Fospropofol vs Propofol for Early Postoperative Nausea and Vomiting Prophylaxis in High-Risk Patients Undergoing Gynecological Laparoscopic Surgery: A Randomized Controlled Trial

Abstract

Background

Postoperative nausea and vomiting (PONV) is a common complication of gynecological laparoscopic surgeries. Although propofol has established antiemetic properties, the efficacy of its water-soluble prodrug, fospropofol, for PONV prophylaxis remains uncertain. The aim of this study was to compare the impact of fospropofol versus propofol on the incidence of PONV in high-risk patients undergoing gynecological laparoscopic surgery.

Methods

In this prospective randomized controlled trial, 102 high-risk (Apfel score ≥3) female patients scheduled for elective gynecological laparoscopy were allocated to receive either fospropofol (FD group, n=51) or propofol (P group, n=51) for induction and maintenance, combined with sevoflurane inhalational anesthesia. The primary outcome was the incidence of PONV within the first 6 h postoperatively.

Results

The incidence of PONV at 6 h was significantly lower in the FD group than in the P group (5.9% vs 19.6%; absolute risk reduction, 13.7%; P=0.038). Multivariable logistic regression confirmed that fospropofol was an independent protective factor (odds ratio 0.219; 95% CI 0.045–0.809; P=0.034). No significant between-group differences were observed in the PACU- or 24-h PONV rates. However, the FD group experienced a longer median time to extubation (14.0 vs 10.0 min, P=0.006) and a lower incidence of PACU pain (51.0% vs 72.5%, P=0.025).

Conclusion

A reduction in early PONV within 6 hours was observed with fospropofol compared to propofol, suggesting a potential role for fospropofol in early PONV prevention.

Clinical Trial Registration

ChiCTR2500114542.

Introduction

Postoperative nausea and vomiting (PONV) is a common and distressing complication, reported in approximately 30% of the general surgical population, that adversely affects patient satisfaction, prolongs recovery, and increases healthcare costs, thereby representing a substantial burden among the approximately 313 million surgeries performed worldwide each year.1,2 Patients undergoing gynecologic laparoscopic surgery are at particularly high risk, with PONV incidence rates exceeding 80% in the absence of adequate prophylaxis due to a combination of patient- and procedure-related factors.1,2

While total intravenous anesthesia with propofol is a well-established strategy for PONV prophylaxis,1–3 inhaled volatile agents such as sevoflurane are still frequently used for anesthesia maintenance despite their well-documented emetogenic properties. This underscores the importance of optimizing other anesthetic components to mitigate the risk of PONV.4 Propofol itself possesses inherent antiemetic effects.1–5 Beyond its role in induction, supplemental propofol infusion during volatile-based anesthesia results in a dose-dependent reduction in the need for rescue antiemetics in the PACU without prolonging recovery time.6

Fospropofol disodium, a water-soluble prodrug of propofol, demonstrates a distinct pharmacokinetic profile characterized by slower onset, more stable hemodynamics, and a prolonged metabolic pathway that releases propofol, phosphate, and formaldehyde.7,8 Pharmacological studies indicate that, compared with conventional propofol, fospropofol undergoes a more prolonged metabolic process (terminal elimination half-life: 478±287 min).9 Given that the antiemetic effect of propofol correlates with its plasma concentration,1 fospropofol may also effectively reduce PONV, potentially with greater or more sustained efficacy. However, prospective RCT data directly comparing these two agents for early PONV under multimodal antiemetic coverage is lacking.

Therefore, the aim of this randomized controlled trial was to determine whether fospropofol provides superior PONV prophylaxis compared with standard propofol in a high-risk surgical population. We hypothesized that fospropofol would reduce the incidence of PONV within the first 6 h after elective gynecologic laparoscopic surgery. The 6-hour postoperative window was selected as the primary endpoint because this period represents the peak incidence of early PONV following gynecological laparoscopic surgery and coincides with the critical period for initiating oral intake and mobilization in enhanced recovery protocols.

Materials and Methods

Study Design

This prospective, randomized, double-blind study was approved by the Institutional Ethics Committee of the Obstetrics and Gynecology Hospital of Fudan University (Ethics No: 2025–251, December 4, 2025). This trial was reported following the Consolidated Standards of Reporting Trials (CONSORT) guidelines and conducted in accordance with the Declaration of Helsinki. The study was registered in the Chinese Clinical Trial Registry (No: ChiCTR2500114542; principal investigator: Li Ma; date of registration: December 15, 2025) before patient enrollment (December 15, 2025). All patients provided written informed consent prior to participation.

Study Population

We enrolled female patients, aged 18–50 years, with an ASA physical status of I or II and a body mass index of 18.5–29.9 kg/m², who were scheduled for elective gynecologic laparoscopic surgery under general anesthesia. All participants were identified as being at high risk for PONV, defined by a simplified Apfel risk score of ≥3. This score assigns one point each for female sex, nonsmoking status, history of PONV or motion sickness, and planned postoperative opioid use. An additional key inclusion criterion was normal preoperative serum alkaline phosphatase levels.

Key exclusion criteria were pregnancy or lactation; moderate-to-severe hepatic or renal dysfunction; significant cardiac or respiratory disease; history of substance abuse, alcohol dependence, or chronic sedative/analgesic use; and any known allergy or contraindication to the study medications.

Randomization and Masking

Patients were randomly allocated to either the fospropofol or propofol group in a 1:1 ratio using a computer-generated sequence created with SAS software (version 9.4; SAS Institute Inc., Cary, NC, USA). The allocation sequence was concealed in sequentially numbered, opaque, sealed envelopes. Upon patient arrival in the operating room, a dedicated researcher who was not involved in subsequent data collection or outcome assessment opened the corresponding envelope, revealed the group assignment, and prepared the assigned study drug for administration. After each randomisation, the envelope number and opening time were recorded, and used envelopes were archived. At the end of the study, an independent investigator verified the integrity of the allocation concealment by confirming that all used envelopes were opened in sequential order and that all unused envelopes remained sealed.

Owing to the distinct visual appearances of the two drug formulations, the attending anesthesiologist responsible for induction and intraoperative management could not be blinded to group assignment. To mitigate potential performance bias, anesthesia procedures were strictly standardized across both groups, including identical targets for sevoflurane MAC, remifentanil infusion rate, BIS range (40–60), fluid administration, pneumoperitoneum pressure, and antiemetic prophylaxis. All postoperative outcome assessors remained blinded to treatment allocation throughout the study.

Anesthesia Procedures

All patients followed standard preoperative fasting guidelines and received no premedication. Upon entering the operating room, an 18-gauge intravenous catheter was placed in the median cubital vein, and a 500-mL bolus of balanced crystalloid solution was administered. Standard monitoring, including electrocardiography, non-invasive blood pressure measurement, pulse oximetry, and BIS, was established. Five minutes before induction, diphenhydramine (20 mg) was administered intravenously. Preoxygenation with fresh gas flow exceeding 6 L/min was initiated 3 min before induction.

For induction, patients in the Propofol group (P Group) received propofol-MCT/LCT, a mixture of long-chain and medium-chain triglycerides in the carrier emulsion (Fresenius Kabi Pharmaceutical Co., Ltd., Bad Homburg, Germany; 10 mg/mL) at 2 mg/kg, whereas those in the Fospropofol group (FD Group) received fospropofol disodium (Yichang Humanwell Pharmaceutical Co., Ltd., Hubei, China; 50 mg/mL) at 15 mg/kg based on the clinical application guideline for fospropofol.10 Both drugs were administered via slow intravenous injection. Loss of consciousness was confirmed by a Modified Observer’s Assessment of Alertness/Sedation score of ≤1. Subsequently, induction was completed with sufentanil (0.3 µg/kg) and cisatracurium (0.15 mg/kg). Tracheal intubation was performed 2 min after administration of the neuromuscular blocking agent when the BIS value was < 60. Mechanical ventilation was initiated with a tidal volume of 8 mL/kg, and the respiratory rate was adjusted to maintain a PETCO₂ of 4.6–5.3 kPa. The FiO₂ was set at 0.5. Dexamethasone (5 mg) was administered intravenously immediately after intubation.

Anesthesia was maintained using a balanced inhalational and intravenous technique. In both groups, sevoflurane was titrated to an end-tidal concentration of approximately 0.5 MAC, and remifentanil was infused at a rate of 0.25 µg · kg⁻¹ · min⁻¹. The propofol group received propofol infusion at 2–4 mg · kg⁻¹ · h⁻¹, whereas the fospropofol group received fospropofol infusion at 4–8 mg · kg⁻¹ · h⁻¹. Infusion rates were adjusted to maintain a BIS value between 40 and 60 and the MAP within 30% of the pre-induction baseline. Intravenous crystalloids were administered at 10–15 mL · kg⁻¹ · h⁻¹, and the pneumoperitoneum pressure was maintained between 12 and 16 mmHg.

Twenty minutes before the anticipated end of surgery, palonosetron (0.25 mg) and dexketoprofen (50 mg) were slowly administered intravenously. At this time, propofol or fospropofol infusion was discontinued, and anesthesia was maintained with sevoflurane and remifentanil to prevent intraoperative awareness. All anesthetic agents were discontinued after surgical closure. High-flow oxygen was administered to facilitate the washout of inhalational anesthetics.

Following surgery, all patients received an ultrasound-guided bilateral transversus abdominis plane block, with 20 mL of 0.25% ropivacaine administered per side. Tracheal extubation was performed once the patient was awake with stable vital signs and satisfactory spontaneous ventilation. If necessary, residual neuromuscular blockade was antagonized using neostigmine (1 mg) and atropine (0.5 mg). Patients were deemed ready for discharge from the PACU when fully awake (as indicated by three consecutive Modified Observer’s Assessment of Alertness/Sedation scores of 5) and with a Modified Aldrete Score of ≥9.

For postoperative analgesia, a standardized patient-controlled intravenous analgesia (PCIA) pump, containing nalbuphine (100 mg) and palonosetron (0.25 mg) diluted in 100 mL of normal saline, was provided. The pump was programmed to deliver a continuous basal infusion at 1.5 mL/h, with a patient-controlled bolus dose of 1.5 mL and a lockout interval of 15 min.

Primary and Secondary Outcomes

The primary endpoint of this study was the incidence of PONV within the first 6 postoperative hours (defined as the 6-hour period following the end of surgery). The secondary endpoints, regarded as exploratory, included: the incidence of PONV, both in the PACU and over the entire 24-h postoperative period; the severity of nausea, assessed using an 11-point numerical rating scale (NRS); the frequency of vomiting episodes (defined as retching, vomiting, or both), evaluated in the PACU and at 6 and 24 h postoperatively; the incidence of adverse events such as respiratory depression, pruritus/paresthesia, hypotension, and bradycardia; and overall patient satisfaction at 24 h after surgery.

Measurements and Data Collection

Study data were systematically collected using standardized case report forms, managed in a secure Microsoft Access database, and assessed exclusively by personnel blinded to treatment allocation. Data were acquired over the entire perioperative period.

Intraoperative monitoring captured the hemodynamic and anesthetic depth parameters at the following time points: baseline (T0), pre-induction (T1), 5 min post-intubation (T2), and surgery conclusion (T3). These parameters included heart rate, blood pressure, SpO₂, and BIS values. The occurrence of bradycardia and hypotension, total anesthesia and surgical duration, estimated blood loss, fluid administration, heart rate at extubation, and the time from cessation of maintenance anesthetics to extubation were also recorded.

In the PACU, a blinded researcher assessed the patients every 10 min following extubation. Nausea and pain severity were evaluated using an 11-point Numerical Rating Scale (NRS; 0 = no symptoms, 1–3 = mild, 4–6 = moderate, and 7–10 = severe), from which average and maximum scores were calculated. The use of rescue analgesics or antiemetic medications and episodes of vomiting were also recorded.

Postoperative follow-up continued on the ward with structured assessments at 6 and 24 h. These evaluations documented the incidence and severity of nausea (NRS), the incidence and frequency of vomiting, and pain scores. At the 24-h time point, we also recorded PCIA pump usage (total bolus attempts and effective deliveries) and assessed overall patient satisfaction with recovery on a scale from 1 (extremely dissatisfied) to 10 (extremely satisfied). All other adverse events were monitored throughout the 24-h period.

All adverse events were managed using a predefined protocol. Hypotension, defined as an MAP decrease of >30% from baseline or a systolic blood pressure of <90 mmHg lasting for more than 10s, was treated with a single intravenous bolus of ephedrine (3–6 mg). Bradycardia, defined as a heart rate of <50 beats per minute persisting for >10s, was treated with atropine (0.5 mg). For PONV, intravenous aprepitant (150 mg) was administered if the nausea NRS score reached ≥4 or if vomiting occurred. Pain management was context-specific. In the PACU, a pain NRS score ≥4 prompted the administration of intravenous sufentanil (10 µg), while on the postoperative ward, the same pain threshold was treated with intravenous acetaminophen (500 mg). Respiratory depression, characterized by hypoxemia (SpO₂ <90% for >15s), was initially managed with jaw-thrust maneuvers and increased oxygen flow, escalating to mask ventilation or nasopharyngeal airway insertion, if necessary.

Statistical Analysis

The sample size was calculated based on a pilot study involving eight participants per group, which indicated a 25% incidence of PONV within 6 h postoperatively in the propofol (control) group. This observed rate was consistent with published literature reporting PONV incidences of approximately 20% in high-risk surgical populations despite multimodal antiemetic prophylaxis.1 We estimated that fospropofol could reduce this incidence to 5% or less. Using R software (version 4.5.1; R Foundation for Statistical Computing, Vienna, Austria) and Zstats 1.0 (https://www.zstats.net/), a sample size of 47 patients per group was determined to be sufficient to detect this difference with 80% power at a two-sided alpha level of 0.05, assuming a 1:1 allocation ratio. Accounting for a potential 10% attrition rate, the final recruitment target was set at 52 patients per group for a total of 104 participants.

All statistical analyses were performed using R (version 4.5.1; R Foundation for Statistical Computing), R Studio (version 2025.09.1+401; R Foundation for Statistical Computing), and GraphPad Prism 10 (version 10.1.2; GraphPad Software, Boston, MA, USA). The normality of continuous variables was assessed using the Shapiro–Wilk test. Normally distributed data are presented as mean (standard deviation) and were compared between groups using an independent two-sample t-test. Non-normally distributed data are summarized as median (interquartile range) and analyzed using the Mann–Whitney U-test. Categorical variables are expressed as numbers (percentages) and were compared using the chi-square test or Fisher’s exact test, as appropriate.

To evaluate the independent association between fospropofol use and the incidence of PONV within 6 h postoperatively, a multivariable logistic regression model was constructed. The dependent variable was the occurrence of PONV within 6 h (yes/no), and the independent variable of interest was the treatment group (fospropofol vs propofol). Covariates were selected a priori based on established risk factors from the Fourth Consensus Guidelines for PONV and the 2025 Chinese Clinical Practice Guidelines for PONV,1,5 and included age, BMI, surgical duration, and the intraoperative use of potentially emetogenic drugs (pituitrin and neostigmine). Variables were entered simultaneously into the model. Results are reported as odds ratios with 95% confidence intervals.

Statistical significance was set at P < 0.05.

Results

Between December 15, 2025, and January 10, 2026, 120 patients were assessed for eligibility. Of these, 104 were enrolled and randomized. The primary efficacy analysis was performed on the modified intention-to-treat (mITT) population (n = 102), excluding two patients (one from each group) who underwent intraoperative conversion to laparotomy (n = 1) or unexpected reoperation (n = 1) (Figure 1). Baseline demographic and perioperative characteristics were well balanced between the two groups, with no statistically significant differences observed (Table 1).

Figure 1.

Flow chart showing study participant recruitment.

Table 1.

Baseline Demographics of Patients

Characteristic	Fospropofol Group (n=51)	Propofol Group (n=51)
Age (y)	40 (35.0,46.0)	43 (38.0,46.0)
Height (cm)	162.0 (158.0,167.0)	160 (158.0,162.0)
Weight (kg)	59.1 (55.0,63.0)	60.0 (53.7,64.5)
BMI (kg/m2)	22.0 (21.4,24.8)	23.6 (20.9,25.2)
ASA classification (n, %)
I	38 (74.5)	34 (66.7)
II	13 (25.5)	17 (33.3)
Apfel score (n, %)
3	37 (72.5)	39 (76.5)
4	14 (27.5)	12 (23.5)
Type of surgery (n, %)
Hysterectomy	14 (27.5)	16 (31.4)
Myomectomy	23 (45.0)	23 (45.0)
Ovarian cystectomy	14 (27.5)	12 (23.6)

Note: Data are shown as median (interquartile range) or number (%).

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

The incidence of PONV within the first 6 h postoperatively was significantly lower in the FD group (3/51, 5.9%) than in the P group (10/51, 19.6%; absolute risk reduction, 13.7%; P=0.038). However, no significant differences were observed between the groups in the incidence of PONV during the PACU stay or over the full 24-h period, or in the severity of nausea, incidence of vomiting. Rescue antiemetic requirements were also comparable: in the PACU, no patients in either group required rescue antiemetics (0% vs 0%; P>0.999); at 6 h (FD: 3.9% vs P: 7.8%; P=0.678); and at 24 h (FD: 17.6% vs P: 13.7%; P=0.586) (Table 2).

Table 2.

Primary and Secondary Outcomes

	Fospropofol Group (n=51)	Propofol Group (n=51)	p value
Primary outcome
Incidence of PONV 6h (n, %)	3(5.9)	10(19.6)	0.038
Secondary outcomes
PACU (0–1h)
Nausea (n, %)	0(0)	4(7.8)	0.118
Nausea level (0/1/2/3)	51/0/0/0	47/4/0/0	0.118
Vomiting (n, %)	0(0)	0(0)	–
Rescue antiemetic (n, %)	0(0)	0(0)	–
Postoperative 6h (0–6h)
Nausea (n, %)	3(5.9)	10(19.6)	0.038
Nausea level (0/1/2/3)	48/1/1/1	41/6/4/0	0.158
Vomiting (n, %)	2(3.9)	1(2.0)	–
Rescue antiemetic (n, %)	2(3.9)	4(7.8)	0.678
Postoperative 24h (0–24h)
Nausea (n, %)	17(33.3)	18(35.3)	0.835
Nausea level (0/1/2/3)	34/8/5/4	33/11/5/2	0.739
Vomiting (n, %)	8(15.7)	7(13.7)	0.780
Rescue antiemetic (n, %)	9(17.6)	7(13.7)	0.586

Note: Data are shown as number (%).

Abbreviation: PONV, postoperative nausea and vomiting.

Perioperative findings revealed notable contrasts (Table 3). The time from cessation of anesthetic maintenance to extubation was significantly longer in the Fospropofol (FD) group (median 14.0 [IQR 10.0, 17.0] min) compared with the Propofol (P) group (median 10.0 [8.0, 15.0] min; P=0.006). Furthermore, the incidence of pain in the PACU was significantly lower in the FD group (26/51, 51.0%) than in the P group (37/51, 72.5%; P=0.025). The incidence of other postoperative adverse events was comparable between the two groups, with no statistically significant differences observed (Table 4).

Table 3.

Data Collected During and After Surgery

	Fospropofol Group (n=51)	Propofol Group (n=51)	p value
Intraoperative period
Operation duration (min)	89.0(59.0,123.0)	85.0(63.0,107.0)	0.705
Anesthesia duration (min)	95.0(65.0,133.0)	93.0(75.0,115.0)	0.703
Bradycardia (n, %)	16(31.4)	13(25.5)	0.510
Hypotension (n, %)	8(15.7)	9(17.6)	0.791
Fluid infusion quantity (mL)	1100(1000,1500)	1200(1000,1500)	0.552
Estimated blood loss (mL)	80.0(50.0,100.0)	100.0(50.0,100.0)	0.547
Tracheal extubation time (min)	14.0(10.0,17.0)	10.0(8.0,15.0)	0.006
HR at tracheal extubation (bpm)	82.0(76.0,90.0)	85.0(77.0,93.0)	0.510
Pituitrin (n, %)	25(49.0)	24(47.1)	0.843
Neostigmine (n, %)	4(7.8)	3(5.9)	–
Postoperative period
PACU
Pain (n, %)	26(51.0)	37(72.5)	0.025
Pain score (0–10)	1.0(0.0,1.0)	1.0(0.0,2.0)	0.081
Rescue analgesic (n, %)	7(13.7)	2(3.9)	0.160
Delayed PACU discharge (n, %)	0(0)	0(0)	–
Ward
Pain score at rest 6h (0–10)	1.0(0.0,1.0)	1.0(0.0,1.0)	0.991
Pain score with movement 6h (0–10)	1.0(0.0.2.0)	1.0(0.0,2.0)	0.822
Pain score at rest 24h (0–10)	1.0(0.0,2.0)	1.0(0.0,2.0)	0.502
Pain score with movement 24h (0–10)	1.0(1.0,3.0)	1.0(1.0,4.0)	0.922
Rescue analgesic (n, %)	7(13.7)	14(27.5)	0.087
Number of presses on PCIA (times)	0.0(0.0,1.0)	0.0(0.0,1.0)	0.924
Oxytocin (n, %)	23(45.0)	23(45.0)	–
Satisfaction (1–10)	10.0(10.0,10.0)	10.0(10.0,10.0)	0.821

Note: Data are shown as median (interquartile range) or number (%).

Abbreviations: PACU, post-anesthesia care unit; PCIA, patient-controlled intravenous analgesia.

Table 4.

Number of Patients with Adverse Events

	Fospropofol Group (n=51)	Propofol Group (n=51)	p value
Respiratory depression/apnea	1(2.0)	2(3.9)	>0.999
Pruritus/paraesthesia	0(0)	0(0)	–
Hypotension	3(5.9)	3(5.9)	–
Bradycardia	1(2.0)	0(0)	>0.999

Note: Data are shown as number (%).

Intraoperative hemodynamics and depth of anesthesia profiles are shown in Figure 2. Key differences emerged at specific timepoints. The MAP was significantly lower in the FD group at 5 min post-intubation (T2:77.1 vs 84.3 mmHg, P=0.004) and at the end of surgery (T3:75.5 vs 80.9 mmHg, P=0.017). Concurrently, the BIS value at T2 was significantly lower in the FD group (median 43.0 [IQR 42.0, 45.0]) than in the P group (median 48.0 [45.0, 50.0]; P<0.001).

Figure 2.

Vital signs at different time points between the two groups (A): HR, heart rate; (B) MAP, mean arterial pressure). Data are mean with error bars showing standard deviation. T0, baseline, T1, before anesthesia induction, T2, 5 minutes after intubation, T3, end of the surgery; P, propofol; FD, fospropofol disodium. * p<0.05; **p<0.01.

The results of the logistic regression analysis identifying factors associated with the incidence of PONV within the first 6 h postoperatively are shown in Table 5. This analysis confirmed that fospropofol treatment remained a significant independent predictor of reduced PONV risk (odds ratio 0.219, 95% CI, 0.045–0.809; P=0.034).

Table 5.

Multivariable Analysis of Potential Risk Factors of PONV at Postoperative 6 h

Variable	OR (95% CI)	p value
Age (y)	0.971(0.886,1.070)	0.527
BMI (kg/m2)	0.844(0.632,1.079)	0.204
Fospropofol	0.219(0.045,0.809)	0.034
Operation duration (min)
≤60	Ref.	–
>60	1.657(0.336,13.190)	0.573
Pituitrin	1.210(0.329,4.598)	0.773
Neostigmine	0.831(0.030,10.220)	0.894
Pain at PACU	2.443(0.524,18.29)	0.304
Tracheal extubation time (min)
Propofol	Ref.	–
Fospropofol	1.016(0.907,1.127)	0.773

Note: Values are presented as OR (95% CI).

Abbreviations: OR, odds ratio; CI, confidence interval; Ref, reference.

Discussion

This study demonstrated that the use of fospropofol for both induction and maintenance of general anesthesia is associated with a significantly lower incidence of PONV compared with propofol within the first 6 h postoperatively. Furthermore, fospropofol use was identified as an independent protective factor against early PONV. These findings confirm that fospropofol is an effective agent for early PONV prophylaxis, offering a duration of action that extends beyond that typically associated with propofol during the early postoperative period (0–6 h).

Propofol is widely used as an intravenous agent for general anesthesia. Its antiemetic properties are plasma concentration-dependent, with the primary clinical effect typically observed within the first 2 h postoperatively, aligning with its pharmacokinetic profile.11 This is supported by clinical evidence, including randomized trials and meta-analyses, demonstrating that propofol-based total intravenous anesthesia is associated with a significantly lower risk of PONV than anesthesia maintained with volatile agents.12 Furthermore, even subhypnotic doses of propofol (eg, 20–40 mg) can be effective as rescue therapy for established PONV.13,14 As a water-soluble prodrug of propofol, fospropofol shares its mechanism of action but exhibits a distinctly different pharmacokinetic profile.15 Pharmacological studies indicate that the terminal elimination half-life (t1/2z) of propofol generated from fospropofol is substantially longer (478 ± 287 min) than that of directly administered propofol (88 ± 48 min).10,15 This prolonged metabolic duration provides a plausible explanation for the extended antiemetic effect observed at the 6-h time point. Our results are corroborated by those of retrospective clinical studies. Ding et al16 reported a significantly lower PONV incidence in the PACU among elderly patients receiving fospropofol for total hip arthroplasty compared with those receiving propofol. Similarly, Zhu et al17 reported a reduced PONV rate with fospropofol in a study on perioperative neurocognitive function in the same patient population. Importantly, our prospective controlled study strengthens this evidence by demonstrating the superior prophylactic effect of fospropofol in a rigorously defined high-risk PONV cohort undergoing gynecological laparoscopy.

PONV is a multifactorial complication, the incidence of which remains considerable in high-risk populations despite optimized management.18 Our study specifically targeted a high-risk cohort, defined by a simplified Apfel score of 3–4, age < 50 years, laparoscopic gynecological surgery, and scheduled postoperative opioid analgesia. Subsequent logistic regression analysis, which controlled for confounders, including age, body mass index, surgical duration, and the use of potentially emetogenic drugs (eg, pituitrin and neostigmine). Multivariable analysis adjusting for predefined confounders suggested that fospropofol was associated with a reduced risk of early PONV. This finding may facilitate clinical relevance for enhanced recovery after surgery protocols, where early postoperative oral intake is a fundamental goal.4,19 The low 6-h PONV incidence of 5.9% observed in the fospropofol group establishes a highly favorable condition for initiating early feeding, thereby promoting patient comfort and facilitating faster recovery, while concurrently minimizing rescue antiemetic use and improving the cost-effectiveness of perioperative care. To be mentioned that both groups received a comprehensive multimodal antiemetic regimen including dexamethasone, palonosetron, diphenhydramine, and transversus abdominis plane block. This robust prophylactic background likely contributed to the low overall PONV rates and may have washed out between-group differences at 24 hours, particularly given palonosetron’s prolonged duration of action (approximately 40 hours). Consequently, the observed benefit of fospropofol was confined to the early postoperative period before the full effect of long-acting antiemetics was established. This heavy-duty prophylactic setup limits generalizability to settings where such comprehensive antiemetic coverage is not routine.

In the present study, patients receiving fospropofol demonstrated significantly lower MAP and BIS values 5 min post-intubation, as well as lower MAP at the end of surgery. This observed hemodynamic and hypnotic profile was consistent with the known pharmacodynamics of fospropofol, which achieves peak propofol concentrations later (approximately 9–15 min post-administration) than directly administered propofol.20 Consistently, a previous study by Wu et al7 documented a more delayed and pronounced reduction in both BIS and blood pressure following fospropofol administration. These differences did not result in a higher incidence of clinically significant hypotension or bradycardia in our cohort, suggesting that the profile was pharmacologically predictable and manageable.

In this study, although fospropofol infusion was discontinued 20 minutes before the anticipated end of surgery, extubation time remained significantly prolonged in the fospropofol group. This is consistent with the known pharmacological characteristics of fospropofol; compared with propofol, its onset and duration of action are slightly prolonged, as documented in Phase III clinical trials7 and the recent randomized controlled trial by Sun et al21 It should also be noted that heart rate at extubation and the incidence of adverse events during PACU stay did not differ significantly between groups. While statistically significant, this 4-minute difference in extubation time may be clinically acceptable in the context of inpatient gynecological laparoscopy, where emergence time is less critical than in ambulatory settings. Nevertheless, this trade-off should be considered when selecting fospropofol for PONV prophylaxis.

This study had several limitations. First, this was a single-center study with an exclusively female cohort, both of which may limit the generalizability of the findings. However, given that female sex is a major risk factor for PONV, the prophylactic benefit of fospropofol may be even more pronounced in a mixed-sex population. Future studies should validate these findings in a multicenter trial with a larger, sex-diverse sample. Second, the mandatory use of opioid-containing PCIA for all participants is a potential confounding factor that may have attenuated the differences in the 24-h PONV incidence. Opioids increase the risk of PONV in a dose-dependent manner, and this effect persists for as long as opioids are used in the postoperative period.1,22 Future studies employing opioid-sparing or opioid-free multimodal analgesia are required to investigate the duration of the protective effects of fospropofol. Third, the multivariable logistic regression included several predictors with only 13 outcome events, raising concerns about overfitting. This analysis was exploratory, and the reported odds ratios should be interpreted with caution. The primary efficacy conclusion is based on the unadjusted between-group comparison. Another limitation is that plasma propofol concentrations were not measured in this study. Consequently, our mechanistic explanations for the extended antiemetic effect of fospropofol, specifically the hypothesis that its prolonged metabolic half-life sustains therapeutic propofol levels beyond the immediate postoperative period, remain speculative. Future pharmacokinetic studies incorporating serial blood sampling are warranted to validate this proposed mechanism and to delineate the precise concentration-effect relationship for PONV prophylaxis. Finally, the anesthesiologists were not blinded to group allocation; however, all postoperative assessments were performed by blinded investigators to minimize bias.

To our knowledge, this is the first prospective randomized controlled trial to evaluate fospropofol for PONV prophylaxis in a specifically defined high-risk population. Compared with propofol, fospropofol was associated with a significantly lower incidence of PONV within the first 6 h postoperatively. This finding suggests a potential role for fospropofol in early PONV prophylaxis. Future larger, multicenter trials are warranted to further establish its broader clinical utility.

Funding Statement

This manuscript was funded by Wu Jieping Medical Foundation (NO. 320.6750.2024-15-36).

Clinical Trial Number and Registry URL

This trial was registered in the Chinese Clinical Trial Registry (No: ChiCTR2500114542; principal investigator: Li Ma; date of registration: December 15, 2025).

Abbreviations

NRS, numerical rating scale; PCIA, patient-controlled intravenous analgesia; PONV, postoperative nausea and vomiting.

Data Sharing Statement

The authors intend to share individual deidentified participant data. Datasets generated during the current study (raw data) are available upon reasonable request. Data and supporting documents will be available through repository deposition. Requests should be directed to the corresponding author: Weijia Du (duweijia10317@fckyy.org.cn). Data will be available immediately upon publication and will remain accessible for a minimum of 5 years from the date of publication.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors declare no competing interests.