Guler, Aygun MD; Satilmis, Tulin MD; Akinci, Seda B. MD; Celebioglu, Bilge MD; Kanbak, Meral MD
Etomidate, an imidazole derivative, is advocated as an anesthetic induction drug for hemodynamically unstable patients because it produces few cardiopulmonary side effects and has a very stable hemodynamic profile. However, it is associated with several disturbing side effects, such as pain on injection, postoperative nausea and vomiting, electroencephalic activation, adrenal suppression, and myoclonus. Fifty to eighty percent of unpremedicated patients may develop myoclonic movements after etomidate administration (1). Myoclonus is especially problematic in nonfasting patients, patients with open eye injuries, or those who have limited cardiovascular reserves.
Various drugs, including opioids or benzodiazepines, have been investigated as pretreatment drugs before induction of anesthesia with etomidate to prevent myoclonic movements (2–5). The effectiveness of pretreatment with N-methyl-d-aspartate (NMDA) receptor antagonists such as ketamine or magnesium sulfate (Mg) to prevent etomidate-induced myoclonus has not been reported.
The aim of this study, therefore, was to compare the effect of pretreatment with Mg and two different doses of ketamine on the incidence and severity of myoclonic movements and pain during induction of anesthesia with etomidate.
With the approval of the Ethics Committee and written informed consent from patients, a prospective, randomized, double-blind study was performed. One-hundred adult ASA physical status I–III patients scheduled for elective surgery were included in the study. Patients with neurological disease, drug allergy, or those who had received analgesics or sedatives within the previous 24 h were excluded. None of the patients was premedicated.
Patients were randomized into 4 groups: ketamine 0.2 mg/kg (group K1, n = 25), ketamine 0.5 mg/kg (group K2, n = 25), Mg 2.48 mmol (60 mg) (group M, n = 25), and normal saline (group C, n = 25). Randomization was achieved using a computer-generated list. Drugs were prepared in a 5-mL syringe outside the operating room, by an anesthesiologist not involved in the induction of anesthesia. In the operating room, patients were monitored with electrocardiogram, pulse oximetry, and noninvasive arterial blood pressure. A 20-gauge cannula was inserted into a vein in the dorsum of the hand and isotonic saline solution, at room temperature, was infused at 15–20 mL · kg−1 · min−1. Neither the anesthesiologist performing the induction nor the patient was aware of the pretreatment drug. Ninety seconds after IV administration of the study drug, anesthesia was induced with IV etomidate 0.2 mg/kg. One minute after etomidate had been given, vecuronium 0.1 mg/kg was given to facilitate tracheal intubation. Three minutes after vecuronium, tracheal intubation was performed. After intubation, anesthesia was maintained with sevoflurane in a mixture of 30% oxygen in 70% nitrous oxide.
Another anesthesiologist, blinded to group allocation, recorded myoclonic movements, pain, and sedation on a scale between 0–3. The sedation of the pretreatment drugs was assessed as 0 = none (alert), 1 = mild (drowsy but responsive to name spoken in normal tone voice), 2 = moderate (responsive only after name is called loudly and/or repeatedly), and 3 = profound (responsive only after mild prodding or shaking), during the 90 s between the injection of the study drug and the etomidate injection. The anesthesiologist inquired about injection pain while infusing the etomidate. The pain was graded using a 4-point scale: 0 = no pain, 1 = mild pain (pain reported only in response to questioning and without any behavioral signs), 2 = moderate pain (pain reported in response to questioning and accompanied by behavioral signs, or pain reported spontaneously without questioning), and 3 = severe pain (strong vocal response or response accompanied by facial grimacing, arm withdrawal, or tears) (6). The intensity of myoclonus was graded clinically as 0 = no myoclonus, 1 = mild myoclonus (movement at the wrist only), 2 = moderate (movement involving the arm only, elbow, or shoulder), and 3 = severe (generalized response or movement in more than one extremity), after the etomidate injection (7). The respiratory rate, heart rate, arterial blood pressure, and peripheral oxygen saturation were recorded before the study drug, after the study drug, before administration of etomidate, and the heart rate, and arterial blood pressure were recorded at 3, 5, 10, 15, and 20 min after etomidate administration.
SPSS 12.0 for Windows software was used for statistical analyses. χ2 test was used to compare categorical variables among the groups. The Kolmogorov-Smirnov test was used to test for normal distribution of the data. For between-group analyses, one-way analysis of variance or the Kruskal-Wallis test was used to compare parametric and nonparametric data, respectively. Student’s t-test and Mann-Whitney U-test were used to compare two groups regarding parametric and nonparametric variables. Repeated-measures analysis of variance was used to compare the arterial blood pressure, heart rate, oxygen saturation, and respiratory rate among the groups with Bonferroni correction for multiple comparisons. If paired samples t-test was P < 0.05, it was considered as significant and was used for within-group analysis. Data are reported as number of patients (%) for categorical variables, mean ± sd (standard deviation) for normally distributed data and median (minimum-maximum) for nonparametric data.
There were no significant differences among the groups regarding age, weight, height, sex, ASA physical status, types of operation, or comorbidities (Table 1). Pretreatment with Mg reduced the incidence and the severity of myoclonic movements after etomidate induction (P < 0.05) (Tables 2 and 3). There were significant differences among the groups in the incidence of respiratory depression, the incidence and severity of sedation, analgesia, and etomidate-induced myoclonic movements (Tables 3 and 4). Sedation and analgesia were more common and more intense in the ketamine groups (Tables 3–5). Mg pretreatment slightly decreased the severity of pain on injection of etomidate (Table 5). Respiratory depression was also more common with ketamine (Table 3). The mean arterial blood pressure and the heart rate were similar among the groups at all measurement times (Figs. 1 and 2). The peripheral oxygen saturation was always >90% and the mean values were also similar among the 4 groups.
We found that pretreatment with Mg 2.48 mmol IV reduced the incidence and intensity of myoclonic movements during induction of anesthesia with etomidate.
We did not find any research about Mg and myoclonus in the literature; therefore, we chose the dose of Mg (2.48 mmol = 60 mg) that was effective in the prevention of pain during the injection of propofol (8). Ketamine was used at a dose of 0.2 mg/kg to prevent withdrawal movements associated with injection of rocuronium by Liou et al. (7). The other ketamine dose (0.5 mg/kg) we chose in this study was the dose previously used for preemptive analgesia (9). Because these doses were chosen rather arbitrarily in our study, further studies are needed with different dosages of these drugs. We waited 90 seconds before etomidate administration to have enough time to assess the sedative effects of the study drugs.
A myoclonus from pain response on injection of etomidate was distinguished by timing of the assessments. We assessed injection pain while we were infusing the etomidate, but myoclonus was assessed after etomidate in order to differentiate among different effects of the pretreatment drugs on pain and on myoclonus.
After Mg pretreatment, 64% of the patients experienced mild-to-moderate pain associated with etomidate injection. However, ketamine 0.2 mg/kg provided better analgesia compared with Mg (44% of the patients experienced pain) and ketamine 0.5 mg/kg provided the best analgesia among the 4 groups (only 28% of the patients in group K2 had pain). These results show that ketamine provided better analgesia. However, ketamine 0.5 mg/kg caused mild-to-severe sedation in all patients and respiratory depression in 80% of the patients.
Previous reports have shown that pretreatment with opioids reduced myoclonic movements and pain during induction of anesthesia with etomidate (2,10). Pretreatment with 100 μg of fentanyl reduced the incidence of myoclonus to 8% (2). The use of larger fentanyl dosages, however, increased the incidence of apnea during induction (10). Studies with other opioids, such as alfentanil and buprenorphine, have not shown any better efficiency (11,12). However, another opioid with very short onset time, sufentanil (0.3 μg/kg), was very effective in reducing myoclonus after etomidate from 80% in the placebo group to 0% in the sufentanil group (4).
Benzodiazepine pretreatment has also been investigated to reduce myoclonus associated with etomidate. Diazepam (0.0625–0.0125 mg/kg IV) or flunitrazepam (0.01 mg/kg IV) failed to reduce myoclonic movements (13,14). Schwarzkopf et al. (5) reported that the incidence of myoclonic movements was significantly less in patients pretreated with 0.015 mg/kg midazolam (20%) compared with placebo (90%) (5).
Although many drugs have been tested to decrease its incidence, the mechanism of etomidate-induced myoclonus is unclear. Doenicke et al. (1) suggested that myoclonus results from subcortical disinhibition, similar to the phenomenon of restless legs during normal human sleep, and is not generated by an epileptic focus.
In our study, Mg decreased the incidence of etomidate-induced myoclonus. The mechanism of the analgesic effect of Mg and ketamine is noncompetitive NMDA receptor antagonism. The activation of NMDA receptors results in an influx of calcium ions which, in turn, stimulates the production of nitric oxide (NO) secondary to the activation of NO synthase and NO has an important role in venous nociception in humans elicited by noxious chemical mediators such as bradykinin (15,16). As a noncompetitive NMDA receptor antagonist, Mg and ketamine may attenuate withdrawal movements or pain caused by various chemical mediators by blocking NMDA receptor activation either in vascular endothelium or in the central nervous system.
Pretreatments with small dosages of ketamine and Mg have been shown to reduce pain, without adverse effects, caused by the injection of propofol (8,17). Also a small dose of ketamine reduced ischemic pain from tourniquet inflation (18). However, we could find no reports in the literature about pretreatment with ketamine or Mg before the etomidate induction.
In conclusion, this is the first reported clinical study showing that Mg administered before etomidate induction reduces myoclonic muscle movements without any side effects. Ketamine was not effective in reducing the myoclonus and it caused respiratory depression and sedation.
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