Intraoperative Low-dose S-ketamine Reduces Depressive Symptoms in Patients with Crohn’s Disease Undergoing Bowel Resection: A Randomized Controlled Trial

doi:10.21203/rs.3.rs-1993450/v1

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Research Article

Intraoperative Low-dose S-ketamine Reduces Depressive Symptoms in Patients with Crohn’s Disease Undergoing Bowel Resection: A Randomized Controlled Trial

https://doi.org/10.21203/rs.3.rs-1993450/v1

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Purpose

We aim to investigate the effect of S-ketamine preconditioning on postoperative depression in patients with CD undergoing bowel resection with mild to moderate depression and to observe whether it can relieve postoperative pain and anti-inflammation.

Methods

A total of 120 adult patients were randomised in to one of the two groups; Patients in the S-ketamine group received 0.25mg/kg S-ketamine intravenous drip under general anesthesia induction, followed by continuous infusion of S-ketamine with 0.12mg/kg/h for more than 30 minutes through target-controlled infusion. Patients in the placebo group received 0.9% saline. The patients in both groups were evaluated by depression scale, pain scale and inflammatory factors at set intervals during a total period of one month starting from the end of operation.

Results

There was no significant difference in preoperative age, sex, body mass index (BMI), PHQ-9, and HAMD-17 scores between the two groups (P > 0.05). The scores of PHQ-9 and HAMD-17 in the S-ketamine group were lower than those in the placebo group on the 1st, 3rd, and 7th day postoperatively (P < 0.05). There was no significant difference in PHQ-9 and HAMD-17 scores between the two groups one month postoperatively (P > 0.05). The NRS scores of PACU, 1 day and 2 days postoperatively in the S-ketamine group were lower than those in the placebo group (P < 0.05). There was no significant difference in NRS score between the two groups at 7 days postoperatively (P > 0.05). There was no significant difference in postoperative complications, hospital stay, CRP, and IL-6 levels on the 1st and 3rd day postoperatively between the two groups (P > 0.05).

Conclusion

In patients with Crohn’s disease undergoing bowel resection with mild to moderate depression, intraoperative infusion of low-dose S-ketamine was effective in relieving depression one week after surgery and reducing postoperative pain two-day.

S-ketamine

Postoperative Depression

Crohn's Disease

Postoperative Pain

Crohn's disease (CD) is a chronic inflammatory disease of the gastrointestinal tract with symptoms evolving in a relapsing and remitting manner [1]. Typically, the peak incidence of CD is 18 to 35 years [2], which means that patients with CD will be plagued by the disease during their most precious years, and nearly 35% of them will develop depressive symptoms [3]. For 70% of patients with CD who need surgery [4], the incidence of preoperative depression may be higher. The CD cohort with the diagnosable psychological condition has been shown to experience a higher rate of disease exacerbation than the CD cohort without psycho complications [5, 6]. At the same time, this depressive mood may make postoperative recovery more difficult, so it is necessary to alleviate postoperative depression.

Ketamine, a widely used anesthetic, is also used to treat depression [3]. The most used ketamine in clinical practice is racemic ketamine, but its use is associated with many complications such as psychotic adverse effects and neurotoxicity [7, 8]. In recent years, S-ketamine has received attention for better efficacy and fewer complications [9, 10]. In 2019, the Food and Drug Administration (FDA) approved S-ketamine nasal spray for the treatment of refractory depression and subsequently received approval from numerous health authorities around the world [11]. This proves that S-ketamine can provide a rapid antidepressant effect in patients with depression in a non-surgical setting. However, whether S-ketamine affects surgical patients is inconclusive, mainly because of differences in the type of surgery, the dosage administered, the interaction with analgesics and the evaluation tools implemented. Studies have shown that small doses of S-ketamine in breast cancer surgery and cervical cancer surgery can reduce postoperative depression [12, 13]. However, the effects of S-ketamine on postoperative depression (POD) and pain in patients with CD have not been studied.

This study aimed to conduct a randomized, double-blind controlled trial to investigate the effect of S-ketamine preconditioning on postoperative depression in patients with CD undergoing bowel resection with mild to moderate depression and to observe whether it can relieve postoperative pain and anti-inflammation. We hypothesized that continuous intraoperative infusion of low-dose S-ketamine could effectively reduce postoperative depression in patients with CD undergoing bowel resection with mild to moderate depression.

2.1 | Study design

In this double-blind, randomized prospective trial, we investigated whether intraoperative use of low-dose S-ketamine could reduce postoperative pain scores and improve anxiety and depression in patients with CD. The research protocol was approved by Jinling Hospital affiliated with Nanjing University Medical College in Nanjing City, Jiangsu Province, and the written informed consent of all subjects was obtained. The study was registered with the ClinicalTrials.gov, and the registration number is NCT05506787.

Patients with CD who were hospitalized and required surgery from September 1st, 2020 to March 1th, 2022 were included. The inclusion criteria were as follows: (a) subjects who volunteered and signed informed consent for the trial, (b) patients aged between 18 and 60, (c) patients with CD who underwent surgery, (d) American Society of Anesthesiologists (ASA) grade Ⅰ~Ⅲ, (e) Hamilton depression score 8–24. Exclusion criteria include: (a) allergy to narcotic drugs or ketamine used, (b) patients with other serious systemic diseases (including severe heart, kidney, and liver disease), (c) chronic opioid therapy (more than twice a week for more than three months), (d) inability to understand the digital pain scale, (e) Hamilton depression score < 8 or > 24.

2.2 | Randomization and masking

Randomization assignments were from a computer-generated random number table. Group distribution and research drug regimens are hidden in sequentially numbered, sealed, opaque envelopes. On the day of the operation, the assistant who had no knowledge of the research program opened the envelope in the order in which the subject registered, reloaded the research drug into a 50 ml syringe, and then labeled the syringe with the designated subject ID. The subjects, anesthesiologists, and follow-up investigators were masked from the subjects’ group assignments. This information is concealed until the recruitment and follow-up of the subjects are completed.

2.3 | Procedures

In this randomized, double-blind, controlled trial, 120 patients who met the inclusion criteria were randomly assigned to two groups, using prepared sealed envelopes and receiving an S-ketamine group or Placebo group. The patients in the S-ketamine group received 0.25 mg/kg intravenous S-ketamine (Jiangsu Hengrui Pharmaceutical Co., Ltd., Jiangsu, China) drip under general anesthesia induction, followed by continuous infusion of S-ketamine with 0.12 mg/kg/h for more than 30 minutes through target-controlled infusion. Drug A: S-ketamine, diluted to 1mg/ml with normal saline, total 50ml). Patients in the placebo group received an intravenous infusion of 0.9% saline during anesthesia induction and were maintained through the infusion pump of drug B (50 ml 0.9% saline) for more than 30 minutes. Patients normally fasted for 12 hours. After the patient arrived in the operating room, a peripheral venous access was established in the right or left antecubital vein, 0.9% normal saline was injected at a rate of 20ml/min, and blood pressure, blood oxygen saturation, end-tidal CO2 pressure, and electrocardiogram monitoring were measured at the same time. Dash-4000 monitoring instrument. Induction of anesthesia with midazolam 40 µg/kg, A or B drug 0.25 mg/kg (20 seconds post-injection), sufentanil 3 µg/kg, propofol 1–2 mg/kg, and cisatracurium 0.2 mg/kg. Continuous infusion of drug A or B at a rate of 0.12 mg/kg/h through an infusion pump. Anesthesia was maintained using a target-controlled infusion of propofol and remifentanil. Then intravenously injected remifentanil 0.2–0.5 mg/(kg·min), dexmedetomidine 0.5 µg/(kg·h), cisatracurium 5–8 mg/(kg·min), 2%-3% sevoflurane inhalation anesthesia. All analgesia was performed by the same team, and the anesthesiologist was blinded to the drugs administered after analgesia induction. Analgesia and surgical procedures were performed by the same team following the same treatment protocol. After surgery, all patients received patient-controlled intravenous analgesia (PCIA), containing dezocine injection (4 vials), 50 µg of sufentanil citrate (1 vial), and ondansetron (1 vial) for continuous PCIA. 24 hours.

2.4 | Date collection

The clinical characteristics of all patients were collected, including age, sex, body mass index (BMI), visual analogue pain score, Hamilton Depression Scale 17-item (HAMD-17) score, Patient Health Questionnaire 9-item (PHQ-9) score, and inflammatory factor levels. Intraoperative results, such as operation time, blood loss, and postoperative results, including hospital stay and complications, were recorded. Numeric Rating Scale (NRS) was used to evaluate the pain in postanesthesia care unit (PACU), 1 day, 2 days and 7 days postoperatively. For the measurement of postoperative depression, PHQ-9 score and HAMD-17 score were used at 1 day, 3 days, 7 days, and 30 days postoperatively. All patients were followed up for at least three months.

2.5 | Outcome measures

The primary outcome was the HAMD-17 score on the 7th day postoperatively. Secondary outcomes included the PHQ-9 and HAMD-17 scores at 1 day, 3 days and 30 days postoperatively; the NRS scores at PACU, 1 day, 2 days and 7 days postoperatively; and the levels of C-reactive Protein (CRP) and interleukin 6 (IL-6) at 1 day and 3 days postoperatively.

2.6| Sample size calculation

Determine the level of hypothesis testing, take α = 0.05, and the test efficiency is 90%. According to the pre-test and other existing literature results, σ = 10, the effect difference D1 = 5, and the dropout rate is calculated as 5%. The primary endpoint considered is the two groups on the 7th day after the operation, the scores of the depression scale were compared, and the sample size calculation software PASS15.0 was used. It is estimated that a total of 120 subjects will be enrolled, 60 cases in the control group and 60 cases in the experimental group.

2.7| Statistical analysis

The continuous results were analyzed by the Kolmogorov-Smirnov test to judge the normality of its distribution. The measured data according to the normal distribution is expressed as the average ± standard deviation, and the measured data of the non-normal distribution is expressed as the median (quartile spacing). Independent t-test, Mann-Whitney U test, χ 2 test, or Fisher exact test were used to compare the baseline characteristics of each group as appropriate. The main endpoints (HAMD-17 score on the 7th day postoperatively) were compared by independent t-test. HAMD-17 and NRS scores at different time points postoperatively were compared by one-way analysis of variance (ANOVA). PHQ-9 scores, CRP, and IL-6 levels at different time points were analyzed by the Mann-Whitney U test. Mann-Whitney U test was used to compare the consumption of postoperative analgesics sufentanil and dezocine. The risk ratio of primary and secondary results and their 95% confidence interval (CI) are reported. The P-value of 0.05 on 2 sides was considered statistically significant for the main results. The statistical significance was based on P < 0.004 on both sides of the secondary results adjusted by the Holm-Bonferroni method to avoid false-positive errors. Statistical analysis was done by SPSS 25.0 software.

From September 1st, 2020 to March 1th, 2022, 151 patients with CD with intestinal obstruction with a PHQ-9 score of 5–20 were screened in Jinling Hospital affiliated with the Medical College of Nanjing University (Fig. 1). Finally, 124 patients were enrolled and randomly assigned to the S-ketamine group (n = 61) and placebo group (n = 63). 1 case lost follow-up in the S-ketamine group and 3 cases in the placebo group. Finally, data from 60 subjects in the S-ketamine group and the placebo group were included in the analysis (Fig. 1). There were no differences in demography, baseline assessment, and general intraoperative parameters (Table 1) between the two groups.

Table 1

**Baseline characteristics**
Variables	Placebo, n = 60	S-ketamine, n = 60	P-value
Age, y	35.2 ± 10.9	35.7 ± 9.3	.774
Sex, male	45(70%)	40 (66.7%)	.315
Weight, kg	52.6 ± 8.4	51.0 ± 8.0	.270
Height, cm	169.8 ± 8.4	168.3 ± 8.7	.361
Body mass index, kg/m2	18.2 ± 2.3	18.0 ± 2.3	.566
Education, senior middle school or above	57 (95%)	55 (91.7%)	.359
Marriage status, married	38 (63.3%)	41 (68.3%)	.564
Smoking history	10 (16.7%)	6 (10%)	.283
Hypertension	1 (1.7%)	1 (1.7%)	1.000
Heart disorders	1 (1.7%)	0 (0)	.500
Disease course, y	7.1 ± 4.9	8.2 ± 5.0	.226
ASA (I/II )	13/47	7/53	.315
PHQ-9	15.2 ± 2.45	15.6 ± 2.65	.454
HAMD-17 score	19.5 ± 3.73	19.0 ± 3.59	.475
Variables are described as number (%) and median (interquartile range). Abbreviations: ASA, American Society of Anesthesiologists; HAMD-17, Hamilton Depression Scale 17-item; PHQ-9, Patient Health Questionnaire 9-item.

Primary and Secondary Outcomes

The main result was the comparison of the HAMD-17 score between the two groups on the 7th day postoperatively. It was found that there was a significant difference between the S-ketamine group and the placebo group (P < 0.05; Table 3). The score of the S-ketamine group was lower than that of the placebo group.

Table 2

Intraoperative and postoperative data
Variables	Placebo, n = 60	S-ketamine, n = 60	P-value
Laparoscopic surgery	18 (30%)	12 (20%)	.206
Blood loss, ml	152.5 ± 89.5	174.2 ± 91.8	.193
Anesthesia duration, min	140.0 (125.0-177.5)	150.0(121.3–180.0)	.721
Sufentani, µg	31.8 (30.5–33.1)	30.4(29.2.0-31.6)	.110
Remifentanil ,µg	623.5 (569.6-677.4)	610.3 (552.7-667.9)	.739
Propofol ,mg	945.9 (870.3-1021.5)	941.0 (853.5-1028.5)	.993
Postoperative opioid used, mg	23.9 ± 8.4	16.4 ± 5.9	༜.050
Time to extubation, min	31.0 (20.5–58.0)	39.5 (22.0-50.8)	.854
PPOI	7 (11.7%)	10 (16.7%)	.432
Complication, n (%)
Nausea	6(10%)	3(5%)	.245
Dizzy	3 (5%)	5(8.3%)	.359
Dysphoria	1 (1.7%)	4 (6.7)	.182
Length of stay ,days	21 (17–25)	20 (16–22)	.185
CRP
before	0.90 (0.50–8.68)	1.30 (0.50–4.70)	.756
1day	69.05 (42.43–87.18)	63.10 (42.58–99.93)	.939
3days	100.50 (49.93–146.60)	99.90 (61.15-157.88)	.797
IL-6
before	15.39 (9.43–20.49)	11.86 (9.38–16.69)	.461
1day	76.98 (37.54–160.80)	89.21 (43.73-164.85)	.398
3days	30.71 (21.74–57.77)	33.65 (21.96–65.89)	.745
Variables are described as number (%) and median (interquartile range). Abbreviations: PPOI, prolonged postoperative ileus; CRP, C-reactive Protein; IL-6, interleukin 6.

Table 3

**HAMD-17 and PHQ-9 total score and change from baseline score at days 7.**
Time point	Absolute score		Change from baseline		Treatment difference
	Placebo	S-ketamine	Placebo	S-ketamine	Treatment difference
	Mean(SD)	Mean(SD)	Mean(SD)	Mean(SD)	Mean(SE)	95%CI	P-value
HAMD-17
Baseline	19.5(3.73)	19.0(3.59)
Day 7	15.5(5.04)	10.7(4.80)	-3.5(2.17)	-8.8(3.27)	-5.3(0.50)	-6.3 to -4.3	< .001
PHQ-9
Baseline	15.2(2.45)	15.6(2.65)
Day 7	13.0(3.44)	8.9(3.45)	-2.2(1.49)	-6.7(2.53)	-4.5(0.38)	-5.2 to -3.7	< .001
HAMD-17 Hamilton Depression Scale 17-item SD standard deviation, PHQ-9 Patient Health Questionnaire 9-item, SE standard error

The secondary results were as follows:

(1) The HAMD-17 score in the S-ketamine group was significantly lower than that in the placebo group on the 1st and 3rd days postoperatively. At the same time, there was no significant difference in HAMD-17 score one month postoperatively between the two groups. The change in the HAMD-17 score over time is shown in figure A. There were significant differences between the two groups on the 1st, 3rd, and 7th day (Bonferroni adjusted P < 0.001)

(2) The PHQ-9 score of the S-ketamine group was significantly lower than that of the placebo group on the 1st, 3rd, and 7th day postoperatively (P < 0.05). At the same time, there was no significant difference in PHQ-9 score one month postoperatively between the two groups. The change in PHQ-9 score over time is shown in figure B.

(3) The NRS scores of the S-ketamine group were significantly lower than those of the placebo group on postoperative PACU, 1 and 2 days (P < 0.05). Meanwhile, the NRS score one week after surgery showed no significant difference between the two groups (P > 0.05). Changes in NRS scores over time are shown in Figure C. There were significant differences between the two groups at PACU, 1, and 2 days (Bonferroni

adjusted P < 0.001)

(4) The consumption of sufentanil and dezocine in the S-ketamine group was significantly lower than that in the placebo group within 2 days after surgery (P < 0.05). The comparison between the two groups is shown in Figure D.

(5) There was no significant difference in the levels of CRP and IL-6 between the two groups on the 1 day and 3 days postoperatively (P > 0.05; Table 2).

There was no significant difference in side effects between the treatment and placebo groups (Table 2). The most common side effects in both groups were dizziness, nausea, and irritability. All side effects are self-limited and do not require medical treatment except for verbal assurance.

Our study found that in patients with CD undergoing bowel resection with mild to moderate depression, continuous intraoperative infusion of low-dose S-ketamine (0.12mg/kg/h) can effectively decrease the HAMD-17 score at one week postoperatively and relieve pain two days postoperatively. However, we did not find that a low dose of S-ketamine had an anti-inflammatory effect on these patients. In addition, S-ketamine does not increase the risk of psychiatric side effects or postoperative complications.

In many studies, S-ketamine has been shown to have rapid antidepressant effects. Our findings increase the possibility that intraoperative use of S-ketamine may improve postoperative mood and enhance resilience in a stressful surgical environment. In 2019, Liu et al. reported that in breast cancer patients with preoperative depression, intraoperative use of S-ketamine (0.125mg/kg during induction and then given according to the experience of the anesthesiologist) could reduce the patient's HAMD-17 score one month after surgery [12]. Wang et al. found that in the mild to moderate depressive patients who underwent laparoscopic total hysterectomy for cervical cancer, the HAMD-17 score of the S-ketamine group (0.25mg/kg/h after induction for 1 hour) was significantly lower than that of the control group in the first 3 days postoperatively [13]. In this study, we found that continuous intraoperative infusion of low-dose S-ketamine (0.25mg/kg during induction, followed by 0.125mg/kg/h) could effectively reduce the HAMD-17 score one week postoperatively in patients with CD with mild to moderate depression. The consistent results of these three studies are that intraoperative administration of S-ketamine can reduce the postoperative HAMD-17 score of patients with mild to moderate depression, but the difference is the duration of the antidepressant effect. This may be related to the type of disease, dosage, and interaction with other drugs. We think that this difference may be related to the dose, although it is impossible to compare the doses of the three studies. Wang et al. found that the antidepressant effect of the high dose group (0.5mg/kg/h after 1 hour of induction) was longer than that of the low dose group (0.25mg/kg/h after 1 hour of induction) [13].

Patients with mild to moderate depressive symptoms screened with PHQ-9 and HAMD- 17 before surgery participated in this study and must ensure population homogeneity to explore the antidepressant effect of S-ketamine. In this study, patients responded well to most of the projects in PHQ-9 and HAMD-17. Although the change in total score is an essential indicator of the change of severity of depressive symptoms, understanding the contribution of specific items to the change of total score is helpful in explaining the effect of treatment. There were statistically significant improvements in items 1, 2, 4, and 6 of PHQ-9 and items 1, 2, 7, and 10 of HAMD-17. Items 1 and 2 of PHQ-9 ("lack of interest/pleasure in doing things" and "feeling depressed, depressed or desperate") were considered to be the main symptoms of depression; depression was diagnosed only when the patient accepted at least one of these two items. These results provide a way for patients to experience clinical improvement, which is more specific than the total score.

The immune inflammatory reaction occurs in both depression and patients with inflammatory bowel disease (IBD), and some inflammatory factors are increased in the body [15]. Abautret-Daly et al. [16] found that the level of serum inflammatory factors in IBD patients with higher anxiety and depression scores was higher than that in patients with lower anxiety and depression scores. Serum CRP levels have been used as markers of disease activity and remission in IBD. CRP increases the permeability of the blood-brain barrier, suggesting that the increase of serum CRP in IBD patients will lead to central nervous system damage [17]. Higher CRP levels suggest a higher risk of developing a new type of depression [18]. Ketamine has anti-inflammatory effects on depression [19]. Studies including patients with treatment-resistant depression showed that pro-inflammatory cytokines (mainly IL-6) decreased 4 hours after a single intravenous injection of ketamine [20]. Another study showed that IL-6 and tumor necrosis factor α (TNF-α) levels decreased rapidly, and there was a correlation between the decline in TNF-α levels and the decrease in the Montgomery Asperger Depression rating scale (MADRS) scores [21]. In this study, we compared the CRP and IL-6 between the two groups at different time points postoperatively and found that the results were not statistically significant. This is different from previous studies [22], but it does not mean that S-ketamine does not have anti-inflammatory effects. Due to the large surgical trauma, the inflammatory response caused by surgery may far exceed the anti-inflammatory effects of ketamine. Therefore, further research is needed.

Many clinical trials have explored the use of ketamine to treat and prevent postoperative pain [23]. Low-dose ketamine (0.1-0.5mg/kg) is thought to relieve postoperative pain management [24, 25] when used as an adjuvant for local anesthetics, opioids, or other analgesics. In this study, we observed that the dosage of opioid analgesics in the S-ketamine group was significantly lower than that in the placebo group within 2 days postoperatively. This finding is similar to previous studies [26, 27], but differs from the results of Wang et al.'s trials on the effects of a single subanesthetic dose of ketamine on pain and mood after laparoscopic surgery, which may be related to the type of medication, the mode of administration and the nature of the disease. Of course, pain relief may help improve depression. However, we found that there was no difference in pain score between the two groups one week postoperatively, but there was a significant difference in depression score, indicating that the postoperative analgesic effect of S-ketamine was not the main factor of antidepressant. At the same time, the reduction of the postoperative opioid dose is of great benefit to the recovery of intestinal function in patients with CD [28].

In our study, we observed that the incidence of hallucination and dizziness was lower in the S-ketamine group. The dose of ketamine was selected as the intervention dose based on the consensus in the literature, which was much lower than the anesthetic dose (2000-3000ng mL-1) and did not cause strong hemodynamic fluctuations and severe psychiatric symptoms [29].

This study has several limitations. First, our study did not detect serum brain-derived neurotrophic (BDNF) and 5-hydroxytryptamine (5-HT) levels, and did not assess the correlation between HAMD-17 score and BDNF and 5-HT. Lepack et al. suggested that the release of BDNF is essential for the antidepressant behavior of ketamine [30]. The study also found that BDNF gene polymorphism is associated with the antidepressant efficacy of ketamine in patients with depression [31]. Secondly, the drugs like Dexmedetomidine used during and after surgery may interact with S-ketamine. Therefore, further research is needed to confirm these findings. Third, we only compared 1 dose of S-ketamine with a placebo but not with oral antidepressants, which often take more than 1 week to be effective. Finally, we only visited the patients 1 month postoperatively, which is far from enough to observe the disease development of patients with CD postoperatively.

In conclusion, this randomized, double-blind controlled study demonstrated that in patients with CD undergoing bowel resection with mild to moderate depression, intraoperative infusion of low-dose S-ketamine effectively relieved depression one week after surgery and reduced postoperative pain two-day. This study provides clinical evidence for applying S-ketamine in the treatment of POD.

DISCLOSURES

Name: Zhen Zhang.

Contribution: This author helped design the study, recruit patients, collect and analyze data, and write and revise the manuscript and accepted the final manuscript.

Name: Zhen-Yu Yuan.

Contribution: This author helped design the study, recruit patients, and accepted the final manuscript.

Name: Wen-Hao Zhang.

Contribution: This author helped design the study, revise the manuscript, and accepted the final manuscript.

Name: Yi-Bo Wang

Contribution: This author helped design the study, write the manuscript, and accepted the final manuscript.

Name: Li-Ying Cui.

Contribution: This author helped analyze the data and interpret the results.

Name: Bo-Xuan Lu.

Contribution: This author helped supervise the data collection and interpret the results.

Name: Yin-Xiao Lu.

Contribution: This author helped design the study, analyze the data, and review the manuscript.

Name: Hao Cheng.

Contribution: This author helped analyze the data and prepare the manuscript.

Name: Jie Zhang.

Contribution: This author helped analyze the data and prepare the manuscript.

Name: Da-Peng Gao.

Contribution: This author helped analyze the data and prepare the manuscript.

Name: Jian-Feng Gong.

Contribution: This author helped design the study, revise the manuscript, and accepted the final manuscript.

Name: Qing Ji.

Contribution: This author was the principal investigator. This author helped design the study, analyze data, write and revise the manuscript, and accepted the final manuscript.

There is no competing interests.

ACKNOWLEDGMENTS

We are grateful for the support of the Department of Anesthesiology and General surgery of Jinling Hospital affiliated to Medical College of Nanjing University.

Financial support and sponsorship: this work was supported by the Anaesthesia Department Research Fund of the Jinling Hospital affiliated to Medical College of Nanjing University.

Conflicts of interest: none.

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Intraoperative Low-dose S-ketamine Reduces Depressive Symptoms in Patients with Crohn’s Disease Undergoing Bowel Resection: A Randomized Controlled Trial

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1 | Introduction

2 | Methods

2.1 | Study design

2.2 | Randomization and masking

2.3 | Procedures

2.4 | Date collection

2.5 | Outcome measures

3 | Result

4 | Discussion

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