Sarkar, Molly MD, PhD*; Laussen, Peter C. MBBS*; Zurakowski, David PhD†; Shukla, Avinash MD*; Kussman, Barry MBBS*; Odegard, Kirsten C. MD*
Etomidate is a carboxylated imidazole hypnotic drug with a rapid onset (5 to 15 s) (1,2) and a short duration of action (initial half-life of 2.5 min) with return to consciousness within 5–14 min owing to rapid biotransformation and redistribution. It has a stable cardiac profile and is commonly used to induce anesthesia in adults who have limited hemodynamic reserve (2–5). However, there are contradictory reports in adults as to the specific effect of etomidate on the circulation. These have ranged from no significant cardiopulmonary effects (4,6) to variable changes in the systemic vascular resistance (SVR) including a decrease in SVR and cardiac index in patients with mitral and aortic valve disease (5), no change in SVR but a significant decrease in heart rate, arterial mean pressure and stroke volume (3), and an increase in SVR and decrease in cardiac index (7). In adult patients with cardiac disease and normal pulmonary vascular resistance (PVR), it has been demonstrated to provide hemodynamic stability with minimal change in pulmonary artery pressure (PAP) or intrapulmonary shunt (5). In an isolated rat lung model, etomidate has also been shown to have no significant effect on PVR (8).
According to the package insert provided by the company that manufactures etomidate (Bedford Laboratories™, Bedford, OH) it is currently not recommended for use in children younger than 10 yr of age because of insufficient data in this patient population. Nevertheless, there are a number of reports of the use of etomidate in children that date back to 1974 (9–12). Etomidate has been reported to have minimal effects on heart and arterial blood pressure in children studied during induction of anesthesia (9), during rapid sequence induction in the emergency department (1,2), during cardiac surgery (10), and in the catheterization laboratory (11). Noninvasive and direct arterial blood pressure and heart rate monitoring were used to follow hemodynamic changes after etomidate administration in these studies. More invasive hemodynamic monitoring has not been used to determine whether a bolus dose of etomidate has specific effects on vascular resistance and cardiac output.
In our clinical practice at Children’s Hospital Boston, we commonly use etomidate to induce anesthesia in young children and infants with congenital heart disease and limited hemodynamic reserve undergoing both cardiac and noncardiac surgery and in the cardiac intensive care unit to facilitate endotracheal intubation. We also use etomidate to induce anesthesia in children with pulmonary hypertension, although the acute effects of etomidate on PVR and PAP are unknown in children.
In this prospective study conducted during cardiac catheterization, we hypothesized that there would not be significant changes in acute hemodynamic variables after a bolus induction dose of etomidate.
After obtaining IRB approval and informed parental consent, 12 children (mean age, 9.2 ± 4.8 yr; age range, 2–16 yr) who were scheduled for cardiac catheterization were prospectively enrolled in this study. Five patients with supraventricular tachyarrhythmias (SVT) underwent anesthesia for a radiofrequency catheter ablation and seven patients with an atrial septal defect (ASD) underwent device closure.
Patients were premedicated at the discretion of the anesthesia team. Two ASD patients received premedication with oral midazolam (0.5-1.0 mg/kg) before IV line placement and another ASD patient received 1.5 cc IM injection of Demerol compound (meperidine 25 mg, promethazine 6.25 mg, and chlorpromazine 6.25 mg/mL). Routine patient monitoring included electrocardiograph, noninvasive arterial blood pressure, pulse oximetry, skin temperature, respiratory rate, and end-tidal carbon dioxide measured by nasal prongs.
While breathing spontaneously in room air, patients were sedated with intermittent IV boluses of morphine and midazolam while vascular access (femoral artery and vein) for catheterization was obtained. Spontaneous ventilation was maintained in our patients to avoid the possible confounding hemodynamic effects of positive pressure ventilation. A balloon-tipped catheter was floated into position in the pulmonary artery (PA) during fluoroscopy for baseline hemodynamic measurements. The measured hemodynamic profile included pressure measurements in the superior vena cava (SVCP), right atrium (RAP), right ventricle (RVP), pulmonary artery (PAP), pulmonary artery wedge, and aortic pressure (AOP). Blood sampling from SVC, RA, RV, PA and femoral artery were obtained for measurement of oxygen saturation via co-oximetry. Once a full hemodynamic and saturation profile had been obtained under IV sedation, and with the patient breathing spontaneously in room air, anesthesia was induced with a single dose of 0.3 mg/kg of etomidate. After induction with etomidate, a repeat hemodynamic profile measuring the aforementioned pressures and saturations was undertaken. During this time, 11 of 12 patients continued to breathe spontaneously in room air and one required assistance with gentle bag/mask ventilation because of hypoventilation. After acquisition of the data, each patient received an IV dose of a nondepolarizing neuromuscular blocking drug (0.1 mg/kg of pancuronium) to facilitate tracheal intubation. General anesthesia then was continued for each patient during the catheterization procedure according to the anesthesia plan.
From the above hemodynamic variables, the ratio of pulmonary to systemic blood flow (Qp:Qs) indexed to body surface area was calculated along with SVR and PVR using an assumed oxygen consumption for body surface area by sex and age (12). All calculations were made taking the dissolved oxygen into account to minimize any error while calculating the pulmonary blood flow (Qp).
Hemodynamic variables were tested for normality using the Kolmogorov-Smirnov statistic and each was found to follow a normal (Gaussian-shaped) distribution. Therefore, continuous data are presented as mean ± sd and data were evaluated parametrically. The paired Student’s t-test was used to evaluate pre- versus postdrug differences in the hemodynamic variables for all patients and for the SVT and ASD groups separately. Analysis of the data was performed with the SPSS software package (version 12.0; SPSS Inc., Chicago, IL). For between-group analysis, analysis of variance with post hoc Dunnett’s t-tests was used to compare the SVT and ASD groups at baseline, postdrug application, and the absolute percentage change for each hemodynamic variable of interest. Power calculations indicated that a total sample size of 12 patients would provide 88% power to detect a 10% change in each of the hemodynamic variables assuming a standard deviation of 10% between pre- and post-etomidate using paired Student’s t-tests (version 5.0, nQuery Advisor; Statistical Solutions, Boston, MA). Therefore, at the design stage of this study, it was planned that with 12 patients, an effect size of 1.0 could be detected for each of the 14 variables (10% change divided by an sd of 10%), and the probability of failing to detect a real difference (false negative) (referred to as a Type II error) was 12%. A two-tailed value of P < 0.01 was used as the criterion for statistical significance to protect against the Type I error rate (false positive) resulting from multiple comparisons (13).
Mean age and weight for the 12 patients (9 females) was 9.2 ± 4.8 years and 33.4 ± 15.4 kg. SVT patients undergoing radiofrequency catheter ablation were older and larger than those undergoing catheterization for ASD device closure (Table 1). The average amount of morphine and midazolam administration for sedation before induction with etomidate is also shown in Table 1.
The mean time from premedication to obtaining vascular access (anesthesia time) was 50.3 ± 15.7 min. The mean time from skin preparation to obtaining vascular access by the catheterizer was 25.1 ± 15.5 min. The mean time to remeasure the hemodynamic profile was 3.5 ± 1.1 min.
The hemodynamic and oxygen saturation data for all patients are shown in Table 2; there were no significant differences before and after etomidate administration in any of the variables. Because the numbers of ASD and SVT patients were small, we performed a separate analysis in each subgroup and could not detect differences in hemodynamic or saturation variables before and after etomidate administration (Table 3). In addition, analysis of variance indicated no significant differences in the amount of change pre- versus post-etomidate between the two groups (all P > 0.01).
Figure 1 presents graphically the mean absolute percent change for heart rate, PAP, AOP, PVR, and SVR. Although the mean absolute percent changes in PVR and SVR were 28% and 23%, respectively, the change was not significant because of the variability among patients.
None of the patients had airway obstruction or myoclonus after etomidate before pancuronium administration, but one patient required assistance with gentle bag/mask ventilation because of hypoventilation. Complete data measurements were obtained for all patients. Subsequent procedures were uneventful and all patients were discharged the following day.
In our study of children undergoing cardiac catheterization using direct hemodynamic measurements there were no clinically significant differences after a bolus injection of etomidate (0.3 mg/kg). Although the numbers are small, when patients were analyzed according to diagnosis, there were no differences before and after etomidate in those patients with a structurally normal heart (SVT) or those with a small volume overload (ASD).
The stable hemodynamic profile of etomidate we found in our small number of children is consistent with adult data (4,6). Previous reports of the hemodynamic effects of etomidate in pediatric patients have reported changes in heart rate and direct or noninvasive arterial blood pressure (1,10). Etomidate has been reported to have a low incidence of clinically significant hypotension based on noninvasive blood pressure measurement when used for rapid sequence tracheal intubation in pediatric patients in the emergency department (1,2). In a large study of nearly 200 infants and children up to 16 years of age, etomidate produced minimal hemodynamic changes during induction of anesthesia (9). In a study comparing etomidate, with ketamine and sodium gamma-hydroxybutyrate in children undergoing cardiac catheterization, etomidate 0.3 mg/kg bolus followed by a continuous infusion during cardiac catheterization did not cause significant changes in heart rate or arterial blood pressure (11).
Our study is the first in children to invasively measure hemodynamic and oxygen saturation data to allow a complete assessment of the changes in systemic and pulmonary blood flow and resistance related to bolus etomidate administration. There was no clinically significant change in PVR after etomidate in the SVT and ASD patients who all had a normal PVR at baseline. There was a slight but insignificant increase in Pco2 after injection of etomidate in the SVT group, which probably reflects hypoventilation. This increase could potentially increase PVR and PAP if there was a reactive pulmonary vasculature. However, etomidate was not associated with an increase in PVR despite the slight increase in Pco2. Additional evaluation in patients with baseline or existing pulmonary hypertension and increased PVR is necessary to determine the safety of etomidate in this patient population. Although there was an insignificant trend toward increased PVR and SVR in the ASD group, it is unknown whether vascular resistance may increase further in patients with a larger Qp:Qs ratio or in patients with ventricular dysfunction.
Besides hemodynamic stability, other advantages for etomidate include improved myocardial oxygen supply to demand ratio (14,15), lack of histamine release (16), absence of malignant hyperthermia (17), lack of effect on hepatic or renal function, and lack of dissociative and hallucinogenic side effects. A major side effect related to etomidate is dose-dependent adrenocortical suppression (18), particularly in response to a continuous infusion. However, there are reports that fail to demonstrate a decrease in cortisol or alterations in the adrenocorticotropic levels in patients after a single bolus dose of etomidate (1,19). In a randomized study investigating the effect of a single induction dose of etomidate on adrenocorticotropic hormone and cortisol levels in pediatric patients undergoing congenital cardiac surgery, plasma cortisol levels decreased with etomidate and remained low up to 24 hours postoperatively, but etomidate was not associated with hemodynamic instability (10). Other disadvantages of etomidate administration include pain on injection (as a result of its acidic pH) (20), involuntary skeletal muscle contractions (myoclonus) owing to disinhibition of extrapyramidal activity (21,22), tremors and seizure (21–23) anaphylactoid reaction (23), and possible inhibition of platelet function (24). We did not measure adrenocortical hormone levels, and none of our patients demonstrated involuntary movements or responded to bolus injection.
Our study is limited by our small sample size and we only studied children with relatively normal hearts. Nevertheless, with each patient acting as their own control, we believe it is possible to conclude that etomidate has minimal hemodynamic effects in at least healthy children sedated with morphine and midazolam. The children in our study who underwent radiofrequency catheter ablation for SVT had structurally normal hearts, and etomidate did not induce a change in heart rate or dysrhythmia. Those with an ASD had only a modest volume load and increased Qp:Qs, and further studies are necessary to determine the hemodynamic changes after etomidate in children and infants with more significant volume or pressure overload, heart failure, and pulmonary hypertension.
The influence of sedation with midazolam or morphine before etomidate administration is uncertain with regard to our results. Both morphine and midazolam have potential hemodynamic side effects that could have altered the hemodynamic measurements we observed after etomidate. We believe the time period over which morphine and midazolam were titrated until vascular access was obtained minimized their effect on hemodynamic measurements at the time of etomidate administration. Measurements of hemodynamic variables from an agitated child are also misleading, and sedation was necessary to gain vascular access in these children before measuring variables under conditions of spontaneous respiration. Further, to measure etomidate’s effect at induction, it was important to avoid both positive pressure ventilation and use of a higher Fio2, thereby maintaining conditions as close as possible to baseline. We were able to achieve this without substantial changes in respiratory function or gas exchange that could influence the hemodynamic measurements after etomidate administration.
We wanted to guard against false positive errors (Type 1) because of the large number of hemodynamic variables tested and thus used a stringent criterion for statistical significance, specifically, a two-tailed value of P < 0.01. The primary aim of this study was to evaluate changes in the outcome variables among all 12 patients, and the study was appropriately powered to detect significant change. There is, however, the possibility of a type II, or false negative, statistical result. When considering all 12 patients together for analysis (Table 2), we calculated the risk for a type II error to be 12%. However, because of the small number of patients in each subgroup (Table 3), there is an increased chance for a false negative result. The calculated power to detect changes in hemodynamic variables in the SVT or ASD groups is only 50%–60% and although we could not detect significant differences in a subgroup analysis, larger numbers of patients in each group are necessary to decrease the possibility of false negative results.
The lack of clinically significant hemodynamic changes after etomidate administration supports the recommendation that etomidate is safe in children. Further work is necessary to determine the hemodynamic profile of etomidate in neonates and in pediatric patients with severe ventricular dysfunction and pulmonary hypertension.
1. Sokolove PE, Price DD, Okada P. The safety of etomidate for emergency rapid sequence intubation of pediatric patients. Pediatr Emerg Care 2000;16:18–21.
2. Bergen JM, Smith DC. A review of etomidate for rapid sequence intubation in the emergency department. J Emerg Med 1997;15:221–30.
3. Criado A, Maseda J, Navarro E, et al. Induction of anaesthesia with etomidate: haemodynamic study of 36 patients. Br J Anaesth 1980;52:803–6.
4. Gooding JM, Weng JT, Smith RA, et al. Cardiovascular and pulmonary responses following etomidate induction of anesthesia in patients with demonstrated cardiac disease. Anesth Analg 1979;58:40–1.
5. Colvin MP, Savege TM, Newland PE, et al. Cardiorespiratory changes following induction of anaesthesia with etomidate in patients with cardiac disease. Br J Anaesth 1979;51:551–6.
6. Gooding JM, Corssen G. Etomidate: an ultrashort-acting nonbarbiturate agent for anesthesia induction. Anesth Analg 1976;55:286–9.
7. Price ML, Millar B, Grounds M, Cashman J. Changes in cardiac index and estimated systemic vascular resistance during induction of anaesthesia with thiopentone, methohexitone, propofol and etomidate. Br J Anaesth 1992;69:172–6.
8. Rich GF, Roos CM, Anderson SM, et al. Direct effects of intravenous anesthetics on pulmonary vascular resistance in the isolated rat lung. Anesth Analg 1994;78:961–6.
9. Kay B. A clinical assessment of the use of etomidate in children. Br J Anaesth 1976;48:207–11.
10. Donmez A, Kaya H, Haberal A, et al. The effect of etomidate induction on plasma cortisol levels in children undergoing cardiac surgery. J Cardiothorac Vasc Anesth 1998;12:182–5.
11. Nguyen NK, Magnier S, Georget G, et al. [Anesthesia for heart catheterization in children: comparison of 3 techniques]. Ann Fr Anesth Reanim 1991;10:522–8.
12. Lock J, Keane JF, Perry SB. Diagnostic and interventional catheterization in congenital heart disease. 2nd ed. Boston/Dordrecht/London: Kluwer Academic Publishers, 2000.
13. Armitage P BG, Matthews JNS. Statistical methods in medical research. 4th ed. Oxford: Blackwell Science Ltd, 2000:137-45.
14. Kettler D, Sonntag H, Donath U, et al. Haemodynamics, myocardial mechanics, oxygen requirement and oxygenation of the human heart during induction of anaesthesia with etomidate [in German]. Anaesthesist 1974;23:116–21.
15. Larsen R, Rathgeber J, Bagdahn A et al Effects of propofol on cardiovascular dynamics and coronary blood flow in geriatric patients: a comparison with etomidate. Anaesthesia 1988;43 Suppl:25–31.
16. Doenicke A, Lorenz W, Beigl R, et al. Histamine release after intravenous application of short-acting hypnotics. A comparison of etomidate, Althesin (CT1341) and propanidid. Br J Anaesth 1973;45:1097–104.
17. Suresh MS, Nelson TE. Malignant hyperthermia: is etomidate safe? Anesth Analg 1985;64:420–4.
18. Fragen RJ, Shanks CA, Molteni A, Avram MJ. Effects of etomidate on hormonal responses to surgical stress. Anesthesiology 1984;61:652–6.
19. Duthie DJ, Fraser R, Nimmo WS. Effect of induction of anaesthesia with etomidate on corticosteroid synthesis in man. Br J Anaesth 1985;57:156–9.
20. Reves JG, Glass PSA, Lubarsky DA. Nonbarbiturate intravenous anesthetics. In: Miller RD, ed. Anesthesia. New York: Churchill Livingstone, 1994.
21. Batjer HH. Cerebral protective effects of etomidate: experimental and clinical aspects. Cerebrovasc Brain Metab Rev 1993;5:17–32.
22. Laughlin TP, Newberg LA. Prolonged myoclonus after etomidate anesthesia. Anesth Analg 1985;64:80–2.
23. Ebrahim ZY, DeBoer GE, Luders H, et al. Effect of etomidate on the electroencephalogram of patients with epilepsy. Anesth Analg 1986;65:1004–6.
24. Gries A, Weis S, Herr A, et al. Etomidate and thiopental inhibit platelet function in patients undergoing infrainguinal vascular surgery. Acta Anaesthesiol Scand 2001;45:449–57.