Esketamine relieves postoperative depression and pain indicators in patients undergoing laparoscopic total hysterectomy

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Methods 135 patients undegoing total laparoscopic hysterectomy were recruited and randomly allocated to three groups. Finally, a total of 127 patients were selected into the statistical analysis, with the final grouping information as follows: sufentanil group (S1, n = 44), sufentanil combined with 0.25mg/kg esketamine group (SK1, n = 42) and sufentanil combined with 0.5mg/kg esketamine group (SK2,n = 41) intraoperatively, then the SK1 and SK2 group were maintained analgesia with esketamine 1 mg/kg patient-controlled intravenous analgesia(PCIA) postoperatively. The peripheral blood serum brain-derived neurotrophic factor (BDNF) level, 5-hydroxytryptamine (5-HT) level, Hamilton Depression Scale (HAM-D) scores, visual analogue scale(VAS) scores and the number of PCIA button pressed times in perioperative period were collected. Meanwhile, the postoperative adverse effects including nausea, vomiting, dizziness, respiratory depression and hallucinations were collected and compared between the three groups. Results Compared with S1 group, the SK1 and SK2 group showed significantly higher serum BDNF and 5-HT levels at the 1th day(d1), d2 and d5 after operation (P < 0.05), and revealed even higher at d1 and d2 after operation in SK2 group(P < 0.05). The HAM-D scores at d1, d2 and d5 post operation were significantly reduced in SK1 and SK2 group (P < 0.05) compared to S1 group, and decreased even lower at d1 and d2 postoperative in SK2 group(P < 0.05), but no significant difference was found among three groups at 1 day before and the d7 after operation. Simultaneously, the VAS scores decreased significantly in SK1 and SK2 group at the 1th hour(1h), 6h, 12h, 24h, and 48h after surgery (P < 0.05), and the PCIA button pressed times were also significantly reduced in SK1 and SK2 group (P < 0.05) during the postoperative 48 hours. Furthermore, the SK1 and SK2 group showed the lower dosage of remifentanil during the surgery(P < 0.05). However, the postoperative adverse effects had no statistical differences among the three groups. Conclusion Esketamine can relieve postoperative depression and pain indicators without the increasing of adverse effects in patients undergoing total laparoscopic hysterectomy. Moreover, the 0.5 mg/kg dosage intraoperatively may have the better alleviation property of depression-related indicators. Trial registration Chinese Clinical Trial Registry (ChiCTR2200065198) Esketamine Laparoscopic total hysterectomy Depression Pain Figures Figure 1 Background Depression has showed an increasing incidence in recent years, especially in the sick population[ 1 ]. A multicenter, large-sample study has reported that the incidence rate of depression in patients hospitalized for physical illness in China was 75.1%[ 2 ]. Laparoscopic total hysterectomy is a common gynecological procedure, which was known as “artificial menopause” and also has been found significantly related with the raised depression risk[ 3 – 4 ]. To date, the Hamilton Rating Scale for Depression(HAM-D) is still one of the gold standard tools which used to assess depression in clinical and related studies[ 5 ]. Recently, ketamine has attracted much attention due to its rapid antidepressant effect in perioperative period[ 6 – 7 ], which was primarily mediated by inhibiting N-methyl-d-aspartate receptors (NMDAR). But on the other hand, the administration of ketamine is associated with a prolonged awakening time and psychotic symptoms such as nightmares and hallucinations[ 8 – 9 ]. Esketamine is the dextro-split of ketamine, it shows double anesthetic-analgesic-hypnotic strength and plasma clearance. And moreover, it can significantly shortern the awakening time and low the incidence of psychiatric side effects[ 10 – 12 ]. Previous studies have confirmed that the bilateral voxel nuclei and cingulate-hippocampus in brain[ 13 – 15 ] and its related neurohumoral factors including 5-hydroxytryptamine (5-HT)[ 16 – 17 ] and brain-derived neurotrophic factor (BDNF)[ 18 – 20 ] were closely related with the development of depression. And the antidepressant efficacy was obviously associated with the structural changes and synaptic remodeling in cingulate-hippocampus[ 21 ]. In addition to this, recent evidences have shown that the acute and chronic pain may also be the vital factor in the development of postoperative depression[ 22 – 24 ]. Up to now, few studies have reported the antidepressant and pain relief effect of esketamine in postoperation of laparoscopic total hysterectomy. In this clinical trial, we aim to evaluate the impact of esketamine on postoperative depression and pain indicators including peripheral blood serum BDNF level, 5-HT level, 24-item HAM-D(HAM-D24), visual analogue scale(VAS) scores and the number of patient-controlled intravenous analgesia(PCIA) button pressed times in patients undergoing laparoscopic total hysterectomy. In the meantime, the postoperative adverse effects were also recorded and we try to provide some valuable references for medical practice of esketamine. Materials and Methods Ethics The Maanshan People's Hospital’s Ethics Committee approved this clinical study (No. 2021-006-003), which was also registered on the China Clinical Trial Registry, with the registration number ChiCTR2200065198 and registration date of October 31, 2022. All subjects provided informed consent prior to participation in the study.The study was conducted in accordance with the Helsinki Declaration (2013 October) and clinical practice guidelines. General information 135 patients who underwent planned laparoscopic total hysterectomy were recruited from Maanshan People's Hospital from November 2022 to December 2023, then randomly allocated to three groups through simple randomization using a computer-generated random sequence (randomization ratio 1:1:1): the sufentanil group (S1, n=44), sufentanil combined with 0.25mg/kg esketamine group (SK1,n=42) and sufentanil combined with 0.5mg/kg esketamine group (SK2,n=41) intraoperatively, then the SK1 and SK2 group were maintained analgesia with esketamine 1 mg/kg patient-controlled intravenous analgesia(PCIA) postoperatively. And a possible 10% attrition rate was considered. The inclusion criteria were as follows: (a) age ranged 30-60 years; (b) body mass index (BMI) ranged 18-30 kg/m 2 ; (c) HAMD score ranged 8-20; (d) followed the criteria defined by the American Society of Anesthesiologists (ASA) for classification as class I-II; (e) the preoperative score of Mini Mental Status Examination (MMSE) was greater than 27 points; (f) approved to voluntarily participate in the investigation and the provision of informed consent for trial participation. The exclusion criteria were as follows: (a) patients with confirmed psychiatric disorders such as diagnosed depression, mania and schizophrenia; (b) patients with chronic cardiac insufficiency (NYHA class III-IV); (c) patients with abnormal liver and kidney function (ALT, AST>3 times the upper limit of normal; estimated glomerular filtration rate less than 60ml/min/1.73m 2 ); (d) severe visual, speech or hearing impairment; (e) increased abnormal intracranial pressure or intraocular pressure; (f) long-term or recent use of sedatives, analgesics, nonsteroidal drugs, glucocorticoids, psychotropic drugs, alcohol or drug abuse; (g) allergy to any of the study drug components. Anesthesia method Series of medical procedures were initiated since the admission of patient to the operating theater, including administration of oxygen, establishment of peripheral venous access and monitoring of various physiological parameters involved noninvasive blood pressure, pulse oximetry, electrocardiogram, body temperature, intraoperative partial pressure of end-expiratory carbon dioxide (PetCO2) and depth of anesthesia (bispectral index [BIS]). General anesthesia was administered through a combination of intravenous and inhalation anesthesia. Rapid intravenous anesthesia was induced with etomidate at a dosage of 0.3 mg/kg, sufentanil at a dosage of 0.3~0.4 μg/kg, midazolam at a dosage of 0.05 mg/kg, and rocuronium at a dosage of 0.6 mg/kg. 2 minutes later, endotracheal intubation and mechanical control of breathing were initiated. Before surgical skin incision, the S1, SK1, and SK2 group received 0.1 µg/kg sufentanil, 0.1 µg/kg sufentanil combined with 0.25 mg/kg esketamine(Lot number:221019BL,Jiangsu Hengrui Medicine Co., Ltd., China), and 0.1 µg/kg sufentanil combined with 0.5 mg/kg esketamine intravenously, respectively. Anesthesia was maintained with 0.5%~1.5% sevoflurane, 3~4 mg/(kg·h) propofol, and 0.2~0.4 μg/(kg·h) remifentanil. The BIS value was preserved between 40~60 intraoperatively, and the concentration of anesthetic drugs was based on blood pressure, heart rate and changes in patient’s other related vital signs. Intermittent administration of Rocuronium bromide at a dosage of 0.15 mg/kg was performed, and discontinued at 45 minutes prior to the completion of the surgical procedure. A further dose of 0.1 µg/kg sufentanil was administered, and sevoflurane inhalation was terminated once the peritoneum was closed. The PCIA system was linked at 10 minutes prior to the end of the surgical procedures. The administration of postoperative PCIA was performed that the S1 group received 2 μg/kg of sufentanil, the SK1 and SK2 groups received a combination of 2 μg/kg of sufentanil and 1 mg/kg of esketamine, and 0.9% sodium chloride solution was utilized to dilute each solution to 100 milliliter(mL). The parameters of PCIA were as follows: first dose, 2 mL; background infusion, 2 mL/h; 1 ml for each self-controlled dose; lock time, 10 min; limit, 10 mL/h. All participants were sedated with 10mg of azelastine at 10mins before the completion of surgical procedure and then sent to the anesthesia resuscitation unit (PACU) after surgery, and we controlled all patients’ postoperative VAS scores within 3 points. Observation indicators All patients’ age, BMI, ASA classification, education level, marital status, childbirth status, operation time, anesthesia time, intraoperative bleeding, and intraoperative anesthetic dosage were recorded. HAM-D scores, peripheral blood serum BDNF and 5-HT levels were collected at 1 day before, the 1th day(d1), d2, d5 and d7 after the operation, respectively. The patients’ VAS scores were recorded at the 1th hour(1h), 6h, 12h, 24h, and 48h after operation; the total number of PCIA button presses and the incidence of adverse reactions including nausea, vomiting, dizziness, respiratory depression and hallucinations were collected during the postoperative 48 hours. The primary outcomes were the HAM-D scores, VAS scores, BDNF and 5-HT levels, with the PCIA button pressed times and the incidence of adverse reactions as the secondary outcomes. Sample Size Calculation The sample size was determined based on the primary outcome (postoperative HAM-D scores ). Using G*Power 3.1 with α=0.05, power=0.80, and effect size f=0.3 derived from prior studies [25], a minimum of 42 patients per group was required for one-way analysis of variance(ANOVA). Accounting for 10% attrition, we recruited 45 patients per group (total N=135). Post-hoc analysis confirmed >80% power with 127 valid cases included in the final analysis. Statistical methods Statistical analysis was performed using statistical package for social sciences(SPSS) 22.0. The normal distribution data were expressed as mean ± standard deviation. One-way ANOVA was used for comparing multiple groups, Kruskal-Wallis H-test for comparing multiple groups of rank data, chi-square test and fisher test were used for comparing rates. A statistically significant variation was determined to be present when P< 0.05. Results Participate Figures Finally, a total of 127 patients were selected into the statistical analysis, with the final grouping information as follows: S1, n=44; SK1,n=42; and SK2,n=41 ( Figure 1 ). Basic preoperative information of patients There were no statistically significant differences in baseline preoperative data among the three groups (P>0.05) ( Table 1 ). Table 1. Comparison of basic preoperative information of patients among groups Variables S1(n=44) SK1(n=42) SK2(n=41) P-value Age, year 48.95±5.23 48.98±4.68 49.15±4.40 0.98 BMI, kg/m 2 24.93±2.58 23.75±2.91 24.39±3.04 0.16 Preoperative MMSE score 28.00±0.89 28.07±0.89 28.24±0.86 0.43 ASA classification 0.83 I 16 17 14 II 28 25 27 Education level 0.91 Primary school 6 4 4 Middle school and high school 31 32 33 University and above 7 6 4 Marital Status 0.93 Unmarried 1 1 1 Married 40 38 38 Divorced 2 2 1 Bereaved spouse 1 1 1 Gravidarum 0.81 0 2 1 1 ≥1 42 41 40 Comparison of patients’ HAM-D scores Compared with S1 group, the HAM-D scores at the d1, d2 and d5 postoperative reduced significantly in SK1 and SK2 group (P<0.05), and even lower at d1 and d2 postoperative in SK2 group(P 0.05). (Table 2). Comparison of postoperative VAS scores The VAS scores was decreased obviously in SK1 and SK2 group at 1h, 6h, 12h, 24h, and 48h postoperative compared to S1 group(P0.05) (Table 2). Table 2. Comparisons of HAM-D and VAS scores among groups Variables S1(n=44) SK1(n=42) SK2(n=41) P-value HAM-D scores 1d before 14.02±1.95 14.31±2.29 14.51±2.23 0.576 1d after 14.18±1.97ab 13.38±1.67ac 12.41±1.73bc <0.01 2d after 12.30±1.75ab 11.55±1.73ac 10.73±1.41bc <0.01 5d after 10.57±1.66ab 9.64±1.50c 9.49±1.27c <0.01 7d after 8.68±1.14 8.52±1.29 8.49±0.95 0.702 VAS scores 1h after 2.57±0.50ab 2.26±0.50c 2.12±0.40c <0.01 6h after 2.70±0.46ab 2.40±0.54c 2.27±0.45c <0.01 12h after 2.52±0.51ab 2.26±0.45c 2.15±0.48c <0.01 24h after 2.43±0.50ab 2.14±0.52c 2.02±0.42c <0.01 48h after 1.93±0.50ab 1.64±0.48c 1.54±0.50c <0.01 a P<0.05, compared with the SK2 group; b P<0.05, compared with the SK1 group; c P<0.05, compared with the S1 group. Comparisons of serum BDNF and 5-HT levels among groups There ware no significant differences in serum BDNF and 5-HT levels at 1 day preoperative and d7 postoperative among all groups (P >0.05). Compared with S1 group, the levels of serum BDNF and 5-HT in SK1 group at d1, d2 and d5 postoperative were significantly increased in SK1 and SK2 group(P<0.05). Compared with SK1 group, the serum BDNF level increased even higher in SK2 group at d1, d2 and d5 postoperative(P<0.05), while 5-HT level showed higher at d1 and d2 postoperative(P<0.05). (Table 3) . Table 3. Comparisons of serum BDNF and 5-HT levels among groups Variables S1(n=44) SK1(n=42) SK2(n=41) P-value BDNF (ng/ml) 1d before 115.32±15.70 112.01±12.26 113.69±16.37 0.589 d1 after 94.94±10.18 ab 100.11±11.26 ac 105.21±12.36 bc <0.01 d2 after 99.72±12.89 ab 107.07±14.66 ac 116.45±15.64 bc <0.01 d5 after 107.70±12.84 ab 114.00±14.92 ac 120.65±14.41 bc <0.01 d7 after 122.29±14.63 122.02±15.33 127.26±14.69 0.199 5-HT (ng/ml) 1d before 537.07±78.40 532.57±80.30 534.20±74.95 0.964 d1 after 450.85±60.91 ab 480.63±69.18 ac 511.01±72.83 bc <0.01 d2 after 462.62±62.64 ab 492.66±70.87 ac 524.30±70.46 bc <0.01 d5 after 475.33±64.07 ab 505.25±70.77 c 531.59±68.68 c <0.01 d7 after 541.88±62.93 541.36±68.81 553.75±65.75 0.625 a P<0.05, compared with the SK2 group; b P<0.05, compared with the SK1 group; c P<0.05, compared with the S1 group. Comparisons of intraoperative and postoperative general information and adverse effects among groups All groups exhibited no significant variations in anesthesia time, surgery time and intraoperative bleeding(P>0.05). Compared with S1 group, the SK1 and SK2 group showed lower intraoperative remifentanil dosage (P 0.05)( Table 4 ) . The postoperative number of PCIA button pressed during the 48 hours postoperative was significantly decreased in SK1 and SK2 groups compared to S1 group(P0.05) ( Table 4 ). In comparison with S1 and SK2 group, the SK1 group showed a slightly reduced incidence of postoperative nausea, vomiting and dizziness, but had no statistical significant during the postoperative 48 hours (P>0.05) ( Table 4 ). Table 4. Comparisons of intraoperative and postoperative general information and adverse effects among groups Variables S1(n=44) SK1(n=42) SK2(n=41) P-value Anesthesia time (min) 127.66±39.72 115.71±27.99 121.80±34.50 0.28 Surgery time (min) 99.80±33.85 89.62±25.36 95.41±30.33 0.30 Intraoperative bleeding volume (ml) 40.23±11.51 41.19±11.73 40.98±11.36 0.92 Complication, n(%) Nausea 7(15.91) 5(11.90) 6(14.63) 0.86 vomiting 5(11.36) 3(7.14) 3(7.32) 0.79 Dizziness 5(11.36) 4(9.52) 5(12.20) 0.94 Respiratory depression 3(6.82) 2(4.76) 2(4.88) 1.00 Hallucinations 3(6.82) 5(11.90) 5(12.20) 0.71 Remifentanil dosage (mg) 0.87±0.22 ab 0.76±0.20 c 0.75±0.22 c 0.02 PCIA button presses number 6.98±0.63 ab 6.67±0.65 c 6.46±0.55 c 0.00 a P<0.05, compared with the SK2 group; b P<0.05, compared with the SK1 group; c P<0.05, compared with the S1 group. Discussion Depression was known as one risk factor of perioperative complication and affected the long-term prognosis of surgical patients[26].Ren et al reported that treatment with 0.3 mg/kg single anesthetic ketamine could alleviate the postoperative anxiety and depression, and reduce the blood IL-8, IL-6, and TNF-α levels simultaneously in subjects with colorectal cancer during the perioperative period of radical colorectal surgery[27].As the dextro-split of ketamine, the utilization of esketamine was authorized by Food and Drug Administration (FDA) for the management of adult patients with depression in March 2019. Moreover, in the concept of multimodal analgesia, esketamine plays a dominant role among non-opioid analgesics as an intravenous anesthetic, which integrates anesthesia, sedation and analgesia. Lei et al has demonstrated that the perioperative opioid dosage was significantly reduced by administering esketamine at a dose of 0.1 mg/kg following induction of anesthesia and keeping it at 0.1 mg/kg/h intraoperatively in patients undergoing thoracoscopic lobectomy[28].Another study revealed that patients who received an continuous perioperative infusion of esketamine(0.3mg/kg/h) following a standard dilution protocol(2.5mg/ml) could also significantly reduce the postoperative opioid requirement and relieve the rebound pain[29].However, some key questions including the effects of esketamine on postoperative depressed mood, pain, the incidence of adverse effects and the optimal dose of esketamine administration in laparoscopic total hysterectomy are still not clear. HAM-D score was used to evaluate the subjective feelings of depressed patients, and four of HAM-D-24 items were substantially connected to response and one related to remission[30]. Meanwhile, accumulating evidences have demonstrated that the levels of peripheral blood BDNF and 5-HT reduced markedly in individuals with depression and both were positively correlated with patients’ depression severity[31-34].In this study, we observed no significant difference in HAM-D scores among all groups of patients who undegoing total laparoscopic hysterectomy at 1d before surgery. However, the HAM-D scores at the d1, d2 and d5 postoperative were significantly decreased in SK1 and SK2 group compared to S1 group (P<0.05), and even lower at d1 and d2 postoperative in SK2 group(P<0.05). Simultaneously, the serum BDNF and 5-HT levels in SK1 and SK2 group increased significantly contrast to S1 group at the d1, d2 and d5 postoperative(P<0.05), and even higher at d1 and d2 in SK2 group(P<0.05). Our findings indicated that esketamine could reduce the indicators of depression in early postoperative period in patients undergoing total laparoscopic hysterectomy. Furthermore, the 0.5 mg/kg of single intraoperative esketamine intravenous push had a better alleviation effect of depression-related indicators. The pathophysiology of perioperative depression is complex and not yet fully elucidated. Experience of pain has been considered to modulate the synaptic connectivity in prefrontal cortex and hippocampus, in addition to the alteration of dopamine signaling obtained from the ventral tegmental area, and these changes may partly contribute to the occurrence of depression[35-36]. Here, despite we have controlled all patients’ postoperative VAS scores within 3 points, we still found the VAS scores decreased significantly in SK1 and SK2 group compared to S1 group at 1h, 6h, 12h, 24h, and 48h post surgery (P<0.05), and the number of postoperative PCIA button pressed time was also reduced in SK1 and SK2 group (P<0.05) during the postoperative 48 hours. Moreover, the SK1 and SK2 group showed an obvious lower intraoperative remifentanil dosage (P<0.05). Our data suggest that the combination use with esketamine intraoperative and postoperative could also reduce the indicators of pain in early postoperative period in patients undergoing total laparoscopic hysterectomy, and which may partly contribute to the postoperative depression indicators remission. Recent studies have reported that the incidence of nausea and vomiting within 24 hours after gynecologic laparoscopic surgery ranged from 28% to 39%[37-38].In this research, we found that the SK1 group exhibited a slightly decreased incidence of postoperative nausea, vomiting and dizziness compared with S1 and SK2 group, whereas none revealed a statistical significant among the groups(P>0.05), which indicate that the combination use of esketamine intraoperative and postoperative don’t increase the incidence of adverse events. In conclusion, this preliminary research demonstrated that the administration of esketamine can relieve early postoperative depression indicators in individuals undergoing total laparoscopic hysterectomy, which may partly related to its better effect on postoperative pain indicators relief; and meanwhile don’t elevate the incidence of adverse effects. A singular intraoperative esketamine sedative dose of 0.5 mg/kg may show the better reduction property of depression-related indicators. However, there were limited cases in this study, further exploration of the exact mechanism are required in a larger sample. Declarations Conflict of Interest The authors state that the investigation was carried out without any business or financial affiliations that may be interpreted as a potential source of conflict of interest. The authors declare that they have no competing interests. Data Sharing Statement The raw data supporting the conclusions of this article will be made available by the authors, upon reasonable request. Disclosure The authors report no conflicts of interest in this work. Funding This investigation was financially supported by the Research Fund of Anhui Medical University (2021xkj243) Author Contribution Jun Jing designed the investigation and drafted the manuscript. Meng-Ying Zhang and Yong-jie Ji were responsible for the ELISA. Li Sun and Wei-hong Yin and Rui Qu examined the data and constructed the graphs. Yuan-hai Li revised the manuscript and are responsible for the data. The last revision of the manuscript was reviewed and authorized by all the authors. Acknowledgments The authors acknowledge gratefully the Department of Anesthesiology, the First Affiliated Hospital of Anhui Medical University for the technical assistance. References Irwin MR, Carrillo C, Sadeghi N, Bjurstrom MF, Breen EC, Olmstead R. 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Effects of Esketamine on Acute and Chronic Pain After Thoracoscopy Pulmonary Surgery Under General Anesthesia: A Multicenter-Prospective, Randomized, Double-Blind, and Controlled Trial. Front Med (Lausanne). 2021;8:693594. Zhu X, Zhang F, You Y, et al. S-Ketamine Exerts Antidepressant Effects by Regulating Rac1 GTPase Mediated Synaptic Plasticity in the Hippocampus of Stressed Rats. Cell Mol Neurobiol. 2023;43(1):299-314. Niu Y, Sheng S, Chen Y, et al. The Efficacy of Group Acceptance and Commitment Therapy for Preventing Post-Stroke Depression: A Randomized Controlled Trial. J Stroke Cerebrovasc Dis. 2022;31(2):106225. Yoshimura R, Okamoto N, Chibaatar E, Natsuyama T, Ikenouchi A. The Serum Brain-Derived Neurotrophic Factor Increases in Serotonin Reuptake Inhibitor Responders Patients with First-Episode, Drug-Naïve Major Depression. Biomedicines. 2023;11(2):584. Yoshimura R, Kishi T, Suzuki A, et al. The brain-derived neurotrophic factor (BDNF) polymorphism Val66Met is associated with neither serum BDNF level nor response to selective serotonin reuptake inhibitors in depressed Japanese patients. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35(4):1022-1025. Katsuki A, Yoshimura R, Kishi T, et al. Serum levels of brain-derived neurotrophic factor (BDNF), BDNF gene Val66Met polymorphism, or plasma catecholamine metabolites, and response to mirtazapine in Japanese patients with major depressive disorder (MDD). CNS Spectr. 2012;17(3):155-163. Wang J, Wang Y, Xu X, Peng S, Xu F, Liu P. Use of Various Doses of S-Ketamine in Treatment of Depression and Pain in Cervical Carcinoma Patients with Mild/Moderate Depression After Laparoscopic Total Hysterectomy. Med Sci Monit. 2020;26:e922028. Guida F, De Gregorio D, Palazzo E, et al. Behavioral, Biochemical and Electrophysiological Changes in Spared Nerve Injury Model of Neuropathic Pain. Int J Mol Sci. 2020;21(9):3396. Gui WS, Wei X, Mai CL, et al. Interleukin-1β overproduction is a common cause for neuropathic pain, memory deficit, and depression following peripheral nerve injury in rodents. Mol Pain. 2016;12:1744806916646784. Hari Y, Satomi S, Murakami C, et al. Remimazolam decreased the incidence of early postoperative nausea and vomiting compared to desflurane after laparoscopic gynecological surgery. J Anesth. 2022;36(2):265-269. Yang H, Gu X, Xu M, et al. Preventing nausea and vomiting after gynecological laparoscopic surgery by patient-controlled intravenous analgesia with a naloxone admixture: A randomized controlled trial. Medicine (Baltimore). 2022;101(29):e29584 Additional Declarations No competing interests reported. Supplementary Files ChiCTR2200065198.xlsx CONSORT.docx Cite Share Download PDF Status: Published Journal Publication published 20 Dec, 2025 Read the published version in BMC Anesthesiology → Version 1 posted Editorial decision: Revision requested 10 Sep, 2025 Reviews received at journal 01 Sep, 2025 Reviewers agreed at journal 29 Aug, 2025 Reviewers agreed at journal 15 Aug, 2025 Reviews received at journal 05 Jun, 2025 Reviewers agreed at journal 05 Jun, 2025 Reviewers invited by journal 05 May, 2025 Editor invited by journal 29 Apr, 2025 Editor assigned by journal 28 Apr, 2025 Submission checks completed at journal 26 Apr, 2025 First submitted to journal 26 Apr, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Medical University","correspondingAuthor":false,"prefix":"","firstName":"Meng-Ying","middleName":"","lastName":"Zhang","suffix":""},{"id":451855208,"identity":"3144b275-3da6-4636-af5a-b02db9006af8","order_by":2,"name":"Wei-hong Yin","email":"","orcid":"","institution":"Maanshan People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Wei-hong","middleName":"","lastName":"Yin","suffix":""},{"id":451855210,"identity":"d5a368a5-bab9-4b5a-8fa0-a6a227a8363a","order_by":3,"name":"Yong-jie Ji","email":"","orcid":"","institution":"Maanshan People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yong-jie","middleName":"","lastName":"Ji","suffix":""},{"id":451855211,"identity":"2ca0e05c-2b1f-4dd9-8be0-75f359b8b6d8","order_by":4,"name":"Li Sun","email":"","orcid":"","institution":"Maanshan People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Li","middleName":"","lastName":"Sun","suffix":""},{"id":451855214,"identity":"c86ea6e9-75ce-43a5-b1cc-ff707ae4b21e","order_by":5,"name":"Rui Qu","email":"","orcid":"","institution":"Maanshan People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Rui","middleName":"","lastName":"Qu","suffix":""},{"id":451855215,"identity":"25bd1a33-c899-4706-81b0-ddf5e740c512","order_by":6,"name":"Yuan-hai Li","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA00lEQVRIiWNgGAWjYBACPmYwdYCBjYGx8UFCRQ1hLWwILczNBg/OHCNCCwNUCwMDe5vkwxZmIrSw85hJ/NxxR56PgbGtIrGBjYG/vTuBgMN4zCR7zzwzbANquZG4Q4ZB4szZDQS1SPC2HWZsk38I1HKGjcFAIpewFsm/bYftQbYUJLYxE6dFGmhLIkgLA5Fa2IqtZdsOJwO1NEsknDnGQ9Av/PyHN95823bYdn4D+8OPPypq5Pjbe/FrYWDgMEDh8hBQDgLsD4hQNApGwSgYBSMaAACqg0F5UgrGMwAAAABJRU5ErkJggg==","orcid":"","institution":"the First Affiliated Hospital of Anhui Medical University","correspondingAuthor":true,"prefix":"","firstName":"Yuan-hai","middleName":"","lastName":"Li","suffix":""}],"badges":[],"createdAt":"2025-04-07 14:08:21","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6395068/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6395068/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12871-025-03570-5","type":"published","date":"2025-12-20T15:58:36+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":82352369,"identity":"9e6db210-4429-4050-a83a-c8a529106243","added_by":"auto","created_at":"2025-05-09 11:01:19","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":184599,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFlow chart of this study\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6395068/v1/a78b3ff21411aa72e66be89a.png"},{"id":98814944,"identity":"006680e7-65f3-486c-aa7d-76c5e9742bd3","added_by":"auto","created_at":"2025-12-22 16:13:06","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":998317,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6395068/v1/aa75689e-f3b0-4b78-98b6-a9c479612ae5.pdf"},{"id":82354066,"identity":"63173753-2177-4823-bcf6-e1ff1b19c936","added_by":"auto","created_at":"2025-05-09 11:09:19","extension":"xlsx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":17589,"visible":true,"origin":"","legend":"","description":"","filename":"ChiCTR2200065198.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-6395068/v1/51578ba0173dda021b0979ac.xlsx"},{"id":82354069,"identity":"27693ade-883e-4b66-afe0-7434ae9d50cf","added_by":"auto","created_at":"2025-05-09 11:09:19","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":39657,"visible":true,"origin":"","legend":"","description":"","filename":"CONSORT.docx","url":"https://assets-eu.researchsquare.com/files/rs-6395068/v1/1b723eafe895d096de1f3b6d.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Esketamine relieves postoperative depression and pain indicators in patients undergoing laparoscopic total hysterectomy","fulltext":[{"header":"Background","content":"\u003cp\u003eDepression has showed an increasing incidence in recent years, especially in the sick population[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. A multicenter, large-sample study has reported that the incidence rate of depression in patients hospitalized for physical illness in China was 75.1%[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Laparoscopic total hysterectomy is a common gynecological procedure, which was known as \u0026ldquo;artificial menopause\u0026rdquo; and also has been found significantly related with the raised depression risk[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. To date, the Hamilton Rating Scale for Depression(HAM-D) is still one of the gold standard tools which used to assess depression in clinical and related studies[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eRecently, ketamine has attracted much attention due to its rapid antidepressant effect in perioperative period[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], which was primarily mediated by inhibiting N-methyl-d-aspartate receptors (NMDAR). But on the other hand, the administration of ketamine is associated with a prolonged awakening time and psychotic symptoms such as nightmares and hallucinations[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Esketamine is the dextro-split of ketamine, it shows double anesthetic-analgesic-hypnotic strength and plasma clearance. And moreover, it can significantly shortern the awakening time and low the incidence of psychiatric side effects[\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePrevious studies have confirmed that the bilateral voxel nuclei and cingulate-hippocampus in brain[\u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] and its related neurohumoral factors including 5-hydroxytryptamine (5-HT)[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] and brain-derived neurotrophic factor (BDNF)[\u003cspan additionalcitationids=\"CR19\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] were closely related with the development of depression. And the antidepressant efficacy was obviously associated with the structural changes and synaptic remodeling in cingulate-hippocampus[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. In addition to this, recent evidences have shown that the acute and chronic pain may also be the vital factor in the development of postoperative depression[\u003cspan additionalcitationids=\"CR23\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eUp to now, few studies have reported the antidepressant and pain relief effect of esketamine in postoperation of laparoscopic total hysterectomy. In this clinical trial, we aim to evaluate the impact of esketamine on postoperative depression and pain indicators including peripheral blood serum BDNF level, 5-HT level, 24-item HAM-D(HAM-D24), visual analogue scale(VAS) scores and the number of patient-controlled intravenous analgesia(PCIA) button pressed times in patients undergoing laparoscopic total hysterectomy. In the meantime, the postoperative adverse effects were also recorded and we try to provide some valuable references for medical practice of esketamine.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003e\u003cstrong\u003eEthics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Maanshan People's Hospital’s Ethics Committee approved this clinical study (No. 2021-006-003), which was also registered on the China Clinical Trial Registry, with the registration number ChiCTR2200065198 and registration date of October 31, 2022. All subjects provided informed consent prior to participation in the study.The study was conducted in accordance with the Helsinki Declaration (2013 October) and clinical practice guidelines.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGeneral information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e135 patients who underwent planned laparoscopic total hysterectomy were recruited from Maanshan People's Hospital from November 2022 to December 2023, then randomly allocated to three groups through simple randomization using a computer-generated random sequence (randomization ratio 1:1:1): the sufentanil group (S1, n=44), sufentanil combined with 0.25mg/kg esketamine group (SK1,n=42) and sufentanil combined with 0.5mg/kg esketamine group (SK2,n=41) intraoperatively, then the SK1 and SK2 group were maintained analgesia with esketamine 1 mg/kg patient-controlled intravenous analgesia(PCIA) postoperatively. And a possible 10% attrition rate was considered.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe inclusion criteria were as follows: (a) age ranged 30-60 years; (b) body mass index (BMI) ranged 18-30 kg/m\u003csup\u003e2\u003c/sup\u003e; (c) HAMD score ranged 8-20; (d) followed the criteria defined by the American Society of Anesthesiologists (ASA) for classification as class I-II; (e) the preoperative score of Mini Mental Status Examination (MMSE) was greater than 27 points; (f) approved to voluntarily participate in the investigation and the provision of informed consent for trial participation.\u003c/p\u003e\n\u003cp\u003eThe exclusion criteria were as follows: (a) patients with confirmed psychiatric disorders such as diagnosed depression, mania and schizophrenia; (b) patients with chronic cardiac insufficiency (NYHA class III-IV); (c) patients with abnormal liver and kidney function (ALT, AST\u0026gt;3 times the upper limit of normal; estimated glomerular filtration rate less than 60ml/min/1.73m\u003csup\u003e2\u003c/sup\u003e); (d) severe visual, speech or hearing impairment; (e) increased abnormal intracranial pressure or intraocular pressure; (f) long-term or recent use of sedatives, analgesics, nonsteroidal drugs, glucocorticoids, psychotropic drugs, alcohol or drug abuse; (g) allergy to any of the study drug components.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAnesthesia method\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSeries of medical procedures were initiated since the admission of patient to the operating theater, including administration of oxygen, establishment of peripheral venous access and monitoring of various physiological parameters involved noninvasive blood pressure, pulse oximetry, electrocardiogram, body temperature, intraoperative partial pressure of end-expiratory carbon dioxide (PetCO2) and depth of anesthesia (bispectral index [BIS]). General anesthesia was administered through a combination of intravenous and inhalation anesthesia. Rapid intravenous anesthesia was induced with etomidate at a dosage of 0.3 mg/kg, sufentanil at a dosage of 0.3~0.4 μg/kg, midazolam at a dosage of 0.05 mg/kg, and rocuronium at a dosage of 0.6 mg/kg. 2 minutes later, endotracheal intubation and mechanical control of breathing were initiated. Before surgical skin incision, the S1, SK1, and SK2 group received 0.1 µg/kg sufentanil, 0.1 µg/kg sufentanil combined with 0.25 mg/kg esketamine(Lot number:221019BL,Jiangsu Hengrui Medicine Co., Ltd., China), and 0.1 µg/kg sufentanil combined with 0.5 mg/kg esketamine intravenously, respectively. Anesthesia was maintained with 0.5%~1.5% sevoflurane, 3~4 mg/(kg·h) propofol, and 0.2~0.4 μg/(kg·h) remifentanil. The BIS value was preserved between 40~60 intraoperatively, and the concentration of anesthetic drugs was based on blood pressure, heart rate and changes in patient’s other related vital signs. Intermittent administration of Rocuronium bromide at a dosage of 0.15 mg/kg was performed, and discontinued at 45 minutes prior to the completion of the surgical procedure. A further dose of 0.1 µg/kg sufentanil was administered, and sevoflurane inhalation was terminated once the peritoneum was closed. The PCIA system was linked at 10 minutes prior to the end of the surgical procedures.\u003c/p\u003e\n\u003cp\u003eThe administration of postoperative PCIA was performed that the S1 group received 2 μg/kg of sufentanil, the SK1 and SK2 groups received a combination of 2 μg/kg of sufentanil and 1 mg/kg of esketamine, and 0.9% sodium chloride solution was utilized to dilute each solution to 100 milliliter(mL). The parameters of PCIA were as follows: first dose, 2 mL; background infusion, 2 mL/h; 1 ml for each self-controlled dose; lock time, 10 min; limit, 10 mL/h. All participants were sedated with 10mg of azelastine at 10mins before the completion of surgical procedure and then sent to the anesthesia resuscitation unit (PACU) after surgery, and we controlled all patients’ postoperative VAS scores within 3 points.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObservation indicators\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll patients’ age, BMI, ASA classification, education level, marital status, childbirth status, operation time, anesthesia time, intraoperative bleeding, and intraoperative anesthetic dosage were recorded.\u003c/p\u003e\n\u003cp\u003eHAM-D scores, peripheral blood serum BDNF and 5-HT levels were collected at 1 day before, the 1th day(d1), d2, d5 and d7 after the operation, respectively.\u003c/p\u003e\n\u003cp\u003eThe patients’ VAS scores were recorded at the 1th hour(1h), 6h, 12h, 24h, and 48h after operation; the total number of PCIA button presses and the incidence of adverse reactions including nausea, vomiting, dizziness, respiratory depression and hallucinations were collected during the postoperative 48 hours.\u003c/p\u003e\n\u003cp\u003eThe primary outcomes were the HAM-D scores, VAS scores, BDNF and 5-HT levels, with the PCIA button pressed times and the incidence of adverse reactions as the secondary outcomes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSample Size Calculation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe sample size was determined based on the primary outcome (postoperative HAM-D scores ). Using G*Power 3.1 with α=0.05, power=0.80, and effect size f=0.3 derived from prior studies [25], a minimum of 42 patients per group was required for one-way analysis of variance(ANOVA). Accounting for 10% attrition, we recruited 45 patients per group (total N=135). Post-hoc analysis confirmed \u0026gt;80% power with 127 valid cases included in the final analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical methods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStatistical analysis was performed using statistical package for social sciences(SPSS) 22.0. The normal distribution data were expressed as mean ± standard deviation. One-way ANOVA was used for comparing multiple groups, Kruskal-Wallis H-test for comparing multiple groups of rank data, chi-square test and fisher test were used for comparing rates. A statistically significant variation was determined to be present when \u003cem\u003eP\u0026lt;\u003c/em\u003e0.05.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eParticipate Figures\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFinally, a total of 127 patients were selected into the statistical analysis, with the final grouping information as follows: S1, n=44; SK1,n=42; and SK2,n=41 (\u003cstrong\u003eFigure 1\u003c/strong\u003e).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBasic preoperative information of patients\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere were no statistically significant differences in baseline preoperative data among the three groups (P\u0026gt;0.05) (\u003cstrong\u003eTable 1\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1.\u0026nbsp;\u003c/strong\u003eComparison of basic preoperative information of patients among groups\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"96%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eVariables\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003eS1(n=44)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e\u0026nbsp;SK1(n=42)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;SK2(n=41)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eAge, year\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e48.95\u0026plusmn;5.23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e48.98\u0026plusmn;4.68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e49.15\u0026plusmn;4.40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e0.98\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eBMI, kg/m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e24.93\u0026plusmn;2.58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e23.75\u0026plusmn;2.91\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e24.39\u0026plusmn;3.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e0.16\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003ePreoperative MMSE score\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e28.00\u0026plusmn;0.89\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e28.07\u0026plusmn;0.89\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e28.24\u0026plusmn;0.86\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e0.43\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eASA classification\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e0.83\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEducation level\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e0.91\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003ePrimary school\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eMiddle school and high school\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eUniversity and above\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMarital Status\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e0.93\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eUnmarried\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eMarried\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eDivorced\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eBereaved spouse\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eGravidarum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e0.81\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e\u0026ge;1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eComparison of patients\u0026rsquo; HAM-D scores\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCompared with S1 group, the HAM-D scores at the d1, d2 and d5 postoperative reduced significantly in SK1 and SK2 group (P\u0026lt;0.05), and even lower at d1 and d2 postoperative in SK2 group(P\u0026lt;0.05). But there were no obvious differences in HAMD scores at 1 day before and the d7 post operation among the three groups(P \u0026gt; 0.05). (Table 2).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eComparison of postoperative VAS scores\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe VAS scores was decreased\u0026nbsp;obviously in SK1 and SK2 group at 1h, 6h, 12h, 24h, and 48h postoperative compared to S1 group(P\u0026lt;0.05), but there were no significant differences between the SK1 and SK2 group (P\u0026gt;0.05) (Table 2).\u003c/p\u003e\n\u003cp\u003eTable 2. Comparisons of HAM-D and VAS scores among groups\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"496\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 91px;\"\u003e\n \u003cp\u003eVariables\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 117px;\"\u003e\n \u003cp\u003eS1(n=44)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 112px;\"\u003e\n \u003cp\u003e\u0026nbsp;SK1(n=42)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 112px;\"\u003e\n \u003cp\u003e\u0026nbsp;SK2(n=41)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eHAM-D scores\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e1d before\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e14.02\u0026plusmn;1.95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e14.31\u0026plusmn;2.29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e14.51\u0026plusmn;2.23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.576\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e1d after\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e14.18\u0026plusmn;1.97ab\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e13.38\u0026plusmn;1.67ac\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e12.41\u0026plusmn;1.73bc\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026lt;0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e2d after\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e12.30\u0026plusmn;1.75ab\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e11.55\u0026plusmn;1.73ac\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10.73\u0026plusmn;1.41bc\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026lt;0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e5d after\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10.57\u0026plusmn;1.66ab\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e9.64\u0026plusmn;1.50c\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e9.49\u0026plusmn;1.27c\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026lt;0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e7d after\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e8.68\u0026plusmn;1.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e8.52\u0026plusmn;1.29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e8.49\u0026plusmn;0.95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.702\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eVAS scores\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e1h after\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2.57\u0026plusmn;0.50ab\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2.26\u0026plusmn;0.50c\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2.12\u0026plusmn;0.40c\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026lt;0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e6h after\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2.70\u0026plusmn;0.46ab\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2.40\u0026plusmn;0.54c\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2.27\u0026plusmn;0.45c\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026lt;0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e12h after\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2.52\u0026plusmn;0.51ab\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2.26\u0026plusmn;0.45c\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2.15\u0026plusmn;0.48c\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026lt;0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e24h after\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2.43\u0026plusmn;0.50ab\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2.14\u0026plusmn;0.52c\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2.02\u0026plusmn;0.42c\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026lt;0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e48h after\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.93\u0026plusmn;0.50ab\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.64\u0026plusmn;0.48c\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.54\u0026plusmn;0.50c\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026lt;0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003csup\u003ea\u003c/sup\u003e P\u0026lt;0.05, compared with the SK2 group; \u003csup\u003eb\u0026nbsp;\u003c/sup\u003eP\u0026lt;0.05, compared with the SK1 group; \u003csup\u003ec\u003c/sup\u003e P\u0026lt;0.05, compared with the S1 group.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eComparisons of serum BDNF and 5-HT levels among groups\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere ware no significant differences in serum\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eBDNF and 5-HT levels at 1 day preoperative and d7 postoperative among all groups (P \u0026gt;0.05). Compared with S1 group, the levels of serum BDNF and 5-HT in SK1 group at d1, d2 and d5 postoperative were significantly increased in SK1 and SK2 group(P\u0026lt;0.05). Compared with SK1 group, the serum BDNF level increased even higher in SK2 group at d1, d2 and d5 postoperative(P\u0026lt;0.05), while\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e5-HT level showed higher at d1 and d2 postoperative(P\u0026lt;0.05). \u003cstrong\u003e(Table 3)\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3.\u0026nbsp;\u003c/strong\u003eComparisons of serum BDNF and 5-HT levels among groups\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"99%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003eVariables\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003eS1(n=44)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e\u0026nbsp;SK1(n=42)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e\u0026nbsp;SK2(n=41)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBDNF\u003c/strong\u003e(ng/ml)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e1d before\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e115.32\u0026plusmn;15.70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e112.01\u0026plusmn;12.26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e113.69\u0026plusmn;16.37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e0.589\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003ed1 after\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e94.94\u0026plusmn;10.18\u003csup\u003eab\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e100.11\u0026plusmn;11.26\u003csup\u003eac\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e105.21\u0026plusmn;12.36\u003csup\u003ebc\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026lt;0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003ed2 after\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e99.72\u0026plusmn;12.89\u003csup\u003eab\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e107.07\u0026plusmn;14.66\u003csup\u003eac\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e116.45\u0026plusmn;15.64\u003csup\u003ebc\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026lt;0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003ed5 after\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e107.70\u0026plusmn;12.84\u003csup\u003eab\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e114.00\u0026plusmn;14.92\u003csup\u003eac\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e120.65\u0026plusmn;14.41\u003csup\u003ebc\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026lt;0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003ed7 after\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e122.29\u0026plusmn;14.63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e122.02\u0026plusmn;15.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e127.26\u0026plusmn;14.69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e0.199\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e5-HT\u003c/strong\u003e(ng/ml)\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e1d before\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e537.07\u0026plusmn;78.40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e532.57\u0026plusmn;80.30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e534.20\u0026plusmn;74.95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e0.964\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003ed1 after\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e450.85\u0026plusmn;60.91\u003csup\u003eab\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e480.63\u0026plusmn;69.18\u003csup\u003eac\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e511.01\u0026plusmn;72.83\u003csup\u003ebc\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026lt;0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003ed2 after\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e462.62\u0026plusmn;62.64\u003csup\u003eab\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e492.66\u0026plusmn;70.87\u003csup\u003eac\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e524.30\u0026plusmn;70.46\u003csup\u003ebc\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026lt;0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003ed5 after\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e475.33\u0026plusmn;64.07\u003csup\u003eab\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e505.25\u0026plusmn;70.77\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e531.59\u0026plusmn;68.68\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026lt;0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003ed7 after\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e541.88\u0026plusmn;62.93\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e541.36\u0026plusmn;68.81\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e553.75\u0026plusmn;65.75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e0.625\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003csup\u003ea\u0026nbsp;\u003c/sup\u003eP\u0026lt;0.05, compared with the SK2 group;\u003csup\u003e\u0026nbsp;b\u0026nbsp;\u003c/sup\u003eP\u0026lt;0.05, compared with the SK1 group; \u003csup\u003ec\u0026nbsp;\u003c/sup\u003eP\u0026lt;0.05, compared with the S1 group.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eComparisons of intraoperative and postoperative general information and adverse effects among groups\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll groups exhibited no significant variations in anesthesia time, surgery time and intraoperative bleeding(P\u0026gt;0.05). Compared with S1 group, the SK1 and SK2 group showed lower intraoperative remifentanil dosage (P \u0026lt;0.05), whereas no obvious difference between the SK1 and SK2 group (P \u0026gt; 0.05)(\u003cstrong\u003eTable 4\u003c/strong\u003e) .\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe postoperative number of PCIA button pressed during the 48 hours postoperative was significantly decreased in SK1 and SK2 groups compared to S1 group(P\u0026lt;0.05), but there were no significant variations between the SK1 and SK2 group (P\u0026gt;0.05) (\u003cstrong\u003eTable 4\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eIn comparison with S1 and SK2 group, the SK1 group showed a slightly reduced incidence of postoperative nausea, vomiting and dizziness, but had no statistical significant during the postoperative 48 hours (P\u0026gt;0.05) (\u003cstrong\u003eTable 4\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4.\u0026nbsp;\u003c/strong\u003eComparisons of intraoperative and postoperative general information and adverse effects among groups\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 35px;\"\u003e\n \u003cp\u003eVariables\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eS1(n=44)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;SK1(n=42)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;SK2(n=41)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 35px;\"\u003e\n \u003cp\u003eAnesthesia time (min)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003e127.66\u0026plusmn;39.72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e115.71\u0026plusmn;27.99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e121.80\u0026plusmn;34.50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e0.28\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 35px;\"\u003e\n \u003cp\u003eSurgery time (min)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003e99.80\u0026plusmn;33.85\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e89.62\u0026plusmn;25.36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e95.41\u0026plusmn;30.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e0.30\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 35px;\"\u003e\n \u003cp\u003eIntraoperative bleeding volume (ml) \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003e40.23\u0026plusmn;11.51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e41.19\u0026plusmn;11.73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e40.98\u0026plusmn;11.36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e0.92\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 35px;\"\u003e\n \u003cp\u003eComplication, n(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 35px;\"\u003e\n \u003cp\u003eNausea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003e7(15.91)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e5(11.90)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e6(14.63)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e0.86\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 35px;\"\u003e\n \u003cp\u003evomiting\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003e5(11.36)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e3(7.14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e3(7.32)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e0.79\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 35px;\"\u003e\n \u003cp\u003eDizziness\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003e5(11.36)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e4(9.52)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e5(12.20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e0.94\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 35px;\"\u003e\n \u003cp\u003eRespiratory depression\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003e3(6.82)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e2(4.76)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e2(4.88)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e1.00\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 35px;\"\u003e\n \u003cp\u003eHallucinations\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003e3(6.82)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e5(11.90)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e5(12.20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e0.71\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 35px;\"\u003e\n \u003cp\u003eRemifentanil dosage (mg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003e0.87\u0026plusmn;0.22\u003csup\u003eab\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e0.76\u0026plusmn;0.20\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e0.75\u0026plusmn;0.22\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e0.02\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 35px;\"\u003e\n \u003cp\u003ePCIA button presses number\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003e6.98\u0026plusmn;0.63\u003csup\u003eab\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e6.67\u0026plusmn;0.65\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e6.46\u0026plusmn;0.55\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e0.00\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003csup\u003ea\u003c/sup\u003e P\u0026lt;0.05, compared with the SK2 group; \u003csup\u003eb\u003c/sup\u003e P\u0026lt;0.05, compared with the SK1 group; \u003csup\u003ec\u0026nbsp;\u003c/sup\u003eP\u0026lt;0.05, compared with the S1 group.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eDepression was known as one risk factor of perioperative complication and affected the long-term prognosis of surgical patients[26].Ren et al\u0026nbsp;reported that treatment with 0.3 mg/kg single anesthetic ketamine could alleviate the postoperative anxiety and depression, and reduce the blood IL-8, IL-6, and TNF-\u0026alpha; levels simultaneously in subjects with colorectal cancer during the perioperative period of radical colorectal surgery[27].As the dextro-split of ketamine, the utilization of esketamine was authorized by Food and Drug Administration (FDA) for the management of adult patients with depression in March 2019. Moreover, in the concept of multimodal analgesia, esketamine plays a dominant role among non-opioid analgesics as an intravenous anesthetic, which integrates anesthesia, sedation and analgesia. Lei et al\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003ehas demonstrated that the perioperative opioid dosage was significantly reduced by administering esketamine at a dose of 0.1 mg/kg following induction of anesthesia and keeping it at 0.1 mg/kg/h intraoperatively in patients undergoing thoracoscopic lobectomy[28].Another study revealed that patients who received an continuous perioperative infusion of esketamine(0.3mg/kg/h) following a standard dilution protocol(2.5mg/ml) could also significantly reduce the postoperative opioid requirement and relieve the rebound pain[29].However, some key questions including the effects of esketamine on postoperative depressed mood, pain, the incidence of adverse effects and the optimal dose of esketamine administration in laparoscopic total hysterectomy are still not clear.\u003c/p\u003e\n\u003cp\u003eHAM-D score was used to evaluate the subjective feelings of depressed patients, and four of HAM-D-24 items were substantially connected to response and one related to remission[30]. Meanwhile, accumulating evidences have demonstrated that the levels of peripheral blood BDNF and 5-HT reduced markedly in individuals with depression and both were positively correlated with patients\u0026rsquo; depression severity[31-34].In this study, we observed no significant difference in HAM-D scores among all groups of patients who undegoing total laparoscopic hysterectomy at 1d before surgery.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eHowever, the HAM-D scores at the d1, d2 and d5 postoperative were significantly decreased in SK1 and SK2 group compared to S1 group (P\u0026lt;0.05), and even lower at d1 and d2 postoperative in SK2 group(P\u0026lt;0.05). Simultaneously, the serum BDNF and 5-HT levels in SK1 and SK2 group increased significantly contrast to S1 group at the d1, d2 and d5 postoperative(P\u0026lt;0.05), and even higher at d1 and d2 in SK2 group(P\u0026lt;0.05). Our findings indicated that esketamine could reduce the indicators of depression in early postoperative period in patients undergoing total laparoscopic hysterectomy. Furthermore, the 0.5 mg/kg of single intraoperative esketamine intravenous push had a better alleviation effect of \u0026nbsp;depression-related indicators.\u003c/p\u003e\n\u003cp\u003eThe pathophysiology of perioperative depression is complex and not yet fully elucidated. Experience of pain has been considered to modulate the synaptic connectivity in prefrontal cortex and hippocampus, in addition to the alteration of dopamine signaling obtained from the ventral tegmental area, and these changes may partly contribute to the occurrence of depression[35-36]. Here, despite we have controlled all patients\u0026rsquo; postoperative VAS scores within 3 points, we still found the VAS scores decreased significantly in SK1 and SK2 group compared to S1 group at 1h, 6h, 12h, 24h, and 48h post surgery (P\u0026lt;0.05), and the number of postoperative PCIA button pressed time was also reduced in SK1 and SK2 group (P\u0026lt;0.05) during the postoperative 48 hours. Moreover, the SK1 and SK2 group showed an obvious lower intraoperative remifentanil dosage (P\u0026lt;0.05). Our data suggest that the combination use with esketamine intraoperative and postoperative could also reduce the indicators of pain in early postoperative period in patients undergoing total laparoscopic hysterectomy, and which may partly contribute to the postoperative depression indicators remission.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eRecent studies\u0026nbsp;have reported that the incidence of nausea and vomiting within 24 hours after gynecologic laparoscopic surgery ranged from 28% to 39%[37-38].In this research, we found that the SK1 group exhibited a slightly decreased incidence of postoperative nausea, vomiting and dizziness compared with S1 and SK2 group, whereas none revealed a statistical significant among the groups(P\u0026gt;0.05), which indicate that the combination use of esketamine intraoperative and postoperative don\u0026rsquo;t increase the incidence of adverse events.\u003c/p\u003e\n\u003cp\u003eIn conclusion, this preliminary research demonstrated that the administration of esketamine can relieve early postoperative depression indicators in individuals undergoing total laparoscopic hysterectomy, which may partly related to its better effect on postoperative pain indicators relief; and meanwhile don\u0026rsquo;t elevate the incidence of adverse effects. A singular intraoperative esketamine sedative dose of 0.5 mg/kg may show the better reduction property of \u0026nbsp; depression-related indicators. However, there were limited cases in this study, further exploration of the exact mechanism are required in a larger sample.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eConflict of Interest\u003c/h2\u003e \u003cp\u003eThe authors state that the investigation was carried out without any business or financial affiliations that may be interpreted as a potential source of conflict of interest. The authors declare that they have no competing interests.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eData Sharing Statement\u003c/h2\u003e \u003cp\u003eThe raw data supporting the conclusions of this article will be made available by the authors, upon reasonable request.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eDisclosure\u003c/h2\u003e \u003cp\u003eThe authors report no conflicts of interest in this work.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThis investigation was financially supported by the Research Fund of Anhui Medical University (2021xkj243)\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eJun Jing designed the investigation and drafted the manuscript. Meng-Ying Zhang and Yong-jie Ji were responsible for the ELISA. Li Sun and Wei-hong Yin and Rui Qu examined the data and constructed the graphs. Yuan-hai Li revised the manuscript and are responsible for the data. The last revision of the manuscript was reviewed and authorized by all the authors.\u003c/p\u003e\u003ch2\u003eAcknowledgments\u003c/h2\u003e \u003cp\u003eThe authors acknowledge gratefully the Department of Anesthesiology, the First Affiliated Hospital of Anhui Medical University for the technical assistance.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eIrwin MR, Carrillo C, Sadeghi N, Bjurstrom MF, Breen EC, Olmstead R. Prevention of Incident and Recurrent Major Depression in Older Adults With Insomnia: A Randomized Clinical Trial. JAMA Psychiatry. 2022;79(1):33-41. \u003c/li\u003e\n\u003cli\u003eYang W, Xiao L, Yuan Z, et al. Anxiety and Depression in Patients With Physical Diseases and Associated Factors: A Large-Scale Field Survey in General Hospitals in China. Front Psychiatry. 2021;12:689787.\u003c/li\u003e\n\u003cli\u003eWilson L, Pandeya N, Byles J, Mishra G. 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J Anesth. 2022;36(2):265-269. \u003c/li\u003e\n\u003cli\u003eYang H, Gu X, Xu M, et al. Preventing nausea and vomiting after gynecological laparoscopic surgery by patient-controlled intravenous analgesia with a naloxone admixture: A randomized controlled trial. Medicine (Baltimore). 2022;101(29):e29584 \u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-anesthesiology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bane","sideBox":"Learn more about [BMC Anesthesiology](http://bmcanesthesiol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bane","title":"BMC Anesthesiology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Esketamine, Laparoscopic total hysterectomy, Depression, Pain","lastPublishedDoi":"10.21203/rs.3.rs-6395068/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6395068/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjective\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo observe the effects of esketamine on postoperative depression and pain indicators in individuals undergoing total laparoscopic hysterectomy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e135 patients undegoing total laparoscopic hysterectomy were recruited and randomly allocated to three groups. Finally, a total of 127 patients were selected into the statistical analysis, with the final grouping information as follows: sufentanil group (S1, n = 44), sufentanil combined with 0.25mg/kg esketamine group (SK1, n = 42) and sufentanil combined with 0.5mg/kg esketamine group (SK2,n = 41) intraoperatively, then the SK1 and SK2 group were maintained analgesia with esketamine 1 mg/kg patient-controlled intravenous analgesia(PCIA) postoperatively. The peripheral blood serum brain-derived neurotrophic factor (BDNF) level, 5-hydroxytryptamine (5-HT) level, Hamilton Depression Scale (HAM-D) scores, visual analogue scale(VAS) scores and the number of PCIA button pressed times in perioperative period were collected. Meanwhile, the postoperative adverse effects including nausea, vomiting, dizziness, respiratory depression and hallucinations were collected and compared between the three groups.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCompared with S1 group, the SK1 and SK2 group showed significantly higher serum BDNF and 5-HT levels at the 1th day(d1), d2 and d5 after operation (P \u0026lt; 0.05), and revealed even higher at d1 and d2 after operation in SK2 group(P \u0026lt; 0.05). The HAM-D scores at d1, d2 and d5 post operation were significantly reduced in SK1 and SK2 group (P \u0026lt; 0.05) compared to S1 group, and decreased even lower at d1 and d2 postoperative in SK2 group(P \u0026lt; 0.05), but no significant difference was found among three groups at 1 day before and the d7 after operation. Simultaneously, the VAS scores decreased significantly in SK1 and SK2 group at the 1th hour(1h), 6h, 12h, 24h, and 48h after surgery (P \u0026lt; 0.05), and the PCIA button pressed times were also significantly reduced in SK1 and SK2 group (P \u0026lt; 0.05) during the postoperative 48 hours. Furthermore, the SK1 and SK2 group showed the lower dosage of remifentanil during the surgery(P \u0026lt; 0.05). However, the postoperative adverse effects had no statistical differences among the three groups.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEsketamine can relieve postoperative depression and pain indicators without the increasing of adverse effects in patients undergoing total laparoscopic hysterectomy. Moreover, the 0.5 mg/kg dosage intraoperatively may have the better alleviation property of depression-related indicators.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eChinese Clinical Trial Registry (ChiCTR2200065198)\u003c/p\u003e","manuscriptTitle":"Esketamine relieves postoperative depression and pain indicators in patients undergoing laparoscopic total hysterectomy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-09 11:01:14","doi":"10.21203/rs.3.rs-6395068/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-09-10T05:11:23+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-01T10:05:44+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"282300761142318316912399401699872504958","date":"2025-08-29T12:51:58+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"253334425075756869080181445932785092824","date":"2025-08-15T10:42:56+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-06-06T02:07:41+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"222331090356181328696075777884128988378","date":"2025-06-06T00:22:51+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-05-05T05:49:43+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-04-29T10:46:37+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-04-28T06:00:14+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-04-26T05:08:14+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Anesthesiology","date":"2025-04-26T05:07:06+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-anesthesiology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bane","sideBox":"Learn more about [BMC Anesthesiology](http://bmcanesthesiol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bane","title":"BMC Anesthesiology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ddff3166-37ff-4b4d-823f-c5d5ab3b3726","owner":[],"postedDate":"May 9th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-12-22T16:09:48+00:00","versionOfRecord":{"articleIdentity":"rs-6395068","link":"https://doi.org/10.1186/s12871-025-03570-5","journal":{"identity":"bmc-anesthesiology","isVorOnly":false,"title":"BMC Anesthesiology"},"publishedOn":"2025-12-20 15:58:36","publishedOnDateReadable":"December 20th, 2025"},"versionCreatedAt":"2025-05-09 11:01:14","video":"","vorDoi":"10.1186/s12871-025-03570-5","vorDoiUrl":"https://doi.org/10.1186/s12871-025-03570-5","workflowStages":[]},"version":"v1","identity":"rs-6395068","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6395068","identity":"rs-6395068","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}