Promethazine for nausea and vomiting prevention after gynaecological laparoscopic surgery：a randomized controlled trial

doi:10.21203/rs.3.rs-3250484/v1

Background: Postoperative nausea and vomiting (PONV) are the postoperative problem that patients undergoing surgery do not want to experience. The incidence of PONV in female patients undergoing laparoscopic surgery is about 40%, and the risk of PONV is as high as 80% in those patients who have not received preventive treatment. At present still did not have the consummation effective solution.

Methods: This prospective, single-centre, two-armed, randomised, double-blind, pilot study was conducted in Gansu Provincial Hospital from June 2021 to March 2022 and included 100 subjects, aged 18–65 years, who underwent nonemergent gynaecological laparoscopic surgery. Before anaesthesia induction, 6.25-mg promethazine or 1-mL saline was intravenously administered. All subjects received postoperative patient-controlled intravenous analgesia and continuous metoclopramide infusion at 50 mg. The primary outcome was the incidence and severity of postoperative nausea and vomiting at 6 h, 24 h, 48 h, and 72 h postoperatively.

Results:The incidence and severity of nausea during the early period (the first 6 h postoperatively) was significantly different between groups (P = 0.043, P = 0.048). A statistically significant difference was found in the incidence and severity within 24 h postoperatively (P = 0.026, P = 0.003). Vomiting incidence and severity were lower than in the control group at the 6 h postoperatively but without statistical difference between the two groups (P = 0.166, P = 0.180). Vomiting incidence and severity were statistically different during the 24 h postoperatively (P = 0.011, P = 0.004). A significant statistical difference was found in the satisfaction between the two groups during the postoperative observation period (P = 0.002).

Conclusion:Preoperative prophylactic promethazine significantly reduced the incidence and severity of postoperative nausea and vomiting within 24 h postoperatively, with few adverse effects and no serious adverse reactions. And the satisfaction of patients is improved.

Clinical Trials Registration Number:（18/12/2021）ChiCTR2100054495

Promethazine

gynaecological laparoscopic surgery

nausea

vomiting

Postoperative nausea and vomiting (PONV) is a subjective feeling of nausea and discomfort and stomach content elimination through the mouth, which most often occurs within 24 h postoperatively, and sometimes lasts up to 72 h.^{1, 2} Known risk factors of high PONV incidence include female sex, non-smoking, PONV history, postoperative opioid use, etc. The incidence of PONV in female patients undergoing laparoscopic surgery is approximately 40%,³ and the risk of PONV is as high as 80% among patients who have not received prophylaxis.⁴ Additionally, PONV may lead to serious consequences, such as aspiration, alkalosis and in particular, increased intra-abdominal pressure, which can lead to serious adverse effects, including wound rupture and bleeding in patients undergoing abdominal surgery.⁵ These do not only affect the patient’s rapid postoperative recovery but also increase their medical burden and reduce their comfort and satisfaction.⁶

In 2016, the American Society for Enhanced Recovery issued an expert statement that ‘All patients should receive PONV prophylaxis in the perioperative period’.⁷ However, at present, the curative effect remained limited, and PONV incidence remained nearly 30% under multi-mode combined therapy.⁸ Promethazine is an antihistamine receptor representative drug, with its anti-nausea and anti-vomiting of mainly antihistamine effect, medulla oblongata inhibition of emetic chemoreceptors, anti-dopamine effect and moderate anticholinergic effect.⁹ Concurrently, promethazine can act on the vestibule, vomiting centre and midbrain medullary receptor through central anticholinergic properties.¹⁰ Bergese et al.¹¹ studied the combination of promethazine with palonosetron and dexamethasone for PONV prevention, with a significant reduction in PONV incidence 24 h postoperatively. In outpatient surgery, promethazine at 12.5 mg in combination with metoclopramide to prevent postoperative nausea and vomiting significantly reduced the PONV incidence.¹² However, previous studies attributed some postoperative adverse reactions to promethazine. Therefore, this prospective, randomised, double-blind trial aimed to explore the effect of promethazine on preventing PONV in high-risk patients and patients who underwent gynaecological laparoscopic surgery.

This prospective, randomised controlled, double-blind trial was approved by the Ethics Committee of Gansu Provincial Hospital in July 2021 (2021 − 231), and written informed consent was obtained from patients. This study included 100 patients who underwent nonemergent gynaecological laparoscopic surgery, aged 18–65 years, with American Society of Anaesthesiologists (ASA) physical status I or II, body mass index of 15–30 Kg/m², surgical duration of not < 1 h and length of hospital stay of > 72 h. The exclusion criteria included asthma, mechanical intestinal obstruction, closed-angle glaucoma, history of alcohol or opioid abuse, preoperative coma, psychiatric symptoms or intellectual disability, abnormal electrocardiograms, cardiovascular disease, liver or renal insufficiency on preoperative examination, pregnant or breastfeeding and patients who were enrolled in other studies. Patients were preoperatively assessed for PONV risk using the simplified PONV score proposed by Apfel et al.¹³

The computer-generated follow-up table was used to divide 100 patients into two groups: promethazine (SHANGHAI Harvest PHARMACEUTICAL.LTD. 1 m:25 mg. 13210602) group and saline group that turned a blind eye to anaesthesiologists and patients and followed up postoperatively. The patient fasted preoperatively and did not receive treatment before entering the operating room. The two groups were anaesthetised using uniform standard anaesthesia. Patients were admitted to the operating room for routine electrocardiogram, non-invasive blood pressure, heart rate (HR), oxygen saturation and bispectral index (BIS) monitoring. Flurbiprofen ester at 50 mg, midazolam at 0.05 mg/kg, sufentanil at 0.4–0.6 ug/kg, etomidate at 0.15–0.3 mg/kg and 0.6 mg/kg of rocuronium were intravenously administered to induce anaesthesia. After anaesthesia induction, radial artery puncture was performed, invasive arterial blood pressure was monitored and central venous pressure was monitored via the right internal jugular vein. Both groups were given additional sufentanil at 0.5 µg/kg before excision to maintain BIS at 40–60, maintain blood pressure fluctuations not exceeding 20% of the basal value and use vasoactive drugs if necessary. Atropine at 0.5 mg is administered for HR of < 50 beats/min. Phenylephrine at 50–100 µg is administered if blood pressure falls by > 20% of the basal value.

Patient-controlled intravenous analgesia (PCIA) pump formulation included nalbuphine at 50 mg + flurbiprofen at 200 mg + metoclopramide compounding at 50 mg + 0.9% normal saline at 150 ml in continuous infusion programmed for 2 mL initial volume, 2 mL/h background continuous volume, 2 mL self-controlled volume and set lock time at 15 min.

Postoperatively, patients were admitted to the postanaesthesia care unit (PACU) with a tracheal catheter. Ramsay scores were used to evaluate the depth of sedation and agitation during PACU admission. Extubation time and PACU stay were recorded. PONV was assessed and the number of nausea and vomiting occurrences and their severity were recorded within 6 h, 24 h, 48 h, and 72 h postoperatively. Nausea intensity was assessed using a 5-point numerical rating scale (NRS: 1 = none, 2 = mild, 3 = moderate, 4 = severe, or 5 = refractory), and vomiting was assessed using a vomiting scale (0 = no vomiting, 1–2 times/day = mild vomiting, 3–5 times/day = moderate vomiting, ≥ 6 times = severe vomiting). Patients who need remedial antiemesis with dexamethasone and nausea and vomiting treatment after 72 h left at the clinician’s discretion were recorded. Patients were assessed for pain 24 h postoperatively using a visual analogue scale (0 being no pain and 10 being intolerable pain). Adverse effects of promethazine, such as drowsiness, coma, or extrapyramidal reactions, should be recorded in detail. Patients are asked about their satisfaction with the PONV control during this procedure using a 4-point rating scale (1 = poor; 2 = fair; 3 = good; 4 = excellent) 72 h postoperatively.

Based on our pre-trial results, PASS 25 was adopted, the β value was set to 0.2 and the α value was set to 0.05 to realise the sample size calculation. Each group had 27 patients. In consideration of the dropping out rate, 41 patients in each group finally took part in the study.

The Statistical Package for the Social Sciences version 25.0 software is used for statistical analysis. The measurement data that conform to the normal distribution is expressed as the mean plus or minus standard deviation (x ± s), and the data description of the counting data adopts the percentage (%). The x² test was used to compare the comparative data of the two groups, and the nonparametric test was used to test the severity of the grade data of the two groups. P-values of < 0.05 were considered a statistically significant difference.

This study randomly screened 100 patients, of whom 4 did not meet the inclusion criteria and 2 declined to participate in the study. In the promethazine group, 1 patient had combined postoperative nerve block analgesia and 5 had their PCIA interrupted; whereas, in the saline group, 2 patients had combined postoperative nerve block analgesia and 4 had their PCIA interrupted; these patients were excluded. Hence, data analysis included 82 patients (41 in each group) (Figure 1). Patient characteristics, operation duration, intraoperative access and PONV risk factors, and type of surgery were comparable between groups (Table 1), without significant differences.

Incidence and severity of PONV

The incidence of nausea during the early period (first 6 h postoperatively) was observed in 4.9% in the promethazine group and 19.5% in the saline group, with significant differences between groups (P = 0.043). The severity of nausea during the first 6 h was also statistically different between groups (P = 0.048). A statistically significant difference was found in the incidence within 24 h postoperatively (P = 0.026) in 9.8% in the promethazine group and 29.3% in the saline group. Concurrently, the severity of nausea was statistically different between the groups (P = 0.003). The incidence of vomiting was 2.4% lower in the promethazine group than in the saline group 6 h postoperatively, but without statistical differences between the two groups (P = 0.166), including the severity (P = 0.180). The incidence of vomiting was statistically different 24 h postoperatively (P = 0.011), with lower severity in the promethazine group than in the saline group (P = 0.004) (Table 2).

This study observed the incidence and severity of PONV at both 48 h and 72 h postoperatively between the two groups, of these, only the incidence of nausea was significantly different at 48 h (P = 0.023), the rest were not statistically different. However, the overall incidence of nausea and vomiting was statistically different between the groups (P = 0.026, P = 0.012) (Table 2, Figure 2).

PACU situation

The time from the end of the operation to the tracheal tube removal was not statistically different between the groups (P = 0.522), as well as the retention time (P = 0.362) and the Ramsay scores in the PACU (P = 0.562) (Table 3).

Opioid consumption

No significant difference was found in the dosage of sufentanil during anaesthesia induction, as well as the remifentanil consumption intraoperatively and the use of nalbuphine postoperatively (P = 0.604, P = 0.840, P = 0.464, respectively). (Table 4).

Postoperative ward situation

The out of bed and ventilation times were not different between the groups (P = 0.714 and P = 0.453, respectively), as well as the postoperative pain score at the 24 h postoperatively, including rest or motion pain (P = 0.504 and P = 0.132, respectively). The most common adverse reactions of promethazine were sedation and drowsiness, with extrapyramidal reactions as the most serious. No difference was found in the sedation (P = 0.152), and no patient in any group experienced drowsiness and extrapyramidal. A statistically significant difference was found in satisfaction between the two groups during the postoperative observation period (P = 0.002) (Table 5).

This study mainly revealed that preoperative prophylactic promethazine injection does not only significantly reduces the incidence of nausea and vomiting in patients undergoing gynaecological laparoscopic surgery at 0–48 h postoperatively but also significantly affected the severity of nausea and vomiting at 0–48 h and 6–24 h postoperatively.

Promethazine has a wide range of anti-nausea and anti-vomiting mechanisms and remarkable effects,¹⁰ and it is one of the drugs recommended in the latest anti-nausea and anti-vomiting guidelines. Additionally, promethazine has a quick effect and a long action time. Promethazine takes effect 3–5 min after intravenous injection, antihistamine generally lasts 6–12 h and sedation lasts 2–8 h. Therefore, promethazine administration before the anaesthesia has certain advantages in preventing PONV.

PONV is considered as nausea, vomiting, or nausea and vomiting within 24 h postoperatively. The promethazine group achieved satisfactory preventive effect 24 h. Concurrently, the incidence of PONV significantly decreased 48 h postoperatively, but the effect of 24 h was more significant than that of 48 h. Further result analysis revealed that the relationship between the pharmacological characteristics and promethazine, and its half-life is approximately 14 h, which provides a basis for preventing PONV in the early postoperative period. A randomised controlled study by D’souza et al. revealed that 4 mg of ondansetron prevented and treated PONV in patients undergoing gynaecological laparoscopic surgery, with 61% incidence of PONV,¹⁴ which was as low as 9.8% within 24 h in our study.

Studies revealed that PONV occurrence may be extended to 72 h postoperatively.¹⁵ We found that the incidence of nausea in the promethazine group was low in the two groups of patients who did not have vomiting at 72 h. First, the incidence of PONV is reduced in the early stage because we give preoperative preventive medicine. Second, both groups of patients received continuous treatment after the metoclopramide administration. Additionally, every patient was treated with PCIA postoperative analgesia, and the reduction of pain degree could also alleviate the occurrence of PONV. Finally, PONV mainly occurs within 24 h postoperatively. Therefore, patients with PONV should be given more attention up to 24 h postoperatively. Preoperative preventive intervention can achieve better results for PONV prevention and treatment.

In recent years, few studies reported on the use of promethazine in preventing PONV. Previous studies revealed that promethazine-induced adverse reaction is the main reason for its clinical limitation.¹⁶ Promethazine has a wide range of anti-nausea and anti-vomiting mechanisms and remarkable effects. Studies revealed no difference in the anti-nausea and anti-vomiting effects between promethazine at 6.25 mg and 12.5 mg, with 6.25 mg having rare adverse reactions.¹⁷ We choose 6.25 mg of prophylactic intravenous injection preoperatively to avoid the side effects of sedation postoperatively, considering that the sedative effect of promethazine lasts for 2–8 h. We observed the situation of all patients in PACU and revealed no difference between the two groups in sedation score, tracheal catheter removal time and PACU retention time. Concurrently, we analysed the consumption of opioids between the two groups and revealed no difference between the two groups, which could exclude the influence of opioids on postoperative sedation. During the 72-h postoperative period, two patients in the promethazine group had dizziness. After inquiry, one of the patients had dizziness caused by prolonged water fasting, and both patients reported relief 12 h postoperatively. This result could not be attributed to promethazine.

Apfel et al.¹³ concluded that the high-risk factors of PONV were female gender, PONV/motion sickness history, non-smoking and postoperative opioid consumption. Each risk factor will increase the risk of PONV by 20%, and females are the strongest risk factors.¹⁸ The relief of PONV in patients with high-risk factors is more clinically significant and challenging. We choose patients with a higher incidence of gynaecological laparoscopic surgery because of the unavailable clear PONV regimen. Previous studies revealed that the incidence of PONV in these patients is as high as 40–80%.^{19, 20} However, our study revealed a PONV incidence of as low as 9.8%, which significantly improves postoperative satisfaction and promotes postoperative rehabilitation of patients.

The idea of using two or more drugs to prevent and treat PONV is called multi-mode prevention and treatment, which is recommended for high-risk patients, but its current exploration revealed no satisfactory results. Therefore, it should be considered whether for effective prevention, early PONV reduction and good perioperative outcome.

Limitations

This study had some limitations. First, the sample size is not large enough to reveal the adverse reactions from using the two drugs together pre- and postoperatively. Second, the main observation indicators are subjective, and there may be a small range of errors.

Preoperative prophylactic administration of promethazine in high-risk patients undergoing gynaecological laparoscopy and using postoperative intravenous analgesia significantly reduced the incidence and severity of PONV within 24 h postoperatively, with few adverse effects and no serious adverse reactions, thereby improving patient satisfaction. Preoperative prophylactic administration of promethazine can be clinically recommended as an alternative method to prevent PONV in gynaecological laparoscopic surgery.

Symbol Description
Abbreviation	Unabbreviated form
PONV	Postoperative nausea and vomiting
ASA	American Society of Anaesthesiologists
HR	Heart rate
BIS	Bispectral index
PCIA	Patient-controlled intravenous analgesia
PACU	Postanaesthesia care unit

Acknowledgements

We would like to thank Professor Yan for his theoretical and technical guidance during the whole trial. Thanks to the anesthesia team of Gansu Provincial Hospital and colleagues who participated in this work.

Data availability statement

The datasets generated and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.

Ethics statement

The studies involving human participants were reviewed and approved by the Ethics Committee of Gansu Provincial Hospital. The patients/participants provided their written informed consent to participate in this study.

Author contributions

Liu Ruijuanparticipated in the design and conduct of the study, data analysis and writing the manuscript.Bi Ruiruiparticipated in implementing of the study, data analysis. Zhang Jiqiang participated in implementing of the study, data analysis.

Yan Wenjun participated in the design and conduct of the study, data analysis, and part of discussion and revision of the manuscript.Li Xiaparticipated in implementing of the study, data analysis.Su Yuxi participated in implementing of the study, data analysis.

Zhang Yani participated in implementing of the study, data analysis.

Funding

The trial was supported by The National Nature Science Fundition of China(81860233) and Gansu Province Anesthesia and Brain Function Clinical Medical Research Center(21JR7RA675) and Gansu natural science foundation(21JR7RA621). The funding source had no involvement in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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TABLE 1. Demographic and clinical patient characteristics

Promethazine group

(n = 41)

Saline group

(n = 41)

P-value

Age (years)

BMI (kg/m²)

Intraoperative access (ml)

Apfel score

3

4

ASA classification (I/II)

Duration of operation (min)

Type of surgery

Tubectomy

Ovariectomy for ovarian lesions

Hysterectomy

47.8 ± 10.0

23.07 ± 3.09

976.2 ± 342.8

31 (75.6%)

29 (70.7%)

31/10

191.61 ± 92.05

2

6

33

49.0 ± 6.9

22.64 ± 3.27

926 ± 388.4

10 (24.4%)

12 (29.3%)

29/12

185.78 ± 93.57

3

7

31

0.026

0.549

0.208

0.207

0.273

0.777

0.833

ASA: American Society of Anaesthesiologists physical status classification. BMI: body mass index

TABLE 2. Incidence and severity of PONV

Promethazine group

(n = 41)

Saline group

(n = 41)

P-value

Incidence of nausea

6 h after surgery (%)

24 h after surgery (%)

48 h after surgery (%)

72 h after surgery (%)

Overall (%)

Severity of nausea

6 h after surgery

(none/mild/moderate/severe/intractable)

24 h after surgery

(none/mild/moderate/severe/intractable)

48 h after surgery

(none/mild/moderate/severe/intractable)

72 h after surgery

(none/mild/moderate/severe/intractable)

Incidence of vomiting

6 h after surgery (%)

24 h after surgery (%)

48 h after surgery (%)

72 h after surgery (%)

Overall (%)

Severity of vomiting

6 h after surgery

(none/mild/moderate/severe)

24 h after surgery

(none/mild/moderate/severe)

48 h after surgery

(none/mild/moderate/severe)

72 h after surgery

(none/mild/moderate/severe)

2 (4.9%)

4 (9.8%)

2 (4.9%)

1 (2.4%)

9.8%

39/1/0/1/0

39/2/0/0/0

40/1/0/0/0

1 (2.4%)

2 (4.9%)

0 (0%)

2.4%

40/0/1/0

41/0/0/0

8 (19.5%)

12 (29.3%)

9 (22%)

2 (4.9%)

29.3%

33/5/2/1/0

29/7/4/1/0

32/7/2/0/0

39/2/0/0/0

4 (9.8%) 10 (24.4%) 2 (4.9%) 0 (0%) 24.4%

37/3/1/0

316/3/0

39/2/0/0

41/0/0/0

0.043

0.026

0.023

0.556

0.026

0.048

0.003

0.022

0.559

0.166

0.011

0.152

1

0.012

0.180

0.004

0.155

1

TABLE 3. Postanaesthesia care unit situation

	Promethazine group (n = 41)	Saline group (n = 41)	P-value
Time-to-extubation (min)	29.8 ± 25.4	24.9 ± 15.7	0.299
Time of PACU (min)	83.4 ± 30.9	71 ± 26.3	0.053
Ramsay scores	2.05 ± 0.22	2.02 ± 0.16	0.562

TABLE 4. Opioid consumption

	Promethazine group (n = 41)	Saline group (n = 41)	P-value
Intraoperative sufentanil (μg)	38.8 ± 2.9	38.4 ± 3.4	0.604
Intraoperative remifentanil (μg)	1216.6 ± 150.3	1148.5 ± 426.5	0.840
Nalbuphine after operation (mg)	35.8 ± 23.9	27.8 ± 23.9	0.464

TABLE 5. Postoperative ward situation

	Promethazine group (n = 41)	Saline group (n = 41)	P-value
Time out of bed (days)	1.33 ± 0.47	1.29 ± 0.46	0.714
Ventilation time (days)	2.13 ± 0.46	2.08 ± 0.36	0.453
VAS score Rest pain Motion pain	0.73 ± 1.18 2 ± 1.43	0.59 ± 0.74 1.6 ± 0.8	0.504 0.132
Satisfaction Poor/OK/Excellent/Satisfactory	1/0/2	7/4/3	0.002
Adverse effects	2 (4.9%)	0 (0%)	0.152
Length of stay (days)	12.8 ± 6.9	12.0 ± 5.1	0.562

No competing interests reported.

Promethazine for nausea and vomiting prevention after gynaecological laparoscopic surgery：a randomized controlled trial

Status:

Version 1

Abstract

Figures

Background

Methods

Results

Dicussion

Limitations

Conclusions

Abbreviations

Declarations

References

Tables

Additional Declarations

Status:

Version 1