Ethics
This randomized controlled trial was approved by the Institutional Review Board of Seoul National University Hospital (number: H-2106-149-1230, date: July 22, 2021) and registered at ClinicalTrials.gov (NCT number: 05005715, date: August 13, 2021). This study followed the Good Clinical Practice guidelines, and the manuscript was written according to the applicable Consolidated Standard of Reporting Trials guidelines. Written informed consent was obtained from all patients before their participation in the study.
Subjects
Patients aged 20–65 years with NFPA who were scheduled to undergo ETS under general anesthesia were included in this study. Patients who had a contraindication to dexmedetomidine (known hypersensitivity to dexmedetomidine, uncontrolled hypertension, severe left ventricular dysfunction, and second- or third-degree heart block); a previous history of ETS within a year; coagulopathy; psychiatric disorder; difficulty in completing the QoR-15 questionnaire; myasthenia gravis or myasthenic syndrome; history of hypersensitivity to propofol, remifentanil, and rocuronium; pregnancy; or breastfeeding were excluded. Patients who had undergone preoperative steroid replacement were also excluded.
Randomization
Group randomization using computer-generated four-sized blocks was performed by an anesthesiologist who was not involved in the study. The patients were randomly assigned to either the dexmedetomidine or control group based on the allocation sequence in a 1:1 ratio. The allocation sequence was contained in sealed envelopes and disclosed before anesthesia induction by a nurse in charge of preparing the study or control drugs in the same volume. As a result, the anesthesiologists, surgeons, and patients were blinded to the randomization.
Study protocol
Before surgery, the serum levels of pituitary hormones (adrenocorticotropic hormone [ACTH], cortisol, triiodothyronine [T3], thyroxine [T4], thyroid stimulating hormone [TSH], growth hormone [GH], insulin-like growth factor 1 [IGF-1], luteinizing hormone [LH], follicle-stimulating hormone [FSH], and prolactin) were measured, and preoperative QoR was evaluated using the QoR-15 questionnaire.
The patients entered the operating room without premedication and were monitored using pulse oximetry, electrocardiography, and noninvasive blood pressure measurements. Anesthesia was induced with continuous infusion of propofol (effect site concentration: 4 µg/mL) and remifentanil (effect site concentration: 4 ng/mL) using a target-controlled device (Orchestra base primea, Fresenius Kabi, Bad Homburg, Germany). After confirming loss of consciousness, rocuronium (0.6–0.8 mg/kg) was administered to facilitate tracheal intubation. Intravenous acetaminophen (1,000 mg) was administered for preemptive analgesia. After tracheal intubation, an arterial catheter was placed in the patient’s radial artery for continuous blood pressure monitoring, and an additional peripheral venous catheter was placed in the patient’s forearm for fluid infusion and drug administration. During anesthetic maintenance, the effect site concentrations of propofol and remifentanil were adjusted to maintain blood pressure within ± 20% of preoperative value and a bispectral index of 30–60. Rocuronium was not administered after tracheal intubation. Mechanical ventilation was controlled to maintain normocapnia.
After anesthetic induction, in the dexmedetomidine group, a loading dose of dexmedetomidine at 1 µg/kg was administered intravenously over 10 min, followed by a maintenance dose of dexmedetomidine at 0.5 µg/kg/h continuous infusion until the end of surgery [12]. In the control group, normal saline was intravenously administered with the same loading volume of dexmedetomidine for 10 min and continuously infused at the same maintenance dose of dexmedetomidine until the end of surgery.
When tumor resection began, blood samples were collected to measure intraoperative pituitary hormones (ACTH, cortisol, T3, T4, TSH, GH, IGF-1, LH, FSH, prolactin, and antidiuretic hormones [ADH]) in both groups. Intraoperative serum interleukin-6 (IL-6) levels were simultaneously measured. Intravenous ramosetron (0.3 mg) and fentanyl (100 µg) were administered 30 min before the end of surgery to prevent postoperative nausea and vomiting (PONV) and postoperative pain. After surgery, patients underwent immediate postoperative brain computed tomography (CT) in the operating room. Subsequently, the administration of propofol, remifentanil, and either dexmedetomidine or normal saline was discontinued, and the patients were transferred to the neurointensive care unit without receiving any additional sedatives or neuromuscular blocking agents. After admission to the neurointensive care unit, immediate postoperative pituitary hormone (ACTH, cortisol, T3, T4, TSH, GH, IGF-1, LH, FSH, and prolactin) tests were conducted. Extubation was performed in the neurointensive care unit when the patients were alert and their spontaneous breathing had sufficiently recovered. The times to emergence and extubation were recorded.
Postoperative QoR was assessed using the QoR-15 questionnaire on postoperative day 1. Briefly, patients were asked 15 questions to assess five domains of patient-reported health status: physical comfort, physical independence, psychological support, emotional state, and pain. The 11-point numerical rating scale of 15 items has a minimum score of 0 (very poor recovery) and a maximum score of 150 (excellent recovery) [11]. Postoperative cortisol levels were measured on postoperative days 1, 2, and 3. Intravenous acetaminophen (1,000 mg) and oral acetaminophen (650 mg) were administered every 8 h before and after resuming oral fluids, respectively. If a patient complained of PONV, intravenous ramosetron (0.3 mg) or metoclopramide (10 mg) was administered. Postoperative pain scores were assessed using a numeric rating scale (NRS; 0, no pain; 10, worst pain imaginable) at 4, 24, and 48 h postoperatively. If NRS score of ≥ 4 was noted, a rescue analgesic (acetaminophen [1000 mg], ketorolac [30 mg], or fentanyl [50 µg]) was intravenously administered. The incidence of rescue analgesic administration and PONV was investigated at 4, 24, and 48 h postoperatively. The incidence of postoperative complications, such as diabetes insipidus, hyponatremia, infection, cerebrospinal fluid leakage, hemorrhage, and hydrocephalus, was noted. Postoperative pituitary function outcomes were investigated 3 months postoperatively.
Study outcomes
The primary outcome measure was the QoR-15 score on postoperative day 1. Secondary outcome measures included preoperative QoR-15 score, perioperative pituitary hormone levels (ACTH, cortisol, T3, T4, TSH, GH, IGF-1, LH, FSH, prolactin, and ADH), intraoperative serum IL-6 levels, postoperative pain scores, incidence of postoperative complications, and pituitary functional outcome at 3 months postoperatively.
ACTH deficiency was diagnosed in the following cases: serum cortisol < 18 µg/dL in the insulin-induced hypoglycemia test, peak cortisol < 18 µg/dL in the short ACTH test, morning cortisol < 8 µg/dL, or random cortisol < 5 µg/dL with a low to normal serum ACTH level [13]. TSH deficiency was defined as free T4 < 0.7 ng/dL with a low to normal TSH level [14]. GH deficiency was identified when peak GH < 3 ng/mL in the insulin-induced hypoglycemia test; if insulin-induced hypoglycemia test was not conducted, GH deficiency was determined by IGF-1 level below normal range, accompanied by deficiencies in ACTH, TSH, and gonadotropin [14]. Gonadotropin deficiency in men was defined as testosterone < 2.7 ng/mL with a low to normal FSH/LH level. In premenopausal women, gonadotropin deficiency was determined by the presence of menstrual disorders [14]. Normal menopause was defined as FSH > 30 mIU/mL and estradiol < 50 pg/mL in female patients with GN deficiency [14].
Sample size calculation
In a previous study, postoperative QoR-15 score on postoperative day 1 was 134.3 ± 17.3 in patients who underwent elective craniotomy [15]. Assuming that postoperative QoR-15 score increases by 10% when dexmedetomidine is administered, a minimum sample size of 27 patients was needed in each group when setting the α and β to 0.05 and 0.2, respectively. Considering a drop rate of 15%, 64 patients were required.
Statistical analysis
Statistical analyses were conducted using the SPSS software (version 25, IBM Corp., Armonk, NY, USA). Categorical variables were presented as the number of patients (proportion), and continuous variables were presented as mean (standard deviation) or median (interquartile range). Pearson’s chi-square test or Fisher’s exact test was used to compare categorical variables based on the expected cell counts. For continuous variables, the Shapiro–Wilk test was first used to assess the normality of data distribution, and the Student’s t-test and Mann–Whitney U-test were used to compare normally distributed and skewed data, respectively. The time × group effects of perioperative pituitary hormone levels and postoperative pain scores were evaluated using repeated-measures analysis of variance. If a significant time × group effect was observed, Bonferroni correction with compensating for multiple comparisons was applied to compare the variables between the two groups at each time point: an alpha of 0.008 (0.05/6) was applied for perioperative serum cortisol levels, and 0.017 (0.05/3) was applied for perioperative serum levels of other pituitary hormones (ACTH, T3, T4, TSH, GH, IGF-1, LH, FSH, and prolactin) and postoperative pain scores. For other variables, p value < 0.05 was considered statistically significant.