Abstract
Introduction
Etomidate is a hypnotic drug widely used as an intravenous anesthetic induction agent. The incidence of etomidate-induced myoclonus has been reported as much as 50–80% after induction making it an undesirable drug for induction.
Objective
Our aim is to use a priming dose of atracurium to suppress etomidate-induced myoclonus during induction of anesthesia.
Methods
In a double-blinded clinical trial 80 patients were randomly given either atracurium (20% of ED95 × kg) or saline as a priming agent. Then, induction of anesthesia was performed using 0.4 mg/kg etomidate. Age, weight, body mass index, bispectral index (BIS) monitor, and duration and grade of myoclonus were recorded.
Results
The demographic characteristics, age, body mass index, BIS score, and weight were not significantly different between the atracurium (ATRA) priming group and control groups. The binomial regression model showed that BMI was an independent predictor variable for myoclonus (OR: 2.1, CI 95%: 1.7–7.5, p = 0.032). In this model, adjusted odds ratios (OR) of myoclonus (multivariate logistic regression analysis) in the control group was 6.6 (95% CI: 1.5–9.7, p = 0.013).
Conclusion
Low-dose atracurium priming could effectively suppress etomidate-induced myoclonus.
Keywords
atracurium; etomidate; myoclonus;
1. Introduction
Etomidate is a non-barbiturate hypnotic drug derived from a carboxylated imidazole and is widely used as an intravenous anesthetic induction agent.1 It has a rapid onset of action and provides cardiovascular stability with minimal respiratory side effects.2 By contrast, etomidate has several adverse effects, including pain at the injection site, especially if formulated with propylene glycol, postoperative nausea/vomiting, electroencephalography (EEG) activation, adrenal suppression, and myoclonus.3, 4 The incidence of myoclonus has been reported as much as 50–80% after etomidate induction.5Myoclonus may increase the risk of regurgitation and aspiration.6 It may also increase the risk of vitreous prolapse after an open-globe injury due to increased intraocular pressure.7 Although the mechanism of the myoclonus is not clear, various drugs, such as opiates, benzodiazepines, and rocuronium are given prior to etomidate induction in order to suppress myoclonus.8, 9, 10However, the drug of choice to reduce the severity and frequency of etomidate-induced myoclonus has not yet been established.
Administration of a subparalyzing dose of nondepolarizing neuromuscular blocking drug could help to prevent the side effect of succinylcholine fasciculation11, 12 or serve as a priming dose of a nondepolarizing drug.13, 14A priming dose of 10% of standard intubating dose (2 × ED95) and a priming interval of 3 minutes have been considered to be effective to reduce fasciculation.15, 16
Among nondepolarizing muscle relaxants (NDMRs), atracurium is an intermediate-acting neuromuscular blocking agent which has two routes of metabolism independent of liver and renal functions.17
Furthermore, atracurium is more accessible and cheaper than other NDMRs, such as rocuronium. These advantages make atracurium unique among NDMRs to be used in certain patients, especially those with hepatic failure. To date there is no investigation regarding the effectiveness of low doses of atracurium to prevent unwanted myoclonus caused by etomidate.
Therefore, we designed a placebo-controlled study to investigate the effects of pretreatment with low-dose IV atracurium on the incidence of myoclonus during induction of anesthesia with etomidate for elective surgeries.
2. Materials and methods
The study was reviewed and approved by the University Hospital Ethics committee (Modarres Hospital) and performed in accordance with the ethical standards laid down in an appropriate version of the 2000 Declaration of Helsinki. Information about the study was imparted comprehensively both in verbal and written forms to all patients or their accompanying consorts. They gave their informed consents prior to their inclusion in the study according to the University Hospital Ethical Board Committee. This study was designed as a double-blinded clinical trial that was conducted in our University Hospital.
We assessed the effects of subparalyzing doses of atracurium to control the myoclonus following injections of etomidate. We selected randomly a total of 80 individuals, aged between 18 years and 75 years, with ASA Class I or Class IV along with mallampati I or II, who were candidates for elective general surgery or urologic surgery under general anesthesia. Patients with neurologic disease or drug allergy, patients who had received analgesics, sedatives, or opioids within the previous 24 hours, or those who had BIS (bispectral index) <40 or >60 during induction were excluded from this study. Patients were allocated to one of two groups in a randomized, double-blinded fashion via random number draws. The atracurium (ATRA) priming group received a low-dose atracurium (20% × ED95 × Kg; n = 40) and those in the control group received placebo (saline; n = 40). The drugs were prepared in a black syringe outside the operating room by a person who was not involved in the induction of anesthesia. Upon arrival at the operating room, electrocardiography electrodes, and pulse oximeter probes were applied for monitoring ECG and oxygen saturation (Spo2). Blood pressure (BP) was measured non-invasively every 3 minutes during the study period. A standard bispectral index (BIS) monitor strip (BIS Quatro, Aspect Medical System Inc., Newton, MA, USA) was placed on the forehead prior to anesthesia. Train of four (TOF) was monitored during the induction period.
Fentanyl (2 mcg/kg) and midazolam (1–2 mg) were given as premedication. One minute after that atracurium (20% of ED95 × kg) was injected. Three minutes later etomidate 0.3 mg/kg was administrated. None of the patients had paralyzing symptoms. After ATRA, priming results of TOF did not show any significant changes, and was four out of four. One minute later atracurium (0.5 mg/kg) was injected and intubation was performed within 2–4 minutes, and TOF was equal to one of four.
Patients were observed continuously for occurrence of myoclonus by an anesthesiologist who was blinded as to group allocation. Myoclonus was defined as an involuntary, short contraction of some muscle fibers of a whole muscle, or of different muscles of one group, leading to a short observable movement of the corresponding body part. Myoclonus was graded as 0 to no fasciculation, 1 to only face, 2 to face and extremities, and 3 to whole body fasciculation. The parametric variables were analyzed by student t-test or ANOVA and Pearson correlation test as appropriate. Statistical analysis was performed using Chi-square test or Mann–Whitney U test, and Spearman correlation coefficients for non-parametric samples. Multiple logistic regression was used to assess the association of cotinine level and asthma severity. A p value < 0.05 was considered statistically significant. Sample size was estimated using sample size calculator software (Raosoft, Seattle, WA, USA) with a 95% confidence interval and p < 0.05 based on a pilot study performed prior to study.
3. Results
The mean age of the patients were 42.5 ± 17.3 years (range 19–86 years). The age, weight, height, gender, systolic and diastolic blood pressure, and ASA class of patients were not significantly different (Table 1). Basal vital signs including blood pressure were not significantly different in the control and ATRA priming groups but basal heart rate was statistically different without clinical significance (Table 1). The mean ± SD of BMI in ATRA (24.76 ± 3.60, n = 40) and control group (25.23 ± 3.55, n = 40) were not significantly different. The incidence of myoclonus was 52.5% (21 patients) in the control group and 22% (9 patients) in the priming group. The frequency of myoclonus was significantly lower in the ATRA priming group (22%) than in the control group (52.5%).The mean duration of myoclonus in the control group was 24.8 seconds (range 2–71 seconds) and 2 seconds (range 1–6 seconds) in the ATRA priming group which was significantly different (p < 0.0001). The distribution of myoclonus according to grades is depicted in Fig. 1.
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In univariate analysis factors associated with myoclonus after etomidate were analyzed. It was important to note that there were no significant differences in genders and age between the ATRA priming group and the control group. In other words, the risk factors were contributing to the myoclonus without confounding factors of age or gender. Very interestingly, by t test and Mann–Whitney U test, all demographic factors including age, gender, and BMI were not significantly different between the ATRA priming group and the control group. The statistical difference in incidence of myoclonus was observed in the Chi-square test between the priming and control groups. More importantly, myoclonus were categorized according to its duration and grade. Grade 2 or 3 myoclonus was observed only in the control group. With regard to these observations, the statistical difference in myoclonus without stratifications for other variables like age and gender were expected without ATRA priming.
The crude odds ratio (OR) of myoclonus in the control group compared with the ATRA priming group was 2.34, 95% CI: 1.22–4.54, p = 0.01. In order to control confounding factors like age, weight, BMI, and severity of disease (ASA class), we used a multivariate analysis with logistic regression for prediction of the probability of the occurrence of myoclonus by fitting data to a logistic curve. The binomial regression model showed that BMI was an independent predictor variable for myoclonus (OR: 2.1, CI 95%: 1.7–7.5, p = 0.032). In this model, adjusted odds ratios (OR) of myoclonus (multivariate logistic regression analysis) in the control group was 6.6 (95% CI: 1.5–9.7, p = 0.013). The odds ratio of 6.6 showed that the odds of myoclonus (all grades) occurring in the control group (no ATRA priming) were almost 6 times more than in the ATRA priming group (ATRA priming). These results showed that ATRA priming had OR of 0.32 (95% CI: 0.32–0.88) with p = 0.026 in multivariate adjusted OR (Table 2).
The odds ratio of Grade 2 myoclonus progression was 1.89 (OR = 1.89, 95% CI: 1.47 –2.56, p = 0.015) in the control group compared with the ATRA priming group. This relationship remained significant after adjustment for gender, weight, BMI, and duration of operation. Based on our regression model, randomization of patients to the ATRA priming group changed myoclonus grades significantly from 3 to 2 and 1 to 0 (B = 0.869, 95% CI: 1.76–5.75, p < 0.001). These data showed the significant benefit of priming ATRA in decreasing myoclonus grade compared with the control group.
4. Discussion
Etomidate could induce myoclonic movements as a side effect in unpremedicated patients during induction of anesthesia with unknown mechanism. Myoclonus has made etomidate an undesirable drug to many anesthesiologists. In contrast to other studies,18 patients in our present study were middle aged (42.5 ± 17.3 years old) and not very sick (ASA I–II). Although it is speculated that a young age could influence the incidence of myoclonus, we have found no such influence of age on the incidence of myoclonic movements after etomidate administration. As the power analysis of the present study was based on the assumption that 50% of patients would experience myoclonic movements, the finding of such movements in almost half of the patients in the control group implies that the present investigation is well designed and reflects the estimate of a population parameter. In the light of the observation of a 30% reduction in the incidence of myoclonus in our study, we assume that our results could be of clinical value.
Priming with ATRA induced a major risk reduction of propagating myoclonus. Previous reports have introduced rocuronium as a priming agent to etomidate use.10 However, the major challenge is the scarcity of this drug in many settings. The advantage of atracurium is its accessibility in many hospital settings.
One advantage of our study is that we used midazolam and fentanyl in both the ATRA priming group and the control group. However, using these drugs as premedication did not decrease myoclonus grade or incidence significantly. Low-dose midazolam as premedication has been introduced as a means to decrease myoclonus during induction of anesthesia with etomidate. However, there are conflicting data concerning the effect of benzodiazepines on etomidate-induced myoclonus.6, 19
Neuromuscular blockers are used mainly to facilitate tracheal intubation and provide surgical relaxation. The intensity of neuromuscular blockade requirements varies with the surgical procedure. Although some investigators claim that pretreatment with a defasciculating dose of a nondepolarizing neuromuscular blocker has no effect, many believe that the pain from fasciculation is at least attenuated.20
Major progress has been made in understanding the exact mechanism of etomidate-induced myoclonus, but many molecular aspects of it are still enigmatic. Etomidate interacts with γ-amino-butyric-acid type A (GABAA) receptors, thus suppressing the central nervous reticular activating system. The theory is that the inhibitory circuits are depressed earlier than excitatory neuronal circuits after etomidate administration.21 With interruption of GABA neurons, skeletal muscle control pathways can become more sensitive, allowing spontaneous nerve transmissions and myoclonus movements.22Based on this hypothesis, benzodiazepines are supposed to suppress etomidate-induced myoclonus. Although both benzodiazepines and opioids have shown some efficacy in suppressing etomidate-induced myoclonus, the lack of comparative studies demonstrating the precise efficacy of these drugs precludes any applications in clinical settings. Besides, patients vary tremendously in their response to anti-myoclonic effects of these drugs. In order to address the controversy and to decrease bias both midazolam and fentanyl were administered at large doses as part of the premedication in both groups. However, neither midazolam nor fentanyl were able to decrease the incidence, duration, or grade of myoclonus in the ATRA priming group or the control group.
In conclusion, low-dose priming with atracurium could effectively suppress etomidate-induced myoclonus. This study provides valuable clinical data to be used in many hospital settings. By using low-dose atracurium as premedication, etomidate as a valuable drug could be properly used in induction of anesthesia without myoclonus as a prominent adverse effect.