The present prospective trial was done with the approval of the Ajou University Hospital Institutional Review Board (AJIRB-MED-OBS-18-170) and registered at ClinicalTrials.gov (ref no.: NCT03622502). Written informed consent was obtained from all participants. Patients with American Society of Anesthesiologists (ASA) physical status scores of 1 or 2 between the ages of 19 to 65 years who had planned septoplasty or endoscopic sinus surgeries were enrolled. Participant exclusion criteria were a potentially difficult airway (Mallampati class 3 or 4), use of angiotensin converting enzyme-inhibitors, severe obesity (body mass index > 35 kg/m2), current smoker, a recent upper airway infection, asthma, and uncontrolled hypertension. According to a randomization generator (http://www.random.org), patients were randomized into a saline group (Group S) or a dexmedetomidine group (Group D).
After patients entered the operating room (no premedication), anesthetic monitoring including non-invasive blood pressure (BP), electrocardiogram, and pulse oximetry monitoring was applied. To monitor the depth of anesthesia, a bispectral index (BIS) sensor was also applied to the patient’s forehead. For anesthesia induction, target-controlled infusion (TCI) was started (propofol Ce of 5.0 µg/mL and remifentanil Ce of 4.0 ng/mL) using an infusion device (Orchestra, Fresenius Vial, France). Two min after administration of rocuronium (0.6 mg/kg), endotracheal intubation was performed using a cuffed tube (inner diameter of 7.5 mm in males and 7.0 mm in females) with a cuff pressure of 20–25 mmHg.
Anesthesia was maintained with propofol Ce of 2.0–3.0 µg/mL and remifentanil Ce of 3.0–5.0 ng/mL. Anesthetic depth was adjusted from a BIS value of 40 to 60. Intraoperative heart rate (HR) and BP were adjusted to within 20% of baseline (before induction of anesthesia). When HR dropped below 45 bpm, atropine (0.5 mg) was administered. When mean BP decreased to less than 20% of baseline mean BP, ephedrine (6 mg) was administered.
Dexmedetomidine (0.5 µg/kg) in Group D and the same volume of normal saline in Group S were infused over 10 min using a syringe pump before completion of surgery. Upon completion of surgery, propofol infusion was halted. Throughout emergence, remifentanil infusion of predetermined Ce was continued for at least 15 min until extubation. Drugs were administered by one researcher (JY Kim) according to the patient’s group identity (dexmedetomidine or normal saline and a pre-determined Ce of remifentanil). Patients’ degree of muscle relaxation was assessed using train-of-four (TOF) monitoring. When the TOF ratio was more than 90%, neostigmine (0.02 mg/kg) and glycopyrrolate (0.004 mg/kg) were injected. Subsequently, assisted ventilation with 100% of inspired oxygen was initiated in response to spontaneous patient breathing. When the patient opened their eyes spontaneously or in response to a verbal command, we confirmed that their spontaneous breathing was sufficient and removed their endotracheal tube. Thereafter, remifentanil was stopped and a facial mask delivering 100% oxygen was applied. The patient was transferred to a post-anesthetic care unit (PACU) after confirming the adequacy of their consciousness and respiration over a 5-min period. In the PACU, the patient was assessed for postoperative nausea and vomiting (PONV). Patient pain was evaluated using a numeric rating scale (NRS), which ranges from 0 (no pain) to 10 (worst possible pain). If the patient suffered from pain rated worse than a 5 or requested painkiller administration, fentanyl (50 µg) was injected. Sedation was also evaluated using a modified Wilson sedation scale [11]. When the modified Aldrete score was ≥ 9, patients were transferred to the ward [12].
Patients were sequentially enrolled using a Dixon’s up-and-down allocation approach, as previously [13]. Patient enrolment continued until both groups reached at least 20 patients and six success-failure pairs. Cough was defined as a sudden expulsion of air with abdominal muscle contraction and classified into one of four grades (grade 0: no cough, grade 1: single cough, grade 2: more than one episode of non-sustained cough, grade 3: sustained and repetitive cough). Cough was assessed from the end of surgery to 5 min after extubation. The Ce of remifentanil was initiated with 2.0 ng/mL in each group. The next patient’s Ce of remifentanil was determined by the previous patient’s cough response. If the patient had no cough or a single cough (grade 0 or 1), we defined this as successful prevention of cough, and the pre-determined Ce of remifentanil for the next patient was lowered by 0.4 ng/mL. If cough was not successfully prevented (grade 2 or 3), we determined the result to be a failure at preventing cough, and the pre-determined Ce of remifentanil for the next patient was increased by 0.4 ng/mL.
During the operations, data on the Ce for propofol and remifentanil, mean BP, HR, pulse oximetry saturation (SpO2), BIS value, respiratory rate, and end-tidal CO2 (EtCO2) were collected at seven time points, namely, baseline (T0), immediately before (T1) and after (T2) the start of dexmedetomidine or saline infusion, upon operation completion (T3), at eye opening (T4), and immediately (T5) and 5 min (T6) after extubation. In addition, the intraoperative use of medications to control BP or HR was recorded.
Cough was assessed by one researcher (HY Kim), from whom patients’ group allocations and the predetermined Ce of remifentanil was concealed. The times elapsed between stopping propofol administration to eye opening (time to eye opening) and from stopping propofol administration to extubation (time to extubation) were recorded. For 5 min after extubation, bradypnea (respiratory rate < 8 breaths/min), laryngospasm, and desaturation (SpO2 < 95%) were recorded. In the PACU, respiratory rate, PONV, pain scores using the NRS, Aldrete score, sedation scale, and stay duration were recorded.
Statistical analyses
The EC50 and EC95 of remifentanil for preventing cough in Group D were the primary study outcomes. To obtain the EC50 by Dixon’s up-and-down method, at least six success-failure pairs and 20 patients were needed [14]. The EC50 of remifentanil was defined as the mean value of the mid-point for each failure-to-success pair. To obtain the EC95 of remifentanil, the isotonic regression method using a pooled-adjacent-violators algorithm and a bootstrapping approach was also used, as previously [15]. No overlap between two EC95 values at 95% confidence interval (CI) was considered a significant difference [16].
Categorical variables were analyzed using the chi-squared or Fisher’s exact tests, and continuous variables were analyzed using independent t-tests or Mann-Whitney U tests. Measured variables were repeatedly analyzed using the linear mixed model (LMM). When the model revealed a significant interaction between group and time, a post-hoc analysis was performed to identify time points which differed significantly. Data are shown as means ± standard deviations (SDs), medians (interquartile range, IQR), or numbers (frequency). A P-value less than 0.05 was considered significant. Statistics were analyzed with SPSS (version 25.0, IBM Corporation, Armonk, NY, USA) and R (version 3.2.5)