The current study was a prospective, randomized, double-blind controlled clinical trial. The study was performed following the tenets of the Declaration of Helsinki. Approval to conduct the study was obtained from the institution review board (IRB) of the Affiliated Hospital of Guizhou Medical University (Ref. No. 2022017 K/IRB). Written informed consent was acquired from all patients. The study protocol was registered at chiCTR.org. (ChiCTR2200058324; principal investigator: CHEN Jiejuan; date of registration: April 06/04/2022, no protocol amendment or study changes after start of the trial). This study was conducted according to the relevant CONSORT guidelines.
A total of 178 female pregnant patients scheduled for painless abortion surgery for pregnancy termination were enrolled in the present study. The patients were aged 18–45 years, had a body mass index (BMI) < 28 kg m− 2, had grade I-II physical status based on the American Society of Anesthesiologists (ASA) criteria, and were diagnosed with early intrauterine pregnancy. The exclusion criteria for the study were as follows: hearing impairment, previous vaginal delivery, modified equine score grade III and above, recent myocardial infarction (within the previous 7 days), known allergy to fentanyl, propofol or esketamine, severe respiratory diseases (pneumonia or congestive heart failure), hepatic and renal failure, history of neurological disorders (seizure at the onset with postictal residual neurological impairments) and convulsions.
The study was conducted using the emergency equipment such as ventilators, monitoring with defibrillator with external pacing facility, and syringe pumps in the abortion operating room of Affiliated Hospital of Guizhou Medical University. Patients were randomly assigned to four groups using computer-generated random numbers placed into separate opaque envelopes, which were opened by the study investigator just before performing the procedure. The study groups were as follows: group F; patients received a combination of 1 μg kg− 1 fentanyl and propofol, group EL; subjects received 0.2 mg kg− 1 esketamine and propofol, group EM; patients were administered with 0.25 mg kg− 1 esketamine and propofol and group EH; participants received 0.3 mg kg− 1 esketamine and propofol. Gynecologists who performed the abortion surgery, all participants, and researchers involved in data collection were blinded to group allocation till the end of the study. All patients underwent fasting for 8 h before going through the procedures.
Standard monitoring was performed after establishing IV access (noninvasive blood pressure, ECG, SpO2). A simple oxygen mask (2–4 L/min) was connected to supply oxygen to the patients. Subsequently, anesthesia induction was started after 3 min of oxygen inhalation.
The patients in group F (n = 45) received intravenous (IV) administration of 1 μg kg− 1 fentanyl for approximately 30 s, followed by 2 mg kg− 1 propofol (IV) for approximately 30 s, and 0.05 mg kg− 1 propofol (IV) when the modified observed assessment of alertness/sedation (MOAA/S) score  was ≥4 at the start of the surgery or 2 min after IV administration of propofol injection and the propofol dosage repeated as required.
Patients in the EL group (n = 45) intravenously received esketamine 0.2 mg kg− 1 for approximately 30 s, followed by 2 mg kg− 1 propofol (IV) for about 30 s, and 0.05 mg/kg propofol (IV) was administered when the MOAA/S score was ≥4 at the start of the surgery or 2 min after IV administration of propofol and the propofol dosage repeated appropriately.
Participants in the EM group (n = 44) were intravenously administered with 0.25 mg kg− 1 esketamine for about 30 s, followed by 2 mg kg− 1 propofol (IV) for approximately 30 s, and 0.05 mg/kg propofol (IV) when the MOAA/S score was ≥4 at the start of the surgery or 2 min after intravenous injection propofol and the propofol dosage repeated as required.
Patients in the EH group (n = 44) received 0.3 mg kg− 1 esketamine (IV) for about 30 s, followed 2 mg kg− 1 propofol (IV) for approximately 30 s, and 0.05 mg/kg propofol (IV) when the MOAA/S score was ≥4 at the start of the surgery or 2 min after intravenous administration of propofol and the propofol dosage repeated appropriately.
The anesthesiologist determined the required additional dose of propofol required to achieve a MOAA/S score ≤ 2. The sedation level of the patient was assessed by determining the MOAA/S score (in a scale of 0 to 5). In this scale, a score of 0 denotes no response to painful stimuli; 1 indicates response to painful stimuli only (squeezing at the Trapezius site); 2 represents response to light pushing and vibration; 3 denotes response to loud or repeated name calling; 4 indicates delayed response to name calling with normal tone; 5 represents sensitive response to name calling with normal tone. All patients were spontaneously breathing during the process.
Any adverse effects of the treatments were recorded and treated. The adverse effects observed in this study included; 1- hypotension: defined as systolic arterial pressure < 80 mmHg, or decreased baseline systolic blood pressure > 20%, which was treated with 5 mg ephedrine IV; 2- Bradycardia: defined as decrease in HR < 50/min, and was treated through IV administration of atropine 0.5 mg; 3- Hypoxia: defined as SpO2 < 90%, treated by assisted manual ventilation using a face mask; 4- Somatic motor reactions, treated with 0.5 mg kg-1 propofol IV; 5- Nausea/vomiting, treated by IV administration of 0.25 mg palonosetron.
Perioperative changes of vital signs including MAP, HR, SPO2, and MOAA/S scores were recorded a minute before administration of the drug (T0), immediately at MOAA/S ≤ 2 points (T1), immediately after the start of the surgery (T2), 1 min after the start of the surgery (T3), immediately after the end of the surgery (T4), and at the moment when the patient woke up from anesthesia (T5).
The total additional propofol dose, surgery time, anesthesia induction time, recovery time (time from last dose to time a MOAA/S score ≥ 4 was achieved), dischargeable time, postoperative pain (VAS score at awakening and VAS score at discharge) and the level of injection pain were recorded.
The discharge criteria evaluation was performed by the investigator 10 min after the end of the surgery and every 5 min thereafter until the subject met the criteria for leaving the hospital accompanied by a family member. Criteria for leaving the hospital were as follows: blood pressure and heart rate fluctuations less than 20% of preoperative basal values and stable for ≥10 min; no or mild pain; no or mild nausea and vomiting; no dizziness under sitting position and at the end of walking; subjects able to walk 2 m or more in a straight line on their own after vital signs were stable and monitoring equipment was removed.
Patients were requested to score their satisfaction level during the procedure to record any painful or other undesirable intra-procedural events after full recovery and when the patients were alert enough to express their attitude regarding the intraprocedural events. The surgeon and anesthesiologist also reported their satisfaction levels on the procedure.
The primary outcome of the present study was the incidence of perioperative hypotension. Secondary outcomes included: incidence of perioperative complications such as bradycardia, hypoxia, somatic motor reactions, and nausea/vomiting. Perioperative changes in vital signs, the total additional propofol dose, surgery time, anesthesia induction time, and recovery time, dischargeable time, postoperative pain (VAS score at awakening and VAS score at discharge) and injection pain were determined.
A review of literature showed that there were no similar previous studies on determination of the sample size at the time of designing the study protocol. Therefore, an external pilot study comprising 10 patients in each group was conducted. The results of the pilot study were not included in the full-scale study. The pilot study showed that the incidence of perioperative complications was 3 (30%) in the F group versus 0 (0%) in the EL group, 0 (0%) in the EM group and 0 (0%) in the EH group. The minimal sample size of patients required to get a statistical power level of 0.90 and alpha level at 0.05 was 36 subjects in each group. The calculated sample size was increased by 20% to 45 participants in each group in case of patient dropout.
Collected data were organized, tabulated, and statistically analyzed using SPSS statistical version 25 software (SPSS Inc., USA).
A F-test was conducted to compare the mean values (age, weight and BMI, the surgery time, the anesthesia induction time, the recovery time, and the dischargeable time) of the four groups and data were presented as mean ± standard deviation (SD). Chi-square test was performed for analysis of independent qualitative data. Fischer’s test was used when chi-square test conditions were not met. ASA, side effects and additional propofol dosage data were presented as numbers and percentages and χ2 test was conducted. A two-sided P-value < 0.05 was considered statistically significant.