This prospective randomized double-blind clinical trial was conducted at the BP Koirala Institute of Health Sciences (BPKIHS) from December 2015 to March 2017. Ethical approval for this study (Ref No. IRC/520/015) was provided by the Institutional review committee of BPKIHS, Dharan, Nepal (Member secretary Dr. Ashish Shrestha) on 24 June 2015. Before enrollment of patients, the trial was registered by the principal investigator (AG) at clinicaltrials.gov (Ref No. NCT02601651). The trial was conducted according to Good Clinical Practice and the Consolidated Standards of Reporting Trials (CONSORT) guidelines.
Patients were screened for eligibility (AG) during the pre-anesthetic visit at the in-patient-unit, the night before surgery. Male patients aged between 18 and 65 years, of ASA physical status I–II, planned for laparoscopic TEP repair of the inguinal hernia were eligible. Patients were excluded if they were obese, unable to comprehend the pain assessment scale, allergic to local anesthetics, on pain medication or anti-arrhythmic drugs, or had, psychiatric disorders, cardiac arrhythmia, hepatorenal disease or epilepsy.
After obtaining written informed consent, all eligible participants were randomly assigned, in a 1:1 ratio, to receive either lidocaine (intervention) or normal saline (placebo comparator) infusion. The anesthesia supporting staff created the trial-group assignment from the computer-based randomization list, which remained secured in sequentially numbered sealed opaque envelopes and concealed until after enrollment.
On the day of surgery, an anesthesia assistant not involved in the study prepared the drug solution after breaking the codes. Patients received one of the two assigned study medications just before the induction of anesthesia: Lidocaine group received an IV bolus of 1.5 mg. kg− 1 lidocaine (Lox 2%®, Neon pharmaceuticals limited, Mumbai, India) followed by a continuous infusion of 2 mg. kg− 1. h− 1 until the tracheal extubation; The saline group received an equal volume of IV 0.9% normal saline (NS) bolus followed by a continuous infusion. Patients, attending anesthesiologists, and the investigator who collected the data and assessed the outcomes were unaware of the trial-group assignment.
Patients received no premedication. During the pre-anesthetic visit, they were educated on the numeric pain rating scale (NRS, 0–10 cm) for postoperative pain, where 0 is no pain and 10 is the worst imaginable excruciating pain. In the operating room, standard monitoring was applied. Just before the induction of anesthesia, patients received the study drug, according to the group allocation. Anesthesia was induced with IV fentanyl 1.5 μg. kg− 1 and propofol 2–2.5 mg. kg− 1 till the cessation of verbal response and the tracheal intubation was facilitated with vecuronium 0.1 mg. kg− 1 IV. The lungs were mechanically ventilated in volume control mode, maintaining the end-tidal carbon dioxide (ETCO2) between 35 and 45 mmHg.
Intravenous paracetamol 1 g was administered for 15 min after tracheal intubation. Pre-incisional infiltration in the three trocar sites was done with 2 ml of 0.25% bupivacaine. Anesthesia was maintained with an air/oxygen mixture (inspired oxygen fraction 0.40) and isoflurane, adjusting the end-tidal concentration of isoflurane to maintain mean arterial pressure (MAP) within 20% of the baseline. IV fentanyl 0.5 μg. kg− 1 was supplemented intraoperatively if MAP and heart rate increased by 20% from the baseline after ensuring adequate end-tidal concentration of isoflurane, neuromuscular blockade and targeted range of ETCO2. The adequate neuromuscular blockade was achieved with supplemental doses of vecuronium IV bolus after observing curare notch in capnograph. Any episode of intraoperative hypotension (MAP < 65 mmHg) and bradycardia (heart rate < 50 beats. min− 1) was treated with ephedrine 5 mg and atropine 0.4 mg IV respectively.
An experienced surgeon performed the TEP laparoscopic surgery for inguinal hernia repair as described elsewhere. Ketorolac 30 mg IV was administered at the end of surgery and scheduled to be given at 8 h intervals. The residual neuromuscular block was reversed with IV neostigmine 0.05 mg. kg− 1 and glycopyrrolate 0.01 mg. kg− 1. Following successful tracheal extubation, the study drug was discontinued and the patient was transferred to the postanesthesia care unit (PACU).
The blinded investigator assessed the postoperative outcomes. The primary outcome was total IV morphine equivalent consumed in the first 24 h. Secondary outcomes were postoperative pain scores (NRS) at rest and on movement, sedation scores recorded using a 5-point scale (0 = alert, 1 = arouses to voice, 2 = arouses with gentle tactile stimulation, 3 = arouses with vigorous tactile stimulation, 4 = lack of responsiveness), the incidence of PONV using a 3-point scale (0 = none, 1 = nausea, 2 = vomiting), time to the first perception of pain (min), time to first void (h), adverse events (lightheadedness, tinnitus, perioral numbness, arrhythmia), quality of recovery based on QoR-40 questionnaire at 24 h after surgery, patient satisfaction for postoperative pain relief using a five-point Likert scale at 24 h following surgery (1-highly satisfied, 2-satisfied, 3-neutral, 4-not satisfied, 5-strongly dissatisfied) and the incidence of chronic post-surgical pain (CPSP) at 3 months.
Pain and sedation scores were assessed at PACU (on arrival, 15 min, 30 min, 1 h, 2 h) and surgical unit (4 h, 6 h, 8 h, 12 h, 24 h). If the NRS score for pain was > 3 at rest, morphine 1 mg IV bolus was administered in the PACU, and repeated at 5 min interval until NRS was ≤3. After 2 h of the stay in the PACU, the patients were transferred to the ward. In the surgical unit, tramadol 50 mg IV was administered for NRS score > 3 and 50 mg was repeated at 10 min interval, up to a maximum dose of 300 mg in the first 24 h for maintaining VAS score for pain ≤3. The amount of tramadol consumed was converted to an equivalent dose of morphine from an online dose equivalent calculator (www.clincalc.com/Opioids). Ondansetron 4 mg IV was administered for persistent nausea (lasting > 5 min) or vomiting. CPSP was defined as pain that developed after a surgical procedure and persisted at least 3 months after surgery. For this, the blinded investigator contacted the patients via telephone at 3 months after surgery. They were asked to answer the following question: Do you feel any pain in the operated area?
The sample size calculation was based on the study by H Kang on postoperative opioid consumption between the lidocaine infusion group and the placebo group in open inguinal hernia surgery. Using an online statistical calculator (G power® version 3.0.1), an estimated sample size of 29 patients in each study group achieved a power of 80% to detect a Cohen's d effect size of 0.76 in the primary outcome measure of opioid consumption, assuming a type I error of 0.05. With an anticipated 10% drop-out, a total of 64 patients were enrolled.
The data were entered into excel software and analyzed using STATA version 13.0 (Stata Corporation, College Station, TX, USA). Histograms and the Shapiro-Wilk test was used to check the normality of the data. Normally distributed data were compared using a 2-tailed t-test for independent samples. Non-normally distributed data were analyzed using the Mann-Whitney U test. For ordinal data, the Kruskal-Wallis test was applied. Chi-square test or Fischer's exact test was used for analyzing the categorical variables as appropriate. The finding with an associated p-value less than 0.05 was considered as statistically significant.
BMC Anesthesiol. 2020;20(137) © 2020 BioMed Central, Ltd.