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ItemIntravenous lignocaine followed by a 24-hour postoperative subcutaneous infusion shortens length of hospital stay after open radical retropubic prostatectomy: a blinded, randomised, placebo-controlled multicentre trialWEINBERG, LAURENCE ( 2014)Introduction: An alternative method of administering lignocaine for its beneficial anti-inflammatory and analgesic effects to improve and accelerate postoperative recovery is to administer the local anaesthetic solution by a continuous intravenous infusion. However, in patients undergoing major abdominal surgery, intravenous lignocaine combined with a 24-hour continuous subcutaneous infusion has not been systematically examined for efficacy and safety. A subcutaneous infusion of lignocaine may be an effective strategy to continue systemic lignocaine into the early postoperative period. Subcutaneous delivery may be more advantageous than an intravenous infusion, being technically easier to deliver, safer and cost-effective. Drug tolerance may also be less likely to develop. A significant advantage of subcutaneous infusions over intravenous drug delivery methods is that plasma levels are more stable, and symptom control may be achieved without the toxic effects of peaks and troughs resulting from episodic drug administration or a prolonged continuous intravenous infusion. However, it is unknown whether this intervention will impact clinically on important postoperative outcomes, such as length of hospital stay and accelerated postoperative rehabilitation. Before a combination of intravenous lignocaine and subcutaneous lignocaine is adopted as a feasible and efficacious technique for patients undergoing major abdominal surgery, it needs to be investigated in a randomised controlled clinical trial to measure its benefits and harm, and to better define its role in therapy. Study aims: The aims of this study are to evaluate whether a combination of intravenous lignocaine followed by a postoperative 24-hour subcutaneous infusion is beneficial in decreasing length of hospital stays, improving analgesia, and reducing opioid consumption compared to placebo. This study will also quantify the safety of this technique in a perioperative setting. The study was designed to test the hypothesis that perioperative systemic lignocaine infusion in this combination enhances recovery and shortens length of hospital stay after an open radical retropubic prostatectomy. Methods: The Austin and Box Hill Human Research Ethics Committees approved this study. This was a blinded, randomised, placebo-controlled, multicentre trial at two university teaching hospitals. Patients undergoing open radical retropubic prostatectomy were randomised to receive intravenous lignocaine (bolus injection 1.5 mg/kg), then an intravenous infusion (1.5 mg/kg/hr) during surgery, followed by iv subcutaneous infusion for 24 hours (1.5 mg/kg/hr) (Lignocaine group), or a Placebo group who received an equal volume of normal saline delivered at the same infusion rates and over the same time period. General anaesthesia, including the use intraoperative opioids, was standardized, and no patient received regional analgesia or anaesthesia, surgical wound catheters, or infiltration of the surgical wound with local anaesthetic solutions. All patients received morphine patient-controlled analgesia postoperatively in a standardized dosing regime. The primary aim of this study is to evaluate whether a combination of intravenous lignocaine followed by a postoperative 24-hour subcutaneous infusion is beneficial in decreasing the length of hospital stay compared to placebo. Important secondary outcomes included comparing intraoperative haemodynamics (heart rate, blood pressure), Bispectral index (BIS), and end-tidal sevoflurane concentrations required to maintain 1 MAC of anaesthesia. In addition, postoperative pain using a Visual Analogue Scale at the incision site measured at rest and with coughing, morphine and rescue analgesia consumption, need for rescue anti-emetic therapy, and patient satisfaction were also evaluated. Opioid-related and lignocaine-related side effects were critically examined including the measurement of plasma lignocaine levels performed in the immediate postoperative period and at 24 hours prior to the discontinuation of the lignocaine subcutaneous infusion. Results: The Lignocaine group had 37 patients and the control group had 38 patients. Patient demographics were similar between groups. The mean duration for surgery was 155.7 minutes (SD: 34.2) for the Lignocaine group and 141.6 minutes (SD: 44.6) for the Placebo group (estimated difference: 14.1 minutes, 95% CI: -4.27 to 32.47, p = 0.13). In the Lignocaine group, the mean highest heart rate recorded was 97.5 beats/minute vs. 103.8 beats/minute in the Placebo group (estimated difference: 6.3 beats/minute; 95% CI: 2.4 to 10.3 beats/minute, p = 0.001). Intraoperatively, the Lignocaine group had lower heart rates [52.1 beats/minute vs. 59.0 beats/minute; estimated difference: 6.8 beats/minute; 95% CI: 3.3 to 10.3 beats/minute, p = 0.001]. The mean BIS is the Lignocaine group was lower than that in the Placebo group (43.4% vs. 49.8%; estimated difference 6.3%, 95% CI: 3.0% to 9.7%, p = 0.001). Despite the BIS being lower in the Lignocaine group, the average concentration of sevoflurane required to maintain 1 MAC of anaesthesia was lower in the Lignocaine group [1.49% vs. 1.89%; estimated difference 0.39%, 95% CI: 0.26% to 0.5%, p = 0.001]. The Lignocaine group had a shorter length of hospital stay [3.3 days (SD: 0.8) vs. 4.7 days (SD: 3.2), estimated difference 1.3 days; 95% CI: 0.2 to 2.4, p = 0.02]. The Lignocaine group required less morphine during the first 24 hours [mean 38 mg (SD: 24) vs. 52 mg (SD: 27); estimated difference 14 mg; 95% CI 2 to 26 mg, p = 0.02]. The mean Visual Analogue Scores for pain at rest one hour postoperatively were 3.73 units for the Placebo group and 1.93 units for the Lignocaine group. On average, the Placebo group scored 1.80 units higher than the Lignocaine group at this time point (95% CI: 0.73 to 2.88, p = 0.001). There was no difference in rest pain at 24 hours. There were also no significant differences in pain on movement over the 24-hour period. Among secondary endpoints, the time taken to tolerate free fluids and a light ward diet were shorter in the Lignocaine group. Time to mobilize was also shorter in the Lignocaine group. Other secondary endpoints were similar. In the Lignocaine group, the mean plasma lignocaine level after surgery was 1.36 mcg/mL (SD: 0.48), range 0.5 mcg/mL to 2.19 mcg/mL; and at 24 hours postoperatively was 3.1 mcg/mL (SD: 0.95); range 1.1 mcg/mL to 4.96 mcg/mL. Lignocaine levels in the Placebo group were always less than 0.5 mcg/mL. No patient experienced complications associated with lignocaine infusion. Conclusions: Intravenous lignocaine followed by a 24-hour subcutaneous infusion resulted in a shorter length of hospital stay and accelerated acute rehabilitation after open radical retropubic prostatectomy. Furthermore, subcutaneous infusion of lignocaine was an effective strategy to continue systemic lignocaine into the early postoperative period. To date, this is the first randomised clinical trial evaluating the use of subcutaneous lignocaine in this setting, and therefore adds to the growing body of literature supporting the use of lignocaine via this route for open abdominal surgery.