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GUENTHER CORSSEN, M.D. EDWARD F. DOMINO, M.D. ROBERT B. SWEET, M.D. Ann Arbor, Michigan*

produce a state of rest in such structures as the cerebral cortex, the diencephalon, certain hormonal relays, and from surgical pain only if cortical and various ganglionic and terminal s y n a p subcortical centers are effectively de- ses. Naturally this artificial hibernapressed. The efficacy of agents used to tion was often marked by circulatory produce such an anesthetic s t a t e has depression resulting from induced hombeen judged according to how fast they eostatic imbalance. could induce optimal cerebral depression The search for other means of selecwith minimal circulatory, respiratory, and metabolic derangements, and how tively blocking the afferent systems inreadily their effects could be overcome. volved in surgical stress has led to increased emphasis on the possibility of Laboritl first drew attention t o the combining analgesic agents with agents need for revising the old conventional that suppress vegetative reflexes. Since approach to general anesthesia when he Janssens introduction of a series of introduced a new concept based on selec- highly potent analgesic and neuroleptic a n anesthetic technic has tive blocking of certain cellular, autonomic, and endocrine mechanisms nor- evolved, called neuroleptanalgesia,6 mally activated as a response to stress. which renders the patient free from Drug combinations capable of causing pain without affecting certain areas of such multifocal inhibition were used to the central nervous system that are
OR MORE THAN
*Departments of Anesthesiology and Pharmacology, The University of Michigan Medical Center, Ann Arbor, Michigan. Read a t the 38th Congress of the International Anesthesia Research Society, March 15-19, 1964, Las Vegas, Nevada. Supported by a grant in aid from the McNeil Laboratories, Inc., Fort Washington, Pennsylvania, and grant MY-02653, USHPS.

century it has comFmonlycan safelyaprotect an organism been accepted thah general anesthesia

Table 1

EFFECTS OF PHENTANYL AND DEHYDROBENZPERIDOL ALONE AND IN COMBINATION O N VITAL SIGNS IN MAN
SE ..
Mean respiratory rate Mean P value

Mean heart rate 2 Before After Before P* value

f E.

lood pressure -t S.E.

After P* value

Before

After

82.6k7.0 <0.05
<0.001

16.6Ik1.6

1.7t0.9

D 60 -+ 5.7 D 63

S 113 210.8

S 121 Ik17.7

* 7.0

S<0.3 D<0.4

101.oIk9.1 <0.6 10.8t1.8

7.5k2.6

<0.3

S155 247.7 S 141.71k34.4 S<0.4 D 68.3k 6.C D 63.3% 6.7 D<0.5

118.0+5.8 <0.05

1 9 . 8 t 1.7

16.lt1.1

<0.05

S 129.6k 7.6 S 124.9Ik 8.1 S<0.4 D 57.9+ 4.1 D 55.7% 2.0 Dc0.6

Phentanyl (0.0088 mg./ 89.45 7.9 kg.1 Phentanyl (0.0088 mg./ kg.) 95.0213.0 followed by dehydrobenzDeridol (0.44 mg./kg.) Dehsdrobenz104.0Ik 9.3 peridol (0.44 mg./kg.) Dehydrobenzperidol (0.44 mg./kg.) 118.0+ 5.8 followed by phentanyl (0.0088 mg./ kg.
<0.01

94.827.2

16.1Ik 1.2

2.5k1.1

<0.001 S 124 5 9.5 S 109.3% 6.7 S<O.l D 5 6 . 7 ~2.1 s 53.3-+ 3.3 D<0.3

*Pair comparison student t test.

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Table 2 EFFECTS OF PHETANYL ALONE AND DEHYDROBENZPERIDOL FOLLOWED BY PHENTANYL ON DURATION OF RESPIRATORY DEPRESSION IN MAN
Mean timo to respiratory arrest in minuta zk S.E.
Mom timo from apnw to (nt respiration in minutes -C S.E.

DN~S

Mean tima from injoetionr to 11 respirations per minutes A S.E.

A. 0.2% saline 5.0 % dextrose followed by phentanyl, 0.0088 mg./kg. B. Dehydrobenzperidol, 0.44 mg./kg. followed by phentanyl, 0.0088 mg./kg. p* value

0.91 -c 0.28

7.60 f 2.13

25.50 f 3.51

1.17 f 0.60
<0.7

11.11f 2.81

33.80 f 14.43
<0.5

A-B

<0.3

administration of phentanyl, most of them became apneic, and no doubt would have died had not respiration been assisted mechanically or by verbally instructing the patient to inhale and exhale deeply. Portions of a typical polygraph record of such phentanyl-induced respiratory depression and apnea and the response of the subject to verbal commands are illustrated in figure 2. In this subject, intravenously administered

phentanyl alone in a dose of 0.0088 mg. per kg. caused respiratory arrest within 100 seconds. The patient then was asked to take a deep breath, blow i t out, count to 3, and to repeat the procedure indefinitely. The patient was able to do this voluntarily for a short time. Later she apparently forgot to continue concentrating on counting and breathing, for she again became apneic, but resumed respiration upon command. It is obvious

Fig. 2. Response to verbal commands during phentanyl-induced apnea in a volunteer patient.

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..

that such voluntary respiration,although it will maintain life, is insufficient under ordinary circumstances, because lapses of memory may occur at any time. It should be stressed that patients under these conditions are completely unaware of the respiratory arrest and must constantly be reminded to breathe until they resume a safe rate and depth of spontaneous respiratory exchange. Relatively large doses of both drugs were purposely chosen for these studies in order to observe significant effects. However, future studies must include lower doses of these agents. An important and unexpected result emerged from these respiratory studies. It was observed that very heavy subjects given a massive total dose of phentanyl based on an equal ratio of mg. per kg. of body weight showed the longest duration of apnea. Plotting the values for body weight versus duration of respiratory arrest revealed a linear relationship between these two parameters. Regression lines were calculated for the separate drug groups. Patients receiving the combination of the two drugs had a steeper slope (b=0.351) to their regression line as opposed to those receiving phentanyl alone (b=0.15), as can be seen by comparing figure 3a and 3b. This appears to indicate a tendency for a synergistic effect of the two drugs. Perhaps because of the small number of patients involved, the slopes of the two groups were not significantly different. Actions on t h e EEG - A tendency for increased alpha rhythm was frequently noted (fig. 2 ) . With afferent stimulation, such as touching the patient's shoulder, transient alpha blockade was observed. Following prolonged apnea with loss of consciousness, delta waves were occasionally recorded which promptly reverted to a normal rhythm upon the administration of oxygen by mask.
CLINICAL STUDIES

In 235 cases (64.6 per cent) there were one or more systemic disorders (physical states 2-4), and 16 were emergency operations (physical states 5-7). Preanesthetic medication consisted of intramuscularly administered pentobarbital or secobarbital combined with atropine sulfate or scopolamine hydrobromide in conventional dosages. As a rule, narcotic analgesics such as morphine
EFFECT OF WEIGHT ON DURATION OF APNEA IN 7 SUBJECTS GIVEN PHENTANYL (0.0088rng/kg) ALONE

WEIGHT IN KG

Fig. 3a. Effect of weight on duration of apnea in 7 subjects given phentanyl (0.0088 mg./kg.) alone.

EFFECT OF WEIGHT ON DURATION OF APNEA IN 7 SUBJECTS GIVEN I.V. DEHYDROBENZPERIDOL ( 0.44 mg/kg 1 FOLLOWED BY PHENTANYL (0.0088 mg /kg 1
25
v)

Methods - The clinical part of this investigation was carried out in the hospital of the University of Michigan Medical Center in Ann Arbor and in the hospital of the Prison of Southern Michigan in Jackson. A total of 359 patients ranging in age from 4 months to 93 years were included in this study ; 97 patients were more than 60 years old, 11of these being over 80.

I-

WEIGHT I N KG

Fig. 3b. Effect of weight on duration of apnea in 7 subjects given intravenous dehydrobenzperidol (0.44 mg./kg.) followed by phentanyl (0.0088 mg./kg.).

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sulfate or meperidine were omitted ; when they were used, the dosages were reduced to one-half or one-third of the usual amounts. Patients of 65 years and older received atropine sulfate either alone or combined with chloral hydrate. In 18 cases, preanesthetic medication was deliberately omitted. For anesthetic medication, the fixed mixture used consisted of dehydrobenzperidol, 1 mg. per ml., combined with phentanyl, 0.02 mg. per ml. When the drugs were administered separately, the concentration of dehydrobenzperidol was 2.5 or 5 mg. per ml., and 0.1 mg. per ml. of phentanyl. During the early phase of the study the fixed mixture was used exclusively, a t dosages ranging from 0.75 to 1.5 ml. per 10 lb. of body weight. Of the 189 patients in this group, 109 received additional increments of the fixed mixture (1 to 3 ml. each) during the course of anesthesia. When the dosage of the fixed mixture was increased to 2 ml. per 10 lb. of body weight, supplemental dosages were rarely given. Separate use of the two agents in ratios and dosages adjusted to individual need was preferred in the latter part of the study. In this group of 170 patients, 75 were given additional increments consisting of phentanyl alone in doses ranging from 0.025 to 0.1 mg. Technic of Drug Administration When the fixed mixture of dehydrobenzperidol and phentanyl was employed, one-fourth of the calculated dose of the mixture was administered intravenously a t a speed of 0.5 ml. per second. One t o 2 minutes after completion of the injection, blood pressure, pulse rate, and respiratory rate were recorded, and if no significant alterations were noted, the remainder of the dose was administered intravenously a t a speed of 0.5 to 1 ml. per second. Nitrous oxide-oxygen (3:1, 2:1, or 1:l) was administered by mask or via endotracheal tube in a semiclosed circle-filter carbon dioxide absorption system. When the drugs were used separately, dehydrobenzperidol was administered first, followed within 2 to 3 minutes by phen tany1. After completion of the operation, the patient was brought to the recovery room and kept there until fully awake,

so considered when he was able to respond adequately to questions.

Muscle Relaxants - Succinylcholine dichloride was used to facilitate endotracheal intubation, and also to combat muscle rigidity occurring after the administration of the dehydrobenzperidolphentanyl combination. Its use intermittently or as an intravenous drip was confined mostly to briefer surgical procedures in which muscle relaxation was required. Succinylcholine combined with hexafluorenium (Mylaxens) as proposed by Foldes and associates12 was preferably used in children undergoing heart surgery, especially in cardiopulmonary bypass procedures, and in neurosurgery. Longer-acting, nondepolarizing muscle relaxants were used in most general surgical procedures.

In 22 patients selected a t random, with and without history of liver impairment, blood samples for liver-function tests (serum glutamic- oxalacetic transaminase, lactic dehydrogenase) were taken preoperatively and on the first, third, fifth, and seventh postoperative days.
Results - With both fixed-mixture and the separate administration of dehydrobenzperidol and phentanyl, a peculiar state of semiconsciousness combined with profound analgesia was produced in every case. Particularly, with dosages of the two drugs ranging from 1.5 mg. and 0.03 mg. and up to 2 mg. and 0.04 mg. per 10 lb. of body weight respectively, the patient invariably would reach this characteristic neuroleptanalgesic state which, in conjunction with nitrous oxide-oxygen anesthesia, permitted minor or major surgical procedures.
In the poor-risk patient such as infants and children with congenital or acquired heart defects, or in patients in the extremes of age the commonly used dose of 2 mg. and 0.04 mg. per 10 lb. of body weight of the two drugs was reduced by a fourth or a half. The effectiveness and predictability of dosages compounded on a mg. per body weight basis appeared to be questionable when applied to unusually heavy or unusually light adult patients. Therefore, adult patients weighing less than 80 pounds received the dose compounded for an 80pound patient while patients weighing more than 200 pounds received not more!

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Number of
Surgical procedures
patients Total

General surgery a. Portal-caval shunt

101

d. B e. Others Neurosurgery a. Craniotomy b. Cervical and lumbar laminectomy c. Chordotomy Thoracic surgery a. Segmentectomy, lobectomy, pneumonectomy b. Imdantation of Dacemaker c. Repair of atrial or ventricular septa1 defects or acquired valvular defects (extracorporeal circulation) d. Other heart surgery (patent ductus arteriosus, mitral stenosis) Urology Orthopedics No surgery Total t h a n t h e dosage calculated f o r 200 pounds. This empirical approach, while of practical usefulness, needs further exploration as t o the proper method of dosing. Surgical operations performed under neuroleptanalgesia o r anesthesia a r e shown in table 3.Duration of procedures ranged from 15 minutes to 91/2 hours; 45 were completed in less than 30 minutes; 207 required from a half-hour to 3 hours ;90 patients required more t h a n 3 hours.
EFFECTS OF ANESTHESIA

34 40

I I
44

22 14 8
64
22 11

24 7

I
51 37
~

I
1

2 359

General Course-After completion of the injection of t h e fixed mixture or, in the case of the separate use of t h e agents, after t h e administration of phentanyl subsequent to dehydrobenzperidol, t h e patient promptly lapsed into t h e state of semiconsciousness with a char-

acteristic facial expression referred to a s mineralization. A breathing mask was applied to the face and inhalation of nitrous oxide-oxygen was begun. The patient was usually apneic a t this point but responded to a command to breathe. After a n average of 5 to 10 inhalations of the gas mixture, consciousness was usually lost. Frequently, during this apneic phase, increased resistance to passive inflation of the chest made adequate ventilation difficult. This period lasted several minutes and subsided spontaneously, although it could readily be overcome by the intravenous administration of small amounts of succinylcholine (20 t o 40 me.). The patient was now ready for operation. In the course of anesthesia, additional increments of phentanyl were administered intravenously when signs of surgical stress appeared (increased heart

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rate, elevation of blood pressure, increased respiratory rate, or irregular breathing). As a rule, the patient could be awakened at any time during surgery by reducing or shutting off the administration of nitrous oxide. Verbal contact could then be established and the patient would respond to questions and commands-opening the eyes, nodding or turning the head, or showing the tongue. Anesthesia was terminated by removing the mask and allowing the patient to breathe air. After awakening, the patient had complete amnesia for the whole anesthetic procedure including t h e period when he may have been awake. For surgical procedures requiring muscle relaxation, or for intrathoracic or neurosurgical procedures, an endotracheal tube was placed with the aid of succinylcholine administered intravenously. In this series, 205 cases were intubated orotracheally or nasotracheally. In 9 cases, partial or complete paralysis of respiratory muscles, with inadequate ventilation, necessitated the use of anticholinergic (atropine) and cholinesterase-inhibiting agents (for example, ProstigmineB-neostigmine) a t the end of the operation. Prompt restoration of adequate respiratory exchange resulted in these cases. Respiration - A marked reduction in respiratory r a t e and depth occurred within 30 seconds to 2 minutes after the intravenous injection of the drug, with apnea ensuing in most of the patients. Respiratory arrest lasted from 3 to 20 minutes, with an average duration of 8 minutes, depending on the dosage used and the age and physical state of the patient. When spontaneous respiration resumed, respiratory depth was first restored followed by an increase in rate. When no muscle relaxants were used during surgery the patient was allowed to breathe spontaneously with assistance from the breathing bag. In the presence of muscle relaxants respiration was controlled. In 2 cases, narcotic-induced apnea extended into postanesthetic recovery, but nalorphine was effective in restoring spontaneous ventilation in both cases. The first patient was an 85-year-old woman weighing 106 pounds, who had received a total of 20 mg. of dehydro-

benzperidol and 0.4 mg. of phentanyl, and whose operation, trigeminal rhizotomy, lasted 21,~ hours. At the end of the operation her depth of respiration appeared adequate, but the respiratory rate was only 4 per minute. One minute after 5 mg. of nalorphine were administered intravenously, the respiratory rate rapidly increased t o 12 and was maintained a t this level. No further postoperative respiratory difficulties were encountered in this patient. The second patient, a 66-year-old woman weighing 160 pounds, was scheduled for insertion of a pacemaker, but the operation was cancelled because of signs of acute intestinal obstruction which appeared after the induction of anesthesia. This patient had received 16 mg. of dehydrobenzperidol combined with 0.64 mg. of phentanyl (25:l) intravenously and was breathing a t a rate of 5 per minute when plans for surgery were abandoned. Five mg. of nalorphine administered intravenously promptly reversed the respiratory depression, and the rate increased from 5 to 16 per minute within 3 minutes. The patient became alert and oriented with the onset of increased respiratory rate. Decreased pulmonary compliance of several minutes duration occurred in 285 cases (79.4 per cent). This condition varied from slight to total inability to inflate the chest. This phenomenon usually occurred a t the completion of the intravenous injection of the mixture or after phentanyl had been given subsequent to dehydrobenzperidol. In the majority of cases the condition was apparently due to muscle rigidity in chest and abdominal wall predominantly. For some cases, increased vocal cord activity seemed to have contributed to this development. Small amounts of succinylcholine (20 to 40 mg.) intravenously resulted invariably in immediate restoration of adequate pulmonary compliance. With the separate injection of the two drugs, this phenomenon was less frequently observed, and it was not recorded following the use of dehydrobenzperido1 alone. Cardiovascular System - Among the volunteer group in the pharmacologic studies (table 1), only slight changes in heart rate were observed following the injection of the separate drugs or the mixture. Similar findings were noted

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among the surgery patients. I n 1 cases served in 58 cases (16.2 per cent). Re1 (3.1 per cent) the pulse rate dropped turn of t h e blood pressure to preinjecmore than 30 per minute following t h e tion levels occurred either spontaneously intravenous injection of the mixture. or with t h e aid of small doses of ephedFive of these patients were unpremedi- rine sulfate (10 t o 15 mg.) or methoxacated prison volunteers who received a n mine hydrochloride (5 t o 15 mg.) intraintravenous dose of 2 mg. and 0.4 mg. venously. per 10 lb. of body weight. Slowing of t h e Except for such occasional hypotenpulse was transient in nature and t h e sive phases during the induction period, rate increased t o preinjection values cardiovascular stability throughout surspontaneously within 5 t o 15 minutes. gery was remarkable. This was particuI n no case w a s b r a d y c a r d i a severe larly true in the poor-risk patient underenough t o require countermeasures. In going major surgery and, in patients 18 cases (5.0 per cent), a n acceleration with congenital or acquired heart deof the pulse rate by more than 30 per fects. minute was recorded. The patients in The alpha-adrenergic blocking action this group had received preanesthetic medication which included either atro- of dehydrobenzperidol and its beneficial pine sulfate or scopolamine hydrobro- effect on the peripheral vascular bed maximally constricted from hypovolemic mide. shock is shown in figure 4. This patient Table 1 shows t h a t in the volunteer had undergone emergency laparotomy group t h e a d m i n i s t r a t i o n of t h e two and splenectomy because of intra-abdrugs alone or in combination did not dominal bleeding following an automoalter t h e arterial blood pressure signifi- bile accident. Several hours later the pacantly. I n the clinical study, an initial tient showed signs of renewed intratransient drop in systolic pressure of abdominal bleeding, with distended abmore than 30 mm. of mercury was ob- domen and signs of impending shock.

Fig. 4 . Course of anesthesia for an exploratory laparotomy in a patient in hemorrhagic shock under neuroleptanalgesia-anesthesia.

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Fig. 5. Comparison of anesthetic course in patient undergoing a dorsal cordotomy on the right and left sides 13 days apart, using two different anesthetic technics.

Brought to the operating room, she was in overt shock with no peripheral pulse detectable and no blood pressure obtainable a t the brachial artery. Figure 5 demonstrates the neurovascular response to dorsal cordotomy in an elderly patient who was emaciated and very ill. A right cordotomy was performed under balanced anesthesia, with markedly profound blood pressure drops during positioning and a t the time of cordotomy. The same patient underwent surgery 13 days later for cordotomy of the left side under neuroleptanalgesia; the course of blood pressure and pulse were notably even throughout the operation. Postanesthetic Period - Emergence was usually rapid after emergence from nitrous oxide anesthesia. In 196 cases (54.6 per cent), the patients were awake in less than 5 minutes, and 136 patients (37.9 per cent) awakened within 6 to 15 minutes. In only 18 cases ( 5 per cent) was recovery prolonged more than 15 minutes. This group included mostly elderly patients recovering from major

abdominal procedures such as portocaval shunt, gastrectomy, esophagectomy, or various neurosurgical operations. The oldest patient in the series, a 93-yearold man recovering from an AustinMoore hip prosthesis, was in this group. Postoperative drowsiness and somnolence often persisted for several hours; however, patients could easily be aroused from this state. Absence of pain was the most significant feature during the early postoperative period. Narcotic analgesics for pain relief were rarely required within the first 6 to 8 hours ; administration of such analgesics usually started not earlier than the first postoperative day. One-fourth the usual dose of morphine sulfate (2 to 3 me.) or meperidine (10 to 20 mg.) was sufficient for pain relief lasting several hours. One patient, a 16-year-old boy who had undergone plastic surgery (rib graft to the mandible), became restless and was given meperidine, 50 mg. intramuscularly, by a surgical assistant in the recovery room. He became unresponsive immediately after this injection and was

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breathing a t a rate of 4 per minute; however, his blood pressure was recorded at 110/70 mm. of mercury. Five mg. of nalorphine administered intravenously resulted in prompt awakening with simultaneous restoration of adequate respiratory function. Emesis occurred in 2 volunteers during t h e respiratory-function study after t h e injection of phentanyl alone. These patients were awake and were able to clear their throat spontaneously and effectively. Three other patients vomited once in the recovery room after they had awakened; two of this group had a gastric suction tube in place. No aspiration of vomitus occurred in these patients. Muscle twitching and jerking in t h e arms and legs were observed in 3 patients. One was a young prison volunteer in excellent physical condition and t h e other two were young adults in t h e clinical series. In all three instances, t h e motor restlessness occurred shortly after the injection of t h e fixed mixture, 2 mg. and 0.04 mg. per 10 lb. of body weight. These muscular movements, apparently of a n e x t r a p y r a m i d a l type, lasted a few minutes and subsided spontaneously. A hallucinatory episode was observed in a healthy 19-year-old man weighing 215 pounds who underwent pulmonaryfunction studies before a n operation for arthrotomy in the left knee. This patient received a total of 43 mg. of dehydrobenzperidol followed b y 0.86 mg. of phentanyl. In the evening of the first postoperative day t h i s p a t i e n t complained of seeing persons coming and going in his room, persons t h a t he knew did not exist. This reaction spontaneously subsided during the following night, and the patient had a n otherwise uneventful recovery. In none of the 22 patients participating in t h e liver-function study was there any significant postoperative alteration in the SGOT and LDH values, which confirms reports of Dobkin and coworkwho performed liver function tests in volunteers after t h e use of dehydrobenzperidol and phentanyl. Deaths - No deaths occurred during anesthesia. Eleven patients died in t h e postoperative period ; details of these cases are summarized in table 7. None

seemed t o be connected with or the result of improper a n e s t h e t i c management.

DISCUSSION

The data presented in this study indicate t h a t the combination of the butyrophenone derivative dehydrobenzperido1 and t h e narcotic analgesic phentanyl can produce a state of general analgesia. It appears t h a t any type of major surgical procedure can be carried out in this state provided t h e patient is kept asleep with the aid of nitrous oxide in oxygen and t h a t appropriate muscle relaxants a r e used when necessary to the surgical procedure. Whether it is appropriate to signify this state neuroleptanalgesia, as proposed by European authors, appears to be more of academic interest than of practical significance. Unlike similar intravenous anesthetic technics commonly referred t o as balanced anesthesia, in which nitrous oxide-oxygen mixtures are combined with ultrashort-acting barbiturates and narcotic analgesics such as morphine sulfate or meperidine, the dehydrobenzperidol-phentanyl-nitrous oxide combination produced remarkable cardiovascular stability. This appeared t o be of particular value for geriatric patients with minimal compensatory reserves, as well as for patients suffering from acquired or congenital heart defects. Cardiovascular integrity in the latter group manifested itself unusually well during and after difficult septa1 or valvular repairs with prolonged periods of extracorporeal circulation. Arterial blood pressures after restoration of spontaneous heart action following cardiopulmonary bypass were consistently higher than those recorded for patients who underwent identical surgical procedures w i t h conventional anesthetic methods. A detailed study on t h e use of neuroleptanalgesia in heart surgery will be reported elsewhere.I5 The adrenergic blocking action of dehydrobenzperidol resulted occasionally in slight to moderate blood pressure drops of transient duration. When hypotension persisted for more than 5 minutes, a small amount of a vasopressor agent, administered intravenously or intramuscularly or both, restored peripheral t o n e promptly i n all instances. Whether this hypotension may be due to a histamine-releasing action of t h e narcotic is being further explored.

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Adrenergic blockade caused by t h e neuroleptic drug appears to affect favorably the peripheral vascular constriction associated with hypovolemic shock. Similar observations were made in surgical patients during episodes of acute massive blood loss. The apparent beneficial effects of peripheral vasodilation resulting from such blockade and its effect on tissue perfusion needs to be further substantiated by laboratory studies and better controlled clinical observations. While the neuroleptic drug alone did not seem to exert any significant action on ventilatory exchange, phentanyl alone or in combination with dehydrobenzperidol caused marked depression of respiratory function, as could be expected of a powerful narcotic analgesic. However, the depressant action of phentanyl appears t o differ from that of other narcotic analgesics in at least two ways: First, the duration of respiratory depression caused by effective dosages of phentanyl is short, as shown by the pharmacologic data presented above, and by the fact that in the clinical series only 2 patients showed narcotic respiratory depression of long enough duration to necessitate the use of nalorphine. Second, cerebral depression does not occur, even in the presence of drug-induced central respiratory paralysis. This feature seems to be unique. Continuation of wakefulness at the onset of apnea makes it possible to maintain verbal contact with the patient and thus encourage him to concentrate on adequate respiration. In our clinical series, patients became unconscious only when the administration of nitrous oxide-oxygen was begun. At this time intravenous succinylcholine could be safely administered to facilitate the placement of the endotracheal tube or to counteract the development of muscle rigidity, particularly that involving the thorax and the abdominal wall. Respiratory insufficiency resulting from such muscle tightness and the frequent inability to inflate the chest properly without the help of relaxants must be considered the most important disadvantage of t h e neuroleptic-analgesic mixture. There is little doubt that phentanyl is the offending component, since such catatonic rigidity was not observed after the administration of dehydro-

benzperidol alone. Age, sex, physical state, or prenanesthetic medication did not seem to affect the incidence or degree of muscle rigidity, but higher dosage and more rapid injection of the drug appeared to cause more abrupt and severe changes in pulmonary compliance. Although the occurrence of lead-pipe rigidity has been observed with other narcotic analgesics, especially in overdosage, the neurophysiologic aspects of this phenomenon deserve further study. With regard to preanesthetic medication, opiates should be avoided or dosages cut drastically, since such agents markedly augment the respiratory-depressant effects of phentanyl. In our studies, anticholinergic agents, particularly atropine sulfate, were found to be essential as part of the preanesthetic medication, since these drugs tend to block the vagal effects of the narcotic on cardiovascular activity. In 5 of the 18 unpremedicated prison volunteers, marked bradycardia with simultaneous hypotension occurred immediately after the intravenous injection of the fixed mixture; this effect was counteracted by atrophine sulfate intravenously in two instances. Also, profuse sweating during surgery was observed in several of the unpremedicated patients but in only one of the properly premedicated subjects. After the period of anesthesia, the patients awakening was usually fast, extremely smooth, and uneventful. Incidents of nausea and vomiting were minimal. A striking feature was the extension of analgesic effects well into the postoperative period. In fact, a number of patients recovering from abdominal surgery did not require narcotic analgesics throughout the whole postoperative course. It is difficult to explain the mechanism of such prolonged pain-relieving effect in a drug which is reported to be fast and short in action. Most important appears to be the potentiating effect of the mixture on other narcotic analgesics. The smallest dosages of morphine sulfate (0.5 mg.), given intramuscularly to infants and children emerging from heart surgery, produced pain relief in these patients for 4 to 6 hours. When the morphine dose was increased to 2 mg., these youngsters became unresponsive for several hours, without impairment of cardiovascular

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cessfully performed under neuroleptic analgesia for t h e treatment of uncontrollable s p a s m of unknown etiology. Both patients were children. They were awake throughout t h e resection phase Extrapyramidal reactions which had and followed commands effectively. Postbeen noted earlier with the haloperidol- operative recovery was uneventful and phenoperidine combination did not occur t h e p a t i e n t s had no memory of t h e postoperatively in this series. events. The amnesic effects are undoubtedly related t o nitrous oxide administraMuscle relaxants of both t h e depolar- tion, for t h e patient volunteers who reizing and nondepolarizing type were em- ceived phentanyl and dehydrobenzperiployed to counteract muscle rigidity dur- do1 remembered details of t h e entire ing surgery, since neuroleptanalgesia polygraph recording procedure as well alone does not provide muscle relaxa- as pertinent conversations during the tion. In children and infants t h e use of study. hexafluorenium combined w i t h small In this type of anesthesia, t h e use of amounts of succinylcholine for muscle relaxation, was particularly effective. the separate drugs is preferred to t h e Occasionally, small amounts of the ul- fixed mixture for various reasons. First, trashort-acting muscle relaxants were it is sounder practice from a pharmacoadministered to keep t h e patient from logic point of view, since the action of moving his extremities. There were few each drug can be controlled and recorded surgical procedures in which no muscle more specifically. Second, hypotensive relaxant was used. It is debatable wheth- response during or immediately after er the frequent need for muscle relax- the injection of the neuroleptic followed ants may be considered another disad- by the narcotic agent appears to be less vantage of this anesthetic technic. I n frequent and lesser in degree. And last, spite of their frequent use in our series, lowered pulmonary compliance during drug-induced muscle relaxation outlast- t h e induction phase is more easily overed surgery in only 8 cases. The effect come by po sit i ve-pr e s s u r e breathing was reversed with a cholinesterase-in- than is t h e case when t h e fixed mixture is used. hibiting agent. activity. Thus, extreme caution should be exercised when narcotics a r e administered for pain relief in patients recovering from neuroleptanalgesia. Of particular interest was t h e applicability of the technic to neurosurgery, especially to certain corticographic procedures for t h e surgical treatment of epileptic seizures with focal predominance. In such cases the surgeon requested that the patient be conscious when t h e electrodes were placed on t h e cerebral cortex, in order to respond to questions about certain sensations and motor functions during the mapping-out procedure. Three young adult patients undergoing this type of surgical procedure were kept awake without pain for 45 minutes to 2 hours, during which time they responded t o various questions by predetermined signs while t h e surgeon proceeded with the placement of electrodes and extirpation of focal areas. I n these cases it was especially fortunate that neuroleptanalgesia did not significantly alter electroencephalographic patterns. There was complete amnesia to t h e entire anesthetic course in these patients. In addition to t h e corticographic procedures, 2 cerebellectomies were sucSUMMARY AND CONCLUSIONS

Pharmacologic and clinical studies involving a new method of inducing surgical anesthesia are described. In appropriate dosages given intravenously, t h e butyrophenone derivative dehydrobenzperidol and the narcotic analgesic phentanyl produced a state of semiconsciousness or mineralization in which patients lay resting and unresistant during surgery. With the addition of nitrous oxide-oxygen mixtures to cause sleep and memory deficit, and muscle relaxants to reduce muscle tone, it was found t h a t any type of minor or major operation could be performed. During prolonged operations, small additional amounts of phentanyl were sufficient to ensure adequate analgesia. As used in 359 cases, this technic ( neuroleptanalgesia ) was particularly valuable in the treatment of elderly and poor-risk patients. Also it offered distinct advantages over conventional anesthetic methods for patients undergoing repair of intracardiac defects with t h e aid of extracorporeal circulation.

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Cardiovascular stability was remarkable throughout prolonged and especially traumatic procedures. The alphaadrenergic blocking action of dehydrobenzperidol appears to be advantageous in cases complicated by massive blood loss or by shock. Postanesthetic recovery was fast and smooth. Freedom from pain extended well into the postoperative period; if narcotic analgesics were eventually required, their dosage could be cut to half or less. The most important disadvantage of the technic was the profound respiratory depression resulting from the intravenous injection of the mixture of the two drugs or from phentanyl alone. The patients wakefulness, however, made it possible for them to cooperate in maintaining respirations during the apneic phase by voluntary breathing. When necessary, opiate antagonists such as nalorphine effectively counteracted the respiratory depression. Another disadvantage was the muscle rigidity involving the thorax and abdominal wall, observed during the induction phase, which resulted in marked resistance to passive inflation of the chest. Intravenously administered succinylcholine, however, provided effective control. Liver function was not affected by these agents during this investigation.

REFERENCES 1 Laborit, H.: Stress and Cellular Func. tion. Philadelphia, J. B. Lippincott Company, 1959. 2 Janssen, P. A. J.: Vergleichende Pharma. kologische Daten ueber sechs neue basische 4-Fluorobutyrophenone-Derivative. Arzneimittelforsch. 11:819, 1961.
3 Janssen, P. A. J.: On the Pharmacology . of Analgesics and Neuroleptics Used for Surgical Anaesthesia. Symposium on Neuroleptanalgesia. Vienna, Austria, The First European Congress of Anaesthesiology, 1962. 4 Janssen, P. A. J., Niemegeers, C. J. E., . Schellekens, K. H. L., Verbruggen, F. J. and Van Nueten, J. M.: The Pharmacology of Dehydrobenzperidol, A New Potent and Short Acting Neuroleptic Agent Chemically Related to Haloperidol. Arzneimittelforsch. 13:205, 1963. 5. Janssen, P. A. J., Niemegeers, C. J. E. and Dony, J. G. H.: The Inhibitory Effect of Fentanyl and Other Morphine-Like Analgesics on the Warm Water Induced Tail Withdrawal Reflex in Rats. Arzneimittelforsch. 13:502, 1963. 6. DeCastro, J. and Mundeleer, P.: Die Neuroleptanalgesie. Auswahl der Praeparate, Bedeutung der Analgesie und der Neurolepsia. Anaesthesist ll:lO, 1962.
7. Nilsson, E. and Janssen, P.: Neuroleptanalgesia, an Alternative to General Anaesthesia. Acta Anaesth. Scand. 5:73, 1961.
8. Ingwar, D. and Nilsson, E.: Central Nervous Effects of Neurolept-analgesia as Induced by Haloperidol and Phenoperidine. Acta Anaesth. Scand. 5:85, 1961.

9. Nilsson, E.: Experience with Neuroleptanalgesia. Anaesthesist 11:17, 1962.

Henschel, W. F.: It is concluded that neuroleptanalge- de 10. neuroleptanalgesie.Principes e t technique la XI11 C0ngrZ.s Fransia opens a new approach to the anes- Cais dAnesthCsiologie, June 1963. thetic management of surgical patients. 11. Holderness, M. C., Chase, P. E. and The technic is effective, simple, safe, and Dripps, R. D.: Narcotic Analgesic and Butynonexplosive, and appears to offer dis- rophenone withANitrous Oxide for General Antinct advantages over conventional esthesia. Anesthesiology 24:336, 1963. methods, with their high incidence of 12. Foldes, F. F., Hillmer, N. R., Molloy, depressant and toxic effects on vital systems. The method deserves clinical R. E. and Monte, A. P.: Potentiation of the Neuromuscular Effect of Succinylcholine by attention. Hexafluorenium. Anesthesiology 21 :50, 1960. Generic and Trade Names of Drugs Phenoperidine-Phenoperidin Phentanyl-Fentanyl, Sublimase Haloperidol-halo per idol Dehy drobenzperidol-Droperidol Phentanyl Dehydrobenzperidol Innovar Hexafluorenium-Mylaxen Neostigmine-Prostigmin Nalorphine-Nalline Meperidine-Demerol, Dolantin

13. Dobkin, A. B., Israel, J. S. and Byles, P. H.: Innovan-N?O Anaesthesia in Normal Man: Effect on Respiration, Circulatory Dynamics, Liver Function, Metabolic Functions, Acid-Base Balance and Psychic Responses. Canad. Anaesth. SOC. J. 11:41, 1964. 14. Nilsson, E.: Origin and Rationale of Neurolept-analgesia. Anesthesiology 24:267, 1963. 15. Corssen, G., Chodoff, P. and Domino, E. F.: Neurolept-Analgesia for Open Heart Surgery. Anesthesiology (In press).

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VOL. 43, NO. 6, Nov.-DEc., 1964

DR. PAUL JANSSEN Janssen Pharmaceutica Research Laboratoria Beerse, Belgium Dr. (:orssens paper is of particular interes 1; in many respects. For a phar-

macologist it is rather gratifying t o see how highly predictable the clinical effects of phentanyl (R 4263) and droperidol (R 4749) really are. Both the desirable and the undesirable properties of these drugs are qualitatively and quantitatively almost indistinguishable in man and in animals.

39th CONGRESS
o the f

I N T E R N A T I O N A L ANESTHESIA RESEARCH SOCIETY

MARCH 28-APRIL 1,1964

MAYFLOWER HOTEL WASHINGTON, D. C.
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