Safety of 96-hour incision-site continuous infusion of ropivacaine for postoperative analgesia after bowel cancer resection

Abstract

The aim of this study was to examine the safety of ropivacaine given to patients as a continuous infusion [0.2% (2 mg/mL), 5 mL/h for 96 hours] into a right lateral transverse incision using a portable elastomeric infusion pump after colon cancer resection. Blood samples were collected throughout the infusion and up to 12 hours after infusion and were analyzed by high-performance liquid chromatography (HPLC) for total and unbound ropivacaine concentrations in plasma. Alpha1 acid glycoprotein (AAG) concentrations were measured at 0 and 48 hours to assess possible changes in ropivacaine protein binding after surgery. Postoperative pain control was assessed using 12 hour visual analog scale (VAS) scores. Patient-controlled analgesia (PCA) using fentanyl was freely available in parallel for breakthrough pain, with usage and consumption compared with a historical cohort. The mean ± SD Cmax total plasma ropivacaine concentration (n = 5) from 12 hours to the end of the infusion was 4.5 ± 2.6 mg/L, comparable with the previously published threshold for CNS toxicity in the most sensitive patient studied (3.4 mg/L). However, the corresponding maximum unbound ropivacaine concentration (ie, the pharmacologically active moiety) of 0.07 ± 0.01 mg/L ranged from four- to sevenfold below the reported toxicity threshold (0.34 mg/L). The apparently greater safety margin seen with unbound ropivacaine may have resulted from a significant increase (mean 63%, P < 0.05) in AAG concentrations measured at 48 hours after surgery. This reduction resulted from the known AAG reaction after surgical intervention, resulting in a reducing unbound ropivacaine fraction throughout the 96 hour infusion in all patients. Mean subjective 12 hour pain scale scores at rest and on movement showed large variability between patients. No signs or symptoms of ropivacaine toxicity were observed or reported on questioning. In this limited sample, extending the infusion period from the presently approved 48 hours to 96 hours seems to be a safe alternative and/or adjunct to standard opiate analgesia after colorectal surgery using a right lateral transverse incision, hence reducing the incidence of opiate adverse effects and enhancing recovery. Unbound ropivacaine concentrations suggest there is scope for testing elevated doses to enhance efficacy further.