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Perineural dexamethasone prolongs the duration of single-injection peripheral nerve block when added to the local anesthetic solution. Postulated systemic mechanisms of action along with theoretical safety concerns have prompted the investigation of intravenous dexamethasone as an alternative, with decidedly mixed results. We aimed to confirm that addition of intravenous dexamethasone will prolong the duration of analgesia after single-injection supraclavicular block compared with conventional long-acting local anesthetic alone or in combination with perineural dexamethasone for ambulatory upper extremity surgery.Seventy-five patients were randomized to receive supraclavicular block using 30-mL bupivacaine 0.5% alone (Control), with concomitant intravenous dexamethasone 8 mg (DexIV), or with perineural dexamethasone 8 mg (DexP). Duration of analgesia was designated as the primary outcome. To test our hypothesis, the superiority of DexIV was first compared with Control and then with DexP. Motor block duration, pain scores, opioid consumption, opioid-related side effects, patient satisfaction, and block-related complications were also analyzed.Twenty-five patients per group were analyzed. The duration of analgesia (mean [95% confidence interval]) was prolonged in the DexIV group (25 hours [17.6–23.6]) compared with Control (13.2 hours [11.5–15.0]; P < 0.001) but similar to the DexP group (25 hours [19.5–27.4]; P = 1). The DexIV group experienced longer motor block (30.1 hours) compared with DexP (25.5 hours) and Control (19.7 hours) groups. Both DexIV and DexP had reduced pain scores, reduced postoperative opioid consumption, and improved satisfaction compared with Control.In a single-injection supraclavicular block with long-acting local anesthetic, the effectiveness of intravenous dexamethasone in prolonging the duration of analgesia seems similar to perineural dexamethasone.