the most significant problem in patients who had received dehydrobenzperidol and phentanyl in a ratio of 100:1 during the initial phase of the study. These patients were undoubtedly depressed and, although awake, did not completely respond to commands for spontaneous and effective coughing. They had to be treated with frequent intratracheal suctioning to avoid accumulation of secretions and development of serious pulmonary complications. When the dose of dehydrobenzperidol was reduced to 0.1 mg. per pound of body weight combined with 0.02 mg. per pound of phentanyl (50:1), this respiratory problem was brought under control.
N E U R O L E P T ANALGESIA AND A N E S T H E S I A
Vol. 49, No. 6 June. 1965
TABLE
NO.
1
AGE
SEX
917
IV.*
ANATOMICAL DIAGNOSIS AND SURGICAL PROCEDURE
T I M E OF DEATH
CAUSE OF DEATH
3 wk.
F
Transposition of great vessels, atrial septum
2
4 mo.
F
Large ASD, closure of defect
On table
Right heart failure
3
8 mo.
M
Large VSD and P D A ; closure of defect, ligation of P D A
27 hr. postop.
" L o w output failure''
4
22 mo.
M
Atrioventricularis communis septum
5
2V4 yr.
M
Tetralogy of Fallot
6
3V2 yr.
M
Severe pulmonary stenosis, infundibular stenosis
6 da. postop.
8 hr. postop. 13 da. postop.
Eenal
Heart
failure
failure
Septicemia
4 da. postop.
Pulmonary hyper tension, " p u m p l u n g " syndrome
7
39 yr.
F
Calcined mitral valve with severe mitral stenosis and insufficient mitral valve, replacement
30 hr. postop.
Cerebral embolism (?)
8
58 yr.
M
Calcified mitral valve with severe mitral stenosis and insufficient mitral valve, replacement
30 hr. postop.
Right heart fail ure, pulmonary hypertension
Pulmonary stenosis, tricuspid 35 da. postop. Septicemia stenosis and insufficiency, tricuspid valvuloplasty •Age, sex, surgical procedure, time and cause of death in 9 patients following neurolept anesthesia. 9
60 yr.
M
Miscellaneous: In 5 children a transient macular rash, covering most of the anterior aspect of the chest and abdominal wall, appeared shortly after completion of the intravenous injection. In all instances this skin reaction faded within a few minutes. Deaths.—In Table IV are listed 9 deaths as to age and sex of patient, surgical procedure, and time and cause of death. None of the deaths were attributable to the anesthetic technique or the drugs used in the management of these patients. DISCUSSION
From the laboratory data presented and the preliminary experience accumulated in 101 patients, it is concluded that the technique of neurolept analgesia and anesthesia is safe and differs from previous methods used for open-heart surgery. The new features which differentiate the neuroleptic technique from conventional procedures may be the lack of cardiac depression, the peculiar type of blockade of alpha effects of epinephrine but not norepineph rine, the potent tranquilization, and the analgesia produced. Since Lillehei has shown the beneficial effects of alpha adrenergic blockade with Dibenzyline in patients undergoing cardiopulmonary bypass, it was of interest to compare the adrenergic blocking properties of this drug with chlorpromazine and dehydrobenzperidol. Both epinephrine and norepinephrine pressor responses were markedly reduced by Dibenzyline. In contrast, chlor-
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CORSSEN ET AL.
J. Thoracic and Cardiovas. Surg.
promazine and dehydrobenzperidol were ineffective in reducing the pressor effects of norepinephrine and, in fact, potentiated this response in some animals. This paradoxical effect of chlorpromazine has been emphasized previously.10 The practical implications of this finding is that one would expect peripheral sympathetic tone to be much more depressed by Dibenzyline than by the other two drugs. This was precisely the effect observed in our clinical studies with the use of dehydrobenzperidol. Statistical analysis of the cardiovascular effects clinically observed with neurolept anesthesia as compared with halothane-nitrous oxide showed that arterial pressures with the former were significantly higher, as shown in Table II. Characteristically the diastolic pressures in both groups were not altered, but there was a significant increase in the mean systolic pressure and perfusion pressure with the neurolept analgesic agents and a significant decrease in systolic pressure with halothane. There was no significant difference in the age of both groups. These results tend to indicate that cardiovascular function is not depressed with neurolept anesthesia. In contrast, halothane can produce a decrease in cardiac output and also a decrease in peripheral resistance. This observation supports the suggestion that halothane has some ganglionic blocking properties as well as the ability to modify the response to epinephrine and norepinephrine. 11 Although one of our original reasons for using neurolept anesthesia was the reported alpha adrenergic blocking properties of dehydrobenzperidol, it turns out that this agent is not a classical alpha adrenergic blocking agent. Both dehydrobenzperidol and chlorpromazine do not block the alpha effects of norepinephrine on blood pressure but only the alpha effects of epinephrine. This may be important in a patient in shock, since epinephrine levels are in creased tenfold. In animal studies, dehydrobenzperidol is a far more potent tranquilizer than chlorpromazine whereas they are equipotent in their cardiovascular effects. Dibenzyline has no tranquilizing effects as measured by depression of conditioned avoidance behavior. The action of the narcotic analgesics tested on conditioned avoidance behavior in rats paralleled their reported potency as analgesics.13 Phentanyl was clearly more potent and shorter acting than morphine sulfate. The shorter duration of action of phentanyl and dehydrobenzperidol is an advantage in the management of anesthetized patients. As a rule, there was a complete absence of pain during the early postanesthetic course. It is difficult to decide whether postoperative pain relief stemmed predominantly from the narcotic part or the tranquilizing part of the mixture. It was noted that the effects of narcotic analgesics are highly selective in blocking avoidance behavior but not escape response. In this respect both of these drugs act more like tranquilizers than analgesics, since one might assume that the escape response of rats to an electric shock would be eliminated or greatly reduced by a narcotic analgesic. Narcotic-induced muscle rigidity with subsequent reduction of pulmonary compliance frequently occurred during the induction phase and must be con-
Vol. 49, No. 6
June, 1965
N E U R O L E P T ANALGESIA AND A N E S T H E S I A
919
sidered a disadvantage of neurolept anesthesia. However, this complication is transient in duration and can easily be brought under control with intravenous succinylcholine. CONCLUSIONS
Dehydrobenzperidol and phentanyl appear to be a safe combination for the anesthetic management of patients undergoing cardiopulmonary bypass for the repair of defects by open-heart surgery. Dehydrobenzperidol provides a unique kind of alpha adrenergic block which does not block the alpha effects of norepinephrine on blood pressure. It does not significantly interfere with cardiovascular function except possibly in patients in shock who have an in crease in circulating epinephrine. In these patients it could only improve perfusion where that particular bed was constricted by epinephrine. Dehydro benzperidol has a shorter duration of action and is more potent than chlorpromazine. In this regard Dibenzyline has no tranquilizing properties. Phentanyl is a potent narcotic analgesic with a rapid onset and short duration. When compared to halothane-nitrous oxide anesthesia, neurolept anesthesia appears to offer the distinct advantage of retaining the inotropic and chronotropic effects of catecholamines on the myocardium, whereas halothane produces myocardial depression. Clinically, the combination of the two drugs with nitrous oxide-oxygen mixtures for sleep and amnesia appears to provide smooth induction of anes thesia, effective pain control during the anesthesia course, and prompt and un eventful recovery with minimum discomfort. The authors wish to express their gratitude to Drs. H. E. Sloan and J . D. Morris, Department of Surgery, Division of Thoracic Surgery, The University of Michigan Medical Center, for their substantial help and cooperation in the course of this study. ADDENDUM
Innovar as used in this study contained phentanyl and dehydrobenzperidol with benzperidol as a byproduct. Recent observations have indicated t h a t the benzperidol fraction of the mixture has substantially aided to produce effective alpha adrenergic blockade. A new preparation of Innovar now available for investigational use lacks the benzperidol fraction and has been found to exert considerably less alpha adrenergic blockade. REFERENCES 1. Lillehei, R. C , Lillehei, C. W., Grismer, J . T., and Levy, M. J . : Plasma Catecholamines in Open Heart Surgery: Prevention of Their Pernicious Effects by Pretreatment With Dibenzyline, S. Forum 14: 269-271, 1963. 2. Janssen, P. A. J . : Vergleichende Pharmakologische Daten ueber sechs neue basische 4'-Fluorobutyrophenone Derivative, Arzneimittelforsch. 1 1 : 819, 1961. 3. Janssen, P . A. J., Niemegeers, C. J . E., and Dony, J . G. H.: The Inhibitory Effect of F e n t a n y l and Other Morphine-Like Analgesics on t h e Warm W a t e r Induced Tail Withdrawal Reflex in Rats, Arzneimittelforsch. 13: 502-507, 1963. 4. DeCastro, J., and Mundeleer, P . : Die Neuroleptanalgesie. Auswahl der P r a e p a r a t e , Bedeutung der Analgesie und der Neurolepsie, Anaesthesist 1 1 : 10-17, 1962. 5. Corssen, G., Domino, E. P., and Sweet, R. B.: Neurolept-Analgesia and Anesthesia: Pharmacologic and Clinical Considerations, Anesth. & Analg. 4 3 : 748-763, 1964. 6. Cook, L., and Weidley, E . : Behavioral Effects of Some Psychopharmacological Agents, Ann. N e w York Acad. Sc. 66: 740, 1957.
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7. Snedecor, G. W.: Statistical Methods, ed. 5, Ames, Iowa, 1956, The Iowa State College Press. 8. Croxton, F . E.: Elementary Statistics With Applications in Medicine and the Biological Sciences, New York, 1959, Dover Publications, Inc. 9. Foldes, F . F., Hillmer, N. E., Molloy, E. E., and Monte, A. P . : Potentiation of the Neuromuscular Effect of Succinylcholine by Hexafluorenium, Anesthesiology 2 1 : 50-58, 1960. 10. CIBA Foundation Symposium: Adrenergic Mechanisms, Boston, 1960, Little, Brown & Company, p. 523. 11. Artusio, J. F . : Clinical Anesthesia, Halogenated Anesthetics, Philadelphia, 1963, F . A. Davis Company, vol. 1, p. 86. 12. Janssen, P . A. J., and Jageneau, A. H . : A New Series of Potent Analgesics. Part 2. Comparative Analgesic Activity, Acute Toxicity and Tolerance Development in E a t s for E875, Morphine, Pethidine and Methadone, J . Pharm. & Pharmacol. 14: 21, 1958.
VOLUME 49 JUNE 1965 NUMBER 6
Thoracic and Cardiovascular Surgery
ja Original
Communications
NEUROLEPT ANALGESIA A N D ANESTHESIA FOR OPEN-HEART SURGERY Pharmacologic Rationale and Clinical Experience Guenter Corssen, M.D., Peter Chodoff, M.D., Edward F. Domino, and Donald R. Kahn, M.D., Ann Arbor,
M.D.,
Mich.
T
wo major problems confront the anesthesiologist in his management of pa tients undergoing surgery for the correction of congenital and acquired heart defects. First is the limited physiologic reserve of these patients. Second, and possibly more important, are the pathophysiologic changes during bypass, which have been shown to be similar to those observed in low perfusion shock even though high flow rates are employed. Anesthetic agents and techniques are required which will afford protection against disturbances in homeostasis and at the same time provide smooth and rapid induction of anesthesia, with minuteto-minute control and prompt reversibility when needed. Agents at our disposal have met such requirements only in part. For exam ple, nonexplosive inhalation anesthetics, such as halothane and methoxyflurane, exert undesirable depressant effects on the myocardium. With "balanced" anes thesia, involving intravenous barbiturates, similar cardiac depression can occur. Cyclopropane is highly flammable and explosive. There is a vital need for agents which will counteract undesirable vascular reactions which may occur during cardiac bypass and which may simulate shock. A thorough understanding of the various pathophysiologic mechanisms that are activated during the extracorporeal phase is, of course, essential to proper and effective therapy. Lillehei 1 was the first to draw attention to the From the Departments of Anesthesiology, Pharmacology and Surgery, Division of Thoracic Surgery, The University of Michigan Medical Center, Ann Arbor, Mich. Received for. publication Nov. 23, 1964. 901
902
COESSEN E T AL.
J. Thoracic and Cardiovas. Surg.
pernicious effects of some vasoactive amines released during cardiopulmonary bypass and to present evidence of the beneficial effects obtained from alpha adrenergic blockade with phenoxybenzamine (Dibenzyline) to counteract exces sive vasoconstriction. From these observations it became apparent that patients exposed to cardiopulmonary bypass present a unique situation for the prophy lactic use of alpha adrenergic blockade. While Dibenzyline seems to be an ex cellent adrenergic blocking agent, its prolonged duration of action is a disad vantage because of the difficulty of controlling its powerful blocking action. Janssen and his associates2 introduced a group of butyrophenones among which dehydrobenzperidol appears to be particularly suitable for use in anes thesia. In the absence of any measurable toxic effects on vital organs, the drug mimics chlorpromazine in its pharmacologic actions, including powerful tranquilizing, antiemetic, antifibrillatory, and, what they have called, its alpha adrenergic blocking properties. When drugs of this type are used in conjunction with short-acting narcotic analgesics, such as phentanyl, a new and potent meperidine-like agent, 3 the result is "neuroleptanalgesia." 4 When the agents are used in conjunction with nitrous oxide-oxygen mixtures, an anesthetic state can be produced which is adequate for any minor or major surgical procedure. This relatively new anesthetic technique appears to exert few side effects. It has re cently been reported to be of particular value in the anesthetic management of patients who are poor surgical risks because of advanced age or for some other reason. 5 The absence of appreciable cardiac depression when these two drugs are used, along with the fact that the adrenergic blocking effects are limited, prompted us to study the application of this technique in anesthetic procedures for open cardiac surgery. It was decided to carry out simultaneous laboratory investigations of the pharmacologic rationale for employing the two drugs mentioned above, dehydro benzperidol and phentanyl. The results presented below provide a theoretical as well as practical basis for the suitability of this new anesthetic approach in the management of patients undergoing open-heart surgery with the aid of cardio pulmonary bypass. E X P E R I M E N T A L STUDY
Methods.—For the study of the cardiovascular effects of various alpha adrenergic blockers, including Dibenzyline, chlorpromazine, and dehydrobenz peridol, 30 adult mongrel dogs of both sexes were used. The animals were anes thetized with pentobarbital (30 mg./Kg., intravenously). An endotracheal tube was placed and artificial ventilation was maintained at 300 ml./air/Kg./min. Blood pressure recordings were obtained through the cannulated femoral artery by means of a mercury manometer with a lever writing on a smoked kymograph. The femoral vein was cannulated for the injection of the test drugs. Epinephrine and norepinephrine wei*e injected intravenously in a dose of 2 fig per kilogram. Increasing doses of Dibenzyline, chlorpromazine, and de hydrobenzperidol, calculated as base, were administered every 15 minutes and the per cent change in blood pressure over control levels was recorded for each
Vol. 49, No. 6 June, 1965
NETJROLEPT ANALGESIA AND ANESTHESIA
903
administration of epinephrine and norepinephrine. After each injection, the venous cannula was flushed with 5 ml. of normal saline. The study of the tranquilizing effects of Dibenzyline, ehlorpromazine, and dehydrobenzperidol was carried out in 60 male Holtzmann rats that weighed between 150 and 400 grams. The modification of the Cook and Weidley 6 con ditioned avoidance pole-jump technique was used. Each rat was given 100 train ing trials before the drug studies. The conditioned stimulus (CS) consisted of a 6-volt buzzer sound lasting 5 seconds, followed by a 5-second unconditioned stimulus (US) consisting of a scrambled electric shock through the grid floor. The parameters of electric stimulation were 60 c.p.s. sine waves at 1 Ma. The CS overlapped the US. Prior to drug testing, the rats were required to meet a criteria of 19 out of 20 successful avoidances. To avoid possible cumulative effects, at least 5 days lapsed between the administration of the drugs. The narcotic analgesics, morphine sulfate and phentanyl, were given only once to each animal, in order to avoid tolerance development. Dose-response curves for all agents were obtained, in addition to an index of duration of action. All data were subjected to statistical analysis, including regression analysis performed according to Snedecor.7 Correlation coefficients for each line were obtained according to Croxton.8 Results.—As expected, increasing doses of Dibenzyline, ehlorpromazine,
51 -v CONTROL
48
Y * y + b[Log(X)2-iO
45 42 39-
X A
3633Q;
CHLORPROMAZINE
Y • 22.6-14.6 QjOfl ( X 2 ) - l . 6 6 ]
DEHYDROBENZPERIDOL DIBENZYLINE
Y « 21.7-11.7 [Log ( X 2 ) - 1 . 7 2 ]
Y » 18.6-35.6 [Log ( X 2 ) - 1 . 4 0 1
30
t 27-1
? + 5 0 % DECREASE O 24 ? 21 I8H LU
£
12 96 3 1.0
2.0 LOG (DOSExK)2)
Fig. 1.—Modification of mean per cent increase in blood pressure response to epinephrine by various adrenergic blocking agents in the pentobarbital-anesthetized dog. To facilitate calcu lation the logarithm of the dose X 100 was used and expressed in the equations of the regres sion lines in this and subsequent figures.
CORSSEN ET AL.
904
J. Thoracic and Cardiovas. Surg.
and dehydrobenzperidol progressively decreased the mean arterial pressor re sponse to intravenous epinephrine. This is illustrated in Fig. 1. In this and the following graphic presentations, each point represents the average response of 3 to 6 animals given cumulative doses of each of the adrenergic blocking agents. Estimates of the potency of the drugs in reducing the pressor response to epi nephrine, calculated from the regression equations and expressed as ED 50 , were 0.16 mg. per kilogram for Dibenzyline, 0.37 mg. per kilogram for chlorpromazine, and 0.36 mg. per kilogram for dehydrobenzperidol. Dibenzyline was the most potent. Chlorpromazine and dehydrobenzperidol were less so; there was no difference between the two. All three agents showed a plateau-like effect when doses larger than 2 mg. per kilogram were used. The effect of higher doses of the three drugs in causing epinephrine reversal is illustrated in Fig. 2. Dibenzyline again was the most potent, while chlor promazine and dehydrobenzperidol were similar but less effective. The alteration of the norepinephrine pressor response by these drugs is 62.555 50 -
X
y=l3.6+l3.l ( L 0 9 X 2 - I . 8 4 )
— CHLORPROMAZINE
o
DIBENZYLINE
A —
DEHYDROBENZPERIDOL
y=26.0+l98(LogX 2 -1.68) y = l 2 . 8 + 7 . 9 ( L o g X 2 -1.95)
Ul
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NEITROLEPT ANALGESIA AND A N E S T H E S I A
Vol. 49, No. June, 1965
x
62.5 60
905
A
55 50
-
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40 35 30 25 UJ
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y • 52.9 -1.24 [Log CX2)-I.84]
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DIBENZYLINE
—I
y =48.2-0.53 [Log(X 2 )-l.95]
y »36.0- I5.3[j-0g ( X 2 ) - I . 6 8 j
1
- 1 —
3.0 1.0 2.0 LOG ( DOSE x I0 2 ) Fig. 3.—Modification of mean per cent increase in blood pressure response to norepinephrine by various adrenergic blocking agents.
graphically shown in Fig. 3. Dibenzyline produced a progressive block of the norepinephrine pressor response. The marked variability observed with chlorpromazine and dehydrobenzperidol may be explained by the fact that both drugs can reduce as well as enhance the pressor effects of norepinephrine. The over-all values indicated that the regression lines of both drugs did not sig nificantly differ from zero correlation (p > 0.4). An index of the tranquilizing action of the. three drugs is their ability to block conditioned avoidance in rats. As illustrated in Fig. 4, the ED 5 0 for de hydrobenzperidol was 0.06 mg. per kilogram and 1.56 mg. per kilogram for chlorpromazine. Thus, dehydrobenzperidol proved in this test to be 26 times as potent in its tranquilizing effect as chlorpromazine. In contrast, Dibenzyline had no effect on conditioned avoidance behavior in rats in doses ranging from 1 mg. to 32 mg. per kilogram. After 8 hours, rats given chlorpromazine still had not recovered, while rats given dehydrobenzperidol were back to normal, indicating that the latter drug has a shorter duration of action.
COESSEN ET AL.
906 100-
J. Thoracic and Cardiovas. Surg.
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AVOIDANCE X —— ' CHLORPROMAZINE Y" 53.6 + 58 [LOG X z -2.3j 2 ESCAPE O — ■ — Y=I9.8 +44.4 S.OG X -2.3]
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2.0 LOG (DOSE x I 0 2 )
Fig. 4.—Modification of conditioned pole-jumping by various alpha adrenergic blocking agents. The per cent blocked avoidance and escape responses are plotted on the Y-axis. The drugs were given subcutaneously and the animals tested before and 60 minutes later.
Narcotic analgesics like morphine sulfate and phentanyl can also block conditioned avoidance behavior (Fig. 5). Phentanyl proved to be over 100 times as potent as morphine sulfate in this regard; its ED 5 0 was 0.04 mg. per kilo gram as compared to 4.58 mg. per kilogram for the latter. It was also noted that phentanyl had a much quicker onset of action followed by a more rapid recovery. CLINICAL STUDY
The series of clinical cases studied included 47 male and 54 female patients ranging in age from 3 weeks to 60 years. Preanesthetic Medication.—In infants and children, preanesthetic medica tion consisted of pentobarbital, 1 to 2 mg. per pound of body weight, combined with seopolamine, 0.1 to 0.2 mg. Adults received a total of 100 to 150 mg. of pentobarbital together with 0.4 mg. of seopolamine. The drugs were given sub cutaneously 90 minutes before induction of anesthesia. No opiates were admin istered as preanesthetic medication in this series of patients.
Vol.49, No. 6 June, 1965
NEUBOLEPT ANALGESIA AND ANESTHESIA
907
100-
/
80-
1/
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to
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ESCAPE X MORPHINE Y = 32 + 2 2 5 I L 0 G X 2 - 2 . 7 7 ) AVOIDANCE O — — Y = 18.5 + 140 (LOG X * - 2 . 7 7 )
*:
t>
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40 o
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2.0 1.0 LOG (DOSExlO 2 )
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3.0
F i g . 5.—Blockade of conditioned p o l e - j u m p i n g of r a t s b y p h e n t a n y l a n d m o r p h i n e s u l f a t e . T h e d r u g s w e r e given s u b c u t a n e o u s ! y a n d t h e a n i m a l s t e s t e d before a n d 30 m i n u t e s l a t e r .
Induction.—Anesthesia was induced by 0.1 to 0.2 ml. per pound of body weight of the fixed mixture containing dehydrobenzperidol 1 mg./l ml. com bined with phentanyl 0.02 mg. per kilogram (50:1)* administered intravenously over a period of approximately 30 to 60 seconds. During the earlier phase of the study, patients received a 100:1 ratio of dehydrobenzperidol to phentanyl (1 mg. of dehydrobenzperidol combined with 0.01 mg. of phentanyl). The in jection was followed by inhalation of 50 per cent to 75 per cent nitrous oxide in oxygen. Intravenous sueeinyleholine (20 to 60 mg.) was given 1 to 2 minutes after starting the administration of nitrous oxide-oxygen to facilitate the place ment of the endotracheal tube. Maintenance.—Anesthesia was maintained with 50 per cent to 75 per cent nitrous oxide in oxygen. Eespiration was controlled by manual pressure on a • I n n o v a r , McNeil L a b o r a t o r i e s , F o r t W a s h i n g t o n , P a .
908
CORSSEN ET AL.
J. Thoracic and Cardiovas. Surg.
breathing bag connected to a semi-closed carbon dioxide absorption system. Small doses of phentanyl (0.025 mg. to 0.1 mg.) were administered intrave nously when signs of surgical stimulation (sudden rise in blood pressure, in crease in pulse rate) indicated the need for elevating the pain threshold. For adequate control of diaphragmatic activity, intravenous increments of 10 to 20 mg. of succinylcholine were administered intermittently, preceded by a single dose (20 to 40 mg.) of hexafluorenium given at the start of surgery to prolong the succinylcholine effect, as proposed by Foldes and his associates.9 Some adult patients received intermittent doses of nondepolarizing muscle relaxants such as d-tubocurarine (3 to 6 mg.) or gallamine (20 to 40 mg.). During bypass, ad ditional small increments of succinylcholine or d-tubocurarine or gallamine were injected into the pump oxygenator to control diaphragmatic movements. Continuous electroencephalographic recordings (left frontal-parietal) and electrocardiographs recordings (Lead II) were obtained in all patients. Pres sures from the femoral artery and femoral vein were also continuously recorded and transmitted to a Grass multichannel recorder. During bypass the lungs were kept inflated with a 50 per cent mixture of nitrous oxide and oxygen. The pump oxygenator consisted of a rotating disc oxygenator with five roller pumps. Venous blood was returned to the pump by gravity and oxy genated blood was returned to the femoral artery. Oxygenation of the blood was achieved with 98 per cent oxygen and 2 per cent carbon dioxide. The blood temperature was controlled by circulation through a heat exchanger. As a rule, the blood temperature during bypass was kept in a range of 30° to 32° C. The superior and inferior venae cavae were cannulated through the right atrial appendage. In aortic valve replacements, coronary perfusion was instituted by inserting catheters into the right and left coronary ostia. The control series included 50 consecutive patients who had recently under gone open-heart surgery under anesthesia induced by halothane-nitrous oxideoxygen. In this group of patients, maintenance concentrations of halothane ranged from 0.5 to 1.0 per cent (Fluotec vaporizer). During the bypass, halo thane was administered via the pump oxygenator, in 0.5 to 1.0 per cent con centrations; after bypass, the anesthesia usually involved nitrous oxide-oxygen mixtures only. Fifty polygraph and perfusion records available from these pa tients were compared with those of 50 consecutive patients in the study series. Systolic and diastolic blood pressures before and after bypass were compared as a nonindependent pair of samples while the perfusion pressures and the ages were analyzed by group comparison.8 Results.—Following intravenous administration of dehydrobenzperidol and phentanyl, all patients lapsed within 1 to 3 minutes into a semiconscious state in which they lay resting and unresistant but were able to follow verbal commands such as "take a deep breath," "open your mouth," etc. However, spontaneous respiration usually ceased. With the inhalation of nitrous oxide-oxygen mix tures, consciousness was lost within 30 to 60 seconds. Frequently at this point pulmonary compliance decreased markedly, making passive inflation of the lungs difficult. Intravenous administration of succinylcholine (20 to 40 mg.) resulted
Vol. 49, No. 6 June, 1965
N E U R O L E P T ANALGESIA AND A N E S T H E S I A TABLE
TYPE OF CARDIAC DEFECT
909
I.*
| NO. OF PATIENTS |
TYPE OF SURGERY
Ventricular septal defect 41 Closure of defect (2 repeat) Closure of defect (1 repeat) 13 Atrial septal defect Repair of stenosis 9 Pulmonic stenosis (valvular and/or infundibular) Mitral valvuloplasty (12 patients) 19 Acquired mitral valve disease (mitral Mitral valve replacement (7 patients) valve stenosis and/or insufficiency) Aortic valvuloplasty (6 patients) 11 Congenital or acquired aortic valve Aortic valve replacement (5 patients) disease (aortic valve stenosis and/or insufficiency) Total correction 4 Tetralogy of Fallot Closure of defect 2 Ostium primum Creation of atrial septum defect 1 Transposition of great vessels Repair of atrioventricularis communis 1 Atrioventricularis communis Total 101 •Types of cardiac defects and surgical repairs carried out under neurolept anesthesia in 101 patients.
invariably in immediate restoration of adequate pulmonary compliance. The endotracheal tube was then placed and the patient was ready for surgery. During the course of surgery the patient could be awakened at any time by simply shutting off the nitrous oxide flow and washing out the breathing bag with oxygen. The patient was able to follow commands, such as to open the eyes or turn the head, and could answer questions readily by nodding the head. Al though some patients were kept awake for prolonged periods, none remembered the episodes of wakefulness when later asked about memory of this event. The types of cardiac effects and surgical procedures involved in operations under neurolept analgesia and anesthesia are summarized in Table I. The average duration of surgery was 3 hours and 10 minutes. In the longest operation, which lasted 8 hours and 30 minutes, the patient was a 43year-old women with mitral and tricuspid stenosis and insufficiency. The short est procedure, lasting 2 hours, was for repair of pulmonic stenosis in a 7-yearold boy. The average duration of cardiopulmonary bypass was 1 hour and 6 minutes. The longest period, 3 hours and 55 minutes, was recorded during replacement of a mitral valve in a 40-year-old woman. The shortest bypass, 18 minutes, was carried out in a 14-year-old boy for repair of a pulmonic stenosis. Spontaneous cardiac activity was maintained throughout the bypass in 90 patients. In the remaining 11, ventricular fibrillation occurred following inter mittent cross-clamping of the aorta, and in 9 of these the sinus rhythm was re stored with a single electroshock from an internal defibrillator (150 v., 1.5 amps., 15 sec. duration). In 1 patient, the heart converted spontaneously to sinus rhythm at the end of the surgical repair (closure of ventricular septal defect). In another patient, a 53-year-old man in a terminal stage of aortic valve disease, fibrillation occurred shortly after the aorta was cross-clamped. The heart con verted to spontaneous rhythm with the sixth defibrillating electroshock. Multiple air emboli found in the coronary system appeared to have contributed to this development.
0
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Fig. 6.—Polygraph record of a 28-year-old white man, 193 pounds, with large interatrial septal defect. Surgery: closure of interatrial septal defect; patient received dehydrobenzperidol 20 mg. and phentanyl 0.4 mg. (ratio 50:1). Note: First arterial pressure recorded after discontinuing bypass, 155/95 mm. Hg.
VENOUS PRESSURE (FEMORAL VEIN ) mm Hg
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Fig. 7.—Polygraph record of a 4-year-old white girl, 29 pounds, with tetralogy of Fallot, physical state 3 (moderate cyanosis, several episodes of congestive heart failure, digitalized). Surgery: complete repair of tetralogy of Fallot; patient received dehydrobenzperidol 6 mg„ and phentanyl 0.06 mg. (ratio 100:1). Note: Ventricular fibrillation occurred 2 minutes after clamping of the aorta. Spontaneous conversion from ventricular fibrillation to sinus rhythm shortly before completion of repair of the defect.
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Fig. 8.—Polygraph record of a 40-year-old white woman, 118 pounds, physical state 3 (severe mitral stenosis and insufflciency, congestive heart failure, digitalized). Surgery: replacement of mitral valve; patient received dehydrobenzperidol 24 mg. and phentanyl 0.48 mg. (ratio 50:1). Note: Spontaneous heartbeat was maintained throughout 3 hours and 55 minutes of cardiopulmonary bypass. First arterial pressure recorded after discontinuing bypass, 120/75 mm. Hg.
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ARTERIAL PRESSURE 120
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Fig. 9.—Polygraph record of a 55-year-old white man, 132 pounds, physical state 4 (severe aortic stenosis and insufficiency, repeated angina attacks, digitalized). Surgery: aortic valve replacement; patient received dehydrobenzperidol 28 mg. and phentanyl 0.56 mg. (ratio 50:1). Note: Conversion from ventricular flbrillation to sinus rhythm with one single electric shock. First arterial pressure recorded after discontinuing bypass, 125/80 mm. Hg.
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7 Ywr old, 67 Ibf REPEAT, PREVIOUS CLOSURE I.V.S.O. 1962 NEUROLEPT - ANALGESIA
n
Fig. 10.—Anesthesia r e c o r d of 5 % - y e a r - o l d w h i t e b o y w h o u n d e r w e n t s u r g e r y for c l o s u r e of v e n t r i c u l a r s e p t a l defect a t t h e a g e of 5 % y e a r s ( F l u o t h a n e - n i t r o u s oxide a n e s t h e s i a , p r o c e d u r e I, dark shadowed area). P a t i e n t r e t u r n e d for r e p e a t of closure of v e n t r i c u l a r s e p t a l defect a t t h e a g e of 7 y e a r s ( n e u r o l e p t a n e s t h e s i a , p r o c e d u r e I I , longitudinal bars). Note: H y p o t e n s i v e episodes before, d u r i n g , a n d a f t e r completion of b y p a s s w i t h F l u o t h a n e - n i t r o u s o x i d e a n e s t h e s i a a s c o m p a r e d t o a d e q u a t e s u s t a i n e d systolic a n d d i a s t o l i c blood p r e s s u r e r e c o r d e d w i t h neurolept anesthesia.
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G.B. 963865 WHITE BOY 5 1/2 Year old, 50 lt». SURGERY CLOSURE I.V.S.D. ANESTHESIA: INDUCTION CYCLOPROPANE MAINTENANCE: FLUOTHANE - N 2 0 - 0 2 , SEMI CLOSEO, CIRCLE ABSORPTION
Vol. 49, No. 6 June, 1965
N E U R O L E P T ANALGESIA AND A N E S T H E S I A TABLE
Neurolept anesthesia Systolic blood pressure Diastolie blood pressure Halothane anesthesia Systolic blood pressure Diastolie blood pressure
915
II.*
MEAN PREPERFUSION PRESSURE
MEAN POSTPERFUSION PRESSURE
SIGNIFICANCE t
113.3 69.6
121.0 73.2
p < 0.05 N. S.
100.2 61.1
93.2 61.2
p < 0.05 N. S.
NEUROLEPT
HALOTHANE
SIGNIFICANCE}
p < 0.001 89.0 98.5 Perfusion pressure 18.2 Age N, S. 23.25 •Mean systolic and diastolie blood pressures recorded before and after cardiopulmonary bypass and average perfusion pressure in 50 consecutive patients anesthetized with neurolept anesthesia and halothane-nitrous oxide anesthesia. Note: Mean systolic blood pressure in the post-perfusion period and average perfusion pressure are increased with neurolept anesthesia and decreased -with halothane-nitrous oxide anesthesia. Both values are statistically significant. tPaired comparison. JGroup comparison.
TABLE I I I . * RECOVERY STATUS
Awake on operating table Awake at return to recovery room Awakening within one hour after return to recovery room No recovery 1 died on table 1 cerebral embolism (?) 1 heart failure Total ♦Postoperative recovery in 101 patients following neurolept anesthesia.
NO. OF PATIENTS
81 10 7
101
Figs. 6, 7, 8, and 9 represent polygraph records of 4 patients undergoing closure of interatrial septal defect, complete repair of tetralogy of Pallot, mitral valve replacement, and aortic valve replacement, respectively. Fig. 10 represents the anesthesia record of a 514-year-old boy who had undergone repair of a ventricular septal defect under halothane-nitrous oxideoxygen anesthesia (procedure I, dark shadow). Eighteen months later the pro cedure was repeated, this time under neurolept anesthesia (procedure II, parallel bars). In Table II are listed mean systolic and diastolie blood pressures before and after cardiopulmonary bypass, as well as the average perfusion pressures, in a total of 100 consecutive patients (50 with neurolept anesthesia and 50 with fluothane-nitrous oxide-oxygen). Table I I I summarizes the various states of recovery following surgery. In this series a patient was considered awake as soon as he responded to questioning and was oriented as to person, time, and place. Postoperative Analgesia.—Most patients were pain-free when awakening on the operating table or arriving in the recovery room. In general, they did not need pain-relieving drugs for the first 6 to 8 hours postoperatively. During the first and second postoperative day, not more than 1 to 2 mg. of morphine
916
CORSSEN ET AL.
J. Thoracic and Cardiovas. Surg.
sulfate, given intramuscularly at 4 to 8 hour intervals, was necessary to keep patients comfortable. Usually on the third postoperative day the administration of narcotic analgesics could be discontinued. In infants and children, intramuscular injections of morphine sulfate at dosages of 0.25 to 0.5 mg. were usually given for pain relief on the first post operative day and repeated at 4 to 8 hour intervals. In a few cases the dose had to be increased to 1 mg. to achieve adequate pain control. It should be noted that patients undergoing neurolept anesthesia should not be given the usual doses of narcotic analgesics postoperatively because of the marked potentiation of action and the possibility of severe respiratory depression. Operative Complications.—At operation, complications attributable to the anesthetic management were few. In 2 infants, arterial perfusion pressures recorded during bypass were below 80 mm. Hg in spite of optimal flow rates produced by the pump oxygenator. After completion of the extracorporeal phase and restoration of effective heart action, arterial pressures were adequate in both patients. In 3 adult patients, the arterial perfusion pressures during bypass rose to values above 120 mm. Hg; the highest value was recorded in 1 patient at 150 mm. Hg. In 2 of these patients the administration of dehydrobenzperidol (10 mg.) into the pump oxygenator resulted in immediate return of the perfusion pressures to normal values which ranged from 100 to 110 mm. Hg. Decreased pulmonary compliance, usually occurring shortly after the completion of the intravenous injection of the dehydrobenzperidol-phentanyl mixture, was observed in the majority of patients in this series. Phentanylinduced muscle rigidity appeared to be the cause of this phenomenon. Intra venous administration of small amounts of suecinylcholine resulted invariably in immediate restoration of adequate pulmonary compliance. Postoperative Complications.—Circulatory: Hypotension, requiring treat ment with vasopressor agents, occurred soon after the operation in 12 cases. In all instances, this complication appeared to be related to the severity of the defect repaired and the ability of the heart to adjust to the altered hemodynamics. Respiratory: Three patients who had received d-tubocurarine during the operation showed signs of inadequate respiratory exchange on awakening, apparently due to the curare effect which was still partially present. All 3 patients responded promptly to conversion with the use of intravenous atropine sulfate and neostigmine methyl sulfate. Inability or unwillingness to cough was the most significant problem in patients who had received dehydrobenzperidol and phentanyl in a ratio of 100:1 during the initial phase of the study. These patients were undoubtedly depressed and, although awake, did not completely respond to commands for spontaneous and effective coughing. They had to be treated with frequent intratracheal suctioning to avoid accumulation of secretions and development of serious pulmonary complications. When the dose of dehydrobenzperidol was reduced to 0.1 mg. per pound of body weight combined with 0.02 mg. per pound of phentanyl (50:1), this respiratory problem was brought under control.
N E U R O L E P T ANALGESIA AND A N E S T H E S I A
Vol. 49, No. 6 June. 1965
TABLE
NO.
1
AGE
SEX
917
IV.*
ANATOMICAL DIAGNOSIS AND SURGICAL PROCEDURE
T I M E OF DEATH
CAUSE OF DEATH
3 wk.
F
Transposition of great vessels, atrial septum
2
4 mo.
F
Large ASD, closure of defect
On table
Right heart failure
3
8 mo.
M
Large VSD and P D A ; closure of defect, ligation of P D A
27 hr. postop.
" L o w output failure''
4
22 mo.
M
Atrioventricularis communis septum
5
2V4 yr.
M
Tetralogy of Fallot
6
3V2 yr.
M
Severe pulmonary stenosis, infundibular stenosis
6 da. postop.
8 hr. postop. 13 da. postop.
Eenal
Heart
failure
failure
Septicemia
4 da. postop.
Pulmonary hyper tension, " p u m p l u n g " syndrome
7
39 yr.
F
Calcined mitral valve with severe mitral stenosis and insufficient mitral valve, replacement
30 hr. postop.
Cerebral embolism (?)
8
58 yr.
M
Calcified mitral valve with severe mitral stenosis and insufficient mitral valve, replacement
30 hr. postop.
Right heart fail ure, pulmonary hypertension
Pulmonary stenosis, tricuspid 35 da. postop. Septicemia stenosis and insufficiency, tricuspid valvuloplasty •Age, sex, surgical procedure, time and cause of death in 9 patients following neurolept anesthesia. 9
60 yr.
M
Miscellaneous: In 5 children a transient macular rash, covering most of the anterior aspect of the chest and abdominal wall, appeared shortly after completion of the intravenous injection. In all instances this skin reaction faded within a few minutes. Deaths.—In Table IV are listed 9 deaths as to age and sex of patient, surgical procedure, and time and cause of death. None of the deaths were attributable to the anesthetic technique or the drugs used in the management of these patients. DISCUSSION
From the laboratory data presented and the preliminary experience accumulated in 101 patients, it is concluded that the technique of neurolept analgesia and anesthesia is safe and differs from previous methods used for open-heart surgery. The new features which differentiate the neuroleptic technique from conventional procedures may be the lack of cardiac depression, the peculiar type of blockade of alpha effects of epinephrine but not norepineph rine, the potent tranquilization, and the analgesia produced. Since Lillehei has shown the beneficial effects of alpha adrenergic blockade with Dibenzyline in patients undergoing cardiopulmonary bypass, it was of interest to compare the adrenergic blocking properties of this drug with chlorpromazine and dehydrobenzperidol. Both epinephrine and norepinephrine pressor responses were markedly reduced by Dibenzyline. In contrast, chlor-
918
CORSSEN ET AL.
J. Thoracic and Cardiovas. Surg.
promazine and dehydrobenzperidol were ineffective in reducing the pressor effects of norepinephrine and, in fact, potentiated this response in some animals. This paradoxical effect of chlorpromazine has been emphasized previously.10 The practical implications of this finding is that one would expect peripheral sympathetic tone to be much more depressed by Dibenzyline than by the other two drugs. This was precisely the effect observed in our clinical studies with the use of dehydrobenzperidol. Statistical analysis of the cardiovascular effects clinically observed with neurolept anesthesia as compared with halothane-nitrous oxide showed that arterial pressures with the former were significantly higher, as shown in Table II. Characteristically the diastolic pressures in both groups were not altered, but there was a significant increase in the mean systolic pressure and perfusion pressure with the neurolept analgesic agents and a significant decrease in systolic pressure with halothane. There was no significant difference in the age of both groups. These results tend to indicate that cardiovascular function is not depressed with neurolept anesthesia. In contrast, halothane can produce a decrease in cardiac output and also a decrease in peripheral resistance. This observation supports the suggestion that halothane has some ganglionic blocking properties as well as the ability to modify the response to epinephrine and norepinephrine. 11 Although one of our original reasons for using neurolept anesthesia was the reported alpha adrenergic blocking properties of dehydrobenzperidol, it turns out that this agent is not a classical alpha adrenergic blocking agent. Both dehydrobenzperidol and chlorpromazine do not block the alpha effects of norepinephrine on blood pressure but only the alpha effects of epinephrine. This may be important in a patient in shock, since epinephrine levels are in creased tenfold. In animal studies, dehydrobenzperidol is a far more potent tranquilizer than chlorpromazine whereas they are equipotent in their cardiovascular effects. Dibenzyline has no tranquilizing effects as measured by depression of conditioned avoidance behavior. The action of the narcotic analgesics tested on conditioned avoidance behavior in rats paralleled their reported potency as analgesics.13 Phentanyl was clearly more potent and shorter acting than morphine sulfate. The shorter duration of action of phentanyl and dehydrobenzperidol is an advantage in the management of anesthetized patients. As a rule, there was a complete absence of pain during the early postanesthetic course. It is difficult to decide whether postoperative pain relief stemmed predominantly from the narcotic part or the tranquilizing part of the mixture. It was noted that the effects of narcotic analgesics are highly selective in blocking avoidance behavior but not escape response. In this respect both of these drugs act more like tranquilizers than analgesics, since one might assume that the escape response of rats to an electric shock would be eliminated or greatly reduced by a narcotic analgesic. Narcotic-induced muscle rigidity with subsequent reduction of pulmonary compliance frequently occurred during the induction phase and must be con-
Vol. 49, No. 6
June, 1965
N E U R O L E P T ANALGESIA AND A N E S T H E S I A
919
sidered a disadvantage of neurolept anesthesia. However, this complication is transient in duration and can easily be brought under control with intravenous succinylcholine. CONCLUSIONS
Dehydrobenzperidol and phentanyl appear to be a safe combination for the anesthetic management of patients undergoing cardiopulmonary bypass for the repair of defects by open-heart surgery. Dehydrobenzperidol provides a unique kind of alpha adrenergic block which does not block the alpha effects of norepinephrine on blood pressure. It does not significantly interfere with cardiovascular function except possibly in patients in shock who have an in crease in circulating epinephrine. In these patients it could only improve perfusion where that particular bed was constricted by epinephrine. Dehydro benzperidol has a shorter duration of action and is more potent than chlorpromazine. In this regard Dibenzyline has no tranquilizing properties. Phentanyl is a potent narcotic analgesic with a rapid onset and short duration. When compared to halothane-nitrous oxide anesthesia, neurolept anesthesia appears to offer the distinct advantage of retaining the inotropic and chronotropic effects of catecholamines on the myocardium, whereas halothane produces myocardial depression. Clinically, the combination of the two drugs with nitrous oxide-oxygen mixtures for sleep and amnesia appears to provide smooth induction of anes thesia, effective pain control during the anesthesia course, and prompt and un eventful recovery with minimum discomfort. The authors wish to express their gratitude to Drs. H. E. Sloan and J . D. Morris, Department of Surgery, Division of Thoracic Surgery, The University of Michigan Medical Center, for their substantial help and cooperation in the course of this study. ADDENDUM
Innovar as used in this study contained phentanyl and dehydrobenzperidol with benzperidol as a byproduct. Recent observations have indicated t h a t the benzperidol fraction of the mixture has substantially aided to produce effective alpha adrenergic blockade. A new preparation of Innovar now available for investigational use lacks the benzperidol fraction and has been found to exert considerably less alpha adrenergic blockade. REFERENCES 1. Lillehei, R. C , Lillehei, C. W., Grismer, J . T., and Levy, M. J . : Plasma Catecholamines in Open Heart Surgery: Prevention of Their Pernicious Effects by Pretreatment With Dibenzyline, S. Forum 14: 269-271, 1963. 2. Janssen, P. A. J . : Vergleichende Pharmakologische Daten ueber sechs neue basische 4'-Fluorobutyrophenone Derivative, Arzneimittelforsch. 1 1 : 819, 1961. 3. Janssen, P . A. J., Niemegeers, C. J . E., and Dony, J . G. H.: The Inhibitory Effect of F e n t a n y l and Other Morphine-Like Analgesics on t h e Warm W a t e r Induced Tail Withdrawal Reflex in Rats, Arzneimittelforsch. 13: 502-507, 1963. 4. DeCastro, J., and Mundeleer, P . : Die Neuroleptanalgesie. Auswahl der P r a e p a r a t e , Bedeutung der Analgesie und der Neurolepsie, Anaesthesist 1 1 : 10-17, 1962. 5. Corssen, G., Domino, E. P., and Sweet, R. B.: Neurolept-Analgesia and Anesthesia: Pharmacologic and Clinical Considerations, Anesth. & Analg. 4 3 : 748-763, 1964. 6. Cook, L., and Weidley, E . : Behavioral Effects of Some Psychopharmacological Agents, Ann. N e w York Acad. Sc. 66: 740, 1957.
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J. Thoracic and Cardiovas. Surg.
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