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Techniques for general anesthesia in miniature pigs
TECHNIQUES IN D.
L.
FOR GENERAL MINIATURE
PIERMATTEI, H.
SWAN
ANESTHESIA PIGS
D.V.M., II,
A GROWING BODY OF LITERATURE suggests the pig as a useful subject for many areas of biomedical and especially cardiovascular, research, [4, 10-121. Booth et ~2. [3] noted that: “Because the pig is an omnivore like man, and allegedly possesses similar physiological and anatomical attributes, its importance as an experimental animal is unequivocal.” There are many similarities of anatomy and physiology between men and pigs, with the heart and circulatory system, alimentary tract, teeth, and diet being particularly remarkable [4]. Anatomic similarities of the cardiovascular system of special interest are the coronary blood supply which is very similar to man in distribution, and the position of the heart [ 121. Expansion of basic swine research efforts seemsjustified by the needs of human research for an additional nonrodent mammal [ 11. From the Surgical Laboratory, Department of Clinics and Surgery, College of Veterinary Medicine, Colorado State University, Fort Collins, Colorado. This study was supported by a grant from The Colorado Heart Association. *Current address: Professor, De artment of VeterSurgery and Radiology, Co f ege of Veterinary iny . Me acme, University of Minnesota, St. Paul, Minn. 55101. fRequest for reprints: Professor (Research), Depart of Veterinary Clinics and Surgery, College of Veterinary Medicine, Colorado State University, Fort Collins, Colorado 80521. Submitted for publication April 1, 1970. to Dr. The authors ex ress their appreciation Donald C. Sawyer f or his interest and suggestions.
M.D.,
PH.D.* D.SC.f
Although John Hunter observed in the eighteenth century that the pig was the most useful animal for laboratory studies, use of this species in the laboratory has been hampered by the size of the animal (up to 800 lb. at maturity), and a lack of understanding of their care, feeding, and handling [4]. The development in the last decade of miniature pigs of 150-300 lb. body weight has resulted in an animal that is very similar to man in body mass and is much more easily kept in the average research laboratory with a minimum of special facilities. Miniature pigs possess all the characteristics of normal swine except that they reach a mature weight between 70 and 140 kg. Minimal, but wellbalanced, feeding will keep any strain at its lower weight range indefinitely. Others [Z, 71 have reported on anesthetic methods in pigs. Gaseous anesthetic agents, particularly halothane, are generally considered to be the best agents for prolonged procedures. The following is a description of methods investigated for anesthetizing pigs for heartlung bypass. METHODS
AND
RESULTS
The subjects for these experiments were Hanford Miniature Swine,+ obtained from the tHanford tory, Batelle
Laboratories, Pacific Memorial Institute.
Northwest
Labora587
JOURNAL OF SURGICAL RESEARCH
VOL. 10 NO. 12, DECEMBER 1970
Colorado State University specific pathogenfree herd. Their ages at time of operation ranged from 412 months, with a mean of 6 months. Weight range was 20-95 kg. with a mean of 51 kg. These animals were maintained on commercial ground hog ration and were allowed free access to water. All were determined to be physically normal at the time of operation. Subjects were randomly selected from the herd, with no attempt made to select animals of a particular sex. Males were routinely castrated between the ages of 8 and 12 weeks,
INDUCTION METHOD 1.: THIAMYLAL SODIUM AND HALOTHANE
The first anesthetic method utilized was patterned after techniques commonly employed in veterinary clinical surgery of small domestic animals. Immediately prior to anesthesia, the pig was weighed on a livestock balanced-beam scales. Accuracy was ++ lb. The pig was then restrained in the transport crate by grasping one ear and with the other hand under the jaw raising the head to rest it on the edge of the crate. Thiamylal sodium,§ lo%, was injected into the marginal ear vein of the opposite ear in the dosage of 12-18 mg./kg.; a 20- or 22gauge, 1 inch needle on a lo-ml. syringe proved most convenient. As soon as the pig was suihciently relaxed by the thiamylal injection it was allowed to assume a left lateral recumbency. An assistant stood at the animal’s back and grasped the maxilla in his left hand. The right hand was used to grasp the tongue, which was simultaneously extended and pulled so as to flex the mandible. While thus opening the mouth as widely as possible, the head and neck were extended and pulled dorsally toward the assistant as much as possible. The anesthetist was then able to introduce a laryngoscope with a long adult-size blade through the mouth and depress the epiglottis with the blade tip. A 4048 French
vinyl-cuffed endotracheal catheter of the Magill design was then passed through the rima glottis into the trachea. Thus intubated, the pig was attached to the anesthetic machine for administration of Halothane. 11 A concentration of 2l/, to 3% Halothane was used for induction, and reduced to between 3/4 and 1% for maintenance. Adult-size breathing tubes and a 3-liter rebreathing bag were employed in the circle absorber system. A frequent difficulty associated with this method was dislodgement of the needle from the vein due to movement of the pig’s head, with resultant inability to deliver a hypnotic dose of barbiturate. Even in the event of injection of a calculated dose of thiamylal sodium, poor relaxation of the jaw and spasm of the larynx was encountered, making intubation difficult. Laryngospasm due to repeated attempts at introducing the endotracheal catheter provoked many hypoxic episodes which necessitated oxygen administration through a canine face mask.
INDUCTION METHOD 2.: SUCCINYLCHOLINE CHLORIDE AND HALOTHANE
An attempt was made to avoid intravenous injections and their resultant difhculty by intramuscular injection of an immobilizing dose of succinylcholine chloridell followed by intubation and administration of Halothane. Succinylcholine chloride was given in a dosage of 1 mg./kg. As soon as relaxation appeared (usually about 1 minute) the animal was ventilated with oxygen administered through the canine face mask. Tracheal intubation was attempted after 1 or 2 more minutes. After intubation Halothane was administered as above. Relaxation and immobilization provided by intramuscular succinylcholine chloride was
Fluothane, Ayerst Laboratories, New York, New
YA. $Surital, Parke-Davis & Co., Detroit, Michigan.
588
Isucostrin, E. R. Squibb Co., New York, New York.
PIERMATTEI AND SWAN: GENERAL ANESTHESIA IN PIGS
inconsistent. In many cases it was impossible to intubate the pig even though the animal was immobilized to the point that spontaneous respiration was abolished. For this reason, this method was discarded. INDUCTION METHOD 3.: FENTANYL-DROPERIDOL AND HALOTHANE
In a continued attempt to eliminate the necessity for intravenous injections as part of the anesthesia-induction process, sedation was produced by intramuscular injection of 0.4 mg. fentanyl and 20 mg. droperidol /14 kg.** Atropine was given simultaneously, 1 mg./20 kg., to prevent bradycardia. Injections were given in either the gluteal or biceps femoris regions of the hindlimb, utilizing a 1.5 to e-inch, H-gauge needle. In approximately 10 minutes the pig was tranquilized sufficiently ,to permit placing a plastic canine face mask over the nose and mouth. Four percent halothane was introduced to the face mask, which was attached to a closed-circle absorber apparatus. Approximately S-10 minutes were required to produce anesthesia of sufficient depth to allow intubation. After placement of the endotracheal catheter anesthesia was maintained with OS-1.5% halothane. Smooth induction of sedation and anesthesia with ease of tracheal intubation were features of this method. No restraint of the animal was required, hence no struggling or excitement was produced. INDUCTION METHOD 4. : FENTANYL-DROPERIDOL, OXYGEN, NITROUS OXIDE, AND HALOTHANE
This method was identical to Method 3 except that 50% nitrous oxide and 50% oxygen were used to volatilize halothane. Reduction of time required for induction of anesthesia to about 5 minutes, and reduction of the amount of halothane used were advantages of this method. This was the technique of choice among those investigated. **Innovar-Vet., McNeil ington, Pennsylvania.
Laboratories,
Fort Wash-
MAINTENANCE
OF ANESTHESIA
The closed-circle absorption technique was employed to maintain anesthesia with halothane. Intermittent vaporization of halothane in concentrations of 0.5-1.5% was needed to maintain a constant level of anesthesia. Respiration was controlled by use of the Bird Mark 4/9 assistor-controller. This machine allowed automated intermittent positivepressure ventilation (IPPV) to be applied through the circle absorption circuit, thus allowing the anesthetist a certain freedom to leave the table and assist with the heart-lung machine. During the cardiopulmonary bypass (CPB ) volatile anesthetics could not be employed because the pulmonary artery was occluded. Since hypothermia was induced in most of the animals relatively little anesthesia was needed during these periods. When needed, 10% thiamylal was titrated into the arterial reservoir of the oxygenator to effect. Worthy of note, however, was the pig’s resistance to the anesthetic effects of hypothermia. These animals routinely exhibited spontaneous respiratory and limb movements at 3031°C if some degree of anesthesia or immobilization was not employed. A second method of maintenance was evaluated in six CPB experiments in an attempt to avoid the cardiac-depressant effects of halothane during the post-bypass period [13]. In this method, anesthesia proceeded as described above until the chest was opened and preparations were being made to start CPB. At that point, the rebreathing system was purged of halothane and an intravenous infusion started, consisting of 0.5 mg. fentanyl and 12.5 mg. droperidol in 100 ml. of saline. This dose was administered in 1 hour, and was preceded by 0.3 mg./kg. of d-tubocurarine chloride. After completion of administration of the initial dose of fentanyl and droperidol, a second intravenous drip of 0.5 mg. fentanyl in 500 ml. saline was established at a rate of 0.1 mg./hour. This method provided very satisfactory anesthesia. The effects of the single dose of d-tubocurarine chloride were well dissipated 589
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in 34 hours, which coincided with completion of chest closure. Lingering effects of the droperidol provided a degree of tranquilization that aided in immediate postoperative care of the animal. Arterial pressure was well maintained after chest closure as long as the fentanyl drip was maintained at 0.1-0.2 mg/ hour. Faster rates caused hypotension. Bradycardia was very noticeable unless atropine (1 mg./20 kg.) was given every 2 hours. The potent analgesic properties of fentanyl were extremely useful during the recovery period. A transternal incision, which is quite painful, was used. Control of the pain resulted in much easier handling of the animal.
POSITWE PRESSURE VENTILATION Initial attempts at controlled respiration by means of the Bird respirator resulted in death of three of six animals. These pigs died in ventricular fibrillation 36-60 minutes after the respirator was turned on. The respirator was set to cycle 16-20 times a minute with a peak inspiratory pressure of 26-25 cm. of water, a negative expiratory pressure of 4-6 cm. water, and a one-to-one inspiratory-expiratory ratio. This peak inspiratory pressure was chosen as just sufficient to provide a visible chest lift during inspiration. However, the incidence of fibrillation suggested that this pressure might be too high, causing interference with right ventricular filling and with pulmonary circulation. Since the hearts entered fibrillation after the animals were placed in dorsal recumbency, this position was also postulated as a cause of fibrillation. Consequently a simple experiment was run to determine effects of positioning and respirator parameters on arterial and central venous pressure, and arterial POZ, PC02, and pH. The pig was anesthetized as previously described. Pressure catheters had been previously placed in the right external carotid artery and the superior vena cava via the right external jugular vein. Observations made during these experiments are recorded in Fig. 1. It was obvious from these data that the method of ventilation previously used (20 590
12,
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1970
cycles/minute, +25 and -6 cm. HzO) resulted in lowered arterial pressure, slightly elevated CVP, and hyperventilation with respiratory alkalosis. Reduction of rate to 121 minute, and pressures to +20 and -6 cm. Hz0 resulted in increased arterial pressure and decreased arterial pH. Some changes were noted when the pig was placed on its back, the most significant being a slight elevation of CVP from 2 to 5 cm. HzO. Arterial PC02 and pH tended toward more normal values. Further reduction of inspiratory peak pressure to 15 cm. HZ0 maintained or improved all values observed. This pressure produced little or no chest movement and it was impossible to estimate tidal volume except by observation of the spirometer on the respirator. As a result of this experiment, the respirator was routinely run at 12 cycles/minute at pressures of + 12 to 15 cm. and -4-6 cm. H,O. No further problems with fibrillation were experienced during the prebypass period that could be attributed to ventilation.
DISCUSSION The greatest single difficulty in working with pigs in biomedical research is the inaccessibility of peripheral blood vessels for percutaneous prmcture. The vessels are small, fragile, and deeply placed under thick, tough, and opaque skin. The marginal ear vein has traditionally been used and is acceptable in some breeds with proper restraint of the animal. Restraint in this case involves placing a rope loop over the upper jaw behind the canine teeth. The rope is then placed through a wall ring mounted high enough so that the pig’s head and neck can be raised until the front feet are almost off the floor. Since the pig will tend to back away and pull on the rope, this immobilizes the head quite well. The miniature pigs used in this study had poorly developed and deeply placed ear veins. The veins were also very fragile, any slight movement of the needle causing laceration of the vessel wall and subsequent hematoma formation. Not uncommonly both veins were “botched” without an anesthetic dose of thi-
PIERMATTEI
AND
110 nem Arterial pressure (mm Hg)
SWAN:
GENERAL
ANESTHESIA
IN
PIGS
5 4
100 90 80
Ilean CVP (cm H20)
3 2
70
1
60
0
200 Arterial
PO2 (mm Hg) 100 c.
7. 7.
4@ Arterial PC02
(mm Hg)
7. Arterlal
30
PH
7.
20
7.
10
7. D.
Preanesthetic
Figure value
1.
Lateral
recumbency;
Respirator:20
cycledmln, -6 cm/H20
f25 to
Lateral
recumbency;
RespIrator:lE
cycles/min, -6 cm/H20
+20 to
Dorsal
recumbency;
Respirator:12
cycles/muI, -6 Cm/H20
+20 to
Fig. 1. Effect on cardiovascular dynamics of varying the rate and pressure limits of mechanical ventilation, using a pressure respirator. . amylal ever having been delivered. It must be understood that even a 25 to 30-kg. pig cannot be manually restrained as can a dog. Their strength, particularly in the neck, is impossible for even an athletic man to overcome without mechanical assistance. The technique of superior vena cava puncture could be employed for intravenous administration of anesthetic but was rejected for these experiments because of the necessity for catheterization of a jugular vein for CPB. We thought the hemorrhage from the venipuncture would interfere with surgical exposure of the vessel. Tracheal intubation of the pig required specific techniques for success. The head and neck had to bt: extended fully in order to align the pharynx and oropharynx. The vocal folds are large and form a very narrow opening into the larynx. The tube must be placed near the dorsal surface of the larynx in order
to pass between the vocal folds and not into a lateral ventricle. Topical anesthesia of the vocal folds would probably facilitate intubation under thiamylal anesthesia. The early difficulties associated with IPPV can be attributed again to the pig’s anatomic characteristics. The traditional clinical method of estimating a normal tidal volume by observing chest wall excursion during inspiration is useless in this animal. The pig’s chest wall is extremely thick and inelastic. During normal spontaneous respiration, it moves very little, diaphragmatic movement predominating. A respirator attached to the tracheal tube would be of extreme value in ventilating thcsc animals. All guesswork could thus be avoided and an adequate tidal volume could be delivered under all conditions of chest wall and lung compliance. The effects of position of the animal did not appear to be so important as the manner 591
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in which IPPV was managed. As can be noted in Fig. lA, arterial pressure varied more as a function of respiratory rate and peak inspiratory pressure than of position. The decision to utilize fentanyl and droperidol anesthesia (termed “neuroleptanalgesia” by DeCastro and Mundeleer [6] was stimulated by the reports of others [S, 8, 91. These workers found this modality to come closer to the ideal anesthetic method for cardiovascular surgery than any other. Indeed, Fox and Fox [S] stated that these agents, properly used, offered a superior type anesthesia “which probably is indeed the technic of choice for cardiac surgery.” Both groups confirmed that this drug combination has remarkably little effect on the heart. The neuroleptic component, droperidol, produces a mild alpha adrenergic blockade which facilitates good peripheral perfusion, and a marked anti-epinephrine effect which protects the heart against arrhythmias. Alpha effects of norepinephrine on blood pressure are not blocked and there is no effect on myocardial contractility. Analgesia without hypotension is provided by fentanyl. It is rapid in action and of short duration, making it flexible in use. Contrarily, halothane and thiamylal, the agents previously used in these experiments, were shown by Sawyer [13] to be less than ideal for heart surgery in pigs. He found halothane to have a marked negative effect on myocardial contractility and thiamylal to produce increased peripheral vascular resistance. It was not possible to make a good evaluation of neuroleptanalgesia in our work due to the high number of other variables associated with the experiments in which it was used. Nevertheless, its use was associated with a mean post-CPB survival time at least as good
592
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as those in which halothane and thiamylal were used. (Not included in this survival time figure for neuroleptanalgesia is one animal that survived the CPB procedure and then died a week later.) This method of anesthesia merits further investigation in cardiac surgery. REFERENCES 1.
2. 3.
4. 5.
6.
7.
8.
9.
10.
11.
12. 13.
Anon. Swine as a laboratory animal in human medical research. J. Amer. Vet. Med. Ass. 153, 1269, 1968. Booth, N. H. Anesthesia in the pig. Fed. Proc. 28: 1547, 1969. Booth, N. H., Maaske, C. A., Hastings, S. A., and Hopwood, M. L. Swine production for biomedical research. Lab. Anim. Care 16:237, 1966. Bustad, L. K. Pigs in the laboratory. Sciences, 214:94, 1966. Corssen, G., Chodoff, P., Domino, E. F., and Kahn, D. R. Neuroleptanalgesia and anesthesia for open-heart surgery. J. Thorac. Cardiov. Surg. 49:901, 1965. DeCastro, J., and Jundeleer, P. Anesthesie sans barbituriques. La neuroleptanalgesie. Anesth. Analg. ( CZeoeZund) 16: 1022, 1959. Dziuk, P. J., Phillips, T. N., and Graber, J. W. Halothane closed-circuit anesthesia in the pig. Amer. J. Vet. Res. 25:1773, 1964. Fox, J. W. C., and Fox, E. J. Neuroleptanalgesia: Technique of choice of cardiac surgery. Southern Med. J. 60:1228, 1967. Fox, J. W. C., Fox, E. J., and Crandell, D. L. Neuroleptanalgesia for heart and major surgery. Arch. Surg. (Chicago) 94:102, 1967. Maaske, C. A., Booth, N. H., and Nielsen, T. W. Experimental right heart failure in swine. Swine in Biomedical Research: 377, 1966. Mieny, C. J., Moore, A. R., Homatas, J., and of the liver in Eisman, B. Homotransplantation pigs. S. Afric. J. Surg. 5:109, 1967. McClellan, R. 0. Applications of swine in biomedical research. Lab. Anim. Care 18:120, 1968. Sawyer, D. C. Cardiovascular effects of anesthetics in miniature swine: Halothane, methpentobarbital, thiamylal. Ph.D. oxyfhrrance, Thesis, Colorado State University, Fort Collins, Colorado 1969.
L.
FOR GENERAL MINIATURE
PIERMATTEI, H.
SWAN
ANESTHESIA PIGS
D.V.M., II,
A GROWING BODY OF LITERATURE suggests the pig as a useful subject for many areas of biomedical and especially cardiovascular, research, [4, 10-121. Booth et ~2. [3] noted that: “Because the pig is an omnivore like man, and allegedly possesses similar physiological and anatomical attributes, its importance as an experimental animal is unequivocal.” There are many similarities of anatomy and physiology between men and pigs, with the heart and circulatory system, alimentary tract, teeth, and diet being particularly remarkable [4]. Anatomic similarities of the cardiovascular system of special interest are the coronary blood supply which is very similar to man in distribution, and the position of the heart [ 121. Expansion of basic swine research efforts seemsjustified by the needs of human research for an additional nonrodent mammal [ 11. From the Surgical Laboratory, Department of Clinics and Surgery, College of Veterinary Medicine, Colorado State University, Fort Collins, Colorado. This study was supported by a grant from The Colorado Heart Association. *Current address: Professor, De artment of VeterSurgery and Radiology, Co f ege of Veterinary iny . Me acme, University of Minnesota, St. Paul, Minn. 55101. fRequest for reprints: Professor (Research), Depart of Veterinary Clinics and Surgery, College of Veterinary Medicine, Colorado State University, Fort Collins, Colorado 80521. Submitted for publication April 1, 1970. to Dr. The authors ex ress their appreciation Donald C. Sawyer f or his interest and suggestions.
M.D.,
PH.D.* D.SC.f
Although John Hunter observed in the eighteenth century that the pig was the most useful animal for laboratory studies, use of this species in the laboratory has been hampered by the size of the animal (up to 800 lb. at maturity), and a lack of understanding of their care, feeding, and handling [4]. The development in the last decade of miniature pigs of 150-300 lb. body weight has resulted in an animal that is very similar to man in body mass and is much more easily kept in the average research laboratory with a minimum of special facilities. Miniature pigs possess all the characteristics of normal swine except that they reach a mature weight between 70 and 140 kg. Minimal, but wellbalanced, feeding will keep any strain at its lower weight range indefinitely. Others [Z, 71 have reported on anesthetic methods in pigs. Gaseous anesthetic agents, particularly halothane, are generally considered to be the best agents for prolonged procedures. The following is a description of methods investigated for anesthetizing pigs for heartlung bypass. METHODS
AND
RESULTS
The subjects for these experiments were Hanford Miniature Swine,+ obtained from the tHanford tory, Batelle
Laboratories, Pacific Memorial Institute.
Northwest
Labora587
JOURNAL OF SURGICAL RESEARCH
VOL. 10 NO. 12, DECEMBER 1970
Colorado State University specific pathogenfree herd. Their ages at time of operation ranged from 412 months, with a mean of 6 months. Weight range was 20-95 kg. with a mean of 51 kg. These animals were maintained on commercial ground hog ration and were allowed free access to water. All were determined to be physically normal at the time of operation. Subjects were randomly selected from the herd, with no attempt made to select animals of a particular sex. Males were routinely castrated between the ages of 8 and 12 weeks,
INDUCTION METHOD 1.: THIAMYLAL SODIUM AND HALOTHANE
The first anesthetic method utilized was patterned after techniques commonly employed in veterinary clinical surgery of small domestic animals. Immediately prior to anesthesia, the pig was weighed on a livestock balanced-beam scales. Accuracy was ++ lb. The pig was then restrained in the transport crate by grasping one ear and with the other hand under the jaw raising the head to rest it on the edge of the crate. Thiamylal sodium,§ lo%, was injected into the marginal ear vein of the opposite ear in the dosage of 12-18 mg./kg.; a 20- or 22gauge, 1 inch needle on a lo-ml. syringe proved most convenient. As soon as the pig was suihciently relaxed by the thiamylal injection it was allowed to assume a left lateral recumbency. An assistant stood at the animal’s back and grasped the maxilla in his left hand. The right hand was used to grasp the tongue, which was simultaneously extended and pulled so as to flex the mandible. While thus opening the mouth as widely as possible, the head and neck were extended and pulled dorsally toward the assistant as much as possible. The anesthetist was then able to introduce a laryngoscope with a long adult-size blade through the mouth and depress the epiglottis with the blade tip. A 4048 French
vinyl-cuffed endotracheal catheter of the Magill design was then passed through the rima glottis into the trachea. Thus intubated, the pig was attached to the anesthetic machine for administration of Halothane. 11 A concentration of 2l/, to 3% Halothane was used for induction, and reduced to between 3/4 and 1% for maintenance. Adult-size breathing tubes and a 3-liter rebreathing bag were employed in the circle absorber system. A frequent difficulty associated with this method was dislodgement of the needle from the vein due to movement of the pig’s head, with resultant inability to deliver a hypnotic dose of barbiturate. Even in the event of injection of a calculated dose of thiamylal sodium, poor relaxation of the jaw and spasm of the larynx was encountered, making intubation difficult. Laryngospasm due to repeated attempts at introducing the endotracheal catheter provoked many hypoxic episodes which necessitated oxygen administration through a canine face mask.
INDUCTION METHOD 2.: SUCCINYLCHOLINE CHLORIDE AND HALOTHANE
An attempt was made to avoid intravenous injections and their resultant difhculty by intramuscular injection of an immobilizing dose of succinylcholine chloridell followed by intubation and administration of Halothane. Succinylcholine chloride was given in a dosage of 1 mg./kg. As soon as relaxation appeared (usually about 1 minute) the animal was ventilated with oxygen administered through the canine face mask. Tracheal intubation was attempted after 1 or 2 more minutes. After intubation Halothane was administered as above. Relaxation and immobilization provided by intramuscular succinylcholine chloride was
Fluothane, Ayerst Laboratories, New York, New
YA. $Surital, Parke-Davis & Co., Detroit, Michigan.
588
Isucostrin, E. R. Squibb Co., New York, New York.
PIERMATTEI AND SWAN: GENERAL ANESTHESIA IN PIGS
inconsistent. In many cases it was impossible to intubate the pig even though the animal was immobilized to the point that spontaneous respiration was abolished. For this reason, this method was discarded. INDUCTION METHOD 3.: FENTANYL-DROPERIDOL AND HALOTHANE
In a continued attempt to eliminate the necessity for intravenous injections as part of the anesthesia-induction process, sedation was produced by intramuscular injection of 0.4 mg. fentanyl and 20 mg. droperidol /14 kg.** Atropine was given simultaneously, 1 mg./20 kg., to prevent bradycardia. Injections were given in either the gluteal or biceps femoris regions of the hindlimb, utilizing a 1.5 to e-inch, H-gauge needle. In approximately 10 minutes the pig was tranquilized sufficiently ,to permit placing a plastic canine face mask over the nose and mouth. Four percent halothane was introduced to the face mask, which was attached to a closed-circle absorber apparatus. Approximately S-10 minutes were required to produce anesthesia of sufficient depth to allow intubation. After placement of the endotracheal catheter anesthesia was maintained with OS-1.5% halothane. Smooth induction of sedation and anesthesia with ease of tracheal intubation were features of this method. No restraint of the animal was required, hence no struggling or excitement was produced. INDUCTION METHOD 4. : FENTANYL-DROPERIDOL, OXYGEN, NITROUS OXIDE, AND HALOTHANE
This method was identical to Method 3 except that 50% nitrous oxide and 50% oxygen were used to volatilize halothane. Reduction of time required for induction of anesthesia to about 5 minutes, and reduction of the amount of halothane used were advantages of this method. This was the technique of choice among those investigated. **Innovar-Vet., McNeil ington, Pennsylvania.
Laboratories,
Fort Wash-
MAINTENANCE
OF ANESTHESIA
The closed-circle absorption technique was employed to maintain anesthesia with halothane. Intermittent vaporization of halothane in concentrations of 0.5-1.5% was needed to maintain a constant level of anesthesia. Respiration was controlled by use of the Bird Mark 4/9 assistor-controller. This machine allowed automated intermittent positivepressure ventilation (IPPV) to be applied through the circle absorption circuit, thus allowing the anesthetist a certain freedom to leave the table and assist with the heart-lung machine. During the cardiopulmonary bypass (CPB ) volatile anesthetics could not be employed because the pulmonary artery was occluded. Since hypothermia was induced in most of the animals relatively little anesthesia was needed during these periods. When needed, 10% thiamylal was titrated into the arterial reservoir of the oxygenator to effect. Worthy of note, however, was the pig’s resistance to the anesthetic effects of hypothermia. These animals routinely exhibited spontaneous respiratory and limb movements at 3031°C if some degree of anesthesia or immobilization was not employed. A second method of maintenance was evaluated in six CPB experiments in an attempt to avoid the cardiac-depressant effects of halothane during the post-bypass period [13]. In this method, anesthesia proceeded as described above until the chest was opened and preparations were being made to start CPB. At that point, the rebreathing system was purged of halothane and an intravenous infusion started, consisting of 0.5 mg. fentanyl and 12.5 mg. droperidol in 100 ml. of saline. This dose was administered in 1 hour, and was preceded by 0.3 mg./kg. of d-tubocurarine chloride. After completion of administration of the initial dose of fentanyl and droperidol, a second intravenous drip of 0.5 mg. fentanyl in 500 ml. saline was established at a rate of 0.1 mg./hour. This method provided very satisfactory anesthesia. The effects of the single dose of d-tubocurarine chloride were well dissipated 589
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in 34 hours, which coincided with completion of chest closure. Lingering effects of the droperidol provided a degree of tranquilization that aided in immediate postoperative care of the animal. Arterial pressure was well maintained after chest closure as long as the fentanyl drip was maintained at 0.1-0.2 mg/ hour. Faster rates caused hypotension. Bradycardia was very noticeable unless atropine (1 mg./20 kg.) was given every 2 hours. The potent analgesic properties of fentanyl were extremely useful during the recovery period. A transternal incision, which is quite painful, was used. Control of the pain resulted in much easier handling of the animal.
POSITWE PRESSURE VENTILATION Initial attempts at controlled respiration by means of the Bird respirator resulted in death of three of six animals. These pigs died in ventricular fibrillation 36-60 minutes after the respirator was turned on. The respirator was set to cycle 16-20 times a minute with a peak inspiratory pressure of 26-25 cm. of water, a negative expiratory pressure of 4-6 cm. water, and a one-to-one inspiratory-expiratory ratio. This peak inspiratory pressure was chosen as just sufficient to provide a visible chest lift during inspiration. However, the incidence of fibrillation suggested that this pressure might be too high, causing interference with right ventricular filling and with pulmonary circulation. Since the hearts entered fibrillation after the animals were placed in dorsal recumbency, this position was also postulated as a cause of fibrillation. Consequently a simple experiment was run to determine effects of positioning and respirator parameters on arterial and central venous pressure, and arterial POZ, PC02, and pH. The pig was anesthetized as previously described. Pressure catheters had been previously placed in the right external carotid artery and the superior vena cava via the right external jugular vein. Observations made during these experiments are recorded in Fig. 1. It was obvious from these data that the method of ventilation previously used (20 590
12,
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1970
cycles/minute, +25 and -6 cm. HzO) resulted in lowered arterial pressure, slightly elevated CVP, and hyperventilation with respiratory alkalosis. Reduction of rate to 121 minute, and pressures to +20 and -6 cm. Hz0 resulted in increased arterial pressure and decreased arterial pH. Some changes were noted when the pig was placed on its back, the most significant being a slight elevation of CVP from 2 to 5 cm. HzO. Arterial PC02 and pH tended toward more normal values. Further reduction of inspiratory peak pressure to 15 cm. HZ0 maintained or improved all values observed. This pressure produced little or no chest movement and it was impossible to estimate tidal volume except by observation of the spirometer on the respirator. As a result of this experiment, the respirator was routinely run at 12 cycles/minute at pressures of + 12 to 15 cm. and -4-6 cm. H,O. No further problems with fibrillation were experienced during the prebypass period that could be attributed to ventilation.
DISCUSSION The greatest single difficulty in working with pigs in biomedical research is the inaccessibility of peripheral blood vessels for percutaneous prmcture. The vessels are small, fragile, and deeply placed under thick, tough, and opaque skin. The marginal ear vein has traditionally been used and is acceptable in some breeds with proper restraint of the animal. Restraint in this case involves placing a rope loop over the upper jaw behind the canine teeth. The rope is then placed through a wall ring mounted high enough so that the pig’s head and neck can be raised until the front feet are almost off the floor. Since the pig will tend to back away and pull on the rope, this immobilizes the head quite well. The miniature pigs used in this study had poorly developed and deeply placed ear veins. The veins were also very fragile, any slight movement of the needle causing laceration of the vessel wall and subsequent hematoma formation. Not uncommonly both veins were “botched” without an anesthetic dose of thi-
PIERMATTEI
AND
110 nem Arterial pressure (mm Hg)
SWAN:
GENERAL
ANESTHESIA
IN
PIGS
5 4
100 90 80
Ilean CVP (cm H20)
3 2
70
1
60
0
200 Arterial
PO2 (mm Hg) 100 c.
7. 7.
4@ Arterial PC02
(mm Hg)
7. Arterlal
30
PH
7.
20
7.
10
7. D.
Preanesthetic
Figure value
1.
Lateral
recumbency;
Respirator:20
cycledmln, -6 cm/H20
f25 to
Lateral
recumbency;
RespIrator:lE
cycles/min, -6 cm/H20
+20 to
Dorsal
recumbency;
Respirator:12
cycles/muI, -6 Cm/H20
+20 to
Fig. 1. Effect on cardiovascular dynamics of varying the rate and pressure limits of mechanical ventilation, using a pressure respirator. . amylal ever having been delivered. It must be understood that even a 25 to 30-kg. pig cannot be manually restrained as can a dog. Their strength, particularly in the neck, is impossible for even an athletic man to overcome without mechanical assistance. The technique of superior vena cava puncture could be employed for intravenous administration of anesthetic but was rejected for these experiments because of the necessity for catheterization of a jugular vein for CPB. We thought the hemorrhage from the venipuncture would interfere with surgical exposure of the vessel. Tracheal intubation of the pig required specific techniques for success. The head and neck had to bt: extended fully in order to align the pharynx and oropharynx. The vocal folds are large and form a very narrow opening into the larynx. The tube must be placed near the dorsal surface of the larynx in order
to pass between the vocal folds and not into a lateral ventricle. Topical anesthesia of the vocal folds would probably facilitate intubation under thiamylal anesthesia. The early difficulties associated with IPPV can be attributed again to the pig’s anatomic characteristics. The traditional clinical method of estimating a normal tidal volume by observing chest wall excursion during inspiration is useless in this animal. The pig’s chest wall is extremely thick and inelastic. During normal spontaneous respiration, it moves very little, diaphragmatic movement predominating. A respirator attached to the tracheal tube would be of extreme value in ventilating thcsc animals. All guesswork could thus be avoided and an adequate tidal volume could be delivered under all conditions of chest wall and lung compliance. The effects of position of the animal did not appear to be so important as the manner 591
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in which IPPV was managed. As can be noted in Fig. lA, arterial pressure varied more as a function of respiratory rate and peak inspiratory pressure than of position. The decision to utilize fentanyl and droperidol anesthesia (termed “neuroleptanalgesia” by DeCastro and Mundeleer [6] was stimulated by the reports of others [S, 8, 91. These workers found this modality to come closer to the ideal anesthetic method for cardiovascular surgery than any other. Indeed, Fox and Fox [S] stated that these agents, properly used, offered a superior type anesthesia “which probably is indeed the technic of choice for cardiac surgery.” Both groups confirmed that this drug combination has remarkably little effect on the heart. The neuroleptic component, droperidol, produces a mild alpha adrenergic blockade which facilitates good peripheral perfusion, and a marked anti-epinephrine effect which protects the heart against arrhythmias. Alpha effects of norepinephrine on blood pressure are not blocked and there is no effect on myocardial contractility. Analgesia without hypotension is provided by fentanyl. It is rapid in action and of short duration, making it flexible in use. Contrarily, halothane and thiamylal, the agents previously used in these experiments, were shown by Sawyer [13] to be less than ideal for heart surgery in pigs. He found halothane to have a marked negative effect on myocardial contractility and thiamylal to produce increased peripheral vascular resistance. It was not possible to make a good evaluation of neuroleptanalgesia in our work due to the high number of other variables associated with the experiments in which it was used. Nevertheless, its use was associated with a mean post-CPB survival time at least as good
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as those in which halothane and thiamylal were used. (Not included in this survival time figure for neuroleptanalgesia is one animal that survived the CPB procedure and then died a week later.) This method of anesthesia merits further investigation in cardiac surgery. REFERENCES 1.
2. 3.
4. 5.
6.
7.
8.
9.
10.
11.
12. 13.
Anon. Swine as a laboratory animal in human medical research. J. Amer. Vet. Med. Ass. 153, 1269, 1968. Booth, N. H. Anesthesia in the pig. Fed. Proc. 28: 1547, 1969. Booth, N. H., Maaske, C. A., Hastings, S. A., and Hopwood, M. L. Swine production for biomedical research. Lab. Anim. Care 16:237, 1966. Bustad, L. K. Pigs in the laboratory. Sciences, 214:94, 1966. Corssen, G., Chodoff, P., Domino, E. F., and Kahn, D. R. Neuroleptanalgesia and anesthesia for open-heart surgery. J. Thorac. Cardiov. Surg. 49:901, 1965. DeCastro, J., and Jundeleer, P. Anesthesie sans barbituriques. La neuroleptanalgesie. Anesth. Analg. ( CZeoeZund) 16: 1022, 1959. Dziuk, P. J., Phillips, T. N., and Graber, J. W. Halothane closed-circuit anesthesia in the pig. Amer. J. Vet. Res. 25:1773, 1964. Fox, J. W. C., and Fox, E. J. Neuroleptanalgesia: Technique of choice of cardiac surgery. Southern Med. J. 60:1228, 1967. Fox, J. W. C., Fox, E. J., and Crandell, D. L. Neuroleptanalgesia for heart and major surgery. Arch. Surg. (Chicago) 94:102, 1967. Maaske, C. A., Booth, N. H., and Nielsen, T. W. Experimental right heart failure in swine. Swine in Biomedical Research: 377, 1966. Mieny, C. J., Moore, A. R., Homatas, J., and of the liver in Eisman, B. Homotransplantation pigs. S. Afric. J. Surg. 5:109, 1967. McClellan, R. 0. Applications of swine in biomedical research. Lab. Anim. Care 18:120, 1968. Sawyer, D. C. Cardiovascular effects of anesthetics in miniature swine: Halothane, methpentobarbital, thiamylal. Ph.D. oxyfhrrance, Thesis, Colorado State University, Fort Collins, Colorado 1969.