The Efficacy and Safety of S-ketamine in Elective Cesarean Section

Study Overview
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Brief Summary
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During the past years, a large number of clinical trials have investigated the use of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist racemic ketamine as an adjunct to local anaesthetics, opioids, or other analgesic agents for the management and prevention of postoperative pain. Actually racemic ketamine not only abolishes peripheral afferent noxious stimulation, but can also prevent the central nociceptor sensitization. S-ketamine, one of two enantiomers of racemic ketamine, has twice the analgesic potency of the racemate. Moreover, S-ketamine shows smaller nervous system and less psychotropic effects than racemic ketamine , which may make the drug more suitable for clinical use. Recently, S-ketamine has been approved to treat refractory depression (TRD) and major depressive disorder (MDD) by the FDA .S-ketamine may have greater clinical significance due to the high rate of maternal depression. Therefore, we plan to explore whether clinical use of S-ketamine can optimize anesthesia protocol and improve maternal prognosis.

Official Title
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The Efficacy and Safety of S-ketamine in Elective Cesarean Section: a Multi-center, Randomized, Double-blind, Placebo-controlled Clinical Study

Conditions
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Anesthesia, Analgesia, Depression, Cesarean Section, Parturition

Intervention / Treatment
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* Drug: S-ketamine
* Other: normal saline
* Drug: S-ketamine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ASA II; Parturients voluntarily sign an informed consent form, fully understands the purpose and significance of the study, and voluntarily abides by the clinical study procedure; Subjects who plan to be elected to undergo cesarean section under continuous combined spinal-epidural anesthesia; Age 18 to 40 years; The expected duration of surgery was less than 2h; Prenatal body mass index (BMI) was less than 35kg/m2。 Exclusion Criteria: Parturients with contraindications to continuous combined spinal-epidural anesthesia (such as history of central nervous system infection, spinal cord or spinal canal disease or surgery history, systemic infection, skin or soft tissue infection at the puncture site, coagulation dysfunction); Those who have a history of stroke, cognitive dysfunction, and epilepsy; Patients with a history of myocardial infarction, angina pectoris, or a serious arrhythmia such as second-degree and above-degree atrioventricular block within 6 months before screening; Pregnancy with other diseases (malignant tumors, hypertension during pregnancy, abnormal thyroid function, etc.); In the non-oxygen state, the peripheral blood oxygen saturation (SpO2) <92%; Subjects whose prolactin is greater than the upper limit of normal during the screening period; Alanine aminotransferase (ALT), aspartate aminotransferase (AST), glutamine transferase (GGT)> 1.5 times than the normal value, and total bilirubin is higher than the upper limit of normal value, and blood creatinine (Cr)>1.2 times than the upper limit of normal value; The effect of combined spinal-epidural anesthesia is not good, and other anesthetics are needed; People with a history of allergies to various foods and drugs; Continuous taking for any reason within 3 months before the screening, including but not limited to: ketamine, non-steroidal anti-inflammatory drugs (aspirin, acetaminophen, indomethacin, diclofenac, ibuprofen, parecoxib) Sodium, etc.), alpha adrenergic receptor agonists (dexmedetomidine hydrochloride, clonidine, etc.), glucocorticoids (dexamethasone hydrochloride, hydrocortisone, methylprednisolone, etc.), antiepileptic ( Carbamazepine, sodium valproate, etc.), sedation (diazepam, estazolam, midazolam, alprazolam, barbital, phenobarbital and chloral hydrate, etc.), Chinese herbal medicine or Chinese patent medicine with pain and sedative effect; There is a history of drug abuse and/or alcohol abuse within 1 year before the screening; Participated in other drug or device trials within 3 months before the screening; Subjects judged by the investigator to be unsuitable to participate in this clinical study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Saline group<br>Parturients were subsequently placed in a supine position with a left lateral tilt (15 ̊). Combined spinal-epidural anesthesia method (CSE) was performed at the L2-L3 or L3-L4 lumbar vertebral interspace, with 10～13mg 0.5% ropivacaine by a needle-through-needle technique. When adequate anesthesia to the T6 dermatome was achieved (Sensory and motor assessments were performed at 1 min intervals using pinprick testing and the modified Bromage score). Parturients received 10ml intravenous normal saline before surgery, If the anesthesia is inadequate, another 5ml 0.5% ropivacaine was given. Morphine hydrochloride 1 mg in saline 10 mL was injected by several times into the epidural space at the end of the operation. After the surgery, their PCA protocol consisted of 150 ug sufentanil and 24ml atropisetron diluted into 150 ml (2ml of basal infusion, a bolus of 0.5ml on demand, lock-out interval of 10 min, last for 48 h postoperatively); | Other: normal saline<br>* Saline group: pregnant women received saline, intravenous drip<br>* Other names: physiological saline;|
| Experimental: K1 group<br>Parturients were subsequently placed in a supine position with a left lateral tilt (15 ̊). Combined spinal-epidural anesthesia method (CSE) was performed at the L2-L3 or L3-L4 lumbar vertebral interspace, with 10～13mg 0.5% ropivacaine by a needle-through-needle technique. When adequate anesthesia to the T6 dermatome was achieved (Sensory and motor assessments were performed at 1 min intervals using pinprick testing and the modified Bromage score). Parturients received 10ml intravenous 0.2mg/kg before surgery, If the anesthesia is inadequate, another 5ml 0.5% ropivacaine was given. Morphine hydrochloride 1 mg in saline 10 mL was injected by several times into the epidural space at the end of the operation. After the surgery, their PCA protocol consisted of 150 ug sufentanil and 24ml atropisetron diluted into 150 ml (2ml of basal infusion, a bolus of 0.5ml on demand, lock-out interval of 10 min, last for 48 h postoperatively); | Drug: S-ketamine<br>* K1 group: pregnant women received 0.2mg/kg S-ketamine, intravenous drip;<br>* Other names: esketamine;|
| Experimental: K2 group<br>Parturients were subsequently placed in a supine position with a left lateral tilt (15 ̊). Combined spinal-epidural anesthesia method (CSE) was performed at the L2-L3 or L3-L4 lumbar vertebral interspace, with 10～13mg 0.5% ropivacaine by a needle-through-needle technique. When adequate anesthesia to the T6 dermatome was achieved (Sensory and motor assessments were performed at 1 min intervals using pinprick testing and the modified Bromage score). Parturients received 10ml intravenous 0.3mg/kg before surgery, If the anesthesia is inadequate, another 5ml 0.5% ropivacaine was given. Morphine hydrochloride 1 mg in saline 10 mL was injected by several times into the epidural space at the end of the operation. After the surgery, their PCA protocol consisted of 150 ug sufentanil and 24ml atropisetron diluted into 150 ml (2ml of basal infusion, a bolus of 0.5ml on demand, lock-out interval of 10 min, last for 48 h postoperatively); | Drug: S-ketamine<br>* K2 group: pregnant women received 0.3mg/kg S-ketamine, intravenous drip;<br>* Other names: esketamine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intraoperative anesthesia effect | Anesthesia effect is graded I-IV. Level I means that it is very satisfactory, while Level IV means other anesthesia methods are needed to complete the operation. We expect to reach level I. | Day 1 | 
| Ramsay Sedation Scale score | The Ramsay Sedation Scale (RSS) was the first scale to be defined for sedated patients and was designed as a test of rousability. The RSS scores sedation at six different levels, according to how rousable the patient is. | Day 1 | 
| Clock-in-the-Box(CIB) | The Clock-in-the-Box (CIB) is a rapidly administered cognitive screening measure which has been previously validated with cognitive screening and neuropsychological assessments. The CIB is scored on a 0-8 point scale and the total score includes two separate subscale scores. The higher scores reflect better performance. | Day 0 & Day 2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PHQ-9 | PHQ-9 is the major depressive disorder(MDD) module of the full PHQ. Used to provisionally diagnose depression and grade severity of symptoms in general medical and mental health settings. Scores each of the 9 DSM criteria of MDD as 0 (not at all) to 3 (nearly every day), providing a 0-27 severity score. Higher PHQ-9 scores are associated with decreased functional status and increased symptom-related difficulties, sick days, and healthcare utilization. | Day 0 & Day 3 & Day 8 & Day 43 | 
| Edinburgh Postnatal Depression Scale(EPDS) | EPDS is a valuable and efficient way of identifying patients at risk for perinatal depression. Mothers who score above 13 are likely to be suffering from a depressive illness of varying severity depression. | Day 3 & Day 8 & Day 43 | 
| Apgar score | The Apgar score is a test given to newborns soon after birth. This test checks a baby's heart rate, muscle tone, and other signs to see if extra medical care or emergency care is needed. The test is usually given twice: once at 1 minute after birth, and again at 5 minutes after birth. | Day 0 | 
| placental transfer of S-ketamine | Placental transfer was evaluated based on the whole blood concentrations of S-ketamine in the maternal and cord blood | Day 0 | 
| blood gas | Blood gases are a group of tests that are performed together to measure the pH and the amount of oxygen (O2) and carbon dioxide (CO2) present in a sample of blood | Day 0 | 
| umbilical arterial (UA)/umbilical venous (UV) ratio | UA/UV ratio was evaluated based on the blood concentrations of S-ketamine in the umbilical arterial and umbilical venous blood | Day 0 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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S-ketamine, efficacy, safety, Postpartum depression