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ETOMIDATE FOR INDUCTION OF ANAESTHESIA AT CAESAREAN SECTION: COMPARISON WITH THIOPENTONE
Br.J. Anaesth. (1979), 51, 135
ETOMIDATE FOR INDUCTION OF ANAESTHESIA AT CAESAREAN SECTION: COMPARISON WITH THIOPENTONE J. W. DOWNING, R. J. R. BULEY, J. G. BROCK-UTNE AND P. C. HOULTON SUMMARY
Thiopentone is a standard induction agent in obstetric anaesthesia (Bradford and Moir, 1969; Baraka et al., 1971; Peltz and Sinclair, 1973; Downing et al., 1976; Mahomedy et al., 1976). However, barbiturates cause some degree of cardiorespiratory depression, influencing maternal-fetal haemodynamics and transplacental exchange (Dundee and Wyant, 1974). Thiopentone crosses the placental barrier and druginduced depression of the newborn may result if a large dose is given to the mother (Finster and Poppers, 1968). It has been suggested that current investigations of various induction agents for Caesarean section are inappropriate in view of the extremely low frequency of drug-induced neonatal depression at elective section (Crawford, 1977). However, these considerations may not apply if the fetus is at risk. Etomidate, the new imidazole i.v. induction agent, has an action rapid in onset and of short duration. There is minimal alteration in cardiorespiratory function and recovery is uneventful (Morgan, Lumley and Whitwam, 1975; Fragen, Caldwell and Brunner, 1976). It does not cause detectable histamine release (Doenicke et al., 1973). Initially, etomidate possessed two undesirable side-effects: pain on injection and excessive involuntary movements during induction. The introduction of a new preparation of etomidate (Hendry, Miller and Lees, 1977) and the use of a rapid induction sequence (Downing et al., 1974) has reduced the frequency of both problems.
J. W. DOWNING, M.B., B.CH., F.F.A.(S.A.), F.F.A.R.C.S.(ENG); R. J. R. BULEY, M.B., B.CH., F.F.A.(S.A.); J. G. BROCK-UTNE, M.A., M.B., B.CH., CAND. MED. (BERGEN), F.F.A.(S.A.)j P . C . HOULTON, M.B., B.S.(HONS), F.F.A.(S.A.); Department of
Anaesthetics, Faculty of Medicine, University of Natal, P.O. Box 17039, Congella, 4013 Durban, S. Africa. 0007-0912/79/020135-06 $01.00
We describe the use of etomidate for anaesthesia at Caesarean section. The results are contrasted with those obtained from a control series receiving thiopentone (Buley et al., 1977). PATIENTS AND METHODS
Sixty mothers who conformed to the criteria of the "clinically acceptable ideal case" (Crawford, 1962) gave consent to the investigation. The patients were not in labour and the membranes were intact. In every patient, placental function was judged to be normal on clinical grounds. Gestational age was 38-42 weeks, confirmed by a positive foam test and an amniotic fluid lecithin-sphyngomyelin ratio greater than 2.5; the fetus was a singleton with vertex presenting. The mother lay on her left side during transfer to the operating theatre for elective Caesarean section. During anaesthesia and surgery a 15° foam rubber wedge was placed under the right buttock, providing left lateral tilt. A standard anaesthetic technique was used similar to that described by Buley and others (1977). In 30 mothers, etomidate was used as the i.v. induction agent in a dose of 0.3 mg kg" 1 and the remaining 30 received thiopentone 3.5 mg kg- 1 (control series). The control series includes 23 patients described in our previous report (Buley et al., 1977). Patients weighing more than 85 kg were excluded from the trial and the dose of the induction agent related to weight was not corrected for pregnancy. Tracheal intubation was facilitated by the simultaneous administration of suxamethonium 1.75 mg kg" 1 or 1 mg kg- 1 with thiopentone or etomidate from the same syringe (Downing et al., 1974). Manual pressure was applied to the cricoid cartilage by an assistant until the tracheal tube cuff was inflated. Ventilation of the lungs was controlled using a Manley ventilator delivering an expired minute © Macmillan Journals Ltd 1979
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Thirty mothers undergoing elective Caesarean section received thiopentone 3.5 mg kg" 1 and 30 received etomidate 0.3 mg kg" 1 for induction of anaesthesia. Subsequent management of anaesthesia was identical in both groups. Maternal to fetal base excess differences and the degree of biochemical correlation between mother and infant were more favourable following etomidate than following thiopentone. The clinical status of the newborn was considered superior with etomidate.
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BRITISH JOURNAL OF ANAESTHESIA
RESULTS
Mothers The average maternal age of the etomidate group (23.9 yr, SEM 1.0) was younger than that of the thiopentone control group (26.8 yr, SEM 0.5) (P< 0.05). The mean body weights of the two groups were comparable; etomidate 71.6 kg, SEM 1.9, v. thiopentone 70.0 kg, SEM 1.9. The arterial blood-gas status of the mothers at delivery (table I) showed respiratory alkalosis with a
TABLE I. Maternal arterial (Ma) blood-gas and acid-base values at delivery (mean ± SEM) in patients receiving thiopentone with nitrous oxide, oxygen and enflurane or etomidate with nitrous oxide, oxygen and enflurane Group Thiopentone
Etomidate
Mean S E M Mean S E M Significance 39.2 [H+] (nmol litre"1) Pco 2 (kPa) 4.23 Po 2 (kPa) 23.7 Base excess -3.6 (mmol litre"1)
0.9
41.7 0.6
P<0.05
0.06
4.16 0.05 22.4 1.1 - 5 . 6 0.3
n.s. n.s. P< 0.005
1.3 0.5
n.s. = not significant.
compensatory metabolic acidosis (more marked in the etomidate group (P< 0.005)) in the majority at delivery. Infants The average induction to delivery (I-D) and uterine incision to delivery (U-D) intervals were similar in both groups (table II). The time to sustained breathing (TSR) by the infants was slightly shorter with etomidate (0.1 >P>0.05), but much shorter than in our previously published left lateral tilt series (TSR thiopentone: left tilt 27.3 s±5.7 v. etomidate 10.8 s ±1.5 (P< 0.005)) (Buley et al., 1977). Apgar scores at 1, 2 and 5 min were similar (table II), a mild degree of neonatal depression (A—C 4-6) being encountered in the first 2 min of life in only three infants of the two groups. The acid-base and blood-gas values obtained from
TABLE II. Time intervals and clinical status of the infants whose mothers received thiopentone with nitrous oxide, oxygen and enflurane or etomidate with nitrous oxide, oxygen and enflurane. (Mean ± SEM) Etomidate
Thiopentone
I-D (min) U-D (s) TSR (s) Apgar score 1-3 4-6 7-8
Mean
SEM
Mean
SEM
Significance
10.1 61.5 19.6
0.6 5.9 4.4
10.5 56.8 10.8
0.5 5.4 1.5
n.s. n.s. 0.1
1 min 2 rain 5 min 1 rnin 2 rain 5 min 0 1 29
0 0 30
0 0 30
0 1 29
0 2 28
0 0 30
n.s. n.s. n.s.
•Original thiopentone left lateral tilt series (Buley et al., 1977); 27.3 s ( + SEM 5.7) v. 10.8 s ( ± S E M 1.5) etomidate, P< 0.005.
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volume of 130 ml kg" 1 designed to maintain maternal Pa C02 within a range 3.7-4.8 kPa. Anaesthesia was maintained with 50% nitrous oxide in oxygen (monitored with an Ohio Airco Model 600 Oxygen Analyser) and enflurane 0.5-0.8%. Further muscle relaxation was provided by i.v. injection of pancuronium 2-4 mg. Following delivery of the infant, pethidine 50 mg was administered i.v. The residual effects of the non-depolarizing drug were antagonized at the end of the procedure with neostigmine 5 mg mixed with atropine 1.2 mg i.v. (Brock-Utne et al., 1978). At the time of delivery maternal arterial and fetal umbilical cord blood samples were obtained and analysed using an IL 413 blood-gas analyser. Results were verified using a Radiometer B.M.S. Mk II blood-gas apparatus. The electrodes were calibrated using standard buffer solutions and certified gases or a Radiometer gas-mixing device. Base excess values were calculated. Student's t test for unpaired data was used in analysing the results. In calculating fetal base excess values, corrections were made for the degree of haemoglobin desaturation in the umbilical cord blood samples (Buley et al., 1977).
ETOMIDATE FOR CAESAREAN SECTION
137
TABLE III. Comparison of umbilical venous (Uv) and arterial Blood-gas and acid-base differences between (Ua) biochemical values, of infants whose mothers received mother and fetus A(Ma —Ua) and A(Ma —Uv) are either thiopentone with nitrous oxide, oxygen and enflurane or etomidate with nitrous oxide, oxygen and enflurane. (Mean ± presented in table IV. BE values are significantly smaller for etomidate than for thiopentone. SEM)
Umbilical venous to arterial differences A(Uv— Ua) representing the fetal internal environment (Dawes, Mott and Widdicombe, 1974) were similar with both drugs.
Group Thiopentone
Etomidate
Mean S E M Mean SEM Significance
Uv Ua Base excess (mmol litre"1) Uv Ua
Biochemical interrelationships 45.3 1.1 51.0 1.3
47.6 0.6 53.3 0.7
n.s. n.s.
Correlation coefficients (r) for maternal arterial v. fetal blood-gas results are shown in table V. The expected close correlation between Ma and Ua TABLE V. Correlation coefficients (r) for
5.34 0.1 6.42 0.14
5.33 0.09 6.43 0.12
n.s. n.s.
4.4 0.17 2.66 0.14
4.30 0.10 2.68 0.08
n.s. n.s.
71.9 2.8 39.9 3.2
71.1 1.6 39.3 2.1
maternal v. fetal blood-gas results in groups receiving either thiopentone with nitrous oxide, oxygen and enflurane or etomidate with nitrous oxide, oxygen and enflurane
n.s. n.s.
Thiopentone
Etomidate
A(Ma-Uv) A(Ma-Ua)
0.83*** 0.76*** 0.08 0.17
0.61*** 0.24 -0.45* -0.52**
[H+] Uv
Ua -4.7 -6.8
0.7 0.7
-6.5 -8.0
0.3 0.3
P<0.05 n.s.
Pco2 Uv Ua
n.s. = not significant.
A(Ma-Uv) A(Ma-Ua)
the umbilical venous (Uv) and arterial (Ua) blood samples in the thiopentone and etomidate groups are compared in table III. There was a relatively greater degree of metabolic acidosis in the infants whose mothers received etomidate.
Thiopentone
Etomidate
Mean S E M Mean SEM Significance [H+] (nmol litre"1)
A(Ma-Uv) 6.1 A(Ma-Ua) 11.8 Pco2 (kPa) A(Ma-Uv) 1.12 A(Ma-Ua) 2.19 Base excess 1 (mmol litre" ) A(Ma-Uv) 2.3 A(Ma-Ua) 3.7 n.s. = not significant.
0.6 0.9
5.9 11.6
+ 0.5 ±0.8
0.9 0.13
1.17 ±0.08 2.27 ±0.11
0.2 0.3
1.3 2.8
+ 0.2 ±0.3
n.s. n.s. n.s. n.s. P< 0.001 P<0.05
0.46* 0.31 -0.11 -0.08
0.58*** 0.50** 0.01 0.05
0.77*** 0.73*** 0.02 -0.09
0.65*** 0.31 0.16 0.47**
Base excess Uv Ua
TABLE IV. Maternal arterial to umbilical venous A(Ma— Uv) and umbilical arterial A(Ma — Ua) differences in women who received either thiopentone with nitrous oxide, oxygen and enflurane or etomidate with nitrous oxide, oxygen and enflurane. (Mean ± SEM)
13
Ma v.
A(Ma-Uv) A(Ma-Ua)
Significance (d.f. = 28): *P < 0.05; **P<0.005; ***P<0.001.
hydrogen ion concentration [H+] and base excess (BE) values was not seen with etomidate. However, r values for Ma v. Uv/Ua Pco 2 were greater with etomidate. With etomidate, a negative correlation emerged between Ma and A(Ma —Uv)/A(Ma—Ua) [H+] and an unusual relationship was apparent between Ma and A(Ma-Ua) BE. DISCUSSION
The first clinical trials of etomidate were encouraging (Doenicke et al., 1973; Morgan, Lumley and Whitman, 1975), and, in view of the increasing number of adverse reactions associated with the administration of other i.v. induction agents (Dundee,
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(nmol litre"1) Uv Ua Pco2(kPa) Uv Ua Po2 (kPa) Uv Ua O 2 saturation
138
Mother and fetus Both groups of patients in this study were placed in the left lateral tilt position (Buley et al., 1977). Although the mothers in the etomidate group were younger on average than the control patients, the mean parity in the two series was comparable. Any advantage accruing to the infants of the etomidate group because of maternal age differences should be offset by the relatively greater degree of maternal acidaemia present in the etomidate group. Unfortunately, blood-gas and acid-base measurements obtained from the umbilical vessels are indicative of the fetal biochemical state only at the time of sampling, and, although our programme attempted to ensure that the only difference in the two groups was the induction agent, we should not disregard other factors which may influence maternal to fetal exchange. Preoperative placental function is important in this regard, but clinical data did not indicate any major differences between the groups .Bloodflowthrough the uterus and placenta is impeded during uterine contraction and is influenced by posture. None of our patients was in labour and t i e effects of posture on chorio-decidual haemodynamics (Downing et al., 1974; Buley et al., 1977) were standardized. Surgical interference and rupture of the membranes also disturb fetal blood-gas homeostasis and this can be difficult to evaluate (Fothergill, Robertson and Bond, 1971). However, all the Caesarean sections were performed by the same group of surgeons using the
same technique, as indicated by the similar I-D and U-D intervals in both groups. Fetal state at delivery, as indicated by Ua sample (Dawes, Mott and Widdicombe, 1954; James et al., 1958), was similar in both groups, except for the decrease in Uv BE with etomidate. When the blood-gas status of the mother is related specifically to the fetal state using the indices A(Ma—Uv) and A(Ma —Ua), etomidate would appear to provide advantages over thiopentone. This was not reflected in the Apgar scores at 1 min. Marx, Mahajan and Miclat (1977) have demonstrated that a correlation exists between the Ua sample and the (A—C) Apgar score only at the moment of birth. The clinical impression that the etomidate group of infants responded more favourably to introduction to the outside environment was reflected to some extent by differences in the time to spontaneous respiration. To evaluate further the cause of this improved fetal tissue perfusion, we examined the effect of etomidate on the biochemical state of umbilical venous (Uv) blood. There was an improvement in Uv BE of the etomidate group. Furthermore, the A(Ma — Uv) BE difference was significantly smaller with etomidate than with thiopentone. Thus there would appear to be improved matching of maternal to placental circulation after the administration of etomidate. This statement is supported further by the close correlation between Ma v. Uv/Ua Pco 2 with etomidate. The absence of a correlation between Ma and Ua [H+] and BE in the etomidate series, coupled with the emergence of a significant negative relationship, Ma v. A(Ma-Uv)/A(Ma-Ua) [H+] and the positive correlation noted for Ma v. A(Ma—Ua) BE (table V) with etomidate, deserves further comment. On pharmacological grounds, fetal cardiovascular haemodynamics and organ perfusion should be maintained better following the injection of etomidate, relative to thiopentone. This may improve the transport of fetal circulating fixed acids to the placenta. A review of the literature reveals that no induction agent investigated for Caesarean section has proved manifestly superior to thiopentone (Bradford and Moir, 1969; Baraka et al., 1971; Peltz and Sinclair, 1973; Downing et al., 1976; Mahomedy et al., 1976; Crawford, 1977). Indeed, James and others (1977) and Magno (1976) were unable to recommend lumbar extradural analgesia over a thiopentone, nitrous oxide, oxygen, volatile agent and relaxant anaesthesia for Caesarean section. Our study of etomidate suggests that this drug may be of particular value in obstetric anaesthesia,
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1976), the drug could represent a useful addition to the obstetric anaesthetist's armamentarium. Etomidate produces rapid anaesthesia in one armbrain circulation time and, unlike thiopentone, it is hydrolysed rapidly to an inactive substance so that recovery is faster than that following barbiturates (Hendry, Miller and Lees, 1977; Lees and Hendry, 1977). Etomidate causes minimal alteration in the cardiorespiratory state (Morgan, Lumley and Whitwam, 1975; Fragen, Caldwell and Brunner, 1976; Gooding and Corssen, 1976), and does not appear to release histamine in detectable quantities (Doenicke et al., 1973). The advent of a new polyethyleneglycol solvent for etomidate has decreased significantly the frequency of pain on i.v. injection (Hendry, Miller and Lees, 1977), and our routine induction technique for Caesarean section (Downing et al., 1974) allows little time for excess movement at induction to be a problem.
BRITISH JOURNAL OF ANAESTHESIA
ETOMIDATE FOR CAESAREAN SECTION especially in the clinically ill fetus whose biochemical status may be served better. Further testing of this hypothesis is indicated. REFERENCES
James, L. S., Weisbrot, I. M., Prince, C. E., Holaday, D. A., and Apgar, V. (1958). The acid-base status of human infants in relation to birth asphyxia and the onset of respiration. J. Pediatr., 52, 379. Lees, N. W., and Hendry, J. G. B. (1977). Etomidate in urological outpatient anaesthesia: a clinical evaluation. Anaesthesia, 32, 592. Magno, R. (1976). Anaesthesia for Caesarean section. The effects upon neonatal respiratory adaption of different methods of anaesthesia for elective Caesarean section. Thesis, Goteborg, p. 20. Mahomedy, M. C , Downing, J. W., Jeal, D. E., and Coleman, A. J. (1976). Anaesthetic induction for Caesarean section with propanidid. Anaesthesia, 31, 205. Marx, G. F., Mahajan, S., and Miclat, M. N. (1977). Correlation of biochemical data with Apgar scores at birth and at one minute. Br. J. Anaesth., 49, 831. Morgan, M., Lumley,. J., and Whitwam, J. G. (1975). Etomidate, a new water soluble non-barbiturate intravenous induction agent. Lancet, 1, 955. Peltz, P., and Sinclair, D. M. (1973). Induction agents for Caesarean section: A comparison of thiopentone and ketamine. Anaesthesia, 28, 37.
ETOMIDATE POUR INDUCTION DE L'ANESTHESIE LORS D'UNE OPERATION CESARIENNE: COMPARAISON AVEC LE THIOPENTONE RESUME
Trente meres devant subir une operation cesarienne a froid ont recu 3,5 mg kg" 1 de thiopentone, alors que 30 autres recevaient 0,3 mg kg- 1 d'etomidate pour l'induction de Panesthesie. La conduite ulterieure de Panesthesie a autrement ete identique dans les deux cas. Les differences excedentaires de la base entre la mere et l'enfant ainsi que le degre de correlation biochimique entre la mere et l'enfant ont ete plus favorables apres l'etomidate qu'apres la thiopentone. Le statut clinique du nouveau-ne a ete consider^ comme etant meilleur avec l'etomidate.
ETOMIDAT ZUR EINLEITUNG DER NARKOSE FUR KAISERSCHNITT: EIN VERGLEICH MIT THIOPENTON ZUSAMMENFASSUNG
Von 60 Muttern, die sich fur einen Kaiserschnitt entschieden hatten, erhielten 30 3,5 mg kg- 1 Thiopenton und 30 OjSmgkg- 1 Etomidat zur Einfuhrung der Narkose. Danach wurde die Narkose in beiden Gruppen identisch weitergefuhrt. Die von der Mutter zum Fetus ubergehenden basalen, unterschiedlichen Uberschiisse und der Grad der biochemischen Wechselbeziehung zwischen Mutter und Kind waren nach Etomidat giinstiger als nach Thiopenton. Der klinische Zustand der Neugeborenen wurde nach. Etomidat fiir iiberlegen ergehalten.
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Baraka, A., O'Brien, M., Aslanian, E., and Saade, R. (1971). Propanidid versus thiopentone for induction of general anaesthesia in elective Caesarean section. Br. J. Anaesth., 43, 609. Bradford, E., and Moir, D. (1969). Anaesthesia for Caesarean section: A comparison of thiopentone and propanidid. Br. J. Anaesth., 41, 274. Brock-Utne, J. G., Downing, J. W., Welman, S., Dimopoulos, G. E., and Moshal, M. G. (1978). Lower esophageal sphincter tone during reversal of neuromuscular blockade by atropine and neostigmine. Anesth. Analg. (Cleve.), 57, 171. Buley, R. J. R., Downing, J. W., Brock-Utne, J. G., and Cuerden, C. (1977). Right versus left lateral tilt for Caesarean section. Br. J. Anaesth., 49, 1009. Crawford, J. S. (1962). Anaesthesia for Caesarean section: a proposal for evaluation, with analysis of a method. Br. J. Anaesth., 34, 179. (1977). Obstetrics, analgesia and anaesthesia. Br. J. Anaesth., 49, 19. Dawes, G. S., Mott, J. C , and Widdicombe, J. C. (1954). The fetal circulation in the lamb. J. Physiol., 126, 563. Doenicke, A., Lorenz, W., Beigl, R., Bezecny, H., Uhlig, G., Kalmar, L., Praetorius, B., and Mann, G. (1973). Histamine release after intravenous application of short acting hypnotics. Br. J. Anaesth., 45, 1097. Downing, J. W., Coleman, A. J., Mahomedy, M. C , Jeal, D. E., and Mahomedy, Y. H. (1974). Lateral table tilt for Caesarean section. Anaesthesia, 29, 696. Mahomedy, M. C , Jeal, D. E., and Allen, P. J. (1976). Anaesthesia for Caesarean section with ketamine. Anaesthesia, 31, 883. Dundee, J. W. (1976). Hypersensitivity to i.v. anaesthetic agents. Br. J. Anaesth., 48, 57. Wyant, G. M. (1974). Intravenous Anaesthesia: Barbiturates: Effect on the body, Ch. 6, p. 76. Edinburgh: Churchill-Livingstone. Finster, M., and Poppers, P. J. (1968). Safety of thiopentone used for induction of general anaesthesia in elective Caesarean section. Anesthesiology, 29, 190. Fothergill, R. J., Robertson, A., and Bond, R. A. (1971). Neonatal acidaemia related to procrastination at Caesarean section. J. Obstet. Gynaecol. Br. Commonw., 78, 1010. Fragen, R. J., Caldwell, N., and Brunner, E. A. (1976). Clinical use of etomidate for anaesthesia induction: A preliminary report. Anesth. Analg. {Cleve.), 55, 730. Gooding, J. M., and Corssen, G. (1976). Etomidate: An ultrashort acting non-barbiturate agent for anesthesia induction. Anaesth. Analg. (Cleve.), 55, 286. Hendry, J. G. B., Miller, B. M., and Lees, N. W. (1977). Etomidate in a new solvent. A clinical evaluation. Anaesthesia, 32, 996. James, F. M., Crawford, J. S., Hopkinson, R., Davies, P., and Naiem, H. (1977). A comparison of general anaesthesia and lumbar epidural analgesia for elective Cesarean section. Anesth. Analg. (Cleve.), 56, 228.
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BRITISH JOURNAL OF ANAESTHESIA ETOMIDATA PARA LA INDUCCION DE ANESTESIA EN SECCION CESAREA: COMPARACION CON TIOPENTONA
SUMARIO Treinta madres sometidas a secci6n cesarea electiva recibieron 3,5 mg kg" 1 de tiopentona y 30 recibieron 0j3 mg kg" 1 de etomidata para induction de anestesia. La
administracion posterior de anestesia fue identica para ambos grupos. Las diferencias entre el exceso basico materno y fetal y el grado de correlation bioquimica entre madre e infante fueron mas favorables tras la administracion j e etomidata que tras la administracion de tiopentona. El estado clinico del recien nacido fue considerado supei ior con etomidata.
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ETOMIDATE FOR INDUCTION OF ANAESTHESIA AT CAESAREAN SECTION: COMPARISON WITH THIOPENTONE J. W. DOWNING, R. J. R. BULEY, J. G. BROCK-UTNE AND P. C. HOULTON SUMMARY
Thiopentone is a standard induction agent in obstetric anaesthesia (Bradford and Moir, 1969; Baraka et al., 1971; Peltz and Sinclair, 1973; Downing et al., 1976; Mahomedy et al., 1976). However, barbiturates cause some degree of cardiorespiratory depression, influencing maternal-fetal haemodynamics and transplacental exchange (Dundee and Wyant, 1974). Thiopentone crosses the placental barrier and druginduced depression of the newborn may result if a large dose is given to the mother (Finster and Poppers, 1968). It has been suggested that current investigations of various induction agents for Caesarean section are inappropriate in view of the extremely low frequency of drug-induced neonatal depression at elective section (Crawford, 1977). However, these considerations may not apply if the fetus is at risk. Etomidate, the new imidazole i.v. induction agent, has an action rapid in onset and of short duration. There is minimal alteration in cardiorespiratory function and recovery is uneventful (Morgan, Lumley and Whitwam, 1975; Fragen, Caldwell and Brunner, 1976). It does not cause detectable histamine release (Doenicke et al., 1973). Initially, etomidate possessed two undesirable side-effects: pain on injection and excessive involuntary movements during induction. The introduction of a new preparation of etomidate (Hendry, Miller and Lees, 1977) and the use of a rapid induction sequence (Downing et al., 1974) has reduced the frequency of both problems.
J. W. DOWNING, M.B., B.CH., F.F.A.(S.A.), F.F.A.R.C.S.(ENG); R. J. R. BULEY, M.B., B.CH., F.F.A.(S.A.); J. G. BROCK-UTNE, M.A., M.B., B.CH., CAND. MED. (BERGEN), F.F.A.(S.A.)j P . C . HOULTON, M.B., B.S.(HONS), F.F.A.(S.A.); Department of
Anaesthetics, Faculty of Medicine, University of Natal, P.O. Box 17039, Congella, 4013 Durban, S. Africa. 0007-0912/79/020135-06 $01.00
We describe the use of etomidate for anaesthesia at Caesarean section. The results are contrasted with those obtained from a control series receiving thiopentone (Buley et al., 1977). PATIENTS AND METHODS
Sixty mothers who conformed to the criteria of the "clinically acceptable ideal case" (Crawford, 1962) gave consent to the investigation. The patients were not in labour and the membranes were intact. In every patient, placental function was judged to be normal on clinical grounds. Gestational age was 38-42 weeks, confirmed by a positive foam test and an amniotic fluid lecithin-sphyngomyelin ratio greater than 2.5; the fetus was a singleton with vertex presenting. The mother lay on her left side during transfer to the operating theatre for elective Caesarean section. During anaesthesia and surgery a 15° foam rubber wedge was placed under the right buttock, providing left lateral tilt. A standard anaesthetic technique was used similar to that described by Buley and others (1977). In 30 mothers, etomidate was used as the i.v. induction agent in a dose of 0.3 mg kg" 1 and the remaining 30 received thiopentone 3.5 mg kg- 1 (control series). The control series includes 23 patients described in our previous report (Buley et al., 1977). Patients weighing more than 85 kg were excluded from the trial and the dose of the induction agent related to weight was not corrected for pregnancy. Tracheal intubation was facilitated by the simultaneous administration of suxamethonium 1.75 mg kg" 1 or 1 mg kg- 1 with thiopentone or etomidate from the same syringe (Downing et al., 1974). Manual pressure was applied to the cricoid cartilage by an assistant until the tracheal tube cuff was inflated. Ventilation of the lungs was controlled using a Manley ventilator delivering an expired minute © Macmillan Journals Ltd 1979
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Thirty mothers undergoing elective Caesarean section received thiopentone 3.5 mg kg" 1 and 30 received etomidate 0.3 mg kg" 1 for induction of anaesthesia. Subsequent management of anaesthesia was identical in both groups. Maternal to fetal base excess differences and the degree of biochemical correlation between mother and infant were more favourable following etomidate than following thiopentone. The clinical status of the newborn was considered superior with etomidate.
136
BRITISH JOURNAL OF ANAESTHESIA
RESULTS
Mothers The average maternal age of the etomidate group (23.9 yr, SEM 1.0) was younger than that of the thiopentone control group (26.8 yr, SEM 0.5) (P< 0.05). The mean body weights of the two groups were comparable; etomidate 71.6 kg, SEM 1.9, v. thiopentone 70.0 kg, SEM 1.9. The arterial blood-gas status of the mothers at delivery (table I) showed respiratory alkalosis with a
TABLE I. Maternal arterial (Ma) blood-gas and acid-base values at delivery (mean ± SEM) in patients receiving thiopentone with nitrous oxide, oxygen and enflurane or etomidate with nitrous oxide, oxygen and enflurane Group Thiopentone
Etomidate
Mean S E M Mean S E M Significance 39.2 [H+] (nmol litre"1) Pco 2 (kPa) 4.23 Po 2 (kPa) 23.7 Base excess -3.6 (mmol litre"1)
0.9
41.7 0.6
P<0.05
0.06
4.16 0.05 22.4 1.1 - 5 . 6 0.3
n.s. n.s. P< 0.005
1.3 0.5
n.s. = not significant.
compensatory metabolic acidosis (more marked in the etomidate group (P< 0.005)) in the majority at delivery. Infants The average induction to delivery (I-D) and uterine incision to delivery (U-D) intervals were similar in both groups (table II). The time to sustained breathing (TSR) by the infants was slightly shorter with etomidate (0.1 >P>0.05), but much shorter than in our previously published left lateral tilt series (TSR thiopentone: left tilt 27.3 s±5.7 v. etomidate 10.8 s ±1.5 (P< 0.005)) (Buley et al., 1977). Apgar scores at 1, 2 and 5 min were similar (table II), a mild degree of neonatal depression (A—C 4-6) being encountered in the first 2 min of life in only three infants of the two groups. The acid-base and blood-gas values obtained from
TABLE II. Time intervals and clinical status of the infants whose mothers received thiopentone with nitrous oxide, oxygen and enflurane or etomidate with nitrous oxide, oxygen and enflurane. (Mean ± SEM) Etomidate
Thiopentone
I-D (min) U-D (s) TSR (s) Apgar score 1-3 4-6 7-8
Mean
SEM
Mean
SEM
Significance
10.1 61.5 19.6
0.6 5.9 4.4
10.5 56.8 10.8
0.5 5.4 1.5
n.s. n.s. 0.1
1 min 2 rain 5 min 1 rnin 2 rain 5 min 0 1 29
0 0 30
0 0 30
0 1 29
0 2 28
0 0 30
n.s. n.s. n.s.
•Original thiopentone left lateral tilt series (Buley et al., 1977); 27.3 s ( + SEM 5.7) v. 10.8 s ( ± S E M 1.5) etomidate, P< 0.005.
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volume of 130 ml kg" 1 designed to maintain maternal Pa C02 within a range 3.7-4.8 kPa. Anaesthesia was maintained with 50% nitrous oxide in oxygen (monitored with an Ohio Airco Model 600 Oxygen Analyser) and enflurane 0.5-0.8%. Further muscle relaxation was provided by i.v. injection of pancuronium 2-4 mg. Following delivery of the infant, pethidine 50 mg was administered i.v. The residual effects of the non-depolarizing drug were antagonized at the end of the procedure with neostigmine 5 mg mixed with atropine 1.2 mg i.v. (Brock-Utne et al., 1978). At the time of delivery maternal arterial and fetal umbilical cord blood samples were obtained and analysed using an IL 413 blood-gas analyser. Results were verified using a Radiometer B.M.S. Mk II blood-gas apparatus. The electrodes were calibrated using standard buffer solutions and certified gases or a Radiometer gas-mixing device. Base excess values were calculated. Student's t test for unpaired data was used in analysing the results. In calculating fetal base excess values, corrections were made for the degree of haemoglobin desaturation in the umbilical cord blood samples (Buley et al., 1977).
ETOMIDATE FOR CAESAREAN SECTION
137
TABLE III. Comparison of umbilical venous (Uv) and arterial Blood-gas and acid-base differences between (Ua) biochemical values, of infants whose mothers received mother and fetus A(Ma —Ua) and A(Ma —Uv) are either thiopentone with nitrous oxide, oxygen and enflurane or etomidate with nitrous oxide, oxygen and enflurane. (Mean ± presented in table IV. BE values are significantly smaller for etomidate than for thiopentone. SEM)
Umbilical venous to arterial differences A(Uv— Ua) representing the fetal internal environment (Dawes, Mott and Widdicombe, 1974) were similar with both drugs.
Group Thiopentone
Etomidate
Mean S E M Mean SEM Significance
Uv Ua Base excess (mmol litre"1) Uv Ua
Biochemical interrelationships 45.3 1.1 51.0 1.3
47.6 0.6 53.3 0.7
n.s. n.s.
Correlation coefficients (r) for maternal arterial v. fetal blood-gas results are shown in table V. The expected close correlation between Ma and Ua TABLE V. Correlation coefficients (r) for
5.34 0.1 6.42 0.14
5.33 0.09 6.43 0.12
n.s. n.s.
4.4 0.17 2.66 0.14
4.30 0.10 2.68 0.08
n.s. n.s.
71.9 2.8 39.9 3.2
71.1 1.6 39.3 2.1
maternal v. fetal blood-gas results in groups receiving either thiopentone with nitrous oxide, oxygen and enflurane or etomidate with nitrous oxide, oxygen and enflurane
n.s. n.s.
Thiopentone
Etomidate
A(Ma-Uv) A(Ma-Ua)
0.83*** 0.76*** 0.08 0.17
0.61*** 0.24 -0.45* -0.52**
[H+] Uv
Ua -4.7 -6.8
0.7 0.7
-6.5 -8.0
0.3 0.3
P<0.05 n.s.
Pco2 Uv Ua
n.s. = not significant.
A(Ma-Uv) A(Ma-Ua)
the umbilical venous (Uv) and arterial (Ua) blood samples in the thiopentone and etomidate groups are compared in table III. There was a relatively greater degree of metabolic acidosis in the infants whose mothers received etomidate.
Thiopentone
Etomidate
Mean S E M Mean SEM Significance [H+] (nmol litre"1)
A(Ma-Uv) 6.1 A(Ma-Ua) 11.8 Pco2 (kPa) A(Ma-Uv) 1.12 A(Ma-Ua) 2.19 Base excess 1 (mmol litre" ) A(Ma-Uv) 2.3 A(Ma-Ua) 3.7 n.s. = not significant.
0.6 0.9
5.9 11.6
+ 0.5 ±0.8
0.9 0.13
1.17 ±0.08 2.27 ±0.11
0.2 0.3
1.3 2.8
+ 0.2 ±0.3
n.s. n.s. n.s. n.s. P< 0.001 P<0.05
0.46* 0.31 -0.11 -0.08
0.58*** 0.50** 0.01 0.05
0.77*** 0.73*** 0.02 -0.09
0.65*** 0.31 0.16 0.47**
Base excess Uv Ua
TABLE IV. Maternal arterial to umbilical venous A(Ma— Uv) and umbilical arterial A(Ma — Ua) differences in women who received either thiopentone with nitrous oxide, oxygen and enflurane or etomidate with nitrous oxide, oxygen and enflurane. (Mean ± SEM)
13
Ma v.
A(Ma-Uv) A(Ma-Ua)
Significance (d.f. = 28): *P < 0.05; **P<0.005; ***P<0.001.
hydrogen ion concentration [H+] and base excess (BE) values was not seen with etomidate. However, r values for Ma v. Uv/Ua Pco 2 were greater with etomidate. With etomidate, a negative correlation emerged between Ma and A(Ma —Uv)/A(Ma—Ua) [H+] and an unusual relationship was apparent between Ma and A(Ma-Ua) BE. DISCUSSION
The first clinical trials of etomidate were encouraging (Doenicke et al., 1973; Morgan, Lumley and Whitman, 1975), and, in view of the increasing number of adverse reactions associated with the administration of other i.v. induction agents (Dundee,
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(nmol litre"1) Uv Ua Pco2(kPa) Uv Ua Po2 (kPa) Uv Ua O 2 saturation
138
Mother and fetus Both groups of patients in this study were placed in the left lateral tilt position (Buley et al., 1977). Although the mothers in the etomidate group were younger on average than the control patients, the mean parity in the two series was comparable. Any advantage accruing to the infants of the etomidate group because of maternal age differences should be offset by the relatively greater degree of maternal acidaemia present in the etomidate group. Unfortunately, blood-gas and acid-base measurements obtained from the umbilical vessels are indicative of the fetal biochemical state only at the time of sampling, and, although our programme attempted to ensure that the only difference in the two groups was the induction agent, we should not disregard other factors which may influence maternal to fetal exchange. Preoperative placental function is important in this regard, but clinical data did not indicate any major differences between the groups .Bloodflowthrough the uterus and placenta is impeded during uterine contraction and is influenced by posture. None of our patients was in labour and t i e effects of posture on chorio-decidual haemodynamics (Downing et al., 1974; Buley et al., 1977) were standardized. Surgical interference and rupture of the membranes also disturb fetal blood-gas homeostasis and this can be difficult to evaluate (Fothergill, Robertson and Bond, 1971). However, all the Caesarean sections were performed by the same group of surgeons using the
same technique, as indicated by the similar I-D and U-D intervals in both groups. Fetal state at delivery, as indicated by Ua sample (Dawes, Mott and Widdicombe, 1954; James et al., 1958), was similar in both groups, except for the decrease in Uv BE with etomidate. When the blood-gas status of the mother is related specifically to the fetal state using the indices A(Ma—Uv) and A(Ma —Ua), etomidate would appear to provide advantages over thiopentone. This was not reflected in the Apgar scores at 1 min. Marx, Mahajan and Miclat (1977) have demonstrated that a correlation exists between the Ua sample and the (A—C) Apgar score only at the moment of birth. The clinical impression that the etomidate group of infants responded more favourably to introduction to the outside environment was reflected to some extent by differences in the time to spontaneous respiration. To evaluate further the cause of this improved fetal tissue perfusion, we examined the effect of etomidate on the biochemical state of umbilical venous (Uv) blood. There was an improvement in Uv BE of the etomidate group. Furthermore, the A(Ma — Uv) BE difference was significantly smaller with etomidate than with thiopentone. Thus there would appear to be improved matching of maternal to placental circulation after the administration of etomidate. This statement is supported further by the close correlation between Ma v. Uv/Ua Pco 2 with etomidate. The absence of a correlation between Ma and Ua [H+] and BE in the etomidate series, coupled with the emergence of a significant negative relationship, Ma v. A(Ma-Uv)/A(Ma-Ua) [H+] and the positive correlation noted for Ma v. A(Ma—Ua) BE (table V) with etomidate, deserves further comment. On pharmacological grounds, fetal cardiovascular haemodynamics and organ perfusion should be maintained better following the injection of etomidate, relative to thiopentone. This may improve the transport of fetal circulating fixed acids to the placenta. A review of the literature reveals that no induction agent investigated for Caesarean section has proved manifestly superior to thiopentone (Bradford and Moir, 1969; Baraka et al., 1971; Peltz and Sinclair, 1973; Downing et al., 1976; Mahomedy et al., 1976; Crawford, 1977). Indeed, James and others (1977) and Magno (1976) were unable to recommend lumbar extradural analgesia over a thiopentone, nitrous oxide, oxygen, volatile agent and relaxant anaesthesia for Caesarean section. Our study of etomidate suggests that this drug may be of particular value in obstetric anaesthesia,
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1976), the drug could represent a useful addition to the obstetric anaesthetist's armamentarium. Etomidate produces rapid anaesthesia in one armbrain circulation time and, unlike thiopentone, it is hydrolysed rapidly to an inactive substance so that recovery is faster than that following barbiturates (Hendry, Miller and Lees, 1977; Lees and Hendry, 1977). Etomidate causes minimal alteration in the cardiorespiratory state (Morgan, Lumley and Whitwam, 1975; Fragen, Caldwell and Brunner, 1976; Gooding and Corssen, 1976), and does not appear to release histamine in detectable quantities (Doenicke et al., 1973). The advent of a new polyethyleneglycol solvent for etomidate has decreased significantly the frequency of pain on i.v. injection (Hendry, Miller and Lees, 1977), and our routine induction technique for Caesarean section (Downing et al., 1974) allows little time for excess movement at induction to be a problem.
BRITISH JOURNAL OF ANAESTHESIA
ETOMIDATE FOR CAESAREAN SECTION especially in the clinically ill fetus whose biochemical status may be served better. Further testing of this hypothesis is indicated. REFERENCES
James, L. S., Weisbrot, I. M., Prince, C. E., Holaday, D. A., and Apgar, V. (1958). The acid-base status of human infants in relation to birth asphyxia and the onset of respiration. J. Pediatr., 52, 379. Lees, N. W., and Hendry, J. G. B. (1977). Etomidate in urological outpatient anaesthesia: a clinical evaluation. Anaesthesia, 32, 592. Magno, R. (1976). Anaesthesia for Caesarean section. The effects upon neonatal respiratory adaption of different methods of anaesthesia for elective Caesarean section. Thesis, Goteborg, p. 20. Mahomedy, M. C , Downing, J. W., Jeal, D. E., and Coleman, A. J. (1976). Anaesthetic induction for Caesarean section with propanidid. Anaesthesia, 31, 205. Marx, G. F., Mahajan, S., and Miclat, M. N. (1977). Correlation of biochemical data with Apgar scores at birth and at one minute. Br. J. Anaesth., 49, 831. Morgan, M., Lumley,. J., and Whitwam, J. G. (1975). Etomidate, a new water soluble non-barbiturate intravenous induction agent. Lancet, 1, 955. Peltz, P., and Sinclair, D. M. (1973). Induction agents for Caesarean section: A comparison of thiopentone and ketamine. Anaesthesia, 28, 37.
ETOMIDATE POUR INDUCTION DE L'ANESTHESIE LORS D'UNE OPERATION CESARIENNE: COMPARAISON AVEC LE THIOPENTONE RESUME
Trente meres devant subir une operation cesarienne a froid ont recu 3,5 mg kg" 1 de thiopentone, alors que 30 autres recevaient 0,3 mg kg- 1 d'etomidate pour l'induction de Panesthesie. La conduite ulterieure de Panesthesie a autrement ete identique dans les deux cas. Les differences excedentaires de la base entre la mere et l'enfant ainsi que le degre de correlation biochimique entre la mere et l'enfant ont ete plus favorables apres l'etomidate qu'apres la thiopentone. Le statut clinique du nouveau-ne a ete consider^ comme etant meilleur avec l'etomidate.
ETOMIDAT ZUR EINLEITUNG DER NARKOSE FUR KAISERSCHNITT: EIN VERGLEICH MIT THIOPENTON ZUSAMMENFASSUNG
Von 60 Muttern, die sich fur einen Kaiserschnitt entschieden hatten, erhielten 30 3,5 mg kg- 1 Thiopenton und 30 OjSmgkg- 1 Etomidat zur Einfuhrung der Narkose. Danach wurde die Narkose in beiden Gruppen identisch weitergefuhrt. Die von der Mutter zum Fetus ubergehenden basalen, unterschiedlichen Uberschiisse und der Grad der biochemischen Wechselbeziehung zwischen Mutter und Kind waren nach Etomidat giinstiger als nach Thiopenton. Der klinische Zustand der Neugeborenen wurde nach. Etomidat fiir iiberlegen ergehalten.
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Baraka, A., O'Brien, M., Aslanian, E., and Saade, R. (1971). Propanidid versus thiopentone for induction of general anaesthesia in elective Caesarean section. Br. J. Anaesth., 43, 609. Bradford, E., and Moir, D. (1969). Anaesthesia for Caesarean section: A comparison of thiopentone and propanidid. Br. J. Anaesth., 41, 274. Brock-Utne, J. G., Downing, J. W., Welman, S., Dimopoulos, G. E., and Moshal, M. G. (1978). Lower esophageal sphincter tone during reversal of neuromuscular blockade by atropine and neostigmine. Anesth. Analg. (Cleve.), 57, 171. Buley, R. J. R., Downing, J. W., Brock-Utne, J. G., and Cuerden, C. (1977). Right versus left lateral tilt for Caesarean section. Br. J. Anaesth., 49, 1009. Crawford, J. S. (1962). Anaesthesia for Caesarean section: a proposal for evaluation, with analysis of a method. Br. J. Anaesth., 34, 179. (1977). Obstetrics, analgesia and anaesthesia. Br. J. Anaesth., 49, 19. Dawes, G. S., Mott, J. C , and Widdicombe, J. C. (1954). The fetal circulation in the lamb. J. Physiol., 126, 563. Doenicke, A., Lorenz, W., Beigl, R., Bezecny, H., Uhlig, G., Kalmar, L., Praetorius, B., and Mann, G. (1973). Histamine release after intravenous application of short acting hypnotics. Br. J. Anaesth., 45, 1097. Downing, J. W., Coleman, A. J., Mahomedy, M. C , Jeal, D. E., and Mahomedy, Y. H. (1974). Lateral table tilt for Caesarean section. Anaesthesia, 29, 696. Mahomedy, M. C , Jeal, D. E., and Allen, P. J. (1976). Anaesthesia for Caesarean section with ketamine. Anaesthesia, 31, 883. Dundee, J. W. (1976). Hypersensitivity to i.v. anaesthetic agents. Br. J. Anaesth., 48, 57. Wyant, G. M. (1974). Intravenous Anaesthesia: Barbiturates: Effect on the body, Ch. 6, p. 76. Edinburgh: Churchill-Livingstone. Finster, M., and Poppers, P. J. (1968). Safety of thiopentone used for induction of general anaesthesia in elective Caesarean section. Anesthesiology, 29, 190. Fothergill, R. J., Robertson, A., and Bond, R. A. (1971). Neonatal acidaemia related to procrastination at Caesarean section. J. Obstet. Gynaecol. Br. Commonw., 78, 1010. Fragen, R. J., Caldwell, N., and Brunner, E. A. (1976). Clinical use of etomidate for anaesthesia induction: A preliminary report. Anesth. Analg. {Cleve.), 55, 730. Gooding, J. M., and Corssen, G. (1976). Etomidate: An ultrashort acting non-barbiturate agent for anesthesia induction. Anaesth. Analg. (Cleve.), 55, 286. Hendry, J. G. B., Miller, B. M., and Lees, N. W. (1977). Etomidate in a new solvent. A clinical evaluation. Anaesthesia, 32, 996. James, F. M., Crawford, J. S., Hopkinson, R., Davies, P., and Naiem, H. (1977). A comparison of general anaesthesia and lumbar epidural analgesia for elective Cesarean section. Anesth. Analg. (Cleve.), 56, 228.
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BRITISH JOURNAL OF ANAESTHESIA ETOMIDATA PARA LA INDUCCION DE ANESTESIA EN SECCION CESAREA: COMPARACION CON TIOPENTONA
SUMARIO Treinta madres sometidas a secci6n cesarea electiva recibieron 3,5 mg kg" 1 de tiopentona y 30 recibieron 0j3 mg kg" 1 de etomidata para induction de anestesia. La
administracion posterior de anestesia fue identica para ambos grupos. Las diferencias entre el exceso basico materno y fetal y el grado de correlation bioquimica entre madre e infante fueron mas favorables tras la administracion j e etomidata que tras la administracion de tiopentona. El estado clinico del recien nacido fue considerado supei ior con etomidata.
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