A Multicenter Study of the Efficacy and Safety of Esketamine for Analgesia During
Phase: PHASE4
Conditions: Fetal or Neonatal Effect of Damage to Placenta From Caesarean Section
Sponsor: Women's Hospital School Of Medicine Zhejiang University

Research program 
Name: A Multicenter Study of the Efficacy and Safety of Esketamine for 
Analgesia During Cesarean Section 
Version: 3.0 
Version date: 2023.7.18 
Project Guidance: 
Group Leader: Chen Xinzhong 
Planned start time: August 2020 
Statistical setting: Women’s Hospital, School of Medicine, Zhejiang 
University 
 
1. Research Background: 
In recent years, with the development of anesthesiology and the 
continuous improvement of anesthesia technology and drugs, the focus of 
anesthesiologists' work has changed from the successful completion of 
surgery in the past to the comfort and safety of the present, and anesthesia 
also pays more attention to reducing the impact of surgical operation and 
anesthesia factors on the physiological, psychological and spiritual 
aspects of patients. Epidural anesthesia is widely used in cesarean section 
because of its good controllability and high safety. Although epidural 

anesthesia can provide relatively perfect analgesia and muscle relaxation, 
it can not completely block the visceral nerve, so the pregnant women 
often cry out due to the pain and discomfort of peritoneal traction during 
the operation to explore the uterus, pull the peritoneum and deliver. Even 
if the block effect is good, the parturients are often accompanied by 
different degrees of mental tension and anxiety due to the fear of surgery. 
These phenomena not only bring painful memories and mental trauma to 
the maternal, but also affect the operation and operation process of the 
surgical operator, resulting in the need to change the anesthesia method or 
the maternal satisfaction with anesthesia is reduced. Therefore, it is 
necessary for epidural anesthesia and cesarean section operation to assist 
appropriate intravenous analgesics in order to reduce the tension, anxiety 
and peritoneal traction reaction of the pregnant women. 
Ketamine is the only intravenous anesthetic with analgesic effect. As 
a non-specific antagonist of methyl-D-aspartate receptor (NMDA), 
ketamine has the characteristics of rapid analgesic effect, short duration 
of anesthetic effect and slight effect on protective reflex of throat, etc. 
Ketamine is widely used in intraoperative and postoperative analgesia, 
which can increase maternal tolerance and comfort of surgery. It has been 
widely used in cesarean section [1]. However, studies have confirmed 
that ketamine can cause hallucinations, delirium, nightmares and other 
mental symptoms, affecting patients' cognitive function and leading to 

postoperative cognitive dysfunction [2,3]. Esketamine is a right-optical 
isomer of ketamine, and its affinity to NMDA, opioid receptor and 
M-choline receptor is 3 to 4 times, 2 to 4 times and 2 times higher than 
that 
of 
levoketamine, 
respectively, 
while 
its 
inhibition 
of 
5-hydroxytryptamine receptor is only half of that of levoketamine, and its 
inhibition of norepinephrine reuptake is stronger [4]. Esketamine 
anesthetic analgesic hypnosis intensity is twice that of ketamine, to 
achieve the same anesthetic effect using only half the dose of the latter. 
The induction dose of intravenous anesthesia is 0.5 to 1 mg/kg, and the 
maintenance dose is 0.5 to 3 mg/kg*h. A single administration of 0.125 ~ 
0.25 mg/kg can achieve analgesic and sedative effects [5]. Since the side 
effects of ketamine are dose-dependent, the use of lower doses of 
esketamine can reduce the occurrence of side effects of anesthesia [6]. 
At present, many narcotic drugs can pass through the placenta to a 
certain extent and have a certain impact on the mother and child. Due to 
the characteristics of the placental barrier, whether a drug passes through 
the placenta and its transport volume are jointly determined by the 
physical and chemical properties of the mother, placenta, fetus and drug. 
Any change in the internal environment of the mother and the fetus can 
have an impact on the way the drug is present. Maternal factors: maternal 
blood concentration, route of administration, internal environment, 
pregnancy complications, etc. Fetal factors: liver development degree, 

internal environment, drug metabolism and excretion ability, etc. 
Placental factors: metabolic environment, hemodynamics, maturity, etc. 
Drug factors: concentration, plasma protein binding power, fat solubility, 
molecular weight, etc. High concentration, low molecular weight, low 
plasma protein binding rate, high fat solubility and maternal fetal acidosis 
can promote placental transfer of drugs [7]. Ketamine is highly fat soluble 
and easily passes the placental barrier. Clinical Guidelines for Obstetric 
anaesthesia (2008) state that ketamine can cross the placenta rapidly, but 
intravenous administration of 1-1.5mg/kg of ketamine has no significant 
effect on the fetus. Chinese Expert Consensus on obstetric anesthesia 
(2017) pointed out that ketamine has advantages for pregnant women 
with asthma and mild hypovolemia, while pregnant women with 
hypertension and severe hypovolemia are contrainidated. Intravenous 
injection of 1-1.5 mg/kg ketamine has no significant effect on the fetus, 
and if the dose is too high, it may cause mental symptoms and increase of 
uterine tone and respiratory depression of the newborn. The Miller 
Anesthesiology report states that 25-50μg of ketamine can be used to 
assist cesarean section when intra spinal anesthesia block is incomplete, 
and that large doses of ketamine (> 2mg/kg) can cause psychiatric 
symptoms and increased uterine tone, as well as lower Apgar scores and 
abnormal muscle tone in newborns. 

However, the analgesic effect of intravenous esketamine for cesarean 
section under intravertebral anesthesia has not been studied, especially 
the analgesic effect and safety of esketamine in cesarean section, such as 
placental transport of the drug and its effects on the newborn and the 
mother have not been clarified. 
 
2. Method 
2.1. Randomization and Blinding 
Random allocations were generated using SPSS software, version 22.0 
(IBM Corp) in a 1:1 ratio. Assignments were concealed in sequentially 
numbered opaque envelopes. Before anesthesia, study coordinators who 
otherwise were not involved in the trial opened the envelopes according 
to 
the 
recruitment 
sequence, 
prepared 
esketamine 
or 
an 
identical-appearing saline placebo, and gave the study drugs to the 
attending anesthesiologists. All patients, anesthesiologists, other health 
care team members, and investigators who were responsible for data 
collection and follow-ups were blinded to group allocation. 
 
2.2. Anesthesia Management and Intervention 
No premedication was administered. In the operating room, heart 

rate and oxygen saturation were monitored continuously, and blood 
pressure was noninvasively measured every 5 minutes. Epidural 
catheterization was performed with parturients in the left lateral decubitus 
position. A 16-G Tuohy needle was used for epidural puncture in the 
L2-L3 intervertebral space. After confirmation of the epidural space by 
the loss of resistance to air method, a catheter was inserted 3 to 4 cm in a 
cephalad direction. Parturients were returned to the supine position with a 
15° tilt to the left. Oxygen was provided at 5 L/min via a face mask. 
A test dose of 5 mL of 1.5% lidocaine was given. After a 5-minute 
observation, 10 mL of 0.75% ropivacaine was given, followed by an 
infusion of 0.75% ropivacaine at 3 to 5 mL/h. The upper sensory block 
was targeted between the T4 and T6 levels. If not achieved, a 
supplemental dose of 5 mL of 0.75% ropivacaine was given. Study drugs 
were administered when the targeted upper sensory block level was 
achieved (approximately 2 minutes before incision). Specifically, 0.25 
mg/kg of esketamine was administered intravenously for 1 minute for 
patients in the esketamine group; the same volume of normal saline was 
injected for patients in the control group. During epidural anesthesia, 
fluid infusion was administered per routine. Blood pressure was 
maintained within 20% from baseline. At the end of surgery, a 
patient-controlled 
epidural 
analgesia 
device 
was 
attached 
for 
postoperative analgesia, which was established with 0.2% ropivacaine 

and programmed to deliver a continuous infusion at 2 mL/h. 
2. 3. Data Collection and Outcome Assessment 
Baseline data included demographic characteristics, pregestational 
comorbidity, number of gravidity and parturitions, duration of gestation, 
and ASA classification. Intraoperative data included durations of 
anesthesia and surgery, fluid balance, use of vasopressors, intervals from 
study drug administration and uterine incision to delivery, and neonatal 
data. Intervals from study drug administration to neonatal delivery and 
from uterine incision to neonatal delivery were also recorded. 
Primary outcomes included maternal pain intensity and sedation 
score immediately after fetal delivery. Pain intensity was assessed with 
the numeric rating scale (NRS; an 11-point scale, with 0 indicating no 
pain and 10 indicating the worst pain). Maternal sedation level was 
assessed with the Ramsay Sedation Scale (with 1 indicating restless; 2, 
completely awake, quiet, and cooperative; 3, drowsy but responding to 
verbal commands; 4, lightly asleep but responding to touch or pain; 5, 
asleep but slowly responding to touch or pain; and 6, deeply asleep and 
does not respond) at the same time points as above. 
Secondary outcomes included maternal pain intensity and sedation 
score at other time points(before anesthesia, immediately after anesthesia, 
surgical incision, 5 minutes after study, end of surgery, 6 hours after 

surgery, and 12 hours after surgery. drug administration), neonatal Apgar 
score assessed at 1 and 5 minutes after birth, and postnatal umbilical vein 
blood gas pH value. Among other outcomes, mean blood pressure, heart 
rate, and pulse oxygen saturation were measured before anesthesia, 
immediately after anesthesia, at incision (2 minutes after study drug 
administration), 5 minutes after study drug administration, immediately 
after fetal delivery (10 minutes after study drug administration), at end of 
surgery, and 1 hour after surgery. The requirement of neonatal ward 
admission and length of hospital stay after surgery were recorded. After 
childbirth, samples of maternal arterial blood, neonatal umbilical arterial 
blood, and umbilical venous blood were collected in the esketamine 
group (n = 13) and stored in a −20 °C refrigerator. Esketamine 
concentrations were measured with reverse-phase high-performance 
liquid chromatography  
    Other Pre-specified Outcomes included Adverse events including 
hypotension, hypertension,  bradycardia, tachycardia and desaturation. 
Adverse events were recorded as Frequency of occurrence between the 
time the patient entered the operating room and the end of surgery.  
Offspring’s neurodevelopment was measured by the Ages and Stages 
Questionnaire, third edition (ASQ-3) at 2 years after birth.The ASQ-3 
assesses 5 developmental domains: gross motor skills, fine motor skills, 
problem-solving ability, communication, and personal and social skills. 

Each domain is assessed by 6 questions ascertaining achievement of 
relevant skills and answered as yes (10 points), sometimes (5 points), or 
not yet (0 points). Scores for individual items are summed to give an 
overall continuous score for each of the 5 domains (possible range, 0-60). 
Mothers' memories of childbirth was assessed by The Birth Memories 
and Recall Questionnaire (BirthMARQ) at 2 years after childbirth,which 
focused on parents’ positive, negative or mixed emotions at the birth/in 
recalling the event. Each item (e.g. ‘my emotions at the time were 
extremely negative’) was rated on a scale ranging from 1 (strongly 
disagree) to 7 (strongly agree). 
 
3. Ethical considerations (subject protection, informed consent, privacy 
and confidentiality, etc.) 
(1) All subjects will sign informed consent before the start of the study, 
and the experimenters will keep patient information and experimental 
results absolutely confidential; 
(2) The purpose of this study was to study the efficacy and safety of 
esketamine for analgesia during cesarean section, and it was carried out 
on the basis of ensuring the normal implementation of daily anesthesia; 
The blood collection operation required by the project is a very mature 
and common test item in clinical practice, so it will not bring any adverse 

effects on the psychological and physiological of the subjects. 
(3) The cost of esketamine is within the scope of medical insurance, 
and the cost of blood sample delivery does not need to charge patients 
additional costs, and will not increase the financial burden on patients; 
(4) Through the study on the effectiveness and safety of esketamine in 
the analgesia during caesarean section, in order to guide the intravenous 
analgesia during epidural anesthesia caesarean section operation, so as to 
reduce the tension and anxiety of parturient women and improve the 
comfort and satisfaction of patients in the perioperative period. 
 
4. Data management 
The Case Report Form shall be filled out by the investigator and must 
be completed by each enrolled case. The completed Case Report Form 
shall be uniformly submitted to the group leader, and the group leader 
shall designate two physicians or secretaries who are not directly 
involved in this experiment to conduct data entry and management. In 
order to ensure the accuracy of the data, two data managers should 
independently make two copies of the input and proofread. After the 
completion of statistical analysis, the statistical analyst will write the 
general and sub-reports of statistical analysis, and submit the analysis 
report to the main researcher of this experiment.