British Journal of Anaesthesia, 131 (4): 673e681 (2023)

doi: 10.1016/j.bja.2023.06.029
Advance Access Publication Date: 7 July 2023
Clinical Practice

CLINICAL PRACTICE

Fosaprepitant for postoperative nausea and vomiting in patients

undergoing laparoscopic gastrointestinal surgery: a randomised
trial
Qingshan Huang1,2,y, Fan Wang1,2,y, Chujun Liang1,2,y, Yabin Huang1,2,y, Yingyin Zhao1,2,
Chuling Liu1,2, Chunmeng Lin1,2, Lizhen Zhang1,2, Shaoli Zhou3, Qiuling Wang1,4, Shan Li1,2,
Ruirui Gong1,2 , Qian Wu2,5, Yuting Gu6, Jinxin Zhang7, Tongfeng Luo1,2, Wei Wang1,2,
Song Zhang1,2, Nassirou Bizo Mailoga1,2, Kai Wang1,2,*, Sanqing Jin1,2,* and Yang Zhao1,2,*
1
Department of Anaesthesia, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China, 2Biomedical
Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China, 3Department of
Anaesthesia, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China, 4Department of Anaesthesia,
Guizhou Daqin Cancer Hospital, Guiyang, China, 5Center for Clinical Research, The Sixth Affiliated Hospital, Sun Yat-sen
University, Guangzhou, China, 6Department of Medical Statistics, The First Affiliated Hospital, Sun Yat-sen University,
Guangzhou, China and 7Medical Statistics and Epidemiology, Sun Yat-sen University, Guangzhou, China

*Corresponding authors. E-mails: wangk28@mail.sysu.edu.cn, jinsq@mail.sysu.edu.cn, zhaoy47@mail.sysu.edu.cn

y
These authors contributed equally to this manuscript.

Abstract
Background: Postoperative nausea and vomiting (PONV) is a major problem after surgery. Even with double prophylactic
therapy including dexamethasone and a 5-hydroxytryptamine-3 receptor antagonist, the incidence is still high in many
at-risk patients. Fosaprepitant, a neurokinin-1 receptor antagonist, is an effective antiemetic, but its efficacy and safety
in combination antiemetic therapy for preventing PONV remain unclear.
Methods: In this randomised, controlled, double-blind trial, 1154 participants at high risk of PONV and undergoing
laparoscopic gastrointestinal surgery were randomly assigned to either a fosaprepitant group (n¼577) receiving fosap-
repitant 150 mg i.v. dissolved in 0.9% saline 150 ml, or a placebo group (n¼577) receiving 0.9% saline 150 ml before
anaesthesia induction. Dexamethasone 5 mg i.v. and palonosetron 0.075 i.v. mg were each administered in both groups.
The primary outcome was the incidence of PONV (defined as nausea, retching, or vomiting) during the first 24 post-
operative hours.
Results: The incidence of PONV during the first 24 postoperative hours was lower in the fosaprepitant group (32.4% vs
48.7%; adjusted risk difference 16.9% [95% confidence interval: 22.4 to 11.4%]; adjusted risk ratio 0.65 [95% CI: 0.57 to
0.76]; P<0.001). There were no differences in severe adverse events between groups, but the incidence of intraoperative
hypotension was higher (38.0% vs 31.7%, P¼0.026) and intraoperative hypertension (40.6% vs 49.2%, P¼0.003) was lower in
the fosaprepitant group.
Conclusions: Fosaprepitant added to dexamethasone and palonosetron reduced the incidence of PONV in patients at
high risk of PONV undergoing laparoscopic gastrointestinal surgery. Notably, it increased the incidence of intraoperative
hypotension.
Clinical trial registration: NCT04853147.

Keywords: anaesthesia; dexamethasone; 5-hydroxytryptamine-3 receptor antagonist; laparoscopic gastrointestinal

surgery; neurokinin-1 receptor antagonists; postoperative nausea and vomiting

Received: 4 April 2023; Accepted: 7 June 2023

© 2023 The Author(s). Published by Elsevier Ltd on behalf of British Journal of Anaesthesia. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
For Permissions, please email: permissions@elsevier.com

673
 674 - Huang et al.
Editor’s key points
 Fosaprepitant is an intravenous prodrug of aprepi-
tant, a neurokinin-1 (NK-1) receptor antagonist.
 PONV risk factors are well known and include lapa-
roscopic gastrointestinal surgery.
 This study clearly demonstrates improved efficacy of
fosaprepitant added to dual antiemetic treatment for
antiemetic prophylaxis (i.e. triple therapy), with
benefits up to 72 h postoperatively.
 The higher incidence of intraoperative hypotension
was observed in the fosaprepitant group.
Postoperative nausea and vomiting (PONV) is a major problem
during the perioperative period.1 Female sex, history of PONV
or motion sickness, non-smoking status, and use of post-
operative opioids are the four risk factors in the Apfel risk
scoring system. Patients with at least three risk factors are
classified as high risk for PONV.2 The surgical procedure is also
associated with PONV. Laparoscopy increases the risk of
PONV3,4 and performing gastrointestinal surgery also pro-
motes PONV because of the handling and resection of the
stomach or bowel.5,6 Therefore, PONV is extremely common in
high-risk patients who undergo laparoscopic gastrointestinal
surgery.
PONV is a highly distressing condition and is associated with
significant patient dissatisfaction.7e9 PONV also increases su-
ture dehiscence, unanticipated hospital admission, and health-
care costs.10,11 PONV prophylaxis is particularly important in
gastrointestinal surgery because of the potential risk of severe
vomiting which can be disastrous for gastrointestinal anasto-
motic stomas. Dexamethasone and a 5-hydroxytryptamine-3 (5-
HT3) receptor antagonist is a common combination therapy
recommended by guidelines,12 but even with this double pro-
phylaxis, the incidence of PONV is still high.
Neurokinin-1 (NK-1) receptor antagonists, which block the
binding of substance P to NK-1 receptors,13 are characterised
by a long duration of action and significant antiemetic effi-
cacy.14,15 Aprepitant is a first-generation NK-1 receptor
antagonist. Because of the oral administration of aprepitant,
its onset is limited by enteral absorption. Fosaprepitant is a
water-soluble drug administered i.v. that is rapidly converted
to aprepitant within 30 min.15 A single infusion of 150 mg
fosaprepitant can replace a 3-day oral regimen of aprepi-
tant.16,17 These advantages make fosaprepitant suitable for
gastrointestinal surgery. Previous studies have suggested the
efficacy of fosaprepitant as a single agent for preventing
PONV,18e20 but its role in combination therapy as a third agent
for preventing PONV remains unclear.
Given the above considerations, we planned this parallel-
arm, double-blind, randomised trial to evaluate the efficacy
and safety of the addition of fosaprepitant to dexamethasone
and palonosetron in preventing PONV in patients at high risk
of PONV undergoing laparoscopic gastrointestinal surgery.
Methods
Trial design and participants
This was a randomised, double-blind, placebo-controlled trial
involving participants undergoing laparoscopic gastrointe-
stinal surgery at the Sixth Affiliated Hospital of Sun Yat-sen
University in China. This study was approved by the Ethics
Committee of the Sixth Affiliated Hospital of Sun Yat-sen
University (2021ZSLYEC-78) and registered at clinicaltrials.gov
(NCT04853147). The protocol and statistical analysis plan are
available in the Supplementary material.
Trial participants
Patients (aged 18e75 yr) with three or four Apfel risk factors
who were scheduled for laparoscopic gastrointestinal surgical
procedures under general anaesthesia were eligible for enrol-
ment. The Apfel risk factors included female sex, history of
PONV or motion sickness, non-smoking status, and use of
postoperative opioids.2 Exclusion criteria included an Amer-
ican Society of Anesthesiologists (ASA) physical status 4, 5 or 6,
severe hepatic dysfunction, contraindications to fosaprepi-
tant, 5-HT3 receptor antagonist or dexamethasone, preoper-
ative use of medications with known antiemetic properties,
mental disorders or inability to communicate, and pregnant
women or nursing mothers.
Randomisation and masking
After written informed consent was obtained, participants
were randomly assigned to the fosaprepitant or placebo group
in a 1:1 ratio. Randomisation was performed by a statistician at
the Center for Clinical Research using a computer-generated
randomised sequence with block sizes of 4 unknown to the
investigators and with stratification by the Apfel score (3 or 4).
The generated sequence was protected and kept in
consecutively numbered opaque envelopes, separate from the
investigators. After the enrolled participants entered the
operating room, a nurse in the anaesthetic pharmacy, who
was not involved in patient care or data collection, opened the
opaque envelope. The same nurse prepared the fosaprepitant
solution (fosaprepitant 150 mg dissolved in normal saline 150
ml) or placebo solution (normal saline 150 ml).
To avoid the treatments from being visually distinguish-
able, the fosaprepitant and normal saline solutions were
contained in opaque, identically wrapped and labelled infu-
sion bags. The infusion tubes were also identical and opaque.
All members involved in participant recruitment, data collec-
tion, and perioperative management were blinded to the
group allocation.
Anaesthetic techniques
Before anaesthesia induction, fosaprepitant or placebo solu-
tion was infused i.v. for about 30 min in the operating room.
Dexamethasone 5 mg and palonosetron 0.075 mg were
administered i.v. at induction in both groups. The anaesthetic
technique was standardised, and fentanyl and midazolam
were not used. General anaesthesia was induced and main-
tained with total i.v. anaesthesia by effect-site target-
controlled infusion of propofol (2e6 mg ml1, Schnider model)
and remifentanil (2e6 ng ml1, Minto model).21e23 The target
concentration was adjusted at any time according to the bis-
pectral index and blood pressure. The target level of the bis-
pectral index was between 40 and 60. Adequate muscle
relaxation was achieved using cisatracurium. The patients
received surgical site infiltration with 0.5% ropivacaine at the
end of surgery. An i.v. patient-controlled analgesic pump
containing hydromorphone was connected at the end of the
surgery. Subsequent other analgesics or antiemetics after
 Fosaprepitant for postoperative nausea and vomiting
Assessed for eligibility (n=1391)
Enrolment
Randomised (n=1154)
Allocated to fosaprepitant (n=577)
• Received fosaprepitant and underwent
laparoscopic gastrointestinal surgery (n=567)
Allocation
• Received fosaprepitant but underwent
gastrointestinal surgery without
laparoscopy (n=5)
• Received fosaprepitant but underwent
laparoscopic surgery only for exploration (n=3)
• Received fosaprepitant but underwent
laparoscopic surgery on other sites (n=2)
Follow-up
Lost to follow-up at 24 h (n=0)
Lost to follow-up at 72 h (n=4)
Lost to follow-up at 120 h (n=8)
Lost to follow-up at 30 days (n=15)
Analysis
Intention-to-treat analysis for primary outcome
(n=577)
Fig 1. Participant recruitment, randomisation, and follow-up in the FDP-PONV trial.
surgery were allowed to be given at any time on the patient’s
request, at the physician’s discretion, or both, and all of these
drugs were recorded.
Outcomes
The primary outcome was the incidence of PONV within the
first 24 h after surgery, defined as nausea, retching, or vomit-
ing.24 Secondary outcomes included the incidence of PONV,
emetic episodes (defined as retching, vomiting, or both24),
nausea and use of rescue antiemetic medication, PONV
severity (measured with the simplified PONV impact scoring
system established by Myles and Wengritzky, a score of 5
was defined as clinically important PONV25), quality of post-
operative recovery (measured with a 15-item quality of
- 675
Excluded (n=237)
• American Society of Anesthesiologists
physical status >3 (n=14)
• With contraindications against drugs used in
this trial (n=54)
• Taking medications with known antiemetic
properties preoperatively (n=23)
• Difficult to communicate (n=57)
• Declined (n=89)
Allocated to placebo (n=577)
• Received placebo and underwent laparoscopic
gastrointestinal surgery (n=569)
• Received placebo but underwent
gastrointestinal surgery without laparoscopy
(n=4)
• Received placebo but underwent laparoscopic
surgery only for exploration (n=3)
• Received placebo but underwent laparoscopic
surgery on other sites (n=1)
Lost to follow-up at 24 h (n=0)
Lost to follow-up at 72 h (n=0)
Lost to follow-up at 120 h (n=10)
Lost to follow-up at 30 days (n=13)
Intention-to-treat analysis for primary outcome
(n=577)
recovery scoring system [QoR-15]26,27), pain intensity
(measured using a numeric rating scale), time to first flatus,
first defecation, fulfilment of the criteria of hospital discharge
after surgery, and health-related quality of life (measured with
EQ-5D-3L28,29). Trained blinded investigators collected infor-
mation about outcomes recorded by either the participants
and their family members or medical staff in the ward every 24
h during the first 120 h after surgery. PONV, emetic episodes,
nausea, use of rescue antiemetics, and PONV severity were
analysed during the 0e24-h, 25e72-h, and 73e120-h post-
operative periods. QoR-15 and pain intensity were analysed at
24, 72, and 120 h after surgery. EQ-5D-3L was recorded before
surgery, at 120 h and 30 days after surgery. The data at 30 days
were collected by telephone. All expected and unexpected
adverse events were recorded. Other prespecified outcomes,
 676 - Huang et al.

including changes in plasma metabolites and overall survival

at 6 months, will be reported in future studies. Table 1 Baseline characteristics. Data are presented as me-
dian (IQR) or number (%). APAIS, Amsterdam Preoperative
Anxiety and Information Scale; IQR, inter-quartile range;
Sample size calculation PONV, postoperative nausea and vomiting; SAS, Self-rating
Anxiety Scale.
Based on previous clinical records of postoperative analgesia
follow-up, the incidence of PONV after laparoscopic gastroin-
Fosaprepitant Placebo
testinal surgery in high-risk patients was ~50%. We conser-
group (n¼577) group
vatively estimated that the addition of fosaprepitant would (n¼577)
reduce the incidence by 10% or more (relative risk 20%).
Therefore, assuming a proportion of 50% in the placebo group Sex
and 40% in the fosaprepitant group, we calculated that 1038 Male 21 (3.6) 19 (3.3)
Female 556 (96.4) 558 (96.7)
participants would be needed to detect this difference with a
Age (yr) 56 (47e64) 57 (49e65)
5% type I error and a power of 90% using a two-sided test. The ASA physical status
final number of patients for enrolment was set at 1154 (577 1 24 (4.2) 15 (2.6)
participants in each group), with consideration of a 10% loss to 2 529 (91.7) 530 (91.9)
follow-up. 3 24 (4.2) 32 (5.5)
Body mass index (kg m2) 22.1 (20e24.3) 22.1 (20e24.3)
Diabetes mellitus 44 (7.6) 62 (10.7)
Statistical analysis Hypertension 128 (22.2) 114 (19.8)
History of chemotherapy 165 (28.6) 150 (26.0)
Outcomes were analysed according to the intention-to-treat
Migraine 66 (11.4) 61 (10.6)
principle, defined as all randomised participants. Before the Motion sickness, history of 333 (57.7) 330 (57.2)
analysis, all missing data and improbable values were checked PONV, or both
against the source data. As the data completeness was 100% Smoking 7 (1.2) 8 (1.4)
for the primary outcome and 97.6% for the secondary Apfel score for the risk of PONV
outcome, missing data were not imputed. Both adjusted and 3 277 (48) 277 (48)
4 300 (52) 300 (52)
unadjusted analyses were performed. The analyses were
Anxiety state
adjusted for Apfel score (3 or 4) and age (18e49 or 50e75 yr). SAS score (standardised) 31.3 (28.8e35) 31.3 (28.8e35)
Categorical data presented as frequencies and percentages APAIS score 10 (6e18) 10 (6e16)
were analysed using the c2 test or Fisher’s exact test. The risk Abdominal access
ratio with a 95% confidence interval (CI) was calculated using Laparoscopic 572 (99.1) 573 (99.3)
Poisson regression with a quasi-Poisson link function. The risk Open 5 (0.9) 4 (0.7)
Type of surgery
difference with a 95% CI was calculated using binomial
Gastrectomy or small 67 (11.6) 76 (13.2)
regression with an identity-link function. Continuous data intestinal resection
presented herein as means and standard deviations or as Colon resection 265 (45.9) 257 (44.5)
medians and inter-quartile ranges (IQR) were analysed using Rectum resection 240 (41.6) 236 (40.9)
the ManneWhitney U-test or generalised estimation equation. Surgery on another site 5 (0.9) 8 (1.4)
Subgroup analysis was stratified by Apfel score, age, and sur-
gical site. Statistical analyses were performed using R software
(R software 4.2.1, R Foundation for Statistical Computing, group (187 [32.4%] vs 281 [48.7%]; adjusted risk
Vienna, Austria) by statisticians at Sun Yat-sen University, difference, 16.9 [95% CI: 22.4 to 11.4]; P<0.001; number
who were blinded to the trial group assignments. A P-value of needed to treat [NNT] 6) (Table 3 and Fig. 2). The reduction in
<0.05 for two-sided tests was considered significant. the primary outcome with fosaprepitant did not differ in the
planned subgroup analyses (Supplementary Fig. S1).
Results
Secondary outcomes
Trial population
Outcomes for nausea or vomiting are shown in Table 3 and
The flow of participants through the trial is shown in Figure 1.
Figure 2. Emetic episodes occurred less frequently in the
Recruitment took place between April 2021 and April 2022, and
fosaprepitant group during the 0e24-h period after surgery (75
the 30-day follow-up period for the last participant ended in
[13%] vs 170 [29.5%]; adjusted risk difference 16.6 [95%
May 2022. Among the 1391 participants screened for eligibility,
CI: 21.2 to 12.1]; P<0.001) and the 25e72-h period after
1154 were randomly assigned to the fosaprepitant group
surgery (71 [12.4%] vs 115 [20.3%]; adjusted risk
(n¼577) or placebo group (n¼577) (Fig. 1). Follow-up data were
difference 10.3 [95% CI: 14.5 to 6.1]; P<0.001). The inci-
available from 1154 (100%) participants for assessments at 24 h
dence of emetic episodes was similar during the 73e120-h
(primary outcome), 1150 (99.7%) participants at 72 h, and 1136
period. Nausea occurred less frequently in the fosaprepitant
(98.4%) participants at 120 h. Contact was made with 1126
group during the 0e24-h period after surgery (186 [32.2%] vs
(97.6%) participants at 30 days to assess adverse events and
281 [48.7%]; adjusted risk difference 17.05 [95% CI: 22.6
quality of life using the EQ-5D-3L. Baseline characteristics and
to 11.6]; P<0.001). Postoperative antiemetic medication was
post-randomisation events during the perioperative period are
used less during the 0e24-h period after surgery (160 [27.7%] vs
shown in Tables 1 and 2.
203 [35.2%]; adjusted risk difference, 7.3 [95% CI: 12.7
to 2.0]; P¼0.007). However, the incidence of nausea, rescue
Primary outcome
antiemetic medication, or PONV during the 25e72-h and
The incidence of PONV within the first 24 h after surgery was 73e120-h periods after surgery were not significantly different
lower in the fosaprepitant group than that in the placebo between groups.
 Fosaprepitant for postoperative nausea and vomiting - 677

Table 2 Post-randomisation characteristics. Data are presented as median (IQR) or number (%). Intraoperative hypotension was
defined as a mean arterial pressure <65 mm Hg for at least 1 min. Intraoperative hypertension was defined as a mean arterial pressure
>110 mm Hg for at least 1 min. Intraoperative bradycardia was indicated by heart rate <50 beats min1 for at least 1 min. Intraoperative
tachycardia was indicated by heart rate >100 beats min1 for at least 1 min. IQR, inter-quartile range.

Fosaprepitant group (n¼577) Placebo group (n¼577) P-value

Duration of surgery (min) 182 (143e240) 187 (147e243) 0.527

Duration of pneumoperitoneum (min) 129 (87e177) 129 (90e181) 0.820
Dose of propofol (mg) 1330 (1050e1720) 1400 (1100e1800) 0.035
Dose of remifentanil (ug) 1423 (1060e2000) 1580 (1160e2030) 0.004
Neostigmine 356 (61.7) 371 (64.3) 0.360
Dose (mg) 1 (0e1) 1 (0e1) 0.274
Intraoperative blood loss (ml) 50 (30e100) 50 (50e100) 0.413
Infusion rate of fluid in operating room (ml kg1 h1) 8.1 (6.6e9.7) 8.6 (7.2e10.5) 0.540
Intraoperative hypotension 219 (38.0) 183 (31.7) 0.026
Intraoperative hypertension 234 (40.6) 284 (49.2) 0.003
Intraoperative bradycardia 181 (31.4) 185 (32.1) 0.8
Intraoperative tachycardia 212 (36.7) 233 (40.4) 0.204
Installation of nasogastric tube 76 (13.2) 74 (12.8) 0.861
Postoperative opioids consumption (morphine equivalents, mg) 38.4 (31.4e46.7) 38.4 (30.1e46.7) 0.568

The severity of PONV, including impact scores and inci-
dence of clinically important PONV, was reduced in the
fosaprepitant group. Impact scale scores of PONV decreased in
the fosaprepitant group during the 0e24-h period after surgery
(0 [IQR, 0e2] vs 0 [IQR, 0e4]; marginal estimate 0.9 [95%
CI: 1.1 to 0.6], P<0.001) and during the 25e72-h period (0
[IQR, 0e2] vs 0 [IQR, 0e3]; marginal estimate 0.5 [95% CI: 0.7
to 0.3], P<0.001) after surgery. Clinically important PONV
occurred less frequently in the fosaprepitant group during the
0e24-h period after surgery (45 [7.8%] vs 117 [20.3%]; adjusted
risk difference 12.9 [95% CI: 16.7 to 9.0]; P<0.001) and the
25e72-h period after surgery (35 [6.1%] vs 89 [15.4%]; adjusted

Table 3 Outcomes for nausea and vomiting in participants assigned to fosaprepitant or placebo after laparoscopic gastrointestinal
surgery. Values are numbers (%) of participants unless stated otherwise. CI, confidence interval; IQR, inter-quartile range; PONV,
postoperative nausea and vomiting. *Risk ratio (95% CI) calculated using Poisson regression with a quasi-Poisson link function. yRisk
difference (95% CI) calculated using binomial regression with an identity-link function. zMarginal estimates calculated with gener-
alised estimation equation. CI, confidence interval; PONV, postoperative nausea and vomiting.

Outcome Fosaprepitant group Placebo group Adjusted for Apfel score and age

Risk ratio (95% CI) P-value Risk difference or P-value

estimate (95% CI)

Participants with PONV

0e24 h (primary outcome) 187/577 (32.4) 281/577 (48.7) 0.65 (0.57e0.76)* <0.001 16.9 (22.41 to 11.4)y <0.001
25e72 h 195/573 (34) 222/577 (38.5) 0.88 (0.75e1.02)* 0.093 5.02 (10.53 to 0.5)y 0.075
73e120 h 121/569 (21.3) 115/567 (20.3) 1.04 (0.83e1.31)* 0.722 0.43 (4.24 to 5.11)y 0.856
Participants with emetic episodes
0e24 h 75/577 (13) 170/577 (29.5) 0.43 (0.34e0.55)* <0.001 16.65 (21.18 to 12.12)y <0.001
25e72 h 71/573 (12.4) 129/577 (22.4) 0.55 (0.42e0.71)* <0.001 10.3 (14.54 to 6.07)y <0.001
73e120 h 52/569 (9.1) 55/567 (9.7) 0.94 (0.65e1.35)* 0.723 0.78 (4.17 to 2.62)y 0.654
Participants with nausea
0e24 h 186/577 (32.2) 281/577 (48.7) 0.65 (0.56e0.75)* <0.001 17.05 (22.56 to 11.55)y <0.001
25e72 h 194/573 (33.9) 219/577 (38) 0.88 (0.76e1.03)* 0.118 4.73 (10.23 to 0.78)y 0.092
73e120 h 119/569 (20.9) 112/567 (19.8) 1.05 (0.84e1.33)* 0.659 0.63 (4.01 to 5.27)y 0.791
Participants with rescue antiemetic medication
0e24 h 160/577 (27.7) 203/577 (35.2) 0.79 (0.67e0.94)* 0.007 7.34 (12.67 to 2.00)y 0.007
25e72 h 171/573 (29.8) 201/577 (34.8) 0.86 (0.72e1.01)* 0.07 4.97 (10.37 to 0.43)y 0.071
73e120 h 114/569 (20.0) 104/567 (18.3) 1.10 (0.87e1.40)* 0.423 1.95 (2.62 to 6.53)y 0.402
PONV severity
Median (IQR) impact scale score of PONV
0e24 h 0 (0e2), n¼577 0 (0e4), n¼577 0.86 (1.09 to 0.63)z <0.001
25e72 h 0 (0e2), n¼573 0 (0e3), n¼577 0.47 (0.69 to 0.25)z <0.001
73e120 h 0 (0e0), n¼569 0 (0e0), n¼567 0.01 (0.18 to 0.16)z 0.915
Clinically important PONV (score of PONV severity 5)
0e24 h 45/577 (7.8) 117/577 (20.3) 0.38 (0.28e0.52)* <0.001 12.86 (16.72 to 9.01)y <0.001
25e72 h 35/573 (6.1) 89/577 (15.4) 0.39 (0.27e0.56)* <0.001 9.61 (12.99 to 6.23)y <0.001
73e120 h 25/569 (4.4) 26/567 (4.6) 0.98 (0.57e1.69)* 0.955 0.07 (2.49 to 2.35)y 0.955
 678 - Huang et al.

a b
*** PONV Emetic episodes
50 50
Percentages of

Percentages of
40 40
participants

participants
***
30 30
48.7 ***
20 34.0
38.5 20
32.4 29.5
10 21.3 20.3 10 22.3
13.0 12.4 9.7
9.1
0 0
0–24 h 25–72 h 73–120 h 0–24 h 25–72 h 73–120 h
Time after surgery Time after surgery
Fosaprepitant group Placebo group Fosaprepitant group Placebo group

c d
*** Nausea Rescue antiemetic medication
50 50
Percentages of

Percentages of
40 40 **
participants

participants
30 30
48.7
20 33.9
38.0 20 35.2 34.8
32.2 29.8
27.7
10 20.9 19.8 10 20.0 18.3

0 0
0–24 h 25–72 h 73–120 h 0–24 h 25–72 h 73–120 h
Time after surgery Time after surgery
Fosaprepitant group Placebo group Fosaprepitant group Placebo group

Fig 2. The rates of PONV, emetic episodes, nausea, and rescue antiemetic medication use during 0e24, 25e72, and 73e120 h after surgery.
(a) The rates of PONV; (b) the rates of emetic episodes; (c) the rates of nausea; (d) the rates of rescue antiemetic medication use. Signifi-
cance was determined by two-tailed c2 test. **P<0.01. ***P<0.001. PONV, postoperative nausea and vomiting.

risk difference 9.6 [95% CI: 13.0 to 6.2]; P<0.001). The
severity of PONV was similar in both groups during the
73e120-h period after surgery.
Outcomes for recovery, pain, and quality of life are shown
in Table 4. The pain intensity at rest or at mobility was
reduced in the fosaprepitant group for up to 72 h, and QoR-15
scores at 24-h after surgery were higher in the fosaprepitant
group (86 [IQR, 74.74e98] vs 84 [IQR, 71e96], P¼0.005), and
length of time from surgery completion to first flatus was
shorter in the fosaprepitant group (46 [IQR, 27e65] vs 50 [IQR,
33e70], P¼0.005). Differences between the length of time from
surgery completion to first defaecation were not significant
(68 [IQR, 45e95.8] vs 72 [IQR, 49e104], P¼0.11). The length to
fulling the criteria for hospital discharge was similar with a
median of 6 days in both groups. There were no differences in
the EQ-5D-3L index score or visual analogue scale at 120 h
and 30 days.
Adverse events
There were no differences in severe adverse events between
groups (Supplementary Table S4). One participant died within
30 days after surgery, which occurred in the placebo group.
Notably, in the fosaprepitant group, the incidence of intra-
operative hypotension increased (219 [38.0%] vs 183 [31.7%],
P¼0.026, number needed to harm [NNH] 17), and the incidence
of hypertension (234 [40.6%] vs 284 [49.2%], P¼0.003, NNH 12)
decreased in the fosaprepitant group (Table 2).
All unadjusted results and the results of NNT are provided
in Supplementary Tables S1eS3.
Discussion
In this large double-blind, randomised controlled trial, we
evaluated the addition of fosaprepitant to dexamethasone
plus palonosetron to prevent PONV in high-risk patients
undergoing laparoscopic gastrointestinal surgery with total
i.v. anaesthesia. We showed for the first time that the
addition of fosaprepitant significantly reduced the incidence
and severity of PONV; reduced the incidence of nausea,
emetic episodes, and the use of rescue antiemetics; and
shortened the time to first flatus after surgery. Notably, we
found that the addition of fosaprepitant increased the inci-
dence of hypotension.
The addition of fosaprepitant to the combined therapy for
PONV has not been fully studied. Although some clinical trials
with small sample sizes of aprepitant in combined therapy
have been conducted, the conclusions were not consistent.
Spaniolas and colleagues30 found that aprepitant and scopol-
amine patches combined with ondansetron plus dexametha-
sone significantly reduced nausea and vomiting after sleeve
gastrectomy. In contrast, Grigio and colleagues31
 Fosaprepitant for postoperative nausea and vomiting - 679

Table 4 Outcomes for recovery and quality of life in participants assigned to fosaprepitant or placebo after laparoscopic gastroin-
testinal surgery. CI, confidence interval; EQ-5D-3L, three-level EuroQol five-dimensions; IQR, inter-quartile range; NRS, numeric rating
scale; PONV, postoperative nausea and vomiting; QoR-15, 15-item quality of recovery scoring system; TTO, time trade-off. *Marginal
estimates calculated with generalized estimation equation.zBetween-group difference for mean change from baseline calculated with
generalised estimation equation. CI, confidence interval; EQ5D-3L, three-level EuroQol five-dimensions; IQR, inter-quartile range; NRS,
numeric rating scale; PONV, postoperative nausea and vomiting; QoR-15, 15-item quality of recovery scoring system; TTO, time trade-
off.

Outcome Fosaprepitant group Placebo group Adjusted for Apfel score and age

Estimate or risk P-value

difference (95% CI)

Median (IQR) QoR-15 score 1.46 (0.47e2.45)* 0.004

at 24 h 86 (75e98), n¼576 84 (71e96), n¼577 3.18 (1.37e4.99)* 0.001
at 72 h 107 (98e114), n¼572 106 (96e113), n¼577 0.96 (0.61 to 2.54)* 0.231
at 120 h 117 (107e123.5), n¼567 117 (110e124), n¼567 0.21 (1.53 to 1.94)* 0.817
Median (IQR) pain score at rest (NRS) 0.09 (0.15 to 0.03)* 0.002
at 24 h 2 (2e2), n¼576 2 (2e2), n¼577 0.15 (0.26 to 0.03)* 0.012
at 72 h 2 (1e2), n¼573 2 (1e2), n¼577 0.11 (0.21 to 0.01)* 0.039
at 120 h 1 (1e2), n¼568 1 (1e2), n¼569 0.03 (0.12 to 0.07)* 0.577
Median (IQR) highest pain score at mobility 0.12 (0.21 to 0.04)* 0.005
(NRS)
0e24 h 3 (3e4), n¼572 4 (3e5), n¼577 0.29 (0.44 to 0.13)* <0.001
25e72 h 3 (2e4), n¼568 3 (2e4), n¼567 0.13 (0.27 to 0.01)* 0.07
73e120 h 2 (2e3), n¼567 2 (2e3), n¼567 0.06 (0.09 to 0.2)* 0.434
Median (IQR) time length
first flatus after surgery (h) 46 (27e65), n¼577 50 (33e70), n¼577 5.08 (8.73 to 1.43)* 0.005
first defaecation after surgery (h) 68 (45e96), n¼574 72 (49e104), n¼577 4.17 (9.31 to 0.97)* 0.112
fulfilling the criteria of hospital discharge 6 (5e8), n¼577 6 (5e8), n¼577 0.23 (0.56 to 1.03)* 0.563
(days)
Mean (SD) EQ-5D-3L (VAS scale)
before surgery 86.5 (11.3), n¼575 85.8 (11.7), n¼577 d d
at 120 h 68.7 (15.1), n¼568 68.0 (15.1), n¼574 0.06 (1.87 to 1.98)z 0.953
at 30 days 86.2 (10.3), n¼562 86.6 (10.3), n¼564 1.11 (2.64 to 0.41)z 0.152
Mean (SD) EQ-5D-3L (TTO value)
before surgery 0.9 (0.1), n¼575 0.9 (0.1), n¼577 d
at 120 h 0.7 (0.2), n¼568 0.7 (0.2), n¼574 0.01 (0.04 to 0.01)z 0.163
at 30 days 0.8 (0.2), n¼562 0.8 (0.2), n¼564 0.01 (0.03 to 0.01)z 0.326

demonstrated that the addition of aprepitant to palonosetron
plus dexamethasone did not reduce the risk of PONV in high-
risk patients undergoing mastectomy. These inconsistent re-
sults may be related to the occurrence of PONV in different
clinical situations and relatively small sample sizes. This
further highlights the complexity of developing a multimodal
PONV prophylaxis regimen and the necessity of conducting
large targeted studies to provide evidence in each specific
clinical setting. Our study provides powerful evidence of the
efficacy of fosaprepitant in the combined therapy for PONV
prophylaxis. In addition, in this study, the severity of PONV
was also measured using the simplified PONV intensity scale
which quantifies clinically important PONV and includes a
patient-centred impact component.25 Our results revealed
that participants in the fosaprepitant group had decreased
PONV scores and fewer cases of clinically relevant PONV up to
72 h after surgery. This suggests that the addition of fosapre-
pitant could lead to a noticeable improvement in the patient-
reported experience.
According to the current guidelines for PONV management,
reducing the baseline risk factors of PONV, such as avoiding
volatile anaesthetics, is also important in the management
strategy. Therefore, we designed this trial in the context of
total i.v. anaesthesia, which was different from most previous
trials.32,33 In addition, the results demonstrated that even in
the presence of total i.v. anaesthesia, the addition of
fosaprepitant to dexamethasone and palonosetron, could
further reduce the risk of PONV to benefit high-risk cohorts.
However, the incidence of PONV seemed to still be high in this
trial. PONV was defined as nausea, retching, or vomiting.
Nausea was also more common than vomiting in previous
trials. The DREAMS trial was a large randomised trial to test
the efficacy of adding dexamethasone to standard treatment
for PONV in gastrointestinal surgery.6 The results showed that
the incidence of nausea was 40~53% and the incidence of
vomiting was only 24~32% in the dexamethasone group,
which was similar to the incidence in our placebo group.
Moreover, the participants in our trial were all at high risk for
PONV and mostly underwent laparoscopic gastrointestinal
surgery, which also contributed to the high incidence of PONV.
Besides, NK-1 receptor antagonists have been shown to be
very effective for vomiting and less satisfactory for the man-
agement of nausea.13,34
Notably, the addition of fosaprepitant affected the intra-
operative blood pressure, which increased the incidence of
hypotension and decreased the incidence of hypertension.
Fosaprepitant is an inhibitor of cytochrome P4503A4
(CYP3A4) and so CYP3A4-metabolised drugs such as fentanyl
or midazolam were avoided in this trial. Intraoperative hypo-
tension was still more frequent, suggesting that drugedrug
interactions between fosaprepitant and anaesthetics used,
such as propofol or remifentanil, may still occur despite their
 680 - Huang et al.
lack of metabolism by CYP3A4. Considering the role of sub-
stance P in the pain pathway, it is possible that fosaprepitant
also has an antinociceptive effect35,36 or synergises with used
anaesthetics. Further studies are needed to determine the
exact interaction between fosaprepitant and propofol or
remifentanil.
This study had several limitations. First, the population
mainly comprised female subjects. The study was designed to
include both sexes, with three or four Apfel risk factors;
however, male subjects rarely achieved Apfel scores >2. Sec-
ond, this was an investigator-initiated trial, and only one
centre was included. The Sixth Affiliated Hospital of Sun Yat-
sen University is highly regarded for gastrointestinal surgery
in China and has >10 departments majoring in gastrointes-
tinal diseases. Third, we did not recruit participants under-
going gynaecological, thoracic, urinary, or craniotomy
surgeries and hence our findings are not generalisable to these
patient populations.
In conclusion, the addition of fosaprepitant to dexameth-
asone and palonosetron reduced both the incidence and
severity of PONV in high-risk patients with PONV undergoing
laparoscopic gastrointestinal surgery with total i.v. anaes-
thesia. Notably, it increased the incidence of intraoperative
hypotension.
Authors’ contributions
Study design: YZ, SJ, KW
Patient recruitment: QH, FW, CL, YH
Data collection: QH, FW, CL, YH, YZ, CL, CL, LZ, SL, QW, RG, TL,
WW, SZ, NBM
Writing of paper: QH, FW, CL, YH, YZ, SJ, KW
Manuscript revision: YZ, SJ, KW, SZ
Statistical analysis: QW, YG, JZ
Data interpretation: QH, FW, CL, YH, YZ, SJ, KW
Final approval of the version to be published: all authors.
Acknowledgements
We thank CHIATAI TIANQING (JiangSu, China) for providing
the fosaprepitant.
Declaration of interest
The authors declare that they have no conflicts of interest.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.bja.2023.06.029.
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Handling editor: Paul Myles