A comparison of ondansetron in preventing postoperative nausea and vomiting for patients with or without preoperative anxiety with painless egg retrieval: a prospective, randomized, controlled trial

Introduction

Preoperative anxiety is a prevalent psychological issue in patients undergoing painless egg retrieval (1). Currently, the global incidence of infertility is progressively rising (2). In vitro fertilization (IVF)-embryo transfer is widely utilized worldwide, and one of the most essential procedures is ultrasound-guided transvaginal puncture egg retrieval (3). Infertile women are afraid of the pain caused by the puncture operation. Moreover, they are concerned about the unknown outcome of the procedure before egg retrieval, which can cause a variety of physiological, and social problems, such as sensitivity, anxiety, lack of self-worth, and social identity (4-6). Excessive, persistent anxiety can lead to a variety of perioperative problems (7,8) and can even endanger the patient’s life (9).

Postoperative nausea and vomiting (PONV) is the most common postoperative complication (10). Female gender, a history of motion sickness, non-smoking status, previous experiences of PONV, and age under 50 years represent significant risk factors for PONV, with female gender emerging as the most influential predictor (11). It is evident that PONV significantly impairs patient recovery, particularly among young women.

It revealed that serotonin (5-HT) controls and regulates many physiological and psychological processes, including mood, learning, memory, circadian rhythm, locomotion, socialization, aggression, etc. (12-14). Furthermore, research has demonstrated a close relationship between 5-HT receptors and nausea and vomiting (15,16). Ondansetron is a highly potent 5-HT₃ receptor antagonist with central and peripheral anti-emetic effects (17). As a result, we discovered that preoperative anxiety and PONV are both related to 5-HT receptors, and whether there is an association between the two is not commonly reported in the literature.

Patients undergoing IVF-embryo transfer are almost exclusively young women, with higher rates of preoperative anxiety and PONV. Some studies have suggested that preoperative anxiety predicts PONV (18,19), but some have concluded that preoperative anxiety is not significantly associated with PONV (20). This trial aimed to investigate the clinical effects of preoperative use of ondansetron for the prevention of PONV in anxious and non-anxious patients undergoing painless egg retrieval and to explore the potential relationship between preoperative anxiety and PONV by detecting pre- and post-surgical levels of 5-HT in anxious and non-anxious patients. We present this article in accordance with the CONSORT reporting checklist (available at https://gs.amegroups.com/article/view/10.21037/gs-24-175/rc).

Methods

Study design

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The Ethics Committee of The First People’s Hospital of Yunnan Province (No. KHLL2023-KY026) approved this prospective, randomized, controlled trial, and patients or their families signed an informed consent form. Patients who underwent painless egg retrieval at The First People’s Hospital of Yunnan Province’s Department of Reproductive Medicine from March 2023 to May 2023 were screened for eligibility.

The clinical research design is shown in Figure 1.

Figure 1 Flowchart of the trial design. SAS, anxiety self-rating scale; AO, patients in the anxiety group received intravenous ondansetron before surgery; AS, patients in the anxiety group received intravenous saline before surgery; NO, patients in the non-anxiety group received intravenous ondansetron before surgery; NS, patients in the non-anxiety group received intravenous saline before surgery.

Sample size calculation

Sample size calculations were based on a previous study on PONV (21). PASS 15.0 software was used for sample size estimation, setting the degree of certainty 1−β=0.80 and the test level α=0.05 (bilateral), then 42 cases of samples were needed in each group. Considering that 10% of the subjects dropped out, a total of 209 research subjects were enrolled in this study, and finally 50 cases were analyzed in each group respectively, which ensured the accuracy and scientificity of the results of the study.

Inclusion criteria

• Patients with an American Society of Anesthesiologists Standard (ASA) classification of I–II, New York Heart Association (NYHA) classification I–II;
• Age 25–45 years old;
• Body mass index (BMI) 18.5–24 kg/m²;
• The standard score of the anxiety self-rating scale was 50–60 points, and the standard score of the SAS of the non-anxiety group was 25–35 points;
• The operation time less than 30 minutes.

Exclusion criteria

• A history of chemoradiotherapy within one week, antiemetic with 5-HT receptor blockers;
• Patients with mental disorders or limited intellectual ability;
• Patients with gastrointestinal, craniocerebral and otogenic diseases that can cause nausea and vomiting;
• Liver and kidney function impairment;
• History of malignancy or severe systemic disease;
• Use of neurotrophic factor-related drugs within three months;
• Patients who are allergic to ondansetron;
• Patients who do not agree to enroll in this clinical trial study.

Randomization

We used SPSS software to generate random numbers at a 1:1 ratio for the anxiety and non-anxiety groups and separated each group into two subgroups. The grouping results were sealed in envelopes and stored from the start till the end of the investigation. The randomized findings of the recruited individuals were distributed to study participants. Anesthesia was delivered by a professional anesthesiologist for each enrolled patient, and researchers collected intraoperative data. Postoperative monitoring was carried out by investigators who were not involved in anesthesia care. During the data-collecting period, there was no communication between the anesthesiologist and the researcher.

Anesthesia methods

Preoperative management and anesthesia monitoring setup

All patients fasted for 8 hours and abstained from drinking for 2 hours before surgery. After the patient entered the operating room, peripheral venous access was obtained and 2 mL of venous blood sample was drawn. The self-rating anxiety scale (SAS) was used to assess patients’ preoperative anxiety half an hour before surgery in the pre-anesthesia care unit, and patients with an SAS standard score of 50–60 points were classified as anxious, while patients with an SAS standard score of 25–35 points were classified as non-anxious. Patients in the anxiety group were randomly allocated in two subgroups: the ondansetron subgroup (AO group) and the placebo subgroup (AS group), while patients in the non-anxiety group were also randomly divided into two subgroups: ondansetron subgroup (NO group) and saline subgroup (NS group). The AO and NO groups received 8 mg (4 mL) of intravenous ondansetron 15 minutes before surgery, while the AS and NS groups received an equivalent volume (4 mL) of normal saline.

The operating position was the lithotomy position, and the mask administered oxygen at a rate of 3–5 L/min. Before anesthesia was administered, the Monitor (Philips IntelliVue MX, USA) monitored the electrocardiogram (ECG), heart rate (HR), pulse, respiratory rate (RR), pulse oxygen saturation (SpO₂), and blood pressure (BP). Before vaginal disinfection, patients were injected 1–2 µg/kg intravenous fentanyl (Human Well Healthcare, 10A11081, China), followed by 1.5–2.0 mg/kg propofol (Corden Pharma S.P.A, RX356, Italy) 2 minutes later. After the patient’s eyelash reflex and consciousness disappeared, the operation was started. The surgeon retrieved eggs through vaginal puncture under ultrasound guidance, penetrated the follicles through the vaginal vault with a single-lumen egg retrieval needle, and suctioned bilateral follicles with a negative pressure of 110 kPa. The anesthesiologist added propofol 0.5 mg/kg/bolus according to the operation time or when the patient has physical movement and moaning. In this study, anesthesia procedures were performed by the same experienced anesthesiologist, and surgical procedures were performed by the same experienced reproductive medicine specialist.

Intraoperative management

When the pulse oximetry reading fell below 90%, mask-positive pressure-assisted ventilation was performed. We employed atropine (Henan Runhong Pharmaceutical Co., Ltd., 2108082, China) to keep the HR between 50–100 beats per minute, and ephedrine (Northeast Pharmaceutical Group CO., Ltd., 230202, China) to keep BP changes within 20% of baseline.

Postoperative management

After the operation, the patients were transferred to the post-anesthesia care unit to continue monitoring their vital signs for 1 hour, 2 mL blood sample is then drawn and they were allowed to return home after their consciousness and orientation returned to normal, and if their vital signs were stable and no adverse reactions were observed.

Blood sample

Blood collector collected 2 mL of venous blood at the time of patients’ admission and 1 hour after the surgery, and the specimens were left at room temperature for 10 minutes and then placed in a centrifuge (Eppendorf AG, Centrifuge 5804R, Leipzig, Germany) for natural coagulation. Samples were centrifuged at 3,000 rpm/separation for 10 minutes, and the supernatant was aspirated with a pipette gun and uniformly placed in a −80 ℃ refrigerator for freezing. Samples were taken out from the refrigerator in advance to equilibrate at room temperature for 1 hour. The kit (FANKEWEI, Cat. # F0755-A, Jiangsu, China) was balanced for 30 minutes. The standard empty and sample wells were then designed on the enzyme label coating plate, and 50 µL of different concentrations of standard were added to the typical wells in turn. In the sample well, 40 µL of sample diluent was added, followed by 10 µL of the sample to be measured. The mixture was gently shaken, and then 100 µL of microplate reagent was added per well. The plate was sealed with a plating film and incubated at 37 ℃ for 60 minutes. After the incubation period, the enzyme label coating plate was taken out and the plate film was uncovered, and the liquid was discarded. The diluted washing solution was left to stand for 30 seconds, discarded, and then spun dry. Subsequently, the absorbance of each well was measured successively at 450 nm using a microplate reader (BIO-TEK, Elx800, Vermont, USA) within 15 minutes.

Indicator recording

First, the patient’s general condition is recorded, including age, height, weight, BMI value, ASA classification, preoperative fasting time, operation time, and risk factors for PONV: past smoking, previous PONV, and history of motion sickness. Second, the patient’s vital signs were recorded at the time of admission (T₁), 3 minutes after anesthesia induction (T₂), and at discharge (T₃), including mean arterial pressure (MAP), HR, SpO₂, and RR, as well as the total amount of fentanyl and propofol during the surgical process. Third, the occurrence of PONV, pain scores and adverse responses (dizziness, drowsiness, and fatigue) within 1 hour was monitored. Finally, their satisfaction and delayed PONV were followed-up by telephone.

SAS

The 20-item SAS employed in this experiment has strong reliability and validity. This assessment, which takes about 10 minutes, captures the patient’s emotional response to stress, and has previously been frequently used to assess preoperative anxiety (22).

PONV

Patients were evaluated according to the World Health Organization (WHO) grading criteria within 24 hours after surgery. Grade 0: no nausea and vomiting; Grade I: nausea, does not affect eating and daily life, 1–2 times a day; Grade II: temporary vomiting can be controlled, 3–5 times a day; Grade III: vomiting requires treatment, 6–10 times a day; Grade IV: uncontrollable vomiting more than 10 times a day.

Analgesia assessment

Postoperative pain was scored via the visual analog scale (VAS) 1 hour after surgery, ranging from 0 (no pain) to 10 (maximum pain). Scores of 1–3 denoted mild pain, 4–6 denoted moderate pain, and 7–10 represented severe pain.

Patient satisfaction

Satisfaction ratings range from 0 (very dissatisfied) to 10 (very satisfied), with higher scores representing greater satisfaction.

Statistical analysis

Subjects who completed the study according to the study protocol were analyzed. Patients with missing values were excluded from the trial. The primary analysis will be by per-protocol (PP). Statistical analysis was performed using SPSS 26.0 (IBM SPSS Inc., Armonk, USA) software. Normally distributed continuous data were described by mean ± standard deviation (SD), analysis of variance (ANOVA) was used for between-group comparison, and paired t-test was used for paired samples for intra-group comparison. Nonnormal quantitative data were expressed as medians [interquartile range (IQR)] and calculated using rank sum or nonparametric tests. The chi-square test was used for comparison of counts, which was represented by n (%). The rank sum test was used for grade data. P value <0.05 was considered statistically significant. All P values are two sided.

Results

From March 2023 to May 2023, 209 female patients who underwent painless egg retrieval in the outpatient clinic of The First People’s Hospital of Yunnan Province were included. 9 patients failed to follow up after surgery and 200 patients were ultimately enrolled in the study (Figure 1).

Patient’s baseline clinical characteristics and risk factors for PONV

The baseline clinical characteristics, including age, BMI, ASA classification, fasting time, and operation time did not show significant differences among the four groups. Similar results were obtained for risk factors for PONV between the groups (Table 1).

Perioperative vital signs of the patients

The P values of MAP, HR, SpO₂ and RR at T₁ (time of admission), T₂ (3 minutes after anesthesia induction), and T₃ (time of discharge) moments were higher than 0.05 in all four groups (Table 2).

Comparison of the incidence of PONV

None of the patients in all four groups developed grade III or IV nausea and vomiting. The incidence of grade II nausea and vomiting in the AS group was higher than that in the NS group and AO group (P<0.05), The incidence of PONV was also higher in the AS group than in the AO group (P<0.05). The four groups did not show significant differences in the incidence of grade I nausea and vomiting (P>0.05) (Table 3, Figure 2).

Figure 2 Postoperative nausea and vomiting in the four groups. *, P<0.05, AO group compared the incidence of grade II PONV to the AS group and NS group compared the incidence of grade II PONV to the AS group. The absence of grade III and IV PONV may be related to the good general condition of the egg retrieval patient and the low amount of anesthetic used during the operation. AO group, anxious ondansetron group; AS group, anxiety saline group; NO group, non-anxious ondansetron group; NS group, non-anxiety saline group; PONV, postoperative nausea and vomiting.

Preoperative and postoperative serum 5-HT value in patients in the anxiety group and non-anxiety group

The serum 5-HT values before and after surgery in the anxiety group were higher than those in the non-anxiety group (P<0.001) (Table 4, Figure 3).

Figure 3 5-HT values (39–361 ng/mL) before and after surgery in the anxiety group and non-anxiety group. *, P<0.05, the non-anxiety group compared to the anxiety group. 5-HT, serotonin.

Comparison of 5-HT values before and after surgery in the same group

The comparison of serum 5-HT before and after surgery between the same groups did not show significant changes (all P>0.05) (Table 5, Figure 4).

Figure 4 5-HT values before and after surgery in the same group. AO group, anxious ondansetron group; AS group, anxiety saline group; NO group, non-anxious ondansetron group; NS group, non-anxiety saline group; 5-HT, serotonin.

Intraoperative anesthetic dosage

The P values for total intraoperative propofol and fentanyl administration were higher than 0.05 in all four groups (P=0.83) and (P=0.45), respectively (Table 6).

Postoperative adverse effects

Differences between the four groups of patients regarding postoperative adverse effects including dizziness, drowsiness, and fatigue showed no significant differences, with (P=0.91, 0.83, 0.57) respectively (Table 7).

Pain scores and satisfaction scores

The four groups of patients had similar postoperative pain scores (P=0.051). Patients in the AS group had lower satisfaction scores than those in the other three groups (P<0.001) (Table 8).

Discussion

Preoperative anxiety is a nervous or tense state of mind caused by a patient’s concerns about disease, operation, anesthesia, and treatment outcomes. Preoperative anxiety has been shown in numerous studies to have a deleterious impact on both intraoperative and postoperative progression (23-25). Gender, age, sleep disturbance, high BMI, preoperative discomfort, and prognosis are all associated with the prevalence of preoperative anxiety (26).

Our study’s results demonstrated that the anxiety group’s serum 5-HT values before and after surgery were higher than those of the non-anxiety group (P<0.05) and that there was no significant difference in the same group’s serum 5-HT before and after surgery (P>0.05). Anxiety and depression have been found to be strongly associated with serum brain-derived neurotrophic factor (BNDF), neurotrophin-3 (NT-3) and 5-HT levels (27), with 5-HT being widely distributed in the central nervous system as an indolamine. It is released by the diaphragm, hippocampus, amygdala, thalamus, and hypothalamus, which is critical in the onset and progression of anxiety and depression (28-30). Many mouse studies have indicated that 5-HTTA₁ and 5-HT₃ receptors are related to anxiety behavior. The modulation of the number of 5-HT auto-receptors on middle suture nuclear neurons can modify adult mice’s anxiety behavior (31,32). Regulation of both 5-HTA₁ and 5-HT₃ receptors has also been proven in studies to diminish anxiety states in adults (33). Furthermore, anxiety states can impact the intestinal microecology and immune cells via the brain-intestinal axis to change the patient’s 5-HT level (34). Our findings are consistent with the above studies.

Although there was no difference in patient baseline clinical characteristics, PONV risk factors, intraoperative condition, or intraoperative medication, the incidence of grade II PONV in patients with preoperative anxiety was significantly higher than that in patients without anxiety (P<0.05). PONV is caused by a complex process involving the vomiting center and the peripheral chemoreceptor trigger area (CRTZ). The former found in the brainstem’s lateral reticular structure, while the latter is situated at the bottom of the fourth ventricle. The blood-brain barrier does not protect CRTZ, which hosts a variety of receptors, including histamine receptors, 5-HT receptors, cholinergic receptors, neurokinin-1 receptors, dopamine receptors, and others. These receptors can directly sense signals from various neurotransmitters, drugs, and metabolites in the blood and cerebrospinal fluid. There are seven subtypes of 5-HT receptors, of which 5-HT₃ receptors are ligand-gated ion channels most closely associated with vomiting (35). Some have shown that two neurotransmitters play a central role in mediating the emetic response: 5-HT, which acts on the 5-HT₃ receptor, and substance P, which targets the NK₁ receptor (36,37). We discovered that preoperative anxiety and PONV share a receptor and patients who develop PONV have higher preoperative anxiety scores (38). As a result, we conclude that preoperative anxiety is a significant cause of PONV and anxiety susceptibility predicts the development of PONV (39). The absence of grade III and IV PONV may be related to the good general condition of the egg retrieval patient and the anesthetic propofol is known as an antiemetic (40). Such an outcome was not predicted at the beginning of our trial, and the specific reasons need to be further investigated.

Ondansetron is a 5-HT₃ receptor antagonist that is commonly used in chemotherapy and PONV (41), and its usual adverse effects include migraines, dizziness, constipation, and other symptoms (42). A meta-analysis revealed that oral or intravenous ondansetron is related to QT interval prolongation, especially in participants over 18 years old (43), confirming the prevalence and severity of its side effects. Ondansetron is entirely and promptly absorbed from the gastrointestinal tract and does not accumulate with repeated oral treatment. Nevertheless, due to first-pass hepatic metabolism, the bioavailability of oral ondansetron is only 60% that of intravenous injection (44). Ondansetron 8 mg IV had a high elimination half-life of 0.26 hours (45), with an average elimination half-life of 3.8±1 hours (46). In addition, during laparoscopic cholecystectomy, there is no difference in the incidence of PONV between ondansetron given one hour before anesthesia induction and ondansetron administered 30 minutes before the completion of operation (47). As ultrasound-guided transvaginal puncture egg retrieval surgery is rather brief, we chose a prophylactic intravenous injection of ondansetron 15 minutes before surgery to provide an anti-emetic effect while also facilitating the detection of PONV. This study discovered that preoperative ondansetron dramatically reduced the incidence of PONV in patients with preoperative anxiety, but there was no significant statistical difference in non-anxious patients. It is thought that preoperative 5-HT levels may be elevated in anxious patients and that the treatment of ondansetron blocks 5-HT receptors, avoiding nausea and vomiting in anxious people. Therefore, we recommend prophylactic ondansetron for PONV in patients with preoperative anxiety but not in non-anxious patients. This approach saves medical costs and prevents unwanted pharmacological side effects, thereby reducing the risk during treatment and decreasing the incidence of PONV by lowering the patient’s anxiety and improving sleep quality (48).

In this study, we chose individuals who underwent painless egg retrieval on an outpatient basis. This operation is quite brief, and the anesthesia medicine is limited to propofol, which is thought to have anti-emetic properties. One study found that all-in-vein anesthesia with propofol reduced the risk of PONV by approximately 25% when compared to inhalation anesthesia (49). In addition, we used very small amounts of ephedrine to maintain BP during surgery because most of the included individuals were healthy young women. Some researchers have suggested that intramuscular injection of 0.5 mg/kg of ephedrine also has a preventive and therapeutic effect on PONV, and may exert its antiemetic effect by minimizing hypotension (50). During our anesthesia, we used a single intravenous dose of 0.1 mg/kg, with a maximum dose of 0.3 mg/kg, but the antiemetic effect of its intravenous route of administration has been rarely reported and more studies are needed. Taking into account the influence of some anesthetic and surgical factors on PONV, the incidence of postoperative PONV in patients in this trial remained as high as 31%. According to the literature, around 17% of patients suffered nausea, and 8% experienced vomiting following outpatient surgery (41), which is lower than the experimental results of our investigation and may be related to the type of operation. This may be due to the fact that infertility exposes married women to family and social pressures, and due to the long treatment period and traditional beliefs of IVF embryo transfer, they tend to be more anxious before surgery than other outpatient patients.

Furthermore, the study conducted a patient satisfaction survey on all four groups of patients and demonstrated that PONV might cause varying degrees of poor medical experience and diminish patient satisfaction. Most studies indicate that preoperative anxiety increases postoperative pain (51). Still, there was no significant difference in pain scores between the anxious and non-anxious groups in this study, possibly due to the relatively small surgical stimulation and mild pain associated with painless egg retrieval compared to major surgery.

Some limitations of our study should be mentioned. First, this study focused on female surgical patients, but the efficacy of ondansetron in combining preoperative anxiety in men or other surgical types of patients with PONV is not clear. Second, the preoperative anxiety of most of the patients included in this study was mild, and patients with moderate or severe anxiety were not included, so the correlation between 5-HT levels and the degree of anxiety has not been studied. Third, the specific mechanism of ondansetron in combating PONV in patients with preoperative anxiety is not clear. These need to be explored in further clinical and basic studies.

Conclusions

The results of this trial showed that individuals with preoperative anxiety had a higher incidence of PONV after painless egg retrieval than those with no anxiety. Ondansetron can minimize the occurrence of PONV in patients with preoperative anxiety but has no discernible preventative effect in non-anxious patients.

Acknowledgments

Funding: This study was funded by the National Natural Science Foundation of China (No. 81300973), Talent Project - Famous Doctor Project of Yunnan Province (Nos. YNWR-MY-2019-060, and XDYC-MY-2022-0029), the Special Fund of the Applied Basic Research Programs of Yunnan Province associated with Kunming Medical University (Nos. 202101AY070001-251, 202201AY070001-178, and 202301AY070001-056), the Basic Research Program of Yunnan Province (No. 202101AS070047), and the Foreign Experts Affairs Bureau of Yunnan Province (No. 202305AQ350012).

Footnote

Reporting Checklist: The authors have completed the CONSORT reporting checklist. Available at https://gs.amegroups.com/article/view/10.21037/gs-24-175/rc

Trial Protocol: Available at https://gs.amegroups.com/article/view/10.21037/gs-24-175/tp

Data Sharing Statement: Available at https://gs.amegroups.com/article/view/10.21037/gs-24-175/dss

Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-24-175/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-24-175/coif). A.K. has received honoraria for lecturing from CSL Behring GmbH (Switzerland) and advisory honoraria from Astrazeneca (Switzerland) and Pharmacosmos (Switzerland). The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Ethical approval for the study was granted by the Ethics Committee of The First People’s Hospital of Yunnan Province (No. KHLL2023-KY026). In addition, all patients or their families have signed the informed consent form. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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