Study design
This study was approved by the Ethics Committee of the Affiliated Hospital of North Sichuan Medical College (2019ER(R)071-01) and registered at the Chinese Clinical Trial Registry (ChiCTR1900024801, Principal investigator: Qin Ye, date of registration: July 28, 2019). All the participants for this prospective, randomized, double-blind, single center clinical trial conducted signed the written informed consents and performed at the Affiliated Hospital of North Sichuan Medical College. All procedures adhered to the applicable CONSORT guidelines (Fig. 1).
Based on a computer-generated table of random numbers, patients were randomly divided into four groups, which used sealed envelopes indicating the allocation: the same volume of normal saline group (NS group), dexmedetomidine 0.4 µg/kg group (D1 group), dexmedetomidine 0.6µg/kg group (D2 group) and dexmedetomidine 0.8 µg/kg group (D3 group). Randomization was performed by an anesthesiologist who was not responsible for perioperative anesthesia management or data collection. The study drugs were administrated by an anesthetic nurse while the anesthesiologists who were responsible for anesthesia did not know the drugs.
Inclusion criteria
120 consecutive patients scheduled for elective LC, aged 18–60 years and with 18.5 kg/m2< body mass index(BMI)<28 kg/m2 and ASA physical classification status of I–II, were enrolled from July 2019 to November 2019.
Exclusion criteria
patients with a history of PONV, motion sickness, gastroparesis, bradycardia, atrioventricular block and severe cardiac dysfunction, diabetes, hypertension, coronary heart disease, liver and kidney function seriously damaged, chronic pain, upper respiratory tract infection, asthma, smoking, allergic to dexmedetomidine. Withdrawal criteria: conversion to open surgery, the operation time over 90 min, massive hemorrhage during surgery, patients refusing to participate.
Anesthesia
Before surgery, all patients fasted for solid food for 12h and clear liquids for 4h, with intramuscular injection of phenobarbital sodium 0.1g and scopolamine butylbromide 20mg 30min in advance. After entering the operating room, the peripheral vein was opened and 10ml/kg/h lactated ringer solution was administered intravenously. HR, systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse oximetry (SpO2), electrocardiography (ECG), end-tidal carbon dioxide (ETCO2) and bispectral index (BIS) were monitored. D1, D2 and D3 groups were provided with 10ml dexmedetomidine containing 4, 6 and 8ug/ml respectively, and the NS group was provided with 10ml normal saline. Dexmedetomidine or normal saline 0.1ml/kg was continuously intravenously injected for 10 min and followed by anesthesia induction. The induction of general anesthesia was administrated by intravenous midazolam 0.03 mg/kg, propofol 1.5-2 mg/kg, sufentanil 0.4 ug/kg and rocuronium 0.6 mg/kg. Then tracheal intubation was performed, followed by mechanically controlled ventilation. The pure oxygen flow was 2L/min, the tidal volume was 8ml/kg, the respiratory rate was 14 times/min and the inhalation/exhalation ratio was 1:2. Respiratory parameters adjusted according to ETCO2 maintained at 35-45 mmHg and SpO2 remained above 98%. Intraoperative anesthesia was maintained by sevoflurane and BIS values were remained at 40-60. After induction of anaesthesia for 40 minutes, 0.2ug/kg sufentanil and 0.2mg/kg rocuronium were added. Analgesics and muscle relaxant were discontinued 30min before the end of surgery and inhalation of sevoflurane was discontinued 10min before. Body temperature of the patients was maintained at about 36℃ during the operation. During surgery, all patients were placed in the position of head upward 30°, left inclination 15°, and abdominal pressure maintained at 12mmHg. After surgery, the patients met the indications of extubation (call for open eyes and tidal volume > 5 ml/kg), and then the catheter was extracted and transferred to the post-anesthesia care unit (PACU). When the blood pressure decrease was greater than 20% of the base value or SBP decreased to 80mmHg, ephedrine was given 6-10mg immediately. When the increase of blood pressure was greater than 20% of the base value or the blood pressure was up to 160/95 mmHg, urapidil 5-10 mg was administrated. When the HR was less than 50 beats per minute, atropine 0.3-0.5mg was given each time. When the HR was greater than 110 beats per minute, esmolol 10 mg was given. When PONV required medication, ondansetron 4 mg was administrated per time. And when the VAS ≥4, tramadol 2 mg/kg was given.
HR, SBP, DBP were measured and recorded at the time of the patients arriving at the operating room (T1), 1 min before intubation (T2), being intubated (T3), 5 min after intubation (T4), establishing pneumoperitoneum (T5), 5 min after establishing pneumoperitoneum (T6), being extubated (T7) and 5 min (T8) and 20 min (T9) after extubation. To record the incidence of hypotension and bradycardia during the operation, operation time (from cutting skin to dressing), anesthesia time (from anesthesia induction to removing the tracheal tube), spontaneous respiratory recovery time (from stopping inhalation of sevoflurane to spontaneous respiratory recovery) and extubation time (from stopping inhalation of sevoflurane to removing tracheal tube). To assess and record the occurrence and severity of cough during recovery period (grade 0: no cough; grade 1: mild, single cough; grade 2: moderate, frequent cough, lasting time<5s, no effect on extubation; grade 3: severe, continuous cough, lasting time≥5s, affecting extubation) [9]. To mark VAS scores (where VAS 0 = no pain, and VAS 10 = worst pain) and PONV (A 4-point scale:1 = absent; 2 = nausea; 3 = retching; and 4 = vomiting) at 20min(t1), 2h(t2), 6h(t3), 12h(t4), 24h(t5), 48h(t6) after operation. Other indicators were recorded, such as postoperative analgesia dosage, agitation, shoulder pain, sleepiness, dizziness and hoarseness.
Statistical analysis
A Previous study has shown that the incidence of cough is 66.7% during the tracheal extubation period in the CON group [4]. We hypothesized that dexmedetomidine infusion before induction could reduce the incidence of cough during emergence by 50% (a power of 80% and α of 0.05), 30 patients required in each group. On account of the 10% drop-out, 33 patients were needed for each group.
Statistical analysis was performed by using SPSS 23.0 statistical software. Continuous variables with normal distribution were expressed as mean ± standard deviation (ẋ ± s), comparison among groups was performed by one-way ANOVA with a post hoc analysis, comparison at different time points was performed by repetitive measurement and analysis of variance with a Bonferroni correction, and categorial variables was determined by Pearson’s X2 test or Fisher’s exact test. P-value <0.05 was considered to statistically significant.