Application of opioid-free general anesthesia for gynecological laparoscopic surgery under ERAS protocol: a non-inferiority randomized controlled trial

Study design

This prospective, randomized single-centre non-inferiority trial was approved by the Institutional Review Board (IRB) of Hefei Hospital affiliated Anhui Medical University (IRB approved registration number: 2021-KeYan-042) and was registered in the Chinese Clinical Trial Registry (ChiCTR2100052761, 05/11/2021). All methods were carried out in accordance with relevant guidelines and regulations. Written informed consent was obtained from all participants.

Participants

Adult female patients assessed as American Society of Anesthesiologists Grades I to III undergoing elective laparoscopic hysterectomy for benign causes under general anesthesia between November 2021 and May 2022 were enrolled, aged 18 ~ 65 years old. Exclusion criteria included: a. allergy to study drugs; b. language, mental, or comprehension impairment; c. a history of drug dependence and alcohol abuse; d. preoperative major organ dysfunction; e. pregnancy; f. participated other clinical trials.

Outcomes

According to Petersen’s study [9], AUC of VAS scores is a suitable indication for evaluating of analgesic effect. We decided that the primary outcome of this study was the AUCVAS from the time of leaving PACU to 48 h after surgery. The secondary outcomes included intraoperative MAP and HR, awakening time and orientation recovery time, number of rescue flurbiprofen axate required, incidence of PONV and perioperative PQSI scores.

Randomization and blinding

All patients were randomly divided into OFA group (Group OFA) or OA group (Group OA). Randomization was conducted using a computer-generated allocation sequence with a 1:1 allocation by an independent investigator. The randomization sequence was placed in sequentially numbered opaque sealed envelopes and revealed by another investigator after the participants’ enrollment, followed by preparing the study drugs wrapped with opaque paper according to the allocated group and delivered them to the operating room. The result of the group allocation was not released until the time of data analysis. Anesthesia was conducted by an experienced anesthesiologist and the outcome assessments were carried out by another one. Participants, anesthesia implementers and outcome assessors were untold of the group allocation.

ERAS protocol [6] 1.

Carbohydrate-rich diet the day before surgery

2.

No mechanical bowel preparation

3.

6 h fast for solids and 2 h fast for clear liquid

4.

Maintain euvolemia during surgery

5.

Preemptive analgesia

6.

Active heating during surgery

7.

Postoperative nausea and vomiting prophylaxis

8.

Restrictive fluid therapy after surgery

9.

Resumption of oral intake of liquids and solids within 24 h after surgery

10.

Removal of bladder catheter 12-24 h after surgery

11.

Active mobilization on the first postoperative day

Anesthetic management

All patients undergoing elective gynecological laparoscopic surgery were treated according to ERAS protocol during perioperative period and no preoperative drugs were administered before induction. All patients received total intravenous anesthesia (TIVA) without inhalation.

Induction of general anesthesia

Routine monitoring devices were set up to monitor noninvasive blood pressure (BP), electrocardiogram (ECG), heart rate (HR), oxygen saturation (SpO2), respiratory rate (RR), partial pressure of end-tidal carbon dioxide (PetCO2) and bispectral (BIS) index of patients. In group OFA, patients received dexmedetomidine (0.5 μg/kg i.v.) in a 10-min period before induction followed by a continuous infusion with 0.1–0.3 μg/kg/min until the end of surgery, and in group OA, the same amount of normal saline was administered in the same way. Anesthesia was induced with midazolam (0.05 mg/kg i.v.), propofol (2–2.5 mg/kg i.v.), cis-atracurium (1–1.5 mg/kg i.v.) in all patients. Esketamine (0.3–0.5 mg/kg i.v.) or sufentanil (0.2–0.4 μg/kg i.v.) were administered as analgesics of induction in group OFA and group OA, respectively. I-gel laryngeal mask airway was intubated in all patients after induction followed by setting the ventilation mode of anesthesia machine to intermittent positive pressure ventilation (IPPV) with tidal volume 6-8 ml/kg and respiratory frequency 10–15/min. PetCO2 was kept at 35-45 mmHg. After induction the skin was sterilized, ultrasound-guided bilateral transversus abdominis plane (TAP) block was performed by linear probe which was placed in transverse position on the midaxillary line in all patients. The external oblique, internal oblique and transversus abdominis were identified successively followed by using a 100 mm 20G disposable needle punctured the skin. When needle-tip was visualized between transversus abdominis and internal oblique, 15 ml of 0.25% ropivacaine was injected bilaterally.

Maintenance of general anesthesia

Intravenous infusion of flurbiprofen axate 50 mg for preventive analgesia were administered 10 min before skin incision in both groups. In group OFA, continuous intravenous infusion of dexmedetomidine 0.1–0.3 μg/kg/min, esketamine 0.3 mg/kg/h [10] and propofol 5–7 mg/kg/h were administered for maintenance of general anesthesia, and continuous intravenous infusion of remifentanil 8–10 μg/kg/h and propofol 5–7 mg/kg/h were administered in group OA. Intermittent bolus intravenous infusion of cis-atracurium was administered for intraoperative muscle relaxation. The infusion rate of drugs was adjusted for maintaining the BIS index at 40–60 and the index of MAP and HR within a 20% range of baseline. Hypotension (MAP < 60 mmHg) was treated with ephedrine 10 mg intravenously and bradycardia (heart rate < 45 bpm) was treated with atropine 0.5 ~ 1 mg intravenously. Hypertension (MAP > 120 mmHg) was treated with urapidil 5 ~ 10 mg intravenously. All drugs were stopped at the end of surgery and intravenous infusion of azasetron 10 mg was administered for preventing PONV.

After anesthesia

Patients were transferred to PACU after surgery. When patient was conscious and responsive according to command as well as the BIS index was more than 90, I-gel was removed.

Postoperative analgesia and acute pain management

All patients received postoperative controlled intravenous analgesia (PCIA). PCIA protocol of group OFA: esketamine 2.5 mg/kg + flurbiprofen axate 2.5 mg/kg + azasetron 30 mg with total amount of 100 ml and constant infusion rate of 2 ml/h, and in group OA: sufentanil 2 µg/kg + flurbiprofen axate 2.5 mg/kg + azasetron 30 mg were administered with the same PCIA parameters as group OFA. A bolus infusion of flurbiprofen axel 50 mg for rescue analgesia if any patients complained of intolerable pain.

Observation indicatorsDemographic data

We collected data on demographic characteristics (including age, BMI, duration of surgery, duration of anesthesia and amount of bleeding).

Intraoperative data

The MAP and HR prior to induction (T1), surgical incision immediately (T2), 30 min after surgical incision (T3), at the end of surgery (T4), and awakening immediately (T5).

Postoperative data Recovery time assessment

Awakening time (i.e. time from withdrawal of drugs to patient opening eyes and nodding according to command) and orientation recovery time (i.e. time from withdrawal of drugs to patient’s orientation to time, place and person) were recorded.

Postoperative pain assessment

All patients were instructed to use a 0 to 10 cm VAS (“0” representing no pain and “10” representing the worst imaginable pain) preoperatively. VAS scores were collected at the time of leaving PACU (T6), 12 h after surgery (T7), 24 h after surgery(T8), 36 h after surgery (T9), 48 h after surgery (T10), and the area under the curve (AUC) of VAS scores while coughing from T5 to T9 were calculated by Graphpad Prism 9.0 software. Number of rescue flurbiprofen axel analgesia required was recorded.

Postoperative adverse events

The incidence of PONV during postoperative 48 h were recorded. Nausea refers to an uneasy feeling in the stomach while vomiting refers to the forceful expulsion of gastric contents [11]. The severity of nausea was assessed on a 4-point scale (0 = none, 1 = mild, 2 = moderate, and 3 = severe) by subjective feeling of patients. Rescue anti-emetic (metoclopramide 5 mg i.v.) was available on request if the nausea score was ≥ 2. Patients were treated with 10 mg of metoclopramide in case of two or more vomiting episodes.

Perioperative sleep quality assessment

PSQI scores were assessed 1 day before the surgery (T0) and 1 month after the surgery (T11). The Pittsburgh Sleep Quality Index (PSQI) is a validated, easy, self-administered questionnaire that assesses sleep quality which participants are asked to recall within the past month [12]. PSQI scores > 5 reflects poor sleep quality. It comprises 19 items forming seven subscales, including: a. sleep quality, b. sleep latency, c. sleep duration, d. sleep efficiency, e. sleep disturbance, f. sleep medication, g. daily dysfunction. Each component has a score that ranges from 0 to 3 and PSQI global score ranges from 0 to 21. PSQI score > 5 represents poor sleep quality (PSQ) (Appendix 1: Pittsburgh Sleep Quality Index (PSQI)).

Sample size calculation

In our pilot study, we enrolled 16 patients randomly being allocated in two groups with 8 patients in each group, and they were not enrolled in the final study. The sample size was calculated by 2-Sample Non-Inferiority test in Power and Sample Size software. The mean AUCVAS was 14.3 and 13.5 in group OFA and group OA, respectively, and standard deviation was 3.0. We assumed that the non-inferiority margin was 2. With 80% power and alpha level of 0.05 (two-tailed), based on the pilot study’s results, the minimum sample size was 78 patients. Considered at least 15% sample drop rate, 90 patients were enrolled finally.

Statistical analysis

All data were analyzed by SPSS software package (version 26.0; IBM Corporation, Armonk, NY). Continuous data were tested for normality using Shapiro–Wilk test. The independent-samples t test was used for analysis of normally distributed measurement data and non-normally distributed data, which were expressed as median (interquartile range) [M(Q)], were analyzed by non-parametric test. Repeated measures analysis of variance was used for inter-group comparison of MAP and HR. The chi-square test was used for comparison between groups for enumeration data. P < 0.05 was defined as statistically significant.

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