EFFECTS OF ALTHESIN ANAESTHESIA AND SURGERY ON CARBOHYDRATE AND FAT METABOLISM IN MAN

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1 Br.jf. Anaesth. (975), 47, 863 EFFECTS OF ALTHESIN ANAESTHESIA AND SURGERY ON CARBOHYDRATE AND FAT METABOLISM IN MAN S. MEHTA AND. BURTON SUMMARY The effects of anaesthesia alone, and associated with surgery, on carbohydrate and fat metabolism were studied in 36 patients by determining the plasma concentrations of cortisol, human growth hormone, insulin, free fatty acids and blood sugar. The differences between the mean blood sugar and plasma cortisol concentrations before induction and during anaesthesia alone were not statistically significant. Blood sugar concentrations increased slightly during minor surgery and increased significantly during body surface and abdominal surgery. The plasma cortisol concentrations increased slightly during minor and body surface surgery but increased significantly during abdominal surgery. lasma insulin and human growth hormone concentrations did not change appreciably during anaesthesia and surgery. During anaesthesia alone and during minor surgery, a significant increase in plasma FFA concentration was observed at 5 min. The hyperglycaemic response in diabetic patients did not differ significantly from that in nondiabetic subjects. The clinical significance of the results is discussed. Changes in carbohydrate metabolism have been recognized since the observation of Claud Bernard in 877, that the blood sugar concentration increased after haemorrhage. More recently, several studies have been designed specifically to investigate the effects of various anaesthetic agents and of surgical stress on carbohydrate and fat metabolism (Dundee and Todd, 958; Clarke, 968; Allison, Tomlin and Chamberlain, 969; Clarke, Johnston and Sheridan, 970; Oyama and Matsuki, 970; Oyama and Takazawa, 97). Although there have been notable advances, during the last decade, in the understanding of the effects of anaesthesia and surgery on metabolic and endocrine functions and the complex interrelationship governing the utilization of body fuels, there are many gaps in our knowledge. Therefore there is probably a need for further evaluation of the metabolic and endocrine changes occurring during various types of anaesthesia and surgery. The present study was undertaken to investigate the effects of on carbohydrate and fat metabolism in 36 patients by determining the concentrations of blood sugar, plasma insulin, free fatty acids (FFA), cortisol and growth hormone (HGH), and to compare the findings with the combined effect of anaesthesia and surgery. S. MEHTA, M.B., B.S., F.F.A.R.C.S.J. BURTON, B.SC, M.C.B., Burnley Group of Hospitals, General Hospital, Oasterton Avenue, Burnley, Lancashire, BB0 Q. ATIENTS AND METHODS Thirty-six adult patients, male and female, ranging in age from 7 to 7 years, were studied. Thirty had no disease other than that necessitating the operation and none had a history of steroid therapy; six patients were suffering from diabetes and in these patients the disease was controlled either by restriction of diet alone or by hypoglycaemic agents. All the patients in the study underwent elective operations. Each patient was premedicated with atropine 0.6 mg i.m., hr before the induction of anaesthesia. Four series of experiments were undertaken, and the number of patients, their ages and weights, the type of operation, and its duration in each series are shown in table I. Series. Ten patients received 0.05 ml/kg as an induction agent, additional doses being given when small movements of the limbs indicated lightening of anaesthesia. The patients belonging to this series underwent minor surgical procedures as indicated in table I. Series. The patients in this series underwent body surface surgery. The induction dose of was similar to that administered in series () and indeed was similar in each series. The trachea was intubated in all patients and anaesthesia was maintained with nitrous oxide 5 litre/min, oxygen litre/min and halothane in concentrations of.5-.0%. A Magill semi-

2 864 BRITISH JOURNAL OF ANAESTHESIA TABLE I. atients studied and operations performed. Average Series No. of patients Age (yr) Wt (kg) Duration of operation (min) performed Sigmoidoscopy Vacuum termination Anal dilatation and skin tag excison D & C and cautery Multiple ligation of varicose veins Repair inguinal hernia Trendelenburg operation Haemorrhoidectomy Local mastectomy Left spermatocele excision Abdominal termination and sterilization Laparotomy Vagotomy and pyloroplasty Anterior resection Cholecystectomy Repair inguinal hernia Cataract. Lens extration Multiple igation of varicose veins Cyclodiathermy closed circuit was used and the patients were allowed to breathe spontaneously. Series 3. In 0 patients undergoing abdominal surgery, anaesthesia was induced with and an endotracheal tube was inserted, as in series (). After endotracheal intubation, anaesthesia was maintained with nitrous oxide 5 litre/min and oxygen litre/min. ancuronium 4-8 mg was injected in divided doses to obtain muscle relaxation and respiration was controlled with a Manley ventilator. Series 4. The effects of anaesthesia and surgery were studied also in the six diabetic patients. These patients were anaesthetized by one of the methods described for the other series. All patients were studied between the hours of 9.00 a.m. and 3.00 p.m., and there was no systematic difference in the time of day during which different groups were investigated. The period of anaesthesia alone before surgery commenced was 30 min in each case. Five blood samples were obtained from each patient from a plastic cannula inserted in a forearm vein. The concentrations of blood sugar, plasma cortisol, free fatty acids and insulin were estimated in all patients immediately before the induction of anaesthesia and at 5-min intervals thereafter for hr. Blood samples for the growth hormone estimation were taken before the induction of anaesthesia and at 30-min intervals thereafter for hr. Blood sugar concentration was estimated by the standard auto-analyser technique which measures the total of reducing substances in blood. The maximum error in individual readings was ±5 mg/00 ml. lasma cortisol concentration was determined by the method of Mattingly (96), the reproducibility of which, expressed as coefficient of variation, was.3%. lasma insulin concentration was estimated by the method of Wide and orath (966) using the harmacia kit. lasma free fatty acids were determined by the colorimetric method of Duncombe (964). Determination of plasma human growth hormone concentration was made according to the radioimmunoassay method of Aitken and colleagues (973). RESULTS Blood sugar The mean changes in blood sugar concentrations in the four series are plotted in figure and are given in detail in table II. No significant changes in blood sugar concentration were observed in the four series during the period of anaesthesia before surgery. However, in patients undergoing body surface surgery (series ) the mean blood sugar concentration increased significantly after 5 min of surgery by 6.9 mg/00 ml, but no significant change was observed at 30 min. In the 0 patients having abdominal surgery (series 3) there were significant increases in

3 ALTHESIN AND CARBOHYDRATE AND FAT METABOLISM 86b mean blood sugar concentration after 5 min (average =.4 mg/00 ml) and after 30 min (average= 8.4 mg/00 ml). In patients undergoing minor surgery (series ) and in diabetic patients (series 4) no significant changes in blood sugar concentration were observed. lasma cortisol Figure shows the mean changes in the plasma cortisol concentrations in the four series and the findings are given in detail in table II. In patients in all four series the changes in plasma cortisol concentrations during anaesthesia alone were not statistically significant. However, during abdominal surgery (series 3) there was a highly significant increase after 5 min which was still present after 30 min (<0.00). No significant changes in plasma cortisol concentrations were observed in the other series during surgery. lasma insulin The mean changes in plasma insulin concentrations during the various series are plotted in figure and are given in detail in table II. The mean plasma insulin concentrations before induction were within the normal range (5-5 (JLU./ml). These concentrations did not vary appreciably during anaesthesia alone nor during minor and body surface surgery. In patients undergoing abdominal surgery (series 3) the mean plasma insulin concentration tended to decrease, but this decrease was not significant. No appreciable changes in the plasma insulin concentration were found in the diabetic patients during either anaesthesia or surgery. lasma free fatty acids Figure shows the mean changes in plasma free fatty acids in the various series and these are given in detail in table II. In the patients belonging to series, anaesthesia alone and surgery produced significant increases in plasma free fatty acid concentrations at 5 min (<0.0). In series, 3 and 4 there was no consistent pattern of change during anaesthesia and surgery, and the mean differences were not significant Time (min) Time (min) FIG..Changes in blood sugar, plasma cortisol, free fatty acids and plasma insulin during anaesthesia alone and surgery. Series = O; Series =#; Series 3 = A; Series 4=A; Al=; Op=operation.

4 TABLE II. Blood sugar, cortisol, insulin, free fatty acid (FFA) and growth hormone concentrations in the four series. Measurements taken before induction, and at 5 min and 30 min after administration of or after operation. Series Series Series 3 Series 4 Blood sugar (mg/00 ml) < < < lasma cortisol l>g/00 ml) < < =» lasma insulin (jxu./ml) lasma FFA (^-equiv/litre) < < ( lasma growth hormone (fiu./ml) Values for are statistically significant as compared with pre-induction.

5 ALTHESIN AND CARBOHYDRATE AND FAT METABOLISM 867 lasma growth hormone The mean changes in growth hormone concentration during various series are plotted in figure and are given in detail in table II. No significant changes were observed. S 0 o g 0 o o a 5 30 Time (min) FIG.. Changes in growth hormone during anaesthesia alone and surgery. Series = O; Series = #; Series 3 = AI Series 4 = Aj Al=j Op=operation. DISCUSSION The blood sugar concentration is regulated by liver function, plasma insulin, growth hormone, cortisol, adrenaline and glucagon. The major hormonal regulator of the metabolic processes is insulin, which interacts with growth hormone, glucocorticoids and catecholamines to promote nutrient storage and synthetic processes and to regulate energy supply to tissues. The bulk of evidence seems to indicate that the disturbances of carbohydrate metabolism during general anaesthesia and surgery are closely related to the activation of the hypothalamic-pituitary-adrenal axis. It has been shown by Clarke (970) that the increase in the blood sugar concentration occurring during operation is proportional to the stress of surgery. In his study the patients, anaesthetized using various anaesthetic techniques, but without surgery, showed no significant increase in blood sugar concentration. The present study did not demonstrate any significant influence of anaesthesia alone on the blood sugar concentration. This study also confirms the findings of previous workers that during body surface and abdominal surgery there were significant increases in blood sugar concentration (Griffiths, 953; Roberts and Cam, 964; Clarke, 970; Oyama and Takazawa, 97; Mehta, 97). Insulin stimulates the synthesis of glycogen in muscle and liver, of lipid in adipose tissues and of protein RNA and DNA in cells generally. In the present study plasma insulin concentrations during anaesthesia alone and during surgery did not change markedly, although the mean insulin concentration tended to decrease during abdominal surgery. Clarke Johnston and Sheridan (970) and Oyama and Takazawa (97) also found no significant change in plasma insulin concentration during anaesthesia and surgery. Human growth hormone is an anabolic hormone which influences the intermediary metabolism of protein, carbohydrate and fat. Large peaks of growth hormone in plasma often occur at the onset of deep sleep and in association with other neural stimuli such as the anticipation of unpleasant sensations and fear (Cart, 97). The initial high concentrations of growth hormone observed in some patients in this study may be a result of emotional reactions before operation; such as fear and apprehension. The present study failed to demonstrate any significant influence of anaesthesia alone and associated with surgery on the plasma growth hormone concentrations, although it was noted that, during surgery, growth hormone concentration increased but failed to reach statistical significance. This finding is in contrast to the effect of surgical stress during general anaesthesia which usually increases plasma growth hormone concentration markedly (Glick et al., 965; Ketterer, owell and Unger, 966; Ross et al., 966; Charters, Odell and Thompson 969; Oyama and Takazawa, 97). Thus anaesthesia would appear to depress the increase of plasma growth hormone concentration caused by surgical stress. The reason for this difference in the response of growth hormone to surgical stress under this anaesthetic agent is unknown. Cortisol acts as a glucogenic steroid by antagonizing some of the actions of insulin (Vandam and Moore, 960). In the absence of surgery we could detect no appreciable effect of anaesthesia on plasma cortisol concentrations. The absence of adrenocorticol stimulation by as judged by the absence of a significant increase in cortisol concentration resembles the effect which is also manifested by thiopentone and propanidid (Clarke, Johnston and Sheridan, 970; Oyama et al., 970). The association of surgical stress with increased adrenocortical activity is well known. Almost all previous studies show that the magnitude of surgery is a much greater stimulus than the anaesthetic agent alone. The present study

6 868 BRITISH JOURNAL OF ANAESTHESIA confirms this finding in patients belonging to series 3 who underwent abdominal surgery, but points to a less marked response during body surface and minor surgery. The hyperglycaemic response to surgery varies with the severity of surgery. Oyama and his associates (970) have shown that major surgery associated with most general anaesthetic techniques is accompanied by an increase in the concentrations of plasma glucose, cortisol and human growth hormone. The plasma insulin concentration is usually unaffected. Though the changes in blood sugar concentration could be explained on the basis of increased sympathetic activity related to stress, the suggestion that excessive quantities of adrenaline are released during surgery has not been confirmed. The present study failed to demonstrate a significant increase in plasma growth hormone during surgery, under anaesthesia. It is therefore possible that the cortisol concentration related to the degree of surgical stress makes a major contribution to the increase in blood sugar concentration. In this study plasma FFA concentrations were increased significantly during anaesthesia alone and during minor surgery. No consistent pattern was observed during body surface surgery and in patients undergoing abdominal surgery the mean FFA concentration increased gradually but did not differ significantly from the mean value before induction. Oyama and Takazawa (97) also found no appreciable change in plasma FFA concentration during halothane anaesthesia alone and during abdominal surgery, although the concentration tended to increase during operation. Our findings appear to differ from those of Clarke, Johnston and Sheridan (970), who observed a significant decrease in the mean FFA concentration during thiopentone-nitrous oxidetubocurarine anaesthesia alone for hr, and a significant increase after hr of abdominal surgery. The cause of the discrepancy between these reports is difficult to explain. Most studies of the effect of anaesthetic drugs and surgery on carbohydrate and fat metabolism in the past, have been carried out in normal healthy subjects. Therefore we have included data from diabetic patients in this study, as it is in these patients that the anaesthetist has to make a specific choice of agents which do not influence blood sugar concentration. Although the number of diabetic patients in this study is small, it seems that the hyperglycaemic response under anaesthesia does not differ essentially from that in non-diabetic subjects. ACKNOWLEDGEMENTS The authors are particularly indebted to the Biochemistry Department of the Burnley General Hospital for making the various biochemical measurements. Thanks are also due to the anaesthetists, surgeons, members of the nursing staff and theatre technicians for their cooperation throughout these studies. We are grateful to Dr J. A. Sutton and Mr K. Fidler of Glaxo Laboratories for their valuable suggestions, financial assistance and statistical analysis of the results of this study, and to Miss M. Jackson for secretarial work. REFERENCES Aitken, J. M., Gallagher, M. J. G., Hart, T. M., Newton, D. A. G., and Craig, A. (973). lasma growth hormone and serum phosphorus concentrations in relation to the menopause and to oestrogen therapy. J. Endocrinol., 59, 593. Allison, S.., Tomlin,. J., and Chamberlain, M. J. (969). Some effects of anaesthesia and surgery on carbohydrate and fat metabolism. Br. J. Anaesth., 4, 588. Can, K. J. (97). An ABC of Endocrinology, p. 9. Boston: Little, Brown. Charters, A. C., Odell, W. D., and Thompson, J. C. (969). Anterior pituitary function during surgical stress and convalescence: radioimmunoassay measurements of blood TSH, LH, FSH, and human growth hormone. J. Clin. Endocrinol. Metab., 9, 63. Clarke, R. S. J. (968). The influence of anaesthesia with thiopentone and propanidid on the blood sugar level. Br. J. Anaesth., 40, 46. (970). The hyperglycaemic response to different types of surgery and anaesthesia. Br. J. Anaesth., 4, 45. Johnston, H., and Sheridan, B. (970). The influence of anaesthesia and surgery on plasma cortisol, insulin and free fatty acids. Br. J. Anaesth., 4, 95. Duncombe, W. G. (964). The colorimetric microdetermination of non-esterified fatty acids in plasma. Clin. Chim. Acta., 9,. Dundee, J. W., and Todd, U. (958). Clinical significance of the effects of thiopentone and adjuvant drugs on blood sugar and glucose tolerance. Br. J. Anaesth., 30, 77. Glick, S. M., Roth, J., Yalow, R. S., and Berson, S. A. (965). The regulation of growth hormone secretion. Recent rog. Horm. Res.,, 4. Griffiths, J. A. (953). The effects of general anaesthesia and hexamethonium, on blood sugar in non-diabetic and diabetic surgical patients. Q. J. Med.,, 405. Ketterer, H., owell, D., and Unger, R. H. (966). Growth hormone response to surgical stress. Clin. Res., 4, 65. Mattingly, D. (96). A simple fluorimetric method of estimation of free -hydroxycorticoids in human plasma. J. Clin. athol., 5, 374. Mehta, S. (97). The influence of anaesthesia with thiopentone and diazepam on the blood sugar level during surgery. Br. J. Anaesth., 44, 75. Oyama, T., Kimura, K., Takazawa, T., Takiguchi, M., and Shibata, S. (970). Effects of propanidid on adrenocorticol function in man. Anesth. Analg. (Cleve.), 49, 39. Matsuki, A. (970). Effects of spinal anaesthesia and surgery on carbohydrate and fat metabolism in man. Br. J. Anaesth., 4, 73. Takazawa, T. (97). Effects of halothane anaesthesia and surgery on human growth hormone and insulin levels in plasma. Br. J. Anaesth., 43, 578. Roberts, R. B., and Cam, J. F. (964). Methoxyflurane: a clinical study of fifty selected cases. Br. J. Anaesth., 36, 494.

7 ALTHESIN AND CARBOHYDRATE AND FAT METABOLISM 869 Ross. H., Johnstone, I. D. A., Welborn, T. A., and Wright, A. D. (966). Effect of abdominal operation on glucose tolerance and serum levels of insulin, GH and hydrocortisone. Lancet,, 563. Vandam, L. D., and Moore, F. D. (960). Adrenocorticol mechanisms related to anesthesia. Anesthesiology,, 53. Wide, L., and orath, J. (966). Radioimmunoassay of proteins with the use of Sephadex-coupled antibodies. Biochim. Biophys. Acta. y 30, 57. EFFETS DE L'ANESTHESIE AR L'ALTHESIN ET DE LA CHIRURGIE SUR LE METABOLISME DES HYDRATES DE CARBONE ET SUR LE METABOLISME DES GRAISSES CHEZ L'HOMME RESUME Les effets de l'anesthesie par l'althesin, seule et en association avec une intervention chirurgicale, sur le metabolisme des hydrates de carbone et des graisses ont ete suivis sur 36 malades par la determination des concentrations de cortisol, d'hormone somatotrope humaine, d'insuline, d'acides non gras dans le plasma et de sucre dans le sang. Les differences entre les concentrations moyennes de sucre dans le sang et de cortisol dans le plasma avant l'induction et pendant l'anesthesie seule n'ont eu aucune signification positive du point de vue statistique. Les concentrations de sucre dans le sang ont legerement augmente, pendant les interventions chirurgicales mineures, et augmente d'une maniere importante pendant les interventions chirurgicales sur la surface du corps et pendant les interventions abdominales. Les concentrations de cortisol dans le plasma ont augmente legerement pendant les interventions mineures et pendant celles effectuees sur la surface du corps, mais elles ont augmente d'une maniere significative pendant les interventions abdominales. Les concentrations d'insuline et d'hormone somatotrope humaine dans le plasma n'ont pas notablement change pendant l'anesthe'sie et les interventions chirurgicales. Sous anesthesie par l'althesin, seule et pendant les interventions chirurgicales mineures on a observe a 5 minutes une augmentation importante des concentrations d'acides non gras dans le plasma. La reaction hyperglycemique chez les diabetiques n'a pas ete tres differente de celle constatee sur les sujets non diabetiques. On traite dans cette communication de la signification clinique des resultats. DIE AUSWIRKUNGEN EINER ALTHESIN- NARKOSE UND EINER OERATION AUF DIE KOHLEHYDRATE- UND DEN FETTMETABOLISMUS BEIM MENSCHEN ZUSAMMENFASSUNG Die Auswirkungen einer narkose allein sowie verbunden mit einer, auf die Kohlehydrate und den Fettmetabolismus wurden bei 36 atienten studiert, indem die lasmakonzentrationen von Kortisol, Wachstumshormonen, Insulin, freien Fettsauren und Blutzucker festgestellt wurden. Die Unterschiede zwischen den mittleren Blutzucker- und lasma-kortisolkonzentrationen vor und wahrend der Narkose waren allein nicht wesentlich, statistisch gesehen. Die Blutzuckerkonzentrationen stiegen bei kleineren en leicht, bei Korperoberflachen- und Unterleibsoperationen stark an. Die lasma-kortisolkonzentrationen stiegen bei kleineren und bei Korperobsrflachenoperationen leicht, bei Unterleibsoperationen aber stark an. Insulin- und Wachstumshormonkonzentrationen veranderten sich wahrend Narkose und kaum. Bei narkose allein und bei kleineren en wurde ein wesentlicher Anstieg in der Konzentration freier Fettsauren nach 5 Minuten beobachtet. Die hyperglykamische Reaktion bei Diabetikern unterschied sich nicht wesentlich von der bei Nicht-Diabetikern. Die klinische Bedeutung dieser Ergebnisse wird diskutiert. EFECTOS DE LA ANESTESIA CON ALTESIN Y LA CIRUGIA EN EL METABOLISMO DE CARBOHIDRATOS Y GRASAS EN EL HOMBRE SUMARIO Se estudiaron los efectos de la anestesia con altesin solamente y asociada con cirugia en el metabolismo de carbohidratos y grasas de 36 pacientes mediante la determination de las concentraciones en el plasma de cortisol, hormonas de crecimiento humano, insulina, acidos no grasos y aziicar en la sangre. Las diferencias entre las concentraciones medias del aziicar de la sangre y de cortisol en el plasma antes de la induccion y durante la anestesia por si sola no tenian importancia estadistica. Las concentraciones en el azucar de la sangre aumentaron ligeramente durante pequefias intervenciones quinirgicas en la superficie de cuerpo, pero aumentaron de manera importante durante intervenciones quirurgicas abdominales. Las concentraciones de insulina y hormonas de crecimiento humano en el plasma no cambiaron de manera apreciable durante la anestesia y la cirugia. Durante la anestesia con altesfn solamente y durante la intervencion quinirgica de menor importancia, se observo un importante aumento de concentraci6n de acidos no grasos en el plasma a los 5 min. La respuesta hiperglicemica en pacientes diabeticos no presento differencias importantes en relaci6n con personas no diabeticas. Se examina la importancia cllnica de los resultados.