This randomized, double-blind, controlled study was conducted after approval of the Institutional Review Board of Chosun University Hospital (2014-04-004) and was registered at http://clinicaltrials.gov (registration number NCT02412150, 09/04/2015).
A total of 139 female patients who are undergoing elective total thyroidectomy under general anesthesia (ASA class 1-2, aged over 20-60 years) in our hospital were enrolled for the study. Patients with conditions as follows were excluded: risk of a difficult airway, history of respiratory disease, chronic cough, or cardiovascular disease, pregnant or breast-feeding woman. All patients agreed to participate in the study after careful explanation and written informed consent for the participation of the study was obtained. Random allocation of the recruited patients in a 1:1 ratio was done according to the computer-generated random numbers, and the sealed envelopes were prepared by an independent anesthesiologist. When the patients agreed to participate in the study, the envelopes were opened in sequential order and the patients were allocated according to the number into two groups: Group D (n=69), Dexmedetomidine (Precedex®, Pfizer, New York, NY) was administered (0.6 μg/kg/hr) after stopping the administration of remifentanil 15 minutes before the end of surgery; Group C (n=70): Normal saline was administered as a control in the same way. For the blindness, an independent nurse and anesthesiologist who does not participate in the anesthetic procedure prepared the study drugs and assessed outcomes. Dexmedetomidine which was diluted to a 50 mL volume (diluted as 0.2 μg/mL) and normal saline were prepared in a code labeled 50 mL syringe according to the coded number of the patients.
Patients were advised for the overnight fasting and premedicated intramuscular midazolam (0.05 mg/kg) before transfer to the operating room (OR). When the patients have arrived at the OR, a monitoring device (Carescape; GE Healthcare, USA) such as electrocardiogram, non-invasive blood pressure, pulse oximetry, neuromuscular monitoring sensor, and bispectral index (BIS) was applied. Induction of anesthesia was performed by the skilled anesthesiologist who was blinded to the allocation of the patient. For the induction, propofol 2.0 mg/kg was administered and targeted effect-site concentration (Ce) of remifentanil was adjusted as 2.0 ng/ml using a target-controlled infusion device (Orchestra® Base Primea, Fresenius-Vial, France) based on a Minto pharmacokinetic models. When the consciousness of the patient was lost, rocuronium bromide (0.8 mg/kg) was administered and endotracheal intubation with armored tube (internal diameter: 7.0 mm) was done after confirming the adequate neuromuscular blockade by train-of-four (TOF) ratio which became 0, and no neuromuscular blocker was used during the surgery. For the maintenance of anesthesia, desflurane with a 50% O2-air mixture was used and the end-tidal concentration of desflurane and the Ce of remifentanil were adjusted according to the BIS score (between 40–60) and vital signs (within 20% of baseline values). The initial tidal volume was set at 8 ml/kg with respiratory rates of 12 breaths per minute which were adjusted to maintain the end-tidal CO2 between 35-40 mmHg and peak inspiratory pressure below 28 mmHg.
When the surgeon informed the subcutaneous suture, which was about fifteen minutes before the end of the surgery, infusion of remifentanil is discontinued, and code labeled syringe was prepared and infused at a rate of 3 ml/kg/hr until the patient wakes up fully and transferred to the postanesthetic care unit (PACU). When the surgeon ended the suture, about five minutes before the end of the surgery, desflurane is discontinued and the patient was ventilated with 100% O2 (5 L/min) and fentanyl for the control of postoperative pain was administered with a patient-controlled analgesia instrument according to the hospital protocol (basal infusion, 0.625 μg/kg/hr without a loading dose; intermittent bolus, 1.0 μg/kg/hr; lockout time, 15min). After the use of reversal agents (pyridostigmine 0.15 mg/kg with glycopyrrolate 0.2 mg/5 mg of pyridostigmine), the recovery from the neuromuscular blockade was confirmed using a neuromuscular monitor (TOF ratio >99%). During the recovery, the patients were asked to open their eyes by the verbal request without any other stimulation or disturbance. When the patient restored spontaneous ventilation and consciousness (BIS score became over 90), careful extubation was done while avoiding irritation and the patient was transferred to the PACU.
The primary outcome of the study was measuring the amount of postoperative bleeding for 3 consecutive days. The amount of postoperative bleeding which is collected in the drainage system was measured by an independent nurse before leaving the PACU and also measured at the ward per 24 hours of time interval. Secondary outcomes such as vital signs, extubation time, recovery time, cough reflex, Ramsay Sedation Scale (RSS), 11-point numeric rating scale (NRS, 0 = no pain and 10 = worst pain imaginable) for the pain measurement, etc. were assessed by independent anesthesiologist and surgeon. The patient’s characteristics, duration of surgery, duration of infusion of study drugs, and the amount of fluid administration during the surgery were recorded. Vital signs such as mean blood pressure (MBP) and heart rate (HR) are measured according to the time interval as follows: T0, before administration of study drugs; T1, 5 minutes after administration of study drugs; T2, 10 minutes after administration of study drugs; T3, 5 minutes after administration of study drugs; T4, just before extubation; T5, 5 min after extubation; T6, after arrival at PACU. During the recovery from the anesthesia (time interval from discontinuing the desflurane to transfer to PACU), coughing reflex was measured and graded according to the severity (Grade 0, no cough; Grade 1, single cough with mild severity; Grade 2, cough persistence less than 5 s with moderate severity; Grade 3, severe, persistent cough for more than 5) . Extubation time (time interval from discontinuing the desflurane to extubate) and recovery time (time interval from discontinuing the desflurane to transferred to the ward) were assessed. About 5 minutes after arrival at the PACU, RSS of the patient is measured as follows: 1, patient anxious and agitated or restless or both; 2, patient cooperative, oriented and tranquil; 3, the patient responds to commands only; 4, asleep or a brisk response to a light glabellar tap or loud auditory stimulus; 5, sluggish response to a light glabellar tap or loud auditory stimulus; 6, no response to a light glabellar tap or loud auditory stimulus . Then, the patients were also classified according to the RSS as follows: agitated, RSS 1; Calm, RSS 2-3; Sedated, RSS 4-6 . In the PACU, the incidence of desaturation (<90%) was assessed as an adverse effect of dexmedetomidine. After the patient was transferred to the ward, the amount of postoperative bleeding and pain score using NRS were assessed daily until the third postoperative day (POD). The duration of the drainage catheter placement after surgery was recorded.
The sample size was calculated using "G*Power3" free software. The effect size was calculated based on a previous study in which the incidence of cough was 55% after a single use of dexmedetomidine infusion . The total sample size was calculated as 136 with the calculated effect size of 0.441, α = 0.05, and a power of 80%. The drop-out rate was assumed as 10% and 70 patients were allocated to each group.
Statistical analyses were performed using SPSS 21.0 (IBM Corporation, Somers, NY, USA). The normality test was done using the Kolmogorov-Smirnov test and the Shapiro-Wilk test. Values are expressed as the mean (SD), median [interquartile range], or the number of patients (%) with exact P values. Normally distributed data (age, height, weight, and BMI) were analyzed with Student’s t-test. Non-normal distributed data (duration of surgery, amount of intraoperative fluid, infusion duration of study drug, extubation time, recovery time, and duration of the drainage catheter placement) were analyzed using Mann–Whitney U-test. Categorical variables (ASA class, coexisting disease, grades of cough response, the incidence of severe cough, and RSS) were analyzed by the Chi-square or Fisher’s exact test. The change in vital signs, NRS score, and amount of postoperative bleeding according to the time sequence were analyzed by repeated-measures two-way ANOVA, and post-hoc testing was performed using the Mann–Whitney U-test. A P value less than 0.05 was considered statistically significant between the two groups.