Effects of Different Doses of Esketamine on Pain Sensitivity of Patients Undergoing Thyroidectomy: A Randomized Controlled Trial

Study Design and Settings

This study was a double-blind randomized controlled clinical trial. It was performed at the First Affiliated Hospital of Zhengzhou University from 9 June 2022 to 31 August 2022. The study was approved by the ethics committee of the First Affiliated Hospital of Zhengzhou University (2021-KY-0858–002), which was registered at www.chictr.org.cn (no. ChiCTR-2200060741, registration data June 09, 2022). This study protocol was performed according to CONSORT guidelines. Before surgery, all participants signed an informed consent form.

Participants

This study enrolled 117 patients. Inclusion criteria: patients scheduled for elective thyroidectomy under general anesthesia, aged 18–60 years, any sex, American Society of Anesthesiologists (ASA) physical status I or II, and body mass index (BMI) of 18–30 kg·m−2. Exclusion criteria: history of thyroid surgery or hyperthyroidism, hypertension or coronary heart disease, chronic pain, opioid drug abuse, allergy to esketamine, renal or liver dysfunction, psychiatric disorders, neurological disease, or refusal to participate in the study.

Based on the random number, all participants were randomly divided at a ratio of 1:1:1:1 into four groups: C, RK1, RK2, RK3. We used the SPSS 26.0 software package (IBM SPSS, Chicago, Illinois, USA) to generate random numbers. An independent nurse divided the patients according to the recruitment sequence and the random number, prepared the study drug, and provided it to the anesthesiologist. The anesthesiologists and investigators responsible for postoperative follow-up were blinded to the group assignments.

Von Frey filament (Stoelting, Wood Dale, IL, USA) is a classic noninvasive tool and widely used in laboratory and clinical studies [20]. Von Frey was used to measure the pain threshold to determine the occurrence of hyperalgesia in this study. All Von Frey filament tests were performed by the same investigator. The measurement environment was quiet and the patient lay flat and relaxed. The tip of the Von Frey filament was placed in contact with the skin surface at right angles, and pressure was applied to bend the filament for 2 s. Pressure was applied from the 60 g filament, when the patient’s sensation changed from light touch to tingling, it was the mechanical pain threshold of the patient. The measurements were repeated at the same position at intervals of 10 s. Mechanical pain threshold around thyroid incision: the mean value was measured 2 cm below the incision midpoint and at both ends of the incision, and non-dominant forearm: the mean value was measured on the skin at 3, 6, and 9 cm from the anterior elbow crease on the medial forearm [21, 22]. A lower mechanical pain threshold indicates greater sensitivity to pain and a lower postoperative pain threshold indicates hyperalgesia.

Protocol

All patients fasted routinely before surgery. Electrocardiography (ECG), noninvasive blood pressure (NBP), oxygen saturation (SpO2), and BIS pectrum index (BIS) were routinely monitored and recorded every 3 min. All patients were injected with 10 ml study drug 5 min before anesthesia induction.

Anesthesia induction: All patients received intravenous propofol (21,121,531, Yangzijiang Pharmaceutical Group Co., Ltd.) 2 mg·kg−1 and remifentanil (20A02171, Yichang Renfu Pharmaceutical Co., Ltd.) 1.5 µg·kg−1. Rocuronium (EA2194, Zhejiang Xianju Pharmaceutical Co., Ltd.) 0.6 mg·kg−1 was injected after the patient lost consciousness. Mechanical ventilation was provided following endotracheal intubation. Anesthesia maintenance: 0.3 µg·kg−1·min−1 remifentanil was continuously pumped intravenously, and 1.5% sevoflurane (22,060,531, Jiangsu Hengrui Medicine Co., Ltd.) was inhaled. During the surgery, the anesthesiologist adjusted the inhalation concentration of sevoflurane on the basis of vital signs and BIS target value of 40–60. Heart rate and mean arterial pressure of the patients were maintained within 20% of baseline. Vasoactive drugs were administered when necessary. Palonosetron (210830CA, Jiangsu Hengrui Medicine Co., Ltd) 0.25 mg was intravenously injected 30 min after the surgery began. Remifentanil and sevoflurane were stopped immediately after surgery. All patients were resuscitated in the postanesthesia care unit (PACU). The nurse assessed the patient’s state of consciousness by calling or patting the shoulder every 3 mins. When the patient was fully awake, swallowing and cough reflexes recovered completely, and breathing air SpO2 was greater than 90%, the endotracheal tube was extubated. Extubation time was recorded. If the NRS score was greater than 4 or the patient required rescue analgesia, flurbiprofen axetil 50 mg was administered.

Outcome Measures

The mechanical pain thresholds measured before surgery as well as at 30 min, 6 h, 24 h, and 48 h after surgery were this study's primary outcomes. NRS scores, the incidence of postoperative hyperalgesia, rescue analgesia, perioperative ephedrine and atropine use, and adverse reactions, including delirium, hallucinations, nausea ,and vomiting were recorded. Compared with the baseline, the postoperative mechanical pain threshold was significantly decreased, and we defined this as hyperalgesia.

Sample Size Calculation

The sample size was determined by the primary outcome of our previous study. The mean ± standard deviation (SD) mechanical pain threshold in groups C, RK1, RK2, and RK3 were 95.6 ± 22.4 g, 101.7 ± 24.5 g, 140.3 ± 50.1 g, and 141.0 ± 41.4 g around the surgical incision 30 min after surgery. We calculated a sample size of 21 participants per group. The significance level was 0.05 (α = 0.05), and the power was 90%. Assuming a 30% attrition rate, we calculated that 30 participants would be required for each group. This study used the PASS 15.0 software (Stata Corp. LP, College Station, Texas, USA) to calculate the sample size.

Statistical Analysis

Kolmogorov–Smirnov test and histograms were used to verify the normal distribution of the data. Quantitative variables were presented as mean ± SD and analyzed using Student's t-test, or median [interquartile range (IQR)] and analyzed using the Mann–Whitney U test. Categorical variables, specified as frequency (f) and number (%), were compared using Pearson’s chi-squared test or Fisher’s exact test. Mechanical pain thresholds were analyzed using two-way repeated measures ANOVA with Bonferroni post hoc comparison. NRS scores were analyzed using the Kruskal–Wallis test. We also used post hoc pairwise comparisons of NRS scores of the four groups at each time point after surgery, and the significance criterion was P < 0.0083 after Bonferroni correction. Hyperalgesia incidence, rescue analgesic requirement, and adverse reactions was compared among the four groups using the Pearson’s chi-squared test or Fisher’s exact test. A P-value < 0.05 was considered statistically significant.

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