Asian Journal of Surgery (2018) 41, 301e306

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ORIGINAL ARTICLE

Relationship between the incidence and risk

factors of postoperative nausea and vomiting
in patients with intravenous
patient-controlled analgesia
Myung Sub Yi, Hyun Kang*, Min Kyoung Kim, Geun-Joo Choi,
Yong-Hee Park, Chong Wha Baek, Yong Hun Jung,
Young Cheol Woo

Department of Anesthesiology and Pain Medicine, Chung-Ang University, College of Medicine, Seoul,
Republic of Korea

Received 16 December 2016; received in revised form 13 January 2017; accepted 16 January 2017
Available online 31 March 2017

KEYWORDS Summary Objective: This study aims to evaluate retrospectively the electronic medical re-
analgesia; cords of surgical patients who received intravenous patient-controlled analgesia, to identify
antiemetics; potential relationships between the incidence and risk factors of postoperative nausea and
patient-controlled vomiting (PONV).
analgesia; Methods: Records of 6773 adult patients who received fentanyl-based intravenous patient-
postoperative nausea controlled analgesia after surgery at Chung-Ang University Hospital between January 1, 2010
and vomiting and December 31, 2015 were reviewed. Multiple logistic regressions were used to identify risk
factors for PONV.
Results: Of 6773 patients, 1216 (18.0%) were recorded to have PONV. In multiple logistic
regression analysis, female gender, nonsmoking status, history of motion sickness or PONV,
use of desflurane and nitrous oxide, and preintubation use of opioid analgesia were indepen-
dent risk factors for PONV.
Conclusions: Despite the use of antiemetic prophylaxis, 18.0% of patients with intravenous
patient-controlled analgesia had PONV. Use of desflurane and nitrous oxide, in addition to risk
factors included in the Apfel score (female gender, nonsmoking status, history of PONV or mo-
tion sickness, and use of postoperative opioids) were identified as independent risk factors. As
the incidence of PONV was 2.8%, 6.0%, 11.7%, 15.2%, 21.1%, 50.0%, and 100% for patients who

* Corresponding author. Department of Anesthesiology and Pain Medicine, Chung-Ang University College of Medicine, 224-1 Heukseok-ro,
Dongjak-gu, Seoul 156-755, Republic of Korea.
E-mail address: [email protected] (H. Kang).

http://dx.doi.org/10.1016/j.asjsur.2017.01.005
1015-9584/ª 2017 Asian Surgical Association and Taiwan Robotic Surgical Association. Publishing services by Elsevier B.V. This is an open
access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
302 M.S. Yi et al.

had 0, 1, 2, 3, 4, 5, and all these risk factors, respectively, risk-adapted, multimodal, or com-
bination therapy should be applied for patients receiving general anesthesia.
ª 2017 Asian Surgical Association and Taiwan Robotic Surgical Association. Publishing services
by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction headache, dizziness, or requirement of rescue antiemetic.

Data were collected only by this nurse, who had received
Postoperative nausea and vomiting (PONV) is one of the training regarding standardized scoring variables [pain vi-
most common complications after general anesthesia and sual analog scale and nausea numerical rating scale (NRS)]
surgery. It can be very unpleasant for patients, who may before the commencement of this study. Data collected by
even consider it the most troublesome experience in the nurse during the first 2 years (2008e2009) were not
addition to postoperative pain.1,2 Various factors, such as included in the analysis.
patient characteristics, the method of anesthesia, and the The data included 21 demographic characteristics, as
type of surgery can affect the incidence of PONV. well as anesthetic, surgical, or PCA-related factors closely
Opioids have an important role in routine postoperative related with the incidence of PONV. Specifically, we
analgesic therapy.3 A previous study showed that up to 75% collected data on age, gender, body mass index, smoking
of patients might suffer from postoperative pain, with up to status, history of PONV or motion sickness, type of anesthetic
30% of them experiencing moderate or severe postoperative agent used (propofol, desflurane, or sevoflurane), and use of
pain.4 Therefore, proper management of postoperative nitrous oxide (N2O) or remifentanil. Additionally, data were
pain is required to improve the quality of outcomes for also collected on the use of anticholinergics (glycopyrrolate)
patients and to prevent postoperative complications. as premedication, preintubation opioid or intraoperative
Patient-controlled analgesia (PCA) allows patients to self- opioid, nefopam, ketorolac, ramosetron, palonosetron or
administer medications to relieve pain and is an effective granisetron in IV-PCA, and reversal agents; the dosage of
method of postoperative pain control.5 However, post- fentanyl in IV-PCA; laparoscopic surgery; and the duration of
operative opioid usage was reported to be a risk factor for surgery. In addition, the severity of pain and nausea, fre-
PONV.6 Therefore, patients receiving intravenous patient- quency of vomiting (expulsion of stomach contents or
controlled analgesia (IV-PCA) have at least one risk factor involuntary retching not productive of stomach contents),
for PONV, suggesting that effective evaluation of PONV and incidence of headache and dizziness, discontinuation of
prophylactic treatment must be considered to reduce or PCA, and administration of rescue antiemetics on Post-
prevent the incidence of PONV. operative Days 0 and 1 were analyzed.
In this retrospective study, we evaluated the incidence The severity of nausea was rated using a five-point NRS as
and identified the risk factors of PONV in patients who follows. If the patient felt absolutely no sensation of nausea,
received IV-PCA treatment and a single dose of prophylactic the score was 0; mild sensation, 1; moderate sensation, 2;
antiemetic. and severe sensation, 3; and if the patient felt as if he/she
was about to vomit, the score was 4. Use of a “rescue anti-
emetic” indicated that an additional antiemetic treatment
2. Methods was given during the postoperative period. According to our
hospital protocol, antiemetics were administered by patient
The present study was approved by the Institutional Review request or when the degree of nausea was 3 or greater on the
Board of Chung-Ang University Hospital (Seoul, Korea) in NRS. Metoclopramide was given as a first-line drug, and if the
August 2016 (C2016173[1916]), and because the study nauseating sensation persisted, ramosetron or palonosetron
involved the evaluation of pre-existing de-identified elec- was administered via the IV route. PONV cases were defined
tronic medical records of patients, the requirement for by the presence of nausea (NRS 1), vomiting, or require-
informed consent was waived. The manuscript was pre- ment of rescue antiemetic medication during Postoperative
pared according to the Strengthening the Reporting of Days 0 and 1.
Observational Studies in Epidemiology guidelines.7 According to our hospital protocol, general anesthesia was
This was a retrospective cohort study involving the maintained at an average of 1.5  1 minimal alveolar con-
evaluation of prospectively collected medical records of centration of desflurane or sevoflurane. Either 0.05e0.10 mg/
6773 patients who received fentanyl-based IV-PCA after kg/min of remifentanil was administered throughout surgery
surgery at Chung-Ang University Hospital between January or a 2 mg/kg bolus of fentanyl was administered 2 minutes
1, 2010 and December 31, 2015. The exclusion criteria for before the intubation with 50% N2O and the volatile anes-
this study were patient age below 19 years and patient thetic given thereafter. If the patient felt pain during anes-
refusal of PCA. thesia, the anesthesiologist administered a 1 mg/kg bolus of
Data were collected by a nurse who had been working in fentanyl for pain control.
our hospital for more than 10 years and as a PCA specialist We used the standardized IV-PCA protocol of the
for more than 5 years. She only undertakes tasks related to Department of Anesthesiology and Pain Medicine in our
IV-PCA and makes rounds of patients who have had IV-PCA institution, which was a continuous infusion of 1 mL/h, as
at least once daily to collect information regarding PONV, well as a bolus of 1 mL with a 15-minute lockout interval.
pain scores, and other postoperative complications such as The 100-mL IV-PCA solution contained fentanyl, ketorolac
Patient-controlled analgesia: Nausea and vomiting risk 303

or nefopam, and ramosetron, palonosetron, or granisetron. 95% CI, 13.053e12.950; p<0.001), and use of preintubation
The correct dosage of fentanyl, ketorolac, or nefopam was opioid (OR, 1.303; 95% CI, 1.086e1.564; p Z 0.004), des-
established according to individual surgery departments, as flurane (OR, 2.209; 95% CI, 1.196e4.083; p Z 0.011), and
well as the expected intensity of pain (mild, moderate, or N2O (OR, 1.536; 95% CI, 1.262e1.868; p < 0.001; Table 3)
severe) after each type of surgery. were statistically significant risk factors for PONV. Chi-
The demographic and clinical characteristics were square test results for linear trend indicated a significant
summarized using descriptive statistics. Continuous vari- increase in the incidence of PONV associated with the
ables were expressed as the mean value  standard devia- number of independent risk factors evaluated (0 Z 2.8%,
tion and categorical variables as an absolute number 1 Z 6.0%, 2 Z 11.7%, 3 Z 15.2%, 4 Z 21.1%, 5 Z 50.0%, and
(percentage). 6 Z 100.0%; p for trend <0.001; Figure 1).
Univariate analysis using logistic regression was per-
formed to calculate the relative risk estimates as odds ra-
tios (ORs) with 95% confidence intervals (CIs) with a two-
sided p value of 0.05 for the identification of the inde- Table 1 Patient, anesthetic and operative characteris-
pendent risk factors for PONV. Multivariate analysis with tics, and postoperative conditions.
backward selection was performed with factors that had Variables n Z 6773
univariate p values of <0.10 upon logistic regression. Mul-
Patient characteristics
ticollinearity diagnostics indicated no multicollinearity is-
Age (y) 50.21  17.91
sues (condition indices <30 and variance influence factor
Gender M:F (n) 2705 (39.9):4068 (60.1)
values <10) between the chosen independent variables in
BMI (kg/m2) 23.83  4.04
this study. The incidence of PONV was calculated for the
Smoking (n) 1239 (18.3)
number of independent risk factors per patient. In addition,
History of PONV or motion 254 (3.8)
a chi-square test for linear trends was used to assess
sickness (n)
changes in the incidence of PONV over the number of in-
dependent risk factors.
Anesthetic factor
A p value of <0.05 was considered statistically signifi-
Premedication (anticholinergic) 1922 (28.4)
cant. All statistical analyses were performed using Statis-
(n)
tical Package for Social Sciences software, version 23.0 (IBM
Preintubation opioid (n) 3889 (57.4)
Corp., Armonk, NY, USA).
Sevoflurane (n) 2690 (39.7)
Desflurane (n) 3863 (57.0)
TIVA (n) 220 (3.2)
3. Results
N2O (n) 4305 (63.6)
Remifentanil (n) 1639 (24.2)
This study included 6773 patients who received opioid- Intraoperative opioid (n) 3901 (57.6)
based IV-PCA after various surgeries at our hospital. The
demographic characteristics and perioperative factors Surgical factor
of the patients included in this study are summarized in Laparoscopy (n) 2037 (30.1)
Table 1. Duration of surgery (min) 161.17  108.63
Of 6773 patients, 4068 (60.1%) were women. The mean
age was 50.21  17.91 years, and 6553 patients (96.7%) PCA-related factor
received volatile anesthesia with either sevoflurane or PCA fentanyl (100 mg) 12.73  3.07
desflurane. N2O was used in 4305 patients (63.6%), and Ketorolac (n) 2039 (30.1)
continuous infusion of remifentanil was used in 1639 pa- Nefopam (n) 3824 (56.5)
tients (24.2%). In 3320 patients (49.0%), 0.05 mg of pal- Antiemetic (n)
onosetron was administered intravenously at the end of the Ramosetron 3055 (45.1)
surgery and was included in PCA for prophylaxis of PONV, Palonosetron 3320 (49.0)
while 3055 patients (45%) received 0.3 mg of ramosetron in Granisetron 398 (5.9)
the same manner. Granisetron (5.9%) was used in other
cases. PONV occurred in 1216 patients (18.0%; Table 1) and Postoperative complication
PCA was discontinued in 416 patients (6.1%), mostly Nausea, retching, and vomiting 1216 (18.0)
because of PONV. (n)
In univariate analysis for PONV, young age; female Headache (n) 44 (0.6)
gender; a low body mass index; nonsmoking status; history Dizziness (n) 150 (2.2)
of PONV or motion sickness; use of preintubation opioid, Discontinuation of PCA (n) 416 (6.1)
desflurane, N2O, or intraoperative opioid; laparoscopic Requirement of rescue 1661 (24.5)
surgery; duration of surgery; and dosage of fentanyl in PCA antiemetic including routine
were risk factors. However, the use of total intravenous order (n)
anesthesia reduced the risk for PONV (Table 2).
By multivariate analysis with logistic regression, female BMI Z body mass index; F Z female; M Z male; n Z number;
N2O Z nitrous oxide; PCA Z patient-controlled analgesia;
gender (OR, 2.900; 95% CI, 2.391e3.518; p < 0.001),
PONV Z postoperative nausea and vomiting; TIVA Z total
nonsmoking status (OR, 1.348; 95% CI, 1.042e1.745;
intravenous anesthesia.
p Z 0.023), history of PONV or motion sickness (OR, 17.548;
304 M.S. Yi et al.

Table 2 Univariate analysis of risk factors for post-

operative nausea and vomiting.
Variables OR 95% CI p
Patient characteristics
Younger age (y) 1.005 1.001e1.009 0.011
Female (n) 3.319 2.805e3.927 <0.001
BMI (kg/m2) 0.962 0.944e0.980 <0.001
Nonsmoking (n) 2.387 1.908e2.994 <0.001
History of PONV or motion 17.339 13.097e22.955 <0.001
sickness (n)

Anesthetic factor
Premedication 1.008 0.868e1.171 0.919
(anticholinergic) (n)
Preintubation opioid (n) 1.419 1.233e1.634 <0.001
Anesthetics (n)
Sevoflurane 1 Figure 1 Incidence of PONV per number of risk factors.
Desflurane 1.341 1.180e1.523 <0.001 Incidence of PONV as a percentage per number of independent
TIVA 0.577 0.379e0.879 <0.001 risk factors, evaluated using chi-square test for linear trend
N2O (n) 1.851 1.588e2.159 <0.001 (0 Z 2.8%, 1 Z 6.0%, 2 Z 11.7%, 3 Z 15.2%, 4 Z 21.1%,
Remifentanil (n) 0.567 0.474e0.679 <0.001 5 Z 50.0%, 6 Z 100.0%, p for trend <0.001). POD Z postoper-
Intraoperative opioid (n) 1.024 1.001e1.046 0.043 ative day; PONV Z postoperative nausea and vomiting.

Surgical factor
various factors including the administration of volatile an-
Laparoscopy (n) 1.215 1.043e1.414 0.012
esthetics, use of postoperative opioids for pain, type of
Duration of surgery (min) 1.001 1.000e1.002 0.026
surgery, and patient characteristics.8 In this retrospective
study evaluating prospectively collected medical records,
PCA-related factor
the incidence of PONV in patients receiving fentanyl-based
PCA fentanyl (100 mg) 1.024 1.001e1.046 0.043
IV-PCA was 18.0%. Risk factors for PONV were female
Ketorolac (n) 0.930 0.802e1.080 0.342
gender, nonsmoking status, history of PONV or motion
Nefopam (n) 1.027 0.896e1.178 0.698
sickness, and use of preintubation opioid, desflurane, or
Antiemetic (n)
N2O. Of these results, female gender, nonsmoking status,
Granisetron 1
and history of PONV or motion sickness correlated with the
Ramosetron 0.973 0.842e1.124 0.532
results of other previous studies. According to Apfel et al,9
Palonosetron 0.945 0.791e1.129 0.645
female gender, nonsmoking status, history of PONV or mo-
BMI Z body mass index; CI Z confidence interval; n Z number; tion sickness, young age, duration of anesthesia, and
N2O Z nitrous oxide; OR Z odds ratio; PCA Z patient- postoperative opioids were risk factors for PONV. Addi-
controlled analgesia; PONV Z postoperative nausea and vomit-
tionally, Koivuranta et al10 suggested a risk score model of
ing; TIVA Z total intravenous anesthesia.
PONV that included female gender, history of PONV, dura-
tion of surgery over 60 minutes, nonsmoking status, and
history of motion sickness as risk factors of PONV.
Table 3 Multivariate analysis of risk factors for post- Postoperative opioid use as a part of PCA is also a known
operative nausea and vomiting. risk factor. As we included patients who were treated only
Variables OR 95% CI p with opioid-based IV-PCA, every participant of this study
Female 2.900 2.391e3.518 <0.001 exhibited at least one risk factor for PONV (postoperative
Nonsmoking 1.348 1.042e1.745 0.023 opioid treatment for pain). In addition, over 60% of the
History of PONV or 17.548 13.053e12.590 <0.001 patients were female and 81.7% nonsmokers. In line with
motion sickness previous studies, these patients were expected to have a
Preintubation opioid 1.303 1.086e1.564 0.004 significantly high risk for PONV.
Desflurane 2.209 1.196e4.083 0.011 Despite the use of opioid-based IV-PCA, the overall inci-
N2O 1.536 1.262e1.868 <0.001 dence of PONV was lower than in a previous study.6 According
to the Apfel et al’s6 simplified risk score, the estimated
CI Z confidence interval; N2O Z nitrous oxide; OR Z odds ratio; probability of PONV was 10%, 21%, 39%, 61%, and 78% if 0, 1,
PONV Z postoperative nausea and vomiting.
2, 3, and 4 risk factors were present, respectively. In this
study, with postoperative use of opioid-based IV-PCA as a
baseline risk factor, the incidence of PONV was 18%, which
4. Discussion was lower than the expected probability according to
Apfel et al. This may be explained by the routine use of
PONV is one of the most common and undesirable compli- prophylactic antiemetics. Furthermore, second-generation
cations after anesthesia and surgery. It is influenced by antiemetics such as ramosetron and palonosetron were
Patient-controlled analgesia: Nausea and vomiting risk 305

mainly used, which demonstrate greater effectiveness itself may increase the blood pressure and heart rate of
compared with first-generation antiemetics. In our analysis, patients by stimulating the sympathoadrenal response.28,29
the effectiveness of palonosetron and ramosetron was Preintubation opioids can be used to minimize hemody-
compared, but no significant difference was found between namic changes during the induction. A 2 mg/kg bolus of
them, consistent with the results of a previous study.11 fentanyl was used in our hospital to minimize the pain
Similar to the results of previous studies, nonsmoking stimulus during laryngoscopy. This use of preintubation
status was an independent risk factor for PONV. Apfel et al12 opioid analgesia was shown to be a significant risk factor for
showed that volatile anesthetics are responsible for PONV PONV.
during the early postoperative period, when the pharmaco- Additionally, laparoscopic surgery itself has been re-
kinetic effects have a marked role in any perceived differ- ported to increase the incidence of PONV.30 However, in
ences. Volatile anesthetic agents are metabolized by this study, although laparoscopy was considered a risk
cytochrome P450 2E1, which can be induced by nicotine and factor for PONV in univariate analysis, it proved to be sta-
polycyclic aromatic hydrocarbons from smoking.13 Thus, the tistically insignificant.
increased induction of liver enzymes in patients who smoke Of note, PONV can still occur after the use of a single
might contribute to a higher rate of metabolism and to faster dose of antiemetic in patients who undergo general anes-
recovery from general anesthesia. Furthermore, nicotine thesia. In this retrospective study, 14.5% of the patients
inhibits the function of 5HT3 receptors,14 which would also showed PONV and 24.5% required additional rescue anti-
affect the outcome of PONV. emetic despite the use of an antiemetic for prophylaxis of
Interestingly, desflurane, N2O, and preintubation use of PONV. PCA was discontinued in 6.1% of the patients because
opioid were also identified as statistically significant risk of PONV. Appropriate action must be taken to reduce or
factors for PONV. Although desflurane was a risk factor for prevent the incidence of PONV and provide better quality
PONV in this study, there is still an unresolved controversy of postsurgery outcomes for patients.
regarding the effect of desflurane and sevoflurane on PONV. The present study had some limitations. First, we eval-
Several studies reported significant differences between uated postoperative conditions associated with IV-PCA once
sevoflurane and desflurane in terms of severity of nausea daily for each patient. The patients answered our questions
and incidence of vomiting. One study reported the in- regarding the NRS scores for nausea, frequency of vomiting
cidences of PONV during 24 hours after breast surgery as per day, and visual analog scale scores for pain and other
22% with isoflurane, 36% with sevoflurane, and 67% with complications including headache, dizziness, and drowsi-
desflurane. Late PONV (PONV in the surgical ward in that ness. This method of evaluation might have caused a recall
study) was significantly more common with desflurane than bias, which could have led to underestimation of the inci-
with sevoflurane.15 In another study, administration of dence of PONV.9 Second, because of the retrospective na-
desflurane was also a risk factor for PONV.3 ture of the study, it was difficult to relate effects to
Owing to its low blood/gas partition coefficient, the causation because of the possibility of unevaluated con-
washout time of desflurane is faster than that of other founding factors. Third, because this was a single-center
volatile agents, and consequently, enables faster recovery study, it might not be possible to generalize the results of
and re-establishment of cognitive function. In addition, this study to a wider population.
desflurane causes more airway irritation compared with
other inhalant agents. Faster emergence from anesthesia,
combined with airway irritation, may contribute to the 5. Conclusions
patient’s early recognition of discomfort and increase the
incidence of reported PONV. In conclusion, female gender, nonsmoking status, history of
In contrast, a meta-analysis by Macario et al16 showed no PONV or motion sickness, use of preintubation opioids, use
difference in the incidence of PONV between desflurane of desflurane, and use of N2O were all identified as inde-
and sevoflurane. Furthermore, Wallenborn et al17 reported pendent risk factors for PONV. The results of our study
no difference between isoflurane, desflurane, and sevo- suggest that combination therapy should be considered to
flurane with respect to frequency or severity of post- control PONV.
operative nausea, vomiting, or both.
The use of N2O also contributed to the incidence of Conflicts of interest
PONV as reported by previous studies.18e21 Apfel et al22 also
showed that substituting N2O with nitrogen reduced the risk
The authors have no conflicts of interest to declare.
of PONV by 12%. A meta-analysis by Fernánadez-Guisasola
et al23 concluded that avoiding nitrous oxide reduced the
risk of PONV. The mechanisms by which nitrous oxide cau- Acknowledgments
ses PONV are not yet clearly defined, but some possible
mechanisms have been suggested. Certain actions of
None.
nitrous oxide on central opioid and dopaminergic re-
ceptors,24,25 changes of middle ear pressure by the diffu-
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