PLASMA FREE FATTY ACID LEVELS DURING GENERAL ANAESTHESIA AND OPERATION EN MAN

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1 Brit. J. Anaesth. (1970),, 11 PLASMA FREE FATTY ACID LEVELS DURING GENERAL ANAESTHESIA AND OPERATION EN MAN BY L. H. COOPERMAN SUMMARY Plasma free fatty acid (FFA) levels were measured during general anaesthesia with ether, cyclopropane and nitrous oxide-halothane. Associated with cyclopropane was a twofold rise in FFA within the first hour of anaesthesia which could be prevented by prior beta-adrenergic blockade, or reversed by either glucose loading or beta blockade. A possible mechanism is sympathetic nervous activation. The elevated FFA may explain the decreased glucose tolerance during cyclopropane anaesthesia. During nitrous oxidehalothane anaesthesia a smaller, but significant, elevation in FFA level occurred, while with ether anaesthesia there was no significant change in FFA level. Explanations for these last two findings are not known. Plasma non-esterified or free fatty acid (FFA) is the form whereby fat is mobilized from the adipose tissue depot and transported to the rest of the body. Once carried to other organs, the FFA can be either re-esterified to triglyceride, incorporated into other lipids, or else oxidized to provide energy for the organism. In fact, in the postabsorptive state the oxidation of FFA provides over half the body's caloric needs and for some organs, e.g. the heart, the proportion can be even higher (Fritz, 1961). Such a circumstance is found in clinical practice where patients are commonly fasted before undergoing general anaesthesia. Yet there has been little study on the effects of anaesthetics on fat metabolism, and especially their effects on FFA mobilization. I have, therefore, measured plasma FFA levels during three types of general anaesdiesia nitrous oxide-halothane, diethyl ether, and cyclopropane. From the changes which occurred, it was hoped that some inference regarding the action of these anaesthetics on FFA metabolism could be made. METHODS The 7 patients studied ranged in age from 11 to 8 years. Two-thirds were female and all were in good health (ASA physical status I and II). None had endocrine disease nor were they receiving hormonal therapy. The elective operative procedures which they underwent were of a wide variety though the majority were either orthopaedic or gynaecological. All had fasted overnight before induction of anaesthesia. Premedication consisted of quinalbarbitone, usually 100 mg, and atropine 0. mg given intramuscularly 1 hour before induction. Cyclopropane was administered with oxygen into a closed circle system, as was ether. Halothane, vaporized from outside the circuit, was added with nitrous oxide-oxygen (1:1) to a semidosed system. Only normal saline solution was infused during the study period except in three instances where whole blood, too, was administered. Thiopentone, mg, was often given for induction and suxamethonium 60 mg and tubocurarine 6-1 mg were used to produce muscular relaxation. Ventilation was assisted or controlled if indicated clinically, though arterial blood gases were not routindy measured. An additional group of eight individuals was studied. These were volunteers aged 1-6 years who were subjects for a study of cerebral circulation (c.bi.) during ether anaesthesia. Anaesthetic management was similar to the patient group. Plasma FFA was measured in blood samples drawn from a superficial vein in the hand or fore- LEE H. COOPERMAN, M.D., Department of Anesthesia, University of Pennsylvania, 00 Spruce Street, Philadelphia, Pennsylvania 1910, U.S.A. This work was supported (in part) by U.S.P.H.S. grant 5-PO1-GM and Special Fellowship 1-F-GM from the National Institute of General Medical Sciences, National Institutes of Health.

2 1 BRITISH JOURNAL OF ANAESTHESIA TABLE I Changes in plasma FFA concentration (jiequiv/l.) during anaesthesia {mean ± SE). Anaesthetic Cyclopropane Nitrous oxidebalothane Ether Cyclopropane Nitrous oxidehalothane Ether No. of patients (c.bif. subjects) Before induction 6 ± ± ± 1 Before induction 61 ± ± ± 1 Time 0 min 86 ± ± ± 1 60 min 107 ± ± ± 60 min 1197 ± ± ± min 9 ± ± ± 87 TABLE II Changes in plasma 1FFA and blood glucose with glucose load after 1 hour anaesthesia. FFA mean ± SE (ji equiv/1.) Blood glucose, mean ± Time from ± induction (min) ± of cyclopropane 10 (i.e. 60 min after glucose load) 606 ± 18 0 Propranolol given after Anaesthetic: cyclopropane Time from induction (min) FFA, mean ± SE Ox equiv/l) Glucose mean Propranolol given just Anaesthetic: cyclopropane FFA, mean ± SE (/x equiv/1.) Glucose mean TABLE III Changes in FFA before and after administration of propranolol. 60 minutes of anaesthesia ± before induction 60 ± ± 89 ± 110 Propranolol IT) ± ± ± 56 16

3 PLASMA FREE FATTY ACID LEVELS DURING ANAESTHESIA 1 arm. The blood was added to heparinized tubes, iced and then centrifuged at a temperature of C. Plasma was separated and the FFA t extracted and measured in duplicate by the Trout modification of Dole's method (Trout, Estes and Friedberg, 1960; Dole and Meinertz, 1960). Coefficient of variation between duplicate samples was.5 per cent No more dian 90 minutes elapsed between obtaining the blood sample and extraction of the FFA. During this time the sample was kept -» at C to minimize lipolysis. In some instances duplicate measurements of blood glucose were made using an enzymatic method. The first sample was drawn within a 15-tninute period before the induction of anaesthesia. Samples were then taken from the same vein 0, 60 and, if possible, 10 minutes after induction. Operation began between ^ 0 and 60 minutes after induction. In four instances 50 per cent dextrose/water was given intravenously (5 g/70 kg) to patients at the end of 1 hour of cyclopropane anaesthesia just after the 60-minute FFA sample had been drawn. Five other patients received propranolol, a betav adrenergic receptor blocking drug intravenously in a dose of 0.15 mg/kg, in addition to cyclopropane anaesthesia. The glucose and the propranolol were given to elucidate the mechanism of the change in FFA noted during cyclopropane anaesthesia. Statistical comparisons were made using Student's t test Significance was attached to a P value of 0.05 or less. RESULTS FFA and glucose changes during anaesthesia. The changes in FFA are detailed in table I. A significant increase (P<0.01) in plasma FFA was found in the first hour of cyclopropane anaesthesia in nineteen patients; there was no further significant change in the six patients studied over a second hour. During halothane-nitrous oxide anaesthesia a similar pattern emerged with a significant rise (P<0.01) by the first 60 minutes of anaesthesia and no significant change during the second hour. Although there was an increase in FFA with both these anaesthetics, die rise associated with cyclopropane was approximately twice that with nitrous oxide-halothane. No significant change in FFA was measured during ether anaesthesia and, in fact, in the eight c.b.f. subjects a significant decline (P<0.01) of FFA occurred after hours of anaesthesia. Effects of glucose infusion during cyclopropane anaesthesia. As shown in table II, following the expected rise in FFA in the first hour of anaesthesia, a glucose load resulted in a reduction of FFA to control levels widiin 1 hour. Effects of beta-receptor blockade. These results are shown in table HI. Propranolol was given after 1 hour of cyclopropane anaesthesia during which time there was the expected rise in FFA. The subsequent beta blockade resulted in a prompt fall in FFA, to control levels, widiin 1 hour. Similarly propranolol, when given just before induction in two patients, prevented the usual rise in FFA. DISCUSSION At a given time die plasma FFA level is die algebraic sum of ingress from adipose and egress into peripheral tissues. There is evidence to indicate diat tissue uptake of FFA is direcdy proportional to plasma level (Steinberg, 196; McElroy, Sieffert and Spitzer, 1960). Thus of prime importance in determining die plasma level is the rate of entry of FFA from adipose tissue. Triglyceride in adipose tissue is hydrolyzed to FFA and glycerol which can dien enter die blood. Hydrolysis is catalyzed by a tissue lipase. Among factors which enhance the activity of diis lipase are adrenaline and noradrenaline, growth hormone, diyroxine and adrenal corticosteroids, diough the latter two have a permissive radier than active role. Catecholamine-induced lipolysis is believed to be mediated by a cyclic AMP system (Sudierland, Robison and Butcher, 1968). Therefore during increased sympadietic nervous activity plasma FFA levels rise. Glucose, togedier widi insulin, has effects opposite to those exerted by die hormones listed above. When glucose and/or insulin levels increase in blood, transport of glucose into cells is enhanced. In adipose cells, intracellular glycolysis dien proceeds at a more rapid rate resulting in an increased concentration of glycerophosphate. Glycerophosphate reacts with FFA to form triglyceride and, therefore, the output of FFA from die adipose cell is HiminkhfH Glycerol, released when tissue lipase hydrolyzes triglyceride, cannot re-esterify with FFA since adipose cells lack die glyceroltinase necessary for phosphorylation of

4 1 BRITISH JOURNAL OF ANAESTHESIA glycerol. Insulin lowers levels of cyclic AMP in fat tissue and has a direct antagonistic action on lipase activity (Sutherland, Robison and Butcher, 1968). Accordingly, after a glucose load, e.g. feeding or glucose tolerance test, plasma FFA levels fall. Conversely in untreated diabetes mellitus, plasma FFA is elevated. Within this framework let us suggest mechanisms explaining variations noted during the three different anaesthetics. The most profound change was seen during cyclopropane anaesthesia. Similarly, this anaesthetic causes a striking increase in sympathetic nervous activity (Price et al., 196, 196). Thus a marked rise in FFA was not unexpected. Adrenergic stimulation resulting in increased release of FFA from lipid depot is believed to be mediated via betaadrenergic receptors (Hagen, 1967). This, perhaps, was the mechanism underlying the FFA increase with cyclopropane and prevention of this increase by beta blockade. The half-life of propranolol is about 0 minutes. It was only after hours of anaesthesia, when presumably the effect of propranolol, given before induction had diminished, that there was an increase in FFA. Similarly, when given after 1 hour of anaesthesia, propranolol resulted in a return of the elevated FFA levels to control values. Propranolol given to unstimulated, awake individuals, has no significant effect on plasma FFA concentration and therefore probably acted via beta-adrenergic blockade in this study (Pinter and Pattee, 1967). Sympathetic nervous hyperactivity is thus one possible way in which cyclopropane can cause increased plasma FFA levels. It is conceivable that it acts in other ways, e.g. directly on enzyme systems, on insulin or other hormone activities as well. Interestingly, die hyperglycaemia occurring with cyclopropane anaesthesia was not blocked by propranolol and thus not mediated by the sympathetic nervous system. Cyclopropane did not block the effect of a glucose load (and presumably endogenous insulin) on FFA. Plasma FFA levels decreased in all cases. In this regard one might speculate on the relation of FFA and blood glucose during cyclopropane anaesthesia. Randle and co-workers (196) have proposed the term "glucose-fatty acid cycle" to denote the interactions between these two substances in stabilizing dieir blood levels. Thus FFA inhibit membrane transport of glucose into die cell and have a similar effect on glycolysis and phosphorylation of glucose already within the cell. This leads to an increase in blood sugar, dien insulin, and finally an enhancement of glucose uptake by die adipose cell This allows esterification of FFA to proceed maximally; FFA release is diminished as is the plasma level. The cycle is then repeated. A decrease in glucose tolerance when plasma FFA levels are elevated has been demonstrated in «- man by Schalch and Kipnis (1965). In their study plasma FFA levels, but not blood glucose, were elevated by die combination of a fat meal and intravenous administration of heparin. They found a close correlation between degrees of impairment of glucose tolerance and die elevation of plasma r FFA. A recent study by Cervenko and Greene (1967) has shown a similar decrease in glucose tolerance during cyclopropane anaesdiesia in man. The elevation in plasma FFA diat occurs widi diis anaesthetic might explain me diminished glucose tolerance, though not the hyperglycaemia which accompanies cyclopropane anaesthesia. Changes noted widi die remaining two anaesdietics studied are more difficult to explain. Halothane is usually thought to have no stimulant effect on die sympadietic nervous system though Klide and Aviado have presented evidence of betaadrenergic stimulation by halothane on die bronchi (Klide and Aviado, 1967), while increased sympadietic activity has been described in one animal species (Millar and Biscoe, 1966). Recendy, evidence has been presented that halodiane depressed myocardial uptake of FFA and diis too could, at least in part, explain die elevated plasma FFA levels (Merrin, 1969). What effects nitrous oxide might have on FFA metabolism are not known diough one would expect diem - to be much smaller than diose of halothane. The stability of FFA levels during edier anaesdiesia is puzzling since increased sympadietic activity, as measured by blood catecholamine levels and nerve recording, is present widi diis agent (Millar and Biscoe, 1966). However, in a study in dogs, Galla and associates (196) also noted a fall, radier dian a rise, in FFA widi edier anaesdiesia. The greater hyperglycaemia widi edier compared to cyclopropane anaesthesia found in die present study may be significant, for it could cause a

5 PLASMA FREE FATTY ACID LEVELS DURING ANAESTHESIA 15 greater inhibition of FFA release from the fat cell. Acid-base balance and depth of anaesthesia were not measured in this study and thus their effects on fat metabolism are difficult to assess. However, they were probably comparable between the three different anaesthetic groups, as was the degree of surgical stimulation. Allison, Tomlin and Chamberlain (1969) showed that this stimulation may have significant effects on FFA levels, although in the present study the two groups receiving ether anaesthesia showed similar changes, but only one of them underwent surgery. More important is our lack of knowledge on the effect of anaesthetics on insulin activity, especially since this is the single most important hormonal influence on lipolysis. REFERENCES Allison, S. P., Tomlin, P. J., and Chamberlain, M. J. (1969). Some effects of anaesthesia and surgery on carbohydrates and fat metabolism. Brit. J. Anaesth., 1, 588. Cervenko, F. W., and Greene, N. M. (1967). Effects of cyclopropane anesthesia on glucose assimilation coefficient of man. Anesthesiology, $, 91. r Dole, V. P., and Meinertz, H. (1960). Microdetermination of long-chain fatty acids in plasma and tissues. J. biol. Chem., 5, 595. Fritz, I. B. (1961). Factors influencing the rates of long-chain fatty acid oxidation and synthesis in mammalian systems. Pkysiol. Rev., 1, 5. Galla, S. J., Henneman, D. H., Schweizer, H. J., and Vandam, L. D. (196). Effects of ether anesthesia on myocardial metabolism in dogs. Amer. J. Physioi, 0, 1. Hagin, J. H. (1967). Sympathetic regulation of «. metabolism. Pharmacol. Rev., 19, 67. Klide, A. M., and Aviado, D. M. (1967). Mechanism for the reduction in pulmonary resistance induced by halothane. J. Pharmacol, exp. Ther., 158, 8. McElroy, W. T., Sieffert, W. L., and Spitzer, J. J. (1960). Relationship of hepatic uptake of free fatty acids to plasma concentration. Proc. Soc. exp. Biol. (N.Y.), 10, 0. * Merrin, R. G. (1969). Myocardial metabolism in the halothane-depressed canine heart. Anesthesiology, 1,0. Millar, R. A., and Biscoe, T. J. (1966). Postganglionic sympathetic discharge and the effect of inhalation anaesthetics. Brit. J. Anaesth., 8, 9. Pinter, E. J., and Pattee, C J. (1967). Effect of /S-adrenergic blockade on resting and stimulated fat mobilization. J. din. Endocr., 7, 11. Price, H. L., Cook, W. A., Deutsch, S., Linde, H. W., y Mishalove, R. D., and Morse, H. T. (196). Hemodynamic and central nervous actions of cyclopropane in the dog. Anesthesiology,, 1. Jones, R. E., Deutsch, S., and Linde, H. W. (196). Ventricular function and autonomic nervous activity during cyclopropane anesthesia in man. J. dm. Invest., 1, 60. Randle, P. J., Garland, P. B., Hales, C. N., and Newsholme, E. A. (196). The glucose fatty acid cycle. Lancet, 1, 785. Schalch, D. S., and Kipnis, D. M. (1965). Abnormalities in carbohydrate tolerance associated with elevated plasma non-esterined fatty adds. J. din. Invest.,, 010. Steinberg, D. (196). The fate of plasma free fatty acids and their effects on tissue metabolism. Metabolism, 1, 16. Sutherland, E. W., Robison, G. A., and Butcher, R. W. (1968). Some aspects of the biological role of adenosine ', ' monophosphate (cyclic AMP). Circulation, 7, 79. Trout, D. L., Estes, E. H., and Friedberg, S. J. (1960). Titration of free fatty acids of plasma: a study of current methods and a new modification. J. Lipid. Res., 1, 199. TAUX D'ACIDE GRAS LIBRE PLASMATIQUE EN COURS D'ANESTHESIE GENERALE ET D'lNTERVENTION CHIRURGICALE CHEZ LHOMME SOMMAIRE Les taux d'acide gras libre plasmatique, ont ti mesures en cours d'anesthesie generate par ether, cyclopropane et oxyde nitreux-halothane. Avec le cyclopropane il y eut une elevation double du taux d'acide gras libre plasmatique au cours de la premiere heure de l'anesthesie, elevation que Ton pourrait eviter par radministration prealahe de beta bloquants ou annuler soit par un apport de glucose, soit de beta bloquants. On evoque comme mecanisme d'action eventuel: une excitation du systerne nerveux sympathique. L'elivation du taux d'acide gras libre du plasma peut expliquer la diminution de la tolerance au glucose pendant l'anesthesie par cyclopropane. Au cours de l'anesthesie obtenue par oxyde nitreuxhalothane, apparait une elevation faible mais significative du taux d'acide gras libre du plasma, alors qu'avec l'anesthesie a\ l'ither on ne constate aucune modification significative de ce taux. On ne connait aucune explication a ces deux faits d'observation. PLASMASPIEGEL VON FREIEN FETTSAUREN WAHREND DER NARKOSE BEI OPERATIONEN AM MENSCHEN ZUSAMMENFASSUNG Die Plasmaspiegel von freien Fettsfluren wurden bestimmt bei Ather-, Cyclopropan- und Halothan- Lachgas-Narkosen. Bei Verwendung von Cyclopropan erhohte sich der Spiegel der freien Fettsauren urn das Doppelte innerhalb der ersten Stunde der Narkose. Dieser Anstieg konnte durch vorherige beta-adrenerge Blockade verhindert werden; er konnte ruckgangig gemacht werden sowohl durch Glucosezufuhr als auch durch Beta-Blockade. Die Aktivierung des sympathischen Nervensystems ist der wahrscheinliche Wirkungsmechanismus. Dutch die erhohten Fettsaurespiegel konnte die verminderte Glucosetoleranz wahrend Cyclopropannarkosen erklart werden. Bei Narkosen mit einem Halothan-Lachgas-Gemisch kam es zu einem geringeren, aber signifikanten Anstieg der freien FettsSuren; dagegen veranderte sich der Spiegel nicht wesentlich bei Athernarkosen. Filr die beiden letzten Beobachtungen gibt es bis jetzt keine Erkiarungen.