Efficacy and Safety of Propofol in Combination With Different Esketamine Doses for Anesthesia During Loop Electrosurgical Excision Procedure
Phase: PHASE4
Conditions: Esketamine, Loop Electrosurgical Excision, Propofol
Sponsor: Qian Wu

The effectiveness and safety of propofol combined with 
different doses of esketamine anesthesia during loop 
electrosurgical excision 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                            January 1,2022 

                    Study protocol 
The effectiveness and safety of propofol combined with different doses 
of esketamine anesthesia during loop electrosurgical excision  
 
1. Backgroud 
   Loop electrosurgical excision procedure (LEEP) is an effective and widely 
used surgical treatment for cervical lesions like:cervical intraepithelial neoplasia
(CIN),cervical erosion,cervicitis and so on [1]. The loop electrosurgical generate
s high frequency electric waves , When contacts with the tissue, it absorbs the
 high frequency electric waves and instantly generates high heat to achieve the
 purpose of tissue resection.Despite LEEP being a simple procedure, it causes 
significant pain and discomfort. It was reported that the mean VAS score durin
g LEEP was as high as 4, even in the presence of local anesthesia [2]. Physic
al movement during the surgery severely impacts the surgeon’s ability to perfor
m the procedure accurately. Therefore, an effective anesthesia regimen is critica
l for a successful LEEP. 
Propofol is common intravenous anesthetic for LEEP, with sedative and amnestic 
properties as well as a rapid onset of action and recovery [3]. However, propofol does 
not have analgesic effects, and it increases the risks of hemodynamic and respiratory 
depression in a dose-dependent manner. Esketamine (ESK),as a derivative of 
phencyclidine is an enantiomer of ketamine, with similar sedative and analgesic effects, 
faster clearance, and lower incidence of toxicity compared with ketamine [4]. 
So far,only a few studies have investigated the application of propofol combined 
with other analgesics in LEEP ,like fentanyl , ketamine or dezocine [5] [6].  
Reference 
[1] Ramirez SI, Lutzkanin A. Management of cervical dysplasia using office loop 
electrosurgical excision procedure. Prim Care. 2021;48:583-595. 
[2] Limwatanapan N, Chalapati W, Songthamwat S, et al. Lidocaine spray versus 
paracervical block during loop electrosurgical excision procedure: A randomized trial. 

J Low Genit Tract Dis. 2018;22:38-41. 
[3] Yan T, Zhang GH, Wang BN, et al. Effects of propofol/remifentanil-based total 
intravenous anesthesia versus sevoflurane-based inhalational anesthesia on the release 
of VEGF-C and TGF-beta and prognosis after breast cancer surgery: a prospective, 
randomized and controlled study. BMC Anesthesiol. 2018;18:131. 
[4] Song N, Yang Y, Zheng Z, et al. Effect of Esketamine Added to Propofol Sedation 
on Desaturation and Hypotension in Bidirectional Endoscopy: A Randomized Clinical 
Trial. JAMA Netw Open. 2023; 6(12):e2347886.  
[5] Oh C, Kim Y, Eom H, et al. Procedural sedation using a propofol-ketamine 
combination (ketofol) vs. propofol alone in the loop electrosurgical excision procedure 
(LEEP): A randomized controlled trial. J Clin Med. 2019;8: 943. 
[6]Liu Z, Zou X, Sun X, et al. Loop electrosurgical excision procedure under propofol 
intravenous anesthesia combined with nano-silver gel in the treatment of cervicitis. Cell 
Mol Biol. 2022;68(3):96-104. 
 
2. Objective and expected outcome 
Objective: This study aims to evaluate the anesthetic effect and safety of propofol 
combined with different doses of ESK in LEEP. 
expected outcome: Propofol combined with esketamine can effectively be used in 
LEEP anesthesia, with less circulatory and respiratory depression, and the postoperative 
recovery is faster and more stable, and the satisfaction is higher than that used alone. 
 
3. Study design and method  
   This is a prospective, double-blind, randomized controlled study.The random-
number table method was used to divide them into control and observation groups. The 
patients were divided into the propofol (2 mg/kg) +normal saline group (group P), 
propofol (1.5 mg/kg) + ESK (0.5 mg/kg) group (group PK1), and propofol (1.5 mg/kg) 
and ESK (0.25 mg/kg) group (group PK2). 

Statistical analysis: Our sample size was based on the results of small sample pre-
experiment. Assume the awakening time as primary outcome. Calculated by PASS 
software ,we will need to study 27 subjects in each group, given power of 0.90 and type 
I error of 0.05. Considering a dropout rate of 10%, the sample size will be 30 patients 
per group, thus a total of 90 patients will be randomized. 
Data was processed and analyzed using SPSS 26.0. Measured data with normal 
distribution was presented as mean ± standard deviation (x ± s) and compared using 
the t-test and one-way ANOVA. Count data was expressed as frequency or percent (%) 
and compared using the χ2 test or Fisher’s exact test. A p < 0.05 was considered 
statistically significant. 
Method of anesthesia：All patients fasted from food for 6 h and from water for 2 h 
prior to surgery. A peripheral venous access was established after the patient was 
admitted into the operating room. The heart rate (HR), SpO2 and blood pressure of the 
patients were monitored using 3-lead ECG, pulse oximeter and non-invasive blood 
pressure monitor. Patients received 5 L/min pure oxygen via oxygen mask 3 minutes 
minimum before anesthesia and during the surgery. 
Group P was an intravenous injection of an equivalent dose of normal saline 
followed by 2 mg/kg of propofol. Group PK1 was an intravenous injection of 0.5 mg/kg 
ESK followed by 1.5 mg/kg of propofol. Group PK2 was an intravenous injection of 
0.25 mg/kg ESK followed by 1.5 mg/kg of propofol. The rate of propofol induction 
should not exceed 40 mg/10 seconds. 
Surgery was initiated when a score of <2 was observed on the modified Observer 

Assessment of Alertness/Sedation scale (MOAA/S)[7](Table 1). If physical movement 
（movement of any part of the body such as: opening the eyes, clamping the legs, 
raising the hands, etc ）occurs during surgery, an additional 1 mg/kg of propofol was 
administered. If SpO2 drops to <95 % during surgery, the jaw thrust maneuver or face 
mask ventilation were performed .After surgery,patients were transferred to the 
recovery room to monitor HR、RR、NIBP and SPO2 ,and were discharged at a MOAA/S 
score of 5. 
Outcome measures：The HR, respiratory rate (RR), mean arterial pressure (MAP) and 
SpO2 after operating room admission and at 1 min and 5 min post-anesthesia, venous 
carbon dioxide (PvCO2) at admission and 5 min post-anesthesia, number of additional 
propofol usage, number of jaw thrust maneuver or face mask ventilation, postoperative 
awakening time (MOAA/S score >4), and incidences of postoperative vertigo, nausea, 
agitation and delirium were recorded for the 3 groups. 
4. Risks/benefits of the study 
This study aims to evaluate the effect of propofol combined with esketamine on 
the circulation and respiratory system, complications and postoperative recovery in 
LEEP surgery, and to guide the choice of anesthetic drugs for LEEP, in order to make 
the operation safer, faster recovery and higher comfort for patients. 
5.Recruitment and protection measures  
Inclusion Criteria:The patients were 20-60 years old and had a BMI of 18-30 kg/m2 
and an ASA physical status grade of I or II.  
Exclusion criteria: 1) Patients who refused to participate; 2) History of hypertension, 

hyperthyroidism, or neurological or mental disorder; 3) Currently taking or has taken 
opioids and non-steroidal anti-inflammatory drugs within 48 h before surgery; 4) 
Participated in other drug clinical trials within 4 weeks; 5) Allergy to ESK or propofol; 
6) History of opioid or ESK addiction.  
Withdrawal criteria: Patients had serious adverse reactions, complications, cardiac 
arrest, malignant arrhythmia and so on during the trial. The subjects withdrew their 
informed consent and asked to withdraw from the study. Investigators need to stop 
subjects for safety reasons. 
6. Informed Concent Process 
At the preoperative visit, patients who met the inclusion criteria were informed by 
the investigator about the trial protocol, how it differed from the usual protocol, and 
how it would not affect surgery or anesthesia, and they provided written informed 
consent. Patients could withdraw from the trial at any time if they wished. 
7. Information about the subjects and confidentiality 
The personal data of all patients in the trial are confidential. Identifying 
information will not be disclosed to members outside the research team unless 
permission is obtained from the patient. After the research is completed and the relevant 
papers are published, the relevant data will be archived in a timely manner as the basis 
for further research. To ensure that the study was conducted in accordance with the 
regulations, the government authorities or members of the ethics review committee 
were allowed to access the personal data of patients at the research sites when necessary.