QUESTIONS UNDER STUDY: Myoclonic movements are common problems during induction of anaesthesia with etomidate. The myoclonus occurring after etomidate administration may represent a form of seizure. Agonistic modulation of the κ opiate receptor may reduce seizures, and butorphanol acts in such a manner. The aim of this randomised, double-blind, placebo-controlled clinical trial was to test our hypothesis that pre-treatment with butorphanol might reduce the incidence and severity of myoclonus induced by etomidate.
METHODS: Patients (108) with American Society of Anaesthesiologists physical status I or II were randomly assigned to one of two groups to receive either 0.015 mg/kgof butorphanol (n = 54) or saline (n = 54) intravenously. At two minutes after infusion of butorphanol or saline, 0.3 mg/kg etomidate was given. The occurrence and severity (observational score of 0–3) of myoclonus was assessed during 2 minutes after administration of etomidate. For each patient, blood pressure (BP), saturation of peripheral oxygen (SpO2), and heart rate (HR) were measured.
RESULTS: The incidence of myoclonus was significantly lower in Group Butorphanol than in Group Saline (13.0% vs 79.6%; RR = 0.163, 95%CI: 0.081–0.329; χ2= 48.265, p <0.0001). The severity levels of myoclonic movement were also significantly lower in Group Butorphanol than in Group Saline (p <0.0001). Throughout the procedure, changes of BP, SpO2, and HR did not differ between the groups. There were no problems with bradycardia or hypotension.
CONCLUSIONS: Infusion of 0.015 mg/kgbutorphanol 2 minutes before etomidate administration is effective for suppressing myoclonus induced by etomidate during induction of general anaesthesia.
Keywords: complications, anaesthetics, etomidate, butorphanol, myoclonus
Etomidate, a non-barbiturate hypnotic drug that provides a stable cardiovascular profile, is advocated as an agent for induction of anaesthesia for haemodynamically compromised patients . This drug is associated, however, with two disturbing side-effects: pain on injection and myoclonus. Pain on injection has been ameliorated by use of a lipid formulation of etomidate (Etomidate-Lipuro®) , but, during induction of anaesthesia, myoclonic movements still develop in ~50‒80% of non pre-medicated patients . Myoclonic movements may lead to patient discomfort and present a problem to those who have only partial cardiovascular reserves. Myoclonus may also be detrimental to patients with open globe injuries and in emergency non-fasting conditions . In patients with epilepsy, myoclonus can enhance focal epileptogenic activity [5, 6].
The neurologic mechanism of myoclonus after etomidate administration is still unclear, but it may represent a type of seizure [7–9]. Agonistic modulation of κ opiate receptors limits seizures [10, 11], and butorphanol acts mainly in this manner . Since the effectiveness of pre-treatment with butorphanol on myoclonic activity has not been previously investigated, the aim of the present study was to test our hypothesis that pre-treatment with butorphanol might reduce the incidence and severity of myoclonus during induction of anaesthesia with etomidate.
Materials and methods
Ethics and trial registration
The Consolidated Standards of Reporting Trials (CONSORT) recommendations for reporting randomised, controlled clinical trials were followed . Ethical approval for this study ( KY020) was provided by the Institutional Ethics Committee of the Second Affiliated Hospital of Nanjing Medical University (Chairperson Prof. Zhou, No. 121, Jiangjiayuan Road, Nanjing, 210011, China.) on 7th December 2012, and this study was registered in Chinese Clinical Trial Registry (ID: ChiCTR-PRC-13003107) on 20th March 2013. All patients involved were informed in regard to the proposal and gave their written, informed consent.
Patients with neurological diseases, drug allergies, and those who had received analgesics, sedatives, or opioids within the previous 24 hours were excluded. A total of 108 patients with American Society of Anaesthesiologists (ASA) physical status I or II (https://www.asahq.org/For-Members/Clinical-Information/ASA-Physical-Status-Classification-System.aspx), aged 20–65 years old, and undergoing general anaesthesia for elective surgical procedures were enrolled.
Patients were randomly assigned to one of two groups. Random tables were generated using SPSS. A total of 108 sealed envelopes were prepared. This study was conducted in the Second Affiliated Hospital of Nanjing Medical University in the period from 25th March 2013 to 22nd August 2013. The study was performed with neither patients nor the assessors’ awareness of the group to which each patient belonged. To assure allocation concealment, the numbers were kept in opaque and sealed envelopes, which were opened by an anaesthesiologist not involved in this study.
Interventions and outcome measures
Patients in the two groups received either butorphanol (0.015 mg/kg; n = 54, Group Butorphanol) or saline (n = 54, Group Saline). Drugs were prepared in black 5-ml syringes outside the operating room by the anaesthesiologist who was not involved in the induction of anaesthesia. The black syringes were indistinguishable regarding colour, volume, and viscosity by the assessors. Before anaesthesia, patients were cannulated (with 20-gauge needles) intravenously on the dorsum of the right forearm. Standard monitors, including those for electrocardiography, non-invasive blood pressure measurement and SpO2, were applied, and 0.9% saline was infused 300 ml/h.
After pre-oxygenation for 2 minutes, the pre-treatment drug was infused for over 30 seconds. At 2 minutes after infusion, anaesthesia was induced with the lipid formulation of etomidate (Etomidate-Lipuro®, 0.3 mg/kg) for 60 s. At 2 minutes after administration of etomidate and evaluation of myoclonus, vecuronium (0.1 mg/kg) and fentanyl (3 μg/kg) were applied to facilitate tracheal intubation.
Patients were observed continuously for myoclonus by an anaesthesiologist who was blinded to the pre-treatment drug. The patients were also not aware of the pre-treatment drug. Myoclonic movements were defined as involuntary short contraction of muscles leading to a short, observable movement of body parts. The intensity of myoclonus was scored as: 0, no myoclonus; 1, mild myoclonus (short movements of a body segment); 2, moderate myoclonus (mild movements of two different muscles); or 3, severe myoclonus (clonic movements in two or more muscle groups or fast adduction of a limb) .
Side effects, including headache, dizziness, and nausea, were checked by another anaesthesiologist who was blinded to the groups in order to avoid bias of the investigators who had observed myoclonus. Heart rate (HR), non-invasive arterial blood pressure (BP), and oxygen saturation (SpO2) were recorded each minute during the study period.
Primary outcome was the incidence of myoclonic movements after etomidate injection. Secondary outcomes were the side-effects (including headache, dizziness, and nausea) of pre-treatment drugs, and HR, BP and SpO2 during the study period.
The frequency of myoclonus in Group Saline was expected to be around 0.7. Power analysis indicated that a sample size of minimal 54 samples per group may have a 90% power to detect a reduction rate of 0.3 with α = 0.05 (1–tailed) and a 15% dropout rate.
Continuous variables were described as mean ± standard deviation (SD) and differences between groups were analysed by using independent-samples t test for normally distributed data. Categorised variables were described as frequency and analysed by the Chi-square (χ2) test. Severity of myoclonic movement in two groups were presented as ranked data (mild, moderate, severe) and compared by the Mann-Whitney-Wilcoxon test. A p-value less than 0.05 was considered to be significant. Relative risk (RR) and 95% confidence intervals (95%CI) were calculated for the effect size estimated for myoclonic movements after etomidate exposure. All statistical analyses were performed using SPSS for Windows (version 13.0; SPSS Inc. Chicago, IL, USA).
In total, 108 participants were recruited for this study. All patients were analysed in their allocated intervention group. In each group, 54 patients were included and the analysis was done by original assigned groups for each group (fig. 1). The demographic characteristics (gender, body weight and ASA physical status) were similar between the two groups (table 1).
There were 47 patients and 11 patients who had no myoclonus after etomidate injection in Group Butorphanol and Group Saline, respectively. Additionally the incidence of myoclonus was significantly lower in Group Butorphanol than in Group Saline (13.0% vs 79.6%; RR = 0.163, 95%CI: 0.081–0.329; χ2 = 48.265, p <0.0001). The severity of myoclonus was graded as mild in 3, moderate in 3, and severe in 1 patient in Group Butorphanol and as mild in 7, moderate in 11, and severe in 25 patients in the Group Saline. The severity levels of myoclonic movement in Group Butorphanol were significantly lower than in Group Saline (p <0.0001) (table 2).
The side-effects were similar in two groups with regard to headache, dizziness, and nausea, as no patients experienced headache, and only a few patients dizziness (4 patients) and nausea (1 patient) in Group Butorphanol. None of the patients experienced these side-effects in Group Saline (table 3).
The changes of BP and HR over the procedure did not differ between two groups. The saturation of peripheral oxygen (SpO2) was >97% in all subjects, All patients showed stable cardiovascular profiles. In no case, was there a problem with bradycardia or hypotension during the study period.
|Table 1: Characteristics of patients in Group Butorphanol and Group Saline.|
|Group Butorphanol(n = 54)||Group Saline(n = 54)||p|
|Age (years)*||44.8 ± 11.0||47.3 ± 12.5||0.272**|
|Weight (kg)*||66.3 ± 10.6||65.7 ± 12.0||0.784**|
|ASA physical status (I/II)||34/20||31/23||0.555***|
|* Values are presented as mean ± SD; ** The independent-samples t test; *** The Chi-square (χ2) test.|
|Table 2: Severity and incidence of myoclonic movement after etomidate injection in two groups.|
(n = 54)
(n = 54)
|RR = Relative risk; 95%CI = 95% confidence intervals.|
* The Mann-Whitney-Wilcoxon test.
|Table 3: Number of side-effects.|
|Group Butorphanol (n = 54)||Group Saline (n = 54)|
The present data show that pre-treatment with 0.015 mg/kg butorphanol reduced the incidence and severity of myoclonic movements during induction of anaesthesia with etomidate.
Comparison to other research
A variety of agents have reduced myoclonus to different extents, the most effective way was by pre-treatment with opioids. Higher doses of opioids effectively reduce myoclonic movements, but at the cost of undesirable side effects, such as apnoea and chest wall rigidity. Pre-treatment with 100, 250, 500 μg of fentanyl administered intravenously 5 min prior to etomidate-induced anaesthesia reduced the incidence of myoclonus (to 33%, 13%, and 0%, respectively) but increased the incidence of apnoea (by 87%, 87%, and 100%, respectively) . For female patients pre-treated with 0.3 μg/kg sufentanil, none experienced myoclonus, while 80% of the patients in placebo group developed myoclonic movements . In this study, midazolam (7.5 mg administered orally one hour prior to induction of anaesthesia), also reduced etomidate-induced myoclonic movements. Furthermore, >60% of patients treated with sufentanil showed mild to severe sedation, and 6 of 20 patients had a respiratory rate <10. The effect of plasma concentrations of remifentanil of 0, 2, or 4 ng/ml, controlled by an infusion system, showed incidences of 81%, 12%, and 0%, respectively . However, in the group pre-treated with 4 ng/ml remifentanil, 40% of patients developed coughs, 45% developed chest wall rigidity, 6% developed apnoea, and 6% showed sedation.
In the present investigation, pre-treatment with 0.015 mg/kgbutorphanol reduced the incidence of myoclonus from 79.6% in the placebo group to 13%. The above side-effects were not seen, except that a few patients in Group Butorphanol complained about dizziness or nausea after administration of butorphanol.
Benzodiazepine analogues have also been investigated to reduce myoclonus. Pre-treatment with 0.015 mg/kg midazolam reduced the incidence of myoclonus from 50% with placebo to 10% , however, intravenous diazepam (0.0625 mg/kg) failed to reduce the incidence .
Other agents have been applied to reduce etomidate-induced myoclonus rate in placebo-controlled clinical trials. Dexmedetomidine (0.5 μg/kg) and thiopental (1.0 mg/kg) reduced the incidence of myoclonus from 64% to 34% and 36%, respectively . Magnesium sulphate (2.48 mmol) reduced the incidence of myoclonus from 72% in a placebo group to 24%, but intravenous ketamine (0.2–0.5 mg/kg) did not reduce the incidence . Rocuronium (0.06 mg/kg) reduced the rate from 63% to 25% , and 20 mg lidocaine reduced the incidence from 25/30 to 17/30 . These compounds have not shown better effects than opioids.
Etomidate is a ligand of γ-amino-butyric-acid (GABA) receptors, which suppress the reticular activating system of central nerves. The myoclonic activity induced by etomidate may be associated with seizures [1-9]. As an agonist, butorphanol mainly binds to and modulates κ opiate receptor, which are involved in anti-seizure activity [10-12], and κ opiate receptor agonists interact with a variety of neurotransmitter systems: (1.) the principal opioid receptors (μ, δ, and κ), (2.) the benzodiazepine-GABA-A chloride channel complex, (3.) GABA-B receptors and (4.) N-methyl-D-aspartate channels . It is likely that the effects of butorphanol on these receptors are responsible for the reduction of myoclonic movements.
In this study, we chose the dose of butorphanol (0.015 mg/kg) since previous studies showed that 1 mg butorphanol was effective in controlling post-anaesthesia shaking and shivering for adult under spinal anaesthesia [24, 25]. We waited 2 minutes before etomidate administration since it took butorphanol about 1.8 ± 0.5 minutes onset time to terminate rigors .
There are some limitations for this clinical trial. First, the main outcome measure (rating of myoclonus) was subjective, but we did not find other accurate and convenient monitoring indicators in the previous clinical studies. Second, we did not investigate the optimal clinical dose of butorphanol on etomidate-induced myoclonus, since there are few previously reported studies on the relationship between butorphanol and myoclonus. Whether higher doses of butorphanol exert stronger inhibitory effects without adverse side effects will be tested in future studies. Third, some patients in the butorphanol group had dizziness and nausea, which might lead to a bias by the investigators. Although we arranged different assessors to evaluate myoclonus or side effects, it still cannot be avoided completely. Due to the low incidence of side-effects in the Group Butorphanol, it does not affect the conclusions.
Intravenous infusion of 0.015 mg/kg butorphanol 2 min before etomidate administration is effective in suppressing etomidate-induced myoclonic movements during induction of general anaesthesia.
Acknowlegement: This work was supported by the Department of Anaesthesiology, the 2nd Affiliated Hospital of Nanjing Medical University, and we thank them for their assistance with the study.
Funding / potential competing interests: This study was conducted in the 2nd Affiliated Hospital of Nanjing Medical University. The registration information can be found on the following website: http://apps.who.int/trialsearch/Trial.aspx?TrialID=ChiCTR-PRC-13003107. None of the authors has any conflict of interest.
Correspondence:Li Zhong, PhD, Key Laboratory of Modern Toxicology (Ministry of Education), School of Public Health, Nanjing Medical University, No. 818 East Tianyuan Road, CN-Jiangsu, Nanjing, 211166, China, Uiuclz[at]126.com
1 Erdoes G, Basciani RM, Eberle B. Etomidate – a review of robust evidence for its use in various clinical scenarios. Acta Anaesthesiol Scand. 2014; 58(4):380–9.
2 Doenicke A, Roizen MF, Nebauer AE, Kugler A, Hoernecke R, Beger-Hintzen H. A comparison of two formulations for etomidate, 2–hydroxypropyl-beta-cyclodextrin (hpcd) and propylene glycol. Anesth Analg. 1994;79:933–9.
3 Doenicke AW, Roizen MF, Kugler J, Kroll H, Foss J, Ostwald P. Reducing myoclonus after etomidate. Anesthesiology. 1999;90:113–9.
4 Berry JM, Merin RG. Etomidate myoclonus and the open globe. Anesth Analg. 1989;69:256–9.
5 Ebrahim ZY, DeBoer GE, Luders H, Hahn JF, Lesser RP. Effect of etomidate on the electroencephalogram of patients with epilepsy. Anesth Analg. 1986;65:1004–6.
6 Gancher S, Laxer KD, Krieger W. Activation of epileptogenic activity by etomidate. Anesthesiology. 1984;61:616–8.
7 Grant IS, Hutchison G. Epileptiform seizures during prolonged etomidate sedation. Lancet. 1983;2:511–2.
8 Reddy RV, Moorthy SS, Dierdorf SF, Deitch RD, Jr., Link L. Excitatory effects and electroencephalographic correlation of etomidate, thiopental, methohexital, and propofol. Anesth Analg. 1993;77:1008–11.
9 Voss LJ, Sleigh JW, Barnard JP, Kirsch HE. The howling cortex: seizures and general anesthetic drugs. Anesth Analg. 2008;107(5):1689–703.
10 Bausch SB, Esteb TM, Terman GW, Chavkin C. Administered and endogenously released kappa opioids decrease pilocarpine-induced seizures and seizure-induced histopathology. J Pharmacol Exp Ther. 1998;284:1147–55.
11 Simonato M, Romualdi P. Dynorphin and epilepsy. Prog Neurobiol. 1996;50(5–6):557–83.
12 Chang K-J, Hazum E, Cuatrecasas P. Novel opiate binding sites selective for benzomorphan drugs. Proc Natl Acad Sci USA. 1981;78:4141–5.
13 Moher D, Hopewell S, Schulz KF, Montori V, Gotzsche PC, Devereaux PJ, et al. CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. BMJ. 2010;340:c869.
14 Stockham RJ, Stanley TH, Pace NL, Gillmor S, Groen F, Hilkens P. Fentanyl pretreatment modifies anaesthetic induction with etomidate. Anaesth Intensive Care. 1988;16:171–6.
15 Hueter L, Schwarzkopf K, Simon M, Bredle D, Fritz H. Pretreatment with sufentanil reduces myoclonus after etomidate. Acta Anaesthesiol Scand. 2003;47:482–4.
16 Ri HS, Shin SW, Kim TK, Baik SW, Yoon JU, Byeon GJ. The proper effect site concentration of remifentanil for prevention of myoclonus after etomidate injection. Korean J Anesthesiol. 2011;61:127–32.
17 Hüter L, Schreiber T, Gugel M, Schwarzkopf K. Low-dose intravenous midazolam reduces etomidate-induced myoclonus: a prospective, randomized study in patients undergoing elective cardioversion. Anesth Analg. 2007;105:1298–302.
20 Guler A, Satilmis T, Akinci SB, Celebioglu B, Kanbak M. Magnesium sulfate pretreatment reduces myoclonus after etomidate. Anesth Analg. 2005;101:705–9.
22 Gultop F, Akkaya T, Bedirli N, Gumus H. Lidocaine pretreatment reduces the frequency and severity of myoclonus induced by etomidate. J Anesth. 2010;24:300–2.
24 Juneja M, Ackerman WE, 3rd, Heine MF, Cases-Cristobal V, Urella RP, Rigor BM. Butorphanol for the relief of shivering associated with extradural anesthesia in parturients. J Clin Anesth. 1992;4:390–3.
25 Bansal P, Jain G. Control of shivering with clonidine, butorphanol, and tramadol under spinal anesthesia: A comparative study. Local Reg Anesth. 2011;4:29–34.
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