A CLINICAL ASSESSMENT OF THE USE OF ETOMIDATE IN CHILDREN

Transcription

1 Br.J. Anaesth. (1976), 48, 207 A CLINICAL ASSESSMENT OF THE USE OF ETOMIDATE IN CHILDREN B. KAY SUMMARY Etomidate 0.2 mg/kg i.v. was used to induce sleep in 198 children. It produced sleep rapidly and safely, with negligible effect on the cardiovascular system and little respiratory depression. Clinical acceptability was reduced by a 27% incidence of pain after injection, a 10% incidence of myoclonia and inadequate dosage in 19%. Etomidate has little analgesic activity and these problems can be reduced by the use of an analgesic as premedication or with induction of anaesthesia, by increasing the induction dose of etomidate to mg/kg, or by changing the formulation of the solution. Etomidate is a new i.v. hypnotic that has been used extensively for the induction of anaesthesia. It is a carboxylated imidazole and is water-soluble. It was presented as the sulphate, with a buffered solvent giving an acid solution (ph 3.3) containing 1.5 mg of the salt in 1 ml. Several advantages have been claimed for etomidate compared with other i.v. induction agents in common use. In animal studies it has a therapeutic index much greater than propanidid or the short-acting barbiturates. In man it has been shown to produce less respiratory depression than methohexitone (Doenicke, 1974), and Bruckner and colleagues (1974) found that it caused only minimal side-effects on the cardiovascular system, compared with Althesin, ketamine, methohexitone and propanidid. Doenicke and colleagues (1973) considered etomidate to be the first i.v. hypnotic agent unlikely to cause histamine release. Induction of sleep by etomidate is rapid (10-15 sec). It is short-acting and its duration of effect is less dependent on redistribution than is the case with the short-acting barbiturates. Complete recovery from hypnotic action occurs more rapidly than after a comparable dose of methohexitone (Kay, 1976), and drowsiness after the anaesthetic does not occur (Kugler, Doenicke and Lamb, 1974). Such apparent advantages warranted a clinical trial in paediatric anaesthetic practice. METHOD Etomidate was used to induce anaesthesia in 198 children between 6 hr and 15 yr of age (mean 5 yr 9 mths). Their weights ranged from 1.9 kg to 68 kg, B. KAY, M.B., CH.B., D.A., F.F.A.R.C.S., Royal Infirmary, Derby. with a mean weight of kg. One hundred and thirty-seven of the children were treated as outpatients. The first 178 of the children received the standard formulation of etomidate supplied by Janssen Pharmaceuticals. For reasons discussed below, however, the last 20 patients in the series received an unofficial formulation, an aqueous solution containing 20% Cremophor EL and etomidate sulphate 3 mg/ml. All the injections were given, and all measurements were made by the author. One of two induction techniques was used. None of the children received premedication. One hundred and sixty children (81 %) were given etomidate 0.2 mg/kg with atropine mg according to age and weight. Thirty-seven received the same agents in the same dosage with fentanyl 25 [xg/kg. Lignocaine 1 mg was added to the etomidate in 99 cases. In each case the combined drugs were injected over a period of 30 sec, using a concealed, painless i.v. injection (Kay, 1972). Anaesthesia was then continued by inhalation of nitrous oxide 75% and oxygen 25% by mask, using a non-rebreathing Ambu valve, or a modified T-piece for infants under 18 months old. In those cases where no fentanyl was given, halothane 2% was added. Observations Overall response. The induction was graded good, fair or poor as an overall clinical impression. Side-effects were recorded as they occurred, or as complaints were made. Complications. Any complications occurring during induction, anaesthesia or recovery, and which might be attributed to etomidate, were noted. Cardiovascular effects. The child's pulse rate and systolic arterial pressure were recorded by palpation

2 208 BRITISH JOURNAL OF ANAESTHESIA TABLE I. Main side-effects in first 178 patients Numbers and approximate percentages* Injection site Total Infants Pain Myoclonia Pain and myoclonia Dorsum of hand Antecubital fossa Other Overall 124 (70%) 40 (22%) 14(8%) (30%) 3 (8%) 3 (50%) 43 (27%) 16 (13%) 2 (5%) 1 (7%) 19 (10%) 7 (6%) 1 (2.5%) 1 (7%) 9 (6%) * Percentages of painful side-effects are from totals excluding infants (see text). of the radial pulse before induction of anaesthesia and 2 min after completion of the i.v. injection. In 59 children the e.c.g. was recorded immediately before injection, then continuously throughout the induction period. The records for these two periods were compared with special reference to the following intervals after the injection. (a) first 10 sec; (b) sec; (c) sec. RESULTS Overall response The induction of anaesthesia with etomidate 0.2mg/kg i.v. was graded as good in 118 children (59%), fair in 77 (39%) and poor in 3 children. The most important reasons for grading induction as less than good were the occurrence of side-effects in 71 children (36%), or inadequate hypnotic effect in 38 (19%), 29 of these suffered from side-effects also. Side-effects. The most frequent side-effects were pain in the arm, usually the upper arm, during injection of etomidate, and purposeless muscle movements occurring between 15 and approximately 120 sec after injection. Complaints of pain or an obvious response to pain after injection occurred in 43 children, myoclonia occurred in 19 and 9 children experienced both effects. Table I shows these findings in detail. No side-effects occurred in the last 20 patients in the series who received the unofficial formulation containing Cremophor EL. In the first 178 patients there were 18 infants aged less than 18 months, who could not express adequately a painful response to injection. Thus the number experiencing painful side-effects was expressed as a percentage of 160. The addition of lignocaine 1 mg to the injectate had little effect on the incidence of pain. Excluding infants, 20 (22.7%) of the 88 children who received lignocaine felt pain, compared with 23 (31.9%) of 72 who did not receive lignocaine. Excluding infants, 4 (12%) of 33 children who received fentanyl with etomidate felt pain, compared with 39 (30.7%) of the 127 children who did not receive fentanyl. Other side-effects of etomidate were rare. Of 161 children who did not receive fentanyl, none had obvious respiratory depression after injection, or exhibited a period of apnoea longer than 10 sec. Of those who received fentanyl, 12 were apnoeic for more than 10 sec. No child required assisted ventilation. There was no instance of hiccup, vomiting, laryngospasm, bronchospasm or allergic reaction to the drugs. Hyperventilation occurred occasionally, apparently in response to pain. Two children micturated during induction. Complications. There were no complications of induction anaesthesia or surgery attributable to etomidate. Cardiovascular effects. The pulse rate increased in almost every case in response to the i.v. atropine; the increase in mean pulse rate is highly significant (P< 0.001) (table II). The change in the mean TABLE II. Effect of induction on pulse rate and systolic arterial pressure Pulse rate (beat/min) Systolic pressure (mmhg) Before induction Mean Range After induction Mean Range systolic arterial pressure was not statistically significant. A few marked changes occurred in individual children. Two had a decrease in systolic pressure greater than 20 mm Hg (130 to 95, and 120 to 95 mm Hg) and five had increases of more than 20 mm Hg, 80 to 120 being the largest.

3 ETOMIDATE INDUCTION IN CHILDREN 209 E.c.g. changes E.c.g. traces before induction of anaesthesia and throughout the induction period were obtained in 59 children aged from 4 days to 15 years. Before induction, 73% of the children exhibited sinus arrhythmia, often associated with a relative bradycardia, and in four children this was associated with atrial extrasystoles. One half of the remaining children (13.5%) exhibited sinus tachycardia, with resting pulse rates between 110 and 150/min. Only the remaining eight children showed a uniform sinus rhythm. After insertion of the i.v. needle, changes in the cardiac rate and e.c.g. pattern were observed during the periods analysed. (a) The first 10 sec after injection. The mean heart rate was increased from a pre-induction rate of 101 beat/min to 127 beat/min. During this period the children were conscious and many felt pain after the injection. There was no increase in heart rate in only five children. Of 18 children with sinus arrhythmia before induction, 14 developed sinus tachycardia, and four reverted to sinus rhythm. (b) sec after injection. The children were asleep, and the effect of tie i.v. atropine was apparent. The mean pulse rate increased to 138 beat/min. In a further 18 children with sinus arrhythmia before induction, 13 developed sinus tachycardia and five sinus rhythm. Three with sinus rhythm developed sinus tachycardia. (c) sec after injection. Anaesthesia was established and the effects of halothane or fentanyl were apparent. The mean heart rate decreased to 134 beat/min. Four patients with sinus arrhythmia and five with sinus tachycardia developed sinus rhythm. Three children with sinus arrhythmia developed sinus tachycardia, three had changes in the reverse direction and three changed from sinus rhythm to sinus tachycardia. In the general examination of the records, extrasystoles occurred not infrequently, usually in association with sinus arrhythmia or sinus tachycardia. Before induction four children with sinus arrhythmia exhibited supraventricular extrasystoles, only one of which persisted in the induction phase, and this for only a few seconds. Extrasystoles occurred after injection in 14 children: in two children in period (a), in whom supraventricular extrasystoles persisted throughout induction; ventricular extrasystoles were seen in period (c), as sinus rhythm changed to sinus tachycardia. In nine children occasional supraventricular extrasystoles were seen in period (b) only, and in three children occasional supraventricular and a single ventricular extrasystole appeared in period (c). It is unlikely that any of the minor e.c.g. changes were attributable to etomidate. One 9-yr-old boy showed e.c.g. changes of probable pathological origin. Before induction he had sinus arrhythmia with a bradycardia varying between 52 and 60 beat/min. Occasional supraventricular ectopics were observed. The induction period trace of the e.c.g. showed the "sick sinus node syndrome" pattern, with numerous aberrant P-waves and atrial and ventricular ectopic beats. As this pattern started immediately after injection, before any of the injected drugs could have reached the heart, etomidate is unlikely to have been the cause of this abnormality. DISCUSSION Etomidate is an i.v. hypnotic agent with reported advantages for induction of anaesthesia. It was disappointing, therefore, during the early stages of this trial to find a high frequency of pain after injection, reducing the average clinical assessment of induction by the drug to less than good. Pain is not uncommon in association with other i.v. induction agents, particularly methohexitone, but it is important that the incidence of pain is reduced to acceptably low levels, particularly in children. With methohexitone, this can be achieved by adding lignocaine 1 mg to the injection (Rowlands, 1969), but this remedy was ineffective in this series. Bergmann and St Necek (1974) found a marked reduction in the incidence of pain after etomidate when fentanyl and droperidol were also given. The improvement in the present series when fentanyl was added was less obvious, probably because fentanyl and etomidate were given together, whereas Bergmann and St Necek gave fentanyl 1-2 min before etomidate. Another factor influencing the incidence of pain after i.v. injection is the site of injection. As with methohexitone, pain is much more likely to be appreciated after a slow injection into a small vein on the dorsum of the hand than after an injection into a large vein in the antecubital fossa (table II). An even greater frequency occurs when tiny veins in the wrist or foot are used. After 178 inductions, with pain after injection remaining a prominent side-effect, a new solvent for etomidate was used: 20% aqueous solution of Cremophor EL. Twenty children received this unofficial formulation, each injection being given into a small vein on the dorsum of the hand. Despite the

4 210 BRITISH JOURNAL OF ANAESTHESIA site of injection, in this small series no child admitted to pain, even on direct questioning. Thus it is likely that a change in formulation of etomidate will reduce or eliminate the incidence of pain following injection. It is understood that the manufacturers are considering this. Purposeless muscle movement occurs frequently after the injection of other induction agents. Dundee and others (1961) have discussed the significance of the dose and concentration of the drug, and the premedication used, and it may be that similar factors influence the incidence of myoclonia after etomidate. Pain may aggravate excitatory muscle reactions to methohexitone, and a similar response may occur with etomidate. Bergmann and St Necek (1974) found a beneficial effect of pethidine as a premedicant and fentanyl injection at induction. It is interesting to note that no myoclonia occurred in the last 20 patients of the present series, possibly because of the absence of pain in this group, and that only one mild case of myoclonia occurred in the patients in whom fentanyl was added to the etomidate. Myoclonia was a minor problem in this trial, with an overall incidence of 10%. This is similar to the experience with methohexitone in these circumstances. More disruptive were the semi-purposive movements that occurred when the mask was applied to the child's face, 15 sec after completion of the injection. It appears that although etomidate 0.2 mg/kg produces sleep as quickly as methohexitone 1.5 mg/kg and for a similar duration, it produces less suppression of reflex movement, again perhaps a reflection of its lack of analgesic properties. It is noticeable that, of the 38 children in whom these movements were recorded, 29 suffered pain after injection. Again, this reaction was not observed in any child who received fentanyl, or in the last 20 patients in the series. To ensure smooth induction of anaesthesia in unpremedicated children who do not receive an analgesic at induction, it would seem necessary to increase the dose of etomidate to 0.3 mg/kg or more. The use of such larger doses of etomidate may produce clinically acceptable induction of anaesthesia. Etomidate is not recommended as the sole agent for short-term anaesthesia, but in a separate small series of 20 children undergoing extraction of one to three deciduous teeth in the dental chair, the dental surgeons were unable to identify the children who received only etomidate mg/kg from those who received only methohexitone mg/kg. All the children received rapid injections into antecubital fossa veins and the incidence of pain and movement was similar in the two groups. ACKNOWLEDGEMENTS I should like to thank Janssen Pharmaceuticals for the supply of Etomidate, and Mrs G. Gessey for analysis of the e.c.g. records. REFERENCES Bergmann, H., and St Necek, (1974). Zur Verwendung des neuen kurzwirkenden i.v. Hypnotikums Etomidate bei Anaesthesien in der operativen, H. N. O. Heilkunde. Proc. Osterreichische Gesellsch. Anaesthesiol. Reanim., Wien (in press). Bruckner, J. B., Gethmann, J. W., Patschke, D., Tarnow, J., and Weymar, A. (1974). Untersuchungen zur Wirkung von Etomidate auf den Kreislauf des Menschen. Anaesthesist, 23, 322. Doenicke, A. (1974). Etomidate, a new intravenous hypnotic. Acta Anaesthesiol. Belg., 3, 307. Lorentz, W., Beigl, R., Bezecny, H., Ublig, G., Kalmar, L. 3 Praetoris, B., and Mann, G. (1973). Histamine release after intravenous application of shortacting hypnotics; a comparison of etomidate, Althesin (CT 1341) and propanidid. Br.jf. Anaesth., 45, Dundee, J. W., Riding, J. E., Barron, D. W., and Nichol, R. M. (1961). Some factors influencing the induction characteristics of methohexitone anaesthesia. Br. J. Anaesth., 33, 296. Kay, B. (1972). Brietal sodium in children's surgery. Anaesthesiol. Resusc, 57, 149. Berlin: Springer-Verlag. (1976). A dose-response relationship for etomidate with some observations on cumulation. Br. J. Anaesth., 48, 213. Kugler, J., Doenicke, A., and Lamb, M. (1974). E.e.g. studies with etomidate; a comparison with other i.v. hypnotic agents. Proc. IV Eur. Congr. Anaesthesiol. Amsterdam: Excerpta Medica. Rowlands, D. E. (1969). Pain after methohexitone. Anaesthesia, 24, 289. EVALUATION CLINIQUE DE L'UTILISATION DE L'ETOMIDATE POUR LES ENFANTS RESUME On a utilise 0,2 mg/kg d'etomidate pour provoquer le sommeil sur 198 enfants. Ce produit a provoque le sommeil rapidement et d'une maniere sure, en ne causant que des effets negligeables sur le systeme cardiovasculaire et tres peu de depression respiratoire. L'acceptabilite clinique a ete diminuee a cause de Pincidence d'une douleur apres Pinjection dans 27% des cas, d'une incidence de myoclonie dans 10% des cas et d'un dosage inad quat dans 19% des cas. L'&omidate a peu d'activite analgesique et ces difficultes peuvent etre diminuees par l'emploi d'une medication analgesique pre-op6ratoire ou par induction de l'anesthesie en augmentant la dose d'induction de l'etomidate a 0,3 ou 0,4 mg/kg, ou encore en modifiant la formule de la solution.

5 ETOMIDATE INDUCTION IN CHILDREN 211 KLINISCHE AUSWERTUNG VON ETOMIDAT BEI KINDERN ZUSAMMENFASSUNG Etomidat wurde in Dosierungen von 0,2mg/kg bei 198 Kindern als Schlafeinleitungsmittel angewandt. Es ergab sich als schnelles und zuverlassiges Mittel mit minimalen Nebenwirkungen auf das kardiovaskulare System und wenig Atemhemmung. Klinische Anwendbarkeit wurde jedoch durch die Tatsache herabgesetzt, dass sich bei 27% des Patientenguts Schmerz nach Injektion ergab, Myoklonie bei 10% und sich die erwahnte Dosierung bei 19% als ungeniigend envies. Als Analgetikum beweist sich Etomidat kaum wirksam, jedoch kann dieses Problem durch Zugabe eines Analgetikums mit der Basisnarkose gelost werden, sowie auch bei der Narkoseeinleitung, in dem man die Einleitungsdosierung des Mittels auf 0,3 oder 0,4 mg/kg erhoht, oder die Formel der Losung andert. UNA VALORACION CLINICA DEL USO DE ETOMIDATO EN NINOS SUMARIO Se uso etomidato 0,2 mg/kg para inducir el suefio en 198 nifios. Produjo suefio sin peligro, con un efecto insignificante sobre el sistema cardiovascular y una ligera depresion respiratoria. Se redujo la aceptabilidad clinica en un 27% de incidencia de dolor despues de una inyeccion, un 10% de incidencia de mioclonia y dosis inadecuada en el 19%. El etomidato tiene escasa actividad analgesica y se pueden reducir estos problemas mediante el uso de un analgesico como premedicacion o con induccion de anestesia, mediante el aumento de la dosis de induccion de etomidato del 0,3 al 0,4 mg/kg o mediante un cambio de formulaci6n de la solucidn.