This prospective, randomized trial was approved by the Institutional Ethics Committee (2020KY071) and was registered at the Chinese Clinical Trial Registry (ChiCTR2100044230). A written informed consent was obtained from all patients enrolled in the study.
Patients with American Society of Anesthesiologists (ASA) physical status classes I or II, aged 20ཞ60 years and scheduled for breast benign lumpectomy between December 2020 and July 2021 were considered eligible to participate in this prospective, randomized clinical trial. Major exclusion criteria were: hypertension; ischemic heart disease; psychiatric disorders; a history of significant hepatic, renal, or cardiac disease; preoperative heart rate (HR) less than 50 beats/min with/without cardiac conduction or rhythm abnormalities; chronic pain treatment or chronic steroid therapy; allergy to the study drugs; refusal to participate in the study; and inability to comprehend VAS. Those who were transferred to a mastectomy because of the malignant pathology were subsequently excluded from the study. Patients were randomized using computer-generated random numbers to received OFA group or OA group anesthesia (n = 30, each group).
Before the study procedure, all the patients were instructed on using a 10 cm visual analog scale (VAS; with “0” mark corresponding to no pain and “10” mark representing the worst imaginable pain). Investigator assessing the postoperative parameters, and the data analyst were blinded to the study. The anesthetist providing anesthesia was not blinded to the study drugs administered.
OFA was defined as the administration of no opioids either pre- or intraoperatively until wound closure, and rescue opioids were only given when the patients were fully awake and had been administered nonopioid analgesics previously. OA was defined as the administration of any opioid during the pre- or intraoperative period. Postoperative opioids (after OFA or OA) were defined as the administration of opioid from the time of wound closure until discharge from the hospital.
All patients received total intravenous anesthesia (TIVA) without inhalation. A bispectral index (BIS) of 40ཞ60 was maintained for monitoring the depth of anesthesia. The method by which OFA was administered consisting of combining Dexmedetomidine-Esketamine-Lidocaine. Dexmedetomine was administered 0.5 µg.kg− 1over 10 min before induction, 0.1 µg.kg− 1 at induction, and an infusion of 0.1 ~ 0.2 µg.kg− 1.h− 1 for maintenance. Lidocaine was administered as 1.5 mg.kg− 1 at induction, followed by an infusion of 1 ~ 1.5 mg.kg− 1.h− 1 for maintenance. Esketamine was administered as 0.1 mg.kg− 1 at induction, 0.25 mg.kg− 1 (maximum 25 mg) before incision, and an infusion of 0.1 ~ 0.2 mg.kg− 1.h− 1 for maintenance.
Sufentanil was administered in the OA group at a dose of 0.2 ~ 0.4 µg.kg− 1 at induction, 0.4 µg.kg− 1 before incision. Remifentanil was followed by a continuous infusion of 0.1 ~ 0.3 µg.kg− 1.h− 1 for maintenance. Midazolam was administered 0.03 ~ 0.04 mg.kg− 1 at induction, propofol was administered 1.5 ~ 2.0 mg.kg− 1 at induction, cisatracurium was administered 0.2 ~ 0.3 mg.kg− 1 at induction in both groups. Propofol was followed by a continuous infusion of 4 ~ 6 mg.kg− 1h− 1 for maintenance in both groups.
After induction of anesthesia, laryngeal mask airway was placed in all patients. Intravenous flurbiprofen axate 50 mg for multimodal analgesia and ondansetron 4 mg for preventing postoperative nausea and vomiting were administered 10 minutes before the end of surgery in both groups. Dexmedetomidine, esketamine, lidocaine, remifentanil, and propofol were stopped at the end of the surgery. Atropine 10 µg.kg− 1 and neostigmine 50 µg.kg− 1 were administered to reverse muscle relaxation. Laryngeal mask airway extubation was performed once the patient was conscious and spontaneous ventilation of the patient was adequate, and the patients were transferred to the postanesthesia care unit (PACU).
Non-invasive blood pressure was assessed at least at 3 min of interval during anesthesia. Hypotension (MAP < 60 mmHg) was treated with ephedrine 6 mg intravenously and bradycardia (heart rate < 45 bpm) was treated with atropine 0.5 ~ 1 mg intravenously. Hypertension (MAP > 120mmHg) was treated with urapidil 5 ~ 10 mg intravenously. Any patient showing VAS ≥ 4 at any point of time was administered intravenous dezocine 5 mg slowly for postoperative rescue analgesia.
The following demographic data were recorded: age, BMI, duration of surgery, amount of bleeding, current or recent motion sickness, or previous PONV. Noninvasive blood pressure and heart rate were recorded at the time points of entering operating room (T0), immediately after induction of anesthesia (T1), immediately after intubation (T2), 1 minute after surgical incision (T3), 5 minutes after surgical incision (T4), and 10 minutes after surgical incision (T5). The cases of receiving ephedrine, urapidil, and atropine were recorded. The time of awakening, recovery time of orientation, cases of increased oral secretion were recorded while patients in PACU. Postoperative pain was assessed at 2 h, 12 h, and 24 h postoperatively using the VAS score. The incidence of adverse events during the first 24 h postoperatively, such as postoperative nausea and vomiting and the number of antiemetics administered after PONV, were also recorded.
We calculated that a sample size of 36 patients per group would maintain 90% power at 5% significance level (two-sided) to detect a difference of 0.35 in the postoperative pain VAS at 2 h after recovery between the two groups, with a SD of 0.43 and an estimated 10% dropout.
Statistical analysis was performed with SPSS V.26.0 (IBM Corp, Armonk, New York, USA) for Windows and GraphPad Prism 8 (GraphPad Software, La Jolla, California, USA) for Windows. Continuous data were tested for normality using the Kolmogorov-Smirnov test. Normally distributed data which were presented as mean ± SD were compared using Student’s T test. Nonnormally distributed data which were presented as median [interquartile range] were compared using the Mann-Whitney U test. Categorical data which were presented as n (%) were compared using the χ² test or Fisher’s exact test, as appropriate. Two-tailed P < 0.05 value was considered to be statistically significant.