etomidate is a potent hypnotic agent with minimal cardiovascular and respiratory adverse effects , providing better hemodynamic stability compared with other induction agents and not triggering histamine release . previous studies reported that at 0.3 mgkg induction doses , etomidate does not cause significant alterations in heart rate , systolic , diastolic , and mean arterial pressures , right atrial pressure , systemic and pulmonary vascular resistance , stroke volume , cardiac index , systemic blood flow , and shunt flow in pediatric patients undergoing congenital cardiac shunt surgery and in adults [ 17 ] . induction of anesthesia with etomidate results in dose - dependent myoclonus in 5080% of patients without premedication . in addition to increasing the risk of aspiration in patients with a full stomach , myoclonus may also increase intraocular pressures and cause problems in patients who will undergo open eye surgery . the incidence of myoclonus is reduced by one - half when pretreatment with 100 g fentanyl 5 minutes before induction of anesthesia is made , but the incidence of apnea is increased . it was shown that midazolam pretreatment decreased myoclonus induced by etomidate , and increasing the dose of midazolam from 0.015 mgkg to 0.05 mgkg did not further decrease the incidence of myoclonus . there are no reported comparative studies that have investigated whether fentanyl or midazolam is a better option in the prevention of myoclonus due to etomidate . the aim of this study was to compare the efficacies of fentanyl , midazolam , or their half - dose combinations in preventing myocloni when they were administered prior to induction of anesthesia with etomidate . this retrospective comparative study was performed based on anesthesia records over a period of 6 months . eighty adult patients with asa i  ii physiologic score and who would undergo various operations under general anesthesia were included in the study . depending on the drugs that would be given before the induction of anesthesia with etomidate , the patients were separated into 4 groups : no pretreatment ( group np ) , fentanyl 1 g / kg ( group f ) , midazolam 0.03 mg / kg ( group m ) , and midazolam 0.015 mg / kg + fentanyl 0.5 g / kg ( group fm ) . the incidence of myoclonus in the no pretreatment group ( group np ) was estimated to be 80% , based on previous studies . power analysis with =0.05 and =0.2 for determining the myoclonus frequency under 50% revealed that each group required a minimum of 17 patients . the patients who received the same anesthetic procedure were selected : 2 minutes after intravenous injections of the pretreatment drugs ( fentanyl , midazolam or combination of both ) , anesthesia is induced with 0.3 mg / kg etomidate ( etomidate - lipuro , b. braun melsungen ag , d-34209 melsungen , germany ) , injected intravenously over a period of 2030 seconds . two minutes after the end of etomidate injection , muscle relaxation with 0.1 mg / kg vecuronium was achieved and endotracheal intubation was performed after another 2 minutes . following etomidate injection , anesthesia was maintained using 1.52.5% concentration of sevoflurane in a mixture of o2 and air that contained 50% o2 . patients who took sedative and analgesic drugs within the 24 hours before the operation were excluded from the study . myoclonic movements were evaluated , which were observed and graded according to clinical severity during the 2 minutes after etomidate injection : 0=no myoclonus , 1=mild myoclonus ( small movements in 1 body segment , such as finger or wrist ) , 2=moderate ( slight movements in 2 or more muscle areas , such as face or shoulder ) , and 3=severe ( intense movements in 2 or more muscle areas , sudden adduction of an extremity ) . the severity of pain due to etomidate injection was evaluated using a 4-grade scale : 0=no pain , 1=mild ( pain reported only when asked ) , 2=moderate ( pain reported without being asked or reported when asked and there were associated behavioral symptoms ) , and 3=severe ( verbal response , grimacing , pulling the arm , tearing in the eyes ) . mean arterial pressure ( map ) and heart rate ( hr ) recordings were evaluated during the time between entrance into the operating room and 5 minutes after intubation . decreases in peripheral oxygen saturation ( spo2 < 90% ) , arrhythmia , and other adverse effects were also evaluated . the data were registered and analyzed using the spss 16.0 for windows software . chi - square test was used for comparison of categorical data between the groups . the distribution of group means was evaluated with kolmogorov - smirnov test , and after they were found to have normal distribution , 1-way analysis of variance was used to compare the hemodynamic parameters between the groups . hemodynamic parameter changes in the groups relative to the baseline during each measurement period were evaluated using repeated measurements analysis of variance . tukey hsd and dunnett tests were used post hoc to determine the groups showing a statistically significant difference . there were no differences between the groups with respect to mean age , weight , height , asa physiologic score , sex distribution , and injection pain ( p>0.05 , table 1 ) . pretreatment with either fentanyl or fentanyl - midazolam combination decreased the frequency and severity of myoclonic movements arising after anesthesia induction with etomidate ( p<0.001 and p<0.05 , respectively ( table 2 ) . during the study period , none of the patients had a decrease in peripheral oxygen saturation , arrhythmia , or any other adverse effects . mean arterial pressure measurements after induction were significantly lower in groups f and fm compared to the no pretreatment group ( p<0.001 ) . intragroup comparison showed that map had significant reductions to the basal values in groups f and fm ( p<0.001 and p<0.01 , respectively ) . all groups except group fm had significant increases in map 2 minutes after intubation ( table 3 ) . intergroup comparisons showed that mean heart rate values after induction were significantly lower in groups f and fm compared to group np . intragroup comparisons showed that group np had significant elevations which later returned to basal values 5 minutes after intubation ( p<0.001 ) . group f never had significant elevations compared to basal values , whereas group m had significant elevations at all periods ( p<0.01 and p<0.001 ) . in group fm , only the hr measurements taken 2 minutes after intubation were significantly higher than basal values ( p<0.01 , table 4 ) . the results of this study show that the incidence of myoclonus was 85% in the no pretreatment group after etomidate injection ; this finding was similar to the others reported in the literature [ 8,1119 ] . the incidence of myoclonus due to etomidate depends on the dosage and speed of injection . in healthy volunteers , doenicke et al .   demonstrated that increased doses of etomidate were correlated with the frequency of myocloni , which was 83% with 0.3 mg / kg etomidate . investigated the effects of slow and rapid etomidate injection rates at 0.3 mg / kg doses on the frequency of myocloni , and observed that 84% of the patients developed myocloni when the drug was administered over a period of 10 seconds , whereas 28% of the patients developed myocloni when the injection was made slowly over a period of 2 minutes . .   showed that myocloni developed in 85% of children given 0.3 mgkg intravenous etomidate over a period of 510 seconds . in our study , we found similar rates of myocloni when etomidate was given over a period of 20 seconds . doenicke showed that after 0.3 mg / kg etomidate , myocloni occurred 80360 ( mean 160 ) seconds after the injection , and lasted 40400 ( mean 160 ) seconds . the duration of clinical observation in etomidate - induced myocloni range from 1 to 3 minutes according to various studies . in these studies applied cardioversion 1 minute after administration of 0.3 mg / kg etomidate , and found that the rate of myoclonus was 50% . investigated the efficacy of magnesium sulphate in the prevention of etomidate - induced myoclonus and gave vecuronium to their patients 1 minute after injection of 0.2 mg / kg etomidate . patients who did not receive premedication and were treated with 0.3 mg / kg etomidate followed by vecuronium 2 and 3 minutes later had 77% and 84% myoclonus rates , respectively . in our study we gave the neuromuscular blocker 2 minutes after 0.3 mg / kg etomidate administration , and observed myoclonic movements during this time . the results in our control group were in concordance with other studies having the same observation period length . when the clinical observation period that aims to detect myoclonic movements is shortened , it may result in the suppression of a possibly delayed myoclonus by a neuromuscular blocker and thereby result in lower rates . we believe further studies are necessary to determine the optimal length of observation needed to determine the incidence of myoclonus after etomidate injection . a study that investigated eeg alterations in patients with etomidate - induced myoclonus stressed the correlation between myoclonus and the increase in delta waves in eeg recordings . in this study , myoclonus was observed to be synchronized with slow and continuous waves on eeg , and it was not a typical seizure . there were no changes except for delta waves in eeg recordings throughout the myoclonic episode . the possible cause of myoclonus during anesthesia induction using etomidate is thought to be subcortical disinhibition . the decreased incidence of myoclonus when using premedication with drugs such as benzodiazepines and fentanyl , which are known to inhibit subcortical neuronal activity , supports this hypothesis . fentanyl is a -opioid receptor antagonist that causes dose - dependent analgesia , respiratory depression , and sedation . the site of action where fentanyl and midazolam prevent the myoclonus occurring after etomidate injection is not clear . however , the prevention of myoclonus by fentanyl and midazolam is a result of inhibition in the central nervous system , although their actions are mediated by different receptors . in our study , fentanyl and midazolam combination was more effective in the prevention of myoclonus compared to use of either drug alone . we observed that the myoclonus rate decreased to 40% ( 8/20 ) in the group that received 1 g / kg fentanyl before anesthesia induction with etomidate , and to 25% ( 6/20 ) in the group that received both 0.5 g / kg fentanyl and 0.015 mg / kg midazolam . although the frequency of myocloni was lower in the group in which fentanyl and midazolam were used together compared to the use of either drug alone , we found that they had no additive or synergistic effect . it has been shown that midazolam and fentanyl display a synergy when used together . however , in the fentanyl+midazolam combination , the use of half the dosage of the drugs compared to when either of them was applied alone can explain why we saw no additive or synergistic effect . reported that premedication with fentanyl decreased etomidate - induced myoclonus in a dose - dependent manner , but it increased the risk of apnea . they observed that none of the patients who received premedication with 500 g fentanyl 5 minutes before anesthesia induction using etomidate had a myoclonus , but all developed apnea . respiratory depression was less when 100 g fentanyl was given , and the rate of myoclonus was 33% . reported that premedication with 100 g fentanyl significantly decreased the rate of etomidate - induced myoclonus ; however , it introduced the risk of respiratory depression . similarly , the rate of myoclonus in our patients premedicated with 1 g / kg fentanyl was 40% , but none of our patients sustained any episodes of apnea or desaturation . myoclonus rates in studies using 100 g fentanyl and in our study were not different , and we believe that lower doses of fentanyl in our study prevented apneic episodes . our results show that 0.03 mg / kg midazolam was not effective in preventing myocloni . reported that in patients undergoing elective cardioversion , 0.015 mg / kg midazolam pretreatment 90 seconds prior to anesthesia induction with 0.3 mg / kg etomidate provided significant reduction in the frequency of myocloni compared to the control group ( 10% vs. 50% ) . used a shorter observation period ( 1 minute ) than our study , and most of their patients were under magnesium treatment , which account for the difference . .   showed that 0.015 mg / kg midazolam significantly reduced the rate of myoclonus compared to the control group ( 20% vs. 90% ) . premedication with oral midazolam and shorter observation period ( 1 minute ) for myoclonus , in contrast to our study , may be the causes for lower incidence . hwang et al .   found that 0.05 mg / kg midazolam pretreatment given 60 seconds prior to induction with 0.3 mg / kg etomidate reduced the rate of myoclonus to 17% , which was 77% in the control group using placebo . we therefore conclude that the efficacy of midazolam in prevention of etomidate - induced myoclonus may be correlated with dose , and studies that are better standardized in that aspect are needed . the injection pain is reported to be significantly less in lipid - emulsified etomidate compared to etomidate dissolved in propylene glycol . we found the injection pain rate of the lipid solution was 010% , which is similar in results in the literature . during evaluation of the hemodynamic effects of etomidate , the control group was also analyzed to exclude the influences of study drugs used in premedication . the results show that etomidate did not cause a significant difference in hemodynamic stability during anesthesia induction . although the increase in hr was statistically significant , the difference was less than 15% compared to basal values . the absence of any recording of the onset time of myoclonus within the 2-minute observation period and of its duration was a limiting factor for our study . studies that will enable investigation of the onset time and duration of myoclonus after etomidate injection may provide us with useful information on the optimal pretreatment time . we found that both the combination of 0.5 g / kg fentanyl with 0.015 mg / kg midazolam and 1 g / kg fentanyl alone were effective in the prevention of myocloni caused by anesthesia induction with etomidate and observed in high rates in patients without premedication . premedication with 0.03 mg / kg midazolam alone was insufficient for the prevention of myoclonus .
backgroundin this retrospective comparative study , we aimed to compare the effectiveness of fentanyl , midazolam , and a combination of fentanyl and midazolam to prevent etomidate - induced myoclonus.material/methodsthis study was performed based on anesthesia records . depending on the drugs that would be given before the induction of anesthesia with etomidate , the patients were separated into 4 groups : no pretreatment ( group np ) , fentanyl 1 gkg1 ( group f ) , midazolam 0.03 mgkg1 ( group m ) , and midazolam 0.015 mgkg1 + fentanyl 0.5 gkg1 ( group fm ) . patients who received the same anesthetic procedure were selected : 2 minutes after intravenous injections of the pretreatment drugs , anesthesia is induced with 0.3 mgkg1 etomidate injected intravenously over a period of 2030 seconds . 
 myoclonic movements are evaluated , which were observed and graded according to clinical severity during the 2 minutes after etomidate injection . 
 the severity of pain due to etomidate injection , mean arterial pressure , heart rate , and adverse effects were also evaluated.resultsstudy results showed that myoclonus incidence was 85% , 40% , 70% , and 25% in group np , group f , group m , and group fm , respectively , and were significantly lower in group f and group fm.conclusionswe conclude that pretreatment with fentanyl or combination of fentanyl and midazolam was effective in preventing etomidate - induced myoclonus .