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ORIGINAL ARTICLE
Year : 2023 | Volume
: 24
| Issue : 1 | Page : 29-35
Comparative assessment of different doses of midazolam to prevent etomidate-induced myoclonus – A randomized, double-blind, placebo-controlled trial
Lokman Manish, Michell Gulabani, Medha Mohta, Geetanjali T Chilkoti
Department of Anaesthesiology and Critical Care, University College of Medical Sciences and GTB Hospital, New Delhi, India
Correspondence Address:
Dr. Michell Gulabani
19/245-246 Second Floor, Malviya Nagar, New Delhi - 110 017
India
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/TheIAForum.TheIAForum_98_22
Background: Etomidate is a popular induction agent, due to its several advantages for example, an extremely stable hemodynamic profile with no effects on sympathetic nervous system and baroreceptors, minimal effect on respiration and also prevents histamine release in healthy patients or in those with reactive airway disease. It, however, may be associated with myoclonus whose incidence has been reported as 50%–80% in nonpremedicated patients. 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. Midazolam has been used as a pretreatment to attenuate myoclonus in different doses with varied results, but the optimal dose has not been established. The present study was planned to compare the effect of three doses of midazolam, i.e., 0.015 mg/kg, 0.03 mg/kg, and 0.05 mg/kg in preventing etomidate-induced myoclonus.
Materials and Methods: This study comprised 164 American Society of Anesthesiologists I/II consenting patients between 18 and 60 years. They were randomly divided into four groups after which pretreatment with normal saline in group M0, midazolam 0.015 mg/kg in group M0.015, 0.03 mg/kg in group M0.03, and 0.05 mg/kg in group M0.05 was administered. The primary outcome was the incidence of myoclonus after etomidate. The secondary outcome measures included severity of myoclonus and changes in hemodynamic parameters. One-way analysis of variance with Bonferroni's correction was used to compare quantitative data. Chi-square test was applied for qualitative data. Further, as there were four groups with multiple comparisons, Bonferroni's correction was applied and P < 0.01 was considered statistically significant.
Results: We observed a significant reduction in the incidence of myoclonus of group M0.015 as compared to group M0 (P < 0.001). A significant reduction in severity of myoclonus was observed in all the three midazolam groups compared to the control group (P < 0.001) without any significance among the patients receiving different doses of midazolam.
Conclusion: We recommend using midazolam pretreatment in a dose of 0.015 mg/kg for prevention of etomidate-induced myoclonus.
Keywords: Etomidate, general anesthesia, hemodynamics, incidence, midazolam, myoclonus
Etomidate is a popular induction agent due to its several advantages, e.g., extremely stable hemodynamic profile, minimal histamine release, cerebral protection, and favorable pharmacokinetics, enabling rapid recovery after a single bolus or continuous infusions.[1],[2],[3] However, it may be associated with some disturbing side effects, such as pain on injection, postoperative nausea and vomiting, adrenal suppression, superficial thrombophlebitis, and myoclonus.[1],[4],[5] The incidence of myoclonus after etomidate administration has been reported as high as 50%–80% in nonpremedicated patients.[4],[5],[6]
Myoclonus refers to sudden, quick, involuntary muscle jerks, either irregular or rhythmic. These movements are caused by muscular contractions.[7] The consequences of this adverse effect can be serious in some groups of patients, e.g., nonfasted emergency patients with the risk of regurgitation and aspiration; those having open globe injuries with an increased risk of prolapse of vitreous material; and patients with limited cardiovascular reserve as these muscle contractions increase myocardial oxygen consumption.[1],[2]
A number of drugs have been studied for the suppression of myoclonus. These include fentanyl, remifentanil, dexmedetomidine, magnesium sulfate, a small dose of etomidate prior to a hypnotic dose, diazepam, and midazolam.[1],[8],[9],[10],[11]
Midazolam appears to be a good choice as it is short acting and does not have a significant effect on respiration and hemodynamics in routinely used doses. It has been administered in different doses to reduce the incidence of etomidate-induced myoclonus with varied results. It has been tried from 0.015 mg/kg to 0.05 mg/kg by various workers.[9],[11]
However, there is a lacuna in the existing knowledge regarding a standard dose for the attenuation of myoclonus. Therefore, the present research was planned to study the effect of different doses of midazolam, i.e., 0.015 mg/kg, 0.03 mg/kg, and 0.05 mg/kg in preventing etomidate-induced myoclonus.
Materials and MethodsAfter approval from the institutional ethics committee, a randomized, double-blind, placebo-controlled study was conducted in the Department of Anaesthesiology and Critical Care. It was registered under the Clinical Trials Registry of India.
The study comprised 164 American Society of Anesthesiologists (ASA) I/II consenting patients between 18 and 60 years of age, scheduled for elective surgical procedures under general anesthesia. Patients with a history suggestive of neuropsychological or neuromuscular disease, history suggestive of adrenal cortical dysfunction, history of allergy to midazolam, epilepsy, those having received any analgesic or sedative within the previous 24 h, and pregnant or lactating women were excluded from the study.
The patients were randomly divided into four groups of 41 patients each, using a computer-generated random number table. Sealed opaque envelopes were used for allocation concealment. The test drug was prepared by a person not involved in the study, and the patient and the investigator were blind to the group allocation.
The patients received pretreatment with normal saline in group M0, midazolam 0.015 mg/kg in group M0.015, midazolam 0.03 mg/kg in group M0.03, and midazolam 0.05 mg/kg in group M0.05 in a total volume of 5 ml.
All the patients received tablet alprazolam 0.5 mg on the night prior to surgery; however, no premedication was given on the day of surgery. In the operating room, after attaching standard monitors, an 18G intravenous catheter was inserted and Ringer's lactate infusion started. The test drug was injected over 30 s. Ninety seconds after that, etomidate 0.3 mg/kg was injected over 20 s. The patient was observed for 60 s, following which vecuronium bromide and morphine were administered and tracheal intubation was performed after 3 min.
The observation for myoclonus continued even after administration of vecuronium as some patients developed myoclonus after 60 s had elapsed. Heart rate (HR), systolic blood pressure, diastolic blood pressure, mean blood pressure (MBP), and oxygen saturation were monitored every minute before and after test drug administration, after etomidate injection, and till 5 min after intubation. The time point 0 min marked the test drug administration, etomidate injection corresponded with 2-min readings, vecuronium administration with 3 min, and intubation with 6-min time point. Thus, the values 6 min onward reflected the effect of tracheal intubation on hemodynamic parameters.
The intensity of myoclonus was graded clinically as 0 = no myoclonus, 1 = mild myoclonus (only mild fasciculation involving the face and/or distal upper and/or lower extremities), 2 = moderate myoclonus (marked movements of the face and/or limbs), and 3 = severe myoclonus (involving limbs and trunk).[9]
The primary outcome was the incidence of myoclonic movements after etomidate injection. The secondary outcome measures included severity of myoclonus after etomidate injection; changes in HR and MBP after test drug injection, after etomidate administration, and after intubation; and incidence of airway complications, e.g., laryngospasm and bronchospasm.
Sample size calculation
Considering the incidence of myoclonus in the placebo group to be 70% and a reduction in the incidence by 50% as clinically significant, using α = 0.05 and β = 0.2, the calculated sample size was 31 patients in each group.[10] However, among the proposed four groups, there were three comparisons with the control group. Therefore, Bonferroni's correction was applied for obtaining significance. Taking this correction into account, 41 patients in each group were studied.
Statistical analysis
Statistical analysis was performed using SPSS version 20. One-way analysis of variance with Bonferroni's correction was used to compare quantitative data comprising demographic profile and hemodynamic parameters. Chi-square test was applied for comparisons of qualitative data, i.e., gender ratio, ASA physical scoring, and incidence and severity of myoclonus among different groups. P < 0.05 was considered statistically significant. Further, as there were four groups with multiple comparisons, Bonferroni's correction was applied and P < 0.01 was considered statistically significant.
ResultsAmong the 188 consecutive patients assessed for eligibility, 166 patients met the inclusion criteria. Two patients refused to give consent and the remaining 164 were included in the study. These 164 patients were randomized into four groups of 41 patients each, using a computer-generated random number table. The CONSORT flow diagram for the study is shown in [Figure 1].
The demographic profile was comparable in the four groups except gender ratio. There were a greater number of female patients overall in the study [Table 1].
Table 1: Demographic profile and American Society of Anesthesiologists gradingThe patients were observed for the occurrence of myoclonus after etomidate administration in all the four groups. This difference in the incidence was statistically significant (P < 0.001) [Table 2]. There was a significant reduction in the incidence of myoclonus in group M0.015 as compared to group M0. (M0.015 vs. M0: P < 0.001). Other differences among various groups were statistically not significant (M0 vs. M0.03, P = 0.109, and M0 vs. M0.05, P = 0.013) (P > 0.01).
Table 2: Incidence of myoclonus after etomidate administration in all four groupsA statistically significant reduction in severity of myoclonus was observed in the three midazolam groups compared to the control group (M0.015 versus group M0: P = 0.0002; group M0.03 versus group M0: P = 0.0085; group M0.05 versus group M0: P = 0.00089). No significant differences in severity of myoclonus were seen among the patients receiving different doses of midazolam [Table 3].
As the occurrence of moderate or severe myoclonus has greater clinical significance as compared to mild myoclonus, patients having moderate-to-severe myoclonus were grouped together and compared with those having mild or no myoclonus. Group M0 had a significantly higher number of patients having moderate-to-severe myoclonus as compared to all three midazolam groups (M0 vs. M0.015: P < 0.001; M0 vs. M0.03: P = 0.001; M0 vs. M0.05: P = 0.001). No significant differences in moderate-to-severe and mild or no myoclonus were seen among the patients receiving different doses of midazolam (P > 0.01) [Table 4].
Table 4: Severity of myoclonus: Moderate/severe versus mild/no myoclonusThe four groups were comparable with respect to hemodynamic variables preoperatively (baseline) [Table 5]. The mean arterial blood pressure was also comparable between the groups after test drug, after etomidate administration, and until 5 min after intubation [Table 6]. No incidence of airway complication, e.g., laryngospasm or bronchospasm, was observed.
DiscussionWe observed a significant reduction in the incidence of myoclonus in group M0.015 as compared to group M0. The severity of myoclonus depicted a significant reduction in all the three midazolam groups, with greater number of patients having moderate-to-severe myoclonus in the control group. However, no differences in the incidence and severity of myoclonus were seen among the three midazolam groups.
Etomidate is known for its unique hemodynamic stability, minimal effect on respiration, and cerebral protection. However, it may be associated with the adverse effect of myoclonus for whose attenuation a number of drugs have been studied. These include fentanyl,[4],[10] remifentanil,[9],[12] sufentanil,[13] dexmedetomidine,[14],[15] propofol,[16] magnesium sulfate,[9] gabapentin,[17] butorphanol,[2],[10] lignocaine,[5] oxycodone,[18] ketamine,[19] a small dose of etomidate prior to hypnotic dose,[11],[20],[21] and midazolam.[4],[9],[15],[22],[23],[24],[25]
Midazolam is a preferable agent for preventing myoclonic movements due to its short duration of action and minimal significant systemic effects.[26] There are studies available in literature having administered midazolam in doses ranging from 0.015 mg/kg to 0.05 mg/kg. However, its optimal dose as pretreatment for attenuation of the myoclonus has not been established, highlighting the need for further randomized controlled trials with larger high-quality samples.[23]
The incidence of myoclonus without midazolam pretreatment in our study was 85%. Several other studies have reported myoclonic activity in 50%–80% of patients receiving etomidate.[10],[11]
The myoclonic movement has been shown to be related to multiple factors such as the patient's age, gender, dose of etomidate, and speed of etomidate injection.[20],[26],[27] The patient's age in our study was similar in all the four groups and hence the difference in incidence of myoclonus cannot be attributed to this factor. Male patients have been seen to have a higher incidence of myoclonus as compared to females.[27] The higher frequency of males in group M0.03 of the present study as compared to females might probably be the reason for the incidence of myoclonus (71%) being highest in this group. The dose and speed of injection of etomidate are also known to affect the frequency of myoclonus. Wasinwong et al. observed an increased frequency of myoclonus with higher doses of etomidate.[22] A slower speed of injection of etomidate over 2 min as compared to injecting over 10–20 s has been associated with decreased incidence of myoclonus.[22],[27] This could be a contributing factor for the high incidence of myoclonus seen in the control group in the present study (85%) as we had used the conventional (0.3 mg/kg) dose of etomidate injected as a bolus over 20 s.
The duration between the completion of test drug as a pretreatment for myoclonus attenuation and the administration of etomidate is also a differentiating factor between studies. In the present study, 90 s was the time, but there are studies, in which this time has ranged from 2 to 4 min.[4],[9],[22],[25] Hence, if we had probably waited for a longer time (>90 s), the effects might have been different.
The incidence of myoclonus with midazolam 0.015 mg/kg pretreatment in the present study was 44%, with a significant reduction when compared with the control group. Many previous studies in the literature have reported a much higher incidence of myoclonus than ours using this dose of midazolam.[9],[13],[15] Sedighinejad et al.[9] and Dey and Kumar[15] reported an incidence of 71.85% and 62.5% when midazolam was administered 2 min before induction of anesthesia. However, in Sedighinejad et al.,[9] a control group was lacking and this has been mentioned as a limitation by them. They compared midazolam 0.015 mg/kg with magnesium sulfate, remifentanil, and low-dose etomidate to observe myoclonus for 90 s. Pretreatment with low-dose etomidate was found to significantly reduce the incidence and severity of myoclonus.
Dey and Kumar[15] compared midazolam 0.015 mg/kg with dexmedetomidine 0.5 μg/kg without a control group and both were administered as an infusion over 10 min prior to induction with etomidate. In this study, dexmedetomidine was found superior in attenuating the myoclonus than midazolam. However, the speed of injection of midazolam 0.015 mg/kg was different from ours (10 min vs. 20 s). Alipour et al.[13] found an even higher incidence of myoclonus, i.e., 84% in patients receiving pretreatment with midazolam 0.015 mg/kg followed by induction after 90 s with etomidate 0.3 mg/kg. However, their main limitation was a much smaller sample size than ours 25 versus 41.
On the other hand, Hüter et al.[24] reported that in patients undergoing elective cardioversion, 0.015 mg/kg midazolam pretreatment 90 s prior to anesthesia induction with 0.3 mg/kg etomidate produced a significant reduction in the frequency of myoclonus compared to the control group (10% vs. 50%). The lower incidence rate of myoclonus in comparison to our study (10% vs. 44%) may be because of magnesium treatment being taken by both groups. Moreover, the patient population in this study was different from ours, all the patients being elderly and belonging to ASA III or IV. In addition, their sample size also was small.
In a recent study[11] comparing midazolam (0.015 mg/kg) and low-dose etomidate (0.03 mg/kg) as pretreatment to ascertain the frequency of myoclonus with etomidate induction, it was concluded that both incidence and intensity of myoclonus were lower in the midazolam group. This finding is in concordance with our results where the incidence of myoclonus was least (44%) in the group administered 0.015 mg/kg midazolam.
Midazolam 0.03 mg/kg pretreatment in our study resulted in 71% incidence of myoclonus. It was lower than that in the control group but could not achieve statistical significance. Our results are in concordance with the results of Isitemiz et al.[4] wherein pretreatment with midazolam 0.03 mg/kg prior to induction of anesthesia with etomidate 0.3 mg/kg resulted in myoclonus in 70% of patients compared to 85% in the control group, without any statistically significant difference. A similar dose was administered by Wasinwong et al.[22] who reported an incidence of myoclonic movement in 78% of cases.
In the present study, myoclonus was observed in 61% of patients receiving midazolam 0.05 mg/kg pretreatment. Our results are in contrast to Malay et al.[28] and Aktolga et al.[29] who reported an incidence of myoclonus of 40% and 37%, respectively, using a similar dose. The lower incidence of myoclonus in these studies as compared to ours could be attributed to the fact that the dose of etomidate used by them was just sufficient to produce a loss of eyelash reflex, in contrast to the full induction dose of 0.3 mg/kg administered by us.
Thus, in the present study, pretreatment with all three doses of midazolam, i.e., 0.015 mg/kg, 0.03 mg/kg, and 0.05 mg/kg, decreased the incidence of myoclonic movements after induction with etomidate 0.3 mg/kg. However, a significant decrease could be achieved only in the 0.015 mg/kg group.
The hemodynamic parameters were preserved and comparable in all the groups at various time intervals suggesting the safety of three doses of midazolam used.
The severity of myoclonus was significantly reduced with all the three midazolam doses as compared to normal saline pretreatment. However, no significant differences were seen among the different doses of midazolam. The use of midazolam was not associated with any significant complications during the study period.
Further recommendations
Supplementary research comparing different doses of midazolam above or below the ones administered in the present study to attenuate the etomidate-induced myoclonus would yield clarity with regard to determining the optimal lowest dose of midazolam without any major adverse effects.
Limitations of the study
Our study had a few limitations. First, the patients belonged to ASA I/II groups, which do not represent the ideal choice for etomidate as an induction agent. Second, the neuromuscular blocker was administered 60 s after etomidate and patients were observed for myoclonic movements during this period, similar to most previous studies. However, in some patients, myoclonus occurred after this period of 60 s, when mask ventilation was started and neuromuscular blocker was being administered. Additionally, the depth of anesthesia could not be monitored during induction, possibly contributing to a lighter plane leading to the development of myoclonus at this stage. Thus, our results could have been different if we had observed for duration longer than 60 s.
conclusionTo conclude, midazolam pretreatment in doses 0.015 mg/kg, 0.03 mg/kg, and 0.05 mg/kg before induction of anesthesia with etomidate 0.3 mg/kg significantly reduces the severity of myoclonus. However, a significant reduction in the incidence of myoclonus was observed with a dose of 0.015 mg/kg only. As the present study could not demonstrate any advantages of higher doses of midazolam, i.e., 0.03 mg/kg and 0.05 mg/kg over the smaller dose, i.e., 0.015 mg/kg, we recommend using midazolam pretreatment in a dose of 0.015 mg/kg for prevention of etomidate-induced myoclonus.
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Conflicts of interest
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References
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