S-Ketamine As An Adjuvant in Patient-controlled Intravenous Analgesia for Prevention of Postpartum Depression: A Randomized Controlled Trial

Yaqian Han Department of Anesthesiology and Perioperative Medicine, Henan University People's Hospital; Henan Provincial People's Hospital, Zhengzhou, China Pule Li Department of Anesthesiology and Perioperative Medicine, Henan Provincial People’s Hospital; People’s Hospital of Zhengzhou University, Zhengzhou, China Mengrong Miao Department of Anesthesiology and Perioperative Medicine, Henan Provincial People’s Hospital; People’s Hospital of Zhengzhou University, Zhengzhou, China Yuan Tao Department of Anesthesiology and Perioperative Medicine, Henan Provincial People’s Hospital; People’s Hospital of Zhengzhou University, Zhengzhou, China Kang Xia Department of Anesthesiology and Perioperative Medicine, Henan Provincial People’s Hospital; People’s Hospital of Zhengzhou University, Zhengzhou, China Jiaqiang Zhang (  Zhangjiq@zzu.edu.cn ) Department of Anesthesiology and Perioperative Medicine, Henan Provincial People’s Hospital; People’s Hospital of Zhengzhou University, Zhengzhou, China


Introduction
Postpartum depression (PPD) is a common psychosocial disorder that can have adversely affect the life of the mother, as well as the baby and family [1]. It has been reported the incidence of PPD is 1%-52.1% in China [2,3], and severe depression that requires hospitalization is more likely to occur after childbirth than in women at any other time [4], because childbirth is a powerful trigger for mania and psychosis, and episodes at this period could substantially increase the risk of suicide, which is a leading cause of maternal death [5]. Therefore, reducing the occurrence of puerperal getting PPD is necessary.
In obvious studies, ketamine has been proved to be a powerful drug to release depression and reduce suicidal tendency in depressed patients [1,6,7]. Some reports have proved that the intravenous injection of ketamine during cesarean section could be effective in preventing postpartum depression until 3 days to 6 weeks [1,3,8]. S-ketamine, the dextral resolution of ketamine, its anesthetic effect is twice as effective as the racemic mixture and about three times as potent as (R)-ketamine [9][10][11][12][13]. Besides, as the side effects of ketamine are dose-dependent, S-ketamine has a lower incidence of adverse events than ketamine when we aimed to arrive at the same sub-anesthetic effect [14]. So we presume that S-ketamine used for PCIA may be a good choice as it can continuedly to infuse for 2 days at about 0.01mg/kg/h. Therefore, we hypothesized that S-ketamine as an adjuvant in patient-controlled intravenous analgesia can prevent postpartum depression.

Study design
The research scheme was approved by the Ethics Committee of Henan Provincial people's Hospital Eligibility criteria included the following: (1) undergoing cesarean delivery in our hospital, (2) the age of puerperal is ≥18 and ≤45, (3) the birth age is ≥36 and ≤42 weeks, (4) BMI 17-36kg/m2, and (5) ASA grade ranged -; Exclusion criteria included: (1) The puerperal has experienced depression and has been diagnosed as depression by a psychiatrist before, (2) the pregnant has experienced domestic violence before, (3) the pregnant with a serious obstetric complication or serious foundational diseases, (4) the newborn has serious genetic or congenital diseases, and (5) multiple pregnancies.

Randomization and blinding
Parturients were randomly assigned in a 1:1 ratio to S-group or C-group using SPSS 25.0. Parturients signed informed consent forms by themselves on the day of undergoing cesarean. Anesthesiologists, parturients, follow-up investigators were blinded throughout the study period. Staff who distribute PCIA generated the random allocation sequence, knew the group assignment of patients.
In our study, EPDS score≥ 10 was considered to diagnose postpartum depression.
Any discomfort (headache, nausea, dizziness, drowsiness, and vomit, et al) will be recorded during they use PCIA.
The scores of EPDS were tested before surgery, 3 days, 14 days, and 28 days after surgery. On the days of 3, 14, 28 days after cesarean, parturients were contacted by phone or WeChat to complete EPDS by investigators.
Adverse events including headache, nausea, dizziness, drowsiness and vomit were recorded during parturients using PCIA.

Sample size and statistical analysis
According to previous studies [2,3], when the EPDS score ≥10 was used as the detection threshold of postpartum depression, the prevalence rate of postpartum depression in China is 28.2%. We assumed that ketamine used for PCIA will reduce postpartum depression to 15%; with 80% statistical power, α = 0.05 for two-tailed tests, PASS 15.0 software yielded a sample size of 300 (150 parturients in each study arm); assuming a 20% drop-out rate, the sample size was nally established at 375.
Continuous variables are presented as the mean ± standard deviation or as the median (min and max range); t-test or Mann-Whitney U test was performed for between-group comparisons. Categorical variables are presented as percentages; these data were compared using X2 test or Fisher's exact test.
The SPSS 25.0 software was used for the statistical analysis. A value of P < 0.05 was considered statistically signi cant for two-tailed tests.

Results
During the time of 1 September 2019 to 15 July 2020, a total of 451 parturients were eligible, 71 parturients chose vaginal delivery for various causes. So 380 were enrolled in this trial, and 53 parturients refused to continuously participate in this study after cesarean section. Thus, 327 parturients were ultimately enrolled in this trial. During 28 days' follow-up, 52 subjects were lost. So, 275 parturients were nally included in analyzed ( Figure 1).

Baseline characteristics
The baseline characteristics of subjects were listed in Table 1 and were well balanced between the S group and C group. Arti cial 14 8 Major family accident 1,2 1 2 0.59 1 We record these data until 28 days after cesarean section, 2 Unemployment, lost families, etc.

Discussion
In this trial, we found that 0.01mg/kg/h S-ketamine used in PCIA for women who undergo cesarean can reduce the incidence of postpartum depression and scores of EPDS within 14 days effectively, simultaneously not increasing side reaction. Besides, PPD was increased along with time owed within 1 month in both groups we observed, which is consistent with the previous studies [1,15,16].
Some reports have shown ketamine's short and rapid effect on reducing parturient's depression symptoms [12,17,18]. However, these reports differed from our study to some extent. In a study by Yao. J et al[8], healthy women scheduled for cesarean delivery were received intravenous ketamine 0.25 mg/kg intraoperative but not postoperative. interestingly, their results showed that PPD was effectively reduced at 1 week postpartum, instead of at 2 weeks and 4 weeks. Besides, the prevalence of adverse events such as headache, hallucination, and dizziness were higher in the ketamine group during the operation. The reason why their results were inconsistent with ours may be because it was only using ketamine once in subanesthetic dose instead of continuing intravenous administrate. our study chose a continuous infusion of 0.01mg/kg/h ketamine used in PCIA, which can last a long time to prevent or therapy depression. The following methodological differences between the current trial and Yao's trial might partially explain the discrepant ndings: intervention differ, compliance with trial protocols, population local distribution, rigor in depression ascertainment.
EPDS scores are usually used to screen for postpartum depression when scores are≥10 [19,20], and it is suggested that depression be tested or diagnosed before 6 weeks postpartum [21][22][23][24][25]. The questionnaire we used was the Chinese version of EPDS, which was proved to be well-validated to Chinese women. In a previous study [16], parturients who were given ketamine 0.5 mg/kg at 10 min after childbirth, and 160 mg ketamine in PCIA postoperative, found that it effectively reduced postpartum depression and postpartum blue in 4 days after cesarean. It can support our result that the incidence of PPD in the S group reduced signi cantly at 3 days and 14 days postoperatively to a certain extent.
Recent studies have demonstrated that a low dose of ketamine can reduce the incidence of anesthetic side reactions [14]. A review recently advised that parturients outside the perioperative setting could use ketamine as an analgesic or sedative to mitigate mood and depression [7], which was corresponded to our results. In our study, the VAS score was signi cantly lower in S-group during they used PCIA. The incidence of headache, nausea, dizziness, drowsiness, and vomit decreased to a certain extent, though no signi cant difference was found.
Earlier research showed that single doses of intravenous S-ketamine or ketamine use during cesarean section delivery may not affect the breastfed infant or lactation [2]. The dose of S-ketamine we administrated is lower than sub-anesthetic, so we believe 0.5mg/Kg S-ketamine diluted in 100ml saline intravenous lasts 48h is safe for both mother and infant [26,27].
This trial also has some limitations. First, the trial sample size is not big enough, and the population is residents. Maybe we should conduct multicenter studies to enroll more subjects in future studies. Second, in studies of Salloum et al, time to relapse depression after successful treatment of ketamine appears to follow a dose-response relationship, where higher dosage leads to increased time to relapse [28,29]. We chose the dose of S-ketamine in PCIA as 0.5mg/Kg, so we don't know if more or fewer doses could show a better effect on preventing postpartum depression. Future research could explore a better dose of Sketamine as an adjuvant in PCIA, which to guide doctors to prevent PPD. Third, we followed up with parturients until 28 days postpartum, because of more mixed factors such as stressful life events, poor social support, poor marital relationship, personal vulnerability, and low socioeconomic status [2,15,[30][31][32][33][34][35], which could in uence the future incidence of PPD along with time ow. By the way, we recorded these elements in 28 days after cesarean section and there was consistency between the two groups.
Maybe those factors could in uence our primary outcomes but we did not record them. Future studies should consider involving these elements in baseline characteristics.

Conclusions
In conclusion, 0.01mg/kg/h S-ketamine as an adjuvant in patient-controlled intravenous analgesia can signi cantly reduce the incidence of postpartum depression within 14 days and relieve postoperative pain within 48h after cesarean section, without increasing the incidence of adverse reactions. This nding supports the e ciency and safety of S-ketamine used in PCIA to reduce postpartum depression. Future researches should include a larger number of parturients in similar studies, and the interactional relationships between serologic indexes and precipitating risk factors for postpartum depression should be explored.  <p> EPDS scores at different time</p><p> # P value 0.05; Day 0, Day 3, Day 14, and Day 28 refers to before cesarean, 3 days,14 days, and 28 days after cesarean.</p> Figure 4 <p> VAS(4a) and RSS(4b) scores at different times during using PCIA.</p><p> **:P 0.05, T1, T2, T3, T4, and T5 means 4h,8h, 12h, 24h, and 48h after they begin using PCIA.</p>