Anesth Analg 2007; 105:1298-1302
© 2007 International Anesthesia Research Society
doi: 10.1213/01.ane.0000287248.25610.c0
ANESTHETIC PHARMACOLOGY
Low-Dose Intravenous Midazolam Reduces Etomidate-Induced Myoclonus: A Prospective, Randomized Study in Patients Undergoing Elective Cardioversion
Lars Hüter, MD,
Torsten Schreiber, MD,
Michael Gugel, MD, and
Konrad Schwarzkopf, MD
From the Klinik für Anästhesiologie und Intensivtherapie, Friedrich-Schiller-Universität Jena, Germany.
 |
Abstract
|
|---|
BACKGROUND: Myoclonic movements are a common problem in unpremedicated patients during induction of anesthesia with etomidate.
METHODS: In a double-blind fashion, 40 patients (ASA physical status III–IV) scheduled for elective cardioversion were randomly assigned to receive either 0.015 mg/kg midazolam or placebo 90 s before the injection of 0.3 mg/kg etomidate. Myoclonic movements and sedation were recorded on a scale between 0 and 3. Pulse oximetry, noninvasive arterial blood pressure, and heart rate were recorded during the study period.
RESULTS: Two patients (10%) in the midazolam group had myoclonic movements after the administration of etomidate, whereas 10 of the 20 patients (50%) receiving placebo experienced such movements (P = 0.006). No other differences were found between the groups; in particular, there was no difference in recovery 5 min after the administration of etomidate.
CONCLUSIONS: IV midazolam 0.015 mg/kg administered 90 s before induction of anesthesia with etomidate is effective in reducing myoclonic movements and does not prolong recovery in unpremedicated patients after short procedures.
|
Introduction
|
|---|
For short-term procedures requiring general anesthesia, rapid clearance of the anesthetic is desirable. Etomidate, because of its minimal respiratory side effects and its favorable hemodynamic profile, is a common choice for short-term procedures (1), especially in the hemodynamically compromised patient. Two undesirable side effects of etomidate are pain on injection and myoclonus. Although the problem of pain on injection has been solved by a new lipid formulation for etomidate (2), the problem of etomidate-induced myoclonus, especially for short-term procedures, has yet to be solved. Myoclonus is seen in up to 90% of patients during induction of anesthesia with etomidate if no supplemental opioids are used (3).
Myoclonus may be of clinical significance in a variety of patients undergoing induction of general anesthesia. In theory, in emergency conditions, the myoclonus may increase the risk of regurgitation and aspiration. As a result of high intraocular pressure, myoclonus might increase the risk of vitreous prolapse after an open globe injury (4). In the case of electric cardioversion, continuous electrocardiogram (ECG) recordings may be disturbed due to the patient’s myoclonic movements (5,6).
A number of drugs have been investigated for suppression of etomidate-induced myoclonus, but the drug of choice for short-term procedures has yet to be identified. Opioids can effectively reduce myoclonic movements (3,7), but at the cost of undesirable side effects, such as apnea (8). Ideally, a pretreatment drug for preventing myoclonic movements should be short-acting, not have significant effects on respiration and hemodynamics, and not prolong recovery from anesthesia.
In an earlier investigation by our group, we compared the effect of pretreatment with low-dose midazolam versus placebo on the incidence of myoclonus after etomidate administration in patients orally premedicated with clorazepate dipotassium the evening before anesthesia and with midazolam 45–60 min before induction of anesthesia with etomidate (9). However, the effect of midazolam on myoclonus in unpremedicated patients has not been investigated. In addition, from our previous study, it remains unclear if the results were affected by the multiple doses of benzodiazepines that had been given (9). Furthermore, in our previous study, we were not able to evaluate the influence of the premedication with IV midazolam on the short-term recovery after etomidate-induced anesthesia.
Accordingly, we designed a placebo-controlled study to investigate the effects of pretreatment with low-dose IV midazolam on the incidence and severity of myoclonus during induction of anesthesia with etomidate for elective cardioversion in unpremedicated patients.
|
METHODS
|
|---|
The study was approved by the Ethics Committee of the Friedrich-Schiller-University, Jena. Before participating, patients gave their written informed consent. Patients without neurologic diseases scheduled for elective cardioversion for atrial fibrillation after cardiac surgery (coronary artery bypass grafting or valve surgery) were included. The study took place between July 2004 and November 2006. The patients were not premedicated. Heart rate, noninvasive arterial blood pressure, and oxygen saturation were recorded every minute during the study period (Intellivue MP 90ç Philips, Hamburg, Germany).
Patients were allocated in a randomized and double-blind fashion to one of two pretreatment groups (n = 20 in each group): midazolam (Midazolam-ratiopharm, Ulm, Germany) 0.015 mg/kg IV or normal saline as placebo. Patients were administered oxygen, and the study drug, prepared in a black syringe, was injected IV. Ninety seconds after the pretreatment, anesthesia was induced with etomidate 0.3 mg/kg (Etomidate-Lipuro, B. Braun Melsungen, Melsungen, Germany). After another 60 s, electric cardioversion was performed with a monophasic cardioverter or defibrillator with 2 J/kg (Corpuls 08/16, GS Elektromedizinische Geräte GmbH, Kaufering, Germany). In all patients, oxygen was supplied with a non-rebreathing mask reservoir system. The ventilation of the patient was assisted with bag and mask, if necessary. The Fio2 was set at 1.0. Ventilation was continuously observed during induction by a physician, who was blinded to treatment groups.
Sedation were assessed on a scale between 0 and 3 at baseline (t0), before the pretreatment drug (t1), before the induction of anesthesia with etomidate (t2), 1 min (t3) and 5 min (t4) after etomidate had been given. The sedation was assessed as 0 = none, 1 = mild (responsive to patient’s name spoken in normal voice), 2 = moderate (responsive to name spoken loudly), and 3 = severe (responsive to a painful stimulus). Heart rate, mean arterial blood pressure, and oxygen saturation were recorded at the same time points. Because of the lack of an evaluated grading scale, the intensity of myoclonus was graded clinically as 0 = no myoclonus, 1 = mild myoclonus (only mild fasciculation involving face and/or distal upper and/or lower extermities), 2 = moderate myoclonus (marked movements of the face and/or limbs), and 3 = severe myoclonus (involving limbs and trunk). Beyond those mentioned above, no other drugs were used between the pretreatment drug and the end of induction.
On the basis of the results of our previous study, we expected the incidence of myoclonus in the placebo group to be 0.7. Power analyses with a = 0.05 and b = 0.2 showed that for a reduction in the incidence of myoclonus of 0.4, a minimum of 19 patients would have to be included. We decided to include 20 patients per group. Statistical analyses were performed with SPSS 14.0. The 
2-test and analysis of variance were used for statistical analysis. For all statistical tests, a value of P < 0.05 was taken as statistically significant.
|
RESULTS
|
|---|
Patient characteristics were not significantly different between the groups (Table 1).
Table 2 lists medications given on the day before cardioversion and on the day of cardioversion. Regarding these co-medications, there were no significant differences between the study groups (Table 2).
Within 60 s after induction with etomidate, 2 of 20 patients (10%) in the midazolam group and 10 of 20 patients (50%) in the placebo group developed myoclonic movements. The intensity of myoclonus was graded as mild in both cases in the midazolam group and as mild in 6, moderate in 3, and severe in 1 patient in the placebo group.
At no time was there a significant difference in sedation score or in short-term recovery (Table 3). None of the patients complained about recall of cardioversion.
View this table:
[in this window]
[in a new window]
|
Table 3. Sedation Score at the Time Point Before the Induction With Etomidate and at Recovery 5 Minutes After Etomidate
|
|
Between groups there was no significant difference regarding heart rate (Fig. 1), noninvasive arterial blood pressure (Fig. 2), respiratory rate, and pulse oximetry readings.
View larger version (7K):
[in this window]
[in a new window]
|
Figure 1. Mean arterial noninvasive blood pressure for the two pretreatment groups. t0 = baseline, t1 = before pretreatment, t2 = before etomidate, t3 = 1 min after etomidate, and t4 = 5 min after etomidate.
|
|
View larger version (6K):
[in this window]
[in a new window]
|
Figure 2. Heart rate in the two pretreatment groups. t0 = baseline, t1 = before pretreatment, t2 = before etomidate, t3 = 1 min after etomidate, and t4 = 5 min after etomidate.
|
|
The overall rate for successful electric cardioversion was 75% regardless of study group. There were no problems with the ECG interpretation during myoclonus in our study group.
|
DISCUSSION
|
|---|
The present data show that IV midazolam 0.015 mg/kg reduces the incidence of myoclonus during elective cardioversion under etomidate-induced anesthesia. Importantly, we did not see adverse effects, such as prolonged recovery from anesthesia or hemodynamic depression, in the midazolam group.
There are conflicting data concerning the effect of benzodiazepines on etomidate-induced myoclonus. The benzodiazepine most investigated to reduce etomidate-induced myoclonus is diazepam (7,10,11). In the study of Kortilla et al. (10), different doses of IV diazepam had no influence on the rate of myoclonus. On the other hand, Doenicke et al. (11) reported a significant reduction of the incidence of myoclonus when diazepam 0.1 mg/kg was given 5 min before etomidate. In that study, however, 25% of the patients were sleepy 8 h after the etomidate infusion. In our previous investigation with low-dose midazolam in premedicated patients, we found a myoclonus rate of 20% (9), which is similar to the results in the present study. However, because in that study surgical procedures lasted >30 min, additional anesthetics were given after induction so that we were unable to assess the effects of midazolam on short-term recovery. For short-term procedures, it is important that the premedication for suppressing myoclonus does not affect recovery from anesthesia. In our study, low-dose IV midazolam did not prolong the action of etomidate nor did it influence short-term recovery.
Etomidate-induced myoclonus may be clinically relevant: Etomidate-induced myoclonus caused vitreous prolapse in a patient with open eye injury (4). Further, ECG leads were detached during myoclonus and a decrease of oxygen saturation measured by pulse oximetry has been repeatedly reported during myoclonic movements (6). On the other hand, etomidate is attractive for short-term anesthesia as in elective cardioversion (12) because it allows early recovery and relative cardiovascular stability. Hence, for short-lasting procedures, any co-medication given for anesthetic or sedative purposes or to reduce myoclonus should not interfere with this favorable pharmacodynamic profile.
In the present study, hemodynamic variables were not significantly different between the midazolam and the placebo group, indicating that the only modest hemodynamic side effects commonly attributed to etomidate were not aggravated by the low dose midazolam. This finding, and the absence of negative effects on recovery time and respiration with the use of midazolam, makes this drug, in our opinion, a suitable choice to reduce etomidate-induced myoclonus during elective cardioversion.
Although opioids have been shown to reduce myoclonus (3,13), their mechanism of action remains unclear. Administration of an opioid may be undesirable for short-term procedures because of potential respiratory depression (3). In an investigation by Stockham et al. (8) using three different doses of fentanyl, it was shown that the incidence of side effects, e.g., apnea is correlated with the reduction of myoclonic movements. In the group receiving 500 µg fentanyl, no patient had myoclonus, but all were apneic. In contrast, in the group receiving 100 µg fentanyl, the respiratory depression was less profound, but the incidence of myoclonus was 33% (8). In an other study, Fassoulaki et al. (14) found no influence on the myoclonic rate, when administering 100 µg fentanyl before the induction of anesthesia with etomidate. In a recent study by Kelsaka et al. (15) investigating the short-acting opioid remifentanil for reduction of etomidate-induced myoclonus, there was no apnea with a dose of 1 µg/kg remifentanil, despite a significant reduction of the myoclonus rate.
Although both benzodiazepines and opioids have shown efficacy in terms of suppressing etomidate-induced myoclonus, the lack of comparative studies demonstrating superiority of one drug over the other precludes a definitive statement on which drug to use in the clinical setting. Until data from such studies become available, on the basis of current data, including the findings of the present study, we suggest that midazolam could be the preferred drug to reduce etomidate-induced myoclonus in less painful or painless procedures requiring anesthesia or sedation (e.g., cardioversion), whereas opioids may be an alternative if a need for postprocedural analgesia is anticipated (e.g., after fracture repositioning or dressing change in traumatized patients).
Despite the variety of drugs potentially reducing the incidence of myoclonic movements after etomidate administration (8,16,17), the mechanism by which this effect is achieved remains unclear. Etomidate interacts with 
-amino-butyric-acid type A (GABAA) receptors suppressing the central nervous reticular activating system. In an electroencephalogram study, Doenicke et al. (17) concluded that myoclonus after etomidate is caused by subcortical disinhibition similar to the phenomenon of restless legs during normal human sleep, and is not caused by an epileptic focus. Another reason could be that the inhibitory circuits are depressed earlier than excitatory neuronal circuits after etomidate administration (18). With interruption of GABA neurones, pathways associated with skeletal muscle control can become more sensitive, allowing spontaneous nerve transmissions to occur. These events can ultimately lead to myoclonic muscle contractions (19). Probably, the different effects of benzodiazepines on the different GABA receptors may explain the mechanism by which these drugs reduce the incidence of myoclonic movements.
Our study has some limitations. First, in patients presenting with atrial fibrillation after cardiac surgery, IV infusion of magnesium is one of the therapeutic options. However, the effects of magnesium on myoclonus were published while our study was in progress (16). Because we did not check magnesium plasma concentrations, and given the potential role of magnesium on myoclonic movements, this may have been a confounding factor in our study. However, in our study, the number of patients treated with magnesium was similar in both groups (Table 2), making significant differences in magnesium plasma levels less likely. Second, the incidence of myoclonus in the placebo group in the present study is somewhat lower than in other studies (3,9,16). In contrast to other studies (3,9,16), patients in the present study were elderly (70 ± 7 yr) and sick (ASA III–IV). We have found no studies regarding the influence of age on the incidence of myoclonic movements after etomidate administration, but one can speculate that there is such an influence on the incidence of myoclonus. Furthermore, as mentioned before, the incidence of co-medication with magnesium was high in both groups. This may be another explanation for the lower than anticipated rate of myoclonus. Because the power analysis of the present study was based on the assumption that 70% of patients would experience myoclonic movements, the finding of such movements in only half of the patients in the placebo group implies that the present investigation is somewhat under-powered. However, in light of the high reduction of 40% of the incidence of myoclonus, we assume that our results are still clinically relevant.
In conclusion, we show that IV midazolam 0.015 mg/kg given 90 s before etomidate administration reduces myoclonic muscle movements during induction of anesthesia for electric cardioversion, but does not prolong short-term recovery from anesthesia.
|
Footnotes
|
|---|
Accepted for publication July 19, 2007.
Address correspondence and reprints request to Dr. Lars Hüter, Klinik für Anästhesiologie und Intensivtherapie, Klinikum der Friedrich-Schiller-Universität Jena, Erlanger Allee 101, 07740 Jena, Germany. Address e-mail to lars.hueter{at}med.uni-jena.de.
|
REFERENCES
|
|---|
- Ford SR, Maze M, Gaba DM. A comparison of etomidate and thiopental anesthesia for cardioversion. J Cardiothorac Vasc Anesth 1991;5:563–5[Medline]
- Doenicke A, Roizen MF, Nebauer AE, Kugler A, Hoernecke R, Beger-Hintzen H. A comparison of two formulations for etomidate, 2-hydroxypropyl-ß-cyclodextrin (HPCD) and propylene glycol. Anesth Analg 1994;79:933–9[Abstract/Free Full Text]
- Hüter L, Schwarzkopf K, Simon M, Bredle D, Fritz H. Pretreatment with sufentanil reduces myoclonus after etomidate. Acta Anaesthesiol Scand 2003;47:482–4[ISI][Medline]
- Berry JM, Merin RG. Etomidate myoclonus and the open globe. Anesth Analg 1989;69:256–9[Free Full Text]
- Shulman MS, Edelmann R. Use of etomidate for elective cardioversion. Anesthesiology 1988;68:656[ISI][Medline]
- van Keulen SG, Burton JH. Myoclonus associated with etomidate for ED procedural sedation and analgesia. Am J Emerg Med 2003;21:556–8[ISI][Medline]
- Giese JG, Stockham RJ, Stanley TH, Pace NL, Nelissen RH. Etomidate versus thiopental for induction of anesthesia. Anesth Analg 1985;64:871–6[Abstract/Free Full Text]
- Stockham RJ, Stanley TH, Pace NL, Gillmor S, Groen F, Hilkens P. Fentanyl pretreatment modifies anaesthetic induction with etomidate. Anaesth Intens Care 1988;16:171–6[ISI][Medline]
- Schwarzkopf K, Hüter L, Simon M, Fritz H. Midazolam pretreatment reduces etomidate-induced myoclonic movements. Anaesth Intensive Care 2003;31:18–20[ISI][Medline]
- Korttila K, Tammisto T, Aromaa U. Comparison of etomidate, in combination with fentanyl or diazepam, with thiopentone as an induction agent for general anaesthesia. Br J Anaesth 1979;51:1151–7[Abstract/Free Full Text]
- Doenicke A, Kugler J, Penzel G, Laub M, Kalmar L, Kilian I, Bezcny H. Hirnfunktion und Toleranzbreite nach Etomidate, einem neuen barbituratfreien i.v. applizierbaren Hypnoticum. Anaesthesist 1973;22:353–66[ISI][Medline]
- Canessa R, Lema G, Urzua J, Dagnino J, Concha M. Anesthesia for elective cardioversion: a comparison of four anesthetic agents. J Cardiothorac Vasc Anesth 1991;5:566–8[Medline]
- Khalil SN, Lawson KS, Hanis CL, Lemak NA, Ruiz RS. Alfentanil decreases myoclonus caused by etomidate. Middle East J Anesthesiol 1999;15:185–92[Medline]
- Fassoulaki A, Pateras C, Kaniaris P. Fentanyl in the prevention of etomidate-induced myoclonus. Cah Anesthesiol 1987;35:201–2[Medline]
- Kelsaka E, Karakaya D, Sarihasan B, Baris S. Remifentanil pretreatment reduces myoclonus after etomidate. J Clin Anesth 2006;18:83–6[ISI][Medline]
- Guler A, Satilmis T, Akinci SB, Celebioglu B, Kanbak M. Magnesium sulfate pretreatment reduces myoclonus after etomidate. Anesth Analg 2005;101:705–9[Abstract/Free Full Text]
- Doenicke AW, Roizen MF, Kugler J, Kroll H, Foss J, Ostwald P. Reducing myoclonus after etomidate. Anesthesiology 1999;90:113–9[ISI][Medline]
- Kugler J, Doenicke A, Laub M. The EEG after etomidate. Anaesthesiol Resusc 1977;106:31–48
- Gancher S, Laxer KD, Krieger W. Activation of epileptogenic activity by etomidate. Anesthesiology 1984;61:616–8[ISI][Medline]
Top
Abstract
Introduction
