A common side effect associated with succinylcholine is postoperative myalgia (POM) (1). The pathogenesis of this myalgia is still unclear, but pretreatment with nondepolarizing neuromuscular blockers apparently fails to decrease the incidence or intensity of POM (2–5). Interestingly, POM is clinically similar to a well-known phenomenon after physical exertion, that is, delayed onset muscular soreness (6). A recent study in sports medicine found an increase of inflammatory variables such as interleukin-6 (IL-6) in direct correlation to the incidence and severity of muscle soreness after unaccustomed muscular stress (7). Inflammation as a cause for succinylcholine-associated myalgia has also been suggested by several authors but without convincing evidence (8–12).
We designed the present study to investigate whether an inflammatory reaction contributes to POM. The incidence and severity of POM in patients pretreated with saline or dexamethasone before succinylcholine was determined. Dexamethasone is a glucocorticoid with a powerful antiinflammatory potency. In addition, in a subgroup receiving succinylcholine pretreated with saline, IL-6 concentrations as a marker of inflammation were determined.
Materials and Methods
After obtaining approval from the institutional ethics committee and informed consent, we included 64 adult patients (ASA physical status I–II) undergoing elective ear-nose-throat surgery. Exclusion criteria were inflammatory disease, obesity (body mass index >30), diabetes, and intake of steroids and nonsteroidal antiinflammatory drugs. During the premedication visit, a postoperative pain questionnaire and the system of numeric analog scale (NAS) for verbal pain and stiffness rating were discussed with the included probands (2) (Appendix 1). To simplify data analyses, the 11 muscle groups were divided into three regions (head/neck/shoulder, trunk, and limbs), and myalgias were graded as none, mild (NAS, 1–3), moderate (NAS, 4–6), or severe (NAS, 7–10). The highest rating of pain in the three regions determined the severity of myalgia.
All patients received midazolam 7.5 mg orally for premedication. Before the induction of anesthesia, two groups were randomized receiving either dexamethasone 8 mg IV (DEX group) or saline IV (SAL group). Three minutes later, a continuous infusion of remifentanil 0.25 μg · kg−1 · min−1 followed by thiopental 5–7 mg/kg IV and succinylcholine 1.5 mg/kg IV was administered; 60 s later, tracheal intubations were performed. Fasciculations were evaluated as follows (5): none = absent, mild = fine fasciculations of the eyes, face, neck, or fingers but without limb movement, moderate = fasciculations involving limbs or trunk, and severe = fasciculations with movement of one or more limbs or movements requiring forceful retention. Anesthesia was maintained with remifentanil 0.15–0.25 μg · kg−1 · min−1 and 0.5 minimum alveolar anesthetic concentration of isoflurane. Twenty minutes before the expected end of surgery, all patients received piritramide 3 mg IV, which is a synthetic opioid with pharmacodynamic properties similar to morphine (13,14). After surgery, piritramide 0.05 mg/kg IV was given by request for the first 24 h, and thereafter, diclofenac was also given.
All patients were visited after surgery 4 times (at 6, 24, 48, and 72 h) on the ward by an investigator blinded to the group assignment. Besides the number of patients with POM and severity of POM, the cumulative incidence (total number of episodes of myalgia during the first 72 h) was determined. Duration of anesthesia and doses of additional analgesic drugs because of muscular pain were documented.
Blood samples for the assay of IL-6 were taken from 10 patients of the SAL group who underwent an additional randomization. Samples were obtained before the induction, 20 min after the induction, at the end of anesthesia, and 6 and 24 h after the end of anesthesia. Blood samples were drawn in EDTA tubes and kept on melting ice until separation of plasma by centrifugation. After centrifugation, plasma was aspirated in 1-mL aliquots and stored at −70°C for later analysis. IL-6 concentrations were determined with a commercially available enzyme-linked immunosorbent assay (ELISA)-Kit (Biosource Europe SA, Nivelles, Belgium; detection limit, 2 pg/mL).
All data were presented as mean (± SD). For statistical analysis, Fisher’s exact test or χ2 test and t-test for unpaired groups were used. Demographic data were compared with Mann-Whitney U-test. Numbers-needed-to-treat (NNT) were calculated (15). A positive NNT indicated how many patients had to be exposed to the intervention (i.e., pretreatment with dexamethasone) to prevent one particular event (i.e., POM) in one patient. According to preset criteria, a NNT between 1 and 5 was considered as clinically relevant. A P value of <0.05 was considered significant. The estimation of the sample size was based on the study of Naguib et al (8). For an 80% power to detect a 55% difference in the incidence of myalgia between the groups with an α = 0.05, 62 patients were required. We enrolled 64 patients, i.e., 32 patients in each group, if not all patients completed the study.
Groups were comparable in age, weight, height, and sex distribution. Also, duration of anesthesia did not differ significantly (Table 1). Analgesic requirements were comparable between the two groups.
Incidence and severity of myalgia did not differ significantly between the two groups: At the assessment of myalgia, i.e., 6, 24, 48, and 72 h after surgery, 15 patients in the DEX group complained 25 times of myalgia compared with 18 patients with 31 episodes of myalgia in the SAL group (not significant). Severe myalgia was reported by five patients in the DEX group versus three patients in the SAL group, and the study groups did not differ in the localization of myalgia (Table 2). At 48 h after surgery, 12 patients in both groups still suffered from myalgia (not significant). To treat POM with dexamethasone, a NNT of 11 (confidence interval, 6.7 to −3) was calculated. We found an increase of IL-6 more than the lower limit of detection for only three patients, but only one patient reported myalgia. No relationship between POM and the increase of IL-6 was found (Table 3).
POM occurs frequently after succinylcholine and is particularly troublesome in outpatients (1,2). This study was designed to investigate whether inflammatory processes cause POM. Naguib et al. (8) were first to show that the preoperative administration of cyclooxygenase inhibitors, i.e., salicylates, could reduce the incidence of POM. Then, McLoughlin et al. (9) postulated an activation of phospholipase A2 and the synthesis of prostaglandins, both proinflammatory, after succinylcholine. Finally, Kahraman et al. (11) reported a significant decrease of prostaglandin E2-like activity and a reduced incidence of POM in patients pretreated with diclofenac. Despite the fact that ketorolac acts in a similar way as salicylates, pretreatment with the more potent ketorolac could not decrease the incidence and severity of POM (12). The authors speculated that the relatively short duration of action of ketorolac, which is only six to eight hours, might explain this discrepancy.
To differentiate succinylcholine-induced myalgia from other causes of POM, perioperative management was standardized, and the type of surgery was uniform (all patients underwent elective ear-nose-throat surgery). Moreover, demographic data and duration of anesthesia were also comparable between the groups (Table 1). Thus, anesthesia- and surgery-related factors contributing to POM were controlled. In this clinical setting, the incidence and severity of myalgia did not differ whether patients were pretreated with dexamethasone or saline before succinylcholine. Based on the results of the present study, there are several explanations why the inflammatory reaction is not the cause of succinylcholine-induced myalgia: first, dexamethasone was chosen for pretreatment because it has the highest antiinflammatory activity of all adrenocortical steroids and thus a much stronger potency than nonsteroidal antiinflammatory drugs to reduce both the synthesis of prostaglandins and inflammatory stimulation (16); as an effective dose for its antiinflammatory action, dexamethasone 8 mg IV has been proposed (17). Moreover, its effective half-life of approximately 48–60 hours should cover the entire postoperative period effectively with one single dose. Thus, if an inflammatory process contributes to succinylcholine-induced myalgia, dexamethasone 8 mg IV should abolish it and thus reduce the intensity of POM. That hypothesis is not supported by our study (Table 2). Whether an earlier administration of dexamethasone would improve its efficacy in reducing succinylcholine-induced myalgia remains speculative. Second, IL-6 is a proinflammatory cytokine and plays a key role in human acute phase protein synthesis. It contributes to the early stages of the acute inflammatory response. The kinetics of clearance is biphasic and consists of a rapid initial elimination corresponding to a half-life of approximately three minutes and of a second smaller decrease corresponding to a half-life of approximately 55 minutes (18). Potential cytokine sources in injured skeletal muscles include infiltrating neutrophils and monocytes-macrophages, activated fibroblasts, and stimulated endothelial cells (19). It is upregulated by other interleukins, interferons, and tumor necrosis factor α and reaches its maximum six hours after physical exercise (7). Under physiological conditions, cytokines are undetectable or are only found in small concentrations in the blood (20). In the present study, any inflammatory origin of succinylcholine-induced myalgia should have led to an increase in the plasma concentration of IL-6 because the influence of general anesthesia for minor surgery on IL-6 production seemed to be only minimal (20), and opioids for postoperative pain management such as piritramide apparently did not modify the cytokine response (21). Moreover, similar to recent findings in sports medicine reporting a significant correlation between muscle soreness after muscular exertion and the plasma concentration of IL-6 (7,19), this increase should be related to the severity of succinylcholine-induced myalgia. We measured the time course of IL-6 in the plasma of 10 patients from the SAL group. However, an increase in IL-6 could only be detected in three patients, but only one of them reported myalgia; no correlation was observed between severity of POM and increase of IL-6 (Table 3).
We conclude that pretreatment with dexamethasone 8 mg IV did not reduce succinylcholine-induced myalgia; no evidence for an inflammatory origin of POM was found.
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© 2003 International Anesthesia Research Society
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