This prospective, randomized, double-blind clinical trial was performed between August 2018 to December 2018 at Peking University First Hospital. The trial was registered at Chictr.org.cn, Number ChiCTR 1800017172, on July 16 2018, http://www.chictr.org.cn/usercenter.aspx. Ethical approval for this study was provided by the Ethics Committee of Peking University First Hospital, Peking, China (Number 2018-130, principal investigator: Zhi Yu Geng) on 25 July 2018. Written informed content was obtained from all patients before enrollment.
We used the methodology previously described by our recent study . Participant screening was performed the day before surgery. The inclusion criteria were: (1) female patients; (2) age between 18 and 65 years old; (3) scheduled for elective laparoscopic myomectomy or laparoscopy-assisted vaginal hysterectomy. Patients who met any of the following criteria were excluded: (1) American Society of Anesthesiologists physical status > II before surgery, (2) previous history of schizophrenia, Parkinson’s Disease, epilepsy and myasthenia gravis, (3) unable to communicate due to comma, dementia and other diseases, (4) obesity defined as BMI (body mass index) > BMI > 30kg m-2, (5) known sick sinus syndrome, severe bradycardia (heart rate < 50 beats per minute), or severe atrioventricular block without pacemaker before surgery, (6) pre-existing of severe hepatic disease (Child-Pugh class C), (7) pre-existing of chronic renal failure (receive renal replacement therapy preoperatively), (8)Neo-adjuvant chemoradiotherapy before surgery, (9) alcoholism or drug abuse, (10) any regimen of antiemetic, glucocorticoids or psychotropic drugs which are known to have an influence on the occurrence of PONV within 24h before surgery.
Randomisation and drug administration
Random numbers were generated by computer software in a 1:1 ratio. Patients were randomized to receive morphine 0.5mg ml-1 with or without dexmedetomidine 1μg ml-1.Study drugs were prepared according to the randomization results by a study coordinator. Anesthesiologist and the investigator responsible for the study outcomes assesssment were blinded.
For patients in the dexmedetomidine group (Group Dex), an initial loading dose of 0.4μg kg-1 dexmedetomidine was given by intravenous infusion 0.5 hour before the end of surgery. PCA was begun with 0.5mg ml-1 morphine plus 1μg ml-1 dexmedetomidine in 100 ml normal saline. While for patients in the control group (Group Ctrl), normal saline was given 0.5 hour before the end of surgery, and PCA was begun with 0.5mg ml-1 morphine in 100 ml normal saline. For all patients, PCA was programmed to deliver a 2ml bolus on-demand with a lockout time of 8 minutes and a background infusion at a rate of 1 ml h-1.
The investigator assessing patients outcomes was blinded to group assignment and blinding was maintained throughout the study period.
Anesthesia and perioperative care
No pre-medication was administered before induction. Routine monitoring included non-invasive blood pressure, pulse oximetry, electocadiogram, Bispectral index and end-tidal carbon dioxide partial pressure were applied intraoperatively.
All patients received dexamethasone 5mg before induction. General anesthesia was induced intravenously with 0.03mg kg-1 midazolam, 2 mg kg-1 propofol, and target controlled infusion of remifentanil with an effect-site concentration of 3ng ml-1. Rocuronium was administered to facilitate laryngeal mask airway insertion. Total intravenous anesthesia was provided with propofol and remifentanil. Bispectral index was maintained between 40 and 60 during surgery and blood pressure was adjusted within ±20% from baseline. Mechanical ventilation was maintained with a mixture of oxygen and air (FiO2 0.5) and an end-tidal carbon dioxide partial pressure was adjusted between 4.6 and 7.3 kilopascals intraoperatively. Lactated Ringer’s solution was infused at a rate of 6 ml kg-1 h-1 throughout the surgery.
Morphine 0.1mgkg-1 and parecoxib sodium 40mg were administered 0.5 hour before the end of surgery. Residual neuromuscularblock was reversed with neostigmine (0.04mg kg-1) and atropine (0.02mg kg-1) at the end of the surgery.
Upon completion of surgery, laryngeal mask airway was removed and the patient was transferred to the post-anesthesia care unit (PACU) for one hour monitoring . The patient-controlled analgesia pump was started and continued until 24h after surgery.
Data were collected by research personnel who were blinded to the randomization and not involved in the clinical care. The 24h observation period started at the time of removal of the laryngeal mask airway. The researcher assessed the patients at 2, 6 and 24h postoperatively. Baseline characteristics of patients such as previous history of PONV, chronic smoking, primary risk score for PONV, co-existing systemic diseases and concurrent medication were recorded. Intra-operative parameters including duration of anesthesia and surgery, doses of anesthetics and analgesics, and total fluid administered were collected. Postoperative data including presence and severity of nausea and vomiting, visual analogue scale (VAS) pain scores, the cumulative dose of PCA morphine, requirement for rescue antiemetics, vital signs, sedation scores, and any adverse events were documented.
The primary outcome was the incidence of PONV over the first 24h postoperative hours. Patients who experienced at least one episode of nausea, vomiting or retching or any combination of these during the first 24 h after surgery were considered to have PONV. Patients were asked to rate their degree of nausea using a four-point scale (0=none, 1=mild, 2=moderate, 3=severe) [14-15]. Postoperative vomiting was defined as at least one episode of vomiting or retching and the PONV score was rated as 4. Tropisetron 5mg was used as the rescue antiemetic. Rescue antiemetics were administered on the following conditions: two or more episodes of vomiting or retching, any nausea lasting for more than 30 min, a ‘severe’ degree of nausea or whenever treatment was requested by the patient.
The secondary outcomes included the VAS scores at 2, 6 and 24 h after surgery, the total 24 h morphine consumption, and the occurrence of adverse events during PACU stay. Pain intensity was assessed at PACU, 2 h, 6 h and 24 h postoperatively using an 11-point VAS on which 0 indicated no pain and 10 indicated the worst pain imaginable. In the PACU, supplemental morphine bolus of 2mg i.v. was administered for moderate pain (VAS≥4). Sedation levels were assessed using the Ramsay sedation scale (1=agitated and uncomfortable, 2=co-operative and orientated, 3=can follow simple directions, 4=asleep but strong response to stimulation, 5=asleep and slow response to stimulation and 6=asleep and no response to stimulation). Over sedation was defined as a sedation score ≥ 4 . Agitation was evaluated using the Ricker sedation-agitation scale and emergence agitation was defined as a sedation-agitation score ≥ 5 .
Sample size calculation
Study sample size was calculated according to our previous studies [3,8], we estimated an incidence of PONV of 50% in the control group for this patient population. A sample size of 55 patients in each group was needed to detect a 50% reduction in the incidence of PONV (from 50 to 25%) with a power of 80% and a two-sided α error of 0.05. To allow for a possible dropout rate of 10%, we aimed to enrol 61 patients in each group.
Categorical data are expressed as number (percentage) and were analysed using the 2 test or the Fisher’s exact test as appropriate. Continuous data are expressed as means (standard deviation [SD]) or medians (interquartile range [IQR]) and were analyzed with the unpaired Student’s t-test or Mann –Whitney U test as appropriate. A two-sided P value less than 0.05 was considered statistically significant. Statistical analysis was performed using the SPSS 22.0 software (SPSS, Inc., Chicago, Illinois, USA).