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EFFECT OF INDUCTION OF ANAESTHESIA WITH ETOMIDATE ON CORTICOSTEROID SYNTHESIS IN MAN
Br.J. Anaesth. (1985), 57,156-159
EFFECT OF INDUCTION OF ANAESTHESIA WITH ETOMIDATE ON CORTICOSTEROID SYNTHESIS IN MAN D. J. R. DUTHIE, R. FRASER AND W. S. NIMMO
PATIENTS AND METHODS
Twelve male patients, aged 23-78 yr (mean 49 yr, SD 17), without evidence of endocrine disease, and undergoing minor surgery, gave informed consent, and were included in the study. The surgical procedures included inguinal herniorrhaphy, ligation of varicose veins, haemorrhoidectomy and excision of sebaceous cysts. No patient was receiving regular medication, and all were premedicated with papaveretum 15 mg and atropine 0.6 mg i.m., approximately 1 h before surgery (mean DAVID J. R. DUTHIE,- M.B., CH.B., F.F.A.R.C.S. (Department of Anaesthesia); ROBERT FRASER, M.SC., PH.D., F.R.S.E. (Medical
Research Council Blood Pressure Unit); WALTER S. NIMMO," Department of M.D., F.R.C.P., F.F.A.R.C.S. (University Anaesthesia); Western Infirmary, Glasgow G i l 6NT. *Present address: Department of Anaesthesia, Sheffield University Medical School, Beech Hill Road, Sheffield S10 2RX.
SUMMARY The effects of a single bolus dose of etomidate 0.3 mg kg~1 or thiopentone 5mgkg~\ on the synthesis of corticosteroid hormones and adrenocorticotrophic hormone (ACTH), were compared for 24 h in 12 patients, undergoing minor surgery under general anaesthesia. Following opioid premedication i.m. and general anaesthesia, plasma cortisoi concentrations decreased transiently within the first hour of anaesthesia in all 12 patients. The six patients who received etomidate had statistically higher plasma 11-deoxycorticosterone concentrations at 4 and 24 h than those who had received thiopentone (P < 0.01). Throughout the study, no difference in plasma cortisoi, corticosterone or ACTH concentrations were found between the two groups. We have demonstrated a biochemical effect of a single bolus dose of etomidate consistent with incomplete inhibition of adrenocortical mitochondria! 11 fi-hydroxylase activity, but no clinically significant adrenocortical suppression.
56 ± 16 min). They were allocated randomly to receive thiopentone 5 mg kg" l or etomidate 0.3 mg kg" 1 i.v. to induce anaesthesia, which was maintained with 1.5% halothane and 67% nitrous oxide in oxygen. Respiration was spontaneous. One patient in each group required tracheal intubation, which was facilitated with suxamethonium 1 mg kg" 1 . Anaesthesia was induced between 10.45 a.m. and 4.15 p.m. and lasted 34 ± 16 min. Blood samples were withdrawn 30 min before, immediately after, and at 15 min, 1,4 and 24 h after the induction of anaesthesia. The plasma was separated, frozen and later analysed for plasma cortisoi, corticosterone, 11-deoxy corticosterone, and ACTH concentrations.
Downloaded from http://bja.oxfordjournals.org/ at University of Michigan on June 19, 2015
An increase in the mortality amongst trauma patients in an intensive care unit, coincident with the introduction of sedation using an infusion of etomidate, was reported by Ledingham and Watt (1983). Suppression of the adrenocortical secretion of cortisoi was demonstrated when etomidate was infused to these patients (Finlay and McKee, 1982; Ledingham et al., 1983; McKee and Finlay, 1983). The continued use of etomidate has been questioned (Committee on Safety of Medicines, 1983; Editorial, 1983), but in the absence of reported adverse effects from single bolus doses, its retention was advocated for the induction of anaesthesia in patients with asthma, drug allergy and peripheral circulatory failure (McDowall, 1983). In this study, the effects of a single bolus dose of etomidate or thiopentone on adrenocorticotrophic hormone (ACTH) production, and corticosteroid synthesis, were investigated in patients undergoing minor surgery under general anaesthesia.
ETOMIDATE INDUCTION AND CORTICOSTEROID SYNTHESIS
157
TABLE I. Patient data (mean values ± SD). ns = not significant (P > 0.05) Induction agent
Age(yr)
Weight (kg)
Group 1: Thiopentone (n = 6)
50 ± 1 8
76±6
10.45 14.00
14.20 15.00
15.10 15.15
32 ± 11
Group 2: Etomidate
48+17
73+10
11.40 11.55
13.00 13.45
14.55 16.15
35 + 21
Duration (min)
Starting time
50CH
400-
200-
3 a.
100-
RESULTS
The two groups did not differ significantly with respect to age, weight, starting time and duration of anaesthesia (table I).
0 1 L TL Time from induction of anaesthesia (h) FIG. 1. Serial plasma cortisol concentrations (mean ± SEM). (All patients n = 12.)
TABLE II. Serial plasma concentrations (mean ± SEM). Thiopentone: n = 6; etomidate: n = 6. *P < 0.01 Induction agent
Time from induction of anaesthesia - 30 min
Omin
15 min
lh
4h
24 h
Cortisol (nmol litre"')
Thiopentone Etomidate
307 ± 37 330 ± 67
225 ± 40 257 ± 43
105 ± 25 211 ±23
234 ± 72 151 ±33
344 ± 134 215 ±40
348 ± 98 445 ±42
Corticosterone (nmol litre"')
Thiopentone Etomidate
4.9 ±1.9 17.4 ±3.4
2.7 ±0.9 3.0± 1.1
2.0 ±0.5 0.7 ±0.2
7.5 ±3.3 1.7± 1.2
18.3 ±11.5 4.7 ±2.3
13.3 ±9.0 3.7 ±1.3
11-Deoxycorticosterone (pmol litre"1)
Thiopentone Etomidate
280 + 50 260 ± 30
220 ± 30 250 ± 20
190 ± 40 260 ± 40
590 ± 270 1700 ± 850
540 ± 200* 21900 ±9200
190 ± 30* 3100 ±910
ACTH (pmol litre"1)
Thiopentone Etomidate
12 ±2.8 15 ±2.9
9.5 ±1.6 14.0 ±2.4
19 ± 6.6 19 + 5.1
17 ±50 15 ±5.4
35 ±19 19 ±6.8
12 ± 3.4 18 ±3.4
Downloaded from http://bja.oxfordjournals.org/ at University of Michigan on June 19, 2015
Plasma corticosterone and 11-deoxycorticosterone concentrations were measured by radioimmunoassay after extraction and partial purification by paper chromatography (Fraser et al., 1975). Plasma cortisol and ACTH concentrations were measured directly using kits supplied by Corning Ltd and CIS (UK) Ltd, respectively. The coefficients of variation of the cortisol, corticosterone, 11-deoxycorticosterone and ACTH assays were 5.8%, 9.9%, 10.1% and 6.0%, respectively. '• The results were analysed for statistical significance using the Mann-Whitney U test.
BRITISH JOURNAL OF ANAESTHESIA
158
TABLE III. Plasma coriisol concentrations (mean values ± SEM). (All patients: n = 12). * Difference from plasma concentration at 1= —30 min; ns = not significant Time from induction of anaesthesia
Cortisol (nmol litre"1) *P
— 30 min
Omin
15 min
lh
4h
24 h
318 ± 3 7
241 ±29
199 + 16
192 ± 39
280 ± 7 1
392 ± 56
ns
<0.01
<0.05
ns
ns
Downloaded from http://bja.oxfordjournals.org/ at University of Michigan on June 19, 2015
date group at 1 h, but the difference did not achieve At no time did the concentrations differ signific- statistical significance. antly between the two groups (fig. 1, table II). Tak- Corticosterone and ACTH concentrations ing all 12 patients together, there were statistically There was wide variation in all measurements and significant decreases in the cortisol concentrations at no trends or statistically significant differences were 15 min (P < 0.01) and 60 min {P < 0.05) from induction of anaesthesia compared with the control noted (table II). concentration (table III). However, cortisol conDISCUSSION centrations remained within the laboratory refer1 ence range (150-690 nmol litre" ). Etomidate 0.3 mg kg" 1 , when used to induce anaesthesia, produced a significant increase in 11deoxycorticosterone concentrations at 4 and 24 h, when compared with thiopentone. No significant changes were seen in the plasma cortisol, ACTH or corticosterone concentrations. 18000n Previously, attention has focused on the readily measured plasma cortisol concentration, and not on 16000 other adrenocortical precursors. The infusion of etomidate has been shown to suppress adrenocortical secretion of cortisol in man (Fellows, Byrne and Etomidate Allison, 1983; Fellows etal., 1983; Sear etal., 1983), animals (Preziosi and Vacca, 1982; Fraser et al., 1984) and in adrenal cells in vitro (Kenyon et al., 1984). Such suppression may prejudice survival in the critically ill patient (Finlay and McKee, 1982; McKee and Finlay, 1983) in whom spontaneous adrenocortical failure is uncommon (Sainsbury, Thiopentone Stoddart and Watson, 1981). =F E (-V2) o e i y T u Large doses of opioids can suppress the cortisolS Time from induction of anaesthesia ( h) stress response after surgery (Hall et al., 1978). The statistically significant (if small) decrease in plasma FIG. 2. Serial plasma 11-deoxycorticosterone concentrations cortisol concentrations at 15 and 60 min in our (mean ± SEM). (All patients n = 12.) patients is similar to that reported in three patients who had received opioid premedication (Sebel, Ver/ 1-Deoxycorticosterone concentrations ghese and Makin, 1983). The transitory decreases in At 4 and 24 h, plasma 11-deoxycorticosterone cortisol concentration are not known to be harmful concentrations were significantly higher in the and are likely to be at least partly a result of the use etomidate group than in the thiopentone group (fig. of opioid premedication and general anaesthesia, a 2, table II). There was some increase in the etomi- common practice which occurred in 37% of patients Cortisol concentrations
ETOMIDATE INDUCTION AND CORTICOSTEROID SYNTHESIS
In summary, we have demonstrated a biochemical effect of a single bolus dose of etomidate 0.3 mg kg" 1 on adrenocortical steroid synthesis. The accumulation of 11-deoxycorticosterone at 4 and 24 h is consistent with the known inhibition of 11 (3-hydroxylase by etomidate (Owen and Spence, 1984). This inhibition was partial, as it failed to reduce the plasma concentrations of the hormones, cortisol and corticosterone, and there was no discernible increase in ACTH concentration. Thus, a bolus dose of etomidate 0.3 mg kg"1 causes no significant adrenocortical suppression. ACKNOWLEDGEMENTS
The technical assistance of Mrs C. D. Holloway and Miss M. C. Ingram is gratefully acknowledged.
REFERENCES
Committee on Safety of Medicines (1983). Letter of June 20, reprinted Lancet, 2, 60. Editorial (1983). Lancet, 2, 24. Fellows, I. W., Byrne, A. J., and Allison, S. P. (1983). Adrenocortical suppression with etomidate. Lancet, 2, 54. Fellows, I. W., Bastow, M. D., Byrne, A. J., and Allison, S. P. (1983). Adrenocortical suppression in multiply injured patients: a complication of etomidate treatment. Br. Med. J., 287, 1835. Finlay, W. E. I., and McKee, J. I. (1982). Serum cortisol levels in severely stressed patients. Lancet, 1, 1414. Fragen, R. J., Shanks, C. A., and Molteni, A. (1983). Effect on plasma cortisol concentrations of a single induction dose of etomidate or thiopentone. Lancet, 2, 625. Fraser, R., Guest, S., Holmes, E., Mason,P. A., Wilson, A., and Young, J. (1975). Comparison of radioimmunoassay and physiochemical methods as a means of estimating plasma aldosterone and plasma 11-deoxycorticosterone concentrations; in Vth Tenovus Workshop on Steroid Radioimmunoassay (eds G. H. D. Cameron, S. G. Hillier and K. Griffitys), p.283. Cardiff: Alpha Omega Alpha. Watt, I., Gray, C. E., Ledingham, I.McA., and Lever, A. F. (1984). The effect of etomidate on adrenocortical function in dogs before and during haemorrhagic shock. Endocrinology, (in press). Hall, G. M., Young, C , Holdcroft, A., and Alaghband-Zadeh, J. (1978). Substrate mobilisation during surgery: a comparison between halothane and fentanyl and anaesthesia. Anaesthesia, 33, 924. Kenyon, C. J., Young, J., Gray, C. E., and Fraser, R. (1984). Exhibition of steroidogenesis in isolated bovine adrenal cells. J. Clin. Endocrinol. Metab., 58, 947. Ledingham, I. McA., Finlay, W. E. I., Watt, I., and McKee, J. I. (1983). Etomidate and adrenocortical function. Lancet, 1, 1434. Watt, I. (1983). Influence of sedation on mortality in critically ill, multiple trauma patients. Lancet, 1, 1270. McDowall, D. G. (1983). Etomidate. Lancet, 2, 168. McKee, J. I., and Finlay, W. E. I. (1983). Cortisol replacement in severely stressed patients. Lancet, 1, 484. Miller, M., Sugden, C. J., and Spence, A. A. (1983). A simple computer based system for recording and retrieving key anaesthetic patient data. Anaesthesia, 37, 367. Owen, H., and Spence, A. A. (1984). Etomidate. Br.J. Anaesth., 56, 555. Preziosi, P., and Vacca, M. (1982). Etomidate and corticotrophic axis. Arch. Int. Pharmacodyn. Ther., 256, 308. Sainsbury, J. R. C , Stoddart, J. C , and Watson, M. J., (1981). Plasma cortisol levels: a comparison between sick patients and volunteers given intravenous cortisol. Anaesthesia, 36, 16. Sear, J. W., Allen, M. C , Gales, M., McQuay, H. J., Kay, N. H., McKenzie, P. J., and Moore, R. A. (1983). Suppression by etomidate of normal cortisol responses to anaesthesia and surgery. Lancet, 2, 1028. Sebel, P. S., Verghese, C , and Makin, H. L. J. (1983). Effect on plasma cortisol concentrations of a single induction dose of etomidate or thiopentone. Lancet, 2, 625. Todd, J. G., Duthie, D. J. R., and Spence, A. A. (1983). Computer-based anaesthetic records. Anaesthesia, 38, 172.
Downloaded from http://bja.oxfordjournals.org/ at University of Michigan on June 19, 2015
who underwent surgery in our hospital between 1982 and 1984 (Miller, Sugden and Spence, 1983; Todd, Duthie and Spence, 1983). Single bolus doses of etomidate 0.3 mg kg~' have not been shown to suppress cortisol secretion abnormally. Fragen, Shanks and Molteni (1983) reported a decrease in cortisol concentration of undisclosed significance in women receiving etomidate, when compared with those who were given thiopentone. As in our study, Sebel, Verghese and Makin (1983) failed to show a difference in plasma cortisol concentrations between patients given either thiopentone or etomidate, and the mean plasma cortisol concentrations in all three studies remained within the physiological range. The disproportionate increase in plasma 11deoxycorticosterone concentrations is consistent with an inhibition of 11 (3-hydroxylase activity and agrees with previous findings in dogs infused with etomidate (Fraser et al., 1984), and in bovine adrenocortical cells incubated with etomidate in vitro (Kenyon et al., 1984). That corticosterone and cortisol concentrations remained within the normal range suggests that the inhibition was incomplete and compensated by an increase in ACTH secretion. However, because of the marked variability in the ACTH concentrations measured, this increase could not be demonstrated statistically. In previous studies, evidence was obtained of additional effects earlier in the biosynthetic pathway, and an interference with mitochondrial corticosteroid mixed function oxidase reactions, possibly by interaction with cytochrome P450, was postulated. Such an effect would not have been apparent from the assays performed here and, if present, may have been less marked because high etomidate concentrations were maintained for a shorter time
159
EFFECT OF INDUCTION OF ANAESTHESIA WITH ETOMIDATE ON CORTICOSTEROID SYNTHESIS IN MAN D. J. R. DUTHIE, R. FRASER AND W. S. NIMMO
PATIENTS AND METHODS
Twelve male patients, aged 23-78 yr (mean 49 yr, SD 17), without evidence of endocrine disease, and undergoing minor surgery, gave informed consent, and were included in the study. The surgical procedures included inguinal herniorrhaphy, ligation of varicose veins, haemorrhoidectomy and excision of sebaceous cysts. No patient was receiving regular medication, and all were premedicated with papaveretum 15 mg and atropine 0.6 mg i.m., approximately 1 h before surgery (mean DAVID J. R. DUTHIE,- M.B., CH.B., F.F.A.R.C.S. (Department of Anaesthesia); ROBERT FRASER, M.SC., PH.D., F.R.S.E. (Medical
Research Council Blood Pressure Unit); WALTER S. NIMMO," Department of M.D., F.R.C.P., F.F.A.R.C.S. (University Anaesthesia); Western Infirmary, Glasgow G i l 6NT. *Present address: Department of Anaesthesia, Sheffield University Medical School, Beech Hill Road, Sheffield S10 2RX.
SUMMARY The effects of a single bolus dose of etomidate 0.3 mg kg~1 or thiopentone 5mgkg~\ on the synthesis of corticosteroid hormones and adrenocorticotrophic hormone (ACTH), were compared for 24 h in 12 patients, undergoing minor surgery under general anaesthesia. Following opioid premedication i.m. and general anaesthesia, plasma cortisoi concentrations decreased transiently within the first hour of anaesthesia in all 12 patients. The six patients who received etomidate had statistically higher plasma 11-deoxycorticosterone concentrations at 4 and 24 h than those who had received thiopentone (P < 0.01). Throughout the study, no difference in plasma cortisoi, corticosterone or ACTH concentrations were found between the two groups. We have demonstrated a biochemical effect of a single bolus dose of etomidate consistent with incomplete inhibition of adrenocortical mitochondria! 11 fi-hydroxylase activity, but no clinically significant adrenocortical suppression.
56 ± 16 min). They were allocated randomly to receive thiopentone 5 mg kg" l or etomidate 0.3 mg kg" 1 i.v. to induce anaesthesia, which was maintained with 1.5% halothane and 67% nitrous oxide in oxygen. Respiration was spontaneous. One patient in each group required tracheal intubation, which was facilitated with suxamethonium 1 mg kg" 1 . Anaesthesia was induced between 10.45 a.m. and 4.15 p.m. and lasted 34 ± 16 min. Blood samples were withdrawn 30 min before, immediately after, and at 15 min, 1,4 and 24 h after the induction of anaesthesia. The plasma was separated, frozen and later analysed for plasma cortisoi, corticosterone, 11-deoxy corticosterone, and ACTH concentrations.
Downloaded from http://bja.oxfordjournals.org/ at University of Michigan on June 19, 2015
An increase in the mortality amongst trauma patients in an intensive care unit, coincident with the introduction of sedation using an infusion of etomidate, was reported by Ledingham and Watt (1983). Suppression of the adrenocortical secretion of cortisoi was demonstrated when etomidate was infused to these patients (Finlay and McKee, 1982; Ledingham et al., 1983; McKee and Finlay, 1983). The continued use of etomidate has been questioned (Committee on Safety of Medicines, 1983; Editorial, 1983), but in the absence of reported adverse effects from single bolus doses, its retention was advocated for the induction of anaesthesia in patients with asthma, drug allergy and peripheral circulatory failure (McDowall, 1983). In this study, the effects of a single bolus dose of etomidate or thiopentone on adrenocorticotrophic hormone (ACTH) production, and corticosteroid synthesis, were investigated in patients undergoing minor surgery under general anaesthesia.
ETOMIDATE INDUCTION AND CORTICOSTEROID SYNTHESIS
157
TABLE I. Patient data (mean values ± SD). ns = not significant (P > 0.05) Induction agent
Age(yr)
Weight (kg)
Group 1: Thiopentone (n = 6)
50 ± 1 8
76±6
10.45 14.00
14.20 15.00
15.10 15.15
32 ± 11
Group 2: Etomidate
48+17
73+10
11.40 11.55
13.00 13.45
14.55 16.15
35 + 21
Duration (min)
Starting time
50CH
400-
200-
3 a.
100-
RESULTS
The two groups did not differ significantly with respect to age, weight, starting time and duration of anaesthesia (table I).
0 1 L TL Time from induction of anaesthesia (h) FIG. 1. Serial plasma cortisol concentrations (mean ± SEM). (All patients n = 12.)
TABLE II. Serial plasma concentrations (mean ± SEM). Thiopentone: n = 6; etomidate: n = 6. *P < 0.01 Induction agent
Time from induction of anaesthesia - 30 min
Omin
15 min
lh
4h
24 h
Cortisol (nmol litre"')
Thiopentone Etomidate
307 ± 37 330 ± 67
225 ± 40 257 ± 43
105 ± 25 211 ±23
234 ± 72 151 ±33
344 ± 134 215 ±40
348 ± 98 445 ±42
Corticosterone (nmol litre"')
Thiopentone Etomidate
4.9 ±1.9 17.4 ±3.4
2.7 ±0.9 3.0± 1.1
2.0 ±0.5 0.7 ±0.2
7.5 ±3.3 1.7± 1.2
18.3 ±11.5 4.7 ±2.3
13.3 ±9.0 3.7 ±1.3
11-Deoxycorticosterone (pmol litre"1)
Thiopentone Etomidate
280 + 50 260 ± 30
220 ± 30 250 ± 20
190 ± 40 260 ± 40
590 ± 270 1700 ± 850
540 ± 200* 21900 ±9200
190 ± 30* 3100 ±910
ACTH (pmol litre"1)
Thiopentone Etomidate
12 ±2.8 15 ±2.9
9.5 ±1.6 14.0 ±2.4
19 ± 6.6 19 + 5.1
17 ±50 15 ±5.4
35 ±19 19 ±6.8
12 ± 3.4 18 ±3.4
Downloaded from http://bja.oxfordjournals.org/ at University of Michigan on June 19, 2015
Plasma corticosterone and 11-deoxycorticosterone concentrations were measured by radioimmunoassay after extraction and partial purification by paper chromatography (Fraser et al., 1975). Plasma cortisol and ACTH concentrations were measured directly using kits supplied by Corning Ltd and CIS (UK) Ltd, respectively. The coefficients of variation of the cortisol, corticosterone, 11-deoxycorticosterone and ACTH assays were 5.8%, 9.9%, 10.1% and 6.0%, respectively. '• The results were analysed for statistical significance using the Mann-Whitney U test.
BRITISH JOURNAL OF ANAESTHESIA
158
TABLE III. Plasma coriisol concentrations (mean values ± SEM). (All patients: n = 12). * Difference from plasma concentration at 1= —30 min; ns = not significant Time from induction of anaesthesia
Cortisol (nmol litre"1) *P
— 30 min
Omin
15 min
lh
4h
24 h
318 ± 3 7
241 ±29
199 + 16
192 ± 39
280 ± 7 1
392 ± 56
ns
<0.01
<0.05
ns
ns
Downloaded from http://bja.oxfordjournals.org/ at University of Michigan on June 19, 2015
date group at 1 h, but the difference did not achieve At no time did the concentrations differ signific- statistical significance. antly between the two groups (fig. 1, table II). Tak- Corticosterone and ACTH concentrations ing all 12 patients together, there were statistically There was wide variation in all measurements and significant decreases in the cortisol concentrations at no trends or statistically significant differences were 15 min (P < 0.01) and 60 min {P < 0.05) from induction of anaesthesia compared with the control noted (table II). concentration (table III). However, cortisol conDISCUSSION centrations remained within the laboratory refer1 ence range (150-690 nmol litre" ). Etomidate 0.3 mg kg" 1 , when used to induce anaesthesia, produced a significant increase in 11deoxycorticosterone concentrations at 4 and 24 h, when compared with thiopentone. No significant changes were seen in the plasma cortisol, ACTH or corticosterone concentrations. 18000n Previously, attention has focused on the readily measured plasma cortisol concentration, and not on 16000 other adrenocortical precursors. The infusion of etomidate has been shown to suppress adrenocortical secretion of cortisol in man (Fellows, Byrne and Etomidate Allison, 1983; Fellows etal., 1983; Sear etal., 1983), animals (Preziosi and Vacca, 1982; Fraser et al., 1984) and in adrenal cells in vitro (Kenyon et al., 1984). Such suppression may prejudice survival in the critically ill patient (Finlay and McKee, 1982; McKee and Finlay, 1983) in whom spontaneous adrenocortical failure is uncommon (Sainsbury, Thiopentone Stoddart and Watson, 1981). =F E (-V2) o e i y T u Large doses of opioids can suppress the cortisolS Time from induction of anaesthesia ( h) stress response after surgery (Hall et al., 1978). The statistically significant (if small) decrease in plasma FIG. 2. Serial plasma 11-deoxycorticosterone concentrations cortisol concentrations at 15 and 60 min in our (mean ± SEM). (All patients n = 12.) patients is similar to that reported in three patients who had received opioid premedication (Sebel, Ver/ 1-Deoxycorticosterone concentrations ghese and Makin, 1983). The transitory decreases in At 4 and 24 h, plasma 11-deoxycorticosterone cortisol concentration are not known to be harmful concentrations were significantly higher in the and are likely to be at least partly a result of the use etomidate group than in the thiopentone group (fig. of opioid premedication and general anaesthesia, a 2, table II). There was some increase in the etomi- common practice which occurred in 37% of patients Cortisol concentrations
ETOMIDATE INDUCTION AND CORTICOSTEROID SYNTHESIS
In summary, we have demonstrated a biochemical effect of a single bolus dose of etomidate 0.3 mg kg" 1 on adrenocortical steroid synthesis. The accumulation of 11-deoxycorticosterone at 4 and 24 h is consistent with the known inhibition of 11 (3-hydroxylase by etomidate (Owen and Spence, 1984). This inhibition was partial, as it failed to reduce the plasma concentrations of the hormones, cortisol and corticosterone, and there was no discernible increase in ACTH concentration. Thus, a bolus dose of etomidate 0.3 mg kg"1 causes no significant adrenocortical suppression. ACKNOWLEDGEMENTS
The technical assistance of Mrs C. D. Holloway and Miss M. C. Ingram is gratefully acknowledged.
REFERENCES
Committee on Safety of Medicines (1983). Letter of June 20, reprinted Lancet, 2, 60. Editorial (1983). Lancet, 2, 24. Fellows, I. W., Byrne, A. J., and Allison, S. P. (1983). Adrenocortical suppression with etomidate. Lancet, 2, 54. Fellows, I. W., Bastow, M. D., Byrne, A. J., and Allison, S. P. (1983). Adrenocortical suppression in multiply injured patients: a complication of etomidate treatment. Br. Med. J., 287, 1835. Finlay, W. E. I., and McKee, J. I. (1982). Serum cortisol levels in severely stressed patients. Lancet, 1, 1414. Fragen, R. J., Shanks, C. A., and Molteni, A. (1983). Effect on plasma cortisol concentrations of a single induction dose of etomidate or thiopentone. Lancet, 2, 625. Fraser, R., Guest, S., Holmes, E., Mason,P. A., Wilson, A., and Young, J. (1975). Comparison of radioimmunoassay and physiochemical methods as a means of estimating plasma aldosterone and plasma 11-deoxycorticosterone concentrations; in Vth Tenovus Workshop on Steroid Radioimmunoassay (eds G. H. D. Cameron, S. G. Hillier and K. Griffitys), p.283. Cardiff: Alpha Omega Alpha. Watt, I., Gray, C. E., Ledingham, I.McA., and Lever, A. F. (1984). The effect of etomidate on adrenocortical function in dogs before and during haemorrhagic shock. Endocrinology, (in press). Hall, G. M., Young, C , Holdcroft, A., and Alaghband-Zadeh, J. (1978). Substrate mobilisation during surgery: a comparison between halothane and fentanyl and anaesthesia. Anaesthesia, 33, 924. Kenyon, C. J., Young, J., Gray, C. E., and Fraser, R. (1984). Exhibition of steroidogenesis in isolated bovine adrenal cells. J. Clin. Endocrinol. Metab., 58, 947. Ledingham, I. McA., Finlay, W. E. I., Watt, I., and McKee, J. I. (1983). Etomidate and adrenocortical function. Lancet, 1, 1434. Watt, I. (1983). Influence of sedation on mortality in critically ill, multiple trauma patients. Lancet, 1, 1270. McDowall, D. G. (1983). Etomidate. Lancet, 2, 168. McKee, J. I., and Finlay, W. E. I. (1983). Cortisol replacement in severely stressed patients. Lancet, 1, 484. Miller, M., Sugden, C. J., and Spence, A. A. (1983). A simple computer based system for recording and retrieving key anaesthetic patient data. Anaesthesia, 37, 367. Owen, H., and Spence, A. A. (1984). Etomidate. Br.J. Anaesth., 56, 555. Preziosi, P., and Vacca, M. (1982). Etomidate and corticotrophic axis. Arch. Int. Pharmacodyn. Ther., 256, 308. Sainsbury, J. R. C , Stoddart, J. C , and Watson, M. J., (1981). Plasma cortisol levels: a comparison between sick patients and volunteers given intravenous cortisol. Anaesthesia, 36, 16. Sear, J. W., Allen, M. C , Gales, M., McQuay, H. J., Kay, N. H., McKenzie, P. J., and Moore, R. A. (1983). Suppression by etomidate of normal cortisol responses to anaesthesia and surgery. Lancet, 2, 1028. Sebel, P. S., Verghese, C , and Makin, H. L. J. (1983). Effect on plasma cortisol concentrations of a single induction dose of etomidate or thiopentone. Lancet, 2, 625. Todd, J. G., Duthie, D. J. R., and Spence, A. A. (1983). Computer-based anaesthetic records. Anaesthesia, 38, 172.
Downloaded from http://bja.oxfordjournals.org/ at University of Michigan on June 19, 2015
who underwent surgery in our hospital between 1982 and 1984 (Miller, Sugden and Spence, 1983; Todd, Duthie and Spence, 1983). Single bolus doses of etomidate 0.3 mg kg~' have not been shown to suppress cortisol secretion abnormally. Fragen, Shanks and Molteni (1983) reported a decrease in cortisol concentration of undisclosed significance in women receiving etomidate, when compared with those who were given thiopentone. As in our study, Sebel, Verghese and Makin (1983) failed to show a difference in plasma cortisol concentrations between patients given either thiopentone or etomidate, and the mean plasma cortisol concentrations in all three studies remained within the physiological range. The disproportionate increase in plasma 11deoxycorticosterone concentrations is consistent with an inhibition of 11 (3-hydroxylase activity and agrees with previous findings in dogs infused with etomidate (Fraser et al., 1984), and in bovine adrenocortical cells incubated with etomidate in vitro (Kenyon et al., 1984). That corticosterone and cortisol concentrations remained within the normal range suggests that the inhibition was incomplete and compensated by an increase in ACTH secretion. However, because of the marked variability in the ACTH concentrations measured, this increase could not be demonstrated statistically. In previous studies, evidence was obtained of additional effects earlier in the biosynthetic pathway, and an interference with mitochondrial corticosteroid mixed function oxidase reactions, possibly by interaction with cytochrome P450, was postulated. Such an effect would not have been apparent from the assays performed here and, if present, may have been less marked because high etomidate concentrations were maintained for a shorter time
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