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WHOLE-BODY AND ORGAN Vo2 CHANGES WITH ENFLURANE, ISOFLURANE, AND HALOTHANE
Br.J. Anaesth. (1975), 47, 813
WHOLE-BODY AND ORGAN Vo2 CHANGES WITH ENFLURANE, ISOFLURANE, AND HALOTHANE R. A. THEYE AND J. D. MICHENFELDER SUMMARY
We have established previously for halothane and isoflurane that the pattern of individual organ contributions to the whole-body decrease in oxygen consumption (Vo2) is similar, that the decrease in myocardial Vo2 is the major component for each, and that the decrease in Vo2 in other organs contributes to a lesser extent (Theye, 1972; Theye and Michenfelder, 1975). These findings support our contention that anaesthetic agents are not general metabolic depressants and help to emphasize that the decrease in whole-body Vo2 with anaesthesia represents a summation of events in individual organs in which an anaesthetic-induced change in function results in a change in metabolic requirements. The present study extended this inquiry to the effects of enflurane and the findings provide the basis for a comparative summary of the effects of halothane, isoflurane, and enflurane in these regards. MATERIAL AND METHODS
In all studies, unpremedicated dogs were anaesthetized with enflurane in a mixture of oxygen in nitrogen. The trachea was intubated with the aid of suxamethonium, which was continued thereafter at a rate of 150 mg/hr. Ventilation was provided by a Harvard pump and nonrebreathing system with appropriate adjustments of the inspired oxygen RICHARD A. THEYE, M.D., JOHN D. MICHENFELDER, M.D.,
Department of Anesthesiology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55901, U.S.A.
concentration (Fio2) and ventilatory volume to maintain PaO2 and PaC02 at 150±5 and 40±2 mm Hg, respectively (mean±SEM). Body and organ temperatures were maintained at 37.0±0.2°C by surface warming. Expired enflurane concentrations were determined by infrared analysis. Intravascular pressures were transduced by strain gauges. Blood-gas values were measured by electrodes at 37.0°C. Blood oxygen content was calculated from Po2 and oxyhaemoglobin concentration (IL CO-Oximeter). Whole-body and organ Vo2 were calculated by means of the Fick equation, using appropriate values for blood flow rate (0) and the arteriovenous oxygen content difference (Cao2—Cv02), and were expressed relative to whole-body weight as determined before induction of anaesthesia. Left and right ventricular external work was calculated from total Q, mean systemic and pulmonary arterial pressures, respectively, and a previously described constant (Theye, 1967). At autopsy, catheter positions were confirmed and organ weights were determined. Values in the dog for minimum alveolar concentration (MAC) of 2.2,1.48, and 0.87%, for enflurane, isoflurane, and halothane, respectively, were the reference points for establishing equivalent levels of enflurane anaesthesia (Joas, Stevens and Eger, 1971). The effect of enflurane on whole-body Vo2 and haemodynamics was determined in 10 dogs (weights: whole-body, 17±2 kgj'heart, 106±17 g). Catheters
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This study was designed to determine the effects of ennurane on canine whole-body and individual organ oxygen consumption (Vo2). Whole-body, myocardial, splanchnic, renal, and skeletal muscle Vo2 were determined at enflurane concentrations equivalent to those used in previous studies with halothane and isoflurane. With increasing enflurane concentrations, whole-body Vo2 decreased progressively. The major component of the decrease was a reduction in myocardial Vo2 resulting from a decrease in myocardial external work as a result of a decrease in cardiac output and arterial pressure. Other organs contributed to a lesser extent to the overall decrease in whole-body Vo2. In each respect the findings with enflurane were not significantly different from those with halothane and isoflurane. These findings add support to the view that anaesthetic agents are not general metabolic depressants and that observed changes in whole-body Vo2 reflect the summated changes in individual organ Vo2 occasioned by an anaesthetic-induced change in organ function and metabolic requirements.
BRITISH JOURNAL OF ANAESTHESIA
814
RESULTS
With increases in the enflurane concentration, wholebody Vo2 decreased progressively (table I); at the greatest concentration the average decrease was 29%. Myocardial Vo2 also decreased progressively, but at a greater rate, resulting in a decrease in the ratio of myocardial to whole-body Vo». The decrease in myocardial Vo2 directly reflected the progressive decrease in myocardial external work, which resulted
from decreases in cardiac output and arterial pressure. The only statistically significant differences between these findings and those with isoflurane and halothane occurred at the greatest anaesthetic concentrations; these differences consisted of a lesser arterial pressure with enflurane than with either isoflurane or halothane and a lesser cardiac output and myocardial Vo2 with enflurane than with isoflurane (t test; unpaired data). The relationship between myocardial Vo2 and left ventricular external work with enflurane anaesthesia established in the right-heart bypass studies was not significantly different from those established previously for isoflurane and halothane (fig. 1). The data from all three studies were pooled to yield a single regression equation: y=2.61+(l.86x^0.16), which was used to calculate the myocardial Vo2 values for the whole-body studies in table I. 24
r
- Halothane Isoflurane 'Enflurane
o o 16
o 5
0 EXTERNAL
4 8 WORK, LV, kg-m/mln
FIG. 1. Regression lines relating myocardial Vo2 (y; ml/min/ 100 g) and left ventricular (LV) work (x; kg-m/min) during anaesthesia with enflurane [y=3.17+(1.68x±0.24)], isoflurane [y=3.21+(1.78x±0.09)] 5 and halothane [y = 1.44 + (2.13x±0.29)] (±SEM).
The effects of enflurane on splanchnic, renal, and skeletal muscle blood flow are summarized in table II. Vo2 values are presented relative to wholebody weight; the blood flow values are based on actual flows of the organ studied. The findings in the gastrocnemius-plantaris group (actual weight, 61 ± 7 g) have been extrapolated to whole-body skeletal muscle using the assumptions applied previously with isoflurane and halothane (0.5% value, 35% of wholebody Vo 2 ; 3.8% value, based on the 16% reduction observed in the muscle studied). With increases in the enflurane concentration, splanchnic, renal, and skeletal muscle Vo2 decreased 19,30 and 16% respectively.
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were placed in the carotid and pulmonary arteries, the right atrium, and the outflow tract of the right ventricle for measurement of pressures, determination of 0 by the indocyanine green dye dilution technique, and sampling of arterial and mixed venous blood. Observations were made in triplicate at enflurane concentrations of 0.5, 2.2, 2.8, and 3.8% in this sequence and, in alternate dogs, in the reverse sequence. (For convenience, results are presented only in terms of increasing concentration.) One hour elapsed at each enflurane concentration with observations in the final 30 min. During these studies myocardial Vo2 was calculated from the values for external work observed and the relationship between myocardial external work and Vo2, as described subsequently. The relationship between myocardial external work and Vo2 during enflurane anaesthesia was determined in four additional dogs (weights: wholebody, 20±2 kg; heart, 127±25 g). Right-heart bypass was established after ligation of the azygos vein, appropriate cannulations of the right atrium, superior and inferior venae cavae, and pulmonary trunk, and preparation of an extracorporeal apparatus that included a reservoir, pump, and heat exchanger. This approach provided for isolation and collection of all myocardial venous flow with opportunities for determination of myocardial 0 (timed collection in graduated cylinder) and (Ca02—Cv02) (Theye, 1967). Observations were made in triplicate at enflurane concentrations of 0.5 and 3.8%. At each concentration, left ventricular work was arranged to approximate to that observed in the whole-body studies by appropriate modifications of blood volume and rightheart bypass pump flow rates. Splanchnic and renal Vo2 (six dogs) and gastrocnemius-plantaris group bilateral muscle Vo2 (six dogs) were determined at enflurane concentrations of 0.5 and 3.8% by surgical methods that provide for separation, direct collection, measurement, and return of the venous blood flow from these organs (Theye and Michenfelder, 1975).
Vo2 CHANGES WITH ENFLURANE, ISOFLURANE, HALOTHANE TABLE I.
815
Metabolic and haemodynamic responses to enflurane (10 dogs: 37°C).
Enflurane expired ( %)
0.27 0.07 0.01
6.44 1.21 0.19
3.8
Mean SEM
Mean iSEM
5.51* 0.19 0.63* 0.05 0.11* 0
5.11* 0.14 0.53* 0.02 0.10* 0
Mean
SEM
4.57* 0.10 0.43* 0.02 0.09* 0
190
9
104
6
87*
5
70*
7
114 18 2
5 1 1
78* 13* 2
2 1 0
70* 12* 3
1 1 0
58* 12* 4*
3 1 1
0.27 0.08
5.34 0.86
2.03* 0.13 0.33* 0.04
1.04* 0.14 0.22* 0.03
1.51* 0.10 0.27* 0.02
•Significantly different (P<0.05) from 0.5 % value by t test; paired data. TABLE I I .
Effects of enflurane on splanchnic, renal, and skeletal muscle Vo 2 and blood flow.
TABLE I I I . Effects of enflurane, isoflurane, and halothane (%, expired") on canine whole-body and regional Vo 2 .
Enflurane expired ( %) 0.5
Mean Vo2, ml/min/kg (wholebody weight) splachnic renal skeletal muscle B lood flow, ml/min (actual flows) splanchnic renal skeletal muscle
Vo2, ml/min/kg of whole-body weight (mean values)
3.8
SEM
Mean
SEM
2.09 0.46 2.25
0.10 0.04 0.18
1.70* 0.32* 1.89*
0.11 0.02 0.15
420 316 7.3
37 48 0.9
352* 231
39 70 0.4
5.8*
Whole-body Myocardial Splanchnic Renal Cerebral Skeletal muscle Other tissues (difference)
Enflurane*
Isonuranef
HalothaneJ
0.5 6.44 1.21 2.09 0.46 0.22
3.8 4.57 0.43 1.70 0.32 0.15
0.4
2.6
6.34 1.37 2.06 0.41 0.20
4.93 0.68 1.91 0.30 0.14
6.46 4.71 1.40 0.57 1.78 1.62 0.42 0.33) 0.22 0.18
2.25
1.89
2.22
1.86
2.26
1.85
0.21
0.08
0.08
0.04
0.38
0.16
0.2
1.5
•Significantly different (P<0.05), t test; paired data.
•Present study. fData from Theye (1972). JData from Theye and Michenfelder (1975).
Although significant decreases in splanchnic and skeletal muscle blood flow occurred, the decreases in Vo2 could not be ascribed to deficiencies in oxygen transport because oxygen tensions in venous blood leaving the organs were maintained at or above the normal values. The only statistically significant difference between these findings with enflurane and those with isoflurane or halothane occurred at the greatest concentration, muscle blood flow decreasing with enflurane and increasing with both isoflurane and halothane. The effects of enflurane, isoflurane, and halothane on whole-body and regional Vo2 are summarized in table III. The enflurane projections are based on the findings of the present study and of an additional study of the effects of enflurane on canine cerebral metabolism in which a 34% decrease in CMR 02 occurred at 2.2% enflurane and was maintained at 4.2% enflurane. These findings were extrapolated to the whole brain using the same assumptions applied
previously with isoflurane and halothane. The only significant difference between either whole-body or any regional Vo2 decrease with enflurane, isoflurane, or halothane anaesthesia was the previously mentioned lesser myocardial Vo2 with enflurane than with isoflurane at the greatest concentrations. With each of these three anaesthetic agents, the myocardial component was the major contributor to the whole-body decrease, with lesser contribution from the other organs. DISCUSSION
The data on whole-body and regional Vo2 effects of enflurane, isoflurane, and halothane, summarized in table III, are the culmination of a series of studies initiated more than a decade ago in the climate of a complacent view of the effects of anaesthesia on Vo2. At the time, it was generally held that anaesthetic agents were general metabolic depressants, which accounted for their effectiveness in providing
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Vo2, whole-body (ml/min/kg) Vo2, myocardial (ml/min/kg) Vos myocardial/Vo2 whole-body Q (ml/min/kg) Pressures (mean, mm Hg) systemic (arterial) pulmonary arterial right atrial External work (kg-m/min) left ventricle right ventricle
2.8
2.2
0.5
Mean !5EM
816
agent. With halothane, the decrease in whole-body Vo2 with increased concentrations of halothane can be reversed by measures that increase cardiac output and arterial pressure, such as volume expansion, heart pacing, and digitalis (Theye and Sessler, 1967). Similarly, Vo2 of the canine kidney is related directly to the rate of tubular reabsorption of sodium (Tna) and changes in renal blood flow and glomerular nitration rate, induced by halothane and methoxyflurane, which result in decreases in Tna and are accompanied by appropriate decreases in renal Vo2 (Theye and Maher, 1971; Messick, Wilson and Theye, 1972). For all these reasons, the notion that anaesthetic agents in clinically useful concentrations are universal, general metabolic depressants should be abandoned and be replaced by the view that whole-body Vo2 during anaesthesia is a summation of individual organ contributions, all of which are subject to a variety of influences. Decreases in myocardial external work or renal Tna induced by anaesthetic agents or other factors tend to result in decreases in myocardial or renal Vo2. Skeletal muscle Vo2 is usually diminished slightly with anaesthesia and paralysis, but may be increased several-fold in response to hypothermia during light anaesthesia without relaxants and most certainly if shivering is present. Cerebral Vo2 is decreased strikingly with barbiturates, less so with other anaesthetic agents, and may be increased if only nitrous oxide or ketamine is used. Splanchnic Vo2 follows closely splanchnic blood flow, and circumstances decreasing such flow contribute to decreases in splanchnic Vo2. Either a decrease or an increase in the body temperature alters the whole-body Vo2 by decreasing or increasing individual organ Vo2 by a direct effect on rate of intracellular biochemical processes (Michenfelder and Theye, 1968). Situations of increased sympathoadrenal activity and catecholamine concentrations tend to lead to increased organ and wholebody Vo2. In our studies, the similarity of effects of enflurane, isoflurane, and halothane on regional and whole-body Vo2 was matched by a similarity of effects on cardiac output, arterial pressure, and renal and splanchnic blood flow. The mechanism involved in the decrease in skeletal muscle Vo2 with these anaesthetic agents is not clear from these or other studies, but it is apparently not related to a decrease in blood flow because Vo2 decreased by a similar amount with each, whereas blood flow decreased with enflurane and increased with isoflurane and halothane.
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anaesthesia and which was, of necessity, accompanied by a reduction in metabolic activity and Vo2. Support for this position was available from a number of sources. To the clinical observer, the external appearances of the anaesthetic state as compared with the awake state clearly suggested a general reduction in metabolic activity. Guedel (1924), among others, extrapolating from experiences with young and old patients to age v. metabolic rate curves, concluded that a requirement for obtaining anaesthesia was a decrease in the overall metabolic rate to a certain value; on this basis, he advocated the use of premedicant drugs. Furthermore, it was established that barbiturates diminished Vo2 in incubated brain tissue (Quastel and Wheatley, 1932) and that a variety of clinical anaesthetic circumstances were usually associated with a decrease in Vo2 (Shackman, Graber and Redwood, 1951). While general anaesthesia is usually associated with a decrease in whole-body Vo2, it is now clear that this is not a requirement for anaesthesia, that anaesthetic agents are not universal metabolic depressants, and that the changes in whole-body Vo2 are the summated changes of organs whose function—and, thereby, the metabolic requirements—have been altered by the anaesthetic. Topkins and Artusio (1956) found that unpremedicated, normothermic patients anaesthetized with either cyclopropane or ether had an increase in Vo2 (averages, 9 and 15%, respectively). Others have demonstrated, in man and in dogs, no decrease in Vo2 with conventional amounts and types of premedicant drugs (morphine, pethidine, alphaprodine, pentobarbitone, hyoscine, and atropine) (Theye, 1975). Cerebral Vo2 is not necessarily decreased with anaesthesia. While thiopentone and halothane decrease CMRo2, ether and cyclopropane have variable effects and nitrous oxide and ketamine increase CMR02 in dogs (Michenfelder and Theye, 1972). The direct relationship between anaestheticinduced change in function and the resultant altered metabolic requirements is most clear for the canine heart. A direct relationship exists between myocardial external work and Vo2 during enflurane, isoflurane, and halothane anaesthesia. For these anaesthetic agents the relationship is not significantly different and is not affected by the anaesthetic concentration. With each, as anaesthetic-induced decreases occur in cardiac output, arterial pressure and, thereby, external work, the metabolic requirements and, thereby, the Vo2 of the heart, decrease. With each, this is the major component of the decrease in wholebody Vo2 with the increase in concentration of the
BRITISH JOURNAL OF ANAESTHESIA
Vo2 CHANGES WITH ENFLURANE, ISOFLURANE, HALOTHANE ACKNOWLEDGEMENTS
This investigation was supported in part by Research Grants HL-4881 and NS-7507 from the National Institutes of Health, Public Health Service, and by grant-in-aid from Ohio Medical Products, a Division of Airco, Inc. REFERENCES
moindre, a l'ensemble de la decroissance de la Vo2 de l'ensemble du corps. Dans chaque cas, les resultats obtenus avec l'enflurane n'ont pas ete tres differents de ceux obtenus avec l'halothane et l'isoflurane. Ces resultats soutiennent le point de vue qui veut que les anesthesiques ne sont pas des agents sedatifs agissant sur le metabolisme general et que les alterations observees dans la Vo2 de l'ensemble du corps representent l'addition des changements crees dans la Vo2 de chacun des organes et occasionnes par une variation provoquee par l'anesthesique dans le fonctionnement de l'organe et dans les besoins du metabolisme.
GANZKORPERLICHE UND ORGANISCHE VO 2 VERANDERUNGEN MIT ENFLURAN, ISOFLURAN UND HALOTHAN ZUSAMMENFASSUNG
Durch diese Untersuchung sollten die Wirkungen von Enfluran auf den Sauerstoffverbrauch (Vo2) des ganzen Korpers und einzelner Organe bei Hunden bestimmt werden. Vo2 des ganzen Korpers sowie myokardial, splanchnisch, renal und von Skelettmuskeln wurde bei Enflurankonzentrationen bestimmt, die denen von Halothan und Isofluran bei friiheren Untersuchungen entsprachen. Bei steigenden Enflurankonzentrationen kam es zu einer progressiven Verringerung des Ganzkorper-Vo2. Der Hauptteil dieser Verringerung war eine Reduzierung in myokardialem Vo2, resultierend aus einer Verringerung der externen myokardialen Arbeit aufgrund einer Senkung des Herzminutenvolumens und des arteriellen Druckes. Andere Organe trugen in geringerem Malie zur allgemeinen Verringerung des Ganzkorper-Vo2 bei. In alien Fallen waren die Ergebnisse mit Enfluran nicht wesentlich verschieden von denen mit Halothan und Isofluran. Durch diese Ergebnisse wird die Ansicht weiter unterstiitzt, dafi Narkosemittel keine allgemeinen metabolischen Beruhigungsmittel sind, und da(3 die beobachteten Veranderungen im gesamtkorperlichen Sauerstoffverbrauch die Summations-veranderungen von Vo2 in einzelnen Cr^anen widerspiegeln, die durch eine narkosebedingte Veranderung der Organfunktion und der metabolischen Erfordernisse entstehen. CAMBIOS DE Vo2 ORGANICOS Y CORPOREOS CON ENFLURANO, ISOFLURANO Y HALOTANO SUMARIO
L'ENFLURANE, L'ISOFLURANE ET L'HALOTHANE PROVOQUENT DES ALTERATIONS DANS LA Vo2 DE L'ENSEMBLE DU CORPS ET DES ORGANES RESUME
Cette 6tude a ete concue pour determiner les effets de Penflurane sur la consommation d'oxygene (Vo2) de chacun des organes et de l'ensemble du corps canin. Les Vo2 de l'ensemble du corps, du myocarde, des nerfs splanchniques, des nerfs renaux et des muscles du squelette ont ete determines a des concentrations d'enflurane ^quivalentes a celles utilises lors des etudes prec^dentes effectuees avec l'halothane et l'isoflurane. Lorsqu'on augmente les concentrations d'enflurane, la Vo2 de l'ensemble du corps decroit progressivement. L'dlement essentiel de cette decroissance est une reduction de la Vo2 du myocarde resultant de la diminution du travail externe du myocarde, lui-meme provenant d'une baisse de la puissance cardiaque et de la pression arterielle. Les autres organes ont contribue mais dans une mesure
Se concibi6 este estudio para determinar lps efectos del enflurano sobre el consumo de oxigeno (Vo2) organico individual y copdreo total en perros. Se determin6 el Vo2 corp6reo, miocardiaco expldcnico, renal y del musculo esqueletico con concentraciones de enflurano equivalentes a las empleadas en estudios anteriores con halotano e isoflurano. Con concentraciones de enflurano cada vez mayores, el Vo2 corporeo disminuy6 progresivamente. El componente mds importante de la disminuci6n fue una reducci6n del Vo2 miocardiaco a partir de una disminuci6n del rendimiento externo miocardiaco como consecuencia de una disminuci6n de la salida cardiaca y presi6n arterial. Otros organos contribuyeron con menor intensidad a la disminucion total del Vo2 corp6reo. Con relaci6n a esto, los hallazgos con enflurano no fueron muy diferentes de los obtenidos con halotano e isoflurano. Estos hallazgos apoyan el punto de vista de que los agentes anestesicos no son debilitantes metab61icos generales y que los cambios observados en el Vo2 corpdreo reflejan los cambios totales del Vo2 de 6rganos individuales ocasionados por un cambio producido por anestesia en la funci6n orgdnica y exigencias metab61icas.
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Guedel, A. E. (1924). Metabolism and reflex irritability in anaesthesia. J.A.M.A., 83, 1736. Joas, T. A., Stevens, W. C , and Eger, E. I., n (1971). Electroencephalographic seizure activity in dogs during anaesthesia. Br. J. Anaesth., 43, 739. Messick, J. M., jr., Wilson, D. M., and Theye, R. A. (1972). Canine renal function and Vo2 during methoxyflurane anesthesia. Anesth. Analg. (Cleve.), 51, 933. Michenfelder, J. D., and Theye, R. A. (1968). Hypothermia: effect on canine brain and whole-body metabolism. Anesthesiology, 29, 1107. (1972). Cerebral metabolic effects of anesthesia in the dog j in Cellular Biology and Toxicity of Anesthetics (ed. B. R. Fink), p. 48. Baltimore: Williams & Wilkins. Quastel, J. H., and Wheatley, A. H. M. (1932). Narcosis and oxidations of the brain. Proc. R. Soc. Land. (Biol.), 112, 60. Shackman, R., Graber, G. I., and Redwood, C. (1951). Oxygen consumption and anaesthesia. Clin. Set., 10, 219. Theye, R. A. (1967). Myocardial and total oxygen consumption with halothane. Anesthesiology, 28, 1042. (1972). The contributions of individual organ systems to the decrease in whole-body Vo2 with halothane. Anesthesiology, 37, 367. (1975). Effects of anesthetics on whole-body oxygen uptake; inClinical Anesthesia, Vol. II, Metabolic Aspects of Anesthesia (ed. P. Cohen) p. 49. Philadelphia: Davis. Maher, F. T. (1971). The effects of halothane on canine renal function and oxygen consumption. Anesthesiology, 35, 54. Michenfelder, J. D. (1975). Individual organ contributions to the decrease in whole-body Vo2 with isoflurane. Anesthesiology, 42, 35. Sessler, A. D. (1967). Effect of halothane anesthesia on rate of canine oxygen consumption. Anesthesiology, 28, 661. Topkins, M. J., and Artusio, J. F., jr. (1956). Effect of cyclopropane and ether on oxygen consumption in unpremedicated surgical patient. Anesth. Analg. (Cleve.), 35, 350.
817
WHOLE-BODY AND ORGAN Vo2 CHANGES WITH ENFLURANE, ISOFLURANE, AND HALOTHANE R. A. THEYE AND J. D. MICHENFELDER SUMMARY
We have established previously for halothane and isoflurane that the pattern of individual organ contributions to the whole-body decrease in oxygen consumption (Vo2) is similar, that the decrease in myocardial Vo2 is the major component for each, and that the decrease in Vo2 in other organs contributes to a lesser extent (Theye, 1972; Theye and Michenfelder, 1975). These findings support our contention that anaesthetic agents are not general metabolic depressants and help to emphasize that the decrease in whole-body Vo2 with anaesthesia represents a summation of events in individual organs in which an anaesthetic-induced change in function results in a change in metabolic requirements. The present study extended this inquiry to the effects of enflurane and the findings provide the basis for a comparative summary of the effects of halothane, isoflurane, and enflurane in these regards. MATERIAL AND METHODS
In all studies, unpremedicated dogs were anaesthetized with enflurane in a mixture of oxygen in nitrogen. The trachea was intubated with the aid of suxamethonium, which was continued thereafter at a rate of 150 mg/hr. Ventilation was provided by a Harvard pump and nonrebreathing system with appropriate adjustments of the inspired oxygen RICHARD A. THEYE, M.D., JOHN D. MICHENFELDER, M.D.,
Department of Anesthesiology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55901, U.S.A.
concentration (Fio2) and ventilatory volume to maintain PaO2 and PaC02 at 150±5 and 40±2 mm Hg, respectively (mean±SEM). Body and organ temperatures were maintained at 37.0±0.2°C by surface warming. Expired enflurane concentrations were determined by infrared analysis. Intravascular pressures were transduced by strain gauges. Blood-gas values were measured by electrodes at 37.0°C. Blood oxygen content was calculated from Po2 and oxyhaemoglobin concentration (IL CO-Oximeter). Whole-body and organ Vo2 were calculated by means of the Fick equation, using appropriate values for blood flow rate (0) and the arteriovenous oxygen content difference (Cao2—Cv02), and were expressed relative to whole-body weight as determined before induction of anaesthesia. Left and right ventricular external work was calculated from total Q, mean systemic and pulmonary arterial pressures, respectively, and a previously described constant (Theye, 1967). At autopsy, catheter positions were confirmed and organ weights were determined. Values in the dog for minimum alveolar concentration (MAC) of 2.2,1.48, and 0.87%, for enflurane, isoflurane, and halothane, respectively, were the reference points for establishing equivalent levels of enflurane anaesthesia (Joas, Stevens and Eger, 1971). The effect of enflurane on whole-body Vo2 and haemodynamics was determined in 10 dogs (weights: whole-body, 17±2 kgj'heart, 106±17 g). Catheters
Downloaded from http://bja.oxfordjournals.org/ at University of California, San Francisco on December 22, 2014
This study was designed to determine the effects of ennurane on canine whole-body and individual organ oxygen consumption (Vo2). Whole-body, myocardial, splanchnic, renal, and skeletal muscle Vo2 were determined at enflurane concentrations equivalent to those used in previous studies with halothane and isoflurane. With increasing enflurane concentrations, whole-body Vo2 decreased progressively. The major component of the decrease was a reduction in myocardial Vo2 resulting from a decrease in myocardial external work as a result of a decrease in cardiac output and arterial pressure. Other organs contributed to a lesser extent to the overall decrease in whole-body Vo2. In each respect the findings with enflurane were not significantly different from those with halothane and isoflurane. These findings add support to the view that anaesthetic agents are not general metabolic depressants and that observed changes in whole-body Vo2 reflect the summated changes in individual organ Vo2 occasioned by an anaesthetic-induced change in organ function and metabolic requirements.
BRITISH JOURNAL OF ANAESTHESIA
814
RESULTS
With increases in the enflurane concentration, wholebody Vo2 decreased progressively (table I); at the greatest concentration the average decrease was 29%. Myocardial Vo2 also decreased progressively, but at a greater rate, resulting in a decrease in the ratio of myocardial to whole-body Vo». The decrease in myocardial Vo2 directly reflected the progressive decrease in myocardial external work, which resulted
from decreases in cardiac output and arterial pressure. The only statistically significant differences between these findings and those with isoflurane and halothane occurred at the greatest anaesthetic concentrations; these differences consisted of a lesser arterial pressure with enflurane than with either isoflurane or halothane and a lesser cardiac output and myocardial Vo2 with enflurane than with isoflurane (t test; unpaired data). The relationship between myocardial Vo2 and left ventricular external work with enflurane anaesthesia established in the right-heart bypass studies was not significantly different from those established previously for isoflurane and halothane (fig. 1). The data from all three studies were pooled to yield a single regression equation: y=2.61+(l.86x^0.16), which was used to calculate the myocardial Vo2 values for the whole-body studies in table I. 24
r
- Halothane Isoflurane 'Enflurane
o o 16
o 5
0 EXTERNAL
4 8 WORK, LV, kg-m/mln
FIG. 1. Regression lines relating myocardial Vo2 (y; ml/min/ 100 g) and left ventricular (LV) work (x; kg-m/min) during anaesthesia with enflurane [y=3.17+(1.68x±0.24)], isoflurane [y=3.21+(1.78x±0.09)] 5 and halothane [y = 1.44 + (2.13x±0.29)] (±SEM).
The effects of enflurane on splanchnic, renal, and skeletal muscle blood flow are summarized in table II. Vo2 values are presented relative to wholebody weight; the blood flow values are based on actual flows of the organ studied. The findings in the gastrocnemius-plantaris group (actual weight, 61 ± 7 g) have been extrapolated to whole-body skeletal muscle using the assumptions applied previously with isoflurane and halothane (0.5% value, 35% of wholebody Vo 2 ; 3.8% value, based on the 16% reduction observed in the muscle studied). With increases in the enflurane concentration, splanchnic, renal, and skeletal muscle Vo2 decreased 19,30 and 16% respectively.
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were placed in the carotid and pulmonary arteries, the right atrium, and the outflow tract of the right ventricle for measurement of pressures, determination of 0 by the indocyanine green dye dilution technique, and sampling of arterial and mixed venous blood. Observations were made in triplicate at enflurane concentrations of 0.5, 2.2, 2.8, and 3.8% in this sequence and, in alternate dogs, in the reverse sequence. (For convenience, results are presented only in terms of increasing concentration.) One hour elapsed at each enflurane concentration with observations in the final 30 min. During these studies myocardial Vo2 was calculated from the values for external work observed and the relationship between myocardial external work and Vo2, as described subsequently. The relationship between myocardial external work and Vo2 during enflurane anaesthesia was determined in four additional dogs (weights: wholebody, 20±2 kg; heart, 127±25 g). Right-heart bypass was established after ligation of the azygos vein, appropriate cannulations of the right atrium, superior and inferior venae cavae, and pulmonary trunk, and preparation of an extracorporeal apparatus that included a reservoir, pump, and heat exchanger. This approach provided for isolation and collection of all myocardial venous flow with opportunities for determination of myocardial 0 (timed collection in graduated cylinder) and (Ca02—Cv02) (Theye, 1967). Observations were made in triplicate at enflurane concentrations of 0.5 and 3.8%. At each concentration, left ventricular work was arranged to approximate to that observed in the whole-body studies by appropriate modifications of blood volume and rightheart bypass pump flow rates. Splanchnic and renal Vo2 (six dogs) and gastrocnemius-plantaris group bilateral muscle Vo2 (six dogs) were determined at enflurane concentrations of 0.5 and 3.8% by surgical methods that provide for separation, direct collection, measurement, and return of the venous blood flow from these organs (Theye and Michenfelder, 1975).
Vo2 CHANGES WITH ENFLURANE, ISOFLURANE, HALOTHANE TABLE I.
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Metabolic and haemodynamic responses to enflurane (10 dogs: 37°C).
Enflurane expired ( %)
0.27 0.07 0.01
6.44 1.21 0.19
3.8
Mean SEM
Mean iSEM
5.51* 0.19 0.63* 0.05 0.11* 0
5.11* 0.14 0.53* 0.02 0.10* 0
Mean
SEM
4.57* 0.10 0.43* 0.02 0.09* 0
190
9
104
6
87*
5
70*
7
114 18 2
5 1 1
78* 13* 2
2 1 0
70* 12* 3
1 1 0
58* 12* 4*
3 1 1
0.27 0.08
5.34 0.86
2.03* 0.13 0.33* 0.04
1.04* 0.14 0.22* 0.03
1.51* 0.10 0.27* 0.02
•Significantly different (P<0.05) from 0.5 % value by t test; paired data. TABLE I I .
Effects of enflurane on splanchnic, renal, and skeletal muscle Vo 2 and blood flow.
TABLE I I I . Effects of enflurane, isoflurane, and halothane (%, expired") on canine whole-body and regional Vo 2 .
Enflurane expired ( %) 0.5
Mean Vo2, ml/min/kg (wholebody weight) splachnic renal skeletal muscle B lood flow, ml/min (actual flows) splanchnic renal skeletal muscle
Vo2, ml/min/kg of whole-body weight (mean values)
3.8
SEM
Mean
SEM
2.09 0.46 2.25
0.10 0.04 0.18
1.70* 0.32* 1.89*
0.11 0.02 0.15
420 316 7.3
37 48 0.9
352* 231
39 70 0.4
5.8*
Whole-body Myocardial Splanchnic Renal Cerebral Skeletal muscle Other tissues (difference)
Enflurane*
Isonuranef
HalothaneJ
0.5 6.44 1.21 2.09 0.46 0.22
3.8 4.57 0.43 1.70 0.32 0.15
0.4
2.6
6.34 1.37 2.06 0.41 0.20
4.93 0.68 1.91 0.30 0.14
6.46 4.71 1.40 0.57 1.78 1.62 0.42 0.33) 0.22 0.18
2.25
1.89
2.22
1.86
2.26
1.85
0.21
0.08
0.08
0.04
0.38
0.16
0.2
1.5
•Significantly different (P<0.05), t test; paired data.
•Present study. fData from Theye (1972). JData from Theye and Michenfelder (1975).
Although significant decreases in splanchnic and skeletal muscle blood flow occurred, the decreases in Vo2 could not be ascribed to deficiencies in oxygen transport because oxygen tensions in venous blood leaving the organs were maintained at or above the normal values. The only statistically significant difference between these findings with enflurane and those with isoflurane or halothane occurred at the greatest concentration, muscle blood flow decreasing with enflurane and increasing with both isoflurane and halothane. The effects of enflurane, isoflurane, and halothane on whole-body and regional Vo2 are summarized in table III. The enflurane projections are based on the findings of the present study and of an additional study of the effects of enflurane on canine cerebral metabolism in which a 34% decrease in CMR 02 occurred at 2.2% enflurane and was maintained at 4.2% enflurane. These findings were extrapolated to the whole brain using the same assumptions applied
previously with isoflurane and halothane. The only significant difference between either whole-body or any regional Vo2 decrease with enflurane, isoflurane, or halothane anaesthesia was the previously mentioned lesser myocardial Vo2 with enflurane than with isoflurane at the greatest concentrations. With each of these three anaesthetic agents, the myocardial component was the major contributor to the whole-body decrease, with lesser contribution from the other organs. DISCUSSION
The data on whole-body and regional Vo2 effects of enflurane, isoflurane, and halothane, summarized in table III, are the culmination of a series of studies initiated more than a decade ago in the climate of a complacent view of the effects of anaesthesia on Vo2. At the time, it was generally held that anaesthetic agents were general metabolic depressants, which accounted for their effectiveness in providing
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Vo2, whole-body (ml/min/kg) Vo2, myocardial (ml/min/kg) Vos myocardial/Vo2 whole-body Q (ml/min/kg) Pressures (mean, mm Hg) systemic (arterial) pulmonary arterial right atrial External work (kg-m/min) left ventricle right ventricle
2.8
2.2
0.5
Mean !5EM
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agent. With halothane, the decrease in whole-body Vo2 with increased concentrations of halothane can be reversed by measures that increase cardiac output and arterial pressure, such as volume expansion, heart pacing, and digitalis (Theye and Sessler, 1967). Similarly, Vo2 of the canine kidney is related directly to the rate of tubular reabsorption of sodium (Tna) and changes in renal blood flow and glomerular nitration rate, induced by halothane and methoxyflurane, which result in decreases in Tna and are accompanied by appropriate decreases in renal Vo2 (Theye and Maher, 1971; Messick, Wilson and Theye, 1972). For all these reasons, the notion that anaesthetic agents in clinically useful concentrations are universal, general metabolic depressants should be abandoned and be replaced by the view that whole-body Vo2 during anaesthesia is a summation of individual organ contributions, all of which are subject to a variety of influences. Decreases in myocardial external work or renal Tna induced by anaesthetic agents or other factors tend to result in decreases in myocardial or renal Vo2. Skeletal muscle Vo2 is usually diminished slightly with anaesthesia and paralysis, but may be increased several-fold in response to hypothermia during light anaesthesia without relaxants and most certainly if shivering is present. Cerebral Vo2 is decreased strikingly with barbiturates, less so with other anaesthetic agents, and may be increased if only nitrous oxide or ketamine is used. Splanchnic Vo2 follows closely splanchnic blood flow, and circumstances decreasing such flow contribute to decreases in splanchnic Vo2. Either a decrease or an increase in the body temperature alters the whole-body Vo2 by decreasing or increasing individual organ Vo2 by a direct effect on rate of intracellular biochemical processes (Michenfelder and Theye, 1968). Situations of increased sympathoadrenal activity and catecholamine concentrations tend to lead to increased organ and wholebody Vo2. In our studies, the similarity of effects of enflurane, isoflurane, and halothane on regional and whole-body Vo2 was matched by a similarity of effects on cardiac output, arterial pressure, and renal and splanchnic blood flow. The mechanism involved in the decrease in skeletal muscle Vo2 with these anaesthetic agents is not clear from these or other studies, but it is apparently not related to a decrease in blood flow because Vo2 decreased by a similar amount with each, whereas blood flow decreased with enflurane and increased with isoflurane and halothane.
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anaesthesia and which was, of necessity, accompanied by a reduction in metabolic activity and Vo2. Support for this position was available from a number of sources. To the clinical observer, the external appearances of the anaesthetic state as compared with the awake state clearly suggested a general reduction in metabolic activity. Guedel (1924), among others, extrapolating from experiences with young and old patients to age v. metabolic rate curves, concluded that a requirement for obtaining anaesthesia was a decrease in the overall metabolic rate to a certain value; on this basis, he advocated the use of premedicant drugs. Furthermore, it was established that barbiturates diminished Vo2 in incubated brain tissue (Quastel and Wheatley, 1932) and that a variety of clinical anaesthetic circumstances were usually associated with a decrease in Vo2 (Shackman, Graber and Redwood, 1951). While general anaesthesia is usually associated with a decrease in whole-body Vo2, it is now clear that this is not a requirement for anaesthesia, that anaesthetic agents are not universal metabolic depressants, and that the changes in whole-body Vo2 are the summated changes of organs whose function—and, thereby, the metabolic requirements—have been altered by the anaesthetic. Topkins and Artusio (1956) found that unpremedicated, normothermic patients anaesthetized with either cyclopropane or ether had an increase in Vo2 (averages, 9 and 15%, respectively). Others have demonstrated, in man and in dogs, no decrease in Vo2 with conventional amounts and types of premedicant drugs (morphine, pethidine, alphaprodine, pentobarbitone, hyoscine, and atropine) (Theye, 1975). Cerebral Vo2 is not necessarily decreased with anaesthesia. While thiopentone and halothane decrease CMRo2, ether and cyclopropane have variable effects and nitrous oxide and ketamine increase CMR02 in dogs (Michenfelder and Theye, 1972). The direct relationship between anaestheticinduced change in function and the resultant altered metabolic requirements is most clear for the canine heart. A direct relationship exists between myocardial external work and Vo2 during enflurane, isoflurane, and halothane anaesthesia. For these anaesthetic agents the relationship is not significantly different and is not affected by the anaesthetic concentration. With each, as anaesthetic-induced decreases occur in cardiac output, arterial pressure and, thereby, external work, the metabolic requirements and, thereby, the Vo2 of the heart, decrease. With each, this is the major component of the decrease in wholebody Vo2 with the increase in concentration of the
BRITISH JOURNAL OF ANAESTHESIA
Vo2 CHANGES WITH ENFLURANE, ISOFLURANE, HALOTHANE ACKNOWLEDGEMENTS
This investigation was supported in part by Research Grants HL-4881 and NS-7507 from the National Institutes of Health, Public Health Service, and by grant-in-aid from Ohio Medical Products, a Division of Airco, Inc. REFERENCES
moindre, a l'ensemble de la decroissance de la Vo2 de l'ensemble du corps. Dans chaque cas, les resultats obtenus avec l'enflurane n'ont pas ete tres differents de ceux obtenus avec l'halothane et l'isoflurane. Ces resultats soutiennent le point de vue qui veut que les anesthesiques ne sont pas des agents sedatifs agissant sur le metabolisme general et que les alterations observees dans la Vo2 de l'ensemble du corps representent l'addition des changements crees dans la Vo2 de chacun des organes et occasionnes par une variation provoquee par l'anesthesique dans le fonctionnement de l'organe et dans les besoins du metabolisme.
GANZKORPERLICHE UND ORGANISCHE VO 2 VERANDERUNGEN MIT ENFLURAN, ISOFLURAN UND HALOTHAN ZUSAMMENFASSUNG
Durch diese Untersuchung sollten die Wirkungen von Enfluran auf den Sauerstoffverbrauch (Vo2) des ganzen Korpers und einzelner Organe bei Hunden bestimmt werden. Vo2 des ganzen Korpers sowie myokardial, splanchnisch, renal und von Skelettmuskeln wurde bei Enflurankonzentrationen bestimmt, die denen von Halothan und Isofluran bei friiheren Untersuchungen entsprachen. Bei steigenden Enflurankonzentrationen kam es zu einer progressiven Verringerung des Ganzkorper-Vo2. Der Hauptteil dieser Verringerung war eine Reduzierung in myokardialem Vo2, resultierend aus einer Verringerung der externen myokardialen Arbeit aufgrund einer Senkung des Herzminutenvolumens und des arteriellen Druckes. Andere Organe trugen in geringerem Malie zur allgemeinen Verringerung des Ganzkorper-Vo2 bei. In alien Fallen waren die Ergebnisse mit Enfluran nicht wesentlich verschieden von denen mit Halothan und Isofluran. Durch diese Ergebnisse wird die Ansicht weiter unterstiitzt, dafi Narkosemittel keine allgemeinen metabolischen Beruhigungsmittel sind, und da(3 die beobachteten Veranderungen im gesamtkorperlichen Sauerstoffverbrauch die Summations-veranderungen von Vo2 in einzelnen Cr^anen widerspiegeln, die durch eine narkosebedingte Veranderung der Organfunktion und der metabolischen Erfordernisse entstehen. CAMBIOS DE Vo2 ORGANICOS Y CORPOREOS CON ENFLURANO, ISOFLURANO Y HALOTANO SUMARIO
L'ENFLURANE, L'ISOFLURANE ET L'HALOTHANE PROVOQUENT DES ALTERATIONS DANS LA Vo2 DE L'ENSEMBLE DU CORPS ET DES ORGANES RESUME
Cette 6tude a ete concue pour determiner les effets de Penflurane sur la consommation d'oxygene (Vo2) de chacun des organes et de l'ensemble du corps canin. Les Vo2 de l'ensemble du corps, du myocarde, des nerfs splanchniques, des nerfs renaux et des muscles du squelette ont ete determines a des concentrations d'enflurane ^quivalentes a celles utilises lors des etudes prec^dentes effectuees avec l'halothane et l'isoflurane. Lorsqu'on augmente les concentrations d'enflurane, la Vo2 de l'ensemble du corps decroit progressivement. L'dlement essentiel de cette decroissance est une reduction de la Vo2 du myocarde resultant de la diminution du travail externe du myocarde, lui-meme provenant d'une baisse de la puissance cardiaque et de la pression arterielle. Les autres organes ont contribue mais dans une mesure
Se concibi6 este estudio para determinar lps efectos del enflurano sobre el consumo de oxigeno (Vo2) organico individual y copdreo total en perros. Se determin6 el Vo2 corp6reo, miocardiaco expldcnico, renal y del musculo esqueletico con concentraciones de enflurano equivalentes a las empleadas en estudios anteriores con halotano e isoflurano. Con concentraciones de enflurano cada vez mayores, el Vo2 corporeo disminuy6 progresivamente. El componente mds importante de la disminuci6n fue una reducci6n del Vo2 miocardiaco a partir de una disminuci6n del rendimiento externo miocardiaco como consecuencia de una disminuci6n de la salida cardiaca y presi6n arterial. Otros organos contribuyeron con menor intensidad a la disminucion total del Vo2 corp6reo. Con relaci6n a esto, los hallazgos con enflurano no fueron muy diferentes de los obtenidos con halotano e isoflurano. Estos hallazgos apoyan el punto de vista de que los agentes anestesicos no son debilitantes metab61icos generales y que los cambios observados en el Vo2 corpdreo reflejan los cambios totales del Vo2 de 6rganos individuales ocasionados por un cambio producido por anestesia en la funci6n orgdnica y exigencias metab61icas.
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Guedel, A. E. (1924). Metabolism and reflex irritability in anaesthesia. J.A.M.A., 83, 1736. Joas, T. A., Stevens, W. C , and Eger, E. I., n (1971). Electroencephalographic seizure activity in dogs during anaesthesia. Br. J. Anaesth., 43, 739. Messick, J. M., jr., Wilson, D. M., and Theye, R. A. (1972). Canine renal function and Vo2 during methoxyflurane anesthesia. Anesth. Analg. (Cleve.), 51, 933. Michenfelder, J. D., and Theye, R. A. (1968). Hypothermia: effect on canine brain and whole-body metabolism. Anesthesiology, 29, 1107. (1972). Cerebral metabolic effects of anesthesia in the dog j in Cellular Biology and Toxicity of Anesthetics (ed. B. R. Fink), p. 48. Baltimore: Williams & Wilkins. Quastel, J. H., and Wheatley, A. H. M. (1932). Narcosis and oxidations of the brain. Proc. R. Soc. Land. (Biol.), 112, 60. Shackman, R., Graber, G. I., and Redwood, C. (1951). Oxygen consumption and anaesthesia. Clin. Set., 10, 219. Theye, R. A. (1967). Myocardial and total oxygen consumption with halothane. Anesthesiology, 28, 1042. (1972). The contributions of individual organ systems to the decrease in whole-body Vo2 with halothane. Anesthesiology, 37, 367. (1975). Effects of anesthetics on whole-body oxygen uptake; inClinical Anesthesia, Vol. II, Metabolic Aspects of Anesthesia (ed. P. Cohen) p. 49. Philadelphia: Davis. Maher, F. T. (1971). The effects of halothane on canine renal function and oxygen consumption. Anesthesiology, 35, 54. Michenfelder, J. D. (1975). Individual organ contributions to the decrease in whole-body Vo2 with isoflurane. Anesthesiology, 42, 35. Sessler, A. D. (1967). Effect of halothane anesthesia on rate of canine oxygen consumption. Anesthesiology, 28, 661. Topkins, M. J., and Artusio, J. F., jr. (1956). Effect of cyclopropane and ether on oxygen consumption in unpremedicated surgical patient. Anesth. Analg. (Cleve.), 35, 350.
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