- Email: [email protected]
THE INFLUENCE OF ANAESTHESIA WITH THIOPENTONE AND DIAZEPAM ON THE BLOOD SUGAR LEVEL DURING SURGERY
Brit. J. Anaesth. (1972), 44, 75
THE INFLUENCE OF ANAESTHESIA WITH THIOPENTONE AND DIAZEPAM ON THE BLOOD SUGAR LEVEL DURING SURGERY S. MEHTA SUMMARY
It has been known since 1956 from the findings of Dundee (1956) that thiopentone produces no appreciable change in the blood sugar level in man. But the rise in blood sugar occurring during surgery differed significantly from that produced by thiopentone alone, and it was suggested that this may have been secondary to the respiratory depression produced by the morphine-thiopentone combination. Initial studies by Clarke and Dundee (1966) showed that anaesthesia with propanidid plus nitrous oxide also caused a rise in blood sugar. Clarke (1968) reported that, during body surface surgery, anaesthesia with thiopentone, nitrous oxide-oxygen was accompanied by a small rise in blood sugar whereas when propanidid was substituted for thiopentone there was a much larger rise. Clarke (1970) has published results showing 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-oxygen in the absence of surgery. Clarke again in 1968 investigated the effect of thiopentone and propanidid on glucose metabolism by carrying out the intravenous glucose tolerance tests during body surface surgery, and found that there is little difference between the results with two agents. As each new anaesthetic agent has become available it has been investigated with respect to its effect on blood sugar. Since no work in connection with the effect of diazepam on blood sugar has been reported, it seemed desirable to undertake such a study and to compare its effect on the blood sugar with that of thiopentone.
METHOD
Investigations were carried out in 70 adult patients of either sex: 66 of these patients had no disease other than the pathology necessitating the operation; 4 patients were suffering from diabetes but the disease was controlled by restriction of diet alone. All patients underwent either body surface operation which consisted of Trendelenburg operation, multiple ligation of varicose veins, herniorrhaphy, or dental extractions. The average operating time was 35 minutes and the mean anaesthetic time was 45 minutes. Four series of experiments were undertaken. Series 1. Twenty patients received thiopentone 4 mg/kg for induction. Series 2. In 40 patients diazepam was used for induction; 30 mg of undiluted diazepam was injected slowly at the rate of 1 ml every 10 sec until it was assumed that the patient was asleep. Failure to respond to auditory stimuli, the absence of the eyelash reflex or the presence of snoring was taken as an indication that the patient was asleep. Series 3. In 6 patients intravenous glucose tolerance tests were performed. A sample for blood sugar estimation was taken immediately before induction with thiopentone or diazepam. A 50 per cent solution of dextrose was injected rapidly in a dose of 0.33 g/kg and blood samples were taken at 10-minute intervals thereafter for a total of 60 minutes. Series 4. The effect of diazepam on blood sugar was studied in 4 diabetic patients whose disease was controlled by restriction of diet alone. S. MEHTA, M.B.,B.S., F.F.A.R.C.S.(ENG.), Burnley Group of
Hospitals, Burnley, England.
Downloaded from http://bja.oxfordjournals.org/ at New York University on April 11, 2015
Although during body surface surgery anaesthesia with thiopentone and diazepam was accompanied by a small rise in blood sugar, the pattern of hyperglycaemic response was different with the two agents. With thiopentone, the rise in blood sugar was sustained throughout the 60-minute period of observation. When diazepam was substituted for thiopentone, although there was a similar rise at 15 minutes, the levels of blood sugar at 30, 45 and 60 minutes were not significantly elevated. The hyperglycaemic response in diabetic patients undergoing surgery during diazepam anaesthesia did not differ significantly from that in the non-diabetic group of patients.
BRITISH JOURNAL OF ANAESTHESIA
76
taken to see that peripheral circulation was good. Observations were made immediately before induction and at 30- and 60-minute intervals thereafter. RESULTS
Series 1 and 2. The changes in blood sugar concentration during body surface and dental surgery are shown in table I. There was a small rise in blood sugar during both thiopentone and diazepam anaesthesia. Widi diiopentone die average difference between die means and the initial mean is significant (P<0.05) at each 15-minute interval but die differences between die means after die beginning of anaesdiesia are negligible. In the case of diazepam, the difference between die mean blood sugar concentration at 15 minutes and the initial value is highly significant (P<0.002) but differences between the means at the odier sampling times and die initial mean are not significant. Again no significant difference between the means at the various sampling times after the beginning of anaesthesia is seen. The operation had started by die time die second sample was taken, so diat it was not possible to distinguish between the effect of anaesdiesia and surgery on the blood sugar. Series 3. To investigate whedier die anaesthetics differed in their effect on glucose metabolism, intravenous glucose tolerance tests were carried out during body surface surgery in 6 patients belonging
TABLE I. Details of patients with average initial blood sugar levels and changes at various time intervals in patients undergoing body surface surgery or dental extraction during anaesthesia induced with thiopentone and diazepam. Series Thiopentone
No. of patients
Age (yr)
(kg)
20
42
60
Wt
StTtistirii parameter
Blood sugar (mg/100 ml) at (min) Initial
15
30
83.8 2.03
83.5 2.08
83.8 2.17
85.0 2.33
6.45
6.10
6.35
7.55
8.35
8.47
8.69
9.11
2.44 <0.05 86.6 1.44
2.27 <0.05 83.4 1.52
2.30 <0.05 83.2 1.58
2.62 <0.05 82.2 1.63
6.65
3.42
3.25
2.18
—
8.35
8.62
8.86
9.04
— —
3.56
1.78 n.s.
1.64 n.s.
1.08 n.s.
Mean 77.4 SE 1.68 Difference between means and initial mean —
45
60
SD
Diazepam
40
45
62
(combined) — t value (38 d.f.) — Probability — Mean 80 SE 1.18 Difference between means and initial mean — SD
(combined) t value (78 d.f.) Probability
Downloaded from http://bja.oxfordjournals.org/ at New York University on April 11, 2015
In each series there were approximately equal numbers of patients of each sex and the age and weight ranges were comparable. Each patient was premedicated with pethidine 100 mg and atropine 0.6 mg intramuscularly 1 hour before induction of anaesthesia. All patients were intubated and anaesthesia was maintained with nitrous oxide (7 l./min), oxygen (3 l./min), muscle relaxation being obtained by injection of alcuronium. Ventilation was controlled throughout the procedure with either a B'easeManley or East-Radcliffe ventilator. Venous blood samples were taken immediately before induction in the anaesthetic room and at 15minute intervals thereafter from a forearm vein via a plastic cannula. Five blood samples were taken from each patient. The operation had started by the time the second blood sample was taken and die fifth sample was obtained after the conclusion of anaesthesia. Blood sugar was estimated by the standard auto-analyzer technique which measures total reducing substances in blood. The maximum error in individual readings was + 5 mg/100 ml. Since respiratory depression widi consequent carbon dioxide retention is known to cause hyperglycaemia, capillary blood was analyzed for Pco2, pH and base excess in 10 patients in series 1, and 15 patients in series 2 (Andersen, Jorgensen and Astrup, 1960). Blood was obtained from the tip of the thumb and drawn rapidly into the capillary tubes. Care was
INFLUENCE OF ANAESTHESIA ON BLOOD SUGAR LEVEL
77
TABLE II. Average blood sugar values in patients who had an intravenous glucose tolerance test during thiopentone or diazepam anaesthesia with alcuronium and IPPV. Blood sugar (mg/100 ml) at (min) YV I
Group Thiopentone
patients (yr) (kg) 2 46 65
Statistical parameter Mean SD
4
Diazepam
44
62
Mean SD
Significance of increases, both groups compared Difference between means SE of differences t Probability
Initial 78.5 4.95 84.25 7.58
5.75 6.12 0.938
30
20
10
50
40
60
185.5 171.0 157.0 146.6 133.5 6.36 5.65 4.24 6.36 4.27 183.8 170.8 158.5 145.0 134.8 8.69 10.80 13.67 8.53 10.43
208.5 4.95 203.8 4.78
4.70 4.18 1.124
1.70
0.2
1.0
1.5
1.3
These differences are all non-sigilificant
No. of patients
Age (yr)
Wt (kg)
52
65
Blood sugar (mg/100 ml) at (min) Statistical parameter
Initial
15
30
45
60
Mean
83.75 5.05 2.52
88.35 3.86 1.93
87.50
88.50 4.43 2.21
85.50 5.26 2.63
SD SE
Significance of increases above diazepam series 2
3.0
1.50
n.s.
to this series (table II). There was little difference between the results with two agents and these differences are statistically non-significant. Series 4. Table III shows the hyperglycaemic response in 4 diabetic patients undergoing body surface surgery following diazepam induction of anaesthesia. The mean rises in blood sugar level at various time intervals did not differ significantly from those obtained in the non-diabetic group of patients who received diazepam for induction of anaesthesia (series 2). The results of acid-base measurements under thiopentone and diazepam anaesthesia with alcuronium and IPPV are shown in table IV. There are no essential differences between the results obtained using either thiopentone or diazepam as inducing agents.
DISCUSSION
Although it is evident from the present study that a small rise in blood sugar occurs under thiopentone and diazepam anaesthesia with nitrous oxide and alcuronium during body surface surgery, the pattern of this hyperglycaemic response is different with the two agents. With thiopentone there was a small but significant rise in blood sugar which was sustained throughout the 60-minute period of observation. When diazepam was used for induction there was a similar rise, which was highly significant at 15 minutes. This was shortlived and at 30, 45 and 60 minutes the blood sugar changes did not reach the level of significance. It is apparent from the study that neither thiopentone nor diazepam was able to prevent the rise in blood sugar initially during the first 15-minute period of surgery. However, this increase in blood sugar was within the range of TABLE IV. Changes in pH Pco2 and base excess during physiological variation. These results also suggest that anaesthesia with thiopentone and diazepam with alcuronium the rise in blood sugar under thiopentone and and IPPV. diazepam anaesthesia is not related to the duration Pco2 Time Base excess PH (min) (mmHg) (m.equiv/1.) of surgery. Both these anaesthetics, however, have similar effect on glucose metabolism. Thiopentone 0 7.41 37.8 (n=10) Diazepam (n=15)
30 60 0 30 60
7.50 7.39 7.40 7.50 7.39
27.8 39.8 39.4 29.0 41.4
-0.3 -0.35 -0.25 -0.02 + 0.05 -0.01
Most studies of the effects of anaesthetic drugs on blood sugar, in the past, have been carried out in normal healthy subjects. It was, therefore, felt desirable to include a few diabetic patients in this study,
Downloaded from http://bja.oxfordjournals.org/ at New York University on April 11, 2015
TABLE III. Changes in blood sugar levels in blood from diabetic patients undergoing body surface surgery following diazepam induction of anaesthesia, with alcuronium and IPPV.
78
each of these factors is responsible for producing the hyperglycaemic response during anaesthesia and surgery. The hyperglycaemic response as a result of surgical stress may produce worsening of the diabetic state in a mild or latent diabetic patient but whether this rise in blood sugar in a healthy person is harmful and should be prevented remains an open question. ACKNOWLEDGEMENTS
I am particularly indebted to the Biochemistry Department of the Burnley General Hospital for making the blood sugar and Astrup measurements. Thanks are also due to the surgeons and the members of the nursing staff for their co-operation throughout these studies. I am grateful to Dr C. G. Burgess, Clinical Research Physician to Roche Products, and Dr Corbett for valuable suggestions and helping with the statistical analysis of the results of this study. REFERENCES
Allison, S. P., Tomlin, P. J., and Chamberlain, M. J. (1969). Some effects of anaesthesia and surgery on carbohydrate and fat metabolism. Brit. J. Anaeslh., 41, 588. Andersen, S., Jorgensen, K., and Astrup, P. (1960). A micro-method for determination of pH, carbon dioxide tension, base excess and standard bicarbonate in capillary blood. Scand. J. Clin. Lab. Invest., 12, 172. Bonstein, J., Krahl, M. E., Marshall, L. B., Gould, M. K., and Armstrong, J. McD. (1968). Pituitary peptides with direct action on the metabolism of carbohydrates and fatty acids. Biochim. biophys. Acta (Amst.), 156, 36. Clarke, R. S. J. (1968). The influence of anaesthesia with thiopentone and propanidid on the blood sugar level. Brit. J. Anaesth., 40, 46. (1970). The hyperglycaemic response to different types of surgery and anaesthesia. Brit. J. Anaesth., 42, 45. Dundee, J. W. (1966). Survey of experimental and clinical pharmacology of propanidid. Anesth. Analg. Curr. Res., 45, 250. Dundee, J. W. (1956). Effect of thiopentone on blood sugar and glucose tolerance. Brit. J. Pharmacol, exp. Ther., 11, 458. Oyama, T., and Takazawa, T. (1971). Effects of halothane anaesthesia and surgery on human growth hormone and insulin levels in plasma. Brit. J. Anaesth., 43, 578. EFFETS DE L'ANESTHESIE PAR THIOPENTONE ET DIAZEPAM SUR LA GLYCEMIE, AU COURS D'UNE INTERVENTION CHIRURGICALE SOMMAIRE
Bien qu'une anesthesie par thiopentone et diazepam, mise en oeuvre au cours d'une intervention chirurgicale en surface, se soit accompagnee dans les deux cas d'une legere augmentation de la glycemie, le type de reponse hyperglycemique a cti different suivant la substance considered. Avec le thiopentone, l'augmentation de la glycemie s'est maintenue tout au long des 60 minutes de la periode d'observation. Lorsque le diazepam a €te substitu^ au thiopentone, on a bien note une augmentation similaire au bout de 15 minutes, mais les taux de glycemie mesures 30, 45 et 60 minutes apres administration de l'anesthesique, n'ont plus presente d'augmentation
Downloaded from http://bja.oxfordjournals.org/ at New York University on April 11, 2015
as it is in these patients that an anaesthetist has to make a specific choice of agents which do not influence the blood sugar level. Although the number of patients in this series is too small to make any analysis of the significance of the results, it seems that the hyperglycaemic response in diabetic patients under diazepam anaesthesia does not differ essentially from that in non-diabetic subjects. The bulk of evidence seems to indicate that these disturbances of carbohydrate metabolism are closely related to activation of the sympatho-adrenal system during anaesthesia and surgery. Though the changes in blood sugar could be explained on the basis of increased sympathetic activity related to the stress, the suggestion that excessive quantities of adrenaline are released during surgery has not been confirmed. More recent work by Allison, Tomlin and Chamberlain (1969) and Clarke (1970) seems to suggest that stress associated with pre-operative anxiety and surgery produces alteration in endocrine function, leading to increased secretion of insulin antagonists such as growth hormone and cortisol. This causes a temporary diabetic state. Glucose homeostasis is partly governed by the hormonal effects of insulin and growth hormone. Insulin is thought to promote the entry of glucose into muscle and fat and it also facilitates glycogen synthesis in liver and muscle. Growth hormone probably regulates the utilization of intracellular glucose and by this means alters sensitivity to insulin. Oyama and Takazawa (1971) have shown that the degree of elevation of plasma HGH during anaesthesia alone is different with various anaesthetic agents. Bonstein and colleagues (1968) described two polypeptides prepared from growth hormone which by their specific actions on certain enzymes of the glycolytic pathway appeared capable of accounting for both the early hypoglycaemic and the later hyperglycaemic actions of growth hormone. The inhibitory polypeptide fraction of growth hormone (ING) inhibits glycolysis and fat synthesis, accelerates breakdown of fat and leads to hyperglycaemia. The second fraction of growth hormone known as acceleratory polypeptide growth hormone (ACG) causes hypoglycaemia and reverses the inhibition produced by ING. This suggests that the polypeptides have a significant function on the normal control of blood sugar in man. The surgical trauma and anaesthetic agents may either produce an increase in the plasma level of ING fraction of growth hormone or inhibit the release of ACG fraction leading to hyperglycaemia. From the available evidence it is not possible to establish to what extent
BRITISH JOURNAL OF ANAESTHESIA
INFLUENCE OF ANAESTHESIA ON BLOOD SUGAR LEVEL significative. Chez des malades diabetiques soumis a des interventions chirurgicales, la reaction hyperglycemique notee sous anesthesie par le Diazepam ne differe pas significativement de celle observee dans le groupe de malades non-diabetiques.
der Diazepam-Narkose wahrend eines chirurgischen Eingriffes beobachtet wurde, unterschied sich nicht wesentlich von der nicht-diabetischen Patientengruppe. INFLUENCIA DE LA ANESTESIA CON TIOPENTONA Y DIACEPAM SOBRE EL NIVEL DEL AZUCAR SANGUINEO DURANTE INTERVENCIONES QUIRUGICAS
DER EINFLUSS DER THIOPENTON- UND DIAZEPAM-NARKOSE AUF DEN BLUTZUCKERSPIEGEL WAHREND DER OPERATION ZUSAMMENFASSUNG
RESUMEN
Aunque durante operaciones sobre la superficie del cuerpo la anestesia con tiopentona y diacepam fue acompanada por una ligera elevacion en el aziicar sanguineo, el patr6n de la respuesta hipoglicemica fue diferente con estos dos agentes. Con tiopentona, la elevacion del azucar sanguineo fue mantenida durante el periodo de observation de 60 minutos. Cuando la tiopentona fue sustituida por diacepam, aunque hubo una elevaci6n semejante a los 15 minutos, los niveles del azucar sanguineo a los 30, 45 y 60 minutos no estaban significativamente elevados. La respuesta hipoglicemica de pacientes diabeticos bajo cirujia durante la anestesia por diacepam no difirio significativamente de la observada en el grupo de pacientes no diabeticos.
THE 3rd EUROPEAN CONGRESS ON PAEDIATRIC
NEUROSURGERY
The congress previously planned to take place in Gottingen on September 21-23, 1972, will be held on September 3-7, 1972. Subjects:
1.
Problems of anaesthesia and postoperative control of neurosurgical baby and infant patients.
2.
Long-term follow-up after neurosurgical interventions in babies and infants.
3.
Neuroradiology of babies and infants.
4.
Recent diagnostic and operative techniques in paediatric neurosurgery.
5.
Demonstrations of rare cases.
6.
Free papers.
For information please write to: Prof. Dr. med. K.-A. Bushe Direktor der Neurochirurgischen Klinik der Universitat Gottingen 3400 Gottingen, Gosslerstrafie 10
Downloaded from http://bja.oxfordjournals.org/ at New York University on April 11, 2015
Obwohl wahrend der Thiopenton- und Diazepam-Narkose wahrend oberflachlichen chirurgischen Eingriffen der Blutzuckerwert einen geringen Anstieg zeigte, ist das Schema der hyperglykamischen Reaktion bei den beiden Substanzen unterschiedlich. Bei Thiopenton hielt der Blutzuckeranstieg wahrend der gesamten Beobachtungszeit von 60 Minuten an. Wurde statt Thiopenton Diazepam gegeben, so kam es zwar nach 15 Minuten zu einem ahnlichen Anstieg, nach 30, 45 und 60 Minuten waren jedoch die Blutzuckerspiegel nicht nennenswert erhoht. Die hyperglykamische Reaktion, die bei Diabetikern nach
79
THE INFLUENCE OF ANAESTHESIA WITH THIOPENTONE AND DIAZEPAM ON THE BLOOD SUGAR LEVEL DURING SURGERY S. MEHTA SUMMARY
It has been known since 1956 from the findings of Dundee (1956) that thiopentone produces no appreciable change in the blood sugar level in man. But the rise in blood sugar occurring during surgery differed significantly from that produced by thiopentone alone, and it was suggested that this may have been secondary to the respiratory depression produced by the morphine-thiopentone combination. Initial studies by Clarke and Dundee (1966) showed that anaesthesia with propanidid plus nitrous oxide also caused a rise in blood sugar. Clarke (1968) reported that, during body surface surgery, anaesthesia with thiopentone, nitrous oxide-oxygen was accompanied by a small rise in blood sugar whereas when propanidid was substituted for thiopentone there was a much larger rise. Clarke (1970) has published results showing 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-oxygen in the absence of surgery. Clarke again in 1968 investigated the effect of thiopentone and propanidid on glucose metabolism by carrying out the intravenous glucose tolerance tests during body surface surgery, and found that there is little difference between the results with two agents. As each new anaesthetic agent has become available it has been investigated with respect to its effect on blood sugar. Since no work in connection with the effect of diazepam on blood sugar has been reported, it seemed desirable to undertake such a study and to compare its effect on the blood sugar with that of thiopentone.
METHOD
Investigations were carried out in 70 adult patients of either sex: 66 of these patients had no disease other than the pathology necessitating the operation; 4 patients were suffering from diabetes but the disease was controlled by restriction of diet alone. All patients underwent either body surface operation which consisted of Trendelenburg operation, multiple ligation of varicose veins, herniorrhaphy, or dental extractions. The average operating time was 35 minutes and the mean anaesthetic time was 45 minutes. Four series of experiments were undertaken. Series 1. Twenty patients received thiopentone 4 mg/kg for induction. Series 2. In 40 patients diazepam was used for induction; 30 mg of undiluted diazepam was injected slowly at the rate of 1 ml every 10 sec until it was assumed that the patient was asleep. Failure to respond to auditory stimuli, the absence of the eyelash reflex or the presence of snoring was taken as an indication that the patient was asleep. Series 3. In 6 patients intravenous glucose tolerance tests were performed. A sample for blood sugar estimation was taken immediately before induction with thiopentone or diazepam. A 50 per cent solution of dextrose was injected rapidly in a dose of 0.33 g/kg and blood samples were taken at 10-minute intervals thereafter for a total of 60 minutes. Series 4. The effect of diazepam on blood sugar was studied in 4 diabetic patients whose disease was controlled by restriction of diet alone. S. MEHTA, M.B.,B.S., F.F.A.R.C.S.(ENG.), Burnley Group of
Hospitals, Burnley, England.
Downloaded from http://bja.oxfordjournals.org/ at New York University on April 11, 2015
Although during body surface surgery anaesthesia with thiopentone and diazepam was accompanied by a small rise in blood sugar, the pattern of hyperglycaemic response was different with the two agents. With thiopentone, the rise in blood sugar was sustained throughout the 60-minute period of observation. When diazepam was substituted for thiopentone, although there was a similar rise at 15 minutes, the levels of blood sugar at 30, 45 and 60 minutes were not significantly elevated. The hyperglycaemic response in diabetic patients undergoing surgery during diazepam anaesthesia did not differ significantly from that in the non-diabetic group of patients.
BRITISH JOURNAL OF ANAESTHESIA
76
taken to see that peripheral circulation was good. Observations were made immediately before induction and at 30- and 60-minute intervals thereafter. RESULTS
Series 1 and 2. The changes in blood sugar concentration during body surface and dental surgery are shown in table I. There was a small rise in blood sugar during both thiopentone and diazepam anaesthesia. Widi diiopentone die average difference between die means and the initial mean is significant (P<0.05) at each 15-minute interval but die differences between die means after die beginning of anaesdiesia are negligible. In the case of diazepam, the difference between die mean blood sugar concentration at 15 minutes and the initial value is highly significant (P<0.002) but differences between the means at the odier sampling times and die initial mean are not significant. Again no significant difference between the means at the various sampling times after the beginning of anaesthesia is seen. The operation had started by die time die second sample was taken, so diat it was not possible to distinguish between the effect of anaesdiesia and surgery on the blood sugar. Series 3. To investigate whedier die anaesthetics differed in their effect on glucose metabolism, intravenous glucose tolerance tests were carried out during body surface surgery in 6 patients belonging
TABLE I. Details of patients with average initial blood sugar levels and changes at various time intervals in patients undergoing body surface surgery or dental extraction during anaesthesia induced with thiopentone and diazepam. Series Thiopentone
No. of patients
Age (yr)
(kg)
20
42
60
Wt
StTtistirii parameter
Blood sugar (mg/100 ml) at (min) Initial
15
30
83.8 2.03
83.5 2.08
83.8 2.17
85.0 2.33
6.45
6.10
6.35
7.55
8.35
8.47
8.69
9.11
2.44 <0.05 86.6 1.44
2.27 <0.05 83.4 1.52
2.30 <0.05 83.2 1.58
2.62 <0.05 82.2 1.63
6.65
3.42
3.25
2.18
—
8.35
8.62
8.86
9.04
— —
3.56
1.78 n.s.
1.64 n.s.
1.08 n.s.
Mean 77.4 SE 1.68 Difference between means and initial mean —
45
60
SD
Diazepam
40
45
62
(combined) — t value (38 d.f.) — Probability — Mean 80 SE 1.18 Difference between means and initial mean — SD
(combined) t value (78 d.f.) Probability
Downloaded from http://bja.oxfordjournals.org/ at New York University on April 11, 2015
In each series there were approximately equal numbers of patients of each sex and the age and weight ranges were comparable. Each patient was premedicated with pethidine 100 mg and atropine 0.6 mg intramuscularly 1 hour before induction of anaesthesia. All patients were intubated and anaesthesia was maintained with nitrous oxide (7 l./min), oxygen (3 l./min), muscle relaxation being obtained by injection of alcuronium. Ventilation was controlled throughout the procedure with either a B'easeManley or East-Radcliffe ventilator. Venous blood samples were taken immediately before induction in the anaesthetic room and at 15minute intervals thereafter from a forearm vein via a plastic cannula. Five blood samples were taken from each patient. The operation had started by the time the second blood sample was taken and die fifth sample was obtained after the conclusion of anaesthesia. Blood sugar was estimated by the standard auto-analyzer technique which measures total reducing substances in blood. The maximum error in individual readings was + 5 mg/100 ml. Since respiratory depression widi consequent carbon dioxide retention is known to cause hyperglycaemia, capillary blood was analyzed for Pco2, pH and base excess in 10 patients in series 1, and 15 patients in series 2 (Andersen, Jorgensen and Astrup, 1960). Blood was obtained from the tip of the thumb and drawn rapidly into the capillary tubes. Care was
INFLUENCE OF ANAESTHESIA ON BLOOD SUGAR LEVEL
77
TABLE II. Average blood sugar values in patients who had an intravenous glucose tolerance test during thiopentone or diazepam anaesthesia with alcuronium and IPPV. Blood sugar (mg/100 ml) at (min) YV I
Group Thiopentone
patients (yr) (kg) 2 46 65
Statistical parameter Mean SD
4
Diazepam
44
62
Mean SD
Significance of increases, both groups compared Difference between means SE of differences t Probability
Initial 78.5 4.95 84.25 7.58
5.75 6.12 0.938
30
20
10
50
40
60
185.5 171.0 157.0 146.6 133.5 6.36 5.65 4.24 6.36 4.27 183.8 170.8 158.5 145.0 134.8 8.69 10.80 13.67 8.53 10.43
208.5 4.95 203.8 4.78
4.70 4.18 1.124
1.70
0.2
1.0
1.5
1.3
These differences are all non-sigilificant
No. of patients
Age (yr)
Wt (kg)
52
65
Blood sugar (mg/100 ml) at (min) Statistical parameter
Initial
15
30
45
60
Mean
83.75 5.05 2.52
88.35 3.86 1.93
87.50
88.50 4.43 2.21
85.50 5.26 2.63
SD SE
Significance of increases above diazepam series 2
3.0
1.50
n.s.
to this series (table II). There was little difference between the results with two agents and these differences are statistically non-significant. Series 4. Table III shows the hyperglycaemic response in 4 diabetic patients undergoing body surface surgery following diazepam induction of anaesthesia. The mean rises in blood sugar level at various time intervals did not differ significantly from those obtained in the non-diabetic group of patients who received diazepam for induction of anaesthesia (series 2). The results of acid-base measurements under thiopentone and diazepam anaesthesia with alcuronium and IPPV are shown in table IV. There are no essential differences between the results obtained using either thiopentone or diazepam as inducing agents.
DISCUSSION
Although it is evident from the present study that a small rise in blood sugar occurs under thiopentone and diazepam anaesthesia with nitrous oxide and alcuronium during body surface surgery, the pattern of this hyperglycaemic response is different with the two agents. With thiopentone there was a small but significant rise in blood sugar which was sustained throughout the 60-minute period of observation. When diazepam was used for induction there was a similar rise, which was highly significant at 15 minutes. This was shortlived and at 30, 45 and 60 minutes the blood sugar changes did not reach the level of significance. It is apparent from the study that neither thiopentone nor diazepam was able to prevent the rise in blood sugar initially during the first 15-minute period of surgery. However, this increase in blood sugar was within the range of TABLE IV. Changes in pH Pco2 and base excess during physiological variation. These results also suggest that anaesthesia with thiopentone and diazepam with alcuronium the rise in blood sugar under thiopentone and and IPPV. diazepam anaesthesia is not related to the duration Pco2 Time Base excess PH (min) (mmHg) (m.equiv/1.) of surgery. Both these anaesthetics, however, have similar effect on glucose metabolism. Thiopentone 0 7.41 37.8 (n=10) Diazepam (n=15)
30 60 0 30 60
7.50 7.39 7.40 7.50 7.39
27.8 39.8 39.4 29.0 41.4
-0.3 -0.35 -0.25 -0.02 + 0.05 -0.01
Most studies of the effects of anaesthetic drugs on blood sugar, in the past, have been carried out in normal healthy subjects. It was, therefore, felt desirable to include a few diabetic patients in this study,
Downloaded from http://bja.oxfordjournals.org/ at New York University on April 11, 2015
TABLE III. Changes in blood sugar levels in blood from diabetic patients undergoing body surface surgery following diazepam induction of anaesthesia, with alcuronium and IPPV.
78
each of these factors is responsible for producing the hyperglycaemic response during anaesthesia and surgery. The hyperglycaemic response as a result of surgical stress may produce worsening of the diabetic state in a mild or latent diabetic patient but whether this rise in blood sugar in a healthy person is harmful and should be prevented remains an open question. ACKNOWLEDGEMENTS
I am particularly indebted to the Biochemistry Department of the Burnley General Hospital for making the blood sugar and Astrup measurements. Thanks are also due to the surgeons and the members of the nursing staff for their co-operation throughout these studies. I am grateful to Dr C. G. Burgess, Clinical Research Physician to Roche Products, and Dr Corbett for valuable suggestions and helping with the statistical analysis of the results of this study. REFERENCES
Allison, S. P., Tomlin, P. J., and Chamberlain, M. J. (1969). Some effects of anaesthesia and surgery on carbohydrate and fat metabolism. Brit. J. Anaeslh., 41, 588. Andersen, S., Jorgensen, K., and Astrup, P. (1960). A micro-method for determination of pH, carbon dioxide tension, base excess and standard bicarbonate in capillary blood. Scand. J. Clin. Lab. Invest., 12, 172. Bonstein, J., Krahl, M. E., Marshall, L. B., Gould, M. K., and Armstrong, J. McD. (1968). Pituitary peptides with direct action on the metabolism of carbohydrates and fatty acids. Biochim. biophys. Acta (Amst.), 156, 36. Clarke, R. S. J. (1968). The influence of anaesthesia with thiopentone and propanidid on the blood sugar level. Brit. J. Anaesth., 40, 46. (1970). The hyperglycaemic response to different types of surgery and anaesthesia. Brit. J. Anaesth., 42, 45. Dundee, J. W. (1966). Survey of experimental and clinical pharmacology of propanidid. Anesth. Analg. Curr. Res., 45, 250. Dundee, J. W. (1956). Effect of thiopentone on blood sugar and glucose tolerance. Brit. J. Pharmacol, exp. Ther., 11, 458. Oyama, T., and Takazawa, T. (1971). Effects of halothane anaesthesia and surgery on human growth hormone and insulin levels in plasma. Brit. J. Anaesth., 43, 578. EFFETS DE L'ANESTHESIE PAR THIOPENTONE ET DIAZEPAM SUR LA GLYCEMIE, AU COURS D'UNE INTERVENTION CHIRURGICALE SOMMAIRE
Bien qu'une anesthesie par thiopentone et diazepam, mise en oeuvre au cours d'une intervention chirurgicale en surface, se soit accompagnee dans les deux cas d'une legere augmentation de la glycemie, le type de reponse hyperglycemique a cti different suivant la substance considered. Avec le thiopentone, l'augmentation de la glycemie s'est maintenue tout au long des 60 minutes de la periode d'observation. Lorsque le diazepam a €te substitu^ au thiopentone, on a bien note une augmentation similaire au bout de 15 minutes, mais les taux de glycemie mesures 30, 45 et 60 minutes apres administration de l'anesthesique, n'ont plus presente d'augmentation
Downloaded from http://bja.oxfordjournals.org/ at New York University on April 11, 2015
as it is in these patients that an anaesthetist has to make a specific choice of agents which do not influence the blood sugar level. Although the number of patients in this series is too small to make any analysis of the significance of the results, it seems that the hyperglycaemic response in diabetic patients under diazepam anaesthesia does not differ essentially from that in non-diabetic subjects. The bulk of evidence seems to indicate that these disturbances of carbohydrate metabolism are closely related to activation of the sympatho-adrenal system during anaesthesia and surgery. Though the changes in blood sugar could be explained on the basis of increased sympathetic activity related to the stress, the suggestion that excessive quantities of adrenaline are released during surgery has not been confirmed. More recent work by Allison, Tomlin and Chamberlain (1969) and Clarke (1970) seems to suggest that stress associated with pre-operative anxiety and surgery produces alteration in endocrine function, leading to increased secretion of insulin antagonists such as growth hormone and cortisol. This causes a temporary diabetic state. Glucose homeostasis is partly governed by the hormonal effects of insulin and growth hormone. Insulin is thought to promote the entry of glucose into muscle and fat and it also facilitates glycogen synthesis in liver and muscle. Growth hormone probably regulates the utilization of intracellular glucose and by this means alters sensitivity to insulin. Oyama and Takazawa (1971) have shown that the degree of elevation of plasma HGH during anaesthesia alone is different with various anaesthetic agents. Bonstein and colleagues (1968) described two polypeptides prepared from growth hormone which by their specific actions on certain enzymes of the glycolytic pathway appeared capable of accounting for both the early hypoglycaemic and the later hyperglycaemic actions of growth hormone. The inhibitory polypeptide fraction of growth hormone (ING) inhibits glycolysis and fat synthesis, accelerates breakdown of fat and leads to hyperglycaemia. The second fraction of growth hormone known as acceleratory polypeptide growth hormone (ACG) causes hypoglycaemia and reverses the inhibition produced by ING. This suggests that the polypeptides have a significant function on the normal control of blood sugar in man. The surgical trauma and anaesthetic agents may either produce an increase in the plasma level of ING fraction of growth hormone or inhibit the release of ACG fraction leading to hyperglycaemia. From the available evidence it is not possible to establish to what extent
BRITISH JOURNAL OF ANAESTHESIA
INFLUENCE OF ANAESTHESIA ON BLOOD SUGAR LEVEL significative. Chez des malades diabetiques soumis a des interventions chirurgicales, la reaction hyperglycemique notee sous anesthesie par le Diazepam ne differe pas significativement de celle observee dans le groupe de malades non-diabetiques.
der Diazepam-Narkose wahrend eines chirurgischen Eingriffes beobachtet wurde, unterschied sich nicht wesentlich von der nicht-diabetischen Patientengruppe. INFLUENCIA DE LA ANESTESIA CON TIOPENTONA Y DIACEPAM SOBRE EL NIVEL DEL AZUCAR SANGUINEO DURANTE INTERVENCIONES QUIRUGICAS
DER EINFLUSS DER THIOPENTON- UND DIAZEPAM-NARKOSE AUF DEN BLUTZUCKERSPIEGEL WAHREND DER OPERATION ZUSAMMENFASSUNG
RESUMEN
Aunque durante operaciones sobre la superficie del cuerpo la anestesia con tiopentona y diacepam fue acompanada por una ligera elevacion en el aziicar sanguineo, el patr6n de la respuesta hipoglicemica fue diferente con estos dos agentes. Con tiopentona, la elevacion del azucar sanguineo fue mantenida durante el periodo de observation de 60 minutos. Cuando la tiopentona fue sustituida por diacepam, aunque hubo una elevaci6n semejante a los 15 minutos, los niveles del azucar sanguineo a los 30, 45 y 60 minutos no estaban significativamente elevados. La respuesta hipoglicemica de pacientes diabeticos bajo cirujia durante la anestesia por diacepam no difirio significativamente de la observada en el grupo de pacientes no diabeticos.
THE 3rd EUROPEAN CONGRESS ON PAEDIATRIC
NEUROSURGERY
The congress previously planned to take place in Gottingen on September 21-23, 1972, will be held on September 3-7, 1972. Subjects:
1.
Problems of anaesthesia and postoperative control of neurosurgical baby and infant patients.
2.
Long-term follow-up after neurosurgical interventions in babies and infants.
3.
Neuroradiology of babies and infants.
4.
Recent diagnostic and operative techniques in paediatric neurosurgery.
5.
Demonstrations of rare cases.
6.
Free papers.
For information please write to: Prof. Dr. med. K.-A. Bushe Direktor der Neurochirurgischen Klinik der Universitat Gottingen 3400 Gottingen, Gosslerstrafie 10
Downloaded from http://bja.oxfordjournals.org/ at New York University on April 11, 2015
Obwohl wahrend der Thiopenton- und Diazepam-Narkose wahrend oberflachlichen chirurgischen Eingriffen der Blutzuckerwert einen geringen Anstieg zeigte, ist das Schema der hyperglykamischen Reaktion bei den beiden Substanzen unterschiedlich. Bei Thiopenton hielt der Blutzuckeranstieg wahrend der gesamten Beobachtungszeit von 60 Minuten an. Wurde statt Thiopenton Diazepam gegeben, so kam es zwar nach 15 Minuten zu einem ahnlichen Anstieg, nach 30, 45 und 60 Minuten waren jedoch die Blutzuckerspiegel nicht nennenswert erhoht. Die hyperglykamische Reaktion, die bei Diabetikern nach
79