THE INFLUENCE OF ANAESTHESIA AND SURGERY ON PLASMA CORTISOL, INSULIN AND FREE FATTY ACIDS

Transcription

1 Brit. J. Anaesth. (1970), 42, 295 THE INFLUENCE OF ANAESTHESIA AND SURGERY ON PLASMA CORTISOL, INSULIN AND FREE FATTY ACIDS BY R. S. J. CLARKE, HILARY JOHNSTON AND B. SHERIDAN SUMMARY The plasma cortisol level of patients anaesthetized for 1 hour with thiopentone and nitrous oxide was found to remain unchanged. During body surface surgery it rose slightly, and during intra-abdominal surgery it rose to more thap double the resting value. The blood sugar under the same circumstances changed in a qualitatively similar manner and the free fatty acids appeared to fall during anaesthesia without surgery, changed litde during body surface surgery, and rose during intra-abdominal surgery. Plasma insulin during both types of surgery showed no significant change. In a previous paper (Clarke, 1970) it was shown that during intra-abdominal surgery under thiopentone, nitrous oxide, tubocurarine anaesthesia, there was a large rise in blood sugar. The extent of the hyperglycaemic response varied with the stress of surgery and there was no significant rise under anaesthesia with thiopentone, nitrous oxide in the absence of surgery. This work is a study of other metabolic changes occurring during intra-abdominal and body surface surgery and during anaesthesia without surgery. The object was to see whether there was a constant relationship between severity of stress and metabolic changes. Since the study began, Plumpton, Besser and Cole (1969) have published findings showing the response of plasma cortisol levels to major and minor surgery. Allison, Tomlin and Chamberlain (1969) have also studied blood sugar, insulin and free fatty acids but they were mainly concerned with the response to a glucose load. There is probably a need for an evaluation of the metabolic changes during various types of surgery since, as was shown by Clarke (1970), anaesthesia maintained by the techniques commonly used in Great Britain has little influence on the change in blood sugar. METHOD The plan of the present investigation was essentially that used by Clarke (1970) and many of the results presented here were obtained in the same patients described in the earlier publication. The same patients were not necessarily studied in all analyses because of difficulty in carrying out estimations at a particular time or the volume of blood required. Blood sugar was estimated in all patients before induction of anaesthesia and at 15-minute intervals thereafter for 1 hour. These results are presented fully in the previous paper but some additional blood sugar measurements on patients undergoing intra-abdominal operations are included in figure 1 and table I. Blood samples were taken for all other estimations before induction of anaesthesia and at 30-minute intervals thereafter for 1 hour. Certain patients were studied under anaesthesia prior to surgery or, in some cases, while an examination under anaesthesia or cystoscopy was performed. The group of body surface operations consisted of procedures such as local mastectomy, inguinal herniorrhaphy and ligation and stripping of varicose veins. Intra-abdominal operations were restricted to those types of surgery in which blood was not required during the first hour of surgery. They comprised mainly cholecystectomy and gastro-enterostomy with or without vagotomy. In all patients having operations the skin incision took place between and 15 minutes after induction of anaesthesia and when the peritoneum was opened this was between 15 and 25 minutes after induction. R. S. J. CLARKE, B.SC, M.D., PH.D., F.F_AJLC.S.; HILARY JOHNSTON, F.LM.L-T.J B. SHERIDAN, F.I.MX.T.; Department of Anaesthetics, The Queen's University of Belfast, and the Department of Biochemistry, Royal Victoria Hospital, Belfast, Northern Ireland.

2 4O-r BLOOO SUGAR -ICM- -3OCM- 6O 3O 6O TIME IN MINUTES TIME IN MINUTES FIG. 1 Changes in conisol, blood sugar, insulin and free fatty acids during anaesthesia without surgery (triangles), body surface surgery (open circles) and intra-sbdominal surgery (closed circles). TABLE I Changes (mean and standard error) in conisol, insulin, free fatty acids and blood sugar in blood from patients during light anaesthesia without surgery, body surface surgery, and intra-abdominal surgery. No surgery Cortisol Gig/0 ml) Free fatty acids (jan/l) Blood sugar (mg/0 ml) Body surface surgery Cortisol Otg/lOO ml) Insulin OiU/ml) Free fatty acids (/im/l) Blood sugar (mg/0 ml) Intra-abdominal surgery Cortisol (Mg/0 ml) Insulin (/tu/ml) Free fatty acids (jua/l) Blood sugar (mg/0 ml) No. of patients 50 Aae (yr) Weight (kg) Initial 13 ± ±5 92 ± ± ± ± ±2.2 14± ± ± 89 ± min Change -2±1.2-60± + 3± ± ± ± ±1.2-5± ± ±2.2 at 60 min -2± ±69 + 4± ± ±113 + ± ± ± ±2.0

3 INFLUENCE OF ANAESTHESIA AND SURGERY ON PLASMA CORTISOL 297 Premedication consisted of atropine 0.6 mg and pethidine mg. Patients undergoing intraabdominal and body surface operations were given thiopentone 5 mg/kg, tubocurarine 30 mg and nitrous oxide-oxygen (6/2 l./min). Further doses of thiopentone 50 mg and tubocurarine 5 mg were given as required to deepen anaesthesia or improve relaxation (to a maximum total dose of thiopentone of 500 mg, and of tubocurarine of 40 mg in the first hour). During the period of anaesthesia without surgery the anaesthetic technique was similar to the above but no relaxant was given and frequent doses of thiopentone were required to maintain anaesthesia. As discussed by Clarke (1970), ir is unlikely that the differences between the two techniques are relevant to the metabolic and hormonal findings. During surgery patients received a slow intravenous infusion of Hartmann's Ringer-lactate solution (0-300 ml) during the period of investigation. All patients were studied between the hours of 9 a.m. and 1 p.m. and there was no systematic difference in the time of day during which different groups were investigated. Plasma cortisol, insulin and free fatty acids were estimated in patients having intra-abdominal surgery and patients having body surface surgery. Cortisol and free fatty acids were also estimated in patients having anaesthesia for 1 hour without surgery. Cortisol (11-OH corticosteroid) was estimated by a modification of the fluorimetric method described by Mattingly (1962). Plasma insulin was estimated by the immunoassay method of Hales and Randle (1963) as supplied by the Radiochemical Centre. The method is based on the competition of insulin in the sample to be assayed and of insulin iodinated with 125 I, for reaction with an antibody which is specific for insulin. The amount of radioactive insulin therefore varies inversely with the concentration of insulin in the assay sample. Normal fasting values are 15 /tu/ml, rising to 158 j after oral glucose in a glucose tolerance test. Free fatty acids were extracted from fresh plasma into heptane and estimated photometrically by Mosinger's modification (19) of Dole's method. Blood sugar was estimated by the standard auto-analyzer technique which measures total reducing substance and has an accuracy of ± 5 mg per cent on random estimations. When a series of samples from one patient is estimated successively the accuracy is increased to about ±2 mg per cent RESULTS Cortisol. The plasma cortisol findings during the three series are plotted in figure 1 and are given in detail in table I. During light anaesthesia for 1 hour without surgery there was no significant change in plasma cortisol. During body surface surgery under a similar type of light anaesthesia the plasma cortisol did rise significantly from a mean of 16 /ig/0 ml pre-operatively to 23 /*g/ 0 ml at 30 minutes ((=6.58; df=9; P<0.001) and to 30 jug/0 ml after 60 minutes ((=8.04; df=9; P<0.001). In the third series of operations involving opening of the peritoneal cavity, the plasma cortisol showed a significantly greater rise than in the body surface series at both 30 minutes ((=4.70; df=18; P<0.001) and at 60 minutes ((=6.60; df=18; P<0.001). The plasma cortisol rose from 14 /ig per 0 ml to 39 /zg per 0 ml after 1 hour. Insulin. The findings for plasma insulin during body surface and intra-abdominal surgery are shown in table I and there is clearly no significant change in the levels during 1 hour of surgery. In view of the absence of change in insulin level during surgery and the relative complexity of the method of analysis it was not measured in the patients anaesthetized without surgery. In interpreting the results it must be realized that the percentage fluctuations in plasma insulin under varying physiological stimuli are much greater than in the other parameters studied. Free fatty acids. The free fatty acid level in the plasma during 1 hour's anaesthesia without surgery fell slightly after 30 minutes but the change was only significant after 60 minutes ((=.2; n=9; P<0.005). Although the decrease was small, every patient showed a fall or no change in free fatty acid content. In the group having body surface operations there was no consistent pattern of change and the mean differences shown in table I are not significant. During intra-abdominal surgery there

4 298 BRITISH JOURNAL OF ANAESTHESIA was a variable pattern at 30 minutes and the small average increase was not significant. However, after 60 minutes every patient showed no change or a rise, the average being highly significant (( = 5.99; n=19; P<0.001). Blood sugar. Many of the results are included in an earlier paper (Clarke, 1970) and it need only be said that during anaesthesia without surgery for 1 hour there was no significant change in blood sugar and during body surface surgery a small but significant increase. In 50 patients having intraabdominal surgery there was again a highly significant rise after 30 minutes (average=21 mg/ 0 ml) and after 60 minutes (average=37 mg/ 0 ml). DISCUSSION It has been shown previously (Clarke, 1970) that there is a hyperglycaemic response to surgery, the extent of which varies with the severity of the surgery. The stimulus evoking this response appears to be any surgical trauma but particularly traction on abdominal viscera. The results of this work also suggested that, while anaesthetic adjuvants can diminish the response, no agent studied can abolish it. It therefore seems likely that the response is a reflex transmitted through the spinal cord, though with some influence from the higher centres. Findings on the motor side of the response are still incomplete, but the suggestion that adrenaline is liberated during major surgery has not been confirmed (Clarke, unpublished work). However, the plasma cortdsol has been found to rise during surgery and the changes with anaesthesia alone, body surface surgery and intra-abdominal surgery are broadly similar to those in blood sugar. The detailed studies of Virtue, Helmreich and Gainza (1957), of Hammond and associates (1958) and of others are fully reviewed by Vandam and Moore (1960). More recent work by Oyama and his colleagues (1968a, b) included also further analysis of the effects of premedication. It seems likely that the plasma cortisol falls with premedication and rises to about the normal resting level after induction with thiopentone, halothane or diethyl ether. There is a further progressive rise during major surgery, though a thiopentone induction is followed by a smaller rise than is a gaseous induction. Oyama and associates (1968a, b) also showed that there was a parallel rise in ACTH level and that presumably this was responsible for the cortisol increase. Apart from increased production, a rise in plasma cortisol could also result from decreased breakdown. A reduction in hepatic blood flow during anaesthesia has been shown by Shackman, Graber and Melrose (1953) and this organ appears to be the main site of conjugation of hydrocortisone (Tyler et al., 1954). Since a difference in hyperglycaemic response was observed between the surface and abdominal operation sites, the possibility remains of interference with hepatic blood flow during intra-abdominal surgery. However, this reasoning would not explain the difference in results between the series in which observations were made during anaesthesia alone and that in which observations were made during body surface surgery. Furthermore, the half-life of cortisol in the body is approximately 2 hours, so that this factor would be of little importance during the first hour of surgery. It seems more likely, therefore, that the production of cortisol is related to the degree of surgical stress. Plumpton, Besser and Cole (1969) have shown a similar rise in plasma cortisol during major surgery and a smaller rise during minor operations. Cortisol acts as a glucogenic steroid by antagonizing the action of insulin (Vandam and Moore, 1960) and since die extent of the cortisol rise varies with the type of surgery, it is possible that it at least contributes to the rise in blood sugar. The negative findings in relation to plasma insulin levels show that there has been no inhibition of insulin production during surgery. Ross and his colleagues (1966) found that the plasma insulin levels were raised 24 hours after abdominal surgery and that this in turn led to an increase in the level of plasma growth hormone, another insulin antagonist. It must be concluded that the development of these changes is gradual but this point is under investigation. Allison, Tomlin and Chamberlain (1959) recorded a significant decline in plasma insulin between the pre-induction level and that after surgery had begun. The restdts in the present series showed a slight downward trend, but even with patients the scatter was too great for any significant fall to be evident

5 INFLUENCE OF ANAESTHESIA AND SURGERY ON PLASMA CORTISOL 299 The plasma free fatty acid level declined significantly in the series of patients anaesthetized without surgery. This was unexpected in view of the absence of significant change in the blood sugar or cortisol. On the other hand, during intraabdominal surgery there was a highly significant rise in free fatty acids after 60 minutes, thus supporting the findings of Allison, Tomlin and Chamberlain (1969). A raised level of free fatty acids usually accompanies a rise in blood sugar and a glucose-triglyceride-fatty acid cycle has been suggested (Randle et al., 1963). Naftalin (1962) also found free fatty acid levels to be high in the postoperative period. ACKNOWLEDGEMENTS We would like to thank the surgeons and theatre stafi of the Professorial Surgical Unit, Royal Victoria Hospital, for their co-operation in the investigations. Thanks are also due to Professor J. W. Dundee of the Department of Anaesthetics and Mr. Desmond Neill of the Department of Biochemistry for help and advice at various stages of the work. REFERENCES Allison, S. P., Tomlin, P. J., and Chamberlain, M. J. (1969). Some effects of anaesthesia and surgery cm carbohydrate and fat embolism. Brit. J. Anaesth., 41, 588. Clarke, R. S. J. (1970). The hypcrglycaemic response to different types of surgery and anaesthesia. Brit. J. Anaesth., 42,. Hales, C. N., and Randle, P. J. (1963). Immunoassay of insulin with insulin-antibody precipitate. Biochem. J., 88, 137. Hammond, W. G., Vandam, L. D., Davis, J. M., Carter, R. D., Ball, M. R., and Moore, F. D. (1958). Studies in surgical endocrinology. IV: Anesthetic agents as stimuli to change in corticosteroids and metabolism. Ann. Surg., 148, 199. Martingly, D. (1962). A simple fluonmetric method for the estimation of free 11 hydroxycortkoid in human plasma. J. din. Path., 15, 374. Mosinger, F. (19). Photometric adaptation of Dole's micro-determination of free fatty acids. J. Lipid Res., 6, 157. Naftalin, L. (1962). Blood ketone and plasma NEFA levels in the immediate postoperative period. Clin. Mm. Acta, 7, 614. Oyama, T., Saito, T., Isomatsu, T., Samejima, N., Uemura, T., and Arimura, A. (1968a). Plasma levels of ACTH and cortisol in man during dkthyl ether anesthesia and surgery. Aneslhesiology, 29, 559. Shibata, S., Mfltusmoto, F., Takiguchi, M., and Kudo, T. (1968b). Effect of halothane anaesthesia and surgery on adrenocortical function in man. Canad. Anaesth. Soc. J., 15, 258. Plumpton, F. S., Besser, G. M., and Cole, P. V. (1969). Gorticosteroid treatment and surgery. I: An investigation of the indications for steroid cover. Anaesthesia, 24, 3. Randle, P. J., Garland, P. B., Hales, C N., and Newsholme, E. A. (1963). The glucose fatty acid cycle: its role in insulin sensitivity and the metabolic disturbance of diabetes mellitus. Lancet, 1, 785. Ross, H., Welborn, T. A., Johnston, I. D. A., and Wright, A. D. C1966). Effect of abdominal operation on glucose tolerance and serum levels of insulin, growth hormone and hydrocortisone. Lancet, 2, 563. Shackman, R., Graber, I. G., and Melrose, D. G. (1953). Liver blood flow and general anaesthesia. Clin. Sci., 12, 307. Tyler, F. H., Schmidt, C D., Eik-Nes, K., Brown, H., and Samuels, L. T. (1954). Role of the liver and the adrenal in producing elevated plasma 17- hydroiycorticosteroid levels in surgery. 7. din. Invest., 33, Vandam, L. D., and Moore, F. D. (1960). Adrenocortical mechanisms related to anesthesia. Anesthesiology, 21, 531. Virtue, R. W., Helmreich, M. L., and Gainza, E. (1957). The adrenal cortical response to surgery. I: The effect of anesthesia on plasma 17-hydroxycorticosteroid levels. Surgery, 41, 549. L'INFLUENCE DE L'ANESTHESIE ET DE LA CHIRURGIE SUR LE TAUX PLASMATIQUE DE CORTISOL, INSULINE ET ACIDES GRAS LIBRES SOMMAIRE On constate aucun changement du taux plasmauque de cortisol chez des patients, anesthesies durant une heure au thiopentone et protoxyde d'azote. II augments legerement au cours de la chirurgie superficielle et attint plus que le double de la valeur au repos durant la chirurgie intra-abdominale. Le sucre sanguin varia dans les mfimes circonstances de maniere qualitativement similaire. Les acddes gras libres semblerent tre recruits durant l'anesthesie sans chirurgie, ne varierent que peu au cours de la chirurgie superficielle et augmenterent durant l'intervention intra-abdominale. On n'observa pas de modifications significatives de l'insuline plasmatique durant l'intervention chirurgicale des deux types. DER EINFLUSS VON NARKOSE UND OPERA- TION AUF DIE PLASMAKONZENTRATIONEN VON CORTISOL, INSULIN UND FREIEN FETTSAUREN ZUSAMMENFASSUNG Die Plasmacortisolspiegel von Patienten blieben wahrend einer einstundigen Narkose mit Thiopenton und Lachgas unverfindert. Bei chirurgischen Eingriffen an der Korperoberflache stiegen die Werte leicht an, bei intra-abdominalen Operationen stiegen die Cortisolspiegel um mehr als das doppelte des ursprunglichen Wertes an. Unter den gleichen Umstanden veranderte sich der Blutzucker in qualitativ ahnucher Weise; die freien Fettsauren schienen unter der Narkose ohne Operation abzusinken, veranderten sich bei chirurgischen Eingriffen an der Korperoberflache nur gereingfugig und stiegen bei intraabdominalen Operationen an. Bei beiden Arten von Operation wurde keine wesentliche Veranderung der Insulinwerte im Plasma festgestellt.