Methods
Study Design
This prospective randomized controlled trial was approved by the Ethics Committee of the Second Affiliated Hospital of Anhui Medical University (approval no.: YX2021-106) and was prospectively registered in the Chinese Clinical Trial Registry (ChiCTR2100053459) on November 21, 2021. The study was conducted from December 2021 to May 2022 in the Department of Anesthesiology and Perioperative Medicine at the Second Affiliated Hospital of Anhui Medical University. This study was conducted in accordance with the Consolidated Standards of Reporting Trials (CONSORT) criteria10 and in compliance with the Helsinki Declaration. Written informed consent was obtained from all the patients.
Patients scheduled to undergo elective thyroidectomy were enrolled in this study. The inclusion criteria were age between 18 and 65 years and American Society of Anesthesiologists physical (ASA) status of I–II. The exclusion criteria were body mass index (BMI) >30 kg m-2, preoperative analgesic and sedative medication, unstable ischemic cardiac disease, severe pulmonary hypertension, uncontrolled hypertension, increased intracranial or intraocular pressure, liver and kidney dysfunction, history of chronic pain, psychiatric disorders or alcohol abuse, allergy to medication used in the study, pregnancy, and lactation.
The enrolled patients were randomly assigned to either the control group (Group CON) or the esketamine group (Group KET) using software at a 1:1 ratio. An assistant who was not associated with the study performed random allocation by preparing coded and sealed opaque envelopes for allocation concealment. A nurse unaffiliated with patient care opened the envelopes shortly before induction and prepared the study medication outside the operating room. The agent used for this study was diluted with NaCl (0.9%) to yield two study drug syringes: a 10-mL syringe containing either 5 mg/mL esketamine or NaCl (0.9%) and a 50-mL syringe containing either 1 mg/mL esketamine or NaCl (0.9%), which were identical in appearance and were labeled as “study medication” with patient number. Thereafter, patients, anesthesiologists, nurses providing postoperative care, surgeons, investigators, and outcome assessors were blinded to the patients’ group allocation and did not have access to randomization until the data analysis was complete.
Based on the assigned group, patients in Group CON received a bolus of 0.1 mL kg-1 intravenous NaCl (0.9%) immediately before incision, followed by NaCl (0.9%) infusion of 0.24 mL kg-1 h-1, which continued until the beginning of wound closure. Patients in Group KET received a bolus of intravenous esketamine (0.5 mg kg-1) immediately before incision, followed by esketamine infusion of 0.24 mL kg-1 h-1 (corresponding to an esketamine dose of 0.24 mg kg-1 h-1) that continued until the beginning of wound closure. An anesthesiologist injected the bolus dose from a 5-mL syringe before incision and initiated infusion from the 50-mL syringe.
After arrival in the operating room, intravenous access was established and vital parameters, including heart rate (HR), electrocardiogram, blood pressure, and pulse oximetry, were monitored throughout the surgery. Intravenous dexamethasone (8–10 mg) was administered to prevent postoperative nausea and vomiting (PONV). General anesthesia induction and tracheal intubation were performed using midazolam (0.05 mg kg-1), sufentanil (0.4 μg kg-1), etomidate (0.3 mg kg-1), and rocuronium (0.9 mg kg-1). Parecoxib sodium (40 mg) was administered after induction for pre-emptive analgesia. Maintenance of anesthesia was achieved by continuous infusion with propofol (4–6 mg kg-1 h-1) and remifentanil (0.15–0.25 μg kg-1 min-1). Muscle relaxation was achieved by weight-adjusted atracurium dosing by the attending anesthesiologist. The assessment of the depth of anesthesia was based on clinical evaluation by the anesthesiologist, and a bolus of sufentanil (5–10 μg) was administered when the patient’s HR or blood pressure increased by >20% from basal measurements. At an appropriate depth of anesthesia, an intermittent bolus of urapidil was administered if the mean arterial pressure (MAP) was >90 mmHg or evaluated by >20% of baseline values. Esmolol was administered if HR was >120 bpm. In case of hypotension, defined as MAP <60 mmHg or reduction by >20% of baseline values, additional fluid and an intermittent bolus of ephedrine were administered. Atropine was administered to patients with severe bradycardia (HR <50 bpm). The dosage of vasoactive agent was at the discretion of the anesthesiologist.
All patients were transferred to the post-anesthesia care unit (PACU) for recovery after extubation. A nurse blinded to the protocols evaluated the pain intensity at rest and coughing using an 11-point numeric rating scale (NRS), which ranged from “0” (meaning no pain) to “10” (meaning worst pain imaginable). When the NRS score was ≥4 or patients verbalized the need for additional pain relief, the attending anesthesiologist reviewed and provided intravenous boluses of sufentanil at 0.1 μg kg-1 for rescue analgesia. The level of alertness/sedation was assessed using the Richmond Agitation Sedation Scale (RASS) 30 min postoperatively. The RASS is a 10-point scale ranging from −5 to +4. A score of −5 denotes a patient who does not respond to voice or physical stimulation, 0 characterizes a calm and alert patient, and +4 denotes a combative and violent patient who poses danger to the staff.11 MAP and HR were recorded perioperatively. Once the PACU discharge criteria were met, patients were transferred to the ward and non-steroidal anti-inflammatory drugs were provided to the patients as needed for pain relief, as reviewed and decided by the attending surgeons.
The opioid-related side effects of PONV and psychotomimetic side effects of nightmares, hallucinations, dizziness, and diplopia were assessed postoperatively. Rescue droperidol was administered for PONV, and psychotomimetic side effects were treated and monitored until discharge according to hospital service guidelines. Patients were interviewed 24 h postoperatively by the attending anesthesiologist using the following questionnaire: 1. What is the last thing you remember before going to sleep? 2. What is the first thing you remember waking up? 3. Do you remember anything between going to sleep and waking up? 4. Did you dream of the procedure? 5. What was the worst thing about your operation?12
The primary outcome was perioperative sufentanil consumption. Secondary outcomes included the NRS pain scores at rest and coughing, evaluated at 0.5, 2, 4, 6, 12, and 24 h postoperatively; quality of sleep in the night following surgery, evaluated using a 4-point scale (1, slept well; 2, disturbed sleep; 3, nightmares; 4, sleepless); time to extubation, defined as time from the end of surgery to extubation; incidences of PONV and psychotomimetic side effects; incidences of hemodynamic instability events; and chronic pain scores in 3 month postoperatively.
Statistical Analysis
The sample size of the study was calculated using PASS V.15.0 (NCSS, Kaysville, UT) for Windows. According to a previous study showing that patients receiving ketamine required 24% less intraoperative opiate medications,13 we accepted that at least a 20% reduction in perioperative sufentanil consumption was clinically significant. Based on the results of our pilot study with five patients in each group (mean sufentanil consumption was 32.0 μg and 25.5 μg for Groups CON and KET, respectively, using a pooled standard deviation [SD] of 5.7), two simple t-tests were performed and the group allocation ratio was 1:1. Considering a power of 0.90, an alpha error of 0.01, and a loss to follow-up rate of 20%, the required sample size for each group was calculated as 30. Therefore, 60 patients were included in the study.
All statistical analyses were performed using SPSS (version 24.0; IBM, Armonk, NY). Statistical significance was set at P<0.05. Kolmogorov–Smirnov tests were used to test the normality of the data distribution. Continuous variables are expressed as mean (SD) or median (interquartile range [interquartile range]). Student’s t-test was used to compare parametric variables with a normal distribution between the two groups. The Mann–Whitney comparison was used to compare parametric variables without a normal distribution. Categorical variables were expressed as numbers (percentages) and intergroup differences were assessed using chi-squared or Fisher’s exact tests, as appropriate.
Repeated measurements of intraoperative hemodynamic parameters and postoperative pain scores were analyzed using a linear mixed model14,15 to evaluate the association between dependent variables over time and esketamine infusion. The Wilcoxon matched-pairs signed-rank test was used for binary comparisons of sleep quality within groups.