Peritoneal Nebulization of Ropivacaine during Laparoscopic Cholecystectomy: Dose Finding and Pharmacokinetic Study

Hindawi Pain Research and Management Volume 2017, Article ID 4260702, 9 pages https://doi.org/10.1155/2017/4260702 Clinical Study Peritoneal Nebulization of Ropivacaine during Laparoscopic Cholecystectomy: Dose Finding and Pharmacokinetic Study Massimo Allegri,1,2,3 Martina Ornaghi,4 Catherine E. Ferland,3,5,6 Dario Bugada,1,2,3,7 Yash Meghani,5 Serena Calcinati,4 Manuela De Gregori,3,7,8 Federica Lovisari,4 Krishnaprabha Radhakrishnan,5 Maria Cusato,9 Stefano Scalia Catenacci,4 Marta Somaini,10 Guido Fanelli,1,2 and Pablo Ingelmo3,5,6 1 Department of Anaesthesia, ICU and Pain Therapy, University Hospital of Parma, Parma, Italy Department of Surgical Sciences, University of Parma, Parma, Italy 3 SIMPAR Group (Study in Multidisciplinary Pain Research), Parma, Italy 4 Department of Anaesthesia and Intensive Care, San Gerardo Hospital of Monza, Milan Bicocca University, Milan, Italy 5 Department of Anaesthesia, Montreal Children’s Hospital, McGill University, Montréal, QC, Canada 6 Alan Edwards Centre for Research on Pain, Montreal, QC, Canada 7 YAP Group (Young Against Pain), Firenze, Italy 8 Pain Therapy Service, IRCCS Fondazione Policlinico San Matteo, Pavia, Italy 9 Laboratory of Clinical Pharmacokinetics, IRCCS Fondazione Policlinico San Matteo, Pavia, Italy 10 Department of Anaesthesia and Intensive Care I, ASST Grande Ospedale Metropolitano Niguarda, University of Milano-Bicocca, Milan, Italy 2 Correspondence should be addressed to Catherine E. Ferland; Received 30 November 2016; Accepted 30 January 2017; Published 20 February 2017 Academic Editor: Volkan Hancı Copyright © 2017 Massimo Allegri et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. Intraperitoneal nebulization of ropivacaine reduces postoperative pain and morphine consumption after laparoscopic surgery. The aim of this multicenter double-blind randomized controlled trial was to assess the efficacy of different doses and dose-related absorption of ropivacaine when nebulized in the peritoneal cavity during laparoscopic cholecystectomy. Methods. Patients were randomized to receive 50, 100, or 150 mg of ropivacaine 1% by peritoneal nebulization through a nebulizer. Morphine consumption, pain intensity in the abdomen, wound and shoulder, time to unassisted ambulation, discharge time, and adverse effects were collected during the first 48 hours after surgery. The pharmacokinetics of ropivacaine was evaluated using high performance liquid chromatography. Results. Nebulization of 50 mg of ropivacaine had the same effect of 100 or 150 mg in terms of postoperative morphine consumption, shoulder pain, postoperative nausea and vomiting, activity resumption, and hospital discharge timing (>0.05). Plasma concentrations did not reach toxic levels in any patient, and no significant differences were observed between groups (𝑃 > 0.05). Conclusions. There is no enhancement in analgesic efficacy with higher doses of nebulized ropivacaine during laparoscopic cholecystectomy. When administered with a microvibration-based aerosol humidification system, the pharmacokinetics of ropivacaine is constant and maintains an adequate safety profile for each dosage tested. 1. Introduction Postoperative pain remains a major problem after laparoscopy, having direct consequences on the patient’s quality of life as well as increasing health care costs [1, 2]. Pain after laparoscopic surgery is usually attributed to surgical manipulations, including intraperitoneal insufflation of carbon dioxide, resulting in peritoneal stretching, diaphragmatic irritation, changes in intra-abdominal pH, and retention of the insufflated gas within the abdominal cavity after surgery [3]. 2 These manipulations also result in the irritation of peritoneal nerves causing visceral and shoulder pain. Previous studies have reported that as many as 80% of patients required opioid analgesia after laparoscopic surgery [1, 4, 5], which also may increase postoperative morbidity and hospital stay [2]. Intraperitoneal nebulization of local anesthetics through microvibration-based aerosol humidification devices combines the analgesic benefits of gas conditioning (humidification) and local anesthetic instillation, allowing for a uniform dispersion of the solution throughout the peritoneum [6]. This method has shown great efficacy in the control of postoperative pain [7–12] and in the reduction of postoperative morphine consumption when compared with both placebo and peritoneal instillation in different clinical scenarios [12–14]. However, in all those studies there were patients experiencing residual pain and requiring significant amount of opioids. Moreover, there was no formal analysis of the least effective dose of local anesthetic. Pharmacokinetic studies on animal models have shown that intraperitoneal cold nebulization of ropivacaine is a safe technique, and the drug’s kinetics is similar to the instillation method [7, 15]. Human studies have confirmed favorable pharmacokinetics and pharmacodynamics of nebulized ropivacaine. Peak concentration is attained between 10 and 30 minutes following the end of aerosolized ropivacaine delivery and the plasma concentration of local anesthetics remained within safe levels even after nebulization of 3 mg/kg of ropivacaine [16]. However, the delivery of high doses of ropivacaine (i.e., 3 mg/kg) may be unnecessary or even impractical due to the long nebulization time with the actual commercially available systems. Moreover, it is possible that lower effective doses could have less and different kinetics due to the postnebulization loses during normal (less controlled) surgical procedures [17]. The aim of this multicenter, double-blind, randomized, controlled phase III clinical trial was to assess if an increase on the doses of nebulized ropivacaine is associated with an increase on its analgesic efficacy expressed through the reduction of morphine consumption after laparoscopic cholecystectomy. As a second aim, we evaluated the possibility of a dose-dependent systemic absorption of ropivacaine, when nebulized in the peritoneal cavity during everyday clinical conditions. 2. Methods After Ethics Committee approval by the two hospitals involved in the study (San Gerardo Hospital, Monza and IRCCS Policlinico S. Matteo, Pavia, Italy), this trial was registered on clinicaltrials.gov (NCT01143025 06/09/2010). The study was designed according to the CONSORT guidelines (https://www.consort-statement.org). 2.1. Patients. All patients in this study provided written informed consent. Eligible patients were adults between 18 and 75 years of age, had an American Society of Anesthesiologist physical status score of I–III, and were scheduled for elective laparoscopic cholecystectomy. Patients were excluded if they had a clinical diagnosis of acute pancreatit (...truncated)