This prospective, randomized, double-blind, controlled clinical trial was approved by the Institutional Research Ethics Committee of the Affiliated Hospital of Yangzhou University, Yangzhou, China. All the participants provided written informed consent following principles of the Helsinki Declaration. Also, this study was registered with ClinicalTrials.gov (NCT03126422).
One hundred and eighty patients, ASA I or II, aged 18 - 65 years, BMI 18.5-30 kg/m2, and scheduled for elective surgeries under general anesthesia between Oct 2017 and May 2018, were enrolled in the study. Exclusion criteria were patients with bradycardia (HR < 50 beats/min), hypotension, impairment of liver or kidney, smoking, asthma, chronic cough, upper respiratory tract infection within the previous 2 weeks, or use of medications that could interfere with this study such as angiotensin-converting enzyme inhibitors, bronchodilators, or steroids.
This study was randomly assigned to four groups with 45 patients each depending on the 10-min pretreated pumping dose of dexmedetomidine, using computer-generated random numbers: group 1 (0 μg•kg-1•min-1), group 2 (0.03 μg•kg-1•min-1), group 3 (0.06 μg•kg-1•min-1) and group 4 (0.09 μg•kg-1•min-1).
No premedication was used in all patients. Venous access was established on the wrist cephalic vein of the nondominant hand with a 20-G intravenous cannula after patients came into the pre-operation room and Ringers’ solution of 8 ml•kg-1•h-1 was transfused. The vertical distance from the drip bottle to the venous access was 80 centimeters in all the cases in this study. The IV cannula was connected to T-connectors for drugs infusion and injection in the operating theater. All patients were monitored with electrocardiogram, noninvasive blood pressure, and SpO2 during the whole study.
Anesthesia induction was standardized and the procedure consisted of the following. Dexmedetomidine (200 μg/2 ml; 181016BP, Hengrui Co., Jiangsu, China) was diluted with normal saline to a concentration of 4 μg/ml. Patients were given dexmedetomidine at a pumped infusion rate of 0, 0.03, 0.06, and 0.09 μg•kg-1•min-1 for 10 min in groups 1, 2, 3, and 4, respectively. In group 1, normal saline was used and the infusion rate was set at 50 ml/h. All the pretreatments were prepared and implemented by an experienced anesthesiologist who was not involved in data collection. Also, all the priming drugs and the infusion pumps were covered with a piece of sheet. Oxygen supply through facemask was given to all the patients. Assisted ventilation was supplied if SpO2 fell below 95% or decreased by 5% from initial value throughout the study. At 10 min after the beginning of pretreatment infusion, the pumping rate of dexmedetomidine was continued at 0.5 µg•kg-1•h-1 in all the groups. Meanwhile, fentanyl (50 μg/ml; 81D05031, Renfu Co., Hubei, China) 4 µg/kg with the injection time of 5 sec was given to all the patients. A stopwatch was used to control the time.
After fentanyl injection, the symptoms of irritating cough including the severity and onset time (the time from the end of fentanyl injection to the beginning of coughing) of cough were recorded for 1 min. Any occurrence of cough was identified as coughing. According to the number of coughs within 1 min after fentanyl injection, the severity of cough was classified to four grades: 0 (no cough), 1 (mild, 1-2 times), 2 (moderate, 3-5 times), and 3 (severe, > 5 times). The recording was done by an anesthesiologist who was unaware of the grouping criteria.
General anesthesia induction was continued following cough cessation or 1 min after fentanyl injection with midazolam 0.05 mg/kg, propofol 1.5-2.5 mg/kg and cisatracurium 0.2 mg/kg to facilitate endotracheal intubation or laryngeal mask insertion. Mechanical ventilation was controlled with tidal volume of 8 ml/kg, at a respiratory rate of 12 breaths/min. The beginning of pretreated-dexmedetomidine use was recorded at 0 min (T0). MAP, HR, and SpO2 were recorded at T0, 3 min (T1), 6 min (T2), 9 min (T3) and 12 min (T4) after the beginning of pretreatment. Side effects of dexmedetomidine, such as bradycardia, hypertension, hypotension, and respiratory depression were recorded during the course. Ephedrine was used if MAP < 60 mmHg or the decrease of MAP > 30% of the basal data. Atropine was used if HR < 50 beats/min or the decrease of HR > 30% of the basal data. The relevant measures taken to deal with the side effects were also recorded.
Sample size determination
In our preliminary study, the incidence of FIC was 48%. A power analysis was performed using the incidence of FIC as the primary variable. We hypothesized that certain dose of 10-min dexmedetomidine priming infusion could reduce the incidence of FIC to 15%. To detect this deference with 90% power at a 5% significance level, 40 patients would be necessary in each group. Therefore, we recruited 45 patients for each group to allow missing data.
Statistical analysis was performed using Statistical Product for Social Sciences (SPSS) software 19.0 for windows. Data were expressed as mean ± SD, number, proportion, or percentage. Quantitative variables were analyzed using one-way ANOVA with repeated measures between groups. One-way ANOVA and post Hoc Bonferroni multiple comparison test were used to compare differences of vital signs between groups after dexmedetomidine infusion and fentanyl injection. Ordinal data were compared with the Kruskal-Wallis test followed, when indicated, with Dunn’s multiple comparison tests. P value of < 0.05 was considered statistically significant.