- Email: [email protected]
Improved Anesthesia for Deep Surface-Induced Hypothermia: The Halothane-Diethyl Ether Azeotrope
Improved Anesthesia for Deep Surface-Induced Hypothermia: The Halothane-Diethyl Ether Azeotrope Murray P. Sands, David H. Dillard, M.D., Eugene A. Hessel 11, M.D., and Donald W. Miller, Jr., M.D.
institution has been used in more than 150 infants undergoing total repair of a variety of congenital cardiac defects [4-6, 15, 17, 22, 251. This clinical experience and extensive laboratory testing [lo, 14, 18-20, 231 demonstrated that ether administered in 100°/~oxygen (OJ was the superior anesthetic over other tested agents for pure surface hypothermia. Ether, however, is explosive, and this prevents the use of the electrocautery and the heart-lung machine. This primary disadvantage of ether led us to study extensively and evaluate other agents including halothane 110, 14, 191, Forane (isoflurane) 1201, and fluroxene.* All of these agents yielded poorer results than ether. This report presents the results of early laboratory and clinical trials utilizing the azeotropic compound of halothane and diethyl ether as the anesthetic for deep surface hypothermia. The azeotropic mixture of halothane and diethyl ether has been described by others [l,3, 71 and used extensively clinically [24, 261, but not for deep surface hypothermia. An azeotropic mixture is one in which certain proportions of two liquids combine to form a solution that behaves physically like a pure compound. Thus, a 0.65 mole fraction of halothane combined with a 0.35 mole fraction of diethyl ether velds a compound with its own specific gravity, boiling point, and vapor pressure (Table 1). FurtherSince August, 1965, a method of surface- more, vaporization or ordinary distillation will induced deep hypothermia developed at this not break down the compound or alter the proportion of its components. The halothaneFrom the Division of Cardiothoracic Surgery, Department diethyl ether azeotrope is nonexplosive in anof Surgery, University of Washington School of Medicine, esthetic concentrations, and we hypothesized Seattle, WA. Aided by funds from United States Public Health Service that it might combine some of the favorable Grant No. HL-19203. features of both ether and halothane. From our We thank Mr. Clifford Pitts and Mr. Robert Thomas whose technical effort and'expertise made this study possible and previous investigations 112, 151 we are aware Ms. Peggy Aspen for manuscript preparation. that ether is most effective when used in 100Y0 Accepted for publication Apr 2, 1979. O2 and that halothane performs best with 95% ABSTRACT The halothane-diethyl ether azeotrope was evaluated in dogs as the anesthetic agent for deep surface hypothermia with total circulatory arrest for open-heart operation. All 10 animals given experienced atrial arazeotrope in 100% oxygen (0,) rhythmias during cooling, and 1 had ventricular fibrillation prior to the completion of cooling at 18' to 20°C. After only 30 minutes' arrest, 8 of the 10 dogs had postoperative motor disturbances. Administering the azeotrope in 95% 0,and 5% carbon dioxide (CO,) yielded markedly improved results characterized by a rapid, smooth cooling course, easy resuscitation following circulatory arrest, and rapid rewarming, and 3 out of 10 dogs experienced mild motor disturbance after 60 minutes of circulatory arrest. This method, when compared with our standard method of ether in 100°/~ O,, resulted in reduced blood lactates and a striking improvement in clinical status on the first postoperative morning. In limited clinical trials, infants undergoing repair of congenital cardiac defects have done well and responded as expected based on the laboratory experience. Since the results with the azeotrope in 95% 0,and 5% C02 were at least as good as, and in several instances better than, those with the standard method employing ether, the nonexplosive characteristic of the azeotrope warrants continued evaluation of this agent.
Address reprint requests to Dr. Dillard, Division of Cardiothoracic Surgery, Department of Surgery, University of Washington School of Medicine, BB 438, RF-25, Seattle, WA 97195.
*Sands MI', Dillard DH, Hessel EA 11, et al: Unpublished data, 1979.
123 0003-4975/80/020123-07$01.25 @ 1978 by Murray P. Sands
124 The Annals of Thoracic Surgery Vol 29 No 2 February 1980
Table 1. Physical Characteristics of Halothane, Ether, and Halothane-Ether Azeotrope
rewarming is accomplished by floating the subject on a plastic sheet over 40°C water. Circulatory arrest is achieved under aseptic condiVapor tions by inflow and outflow occlusion through a Boiling Pressure Point at 2 4 0 ~ right fourth intercostal space thoracotomy. Specific at 760 and740 Cardioplegia is induced by injecting 30 ml of Gravity mm Hg mm Hg Anesthetic at 25°C ("C) Young's solution* into the aortic root proximal to the aortic cross-clamp. The animals are reHalothane 1.861 50.62 264 suscitated by manual massage and the intrave0.715 34.20 442 Diethyl ether nous administration of 300 mg of calcium chloAzeotropic 1.487 52.25 246a mixture [7] ride to reverse the effects of Young's solution. Cardioversion, when necessary, is accom"The vapor pressure at 24°C reported by Boivin and coworkers [l] is about 213 mm Hg, which is 33 mm Hg lower plished with 50 volt alternating current electhan that later reported by Criscuolo and Wilson [31, appar- troshock. ently the result of a typographical error in the paper by In this study, Groups I1 and I11 receiving Boivin and colleagues. azeotrope were managed by the same protocol except that the azeotrope was administered 0, and 5% carbon dioxide (CO,) [14, 18, 191. from a Fluotec Mark I11vaporizer at flow rates of Therefore, in this study the azeotrope was 8 to 10 liters per minute in an open (nonrebreathing) circuit. tested both with and without CO,.
Material and Methods Twenty-five adult mongrel dogs were randomly assigned to three groups that were studied concurrently. Group I (control) animals (5 dogs) were subjected to our extensively studied technique of deep surface hypothermia [12, 13, 151, which employs ether anesthesia in 100% 0, and a 60-minute period of circulatory arrest at 18" to 20°C rectal temperature. Group I1 animals (10 dogs) were cooled to 18" to 20°C with the halothane-diethyl ether azeotrope in 100% 0, and were arrested for 30 minutes. Group I11 (10 dogs) were cooled to 18" to 20°C with the azeotrope in 95% 0, and 5% CO, and were arrested for 60 minutes.
Hypothermia Technique The details of our surface-induced hypothermia method are standardized and have been reported previously [12, 13, 151. Briefly, it includes the use of deep ether anesthesia in 100% O,, the maintenance of normothermic minute ventilation throughout, so as to gradually induce a respiratory alkalosis (pH = 7.6 to 7.8) by the completion of cooling, and the administration of 10% low molecular weight dextran (1gm Of body weight) between 35" and per 25°C during cooling. Ether is given through a rebreathing circuit including soda-lime canisters. Cooling is by ice-water immersion, and
Sampling and Monitoring After the animals were anesthetized, all sampling and monitoring were done through polyethylene catheters inserted into the abdominal aorta and inferior vena cava through the femoral vessels. Arterial and central venous pressures and the electrocardiogram were monitored and recorded with a physiological recording system (Hewlett-Packard model 7788A) equipped with appropriate amplifiers. Arterial samples were drawn periodically for blood gas, hematocrit and lactate determinations. The pH, partial pressure of carbon dioxide (Pc0.J and partial pressure of oxygen were determined with a blood gas analyzer (model 113, Instrumentation Laboratories Inc.) at 37°C. Temperature correction to the animal's rectal temperature at the time of sampling and acid-base calculations were done with standard Severinghaus nomograms. Lactate determinations were done by our clinical laboratories using methods described elsewhere [9, 11, 161. Rectal and esophageal temperatures were monitored with telethemometer probes (Yellow Springs Instrument Company). *This solution consists of the following: 0.81 g m of potassium citrate; 2.46 gm of magnesium sulfate; 0.001 gm of neostigmine methylsulfate; water in sufficient quantity to make ml of solution; and pH adjusted to 7,4 with sodium bicarbonate.
125 Sands et al: Improved Anesthesia for Deep Hypothermia
Data were tabulated and computer-processed to provide the mean values k 1 standard deviation for each category. Statistical significance was evaluated with the two-tailed Student's t test.
Azeotrope Preparation The agent is formed by combining halothane, 68.3 vol per 100 ml, and diethyl ether, 31.7 vol per 100 ml. In the liquid phase, this is most easily accomplished by using a graduate to measure into a separate container 68.3 ml of halothane and 31.7 ml of diethyl ether (because the combined volume is slightly less than the sum of the individual volumes). The mixture warms slightly as the azeotrope is formed. The container can be agitated gently to hasten the mixing of the azeotrope, which is immediately used to charge a Fluotec or copper kettle-type vaporizer. Although the mixture has been shown to be stable over a period of many months [l], fresh azeotrope was prepared for each procedure during this study. Results All dogs survived and were followed for a minimum of three weeks. Table 2 summarizes the operative and postoperative course in the three groups.
Hypothermia The cooling procedure in ether-anesthetized dogs of Group I was uneventful and consistent with our previously reported experience. In Group I1 (azeotrope in 100% 02),Fluotec settings of 2.0 to 2.5% provided adequate anesthesia to abolish shivering at the onset of cooling. As cooling progressed, anesthetic concentrations were gradually reduced to 0.25% by 20°C. All of these animals had bizarre, frequently low voltage and irregular P waves suggestive of a wandering atrial pacemaker at some time during cooling, and 1 dog fibrillated at 21.4"C prior to elective arrest. Animals in Group I11 (azeotrope in 95% O2 and 5% COz) required less anesthetic with initial settings of 1.5 to 2.0%, which were gradually reduced to 0.1% by 20°C. No arrhythmias were encountered that could not be controlled by adjusting the anesthetic, although when anesthesia was experimentally lightened, a rapid junctional
rhythm followed by a ventricular tachyarrhythmia developed between 32" and 28°C during cooling. One dog was given twice the usual anesthetic concentration at 20°C and had atrial arrest, a junctional bradycardia of 6 beats per minute, and ventricular fibrillation. Shivering was not observed, but 3 dogs in Group I11 displayed respiratory movements controlled with 1 mg of pancuronium bromide; no differences were noted in the variables measured as a result of the pancuronium bromide. Following arrest, resuscitation with manual massage was easily accomplished in all groups. Consistent with past experience, all dogs in Group I, arrested for 60 minutes, required one or two 50 pg doses of epinephrine to support mean arterial pressure immediately following resuscitation. None of the animals given an azeotrope required epinephrine except 2 in Group 111. In those 2, cardiac function was temporarily compromised due to technical errors. Dogs in Group I cooled at a rate of 17.2 f 3.0 sec/kg/"C, which was significantly faster ( p < 0.05) than the 21.0 k 2.9 sec/kg/"Cmeasured in Group 11. Group I11 dogs cooled more quickly (12.6 f 3.0 sec/kg/"C) than either Group I or Group I1 dogs ( p < 0.02 and p < 0.001, respectively). The total rewarming time was similar (36.8 f 5.5 sec/kg/"Cand 35.8 k 4.8 sec/kg/"C)in Groups I and I11 but significantly prolonged ( p < 0.01) in Group I1 at 46.7 f 3.7 sec/kg/"C.Since hemodynamics improve with rewarming, the initial speed of rewarming determines how rapidly cardiac function can be stabilized following resuscitation; accordingly, the time required for the first 5°C of rewarming was measured. Group I dogs required 36.2 f 6.1 secl kg/"C; Group I1 dogs, 41.3 f 5.6 sec/kg/"C; and Group I11 dogs, 28.0 f 5.5 sec/kg/"C. Thus the first 5°C of rewarming was significantly shorter in Group I11 than in Group I or Group I1 ( p < 0.05 and p < 0.001, respectively).
Hemodynamic Changes Mean arterial pressure and heart rate declined with temperature and increased with rewarming in all groups. As noted in Table 3, the mean arterial pressure during cooling in animals in Group I11 was significantly less than in Group I dogs. Pulse pressures were significantly reduced in Group I1 when compared with Group I
126 The Annals of Thoracic Surgery Vol 29 No 2 February 1980
Table 2. Details of Technique, Operative Course, and Results No. of
Group
Dogs
Body Weight (kg)
Anesthetic Agent
Respiratory Gases
Cooling Time (sec/kgl"C)"
I
5
18.2 f 1.39
Ether
100%
0 2
17 f 3.0
I1
10
17.0 f 1.23
Azeotrope
100%
0 2
2 1 f 2.9b
I11
10
17.5 k 1.97
Azeotrope
95% O2 and
5%
13 f 3.0baC
co2
"Cooling and rewarming times include k 1 standard deviation. bIndicates significant difference (p < 0.05) compared with Group I. 'Indicates significant difference (p < 0.05) compared with Group 11. AV = atrioventricular.
at control (control values refer to those obtained immediately prior to cooling), 30" and 25°C during cooling, and 25" and 35°C during rewarming. All animals given an azeotrope had heart rates significantly below those of the ether group at control and during the early cooling period, but the results were more variable thereafter. Data for dogs anesthetized with ether in 100°/~ 0, and for those anesthetized with azeotrope in 95% 0, and 5% CO, are displayed graphically in the Figure.
not eat or drink, while the azeotrope-anesthetized animals appeared completely recovered in that all were active and had a good appetite. Neurological assessment by a blinded observer revealed that 2 of the 5 dogs in Group I, arrested for 60 minutes, had mild gait disturbances (hypermetria or high-stepping gait); while in the azeotrope groups, 8 of the 10 dogs in Group 11, arrested for 30 minutes, and 3 of the 10 dogs in Group 111, arrested for 60 minutes, displayed hypermetria.
Blood Gas and Acid-Base Analysis The blood gas and pH data shown in Table 3 are consistent with the ventilation regimen for each group. As cooling progressed, minute volumes were mechanically maintained so that animals with an anesthetic in 100% 0, developed increasing pH and decreasing Pco, regardless of the anesthetic used. Animals in Group I11 had significantly lower pH and higher Pco, than those in Group I until the completion of rewarming when the pH values were similar. Computed bicarbonate levels were consistently higher in animals with an azeotrope following the onset of cooling, and lactate levels were uniformly significantly lower in both groups with an azeotrope.
Clinical Results Halothane-ether azeotrope in 95% 0, and 5% COz has been utilized as the anesthetic during open-heart operation under surface-induced hypothermia in 3 infants. They were 7, 9, and 11 months old and underwent intraatrial venous transposition repair of transposition of the great arteries, aortic valve commissurotomy and mitral annuloplasty, and correction of tetralogy of Fallot, respectively. They weighed 6.7, 9.1, and 6.7 kg, respectively, and were arrested for 31, 30, and 48 minutes at 19", 20", and 20"C, respectively. Resuscitation and rewarming proceeded smoothly with this anesthetic agent, and all survived.
Postoperative Results Ether-anesthetized animals remained lethargic on the first postoperative morning and would
Comment We have evaluated various anesthetic regimens for surface-induced deep hypothermia: ether in 100% O2 and in 95% 0, and 5% COz [15, 18,
127 Sands et al: Improved Anesthesia for Deep Hypothermia
Circulatory Arrest (min)
Rewarming Time (sec/kg/°C)a
60
37 k 5.5
30
46 f 3.7b
60
36 f 4 . F
Late Survival
Complications Infrequent ventricular tachyarrhythmia if anesthesia too light Atrial arrhythmias (10 dogs); ventricular fibrillation (1dog) Infrequent AV nodal or ventricular arrhythmias eliminated with anesthetic manipulation; ventricular fibrillation (1dog) (anesthesia too deep)
Gait Disturbances
5
2
10
8
10
3
Table 3. Blood Gas and Acid-Base Analysis and Hemodynamic Data Rectal Temperature Variable Group PH
Pco,
Control
30°C
25°C
20T
III
7.42 f .06 7.49 f .03' 7.28 f .05a
7.48 f .06 7.57 f .09' 7.33 f .07a
7.57 2 .07 7.63 f .13 7.34 f .07a
7.69 & .04 7.66 f .18 7.36 f .07'
7.53 f .05 7.51 f .23 7.24 f .06s
7.48 f .07 7.49 f .17 7.23 f .06=
7.40 f .07 7.44 f .14 7.26 f .058
7.28 f .09 7.42 f . O F 7.25 f .07
I I1 I11
34.5 f 2.8 31.4 5.4 54.9 f 6.4'
25.3 f 3.6 26.2 f 6.1 40.6 f 6.48
16.9 k 1.6 21.4 f 7.9 40.3 f 5.58
11.2 f 0.9 19.4 f 9.0 36.0 f 4.8O
12.2 f 2.7 21.0 f 12.3 31.8 f 7.8.
12.7 f 1.6 20.9 8.8 39.9 f 6.5'
+
17.4 f 2.7 28.1 f 11.0 47.7 f 7.5a
28.5 f 7.7 31.2 7.4 53.0 f 8.58
I
17.9 f 3.1 22.8 f 3.4s 24.1 f 4.Ze
14.8 f 3.0 20.1 k 3.1a 21.3 f 4.78
13.2 f 2.1 19.3 f 2.3. 19.7 f 3.4=
9.7 f 1.6 13.8 ? 2.Z8 13.4 f 2.98
9.0 f 1.3 14.3 f 2.4' 16.6 f 2.2'
10.2 f 0.8 16.9 f 2 . P 20.3 f 2.38
13.0 f 2.7 19.2 f 2 . P 22.3 f 3.1a
-3.4 f 2.7 2.7 f 3.2* -1.7 f 4.9
-3.8 k 4.3 1.2 f 2.7= -3.6 f 5.4
-2.8 f 2.8 0.5 f 2.4' -4.8 f 4.2
I I1
+
I11
21.5 f 2.2 22.8 f 4.1 24.9 f 4.4
BE
I I1 111
-1.4 f 2.7 1.3 f 3.6 -0.6 f 5.9
Lactate
I I1 111
HC03
11
I I1
2.7 f 0.6 1.8 f 0.7a 1.0 f 0.28
20T
-9.0 f 1.2 -7.0 f 3.3 -13.8 f 3.4
4.3 f 0.8 2.2 f 2.4. 0.5 f 0.Z8
6.8 f 1.7 3.9 f 0.7. 1.9 f 0.7*
25°C
30°C
-11.4 f 2.7 -6.2 f 3.7' -11.0 f 3.0
-11.4 f 1.8 -4.6 f 3.9' -6.7 f 2.8'
35°C
+
-12.2 f 3.7 -3.1 f 3.1' -5.3 f 3.88 8.9 f 1.0 3.1 f 1.48 1.8 f 0.68
492 f 28 569 f 50a 513 f 39
484 f 43 605 f 648 514 f 71
482 f 29 556 f 81' 514 f 39
400 f 104 299 f 139 450 f 53
390 f 108 275 f 125 4 3 4 f 40
332 f 122 384 f 150 457 f 63
397 f 106 408 f 102 430 f 71
In
451 f 38 489 f 22 479 f 69
MAP
I I1 In
117 f 4 117 f 8 90 f 16'
114 f 12 105 f 15 83 f 1 1 a
114 f 11 96 f lla 82 f 12s
85 & 13 88 f 12 62 f 7.
45+ 8 70 f 23O 55 f 13
70 f 23 97 f 21 91 f 24
104 f 11 111 f 7 103 f 11
107 f 19 105 f 17 122 f 15
PP
I I1 I11
64 f 19 4 2 f 7a 44 f 12
39f 8 27 f 5a 45 f 10
38 f 12 22 f 4a 40 f 48
22f 8 21f 6 32+ 5
28 f 10 24f 6 29f 5
28 f 10 17 f 5' 31f 7
34 f 10 25f 5 29+ 9
56 f 13 34f 98 60 f 13
I
I1 III
3.6 f 1.3 4.4 f 1.2 2.7 f 1.3
5.4 f 1.0 5.9 f 2.2 4.2 f 2.2
6.1 & 2.7 6.3 f 2.7 5.9 f 2.2
6.2 k 3.0 7.4 f 1.8 6.2 f 1.9
5.3 f 2.4 4.5 f 3.3 6.3 f 5.0
5.5 f 2.6 4.5 f 3.4 2.7 f 1.7a
4.4 f 2.5 4.6 f 2.5 1.3 f 1.7a
4.3 f 1.8 3.9 f 3.3 2.7 f 1.9
I I1 In
188 f 9 116 f 27' 128 f 128
107 f 8 83 f 13a 87 f 158
67f 3 60f 8 68f 9
41f 5 31 f 4s 38f 8
41f 7 41f 7 59 f 128
68f 6 76 f 10 76f 7
112 f 10 100 f 15 91 f l Z a
134 f 20 121 f 21 121 f 13
PO,
CVP
HR
'
aIndicates significant difference ( p < 0.05) compared with the baseline group, Group I. All values include f 1 standard deviation.
Pco2= partial pressure of carbon dioxide; H C 0 3 = bicarbonate radical; BE = base excess; Po, = partial pressure of oxygen; MAP = mean arterial pressure; PP = pulse pressure; CVP = central venous pressure; HR = heart rate.
128 The Annals of Thoracic Surgery Vol 29 No 2 February 1980
200-
Based on these investigations, ether in 100°/~ 0, has served as our anesthetic regimen of
1609,
$
.p.
1208040 0-
&
120-
L
-
4
\
'
80-
c
40-
E C
h
4
{
-C 5
Rectal Temperature ("C)
A comparison of heart rate and mean arterial pressure between the dogs anesthetized with ether in 100% O2 (solid circles) and those anesthetized with azeotrope in 95% O2and 5% CO, (open circles). Bars indicate f 1 standard deviation.
191; halothane in 100% 0, and in 95% 0, and 5% CO, both with [19] and without [lo, 14, 191 perfusion rewarming; nitrous oxide in 100% 0, [14]; Forane in 100% O, in 98% 0, and 2% CO,, and in 95% 0, and 5% CO, [201; and fluroxene in 100% O,.* We found that ether in 100% 0, consistently yielded superior results in inducing surface hypothermia to levels well below 20°C without producing arrhythmias, and, after 60 minutes of arrest, resuscitation and surface rewarming were easily accomplished with minimal use of cardiotonic drugs. The incidence of postoperative gait disturbance (hypermetria or high-stepping gait) presumed to be of neurogenic origin was lower than after other forms of anesthetic. In contrast, animals subjected to deep hypothermia with halothane in 100% 0, all had gait disturbances, even after only 30 minutes of circulatory arrest. Adding 5% CO, to the respiratory gases decreased the incidence of neurological disorders but increased the incidence of ventricular fibrillation during cooling at low temperatures and made resuscitation more difficult. "Sands MP, Dillard DH, Hessel EA 11, et al: Unpublished data, 1979.
choice for our clinical practice of surfaceinduced deep hypothermia for the past thirteen years [4-6, 13, 15, 17, 22, 251. But, ether is an explosive agent and in the adult dog, 60 minutes of circulatory arrest is followed by the development of mild gait disturbance in about 60% of cases. In this study, we evaluated the azeotropic mixture of halothane and ether both with and without CO,. Without CO,, the dogs showed neurological disturbances even after 30 minutes of arrest, cooling time was significantly longer, and the incidence of arrhythmia was significantly greater. For these reasons, arrest periods beyond 30 minutes were not studied in this group. With 5% CO,, arrhythmias were not a problem and the incidence of neurological dysfunction was low. The role of 5% CO, in improving the results with azeotrope requires additional study. We have previously found that ether in 100% 0, changed regional distribution of cardiac output under normothermic conditions but that the addition of surface cooling resulted in no further change [231; thus, we were unable to document cold-induced vasoconstriction. Halothane in 100% O,, however, appeared to result in some degree of cerebral vasoconstriction during cooling [14]. Also, animals given ether in 100% 0, had higher cardiac outputs during surface cooling than animals given halothane in 100% 0, [lo]. These differences may be related to the fact that halothane is a more potent myocardial depressant than ether [2]. In our studies, deep ether anesthesia (third plane, third stage) was employed [12, 151, but only moderate depth could be achieved with halothane [14]. Since vasomotion is inhibited under deep anesthesia [8], it is possible that the dogs more deeply anesthetized with ether may not benefit from the use of 5% CO,, while in the dogs more lightly anesthetized with halothane, 5% CO, may improve peripheral circulation. Hypothetically, the fractional distribution of cardiac output associated with lighter azeotrope (95% 0, and 5% CO,) anesthesia and reduced pH may favor anoxiaintolerant organ systems, with the role of the
129 Sands et al: Improved Anesthesia for Deep Hypothermia
ether fraction being an increased cardiac output due to sympathetic stimulation [21]. Results with the halothane-diethyl ether azeotrope in 95% O2 and 5% COzwere at least as good as, and in several instances better than, those with the standard method employing ether in 100% 02.The obvious advantages of being able to use electrocautery and cardiopulmonary bypass during combined hypothermia procedures without having to first eliminate an explosive anesthetic, warrant continued evaluation of this agent.
References 1. Boivin PA, Hudon F, Jacques A: Properties of the
fluothane-ether anesthetic. Can Anaesth SOCJ 5:409, 1958 2. Brown BR, Crout JR: A comparative study of the effects of five general anesthetics on myocardial contractility. Anaesthesia 34:236, 1971 3. Criscuolo D, Wilson RD: A method for vapor pressure determination of the fluothane-ether azeotrope. Tex Rep Biol Med 22:315, 1964 4. Dillard DH, Mohri H, Hessel EA 11, et al: Correction of total anomalous pulmonary venous drainage in infancy utilizing deep hypothermia with total circulatory arrest. Circulation 35, 36:Suppl 1:105, 1967 5. Dillard DH, Mohri H, Merendino KA: Correction of heart disease in infancy utilizing deep hypothermia and total circulatory arrest. J Thorac Cardiovasc Surg 61:64, 1971 6. Dillard DH, Mohri H, Merendino KA, et al: Total surgical correction of transposition of the great arteries in children less than six months of age. Surg Gynecol Obstet 129:1258, 1969 7. Hall KD, Norris F, Downs S: Physical chemistry of halothane-ether mixtures. Anaesthesia 21:522, 1960 8. Hershey SG, Zweifach BW, Rovenstine EA: Effects of depth of anesthesia on behavior of peripheral vascular bed. Anaesthesia 14:245, 1953 9. Hohorst HJ: In Methods of Enzymatic Analysis. First edition. Edited by HH Bergmeyer. Weinheim, Chemie, 1962, p 622 10. Ishitoya T, Sat0 S, DiBenedetto G, et al: Oxygen consumption during surface-induced deep hypothermia under halothane anesthesia. Ann Thorac Surg 23:52, 1977 11. Lundholm L, Mohme-Lundholm E, Vamos N: Lactic acid with L(+) lactic acid dehydrogenase from rabbit muscle. Acta Physiol Scand 58:243, 1963 12. Mohri H, Barnes RW, Winterscheid LC, et al: Challenge of prolonged suspended animation: a new method of surface-induced deep hypothermia. Ann Surg 168:779, 1968
13. Mohri H, Dillard DH, Crawford EW, et al: Method of surface-induced deep hypothermia for open heart surgery in infants. J Thorac Cardiovasc Surg 58:262, 1969 14. Mohri H, Dillard DH, Merendino KA: Hypothermia: halothane anesthesia and the safe period of total circulatory arrest. Surgery 72:345, 1972 15. Mohri H, Hessel EA 11, Nelson RJ, et al: 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. Olsen GF: Optimal conditions for the enzymatic determinations of L-lactic acid. Clin Chem 8:1, 1962 17. Rittenhouse EA, Mohri H, Morgan BC, et al: Electrocardiographic changes in infants undergoing surface-induced deep hypothermia. Am Heart J 79:167, 1970 18. Sands MP, Sat0 S, Mohri H, et al: Electrocardiographic changes during surface-induced deep hypothermia: the influence of ether, halothane, carbon dioxide, and perfusion rewarming. Ann Thorac Surg 19:386, 1975 19. Sat0 S, Vanini V, Mohri H, et al: A comparative study of the effects of carbon dioxide and perfusion rewarming on limited circulatory occlusion during surface hypothermia, under halothane and ether anesthesia. Ann Surg 180:192, 1974 20. Sat0 S, Vanini V, Sands MP, et al: The use of Forane anesthesia for surface-induced deep hypothermia. Ann Thorac Surg 20:299, 1975 21. Skovsted P, Price HL: Central sympathetic excitation caused by diethyl ether. Anaesthesia 32:202, 1970 22. Stevenson JG, Stone EF, Dillard DH, et al: Intellectual development of children subjected to prolonged circulatory arrest during hypothermic open heart surgery in infancy. Circulation 49, 5O:Suppl2:54, 1974 23. Su JY, Amory DW, Sands MP, et al: Effects of ether anesthesia and surface-induced hypothermia on regional blood flow. Am Heart J 97:53, 1979 24. Wilson RD, Tarrow AB, Garvin S: Hepatic effects of halothane: a clinical and laboratory evaluation of 10,129 administrations. Anesth Analg (Cleve) 43:40, 1964 25. Wong KC, Mohri H, Dillard DH, et al: Deep hypothermia and diethyl ether anesthesia for open heart surgery in infants: a clinical report of eight years experience. Anesth Analg (Cleve) 53:765, 1974 26. Wyant GM, Cockings EC, Muir JM: Clinical experiences with azeotropic mixture of halothane and diethyl ether, report of over 6,000 cases. Anesth Analg (Cleve) 42:188, 1963
institution has been used in more than 150 infants undergoing total repair of a variety of congenital cardiac defects [4-6, 15, 17, 22, 251. This clinical experience and extensive laboratory testing [lo, 14, 18-20, 231 demonstrated that ether administered in 100°/~oxygen (OJ was the superior anesthetic over other tested agents for pure surface hypothermia. Ether, however, is explosive, and this prevents the use of the electrocautery and the heart-lung machine. This primary disadvantage of ether led us to study extensively and evaluate other agents including halothane 110, 14, 191, Forane (isoflurane) 1201, and fluroxene.* All of these agents yielded poorer results than ether. This report presents the results of early laboratory and clinical trials utilizing the azeotropic compound of halothane and diethyl ether as the anesthetic for deep surface hypothermia. The azeotropic mixture of halothane and diethyl ether has been described by others [l,3, 71 and used extensively clinically [24, 261, but not for deep surface hypothermia. An azeotropic mixture is one in which certain proportions of two liquids combine to form a solution that behaves physically like a pure compound. Thus, a 0.65 mole fraction of halothane combined with a 0.35 mole fraction of diethyl ether velds a compound with its own specific gravity, boiling point, and vapor pressure (Table 1). FurtherSince August, 1965, a method of surface- more, vaporization or ordinary distillation will induced deep hypothermia developed at this not break down the compound or alter the proportion of its components. The halothaneFrom the Division of Cardiothoracic Surgery, Department diethyl ether azeotrope is nonexplosive in anof Surgery, University of Washington School of Medicine, esthetic concentrations, and we hypothesized Seattle, WA. Aided by funds from United States Public Health Service that it might combine some of the favorable Grant No. HL-19203. features of both ether and halothane. From our We thank Mr. Clifford Pitts and Mr. Robert Thomas whose technical effort and'expertise made this study possible and previous investigations 112, 151 we are aware Ms. Peggy Aspen for manuscript preparation. that ether is most effective when used in 100Y0 Accepted for publication Apr 2, 1979. O2 and that halothane performs best with 95% ABSTRACT The halothane-diethyl ether azeotrope was evaluated in dogs as the anesthetic agent for deep surface hypothermia with total circulatory arrest for open-heart operation. All 10 animals given experienced atrial arazeotrope in 100% oxygen (0,) rhythmias during cooling, and 1 had ventricular fibrillation prior to the completion of cooling at 18' to 20°C. After only 30 minutes' arrest, 8 of the 10 dogs had postoperative motor disturbances. Administering the azeotrope in 95% 0,and 5% carbon dioxide (CO,) yielded markedly improved results characterized by a rapid, smooth cooling course, easy resuscitation following circulatory arrest, and rapid rewarming, and 3 out of 10 dogs experienced mild motor disturbance after 60 minutes of circulatory arrest. This method, when compared with our standard method of ether in 100°/~ O,, resulted in reduced blood lactates and a striking improvement in clinical status on the first postoperative morning. In limited clinical trials, infants undergoing repair of congenital cardiac defects have done well and responded as expected based on the laboratory experience. Since the results with the azeotrope in 95% 0,and 5% C02 were at least as good as, and in several instances better than, those with the standard method employing ether, the nonexplosive characteristic of the azeotrope warrants continued evaluation of this agent.
Address reprint requests to Dr. Dillard, Division of Cardiothoracic Surgery, Department of Surgery, University of Washington School of Medicine, BB 438, RF-25, Seattle, WA 97195.
*Sands MI', Dillard DH, Hessel EA 11, et al: Unpublished data, 1979.
123 0003-4975/80/020123-07$01.25 @ 1978 by Murray P. Sands
124 The Annals of Thoracic Surgery Vol 29 No 2 February 1980
Table 1. Physical Characteristics of Halothane, Ether, and Halothane-Ether Azeotrope
rewarming is accomplished by floating the subject on a plastic sheet over 40°C water. Circulatory arrest is achieved under aseptic condiVapor tions by inflow and outflow occlusion through a Boiling Pressure Point at 2 4 0 ~ right fourth intercostal space thoracotomy. Specific at 760 and740 Cardioplegia is induced by injecting 30 ml of Gravity mm Hg mm Hg Anesthetic at 25°C ("C) Young's solution* into the aortic root proximal to the aortic cross-clamp. The animals are reHalothane 1.861 50.62 264 suscitated by manual massage and the intrave0.715 34.20 442 Diethyl ether nous administration of 300 mg of calcium chloAzeotropic 1.487 52.25 246a mixture [7] ride to reverse the effects of Young's solution. Cardioversion, when necessary, is accom"The vapor pressure at 24°C reported by Boivin and coworkers [l] is about 213 mm Hg, which is 33 mm Hg lower plished with 50 volt alternating current electhan that later reported by Criscuolo and Wilson [31, appar- troshock. ently the result of a typographical error in the paper by In this study, Groups I1 and I11 receiving Boivin and colleagues. azeotrope were managed by the same protocol except that the azeotrope was administered 0, and 5% carbon dioxide (CO,) [14, 18, 191. from a Fluotec Mark I11vaporizer at flow rates of Therefore, in this study the azeotrope was 8 to 10 liters per minute in an open (nonrebreathing) circuit. tested both with and without CO,.
Material and Methods Twenty-five adult mongrel dogs were randomly assigned to three groups that were studied concurrently. Group I (control) animals (5 dogs) were subjected to our extensively studied technique of deep surface hypothermia [12, 13, 151, which employs ether anesthesia in 100% 0, and a 60-minute period of circulatory arrest at 18" to 20°C rectal temperature. Group I1 animals (10 dogs) were cooled to 18" to 20°C with the halothane-diethyl ether azeotrope in 100% 0, and were arrested for 30 minutes. Group I11 (10 dogs) were cooled to 18" to 20°C with the azeotrope in 95% 0, and 5% CO, and were arrested for 60 minutes.
Hypothermia Technique The details of our surface-induced hypothermia method are standardized and have been reported previously [12, 13, 151. Briefly, it includes the use of deep ether anesthesia in 100% O,, the maintenance of normothermic minute ventilation throughout, so as to gradually induce a respiratory alkalosis (pH = 7.6 to 7.8) by the completion of cooling, and the administration of 10% low molecular weight dextran (1gm Of body weight) between 35" and per 25°C during cooling. Ether is given through a rebreathing circuit including soda-lime canisters. Cooling is by ice-water immersion, and
Sampling and Monitoring After the animals were anesthetized, all sampling and monitoring were done through polyethylene catheters inserted into the abdominal aorta and inferior vena cava through the femoral vessels. Arterial and central venous pressures and the electrocardiogram were monitored and recorded with a physiological recording system (Hewlett-Packard model 7788A) equipped with appropriate amplifiers. Arterial samples were drawn periodically for blood gas, hematocrit and lactate determinations. The pH, partial pressure of carbon dioxide (Pc0.J and partial pressure of oxygen were determined with a blood gas analyzer (model 113, Instrumentation Laboratories Inc.) at 37°C. Temperature correction to the animal's rectal temperature at the time of sampling and acid-base calculations were done with standard Severinghaus nomograms. Lactate determinations were done by our clinical laboratories using methods described elsewhere [9, 11, 161. Rectal and esophageal temperatures were monitored with telethemometer probes (Yellow Springs Instrument Company). *This solution consists of the following: 0.81 g m of potassium citrate; 2.46 gm of magnesium sulfate; 0.001 gm of neostigmine methylsulfate; water in sufficient quantity to make ml of solution; and pH adjusted to 7,4 with sodium bicarbonate.
125 Sands et al: Improved Anesthesia for Deep Hypothermia
Data were tabulated and computer-processed to provide the mean values k 1 standard deviation for each category. Statistical significance was evaluated with the two-tailed Student's t test.
Azeotrope Preparation The agent is formed by combining halothane, 68.3 vol per 100 ml, and diethyl ether, 31.7 vol per 100 ml. In the liquid phase, this is most easily accomplished by using a graduate to measure into a separate container 68.3 ml of halothane and 31.7 ml of diethyl ether (because the combined volume is slightly less than the sum of the individual volumes). The mixture warms slightly as the azeotrope is formed. The container can be agitated gently to hasten the mixing of the azeotrope, which is immediately used to charge a Fluotec or copper kettle-type vaporizer. Although the mixture has been shown to be stable over a period of many months [l], fresh azeotrope was prepared for each procedure during this study. Results All dogs survived and were followed for a minimum of three weeks. Table 2 summarizes the operative and postoperative course in the three groups.
Hypothermia The cooling procedure in ether-anesthetized dogs of Group I was uneventful and consistent with our previously reported experience. In Group I1 (azeotrope in 100% 02),Fluotec settings of 2.0 to 2.5% provided adequate anesthesia to abolish shivering at the onset of cooling. As cooling progressed, anesthetic concentrations were gradually reduced to 0.25% by 20°C. All of these animals had bizarre, frequently low voltage and irregular P waves suggestive of a wandering atrial pacemaker at some time during cooling, and 1 dog fibrillated at 21.4"C prior to elective arrest. Animals in Group I11 (azeotrope in 95% O2 and 5% COz) required less anesthetic with initial settings of 1.5 to 2.0%, which were gradually reduced to 0.1% by 20°C. No arrhythmias were encountered that could not be controlled by adjusting the anesthetic, although when anesthesia was experimentally lightened, a rapid junctional
rhythm followed by a ventricular tachyarrhythmia developed between 32" and 28°C during cooling. One dog was given twice the usual anesthetic concentration at 20°C and had atrial arrest, a junctional bradycardia of 6 beats per minute, and ventricular fibrillation. Shivering was not observed, but 3 dogs in Group I11 displayed respiratory movements controlled with 1 mg of pancuronium bromide; no differences were noted in the variables measured as a result of the pancuronium bromide. Following arrest, resuscitation with manual massage was easily accomplished in all groups. Consistent with past experience, all dogs in Group I, arrested for 60 minutes, required one or two 50 pg doses of epinephrine to support mean arterial pressure immediately following resuscitation. None of the animals given an azeotrope required epinephrine except 2 in Group 111. In those 2, cardiac function was temporarily compromised due to technical errors. Dogs in Group I cooled at a rate of 17.2 f 3.0 sec/kg/"C, which was significantly faster ( p < 0.05) than the 21.0 k 2.9 sec/kg/"Cmeasured in Group 11. Group I11 dogs cooled more quickly (12.6 f 3.0 sec/kg/"C) than either Group I or Group I1 dogs ( p < 0.02 and p < 0.001, respectively). The total rewarming time was similar (36.8 f 5.5 sec/kg/"Cand 35.8 k 4.8 sec/kg/"C)in Groups I and I11 but significantly prolonged ( p < 0.01) in Group I1 at 46.7 f 3.7 sec/kg/"C.Since hemodynamics improve with rewarming, the initial speed of rewarming determines how rapidly cardiac function can be stabilized following resuscitation; accordingly, the time required for the first 5°C of rewarming was measured. Group I dogs required 36.2 f 6.1 secl kg/"C; Group I1 dogs, 41.3 f 5.6 sec/kg/"C; and Group I11 dogs, 28.0 f 5.5 sec/kg/"C. Thus the first 5°C of rewarming was significantly shorter in Group I11 than in Group I or Group I1 ( p < 0.05 and p < 0.001, respectively).
Hemodynamic Changes Mean arterial pressure and heart rate declined with temperature and increased with rewarming in all groups. As noted in Table 3, the mean arterial pressure during cooling in animals in Group I11 was significantly less than in Group I dogs. Pulse pressures were significantly reduced in Group I1 when compared with Group I
126 The Annals of Thoracic Surgery Vol 29 No 2 February 1980
Table 2. Details of Technique, Operative Course, and Results No. of
Group
Dogs
Body Weight (kg)
Anesthetic Agent
Respiratory Gases
Cooling Time (sec/kgl"C)"
I
5
18.2 f 1.39
Ether
100%
0 2
17 f 3.0
I1
10
17.0 f 1.23
Azeotrope
100%
0 2
2 1 f 2.9b
I11
10
17.5 k 1.97
Azeotrope
95% O2 and
5%
13 f 3.0baC
co2
"Cooling and rewarming times include k 1 standard deviation. bIndicates significant difference (p < 0.05) compared with Group I. 'Indicates significant difference (p < 0.05) compared with Group 11. AV = atrioventricular.
at control (control values refer to those obtained immediately prior to cooling), 30" and 25°C during cooling, and 25" and 35°C during rewarming. All animals given an azeotrope had heart rates significantly below those of the ether group at control and during the early cooling period, but the results were more variable thereafter. Data for dogs anesthetized with ether in 100°/~ 0, and for those anesthetized with azeotrope in 95% 0, and 5% CO, are displayed graphically in the Figure.
not eat or drink, while the azeotrope-anesthetized animals appeared completely recovered in that all were active and had a good appetite. Neurological assessment by a blinded observer revealed that 2 of the 5 dogs in Group I, arrested for 60 minutes, had mild gait disturbances (hypermetria or high-stepping gait); while in the azeotrope groups, 8 of the 10 dogs in Group 11, arrested for 30 minutes, and 3 of the 10 dogs in Group 111, arrested for 60 minutes, displayed hypermetria.
Blood Gas and Acid-Base Analysis The blood gas and pH data shown in Table 3 are consistent with the ventilation regimen for each group. As cooling progressed, minute volumes were mechanically maintained so that animals with an anesthetic in 100% 0, developed increasing pH and decreasing Pco, regardless of the anesthetic used. Animals in Group I11 had significantly lower pH and higher Pco, than those in Group I until the completion of rewarming when the pH values were similar. Computed bicarbonate levels were consistently higher in animals with an azeotrope following the onset of cooling, and lactate levels were uniformly significantly lower in both groups with an azeotrope.
Clinical Results Halothane-ether azeotrope in 95% 0, and 5% COz has been utilized as the anesthetic during open-heart operation under surface-induced hypothermia in 3 infants. They were 7, 9, and 11 months old and underwent intraatrial venous transposition repair of transposition of the great arteries, aortic valve commissurotomy and mitral annuloplasty, and correction of tetralogy of Fallot, respectively. They weighed 6.7, 9.1, and 6.7 kg, respectively, and were arrested for 31, 30, and 48 minutes at 19", 20", and 20"C, respectively. Resuscitation and rewarming proceeded smoothly with this anesthetic agent, and all survived.
Postoperative Results Ether-anesthetized animals remained lethargic on the first postoperative morning and would
Comment We have evaluated various anesthetic regimens for surface-induced deep hypothermia: ether in 100% O2 and in 95% 0, and 5% COz [15, 18,
127 Sands et al: Improved Anesthesia for Deep Hypothermia
Circulatory Arrest (min)
Rewarming Time (sec/kg/°C)a
60
37 k 5.5
30
46 f 3.7b
60
36 f 4 . F
Late Survival
Complications Infrequent ventricular tachyarrhythmia if anesthesia too light Atrial arrhythmias (10 dogs); ventricular fibrillation (1dog) Infrequent AV nodal or ventricular arrhythmias eliminated with anesthetic manipulation; ventricular fibrillation (1dog) (anesthesia too deep)
Gait Disturbances
5
2
10
8
10
3
Table 3. Blood Gas and Acid-Base Analysis and Hemodynamic Data Rectal Temperature Variable Group PH
Pco,
Control
30°C
25°C
20T
III
7.42 f .06 7.49 f .03' 7.28 f .05a
7.48 f .06 7.57 f .09' 7.33 f .07a
7.57 2 .07 7.63 f .13 7.34 f .07a
7.69 & .04 7.66 f .18 7.36 f .07'
7.53 f .05 7.51 f .23 7.24 f .06s
7.48 f .07 7.49 f .17 7.23 f .06=
7.40 f .07 7.44 f .14 7.26 f .058
7.28 f .09 7.42 f . O F 7.25 f .07
I I1 I11
34.5 f 2.8 31.4 5.4 54.9 f 6.4'
25.3 f 3.6 26.2 f 6.1 40.6 f 6.48
16.9 k 1.6 21.4 f 7.9 40.3 f 5.58
11.2 f 0.9 19.4 f 9.0 36.0 f 4.8O
12.2 f 2.7 21.0 f 12.3 31.8 f 7.8.
12.7 f 1.6 20.9 8.8 39.9 f 6.5'
+
17.4 f 2.7 28.1 f 11.0 47.7 f 7.5a
28.5 f 7.7 31.2 7.4 53.0 f 8.58
I
17.9 f 3.1 22.8 f 3.4s 24.1 f 4.Ze
14.8 f 3.0 20.1 k 3.1a 21.3 f 4.78
13.2 f 2.1 19.3 f 2.3. 19.7 f 3.4=
9.7 f 1.6 13.8 ? 2.Z8 13.4 f 2.98
9.0 f 1.3 14.3 f 2.4' 16.6 f 2.2'
10.2 f 0.8 16.9 f 2 . P 20.3 f 2.38
13.0 f 2.7 19.2 f 2 . P 22.3 f 3.1a
-3.4 f 2.7 2.7 f 3.2* -1.7 f 4.9
-3.8 k 4.3 1.2 f 2.7= -3.6 f 5.4
-2.8 f 2.8 0.5 f 2.4' -4.8 f 4.2
I I1
+
I11
21.5 f 2.2 22.8 f 4.1 24.9 f 4.4
BE
I I1 111
-1.4 f 2.7 1.3 f 3.6 -0.6 f 5.9
Lactate
I I1 111
HC03
11
I I1
2.7 f 0.6 1.8 f 0.7a 1.0 f 0.28
20T
-9.0 f 1.2 -7.0 f 3.3 -13.8 f 3.4
4.3 f 0.8 2.2 f 2.4. 0.5 f 0.Z8
6.8 f 1.7 3.9 f 0.7. 1.9 f 0.7*
25°C
30°C
-11.4 f 2.7 -6.2 f 3.7' -11.0 f 3.0
-11.4 f 1.8 -4.6 f 3.9' -6.7 f 2.8'
35°C
+
-12.2 f 3.7 -3.1 f 3.1' -5.3 f 3.88 8.9 f 1.0 3.1 f 1.48 1.8 f 0.68
492 f 28 569 f 50a 513 f 39
484 f 43 605 f 648 514 f 71
482 f 29 556 f 81' 514 f 39
400 f 104 299 f 139 450 f 53
390 f 108 275 f 125 4 3 4 f 40
332 f 122 384 f 150 457 f 63
397 f 106 408 f 102 430 f 71
In
451 f 38 489 f 22 479 f 69
MAP
I I1 In
117 f 4 117 f 8 90 f 16'
114 f 12 105 f 15 83 f 1 1 a
114 f 11 96 f lla 82 f 12s
85 & 13 88 f 12 62 f 7.
45+ 8 70 f 23O 55 f 13
70 f 23 97 f 21 91 f 24
104 f 11 111 f 7 103 f 11
107 f 19 105 f 17 122 f 15
PP
I I1 I11
64 f 19 4 2 f 7a 44 f 12
39f 8 27 f 5a 45 f 10
38 f 12 22 f 4a 40 f 48
22f 8 21f 6 32+ 5
28 f 10 24f 6 29f 5
28 f 10 17 f 5' 31f 7
34 f 10 25f 5 29+ 9
56 f 13 34f 98 60 f 13
I
I1 III
3.6 f 1.3 4.4 f 1.2 2.7 f 1.3
5.4 f 1.0 5.9 f 2.2 4.2 f 2.2
6.1 & 2.7 6.3 f 2.7 5.9 f 2.2
6.2 k 3.0 7.4 f 1.8 6.2 f 1.9
5.3 f 2.4 4.5 f 3.3 6.3 f 5.0
5.5 f 2.6 4.5 f 3.4 2.7 f 1.7a
4.4 f 2.5 4.6 f 2.5 1.3 f 1.7a
4.3 f 1.8 3.9 f 3.3 2.7 f 1.9
I I1 In
188 f 9 116 f 27' 128 f 128
107 f 8 83 f 13a 87 f 158
67f 3 60f 8 68f 9
41f 5 31 f 4s 38f 8
41f 7 41f 7 59 f 128
68f 6 76 f 10 76f 7
112 f 10 100 f 15 91 f l Z a
134 f 20 121 f 21 121 f 13
PO,
CVP
HR
'
aIndicates significant difference ( p < 0.05) compared with the baseline group, Group I. All values include f 1 standard deviation.
Pco2= partial pressure of carbon dioxide; H C 0 3 = bicarbonate radical; BE = base excess; Po, = partial pressure of oxygen; MAP = mean arterial pressure; PP = pulse pressure; CVP = central venous pressure; HR = heart rate.
128 The Annals of Thoracic Surgery Vol 29 No 2 February 1980
200-
Based on these investigations, ether in 100°/~ 0, has served as our anesthetic regimen of
1609,
$
.p.
1208040 0-
&
120-
L
-
4
\
'
80-
c
40-
E C
h
4
{
-C 5
Rectal Temperature ("C)
A comparison of heart rate and mean arterial pressure between the dogs anesthetized with ether in 100% O2 (solid circles) and those anesthetized with azeotrope in 95% O2and 5% CO, (open circles). Bars indicate f 1 standard deviation.
191; halothane in 100% 0, and in 95% 0, and 5% CO, both with [19] and without [lo, 14, 191 perfusion rewarming; nitrous oxide in 100% 0, [14]; Forane in 100% O, in 98% 0, and 2% CO,, and in 95% 0, and 5% CO, [201; and fluroxene in 100% O,.* We found that ether in 100% 0, consistently yielded superior results in inducing surface hypothermia to levels well below 20°C without producing arrhythmias, and, after 60 minutes of arrest, resuscitation and surface rewarming were easily accomplished with minimal use of cardiotonic drugs. The incidence of postoperative gait disturbance (hypermetria or high-stepping gait) presumed to be of neurogenic origin was lower than after other forms of anesthetic. In contrast, animals subjected to deep hypothermia with halothane in 100% 0, all had gait disturbances, even after only 30 minutes of circulatory arrest. Adding 5% CO, to the respiratory gases decreased the incidence of neurological disorders but increased the incidence of ventricular fibrillation during cooling at low temperatures and made resuscitation more difficult. "Sands MP, Dillard DH, Hessel EA 11, et al: Unpublished data, 1979.
choice for our clinical practice of surfaceinduced deep hypothermia for the past thirteen years [4-6, 13, 15, 17, 22, 251. But, ether is an explosive agent and in the adult dog, 60 minutes of circulatory arrest is followed by the development of mild gait disturbance in about 60% of cases. In this study, we evaluated the azeotropic mixture of halothane and ether both with and without CO,. Without CO,, the dogs showed neurological disturbances even after 30 minutes of arrest, cooling time was significantly longer, and the incidence of arrhythmia was significantly greater. For these reasons, arrest periods beyond 30 minutes were not studied in this group. With 5% CO,, arrhythmias were not a problem and the incidence of neurological dysfunction was low. The role of 5% CO, in improving the results with azeotrope requires additional study. We have previously found that ether in 100% 0, changed regional distribution of cardiac output under normothermic conditions but that the addition of surface cooling resulted in no further change [231; thus, we were unable to document cold-induced vasoconstriction. Halothane in 100% O,, however, appeared to result in some degree of cerebral vasoconstriction during cooling [14]. Also, animals given ether in 100% 0, had higher cardiac outputs during surface cooling than animals given halothane in 100% 0, [lo]. These differences may be related to the fact that halothane is a more potent myocardial depressant than ether [2]. In our studies, deep ether anesthesia (third plane, third stage) was employed [12, 151, but only moderate depth could be achieved with halothane [14]. Since vasomotion is inhibited under deep anesthesia [8], it is possible that the dogs more deeply anesthetized with ether may not benefit from the use of 5% CO,, while in the dogs more lightly anesthetized with halothane, 5% CO, may improve peripheral circulation. Hypothetically, the fractional distribution of cardiac output associated with lighter azeotrope (95% 0, and 5% CO,) anesthesia and reduced pH may favor anoxiaintolerant organ systems, with the role of the
129 Sands et al: Improved Anesthesia for Deep Hypothermia
ether fraction being an increased cardiac output due to sympathetic stimulation [21]. Results with the halothane-diethyl ether azeotrope in 95% O2 and 5% COzwere at least as good as, and in several instances better than, those with the standard method employing ether in 100% 02.The obvious advantages of being able to use electrocautery and cardiopulmonary bypass during combined hypothermia procedures without having to first eliminate an explosive anesthetic, warrant continued evaluation of this agent.
References 1. Boivin PA, Hudon F, Jacques A: Properties of the
fluothane-ether anesthetic. Can Anaesth SOCJ 5:409, 1958 2. Brown BR, Crout JR: A comparative study of the effects of five general anesthetics on myocardial contractility. Anaesthesia 34:236, 1971 3. Criscuolo D, Wilson RD: A method for vapor pressure determination of the fluothane-ether azeotrope. Tex Rep Biol Med 22:315, 1964 4. Dillard DH, Mohri H, Hessel EA 11, et al: Correction of total anomalous pulmonary venous drainage in infancy utilizing deep hypothermia with total circulatory arrest. Circulation 35, 36:Suppl 1:105, 1967 5. Dillard DH, Mohri H, Merendino KA: Correction of heart disease in infancy utilizing deep hypothermia and total circulatory arrest. J Thorac Cardiovasc Surg 61:64, 1971 6. Dillard DH, Mohri H, Merendino KA, et al: Total surgical correction of transposition of the great arteries in children less than six months of age. Surg Gynecol Obstet 129:1258, 1969 7. Hall KD, Norris F, Downs S: Physical chemistry of halothane-ether mixtures. Anaesthesia 21:522, 1960 8. Hershey SG, Zweifach BW, Rovenstine EA: Effects of depth of anesthesia on behavior of peripheral vascular bed. Anaesthesia 14:245, 1953 9. Hohorst HJ: In Methods of Enzymatic Analysis. First edition. Edited by HH Bergmeyer. Weinheim, Chemie, 1962, p 622 10. Ishitoya T, Sat0 S, DiBenedetto G, et al: Oxygen consumption during surface-induced deep hypothermia under halothane anesthesia. Ann Thorac Surg 23:52, 1977 11. Lundholm L, Mohme-Lundholm E, Vamos N: Lactic acid with L(+) lactic acid dehydrogenase from rabbit muscle. Acta Physiol Scand 58:243, 1963 12. Mohri H, Barnes RW, Winterscheid LC, et al: Challenge of prolonged suspended animation: a new method of surface-induced deep hypothermia. Ann Surg 168:779, 1968
13. Mohri H, Dillard DH, Crawford EW, et al: Method of surface-induced deep hypothermia for open heart surgery in infants. J Thorac Cardiovasc Surg 58:262, 1969 14. Mohri H, Dillard DH, Merendino KA: Hypothermia: halothane anesthesia and the safe period of total circulatory arrest. Surgery 72:345, 1972 15. Mohri H, Hessel EA 11, Nelson RJ, et al: 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. Olsen GF: Optimal conditions for the enzymatic determinations of L-lactic acid. Clin Chem 8:1, 1962 17. Rittenhouse EA, Mohri H, Morgan BC, et al: Electrocardiographic changes in infants undergoing surface-induced deep hypothermia. Am Heart J 79:167, 1970 18. Sands MP, Sat0 S, Mohri H, et al: Electrocardiographic changes during surface-induced deep hypothermia: the influence of ether, halothane, carbon dioxide, and perfusion rewarming. Ann Thorac Surg 19:386, 1975 19. Sat0 S, Vanini V, Mohri H, et al: A comparative study of the effects of carbon dioxide and perfusion rewarming on limited circulatory occlusion during surface hypothermia, under halothane and ether anesthesia. Ann Surg 180:192, 1974 20. Sat0 S, Vanini V, Sands MP, et al: The use of Forane anesthesia for surface-induced deep hypothermia. Ann Thorac Surg 20:299, 1975 21. Skovsted P, Price HL: Central sympathetic excitation caused by diethyl ether. Anaesthesia 32:202, 1970 22. Stevenson JG, Stone EF, Dillard DH, et al: Intellectual development of children subjected to prolonged circulatory arrest during hypothermic open heart surgery in infancy. Circulation 49, 5O:Suppl2:54, 1974 23. Su JY, Amory DW, Sands MP, et al: Effects of ether anesthesia and surface-induced hypothermia on regional blood flow. Am Heart J 97:53, 1979 24. Wilson RD, Tarrow AB, Garvin S: Hepatic effects of halothane: a clinical and laboratory evaluation of 10,129 administrations. Anesth Analg (Cleve) 43:40, 1964 25. Wong KC, Mohri H, Dillard DH, et al: Deep hypothermia and diethyl ether anesthesia for open heart surgery in infants: a clinical report of eight years experience. Anesth Analg (Cleve) 53:765, 1974 26. Wyant GM, Cockings EC, Muir JM: Clinical experiences with azeotropic mixture of halothane and diethyl ether, report of over 6,000 cases. Anesth Analg (Cleve) 42:188, 1963