The 90% effective dose of ciprofol and propofol with S-ketamine for painless abortion: a randomized,double-blind,sequential dose-finding trial

Abstract

Background:

Unlike the propofol–opioids combination, a single dose of S-ketamine with propofol achieves the same anesthetic effects while effectively minimizing adverse reactions in painless abortion. Ciprofol, a novel analog of propofol, has distinct advantages, its application in painless abortion is underexplored.

Objectives:

To investigate a 90% effective dose (ED₉₀) of ciprofol and propofol with S-ketamine for painless abortion.

Design:

This prospective biased coin up-and-down (BCUD) sequential dose-finding study aimed to estimate the ED₉₀ of ciprofol when administered with 0.15 mg/kg S-ketamine in painless abortion while comparing adverse effects incidence with the ED₉₀ of propofol when combined with the same dose of S-ketamine.

Methods:

Eighty patients were recruited and randomly allocated to either ciprofol or propofol groups, with initial doses of 0.375 mg/kg and 1.5 mg/kg, respectively. The dose for the subsequent patient in the study was based on the response of the preceding patient, following the BCUD design. The study estimated the ED₉₀ using isotonic regression. Secondary outcomes, including the incidence of injection pain, vital signs, and adverse events, were recorded and compared between the two groups.

Results:

The ED₉₀ of ciprofol with 0.15 mg/kg S-ketamine was 0.498 mg/kg (95% confidence interval: 0.498–0.510), while the ED₉₀ of propofol with 0.15 mg/kg S-ketamine was 1.99 mg/kg (95% confidence interval: 1.98–2.16). Patients in the ciprofol group had a lower incidence of respiratory pause (7.5% vs 52.5%; p < 0.001). Other adverse events and recovery time were comparable between groups.

Conclusion:

Compared to propofol and S-ketamine combination, ciprofol and S-ketamine are equally effective with reduced respiratory depression. Thus, clinicians should consider a dose of 0.5 mg/kg ciprofol with 0.15 mg/kg S-ketamine for painless abortion.

Trial registration:

http://www.chictr.org.cn; ChiCTR2400086522; July 5, 2024.

Plain language summary

The 90% effective dose of ciprofol and propofol in painless abortion

Why was this study done? Compared with propofol-opioids combination, propofol with S-ketamine has been reported to achieve the same anesthetic effects with less adverse effects in painless abortion. Ciprofol is a newly developed structural analog of propofol. However, there is limited reporting on the combination of ciprofol with a single dose of S-ketamine in painless abortion.

What did the researchers do? The research team recruited 80 patients undergoing painless abortion, found out the 90% effective dose of ciprofol and propofol with 0.15 mg/kg S-ketamine by using biased coin up-and-down design and compared the incidence of adverse events between the two drugs.

What did the researchers find? The 90% effective dose of ciprofol with 0.15 mg/kg S-ketamine was 0.498 mg/kg, while the 90% effective dose of propofol with 0.15 mg/kg S-ketamine was 1.99 mg/kg in painless abortion. Patients in the ciprofol group had a lower incidence of respiratory pause.

What do the findings mean? A dose of 0.5 mg/kg ciprofol with 0.15 mg/kg S-ketamine is recommended in painless abortion.

Keywords

abortion ciprofol propofol S-ketamine

Introduction

Painless abortion is commonly used for early pregnancy termination. Despite the brief surgical duration, patients often experience severe pain during the procedure, necessitating the use of analgesics and anesthetics.¹

Propofol is a widely used anesthetic agent with a fast onset and quick recovery time.² However, it also has side effects, such as respiratory depression, hypotension, and injection pain. Ketamine is an N-methyl-D-aspartate receptor (NMDA) antagonist, with a wide spectrum of dose-dependent pharmacologic effects, including analgesia, sedation, and dissociative anesthesia. Sub-dissociative dose of ketamine (0.1–0.6 mg/kg) was used for the management of acute pain.³ S-ketamine is a right-handed split of ketamine and is two-fold more effective and longer acting than ketamine, with a lower incidence of psychotropic side effects.^4,5 Studies indicate that a single dose of S-ketamine (0.15–0.3 mg/kg) in combination with propofol offers effective anesthesia while reducing the occurrence of hypoxia, hypotension, injection pain, and the need for additional propofol dose in short-duration procedures compared to the combination with propofol and opioids.^6,7

Ciprofol is a newly developed structural analog of propofol and a short-acting intravenous drug for induction and maintenance anesthesia,⁸ which has been reported to have less injection pain, more stable hemodynamics, and less respiratory depression than propofol,⁹ and inducing comparable sedation or anesthesia as propofol. As respiratory depression is a great concern in non-intubated intravenous anesthesia, ciprofol and S-ketamine seem to be a favorable option for procedural sedation/anesthesia. However, there is limited reporting on the combination of ciprofol with a single dose of S-ketamine. Our study aimed to determine the 90% effective dose (ED₉₀) of ciprofol and propofol with a low dose of S-ketamine in patients undergoing painless abortion using a biased coin up-and-down (BCUD) design and to compare the incidence of adverse events between the two drugs.

Methods

Participants

The reporting of this study conforms to the CONSORT statement¹⁰ (CONSORT Checklist in the Supplemental Material), and all experiments were conducted in accordance with the principles of the Helsinki Declaration.

A total of 80 female patients, aged 18–45 years, with a body mass index (BMI) within 18.5–28 kg/m², American Society of Anesthesiologists (ASA) Grades I or II, and undergoing painless abortion in the International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University were recruited half an hour before surgeries from July 8, 2024, to August 30, 2024.

Exclusion criteria included ASA physical status Grade more than II, baseline peripheral oxygen saturation (SpO₂) <95%, comorbidities such as diabetes mellitus, hypertension, hepatic or renal insufficiency, obstructive sleep apnea syndrome, or a known allergy to anesthesia drugs, and a history of egg or soya bean allergy. Patients who refused to participate were also excluded.

Trial design

This was a prospective, double-blind, randomized, BCUD sequential dose-finding trial. After providing informed consent, each patient would receive an opaque sealed envelope with their group number in it, the ciprofol with S-ketamine group (ciprofol group) and the propofol with S-ketamine group (propofol group), with 40 patients in each group. The group number was randomly generated by a research assistant using SPSS for Windows version 18.0 (SPSS Inc., Chicago, IL, USA). The research assistant opened the randomization envelopes and prepared the drugs before the surgeries. The anesthesiologists in charge of observation and the patients were blinded to the drugs and doses used.

Intervention

Patients were instructed to stop solid food intake for 8 h and clear liquids for 4 h before anesthesia. No sedative premedication was administered before induction.

After entering the operating room, patients were given routine nasal catheter oxygen inhalation at a rate of 2 L/min. Continuous routine monitoring, including noninvasive blood pressure, electrocardiogram, pulse oximetry, and end-tidal CO₂ (EtCO₂) (Capnoline H O₂, Philips, Amsterdam, Netherlands), was done. The baseline mean arterial pressure, heart rate, and respiratory rate were recorded. Subsequently, an intravenous line was established using a 22-gauge cannula, and a Ringer’s lactate infusion (10 mL/kg/h) was given.

The patient was asked to turn her head to the left or right to diminish upper-airway obstruction.¹¹ S-ketamine 0.15 mg/kg (Aisi; Hengrui Pharmaceutical, Jiangsu, China) was administered within 5 s. Sixty seconds later, the patient was administered the research dose of ciprofol (Sishuning, Haisco, Liaoning, China) or 1% propofol (Jingan, Fresenius Kabi Austria GmbH, Beijing, China) in 30 s. The complaint of injection pain from the patient was recorded. Ciprofol or propofol was prepared by a research assistant and administered by an anesthesiologist. The syringe containing ciprofol or propofol had its scale line concealed by stickers, ensuring that the anesthesiologist and patients were blinded to the drugs and doses used.

The surgery was initiated 30 s after the administration of ciprofol or propofol and the patient achieved a Modified Observer’s Assessment of Alertness/Sedation score of ⩽1.¹²

The heart rate, respiratory rate, EtCO₂, and pulse oximetry were monitored continuously, and mean arterial pressure was recorded every minute. An atropine dose of 0.3 mg was administered if bradycardia (heart rate below 50 beats/min) occurred.¹³ The chin was immediately lifted if the EtCO₂ wave disappeared to avoid glossoptosis, and the lowest SpO₂ was recorded. A bolus of 3 mL propofol (30 mg)¹⁴ or ciprofol (7.5 mg) was given whenever a body movement that interrupted surgery¹⁵ including head or limb elevation was reported by the operating room nurses or the gynecologists. The rescue propofol or ciprofol was also prepared by the research assistant to maintain the blind nature of the grouping. Recovery time (from the last injection of ciprofol or propofol to eye-opening to verbal command) was recorded. Other adverse events,^15–17 including hypotension (a 20% decrease in mean arterial pressure from baseline), hypertension (a 20% increase in mean arterial pressure from baseline), bradycardia (<50 beats/min), tachycardia (>100 beats/min), respiratory pause (loss of EtCO₂ wave ⩾15 s), the occurrence of SpO₂ <95%, physical movement, salivation, and psychoactive effects such as agitation, nightmares, hallucinations, and delirium, were recorded. Flurbiprofen 50 mg was administered intravenously at the end of the surgery.

After surgery, the patient was transferred to the post-anesthesia care unit (PACU). In PACU, heart rate and pulse oximetry were monitored continuously, and blood pressure was measured every 5 min. Pain numerical rating scale (NRS) ranging from 0 (no pain) to 10 (worst possible pain)¹⁸ was evaluated every 10 min. The Aldrete scale score¹⁹ was evaluated 30 min after entrance into the PACU by a nurse. Adverse events such as pain NRS ⩾4, dizziness, fatigue, delirium, and any recalls of nightmares or hallucinations were recorded in PACU.

Design of the sequential dose-finding study

The dose of propofol used was 1.5 mg/kg, while ciprofol, was 0.375 mg/kg for the initial patient in each group, respectively. Subsequent patient doses were determined based on the response of the previous patient. If the patient did not have any body movement¹⁵ in 5 min since the painless abortion surgery began, the dose of propofol or ciprofol was considered a success, and the next patient was randomly assigned a dose with a 1/9th chance of receiving a lower dose (decreased by 0.25 mg/kg in propofol dose or decreased by 0.025 mg/kg in ciprofol dose) or an 8/9th chance of receiving the same dose as the previous patient. Otherwise, the propofol or ciprofol dose was considered failed and the dose for the next patient was increased by 0.25 mg/kg or 0.025 mg/kg, respectively. The floor and ceiling doses of propofol dose were 1.5 mg/kg and 3 mg/kg, respectively, while those of ciprofol were 0.375 mg/kg and 0.6 mg/kg. The research dose of propofol or ciprofol was prepared by the research assistant using an Excel table designed by a statistician.

Outcomes

The primary outcome of this study focused on the ED₉₀ (the dose that would be effective for 90% of the population)²⁰ of ciprofol and propofol with 0.15 mg/kg S-ketamine for patients undergoing painless abortion surgery. “Effective” was defined as the patient did not have any body movement¹⁵ in 5 min since the surgery began. Secondary outcomes included vital signs and adverse events, including injection pain, respiratory pause, occurrence of SpO2 <95%, hypotension, hypertension, tachycardia, bradycardia, salivation, dizziness, fatigue and psychoactive effects. In addition, the demographic characteristics of the patients were systematically recorded.

Sample size calculation

Pace et al. suggested that the stopping rule of enrolling 20–40 patients in a BCUD-based sequential dose-finding study will provide stable estimates of the target dose in most realistic cases.²¹ Therefore, the sample size of each group was set at 40.

Statistical analysis

The ED₉₀ was defined as the dose of ciprofol or propofol associated with the successful primary outcome in 90% of the study population, and it was estimated using the isotonic regression method.^20,21 The 95% confidence interval (CI) of the isotonic regression estimator of ED₉₀ was obtained by a bias-corrected percentile method employing 2000 bootstrap replications.²¹ Isotonic regression and bootstrapping were performed by the study statistician using R version 3.4.4. (R Foundation for Statistical Computing, Vienna, Austria).

Demographic characteristics and secondary outcome estimates were reported as means (standard deviation), median (interquartile range) and numbers (proportions). Parametric data were analyzed using the t-test and non-parametric data were analyzed using the Mann–Whitney test. Proportions were compared using Chi-square and Fisher exact tests, as applicable. Preoperative hemodynamic parameters were evaluated using multiple t-tests, and statistical significance was determined using the Holm–Sidak method, with alpha = 0.05. Statistical comparisons were performed using the SPSS for Windows version 18.0 (SPSS Inc.) and GraphPad Prism 8 for Windows (GraphPad Software, San Diego, CA, USA). Statistical significance was defined as a p-value <0.05.

Results

The patients were recruited from July 8, 2024 to August 30, 2024. The patient recruitment and follow-up process are presented in Figure 1. Data from 40 patients in each group were included in the final analysis, and the characteristics were comparable between the two groups (Table 1).

Figure 1.

Flow chart of participants in the study.

Table 1.

Patients’ characteristics.

Characteristics	Ciprofol (n = 40)	Propofol (n = 40)	p Value
Age, years	34.35 (5.36)	34.10 (5.30)	0.834
Height, cm	161.18 (4.42)	162.25 (5.54)	0.340
Weight, kg	60.31 (8.29)	60.14 (10.99)	0.937
BMI, kg/m²	23.13 (2.80)	22.28 (3.03)	0.647
ASA physical status classification
I	18 (45.0)	22 (55.0)	0.503
II	22 (55.0)	18 (45.0)	0.503
Gravidity	3.00 (2.00, 4.25)	3.00 (2.00, 4.00)	0.146
Parity	1.00 (1.00, 2.00)	1.00 (0.00, 2.00)	0.096
Gestational weeks, week	12.45 (4.45)	11.18 (4.95)	0.229

Data are presented as mean (standard deviation), median (interquartile range), or number (percentage), as appropriate.

ASA, American Society of Anesthesiologists; BMI, body mass index.

The sequence of effective and ineffective doses of ciprofol and propofol is presented in Figure 2. The doses used in the ciprofol group were 0.375, 0.400, 0.425, 0.450, 0.475, 0.500, and 0.525 mg/kg, while 0.550, 0.575, and 0.600 mg/kg were never used. The propofol group doses were 1.5, 1.75, 2.00, and 2.25 mg/kg, while 2.50, 2.75, and 3.00 mg/kg were never used. The ED₉₀ of ciprofol with 0.15 mg/kg S-ketamine was 0.498 mg/kg (95% CI: 0.498–0.510), and the ED₉₀ of propofol with 0.15 mg/kg S-ketamine was 1.99 mg/kg (95% CI: 1.98–2.16) for patients undergoing a painless abortion.

Figure 2.

The patient allocation sequence and the response to the assigned dose of ciprofol (a) and propofol (b). The patient sequence number (X-axis) is the order of patient exposures using the BCUD design. The assigned dose levels are presented on the Y-axis. An effective dose is denoted by a circle, while an ineffective dose is denoted by a triangle.

Compared to the propofol group, patients in the ciprofol group exhibited a lower heart rate at 1 min (75.78 ± 11.13 bpm vs 80.70 ± 9.10 bpm, p < 0.05) and 3 min (76.2 ± 11.94 vs 83.38 ± 17.30 bpm, p < 0.05) after surgery began. A higher respiratory rate (21.70 ± 5.60 per min vs 14.47 ± 9.68 per min, p < 0.001) was observed in the ciprofol group 1 min after surgery began. No difference in heart rate and respiratory rates was noted at other time points between the two groups. The mean arterial pressure of the two groups over time was comparable (Figure 3).

Figure 3.

Serial changes in MAP, HR, and RR over time of two groups. (a) Serial changes in MAP over time. (b) Serial changes in HR over time. (c) Serial changes in RR over time.

When all the patients were taken into account, the ciprofol group exhibited fewer respiratory pauses (7.5% vs 52.5%, p < 0.001) and a lower incidence of SpO₂ <95% (0% vs 15%, p < 0.05). When only patients without additional bolus were taken into account, the incidence of respiratory pause was also lower in the ciprofol group (1/25 [4.0%] vs 13/28 [46.4%], p < 0.001), so was the incidence of SpO₂ <95% (0/25 [0%] vs 6/28 [21.4%], p < 0.05). Recovery time and other adverse events, including hypotension, hypertension, tachycardia, bradycardia, injection pain, dizziness, fatigue, psychoactive effects, and salivation, were comparable between the two groups (Table 2).

Table 2.

Patients’ outcomes.

Variable	Ciprofol (n = 40)	Propofol (n = 40)	p Value
During induction and surgery
Injection pain	0 (0)	4 (10)	0.116
Respiratory pause	3 (7.5)	21 (52.5)	<0.001
SpO₂ <95%	0 (0)	6 (15)	0.02
Hypotension	14 (35)	11 (27.5)	0.630
Hypertension	4 (10)	6 (15)	0.737
Tachycardia	4 (10)	8 (20)	0.348
Bradycardia	0 (0)	0 (0)	1
Additional drug bolus, times	0 (0,1)	0 (0,1)	0.727
Salivation	1 (2.5)	0 (0)	1
Duration of operation, min	5.92 (2.18)	6.82 (2.93)	0.123
Recovery time, min	8.35 (2.07)	8.75 (3.02)	0.492
In PACU
Dizziness	2 (5)	6 (15)	0.263
Fatigue	3 (7.5)	7 (17.5)	0.311
Psychoactive effects	0 (0)	0 (0)	1
NRS ⩾4	1 (2.5)	2 (5)	1
Aldrete score^a ⩾9	40 (100)	40 (100)	1

Data are presented as mean (standard deviation), median (interquartile range), or number (percentage), as appropriate.

At 30 min in PACU.

NRS, numerical rating scale; PACU, post-anesthesia care unit.

Details of important outcomes, such as success rate, additional bolus times, the occurrence of SpO₂ <95% and respiratory pause for each propofol and ciprofol dose subgroup are shown in Table 3. The occurrence of SpO₂ <95% was lower (0% vs 13.8%, p = 0.117) though not of statistically significance, and respiratory pause was statistically lower (51.7% vs 4.2%, p < 0.001) in the subgroup (0.5 mg/kg) that close to ED₉₀ of ciprofol than those in the subgroup (2 mg/kg) that close to ED₉₀ of propofol of the study.

Table 3.

Important outcomes for each subgroup dose of propofol and ciprofol.

Variable	Propofol dose (mg/kg)
	1.5 (n = 1)		1.75 (n = 3)		2 (n = 29)		2.25 (n = 7)
Success rate (%)	0 (0.0)		0 (0.0)		27 (93.1)		7 (100.0)
Additional bolus times (%)
0	0 (0.0)		0 (0.0)		21 (72.4)		7 (100.0)
1	0 (0.0)		2 (66.7)		6 (20.7)		0 (0.0)
2	1 (100.0)		1 (33.3)		2 (6.9)		0 (0.0)
SpO₂ <95% (%)	0 (0.0)		0 (0.0)		4 (13.8)		2 (28.6)
Respiratory pause (%)	1 (100.0)		3 (100.0)		15 (51.7)		2 (28.6)
Variable	Ciprofol dose (mg/kg)
	0.375 (n = 1)	0.4 (n = 1)	0.425 (n = 1)	0.45 (n = 1)	0.475 (n = 5)	0.5 (n = 24)	0.525 (n = 7)
Success rate (%)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	23 (95.8)	7 (100.0)
Additional bolus times (%)
0	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	19 (79.2)	6 (85.7)
1	1 (100.0)	1 (100.0)	1 (100.0)	1 (100.0)	5 (100.0)	5 (20.8)	1 (14.3)
2	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
SpO₂ <95% (%)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
Respiratory pause (%)	0 (0.0)	1 (100.0)	0 (0.0)	1 (100.0)	0 (0.0)	1 (4.2)	0 (0.0)

Data are presented as numbers (percentages).

Discussion

In this sequential dose-finding study utilizing BCUD methodology, the estimated ED₉₀ of ciprofol with 0.15 mg/kg S-ketamine was 0.498 mg/kg (95% CI: 0.498–0.510), while the ED₉₀ of propofol with 0.15 mg/kg S-ketamine was 1.99 mg/kg (95% CI: 1.98–2.16) for painless abortion.

Our results suggest that ciprofol is approximately four times more potent than propofol in inducing satisfactory anesthesia for painless abortion, This observation aligns with previous studies in procedures such as colonoscopy,²² endoscopic submucosal dissection (ESD), endoscopic retrograde cholangiopancreatography (ERCP), and flexible bronchoscopy (FB).¹² Teng et al. reported rapid onset and recovery, along with high satisfaction ratings, using 0.4 and 0.5 mg/kg doses of ciprofol combined with 50 μg fentanyl for colonoscopy in phase II clinical trials, which is comparable to 2 mg/kg dose of propofol.²² Zhong et al. demonstrated 100% success rates of sedation or anesthesia for procedures like ESD, ERCP, and FB when administering ciprofol 6 or 8 mg/kg/h, and propofol at 40 mg/kg/h for 3 min induction, with remifentanil or S-ketamine as an adjuvant.¹² Ciprofol, classified as a novel 2,6-disubstituted phenol derivative, has been reported to possess safety and tolerability parameters similar to propofol, along with a lower incidence of respiratory depression.²³ Our study supports these findings, showing less incidence of respiratory pause and SpO₂ <95% in the ciprofol group. In addition, higher respiratory rates in the ciprofol group were found in the first minute after the surgery began, indicating a reduced likelihood of respiratory depression in the ciprofol group.

Ciprofol also exhibits a lower incidence of injection pain compared to propofol.^24–26 None of the patients in the ciprofol group experienced injection pain, while 10% of patients in the propofol group reported injection pain in our study. Although the difference was not statistically significant, it may be attributed to the prior intravenous administration of S-ketamine. Pretreatment with ketamine or S-ketamine has previously been reported to reduce the incidence of propofol injection pain.^7,27 In a report by Fu et al., it was recorded that the incidence rate of injection pain was 67% in the propofol group and 29% in the S-ketamine and propofol group when the vein of the hand dorsum is used as the injection site.⁷ Our incidence rate was significantly lower than 29%, suggesting that the median cubital vein for drug injection might contribute to further alleviating injection pain. According to Scott et al., little pain occurred when the drug was injected into a large vein in the antecubital fossa.²⁸

Fast onset and recovery are part of the advantages of propofol, the pharmacokinetic properties of ciprofol are reported to be similar to that of propofol.²⁹ In the phase IIb trial, the recovery time from the last administration to full alertness was 12.9 min in the 0.5 mg/kg ciprofol group, approximately 2 min longer than the 2 mg/kg propofol group.²² Meanwhile, Zhong et al. found that recovery time and PACU discharge time between ciprofol and propofol were comparable.¹² Notably, in our study, patients in both groups achieved Aldrete scores exceeding 9 at the 30-min mark.

Propofol is associated with a high incidence of hypotension,²⁹ and ciprofol has been reported to induce less hypotension than propofol.^12,30 However, other studies have reported a similar incidence rate of hypotension between ciprofol and propofol.^22,26 The incidence of hypotension was comparable between the two groups in this study. Administering low-dose S-ketamine as an adjuvant can decrease the incidence of hypotension^31,32 and reduce the required dose of propofol or ciprofol used.³³ S-ketamine, the dextrorotatory isomer of ketamine, possesses twice the potency of ketamine in terms of hypnotic and analgesic effects, with fewer psychiatric adverse effects.^34,35 Psychiatric adverse effects such as agitation or nightmares were reported when 1.5 mg/kg propofol was combined with 0.2 mg/kg S-ketamine during painless gastrointestinal endoscopy, whereas no such adverse effects happened when propofol was combined with 0.1 mg/kg S-ketamine.³⁶ In our study, a dose of 0.15 mg/kg S-ketamine was chosen as the adjuvant of propofol or ciprofol, and no psychiatric symptoms were observed. The incidence of dizziness in our study was 5%–15%. Zhan et al. reported that the incidence of dizziness was between 9.2% and 16.9% with different doses of S-ketamine, and 10.8% of patients experienced dizziness even without S-ketamine.³⁶ A subanesthetic dose of S-ketamine can provide an analgesic effect and may serve as an alternative to opioids in painless abortion.⁶ In our study, 0.15 mg/kg S-ketamine together with flurbiprofen 50 mg produced effective analgesia and few patients experienced an NRS score of ⩾4 during their stay in PACU.

Limitations

This study has several limitations. First, the estimated propofol or propofol dose was based on patients with a BMI within 18.5–28 kg/m² in the study. For patients who are exceptionally thin or overweight, the recommended dose may be too low or high. Therefore, further research should be conducted to determine the appropriate initial doses for these two drugs in underweight or obese patients. Second, successful anesthesia was defined as no movement occurring within 5 min since the surgery began; however, we observed that the mean duration of the operation was approximately 6 min during statistical analysis. Given that higher doses of propofol or ciprofol may lead to increased incidences of adverse effects, than the doses we recommended, and since most movements after 5 min could be managed with one or two boluses of propofol or ciprofol, we did not recommend higher doses of the two drugs for painless abortion. Third, the study’s sample size of 80 patients may limit the generalizability of the findings and reduce statistical power, potentially affecting the reliability of the results. Further research with a large sample size could be carried out based on the effectiveness and safety of the ED₉₀ of ciprofol with S-ketamine for painless abortion.

Conclusion

In this sequential dose-finding study, the ED₉₀ of ciprofol with 0.15 mg/kg S-ketamine was 0.498 mg/kg (95% CI: 0.498–0.510) during painless abortion. In addition, the ED₉₀ of propofol with 0.15 mg/kg S-ketamine was 1.99 mg/kg (95% CI: 1.98–2.16). When compared to the combination of propofol with S-ketamine, ciprofol with S-ketamine is equally effective with reduced respiratory depression. Therefore, clinicians should consider a dose of 0.5 mg/kg for ciprofol with 0.15 mg/kg S-ketamine for painless abortion.

Supplemental Material

sj-doc-1-taw-10.1177_20420986251328673 – Supplemental material for The 90% effective dose of ciprofol and propofol with S-ketamine for painless abortion: a randomized, double-blind, sequential dose-finding trial

Supplemental material, sj-doc-1-taw-10.1177_20420986251328673 for The 90% effective dose of ciprofol and propofol with S-ketamine for painless abortion: a randomized, double-blind, sequential dose-finding trial by Qiang Tao, Qiao Shi, Tao Xu and Shanshan Ye in Therapeutic Advances in Drug Safety

Footnotes

Acknowledgements

None.

Declarations

ORCID iDs

Qiang Tao

Qiao Shi

Tao Xu

Shanshan Ye

Supplemental material

Supplemental material for this article is available online.

References

Tas

Mıstanoglu

Darcın

, et al. Tramadol versus fentanyl during propofol-based deep sedation for uterine dilatation and curettage: a prospective study. J Obstet Gynaecol Res 2014; 40(3): 749–753.

Sethi

Sindhi

Verma

, et al. Dexmedetomidine versus propofol in dilatation and curettage: an open-label pilot randomized controlled trial. Saudi J Anaesth 2015; 9(3): 258.

Beaudrie-Nunn

Wieruszewski

Woods

, et al. Efficacy of analgesic and sub-dissociative dose ketamine for acute pain in the emergency department. Am J Emerg Med 2023; 70: 133–139.

Marland

Ellerton

Andolfatto

, et al. Ketamine: use in anesthesia. CNS Neurosci Ther 2013; 19(6): 381–389.

Wang

Huang

Yang

, et al. Pharmacokinetics and safety of esketamine in Chinese patients undergoing painless gastroscopy in comparison with ketamine: a randomized, open-label clinical study. Drug Des Devel Ther 2019; 13: 4135–4144.

Chen

Zou

, et al. Effect of different doses of esketamine compared with fentanyl combined with propofol on hypotension in patients undergoing painless abortion surgery: a prospective, randomized, double-blind controlled clinical trial. BMC Anesthesiol 2022; 22(1): 305.

Wang

, et al. Pretreatment with low-dose esketamine for reduction of propofol injection pain: a randomized controlled trial. Pain Res Manag 2022; 2022: 4289905.

Teng

Wang

, et al. Pharmacokinetic and pharmacodynamic properties of ciprofol emulsion in Chinese subjects: a single center, open-label, single-arm dose-escalation phase 1 study. Am J Transl Res 2021; 13(12): 13791–13802.

Zhang

Liu

, et al. Comparison of ciprofol–alfentanil and propofol–alfentanil sedation during bidirectional endoscopy: a prospective, double-blind, randomised, controlled trial. Dig Liver Dis 2024; 56(4): 663–671.

10.

Schulz

Altman

Moher

CONSORT 2010 Statement: updated guidelines for reporting parallel group randomized trials. Obstet Gynecol 2010; 115(5): 1063–1070.

11.

Ono

Otsuka

Kuroda

, et al. Effects of head and body position on two- and three-dimensional configurations of the upper airway. J Dent Res 2000; 79(11): 1879–1884.

12.

Zhong

Zhang

Fan

, et al. Efficacy and safety of ciprofol for procedural sedation and anesthesia in non-operating room settings. J Clin Anesth 2023; 85: 111047.

13.

Sun

, et al. Effect of intravenous lidocaine on the ED50 of propofol for inserting gastroscope without body movement in adult patients: a randomized, controlled study. BMC Anesthesiol 2022; 22(1): 319.

14.

Liu

Wan

Shao

LJZ

, et al. Estimation of effective dose of propofol mono-sedation for successful insertion of upper gastrointestinal endoscope in healthy, non-obese Chinese adults. J Clin Pharm Ther 2021; 46(2): 484–491.

15.

Zheng

Huang

Mai

, et al. The median effective dose of propofol combined with butorphanol during artificial abortion: a randomized controlled trial. Front Med 2023; 10: 1226495.

16.

Feng

Wang

, et al. Low dose of esketamine combined with propofol in painless fibronchoscopy in elderly patients. Medicine (Baltimore) 2022; 101(50): e31572.

17.

Deitch

Rowden

Damiron

, et al. Unrecognized hypoxia and respiratory depression in emergency department patients sedated for psychomotor agitation: pilot study. West J Emerg Med 2014; 15(4): 430–437.

18.

Renne

Argandykov

, et al. Comparison of an emoji-based visual analog scale with a numeric rating scale for pain assessment. JAMA 2022; 328(2): 208.

19.

Marshall

Chung

Discharge criteria and complications after ambulatory surgery. Anesth Analg 1999; 88(3): 508–517.

20.

Oron

Souter

Flournoy

Understanding research methods: up-and-down designs for dose-finding. Anesthesiology 2022; 137(2): 137–150.

21.

Pace

Stylianou

Warltier

DC.

Advances in and limitations of up-and-down methodology. Anesthesiology 2007; 107(1): 144–152.

22.

Teng

Wang

, et al. Efficacy and safety of ciprofol for the sedation/anesthesia in patients undergoing colonoscopy: phase IIa and IIb multi-center clinical trials. Eur J Pharm Sci 2021; 164: 105904.

23.

Teng

, et al. Sedation effects produced by a ciprofol initial infusion or bolus dose followed by continuous maintenance infusion in healthy subjects: a phase 1 trial. Adv Ther 2021; 38(11): 5484–5500.

24.

Hung

Chen

, et al. A systematic review and meta-analysis comparing the efficacy and safety of ciprofol (HSK3486) versus propofol for anesthetic induction and non-ICU sedation. Front Pharmacol 2023; 14: 1225288.

25.

Chen

Guo

Yang

, et al. Comparison and clinical value of ciprofol and propofol in intraoperative adverse reactions, operation, resuscitation, and satisfaction of patients under painless gastroenteroscopy anesthesia. Contrast Media Mol Imaging 2022; 2022: 9541060.

26.

Wang

Liu

, et al. Comparison of ciprofol (HSK3486) versus propofol for the induction of deep sedation during gastroscopy and colonoscopy procedures: a multi-centre, non-inferiority, randomized, controlled phase 3 clinical trial. Basic Clin Pharmacol Toxicol 2022; 131(2): 138–148.

27.

Desousa

Pain on propofol injection: causes and remedies. Indian J Pharmacol 2016; 48(6): 617.

28.

Scott

RPF

Saunders

Norman

Propofol: clinical strategies for preventing the pain of injection. Anaesthesia 1988; 43(6): 492–494.

29.

Liu

, et al. Ciprofol: a novel alternative to propofol in clinical intravenous anesthesia? BioMed Res Int 2023; 2023: 7443226.

30.

Qin

Ming

SP.

Effect of ciprofol on induction and maintenance of general anesthesia in patients undergoing kidney transplantation. Eur Rev Med Pharmacol Sci 2022; 26(14): 5063–5071.

31.

Sayed Morteza

Shetabi

Tarashikashani

. Comparison between the effects of propofol-ketamine and propofol-fentanyl for sedation in cataract surgery. Sci J Kurd Univ Med Sci 2019; 24(2): 30–40.

32.

Shetabi

Nazemroaya

Shafa

, et al. Comparison of the efficacy of two drug combination, ketofol and fenofol, on sedation and analgesia in patients under the surgery of port catheter placement and removal. Sci J Kurd Univ Med Sci 2019; 36(505): 1421–1427.

33.

Song

Yang

Zheng

, 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.

34.

Wang

Deng

, et al. Efficacy and safety of esketamine for supplemental analgesia during elective cesarean delivery: a randomized clinical trial. JAMA Netw Open 2023; 6(4): e239321.

35.

Molero

Ramos-Quiroga

Martin-Santos

, et al. Antidepressant efficacy and tolerability of ketamine and esketamine: a critical review. CNS Drugs 2018; 32(5): 411–420.

36.

Zhan

Liang

Yang

, et al. Efficacy and safety of subanesthetic doses of esketamine combined with propofol in painless gastrointestinal endoscopy: a prospective, double-blind, randomized controlled trial. BMC Gastroenterol 2022; 22(1): 391.

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