A Randomized, Double-Blind Comparison of Rocuronium, d-Tubocurarine, and "Mini-Dose" Succinylcholine for Preventing Succinylcholine-Induced Muscle Fasciculations

Several methods have been used to prevent or attentuate succinylcholine-induced muscle fasciculations (SIMF), including pretreatment with lidocaine [1], diazepam [2], diphenylhydantion [3], and subparalyzing doses of nondepolarizing muscle relaxants [4] or succinylcholine (SCH) [5-7]. Previous investigations comparing d-tubocurarine (DTC) with the defasciculating drugs atracrium (ATR) [4,8], pancuronium (PAN) [4,9], vecuronium (VEC) [4,9], gallamine [4], and alcuronium [4] have shown DTC to be the most effective in inhibiting SIMF. The effectiveness of rocuronium (ROC) in preventing SIMF has not been determined. We designed the present study to compare the effectiveness of ROC with DTC and "mini-dose" SCH in preventing SIMF. Methods After approval by our institutional review board and patient consent, 101 ASA physical status I and II male and female patients aged 18-65 yr undergoing either inpatient or outpatient surgery under general endotracheal anesthesia were selected. Exclusion criteria included suspected difficult tracheal intubation, increased intraocular or intracranial pressure, malignant hyperthermia, atypical plasma cholinesterase, hyperkalemia, hypertension, or treatment with any drug having muscle relaxant properties. No patient had significant cardiovascular, renal, neuromuscular, or hepatic disease. The type of surgical procedure and position during surgery were not standardized. Baseline blood pressure (BP) and heart rate (HR) were recorded before pretreatment. The patients were randomly assigned to one of five groups: Group 1 (n = 21) received saline (NS), Group 2 (n = 20) received 0.03 mg/kg ROC, Group 3 (n = 20) received 0.05 mg/kg ROC, Group 4 (n = 20) received 0.05 mg/kg DTC, and Group 5 (n = 20) received 0.03 mg/kg SCH. The drugs were administered in a double-blind manner from syringes containing a standardized volume of 3 mL. One minute after administration of the pretreatment drug, patients were asked a series of questions regarding the side effects of the treatment. Specifically, they were asked whether they experienced pain on injection, shortness of breath, chest heaviness, nausea, or weakness. Fifty micrograms of fentanyl IV was administered 2 min after pretreatment, and the BP and HR were obtained 1 min later. Thiopental 4-5 mg/kg IV was administered 3 min and 30 s after pretreatment, mask ventilation was established, and SCH 1.5 mg/kg IV was administered. Fasciculations were graded by a blind observer and anesthetist on the following scale: no fasciculations = 0; mild, fine fasciculations of the eyes, neck, face, or fingers without limb movement = 1; moderate fasciculations occurring at more than two sites or obvious limb movement = 2; vigorous or severe, sustained, and widespread fasciculations = 3. Intubating conditions were recorded by the blind anesthetist performing tracheal intubation on the following scale: well relaxed, no patient movement during intubation, vocal cords not moving = satisfactory; minor patient movement or vocal cords moving = fair; obvious patient movement, bucking, or coughing during intubation = poor. All patients were contacted on the first postoperative day by a single blind interviewer. Patients were questioned regarding postoperative myalgia (POM), and the answers were graded as follows: minor stiffness limited to one area of the body = mild; muscle pain or stiffness noticed spontaneously by the patient, which may have required analgesic therapy = moderate; generalized, severe, or incapacitating discomfort = severe. Fasciculation score comparisons were analyzed by using Fischer's exact test and Catmod procedure and were confirmed by dichotomizing the variable for fasciculation into whether fasciculations were present. A P value <0.0001 was considered statistically significant. Differences in the overall fasciculation and dichotomized scores were further investigated using pairwise comparisons; because of multiple comparisons, a P value <0.005 was considered significant. Intubation grade comparisons were analyzed by using the Catmod procedure and Fisher's exact test. Correlation between the fasciculation score and POM was determined by using Spearman's correlation and was confirmed by using chi squared analysis. Side effect comparisons were analyzed by using Fisher's exact test. Results Data were collected intraoperatively for 101 patients; 97 were questioned postoperatively, and 4 were lost to follow-up. There were no statistical differences among the groups with respect to gender, weight, age, or inpatient versus outpatient classification. Vigorous fasciculations occurred in 20% of the patients after SCH pretreatment. Fasciculations were absent in 90% of Group 2 patients, whereas 10% had vigorous fasciculations (Table 1). In Group 3, 75% did not fasciculate, whereas 10% had mild and 15% had moderate fasciculations. Fasciculations were absent in 80% and mild in 10% of Group 4 patients. In Group 5, 10% had mild, 40% had moderate, and 20% had vigorous fasciculations. Pretreatment with ROC and DTC decreased the incidence and severity of fasciculations significantly (P < 0.0001) compared with NS and mini-dose SCH. There was no difference in the presence or severity of fasciculations between the two ROC groups or between either ROC group and DTC. The presence or severity of fasciculations in patients who received either NS or mini-dose SCH did not differ significantly.Table 1: Fasciculation Scores in the Five Pretreatment GroupsThe P value obtained from the Catmod procedure was 0.4565 and was 0.1774 using Fischer's exact test, which indicates that there was no difference among the study groups with respect to intubation grade (Table 2). Intubating conditions were considered satisfactory in 60%, fair in 35%, and poor in 5% of Group 2. In Group 3, intubating conditions were satisfactory in 80%, fair in 15%, and poor in 5%. In Group 4, 75% had satisfactory intubation grades, 10% were fair, and 15% were poor. Group 5 had satisfactory intubating conditions in 80% and fair conditions in 20% of patients.Table 2: Intubation Grades in the Five Pretreatment GroupsThe incidence of POM was 11.5%. There was no significant difference in the incidence of POM based on gender or inpatient versus outpatient status. Furthermore, there was no significant association between fasciculations and POM (Table 3). Analysis of the side effects of pretreatment revealed no significant difference among the groups.Table 3: Correlation Between Fasciculations and Postoperative MyalgiasDiscussion The effectiveness of subparalyzing doses of SCH and nondepolarizing neuromuscular blocking (NDMB) drugs in attentuating or preventing fasciculations has been shown to be both drug-specific and dependent on the optimal interval between pretreatment and SCH administration [9]. Fasciculations are the result of antidromically conducted axonal depolarizations initiated by SCH binding on prejunctional nicotinic cholinergic receptors [3]. The probability of blocking SIMF is greatest with DTC, followed by ATR, PAN, and VEC [9]. It has been suggested that the lower probability of fasciculations occurring with DTC and ATR is associated with the greater affinity of these drugs for prejunctional cholinoceptors compared with PAN and VEC [9,10,11]. This may reflect differences in drug potency, which influences receptor binding and the speed of onset of action [12]. Pinchak et al. [9] have established that the interval necessary to prevent SIMF in 90% of patients (WT90) after pretreatment at equipotent doses also follows the above rank order, with DTC having the shortest wait time (WT90 3.02 min). The WT90s for ATR, PAN, and VEC are 3.26, 5.35, and 6.36 min, respectively [9]. The speed with which NMB occurs at the postjunctional receptor is inversely proportional to drug potency [13], and a similar phenomenon may exist at the prejunctional receptor [9]. If this postulate is correct, then ROC's (95% effective dose [ED95] 0.3 mg/kg) onset of action and effectiveness in blocking SIMF should be intermediate to DTC (ED95 0.5 mg/kg, WT90 3.02 min) and ATR (ED (95) 0.2 mg/kg, WT90 3.26 min) at equipotent doses. Consequently, we chose a 3.5-min interval for this study based on this supposition and administered a dose equivalent to 10% of the ED95 of each drug. The larger dose of ROC (16.6% of the ED95) administered was chosen arbitrarily, based on familiarity with this dose in our clinical setting. There was no statistical difference between ROC and DTC in preventing SIMF at the 3.5-min wait time at equipotent doses, which supports the postulate that drug potency influences prejunctional receptor binding and speed of onset of action. The actual interval for ROC was not determined in our study and warrants further investigation. The administration of the larger dose of ROC did not increase the effectiveness of the drug in preventing SIMF, contrary to previous work, which suggested that defasciculation is improved by increasing the dosage [14]. Additionally, although it seems from our data that minidose SCH is less effective in preventing or diminishing fasciculations than the NDMBs, these data may be misleading, because application of the 3.5-min interval to SCH pretreatment would allow for significant hydrolysis of the drug by plasma cholinesterase. Future double-blind comparisons of mini-dose SCH to the NDMBs in preventing SIMF should incorporate standardized intervals beginning at 60 s to accurately evaluate efficacy. Pretreatment with NDMBs produces resistance to SCH and consequent deterioration in intubating conditions that can be overcome by increasing the intubating dose of SCH to 1.5 mg/kg [14-19]. Antagonism of depolarizing blockade results from the competitive action of the NDMB with SCH at the postjunctional nicotinic cholinergic receptor [alpha]-subunits [20]. In a comparison of equipotent doses of DTC, PAN, and VEC, Erkola et al. [4] demonstrated that pretreatment with DTC and PAN resulted in better intubating conditions than pretreatment with VEC. In their study, waiting only 3 min between defasciculation and SCH administration may have resulted in variable SCH resistance, given the differing potency and onset of action of NDMBs. Pinchak et al. [9] reported better intubating conditions associated with DTC pretreatment than for ATR, VEC, and PAN [9]. These defasciculants were studied at waiting times ranging from 0.6 to 5 min; however, a smaller dose of DTC was administered compared with the other NDMBs studied. Pinchak et al. [9] suggest that this may have increased SCH resistance. This was not confirmed in the present study, as increasing the dose of ROC did not result in a deterioration in intubating conditions. We found no significant difference in intubating conditions between equipotent doses of ROC and DTC, which suggests that the interval and/or potency in producing antagonism of depolarizing blockade by ROC approximates that of DTC. Intubating conditions were satisfactory in 80% of the patients receiving minidose SCH, as would be expected when depolarizing neuromuscular blockade is unopposed. We could not demonstrate any difference in the occurrence of side effects among Groups 2-5, even with the larger dose of ROC. Although others have cited pain on injection as an untoward side effect of ROC [21-23], we found no significant differences regarding pain on injection among any of the study groups, including Group 1. The ROC administered in our study was diluted to a standardized volume of 3 mL, which may have prevented this response. Others have demonstrated that POM occurs more frequently after outpatient [6,24-26] and minor surgical procedures [25,27], and that it is more common in women [28,29]. Pretreatment with NDMBs has not been shown to decrease the incidence of POM after major abdominal surgery [30], nor is there a strong correlation between visible fasciculations and POM [24]. We found no statistically significant difference among the study groups with respect to gender or inpatient versus outpatient classification. However, we did not limit our study population to those undergoing a single type of surgical procedure with similar surgical positioning, which may have influenced the results. As in previous reports [8,24], we found no correlation between fasciculations and POM, nor was there a significant difference in the incidence of POM between any of the study drugs administered and NS. In summary, our study is the first to compare ROC with DTC for defasciculating pretreatment before SCH. The results show that ROC is as efficacious as DTC in preventing muscle fasciculations at equipotent doses. Further, there seems to be no significant difference in intubating conditions, postoperative myalgias, or the development of side effects between DTC and ROC. The authors thank Renee Hebert, MS, and Yuko Palesch, PhD, for their assistance in the statistical analysis of the data.