This prospective, randomized, double-blinded, placebo-controlled trial was approved by the Samsung Medical Center Research Ethics Board, Seoul, Korea (SMC 2018–08–022-002), and was prospectively registered with an extension of the Clinical Trial Registry of Korea (http://cris.nih.go.kr; identifier, KCT0003636; principal investigator, Ji Seon Jeong) on November 21, 2018. This study was adhered to CONSORT guideline. One investigator identified eligible patients from the surgeon’s operating list and contacted them the day before surgery to inform them of the study protocol. Written informed consent was obtained from all participants. We enrolled 46 adult patients with American Society of Anesthesiologists Physical Status classification I to III scheduled for elective endoscopic transnasal transseptal TSA surgery for the excision of nonfunctioning pituitary adenoma between January 2019 and April 2019, at Samsung Medical Center, Seoul, Korea. We included only the patients with nonfunctioning pituitary adenoma that were not associated with clinical evidence of hormonal hypersecretion approved by preoperative hormonal tests. We excluded patients with adrenal disorder or pheochromocytoma, as well as those who refused to participate in this study, those with a history of cardiac, renal, or hepatic disease; preexisting atrioventricular block, conduction disorder, or arrhythmia; or allergy to study drugs. We further excluded patients scheduled to undergo planned biopsy of the tumor and revision surgery.
Randomization and blinding
A member of the Samsung Medical Center who was not otherwise involved in the study performed computer-generated block randomization (www.randomizer.org) at a 1:1 ratio: dexmedetomidine group (n = 23) and control group (n = 23). Allocation of patients to each study group was concealed in an opaque envelope that was opened only by the hospital pharmacist who was not involved in either perioperative management or outcome assessment. The hospital pharmacist prepared visually identical study solutions in 50-mL syringes and labeled them using deidentified study code names for double-blinding. The 50-mL syringes contained 2 mL of 200 mcg dexmedetomidine (Dexmedine Inj, Hana Pharmacy, Seoul, Korea) in 48 mL of 0.9% saline to make a total volume of 50 mL (4 mcg/mL) for the dexmedetomidine group, or 50 mL of 0.9% saline for the control group. All enrolled patients, the anesthesiologist performing perioperative management, care givers, every other observer assessing the patient outcomes, and one surgeon who performed all the surgeries were blinded to group allocation until the end of study.
Interventions and intraoperative management
After applying standard monitoring including electrocardiogram, non-invasive arterial blood pressure measurement, and pulse oximetry, all patients received standardized general anesthesia comprising propofol and remifentanil using syringe pump in target-controlled infusion (TCI) mode (Injectomat TIVA Agilia, Fresinius KABI, France) as a standard of our center. The pharmacokinetic sets used to calculate target effect-site concentrations (Ce) for propofol and remifentanil were Marsh and Minto models, respectively. Ce was set to 3–5 mcg/mL for propofol and 1–3 mcg/mL for remifentanil. During the maintenance of anesthesia, the propofol dose was adjusted to achieve a target bispectral index of 40–60, and the remifentanil dose was adjusted to maintain the mean arterial blood pressure and heart rate within 20% of the preinduction values. Immediately after the induction of general anesthesia, the patients underwent an arterial line cannulation for invasive continuous arterial pressure monitoring and blood sampling, and the study drugs were administered using a syringe pump until 30 min before the end of surgery. The dexmedetomidine group received intravenous dexmedetomidine at a loading dose of 1 mcg/kg over 10 min, followed by a maintenance dose of 0.2–0.7 mcg/kg/h. The maintenance dose of dexmedetomidine was started at a dose of 0.7 mcg/kg/h and was reduced by 0.1 intervals if there was no effect after treatment of hypotension or bradycardia. The control group received intravenous 0.9% saline at the same volume. To treat bradycardia (heart rate < 50 beats per minutes) or hypotension (decreases in mean blood pressure > 20%), the doses of propofol and remifentanil were adjusted first. If it was ineffective, intravenous atropine (0.25–0.5 mg) or ephedrine (2.5–5 mg) was administered for the treatment of bradycardia or hypotension, respectively. After that, we reduced the dose of dexmedetomidine lastly. All patients received 0.1 mg/kg of intravenous hydromorphone before the end of surgery for postoperative analgesia. TCI infusion was maintained until the end of surgery even though the study drug was stopped 30 min before the end of surgery. All patients were extubated after the end of surgery and prior to being transferred to the post-anesthesia care unit (PACU). All surgeries were performed by a single neurosurgeon .
After the end of surgery, the patients were transferred to the PACU, and stayed there until they met the PACU discharge criteria. Postoperative supplemental analgesia was standardized. Pain severity was measured at rest by using a numerical rating scale (NRS; 11-point scale where 0 = no pain and 10 = worst pain). Patients with NRS scores > 4 were treated using rescue analgesics comprising intravenous ketorolac 30 mg. If this was ineffective after 15 min, intravenous pethidine 25 mg was administered. Postoperative nausea or vomiting was treated using intravenous metoclopramide 10 mg. The level of sedation was assessed during the PACU stay by using the Richmond Agitation-Sedation Scale (RASS) , and the duration of sedation was defined as the time from the end of surgery to the time of reaching the score of 0 on the RASS at the PACU. The Glasgow Coma Scale (GCS) was measured at alert and calm state to assess the overall level of consciousness after surgery in PACU. Blinded PACU nurses recorded all PACU data, including opioid consumption, presence or absence of nausea or vomiting, pain scores, and GCS scores.
Blood samples (7 mL) for the measurement of plasma epinephrine and norepinephrine levels were collected through radial arterial cannulation at two predetermined time points: 10 min before surgery (T1), which corresponded to the time immediately after radial arterial cannulation, and the end of drug infusion (i.e., 30 min before the end of surgery) (T2). The collected blood samples were centrifuged, and the plasma and serum were separated and frozen at − 80 °C until analysis. Plasma concentrations of epinephrine and norepinephrine were analyzed by using high-performance liquid chromatography (HPLC) (Agilent 1200 HPLC system, Agilent Technologies, CA, USA) with electrochemical detection by a blinded laboratory investigator. An HPLC kit (Plasma Catecholamines by HPLC, Bio-Rad Laboratories, Hercules, CA, USA) including all reagents, calibrators, controls and column was used. The linear assay range was 10–2000 pg/mL for both epinephrine and norepinephrine. The intra- and inter-day assay precisions were coefficient of variation ≤10% at two concentrations for each analyte. We participated in the proficiency testing provided by the Korean Association of External Quality Assessments Service twice a year. Glucose level was measured using a blood gas/chemistry analysis device (RAPIDLAB1265, Siemens Healthcare Diagnostics Inc., Berlin, Germany) at the same predetermined time intervals (T1 and T2).
Intraoperative hemodynamic variables (mean blood pressure and heart rate) were automatically recorded in the electronic medical records. Intraoperative propofol and remifentanil consumption was also recorded.
The primary outcome was the change in perioperative serum norepinephrine level. The secondary outcomes included perioperative serum epinephrine and glucose levels, dexmedetomidine-related side effects (hypotension, bradycardia, and sedation), the incidence of postoperative nausea or vomiting, and postoperative pain score measured at discharge from PACU.
The sample size was calculated on the basis of the findings of a previous study by Aho et al.  The mean difference (standard deviation [SD]) in serum norepinephrine levels between the baseline and the highest level during surgery between patients who received intramuscular dexmedetomidine and those who received 0.9% saline was 2.2 (1.5) mcg/dL. We expected that, compared to the controls, patients receiving intravenous dexmedetomidine would show a reduction in serum norepinephrine level by at least 50% . We calculated that 21 patients per group were required to detect this degree of difference with a power of 80% and an α = 0.05. Considering a 10% dropout rate, we decided to enroll 46 patients in total.
After determining the normality of data distribution by using the Shapiro-Wilk test, continuous variables were analyzed using the t test or Mann-Whitney U test as appropriate. Parametric and non-parametric data were reported as mean ± SDs and median [interquartile ranges], respectively. Categorical variables were analyzed using the chi-square test or Fisher’s exact test. Bonferroni correction was used for multiple comparisons. Data analysis was conducted using IBM SPSS Statistics for Windows/Macintosh, Version 25.0 (IBM Corp., Armonk, NY, USA). For all analyses, a P-value < 0.05 was considered significant, and two-sided tests were used.
Availability of data and materials
The datasets generated and/or analysed during the current study are available from the corresponding author on reasonable request.