EFFECTS OF HALOTHANE ANAESTHESIA AND SURGERY ON HUMAN GROWTH HORMONE AND INSULIN LEVELS IN PLASMA

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1 Brit. J. Anaesth. (),, EFFECTS OF HALOTHANE ANAESTHESIA AND SURGERY ON HUMAN GROWTH HORMONE AND INSULIN LEVELS IN PLASMA BY TSUTOMU OYAMA AND T. TAKAZAWA SUMMARY A study was undertaken to investigate the effects of halothane anaesthesia alone on carbohydrate and fat metabolism in twenty male surgical patients by determining plasma growth hormone (HGH), insulin, glucose and free fatty acids (FFA), and to compare these with the effects of anaesthesia plus surgery. The plasma HGH level during halothane anaesthesia alone for minutes was slightly increased, and rose significantly during operation and in the postoperative period. The peak level was achieved 0 minutes after the start of surgery. Plasma insulin levels did not change appreciably during anaesthesia alone or during surgery. Blood glucose levels increased slightly during anaesthesia alone, and rose significantly during operation and in the postoperative period. The plasma FFA level did not change during halothane anaesthesia alone, but rose slightly (but insignificantly) during operation and in the postoperative period. The clinical significance of the results is discussed. The present study was undertaken to investigate the effects of halothane anaesthesia alone on carbohydrate and fat metabolism in 0 patients by determining plasma growth hormone (HGH), insulin, blood glucose and free fatty acids (FFA), and to compare these with the effects when an operation is superimposed upon anaesthesia. Human growth hormone of the anterior pituitary gland is known to be related not only to growth but also to the metabolism of glucose, fat and protein (Knobil and Hotchkiss, ; Matsuzaki and Raben, ). Large rises in plasma HGH concentration during surgical stress have recently been reported (Schalch, ; Glick et al., ; Ross et al., ; Charters, Odell and Thompson, ; Ketterer, Powell and Unger, ; Oyama and Takazawa, 0; Oyama and Takiguchi, 0). Furthermore, Oyama and associates have recently demonstrated that various anaesthetic agents influence plasma levels of HGH in man (Oyama and Matsuki, 0; Oyama and Takazawa, 0; Oyama and Takiguchi, 0). Clarke, Johnston and Sheridan (0) showed that there was no significant change in plasma insulin levels during hour of surgery. Participation of HGH in the metabolic responses to acute stress has been suggested by Glick and associates (). MATERIAL AND METHOD Twenty male patients, ranging in age from to years, were the subjects of the study. All underwent elective operations, gastro-intestinal and orthopaedic surgery, and none had hepatic, renal, or endocrine disease, nor a history of steroid therapy. The average operating time was hours and 0 minutes, and the mean anaesthetic time was hours. The type of operation and the ages of the patients are shown in table I. They did not receive food or water for at least hours before induction of anaesthesia. Each patient was premedicated with pentobarbitone 0 mg orally J hours before and atropine 0. mg and pethidine mg intramuscularly hour before the induction of anaesthesia. Halothane anaesthesia was induced at 0 a.m. with an inspired concentration of - per cent, delivered from a Fluotec Mark II vaporizer, combined with nitrous oxide ( l./min) and oxygen ( l./min). After endotracheal intubation had been carried out following suxamethonium 0 mg, anaesthesia was maintained with halothane, nitrous oxide ( l./min) and oxygen ( l./min). Tubo- T. OYAMA, M.D.; T. TAKAZAWA, M.D.; Department of Anesthesia, Hirosaki University School of Medicine, Hirosaki, Aomori-Ken, Japan.

2 BRITISH JOURNAL OF ANAESTHESIA 0 TABLE I Patients (all male) and operations. Age (yr) 0 0 Weight (kg) Operations Cholecystectomy O steotomy of right leg Sigmoidectomy Spinal fusion Spinal fusion Skin transplantation Repair of skull Laminectomy Repair of skull Curettage of leg bone curarine - mg in divided doses was injected during intra-abdominal operations when needed. Ventilation was controlled or assisted intermittently throughout procedure. A moderate depth of anaesthesia was maintained according to clinical judgement, based on signs including blood pressure, pulse rate, and somatic reflex responses to the surgical stimulation. In addition, occasional observation, e.e.g. and gas - chromatographic analysis of arterial halothane concentrations by the method of Oyama and associates () were made. Arterial halothane levels were. +. mg/0 ml (± = standard error),. ±. mg/ 0 ml and. ±. mg/0 ml, minutes, 0 minutes and minutes after the induction of halothane anaesthesia respectively. Levels ranged from.±. to.±. mg/0 ml during operation, which indicates the moderate depth of halothane anaesthesia. Normal saline 0-00 ml was infused until minutes after the beginning of the operation, low molecular weight dextran in per cent glucose 00 ml being infused throughout the rest of the operation. Blood was transfused when blood loss exceeded 00 ml. Eight blood samples were obtained from each patient: () at 0 a.m. immediately before induction of anaesthesia (this sample served as a control value); () the next three after, 0, and minutes of halothane anaesthesia but before the start of the operation; () a further three, 0, and 0 minutes after the start of the operation; and () lastly after the conclusion of the anaesthesia when tie patient was fully awake in the recovery room. On each occasion ml of venous blood was collected in a heparinized syringe, rapidly transferred to a tube, and centrifuged within 0 minutes of collection. One ml of each plasma sample was kept at -0 C, and was thawed within one month, just prior to radioimmunoassay for growth hormone and insulin. One ml of plasma was kept at C for analysis of FFA (free fatty acids=nonesterified fatty acids (NEFA)), and 0. ml of blood was used to measure blood glucose. Determination of plasma HGH was made according to the method of Schalch and Parker (). The analysis of plasma insulin was made by the method of Morgan and Lazarow (). These double antibody methods were based on the principle of radioimmunoassay utilizing I. The recovery rates for HGH and insulin were and per cent respectively. The blood glucose level was determined by the method of Somogyi (), and plasma FFA was determined by the colorimetric method of Duncombe (). RESULTS Plasma growth hormone. The mean control plasma growth hormone (HGH) level in 0 male patients after receiving premedication, immediately before induction of anaesthesia was. /zg/ml, which was below the normal upper limit of jug/val. The mean presurgical concentration of HGH in plasma after 0 minutes and minutes of halothane anaesthesia rose to.,«g/ml and. //g/ml respectively. These values were not significantly elevated above the control level (fig. ; table II). Plasma levels significantly increased to.,ug/ml (P<0.0),. ^/g/ml (P<0.00), and. /<g/ml (P< 0.00) minutes, 0 minutes and hour respectively after the start of the operation. It decreased to ±. jug/ml in the recovery room when the patient awoke fully.

3 HALOTHANE ANAESTHESIA AND HUMAN GROWTH HORMONE TABLE II Plasma HGH levels during halothane anaesthesia and surgery (\Lglml). 0 Mean ±SE P Pre-induction During anaesthesia Time (min) During operation <0.0* <0.00* <0.00* Recovery room <0.0* Statistically significant compared with pre-induction. =Statistically not significant. TABLE III Plasma insulin levels during halothane anaesthesia and surgery (y-ujml). 0 Mean ±SE P Pre-induction lo.l.... During anaesthesia Time (min]) During operation Recovery Room

4 BRITISH JOURNAL OF ANAESTHESIA c 0 Anes. 0 0 Pre- Anes. ind. Op TIME (min.) FIG. R.R. Plasma levels of HGH and insulin during halothane anaesthesia and surgery E o 0 O o O 0 0 "00 0 a SE. Pre- Ane. Op. R.R. ind. ' 0' ' ' 0' 0' Time (min.) FIG. Plasma levels of glucose and FFA during halothane anaesthesia and surgery. Plasma insulin. The mean pre-anaesthetic control insulin level in plasma in 0 patients was. /tu/ml which was within the normal range (- ^U/ml). This level did not vary appreciably during halothane anaesthesia alone, during operation or in the postoperative period (table III; fig. ). Blood glucose. The mean control pre-anaesthetic blood glucose level in 0 patients was mg/0 ml. It rose to mg/0 ml during halothane anaesthesia alone for minutes (table IV); this change was not significant. It increased significantly to mg/0 ml (P<0.00) and mg/0 ml (P<0.00) 0 minutes and hour respectively after the start of operation. It rose further to mg/0 ml (P<0.00) in the postoperative period (fig. ). Plasma free fatty acids (FFA). The mean control pre-anaesthetic plasma FFA level in 0 patients was 0 ft equiv/., and the level did not appreciably change during anaesthesia. It gradually increased to fi equiv/., hour after the start of the operation. It increased further to (i equiv/. in the recovery room. However, these values were not significantly different from the control level (table V). Arterial blood gases. Arterial ph varied from (mean± standard error) under control conditions to. ± 0.0 during anaesthesia and operation. Arterial Pco before induction was +. mm Hg (mean±se) and varied from 0.+. to. ±.0 mm Hg during anaesthesia and operation. It was 0. + mm Hg in the recovery room. Arterial Po was.+. mm Hg (+ SE) before anaesthesia. During the procedure it changed from. ±0. to. + mm Hg, and base excess varied from -0. to +.. These data indicate that there was no appreciable hypoxia, carbon dioxide retention or metabolic acidosis during the study period. DISCUSSION The present study demonstrated that the plasma growth hormone levels in patients who had been

5 HALOTHANE ANAESTHESIA AND HUMAN GROWTH HORMONE Mean ±SE P TABLE IV Plasma glucose levels during halothane anaesthesia and surgery (mg/loo ml). Pre-induction During anaesthesia Time (min) During operation <0.00* * Statistically significant compared with pre-induction. 0 - < 0.00* Recovery room <0.00* Mean ±SE P Pre-induction TABLE V Plasma FFA levels during halothane anaesthesia and surgery (^ equiv/l.) During anaesthesia Time (min) During operation Recoverv room

6 BRITISH JOURNAL OF ANAESTHESIA premedicated with pentobarbitone, pethidine and atropine were within normal limits (less than ^ug/ml). Halothane anaesthesia alone for minutes insignificantly elevated the plasma HGH level. It reached a peak 0 minutes after the start of the operation. The plasma HGH level fell in the recovery room, although it was still significantly higher than the control value. In contrast with other anaesthetic agents, such as methoxyflurane, diethyl ether and neuroleptanaesthesia consisting of droperidol and pethidine (Oyama and Takazawa, ; Oyama and Takiguchi, 0), halothane anaesthesia failed to increase the plasma HGH level significantly. Our present study indicates that the degree of elevation of plasma HGH during anaesthesia alone is different with various anaesthetic agents, and it appears not to be qualitative, but to be a quantitative difference. Speculation concerning the reasons for this phenomenon is beyond the scope of the present study. Schalch (), Charters, Odell and Thompson () and Ketterer, Powell and Unger () observed a transient acute peak of HGH in plasma hour after the start of operation, which fell to control level from to several hours later. However, they failed to evaluate the effects of anaesthesia alone. The growth hormone of the anterior pituitary is an anabolic hormone which increases uptake and synthesis of amino acids. It has also diabetogenic and anti-insulin effects, in that it reduces peripheral utilization and uptake of glucose, decreases glucose tolerance, and increases retention of glycogen. It enhances mobilization of fatty acids from adipose tissue and increases FFA in blood (Knobil and Hotchkiss, ; Matsuzaki and Raben, ). In accordance with our other previous studies (Oyama and Matsuki, 0; Oyama and Takazawa, 0; Oyama and Takiguchi, 0), plasma insulin levels during halothane anaesthesia alone, and during surgery, did not change markedly. Although they did not measure plasma insulin levels during anaesthesia consisting of thiopentone, nitrous oxide-oxygen and tubocurarine, Clarke, Johnston and Sheridan (0) found no significant change in it during surgery. Blood glucose levels rose insignificantly during halothane anaesthesia alone but were elevated significantly during operation and in the postoperative period. As in our previous studies with other forms of anaesthesia (Oyama and Matsuki, 0; Oyama and Takazawa, 0; Oyama and Takiguchi, 0), blood FFA levels did not change appreciably during halothane anaesthesia alone, but tended to rise during operation and to reach peak levels in the recovery phase. Blood FFA levels in either the patients undergoing intraabdominal procedures or in the patients undergoing orthopaedic procedures, during anaesthesia alone or surgery, did not differ significantly from each control pre-induction value. Our present finding appears to differ from those of Clarke, Johnston and Sheridan (0) and of Cooperman (0). The former authors observed slight but significant decreases in the mean FFA level in plasma during thiopentone-nitrous oxide-tubocurarine anaesthesia alone for hour, but a significant increase after hour of abdominal surgery. Cooperman (0) found significant elevation of plasma FFA levels during nitrous oxide-halothane anaesthesia. The cause of the discrepancy between these reports is difficult to explain. It is well known that surgical stress increases blood glucose by increasing glycolysis and gluconeogenesis. Furthermore, these phenomena have been attributed to sympatho-adrenal stimulation (Henneman and Vandam, ). However, Greene () doubts the role of the sympathetic nervous system in the development of hyperglycaemia in association with inhalation anaesthetics, particularly halothane, and has pointed out that halothane depresses sympathetic nervous activity. Allison, Tomlin and Chamberlain () observed that halothane was unable to prevent the rise in blood sugar and FFA, or the suppression of insulin response to glucose associated with surgery. Growth hormone participates in the physiological regulation of carbohydrate metabolism. The interplay and proper balance of insulin and growth hormone seem to be very important for the normal regulation of fat and carbohydrate metabolism. In patients suffering from diabetes mellitus, growth hormone exerts a diabetogenic effect. An anaesthetic agent, such as halothane, which does not increase plasma growth hormone or blood glucose, nor decreases plasma insulin, may be preferable in diabetic patients.

7 HALOTHANE ANAESTHESIA AND HUMAN GROWTH HORMONE REFERENCES Allison, S. P., Tomlin, P. J., and Chamberlain, M. J. (). Some effects of anaesthesia and surgery on carbohydrate and fat metabolism. Brit. J. Anaesth.,,. Charters, A. C, Odell, W. D., and Thompson, J. C. (). Anterior pituitary function during surgical stress and convalesence: radioimmunoassay measurements of blood TSH, LH, FSH, and growth hormone. J. clin. Endocr.,,. Clarke, R. S. J., Johnston, H., and Sheridan, B. (0). The influence of anaesthesia and surgery on plasma cortisol, insulin and free fatty acids. Brit. J. Anaesth.,,. Cooperman, L. H. (0). Plasma free fatty acid levels during general anaesthesia and operation in man. Brit. J. Anaesth.,,. Duncombe, W. G. (). The colorimetric microdetermination of long-chain fatty acids. Biochem. J.,,. Glick, S. M., Roth, J., Yalow, R. S., and Berson, S. A. (). The regulation of growth hormone secretion. Recent Progr. Hormone Res.,,. Greene, N. M. (). Inhalation Anesthetics and Carbohydrate Metabolism, p.. Baltimore: Williams and Wilkins. Henneman, D. H., and Vandam, L. D. (). The metabolic consequences of epinephrine and insulin administered during ether anesthesia in man. Anesthesiology,,. Ketterer, H., Powell, D., and Unger, R. H. (). Growth hormone response to surgical stress. Clin. Res.,,. Knobil, E., and Hotchkiss, J. (). Growth hormone. Ann. Rev. Physiol,,. Matsuzaki, F., and Raben, M. S. (). Growth hormone, Ann. Rev. Pharmacol.,,. Morgan, C. R., and Lazarow, A. (). Immunoassay of insulin: two antibody system. Diabetes,,. Oyama, T., and Matsuki, A. (0). Effects of spinal anaesthesia and surgery on carbohydrate and fat metabolism in man. Brit. J. Anaesth.,,. Matsumoto, F., Sato, K., and Kamada, M. (). Measurement of anesthetic gas concentration using gas chramatography, Jap. J. Anesth.,,. Takazawa, T. (0). Effect of methoxyflurane anaesthesia and surgery on human growth hormone and insulin levels in plasma. Canad. Anaesth. Soc. J.,,. (). Effects of diethyl ether anaesthesia and surgery on carbohydrate and fat metabolism in man. Canad. Anaesth. Soc. J.,,. Takiguchi, M. (0). Effects of neuroleptanaesthesia on plasma levels of growth hormone and insulin. Brit. J. Anaesth.,,. Ross, H., Johnstone, I. D. A., Welbon, T. A., and Wright, A. D. (). Effect of abdominal operation on glucose tolerance and serum levels of insulin, GH, and hydrocortisone. Lancet,,. Schalch, D. S. (). The influence of physical stress and excercise on GH and insulin secretion in man. J. Lab. clin. Med.,. Parker, M. L. (). A sensitive double antibody immunoassay for human growth hormone in plasma. Nature, 0,. Somogyi, M. (). Notes on sugar determination. J. biol. Chem.,,. EFFETS DE L'ANESTHESIE A L'HALOTHANE ET LA CHIRURGIE SUR LES TAUX PLASMATIQUES DE L'HORMONE DE CROISSANCE HUMAINE ET DE L'INSULINE SOMMAIRE Une etude a ete' faite pour determiner les effets de Panesthesie a l'halothane seule sur le metabolisme des hydrates de carbone et des lipides chez vingt patients chirurgicaux masculins, en determinant Phormone de croissance (HGH), l'insuline, la glucose et les acides gras libres dans le plasma, et en comparant ceux-ci avec les effets combines de Panesthesie et chirurgie. Le taux plasmatique du HGH durant l'anesthesie a l'halothane seule pendant minutes augmenta legerement, et s'eleva significativement durant l'operation et au cours de la periode postoperatoire. Le maximum fut observe 0 minutes apres le debut de Pope'ration. Les taux plasmatiques d'insuline ne changerent pas de maniere appreciable durant l'anesthesie seule ni durant la chirurgie. La glyce'mie augmenta legerement durant Panesthesie seule, et significativement durant l'operation et la periode postoperatoire. Les acides gras libres dans le plasma ne changerent pas durant Panesthesie a l'halothane seule mais augmenterent legerement, toutefois pas significativement, au cours de l'operation et de la periode postoperatoire. L'importance clinique de ces observations est discutee. WIRKUNGEN VON HALOTHANNARKOSE UND CHIRURGISCHEN EINGRIFFEN AUF DEN PLASMASPIEGEL VON WACHSTUMSHORMON UND INSULIN ZUSAMMENFASSUNG In dieser Studie wurde die Wirkung einer Halothannarkose allein und im Zusammenhang mit chirurgischen Eingriffen auf den Kohlenhydrat- und Fettstoffwechsel bei 0 mannlichen chirurgischen Patienten untersucht. Zur Bestimmung gelangten Wachstumshormon (HGH), Insulin, Glucose und freie Fettsauren (FFA) im Plasma. Der Plasmaspiegel von HGH war wahrend einer minutigen Halothannarkose allein leicht erhoht, um wahrend einer Operation und in der postoperativen Periode signifikant anzusteigen. Der hochste Werte wurde 0 Minuten nach Beginn der Operation erreicht. Das Plasmainsulin anderte sich wahrend der Narkose mit und ohne Operation nicht wesentlich. Die Blutglucose stieg wahrend der Narkose allein leicht, wahrend einer Operation und in der postoperativen Periode signifikant an. Die freien Fettsauren im Plasma a'nderten sich, wahrend der Halothannarkose allein nicht, ein geringer, (jedoch nicht signifikanter) Anstieg zeigte sich wahrend einer Operation und in der postoperativen Periode. Die klinische Bedeutung dieser Ergebnisse wird diskutiert. EFECTO DE LA ANESTESIA POR HALOTANO Y OPERACIONES QUIRURGICAS SOBRE LA HORMONA DEL CRECIMIENTO HUMANA Y LOS NIVELES DE INSULINA EN EL PLASMA RESUMEN Fue llevado a cabo un estudio para investigar los efectos de la anestesia por halotano sola sobre el metabolismo de carbohidratos y lipoides en veinte pacientes quirurgicos varones mediante determinacin de la hormona del crecimiento en plasma (HGH),

8 0 BRITISH JOURNAL OF ANAESTHESIA insulina, glucosa y acidos grasos libres (FFA) y para comparer estos con los efectos de la anestesia mas cirugia. El nivel plasmatico de HGH durante le anestesia por halotano sola durante minutos estaba ligeramente aumentado, y aumento significativamente durante la operation y en el periodo posoperatorio. El nivel pico fue alcanzado 0 minutos despues de comenzar la operation quinirgica. Los niveles plasmaticos de insulina no cambiaron de forma perceptible durante la anestesia sola o durante la operation. Los niveles de glucosa en sangre aumentaron ligeramente durante la anestesia sola y ascendieron significativamente durante la operation y en el periodo posoperatorio. El nivel plasmatico de FFA no cambio durante la anestesia por halotano sola, pero ascendio ligeramente (pero de forma no significative) durante la operation y en el periodo posoperatorio. Se discute la signification clinica de los resultados. CORRESPONDENCE The following reply to Dr Jewell's letter (p. ) has been received: Sir, We agree with many of the points raised by Dr Jewell, indeed we could hardly do less as we raised them ourselves in the article. The work which we undertook had two main purposes. Firstly, to see whether nitrous oxide/halothane anaesthesia was suitable for animal work rather than the more commonly used pentobarbitone or chloralose anaesthesia, especially in the investigation of drugs which may have a use in anaesthesia. We found that dogs so anaesthetized were satisfactory for this purpose. Secondly, to ascertain the effect of beta-blockade on anaesthetized dogs. For this purpose we chose drugs said to be free from direct myocardial depression, a property not shared by the earlier drug propranolol. Because our groups of dogs turned out not to be comparable, we eschewed any attempt to compare the two drugs. The dosage chosen was high compared with the recommended doses for humans, because we wished the beta-blockade to be virtually complete and we had neither the time nor the resources to pursue the much more lengthy process of establishing a dose/response relationship. We cannot see why an overdose of a cardioselective beta-blocker should cause of itself negative inotropism and, if we understand him aright, Dr Jewell is now saying that, in low dosage, beta-blockade without myocardial depression occurs but, in high dosage, depression does appear. We would certainly be prepared to accept this view and wonder what his opinion would be of the high dosage of practolol used by some workers (Johnstone, ; Jenkins, 0). However, we believe the main cause for the negative inotropic effect we observed was probably due to reversal of the positive beta-stimulation accompanying halothane anaesthesia, thus allowing the pure depression of the halothane to appear. The point about atropine is certainly valid but none of our dogs showed the extreme bradycardia one would associate with vagal overactivity. It is of particular interest that virtually all the dogs reached approximately the same level of haemodynamic function after beta-blockade regardless of their initial levels. Enhanced vagal activity would have caused those not initially beta-stimulated to have suffered a larger fall in function than occurred. Dr Jewell will now be aware that we have also published work (Stephen, Davie and Scott, ) on the use of practolol, oxprenolol and alprenolol in humans undergoing nitrous oxide/halothane anaesthesia following atropine premedication. The results of these studies showed that there was a fall in cardiac output and a rise in central venous pressure following these drugs. The different results obtained by Mathias and Payne (0) may be due to the higher dosage used by us. If so, it would again appear that with such dosage these drugs may have negative inotropic effects of their own. We are well aware that the manufacturers of the drug claim that only practolol is truly cardio-selective, but this view has been challenged especially in regard to the risk of bronchospasm (Bernecker and Roetscher, 0). A. J. STRONG M. F. MACNICOL I. T. DAVIE D. B. SCOTT Edinburgh REFERENCES Bernecker, C, and Roetscher, I. (0). The beta blocking effects of practolol in asthmatics. Lancet,,. Jenkins, A. V. (0). Adrenergic beta-blockade with practolol during bronchoscopy. Brit. J. Anaesth.,,. Johnstone, M. (). ICI 0, during halothane anaesthesia in surgical patients. Brit. J. Anaesth.,,. Mathias, J. A., and Payne, J. P. (0). Practolol in the management of cardiac dysrhythmias in patients anaesthetized with halothane. Brit. J. Pharmacol., 0,, P. Stephen, G. W., Davie, I. T., and Scott, D. B. (). Haemodynamic effects of beta-receptor blocking drugs during nitrous oxide/halothane anaesthesia. Brit. J. Anaesth.,, 0.