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The Use of Forane Anesthesia for Surface-Induced Deep Hypothermia
The Use of Forane Anesthesia for Surface-Induced Deep Hypothermia Shigekazu Sato, M.D., Vittorio Vanini, M.D., Murray P. Sands, K. C. Wong, M.D., Hitoshi Mohri, M.D.," a n d K. Alvin Merendino, M.D. ABSTRACT The effects of Forane anesthesia for deep surface hypothermia with 30 minutes of total circulatory occlusion were evaluated. With 100%026 of 7 dogs developed motor disorders postoperatively, while 3 of 5 with 98% OJ2% COz and none with 95% 02/5% COz developed motor disorders. Cooling was uneventful except for 1 episode of ventricular fibrillation in the 5% COz group at 23°C. Resuscitation was easy, but the early rewarming period was characterized by repeated episodes of ventricular fibrillation and delayed recovery of cardiac function, especially in the 100% 0, group. Blood lactate levels remained low during cooling and gradually increased during rewarming in all groups, with the highest levels in the 100%0, group and the lowest in the 5% C02 group. It is concluded that Forane can be used for surface hypothermia with 30 minutes' circulatory occlusion when administered in 95% OJ5% C02.A comparison of these results with previously reported series indicates that Forane is inferior to ether but may be superior to halothane for surface hypothermia.
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orrection of congenital heart disease in early infancy has gained popularity in recent years, and the concept of attempting early repair has been considered successful 11, 2, 4, 7, 11, 16, 20, 221. Many surgeons use surface hypothermia with total circulatory arrest [2,6-8,11,15,16, 221, while others [l, 4, 51 prefer extracorporeal circulation. At this institution, early correction of congenital heart disease has been carried out utilizing surface hypothermia since 1965 [6-8, 151. Based on our experimental results, we prefer ether to other anesthetic agents in our clinical protocol, while halothane is the agent of choice in many other institutions [2,16, 221. Our experimental studies have demonstrated the superiority of ether anesthesia to halothane anesthesia for hypothermic applications [ 14,18,19]. However, the explosive characteristics, slow induction, and slow recovery associated with ether are considered to be shortcomings of this agent. From the Department of Surgery, the Division of Cardiothoracic Surgery, and the Department of Anesthesiology of the University Hospital, University of Washington School of Medicine, Seattle, Wash. Aided by U.S. Public Health Service Grant no. 13517, Unit 7, and NICH HD 02272, and by grants from the American Heart Association and the Northeastern Chapter of the Washington State Heart Association. We would like to thank the Ohio Medical Products Company for supplying Forane for this study. *Established Investigator, American Heart Association. This work was done during the tenure of the Investigatorship. Accepted for publication Mar. 25, 1975. Address reprint requests to Dr. Mohri, Department of Surgery, RF-25, University Hospital, Seattle, Wash. 98195.
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SAT0 ET AL. difluoromethyl ether) has Compound 469 (l-chloro-2,2,2-trifluoroethyl been extensively studied. This volatile agent, named Forane, possesses strong vasodilative and muscle relaxant abilities, allows for rapid recovery after its withdrawal, and is nonexplosive [12, 13, 213. The present study was undertaken to evaluate the use of Forane for surface-induced deep hypothermia with a limited period of total circulatory occlusion.
Materials and Method Seventeen adult mongrel dogs with an average weight of 16.5 kg were subjected to deep hypothermia and total circulatory occlusion for 30 minutes. These dogs were divided into three groups according to the applied respiratory gas mixture, the only variable in this experiment. One hundred percent oxygen was used in 7 of these dogs, 98% 042% C 0 2in 5 dogs, and 95% 045% C 0 2in the remaining 5 dogs. Usual ventilation levels for normothermia were maintained throughout the hypothermic procedure using a Palmer volume-constant respirator, thus producing relative hyperventilation at hypothermia. Anesthesia was induced with thiamylal sodium and maintained with Forane. A Fluotec Mark I1 vaporizer, nonrebreathing circuit, and endotracheal tube were utilized. No specific premedication except atropine sulfate in a dose of 0.02 mg per kilogram of body weight was used. Judgment of depth of anesthesia was by clinical assessment, based on levels deep enough to prevent shivering during hypothermia. Cooling was carried out by immersing dogs in ice water until the rectal temperature dropped to 22°C. During cooling from 35" to 25"C, a total dose of 10 mVkg of 10%low-molecular-weightDextran was administered to improve microcirculation. The chest was opened and total circulatory occlusion for 30 minutes was established by cross-clamping the cavae and great arteries and injecting Young's solution* into the aortic root for cardioplegia. Cardiac resuscitation was carried out by manual massage after releasing inflow and outflow occlusions. After 3 minutes of cardiac massage, blood samples were collected and surface rewarming initiated in a warm water bath with a plastic sheet interposed and an additional heat lamp. Approximately 300 mg of calcium chloride was given intravenously to counteract the potassium effects of Young's solution. When the heart regained a normal beat spontaneously, it was assisted only by mechanical or electrical pacing or by supportive cardiac massage. If it fibrillated, it was defibrillated by a 50 volt AC shock. During resuscitation and rewarming, the use of cardiotonic agents (except the calcium chloride mentioned above), vasopressors, and sodium bicarbonate was avoided in most cases. However, in some, the use of one or two 0.05 cc doses of 1:1,000 adrenaline was lifesaving. Rewarming was discontinued at a rectal temperature of 35°C. All dogs were allowed to live for at least three weeks to assess the presence of neurological disorders. *Young's solution: 0.81 gm of potassium citrate; 2.46 gm of magnesium sulfate; 0.001 mg of neostigmine methylsulfate; H,O qs to 100 ml; pH adjusted to 7.4 with NaHC03.
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Blood samples for measurement of blood gases, pH, glucose, and lactate were collected through a catheter placed in the abdominal aorta. Mixed venous blood samples were obtained through a catheter placed in the right ventricle. Samples were taken at normothermia; at 30" and 25°C of cooling; before induction of circulatory occlusion; after 3 minutes of cardiac massage during resuscitation; at 25",30", and 35°C of rewarming; and the following morning. Blood gases and pH were measured by a Radiometer Model 27 pH meter. Electrode temperatures were preadjusted to the aforementioned sampling temperatures to eliminate calculation errors. T h e blood concentration of Forane was measured by chromatography as described by Fink and Morikawa [9]. Blood glucose and lactate levels were determined by the methods of Brown [31 and enzymatic fluorometric methods [lo], respectively. The six standard limb ECG leads were recorded using a Hewlett-Packard Model 88 11A Bioelectric Amplifier and a Model 7788A recorder. Changes in P-R, QRS, Q-T, and R-R intervals were analyzed and abnormal wave patterns evaluated.
Results Overall results are summarized in the Table. All 17 dogs tolerated the procedure. N o detectable sensory neurological disorders were found in any animals. However, 6 of 7 dogs ventilated with 100% O2 and 3 of 5 dogs with 98% 042% C 0 2 later developed a motor disturbance affecting the front legs (high-stepping gait) [151. No motor disturbances were seen in any of the dogs that were ventilated with 95% 045% C02. Anesthesia was induced and maintained uneventfully throughout the hypothermic procedure except in 1 dog given 5% C02that developed ventricular fibrillation during cooling at 23°C. Changes in heart rate were similar in all groups. The heart rate gradually decreased with cooling and reached around 30 beats per minute at 20°C (Fig. 1). During rewarming, heart rates climbed graduRESULTS OF FORANE ANESTHESIA WITH VARIOUS VENTILATION PROTOCOLS IN 17 DOGS
Data No. of dogs Body weight (kg) Ventilated gases Ventricular fibrillation during cooling Duration of cooling (min) Duration of rewarming (min) Postoperative motor disorders
Experimental Group 2
3
7 16.7 -t- 3.0 100% 0 2 0
5 16.2 f 1.2 98% Oz/2% COZ 0
5 16.8k 1.9 95% 0 4 5 % COZ 1
86.3 & 20.5 206.3 f 34.7
87.4 f 19.6 221.8 & 25.0
84.42 16.3 226.2 & 23.7
6
3
0
1
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FIG. 1 . Alterations in heart rate and mean arterial blood pressure during hypothemic procedures with 30 minutes' circulatory arrest under Forane anesthesia. (Open triangles indicate changes in Group 1 - surface hypothermiu, 100% 0,. Open circles indicate changes in Group 2 - surface hypothermiu, 98 % 02/2% GO,.Closed circles indicate changes in Group3 - surface hypothermia with 95% 02/5%GO,. Mean ualue is plotted.)
ally up toward normal with increase in body temperature. The rate of increase, however, was much greater than the rate of decrease during cooling. Changes in mean aortic pressures duringcooling were similar in groups given 100% 0, and 98% OJ2% CO,. There was a slight pressure drop to 25°C and a rather steep fall thereafter. Mean aortic pressure in the 5% CO, group was low from the beginning and remained lower than in the other two groups. During rewarming following 30 minutes of cardiac arrest, mean aortic pressures were similar in all groups and increased gradually except in the 2% CO, group, in which a precipitous and significant increase in pressure was noted at 30" and 35°C. The required time for cooling was similar in all groups (see the Table). Initial restoration of cardiac function was easy in all groups and was comparable to that in the ether-anesthetized series previously reported despite significantly poorer venous blood return in the animals given Forane. However, cardiac performance thereafter was poorer than with ether, and many dogs had repeated episodes of ventricular fibrillation that required repeated cardiac massage and multiple electrical defibrillations. One of 7 with 100%O,, 3 of 5 with 2% COz,and 1 of 5 with 5% CO, were resuscitated without electrical defibrillation; but even in these dogs supportive measures such as assisting cardiac massage or adrenaline occasionally were necessary. The 5% CO, group required more supportive measures than the other two groups. The average time needed for successful resuscitation was 8.5 minutes for the 100 %O, group, 7.6 minutes for the 2% CO, group, and 16.0 minutes for the 5% CO, group. Changes in P-R, QRS, Q-T, and R-R intervals and Q T m (QTc) are depicted in Figure 2. During cooling these factors showed monotonous incremental increases related to temperature drop, and there was no major difference among groups except for marked prolongation of the Q-T interval in the 100%0, group at 20°C and a slightly reduced QTc below 25°C in the 5% CO, group. An abnormal wave pattern (J wave [IS]) appeared frequently in all groups during cooling when temperatures fell below 25°C. The incidence of J wave appearance was slightly higher in the 100% 0, group than in the COz groups. 302
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FIG. 2. Alterations in R-R P-R, QRS, and Q-T intervals and QT& (QTc) during hypothemnic procedures with 3 0 minutes' circulatory arrest under Forane anesthesia. (Symbols same as in Fig. 1 .)
9 2
O4 Control 35
30 25
20
I -
Rectal temperoture
io
('C
25 52 35
During rewarming, a conducted sinoatrial rhythm could not be established until the temperature was well over 20°C. In the 5% CO, group all returned to sinus rhythm by 25"C, while 2 of 5 dogs in the 2% CO, group did not convert to sinus rhythm until 30°C. The 100%0, group showed wide variation in the temperature required for conversion to sinus rhythm. One animal in the 5% CO, group suddenly fibrillated at 23°C duringcooling. Premature atrial contractions had been noted at 25"C, with the subsequent QRS occurring very close to or in the T wave of the previous complex. There had been no ventricular arrhythmia prior to fibrillation. After fibrillation, external massage and externally applied 200 watt-sec DC countershock did not produce cardioversion. The chest was opened, and internal massage followed by a single 50 volt shock resulted in cardioversion 7 minutes following the onset of fibrillation. The procedure was continued without further incident. Following resuscitation a multifocal ventricular rhythm developed, presumably due to the anoxic insult and cardiac massage. During cooling changes in blood glucose levels were similar in all groups; blood glucose tended to increase during rewarming, especially in the 100% O2 group (Fig. 3). Lactate levels remained within the normal range in all groups during cooling, although the 100%0, group showed slightly higher levels and the COz groups showed a decreasing trend with temperature drop. Following resuscitation and during rewarming, lactate levels increased in all groups. Lactate levels were highest in the 100%O2group, followed by the 2% CO, group; the 5% C 0 2 group had the lowest levels. However, absolute blood lactate values were never above 3 to 4 mEq per liter, even in the 100% 0, group. For induction and maintenance of anesthesia during cooling to 30"C, anesVOL. 20, NO. 3, SEPTEMBER, 1975
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FIG. 3 . Alterations in blood glucose and lactate during hypothermic procedures with 30 minutes’ circulatory arrest under Forane anesthesia. Mean value ? one standard deviation (vertical bars) are plotted. (Symbols same as in Fig. 1 .)
thesia levels were set at 1.0 to 1.5% on the Fluotec scale. Mean Forane blood levels were 2.10,2.78, and 3.00~01 per 100 ml beforecoolingand 2.75,3.30, and3.80 vol per 100 ml at 30°C during cooling in the 100%O,, 2% CO,, and 5% CO, groups, respectively. With reduced Fluotec settings of 0.5 to 1.O% thereafter, blood Forane levels became 2.10,2.80, and 2.70 vol per 100 ml at 25°C and 1.23,2.86, and 3.00 vol per 100 ml at 20°C in these groups, respectively. During the rewarming period, and with Fluotec settings of 0.5 to l.O%, blood Forane levels were 1.20, 1.94, and 2.50 vol per 100 ml at the initial period of rewarming; 1.43,2.30, and 2.30 vol per 100 ml at 25°C; 1.90,2.54, and 4.10 vol per 100 ml at 30°C; and 1.50, 2.68, and 4.20 vol per 100 ml at the end of rewarming. Changes in arterial and venous blood pH, Pco,, and Po, are demonstrated in Figure 4. As the method implies, the 100% O2 group developed respiratory alkalosis, while the 5% C 0 2 group was slightly acidotic and had high Pco, levels. The 2% CO, group ranged between these levels.
Comment This study clearly demonstrates that carbon dioxide in the gas mixture is mandatory when Forane anesthesizi is utilized with surface-induced deep hypothermia and total circulatory occlusion. The motor disorder, so-called highstepping gait [ 151, also developed in dogs subjected to 30 minutes of circulatory occlusion at 18°C under halothane/lOO% O2 anesthesia, as demonstrated previously [ 191. Using 5% CO, with halothane anesthesia, 1 of 5 dogs developed gait disturbance. On the other hand, we have demonstrated the absence of such neurological disorders after the same period of cardiac arrest under ether/l00% O2 anesthesia [15]. The reason for this difference between ether, Forane, and halothane anesthesia is not clear. Since the latter two anesthetics possess a greater vasodilative effect than the former, it is probably not due to poor tissue perfusion. Cooling alone seems not to be the cause of the motor disturbance, since dogs
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Forane Anesthesiafor Deep Surface Hypothemzia
FIG. 4 . AlterationsinpH, Pcoa andPo2during hypothemtic procedures with 3 0 minutes' circulatory arrest under Forane anesthesia. (Thick lines indicate changes in arterial blood samples, and thin lines represent changes in venous samples. Symbols same as in Fig. 1 .)
subjected only to cooling and warming without circulatory arrest were neurologically normal. Hemodynamics during cooling were comparable with Forane and ether anesthesia except for the slightly higher incidence of arrhythmias with Forane. There were no significant differences between the 100% O2and 5% CO2 groups with Forane. Slow recovery of hemodynamics at resuscitation and during rewarming may cause some difference in the outcome. The different results may depend on variations in tissue oxygen utilization or oxygen transfer from blood to tissue with different anesthetics. The use of carbon dioxide at a level of 5% may beneficially influence oxygen delivery to tissue by shifting the oxyhemoglobin dissociation curve back toward the right. The higher blood lactate levels in the 100% O2 group also suggest possible lesser oxygen availability in the tissue. Before intentional cardiac arrest is induced, tissues may develop latent anoxia that will shorten the safe circulatory occlusion time. The reason why tissues have greater tolerance for anoxia with ether anesthesia [ 17,193, even with 100% 02,is not known. Cardiac arrhythmia associated with Forane anesthesia was similar in incidence and degree to that with halothane anesthesia during hypothermia. This result is rather different from previous reports [ 12,211, in which greater myocardial stability with Forane over halothane at normothermia was documented. The frequency of nodal arrhythmias during cooling, the slightly reduced hemodynamic function with subsequent delayed recovery of cardiac function, and a higher incidence of cardiac arrhythmia during rewarming with Forane anesthesia suggest that ether anesthesia is superior when used for surface hypothermia. However, Forane anesthesia can be utilized for surface hypothermia and 30 minutes of total circulatory occlusion when it is administered with 95% 0 $ 5 % COP. The maximum duration of safe circulatory occlusion with Forane anesthesia should be explored.
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References 1. Baffes, T. G. Total body perfusion in infants and small children for open heart surgery. J Pediatr Surg 3:557, 1968. 2. Barratt-Boyes, B. G., Simpson, M., and Neutze, J. M. Intracardiac surgery in neonates and infants using deep hypothermia with surface cooling and limited cardiopulmonary bypass. Circulation 43, 44 (Suppl): 1, 1971. 3. Brown, M. E. Ultra-micro sugar determinations using 2,9-dimethyl-l,10phenanthroline hydrochloride (Neocuproine). Diabetes 10:60, 1961. 4. Ching, E., DuShane, J. W., McGoon, D. C., and Danielson, G. K. Total correction of cardiac anomalies in infancy using extracorporeal circulation: Surgical considerations and results of early operation. J Thorac Cardiovasc Surg 62: 117, 1971. 5. Cooley, D. A., and Hallman, G. L. Surgery during the first year of life for cardiovascular anomalies: Review of 500 consecutive operations. J Cardioumc Surg (Torino) 5:584, 1964. 6. Dillard, D. H., Mohri, H., Hessel, E. A., 11, Anderson, H. N., Nelson, R. J., Crawford, E. W., Morgan, B. C., Winterscheid, L. C., and Merendino, K. A. Correction of total anomalous pulmonary venous drainage in infancy utilizing deep hypothermia with total circulatory arrest. Circulation 35, 36 (Suppl): 105, 1967. 7. Dillard, D., Mohri, H., and Merendino, K. A. Correction of heart diseases in infancy utilizing deep hypothermia and total circulatory arrest.J Thorac Cardiovasc Surg 6 1:64, 1971. 8. Dillard, D. H., Mohri, H., Merendino, K. A,, Morgan, B. C., Baum, D., and Crawford, E. W. Total surgical correction of transposition of the great arteries in children less than six months of age. Surg Gynecol Obstet 129:1258, 1969. 9. Fink, D. R., and Morikawa, K. Simplified method for the measurement of volatile anesthetics in blood by gas chromatography. Anesthesiology 32:451, 1970. 10. Hohorst, H. J. MethodsofEngmaticAnalysG (lsted). Weinheim: VerlagChemie, 1962. P 622. 11. Horiuchi, T., Koyamada, K., Matano, I., Mohri, H., Komatsu, T., Honda, T., Abe, T., Ishitoya, T., Sagawa, Y., Matsuzawa, K., Matsumura, M., Tsuda, T., Ishizawa, E., Ishikawa, S., Suzuki, H., and Saito, Y. Radical operation for ventricular septa1defect in infancy.J Thorac Cardiovmc Surg 46:180, 1963. 12. Joas, T. A., and Stevens, W. C. Comparison of the arrhythmic doses of epinephrine during Forane, halothane and Fluroxene anesthesia in dogs. Anesthesiology 35:48, 1971. 13. Miller, R. D., Eger, E. I., 11, Way, W. L., Stevens, W. C., and Dolan, W. M. Comparative neuromuscular effects of Forane and halothane alone and in combination with d-tubocurarine in man. Anesthesiology 35:38, 1971. 14. Mohri, H., Dillard, D. H., and Merendino, K. A. Hypothermia: Halothane anesthesia and the safe period of total circulatory arrest. Surgery 72:345, 1972. 15. Mohri, H., Hessel, E. A., 11, Nelson, R. J., Matano, I., Anderson, H. N., Dillard, D. H., and Merendino, K. A. Use of Rheomacrodex and hyperventilation in prolonged circulatory arrest under deep hypothermia induced by surface cooling -method for open heart surgery in infants. Am J Surg 112: 241, 1966. 16. Mori, A., Muraoka, R., Yokota, Y., Okamoto, Y., Ando, F., Fukumasu, H., Oku, H., Ikeda, M., Shirotani, H., and Hikasa, Y. Deep hypothermia combined with cardiopulmonary bypass for cardiac surgery in neonates and infants. J Thorac Cardiovmc Surg 64:422, 1972. 17. Perna, A. M., Gardner, T. J., Tabaddor, K., Brawley, R. K., and Gott, V. L. Cerebral metabolism and blood flow after circulatory arrest during deep hypothermia. Ann Surg 178:85, 1973. 18. Sands, M. P., Sato, S., Mohri, H., Guntheroth, W. G., and Merendino, K. A. Electrocardiographic changes during surface-induced deep hypothermia: The influence of ether, halothane, carbon dioxide, and perfusion rewarming. Ann Thorac Surg 19:386, 1975. 19. Sato, S., Vanini, V., Mohri, H., and Merendino, K. A. A comparative study of the
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Forane Anesthesiafor Deep Surface Hypothermia effects of carbon dioxide and perfusion rewarming on limited circulatory occlusion during surface hypothermia, under halothane and ether anesthesia. Ann Surg 10:192, 1974. 20. Starr, A., Bonchek, L. I., and Sunderland, C. 0. Total correction of tetralogy of Fallot in infancy. J Thmac Cardiovasc Surg 65:45, 1973. 21. Stevens, W. C., Cromwell, T. H., Halsey, M. J., Eger, E. I., 11, Shakespeare, T. F., and Bahlman, S. H. The cardiovascular effects of a new inhalation anesthetic, Forane, in human volunteers at constant arterial carbon dioxide tension. Anesthesiology 35:8,197 1. 22. Subramanian, S., and Wagner, H. Correction of transposition of the great vessels in infants under surface-induced deep hypothermia. Ann Thorac Surg 16:391, 1973.
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orrection of congenital heart disease in early infancy has gained popularity in recent years, and the concept of attempting early repair has been considered successful 11, 2, 4, 7, 11, 16, 20, 221. Many surgeons use surface hypothermia with total circulatory arrest [2,6-8,11,15,16, 221, while others [l, 4, 51 prefer extracorporeal circulation. At this institution, early correction of congenital heart disease has been carried out utilizing surface hypothermia since 1965 [6-8, 151. Based on our experimental results, we prefer ether to other anesthetic agents in our clinical protocol, while halothane is the agent of choice in many other institutions [2,16, 221. Our experimental studies have demonstrated the superiority of ether anesthesia to halothane anesthesia for hypothermic applications [ 14,18,19]. However, the explosive characteristics, slow induction, and slow recovery associated with ether are considered to be shortcomings of this agent. From the Department of Surgery, the Division of Cardiothoracic Surgery, and the Department of Anesthesiology of the University Hospital, University of Washington School of Medicine, Seattle, Wash. Aided by U.S. Public Health Service Grant no. 13517, Unit 7, and NICH HD 02272, and by grants from the American Heart Association and the Northeastern Chapter of the Washington State Heart Association. We would like to thank the Ohio Medical Products Company for supplying Forane for this study. *Established Investigator, American Heart Association. This work was done during the tenure of the Investigatorship. Accepted for publication Mar. 25, 1975. Address reprint requests to Dr. Mohri, Department of Surgery, RF-25, University Hospital, Seattle, Wash. 98195.
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SAT0 ET AL. difluoromethyl ether) has Compound 469 (l-chloro-2,2,2-trifluoroethyl been extensively studied. This volatile agent, named Forane, possesses strong vasodilative and muscle relaxant abilities, allows for rapid recovery after its withdrawal, and is nonexplosive [12, 13, 213. The present study was undertaken to evaluate the use of Forane for surface-induced deep hypothermia with a limited period of total circulatory occlusion.
Materials and Method Seventeen adult mongrel dogs with an average weight of 16.5 kg were subjected to deep hypothermia and total circulatory occlusion for 30 minutes. These dogs were divided into three groups according to the applied respiratory gas mixture, the only variable in this experiment. One hundred percent oxygen was used in 7 of these dogs, 98% 042% C 0 2in 5 dogs, and 95% 045% C 0 2in the remaining 5 dogs. Usual ventilation levels for normothermia were maintained throughout the hypothermic procedure using a Palmer volume-constant respirator, thus producing relative hyperventilation at hypothermia. Anesthesia was induced with thiamylal sodium and maintained with Forane. A Fluotec Mark I1 vaporizer, nonrebreathing circuit, and endotracheal tube were utilized. No specific premedication except atropine sulfate in a dose of 0.02 mg per kilogram of body weight was used. Judgment of depth of anesthesia was by clinical assessment, based on levels deep enough to prevent shivering during hypothermia. Cooling was carried out by immersing dogs in ice water until the rectal temperature dropped to 22°C. During cooling from 35" to 25"C, a total dose of 10 mVkg of 10%low-molecular-weightDextran was administered to improve microcirculation. The chest was opened and total circulatory occlusion for 30 minutes was established by cross-clamping the cavae and great arteries and injecting Young's solution* into the aortic root for cardioplegia. Cardiac resuscitation was carried out by manual massage after releasing inflow and outflow occlusions. After 3 minutes of cardiac massage, blood samples were collected and surface rewarming initiated in a warm water bath with a plastic sheet interposed and an additional heat lamp. Approximately 300 mg of calcium chloride was given intravenously to counteract the potassium effects of Young's solution. When the heart regained a normal beat spontaneously, it was assisted only by mechanical or electrical pacing or by supportive cardiac massage. If it fibrillated, it was defibrillated by a 50 volt AC shock. During resuscitation and rewarming, the use of cardiotonic agents (except the calcium chloride mentioned above), vasopressors, and sodium bicarbonate was avoided in most cases. However, in some, the use of one or two 0.05 cc doses of 1:1,000 adrenaline was lifesaving. Rewarming was discontinued at a rectal temperature of 35°C. All dogs were allowed to live for at least three weeks to assess the presence of neurological disorders. *Young's solution: 0.81 gm of potassium citrate; 2.46 gm of magnesium sulfate; 0.001 mg of neostigmine methylsulfate; H,O qs to 100 ml; pH adjusted to 7.4 with NaHC03.
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Blood samples for measurement of blood gases, pH, glucose, and lactate were collected through a catheter placed in the abdominal aorta. Mixed venous blood samples were obtained through a catheter placed in the right ventricle. Samples were taken at normothermia; at 30" and 25°C of cooling; before induction of circulatory occlusion; after 3 minutes of cardiac massage during resuscitation; at 25",30", and 35°C of rewarming; and the following morning. Blood gases and pH were measured by a Radiometer Model 27 pH meter. Electrode temperatures were preadjusted to the aforementioned sampling temperatures to eliminate calculation errors. T h e blood concentration of Forane was measured by chromatography as described by Fink and Morikawa [9]. Blood glucose and lactate levels were determined by the methods of Brown [31 and enzymatic fluorometric methods [lo], respectively. The six standard limb ECG leads were recorded using a Hewlett-Packard Model 88 11A Bioelectric Amplifier and a Model 7788A recorder. Changes in P-R, QRS, Q-T, and R-R intervals were analyzed and abnormal wave patterns evaluated.
Results Overall results are summarized in the Table. All 17 dogs tolerated the procedure. N o detectable sensory neurological disorders were found in any animals. However, 6 of 7 dogs ventilated with 100% O2 and 3 of 5 dogs with 98% 042% C 0 2 later developed a motor disturbance affecting the front legs (high-stepping gait) [151. No motor disturbances were seen in any of the dogs that were ventilated with 95% 045% C02. Anesthesia was induced and maintained uneventfully throughout the hypothermic procedure except in 1 dog given 5% C02that developed ventricular fibrillation during cooling at 23°C. Changes in heart rate were similar in all groups. The heart rate gradually decreased with cooling and reached around 30 beats per minute at 20°C (Fig. 1). During rewarming, heart rates climbed graduRESULTS OF FORANE ANESTHESIA WITH VARIOUS VENTILATION PROTOCOLS IN 17 DOGS
Data No. of dogs Body weight (kg) Ventilated gases Ventricular fibrillation during cooling Duration of cooling (min) Duration of rewarming (min) Postoperative motor disorders
Experimental Group 2
3
7 16.7 -t- 3.0 100% 0 2 0
5 16.2 f 1.2 98% Oz/2% COZ 0
5 16.8k 1.9 95% 0 4 5 % COZ 1
86.3 & 20.5 206.3 f 34.7
87.4 f 19.6 221.8 & 25.0
84.42 16.3 226.2 & 23.7
6
3
0
1
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FIG. 1 . Alterations in heart rate and mean arterial blood pressure during hypothemic procedures with 30 minutes' circulatory arrest under Forane anesthesia. (Open triangles indicate changes in Group 1 - surface hypothermiu, 100% 0,. Open circles indicate changes in Group 2 - surface hypothermiu, 98 % 02/2% GO,.Closed circles indicate changes in Group3 - surface hypothermia with 95% 02/5%GO,. Mean ualue is plotted.)
ally up toward normal with increase in body temperature. The rate of increase, however, was much greater than the rate of decrease during cooling. Changes in mean aortic pressures duringcooling were similar in groups given 100% 0, and 98% OJ2% CO,. There was a slight pressure drop to 25°C and a rather steep fall thereafter. Mean aortic pressure in the 5% CO, group was low from the beginning and remained lower than in the other two groups. During rewarming following 30 minutes of cardiac arrest, mean aortic pressures were similar in all groups and increased gradually except in the 2% CO, group, in which a precipitous and significant increase in pressure was noted at 30" and 35°C. The required time for cooling was similar in all groups (see the Table). Initial restoration of cardiac function was easy in all groups and was comparable to that in the ether-anesthetized series previously reported despite significantly poorer venous blood return in the animals given Forane. However, cardiac performance thereafter was poorer than with ether, and many dogs had repeated episodes of ventricular fibrillation that required repeated cardiac massage and multiple electrical defibrillations. One of 7 with 100%O,, 3 of 5 with 2% COz,and 1 of 5 with 5% CO, were resuscitated without electrical defibrillation; but even in these dogs supportive measures such as assisting cardiac massage or adrenaline occasionally were necessary. The 5% CO, group required more supportive measures than the other two groups. The average time needed for successful resuscitation was 8.5 minutes for the 100 %O, group, 7.6 minutes for the 2% CO, group, and 16.0 minutes for the 5% CO, group. Changes in P-R, QRS, Q-T, and R-R intervals and Q T m (QTc) are depicted in Figure 2. During cooling these factors showed monotonous incremental increases related to temperature drop, and there was no major difference among groups except for marked prolongation of the Q-T interval in the 100%0, group at 20°C and a slightly reduced QTc below 25°C in the 5% CO, group. An abnormal wave pattern (J wave [IS]) appeared frequently in all groups during cooling when temperatures fell below 25°C. The incidence of J wave appearance was slightly higher in the 100% 0, group than in the COz groups. 302
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FIG. 2. Alterations in R-R P-R, QRS, and Q-T intervals and QT& (QTc) during hypothemnic procedures with 3 0 minutes' circulatory arrest under Forane anesthesia. (Symbols same as in Fig. 1 .)
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During rewarming, a conducted sinoatrial rhythm could not be established until the temperature was well over 20°C. In the 5% CO, group all returned to sinus rhythm by 25"C, while 2 of 5 dogs in the 2% CO, group did not convert to sinus rhythm until 30°C. The 100%0, group showed wide variation in the temperature required for conversion to sinus rhythm. One animal in the 5% CO, group suddenly fibrillated at 23°C duringcooling. Premature atrial contractions had been noted at 25"C, with the subsequent QRS occurring very close to or in the T wave of the previous complex. There had been no ventricular arrhythmia prior to fibrillation. After fibrillation, external massage and externally applied 200 watt-sec DC countershock did not produce cardioversion. The chest was opened, and internal massage followed by a single 50 volt shock resulted in cardioversion 7 minutes following the onset of fibrillation. The procedure was continued without further incident. Following resuscitation a multifocal ventricular rhythm developed, presumably due to the anoxic insult and cardiac massage. During cooling changes in blood glucose levels were similar in all groups; blood glucose tended to increase during rewarming, especially in the 100% O2 group (Fig. 3). Lactate levels remained within the normal range in all groups during cooling, although the 100%0, group showed slightly higher levels and the COz groups showed a decreasing trend with temperature drop. Following resuscitation and during rewarming, lactate levels increased in all groups. Lactate levels were highest in the 100%O2group, followed by the 2% CO, group; the 5% C 0 2 group had the lowest levels. However, absolute blood lactate values were never above 3 to 4 mEq per liter, even in the 100% 0, group. For induction and maintenance of anesthesia during cooling to 30"C, anesVOL. 20, NO. 3, SEPTEMBER, 1975
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FIG. 3 . Alterations in blood glucose and lactate during hypothermic procedures with 30 minutes’ circulatory arrest under Forane anesthesia. Mean value ? one standard deviation (vertical bars) are plotted. (Symbols same as in Fig. 1 .)
thesia levels were set at 1.0 to 1.5% on the Fluotec scale. Mean Forane blood levels were 2.10,2.78, and 3.00~01 per 100 ml beforecoolingand 2.75,3.30, and3.80 vol per 100 ml at 30°C during cooling in the 100%O,, 2% CO,, and 5% CO, groups, respectively. With reduced Fluotec settings of 0.5 to 1.O% thereafter, blood Forane levels became 2.10,2.80, and 2.70 vol per 100 ml at 25°C and 1.23,2.86, and 3.00 vol per 100 ml at 20°C in these groups, respectively. During the rewarming period, and with Fluotec settings of 0.5 to l.O%, blood Forane levels were 1.20, 1.94, and 2.50 vol per 100 ml at the initial period of rewarming; 1.43,2.30, and 2.30 vol per 100 ml at 25°C; 1.90,2.54, and 4.10 vol per 100 ml at 30°C; and 1.50, 2.68, and 4.20 vol per 100 ml at the end of rewarming. Changes in arterial and venous blood pH, Pco,, and Po, are demonstrated in Figure 4. As the method implies, the 100% O2 group developed respiratory alkalosis, while the 5% C 0 2 group was slightly acidotic and had high Pco, levels. The 2% CO, group ranged between these levels.
Comment This study clearly demonstrates that carbon dioxide in the gas mixture is mandatory when Forane anesthesizi is utilized with surface-induced deep hypothermia and total circulatory occlusion. The motor disorder, so-called highstepping gait [ 151, also developed in dogs subjected to 30 minutes of circulatory occlusion at 18°C under halothane/lOO% O2 anesthesia, as demonstrated previously [ 191. Using 5% CO, with halothane anesthesia, 1 of 5 dogs developed gait disturbance. On the other hand, we have demonstrated the absence of such neurological disorders after the same period of cardiac arrest under ether/l00% O2 anesthesia [15]. The reason for this difference between ether, Forane, and halothane anesthesia is not clear. Since the latter two anesthetics possess a greater vasodilative effect than the former, it is probably not due to poor tissue perfusion. Cooling alone seems not to be the cause of the motor disturbance, since dogs
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FIG. 4 . AlterationsinpH, Pcoa andPo2during hypothemtic procedures with 3 0 minutes' circulatory arrest under Forane anesthesia. (Thick lines indicate changes in arterial blood samples, and thin lines represent changes in venous samples. Symbols same as in Fig. 1 .)
subjected only to cooling and warming without circulatory arrest were neurologically normal. Hemodynamics during cooling were comparable with Forane and ether anesthesia except for the slightly higher incidence of arrhythmias with Forane. There were no significant differences between the 100% O2and 5% CO2 groups with Forane. Slow recovery of hemodynamics at resuscitation and during rewarming may cause some difference in the outcome. The different results may depend on variations in tissue oxygen utilization or oxygen transfer from blood to tissue with different anesthetics. The use of carbon dioxide at a level of 5% may beneficially influence oxygen delivery to tissue by shifting the oxyhemoglobin dissociation curve back toward the right. The higher blood lactate levels in the 100% O2 group also suggest possible lesser oxygen availability in the tissue. Before intentional cardiac arrest is induced, tissues may develop latent anoxia that will shorten the safe circulatory occlusion time. The reason why tissues have greater tolerance for anoxia with ether anesthesia [ 17,193, even with 100% 02,is not known. Cardiac arrhythmia associated with Forane anesthesia was similar in incidence and degree to that with halothane anesthesia during hypothermia. This result is rather different from previous reports [ 12,211, in which greater myocardial stability with Forane over halothane at normothermia was documented. The frequency of nodal arrhythmias during cooling, the slightly reduced hemodynamic function with subsequent delayed recovery of cardiac function, and a higher incidence of cardiac arrhythmia during rewarming with Forane anesthesia suggest that ether anesthesia is superior when used for surface hypothermia. However, Forane anesthesia can be utilized for surface hypothermia and 30 minutes of total circulatory occlusion when it is administered with 95% 0 $ 5 % COP. The maximum duration of safe circulatory occlusion with Forane anesthesia should be explored.
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References 1. Baffes, T. G. Total body perfusion in infants and small children for open heart surgery. J Pediatr Surg 3:557, 1968. 2. Barratt-Boyes, B. G., Simpson, M., and Neutze, J. M. Intracardiac surgery in neonates and infants using deep hypothermia with surface cooling and limited cardiopulmonary bypass. Circulation 43, 44 (Suppl): 1, 1971. 3. Brown, M. E. Ultra-micro sugar determinations using 2,9-dimethyl-l,10phenanthroline hydrochloride (Neocuproine). Diabetes 10:60, 1961. 4. Ching, E., DuShane, J. W., McGoon, D. C., and Danielson, G. K. Total correction of cardiac anomalies in infancy using extracorporeal circulation: Surgical considerations and results of early operation. J Thorac Cardiovasc Surg 62: 117, 1971. 5. Cooley, D. A., and Hallman, G. L. Surgery during the first year of life for cardiovascular anomalies: Review of 500 consecutive operations. J Cardioumc Surg (Torino) 5:584, 1964. 6. Dillard, D. H., Mohri, H., Hessel, E. A., 11, Anderson, H. N., Nelson, R. J., Crawford, E. W., Morgan, B. C., Winterscheid, L. C., and Merendino, K. A. Correction of total anomalous pulmonary venous drainage in infancy utilizing deep hypothermia with total circulatory arrest. Circulation 35, 36 (Suppl): 105, 1967. 7. Dillard, D., Mohri, H., and Merendino, K. A. Correction of heart diseases in infancy utilizing deep hypothermia and total circulatory arrest.J Thorac Cardiovasc Surg 6 1:64, 1971. 8. Dillard, D. H., Mohri, H., Merendino, K. A,, Morgan, B. C., Baum, D., and Crawford, E. W. Total surgical correction of transposition of the great arteries in children less than six months of age. Surg Gynecol Obstet 129:1258, 1969. 9. Fink, D. R., and Morikawa, K. Simplified method for the measurement of volatile anesthetics in blood by gas chromatography. Anesthesiology 32:451, 1970. 10. Hohorst, H. J. MethodsofEngmaticAnalysG (lsted). Weinheim: VerlagChemie, 1962. P 622. 11. Horiuchi, T., Koyamada, K., Matano, I., Mohri, H., Komatsu, T., Honda, T., Abe, T., Ishitoya, T., Sagawa, Y., Matsuzawa, K., Matsumura, M., Tsuda, T., Ishizawa, E., Ishikawa, S., Suzuki, H., and Saito, Y. Radical operation for ventricular septa1defect in infancy.J Thorac Cardiovmc Surg 46:180, 1963. 12. Joas, T. A., and Stevens, W. C. Comparison of the arrhythmic doses of epinephrine during Forane, halothane and Fluroxene anesthesia in dogs. Anesthesiology 35:48, 1971. 13. Miller, R. D., Eger, E. I., 11, Way, W. L., Stevens, W. C., and Dolan, W. M. Comparative neuromuscular effects of Forane and halothane alone and in combination with d-tubocurarine in man. Anesthesiology 35:38, 1971. 14. Mohri, H., Dillard, D. H., and Merendino, K. A. Hypothermia: Halothane anesthesia and the safe period of total circulatory arrest. Surgery 72:345, 1972. 15. Mohri, H., Hessel, E. A., 11, Nelson, R. J., Matano, I., Anderson, H. N., Dillard, D. H., and Merendino, K. A. Use of Rheomacrodex and hyperventilation in prolonged circulatory arrest under deep hypothermia induced by surface cooling -method for open heart surgery in infants. Am J Surg 112: 241, 1966. 16. Mori, A., Muraoka, R., Yokota, Y., Okamoto, Y., Ando, F., Fukumasu, H., Oku, H., Ikeda, M., Shirotani, H., and Hikasa, Y. Deep hypothermia combined with cardiopulmonary bypass for cardiac surgery in neonates and infants. J Thorac Cardiovmc Surg 64:422, 1972. 17. Perna, A. M., Gardner, T. J., Tabaddor, K., Brawley, R. K., and Gott, V. L. Cerebral metabolism and blood flow after circulatory arrest during deep hypothermia. Ann Surg 178:85, 1973. 18. Sands, M. P., Sato, S., Mohri, H., Guntheroth, W. G., and Merendino, K. A. Electrocardiographic changes during surface-induced deep hypothermia: The influence of ether, halothane, carbon dioxide, and perfusion rewarming. Ann Thorac Surg 19:386, 1975. 19. Sato, S., Vanini, V., Mohri, H., and Merendino, K. A. A comparative study of the
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Forane Anesthesiafor Deep Surface Hypothermia effects of carbon dioxide and perfusion rewarming on limited circulatory occlusion during surface hypothermia, under halothane and ether anesthesia. Ann Surg 10:192, 1974. 20. Starr, A., Bonchek, L. I., and Sunderland, C. 0. Total correction of tetralogy of Fallot in infancy. J Thmac Cardiovasc Surg 65:45, 1973. 21. Stevens, W. C., Cromwell, T. H., Halsey, M. J., Eger, E. I., 11, Shakespeare, T. F., and Bahlman, S. H. The cardiovascular effects of a new inhalation anesthetic, Forane, in human volunteers at constant arterial carbon dioxide tension. Anesthesiology 35:8,197 1. 22. Subramanian, S., and Wagner, H. Correction of transposition of the great vessels in infants under surface-induced deep hypothermia. Ann Thorac Surg 16:391, 1973.
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