Journal of Anesthesia
https://doi.org/10.1007/s00540-020-02777-9

ORIGINAL ARTICLE

Effect of scheduled intravenous acetaminophen on postoperative
nausea and vomiting in patients undergoing laparoscopic gynecologic
surgery
Hideki Taniguchi1 · Mari Nagahuchi2 · Takaaki Kamada2 · Kikuko Suga2 · Tomoyuki Sato2 · Tomomi Ueda2 ·Tatsuo Yamamoto2
Received: 16 January 2020 / Accepted: 4 April 2020
© Japanese Society of Anesthesiologists 2020

Abstract
Purpose The aim of this study was to assess the effect of scheduled intravenous acetaminophen (SIVA) on the incidence of
postoperative nausea and vomiting (PONV) in patients undergoing laparoscopic gynecologic surgery (LGS).
Methods This retrospective observational study identified consecutive patients who underwent LGS at our institution fromJanuary to November of 2017 and were managed with either our hospital’s old protocol (Group H) or a new protocol using
SIVA (Group S). Primary outcomes included the incidences of PONV and the amount of additional antiemetic requiredin the postoperative period. The secondary outcomes included the pain score on postoperative day 1, the requirement for
additional analgesic medications, and the length of hospitalization (LOH).
Results Patients in Group S had significantly lower incidences of PONV from postoperative days 0 to 1 and required significantly less antiemetics or tramadol than those in Group H (P = 0.0085). Patients at a low risk for PONV in Group S hadsignificantly lower incidences of PONV than those in Group H (P = 0.0129). Further, the amount of additional tramadol
required was lower in Group S than in Group H (P = 0.0021).
Conclusion Introduction of SIVA into the postoperative pain management protocol of LGS may reduce the incidence of
PONV and the amount of adjunctive antiemetic medication required from postoperative days 0 to 1. In patients undergoing
LGS, PONV prophylaxis using antiemetics should be prescribed depending on PONV risk profile; however, SIVA prophylaxis can be used in all patients regardless of PONV risk profile.
Keywords Scheduled intravenous acetaminophen · Acetaminophen · Laparoscopic gynecologic surgery · Opioid sparing ·Postoperative nausea and vomiting

Introduction
Evidence-based guidelines for the perioperative care ofpatients undergoing various surgical procedures havebeen published by the Enhanced Recovery After Surgery(ERAS) Society [1, 2]. ERAS guidelines for gynecologic/
oncologic surgeries (ERASG) have recently been updated* Hideki Taniguchi
hstani@aol.jp
1

Perioperative Support Center, Saiseikai Yokohamashi Tobu
Hospital, 3‑6‑1 Shimo‑Sueyoshi, Tsurumi‑Ku, Yokohama,
Kanagawa 230‑8765, Japan2

Department of Anesthesiology, Saiseikai Yokohamashi Tobu
Hospital, Yokohama, Kanagawa, Japanand recommend scarce opioid administration in patients
undergoing gynecologic or oncologic surgical procedures
to facilitate an earlier return of bowel function and a shorter
length of hospitalization (LOH). Moreover, according tothese guidelines, multimodal non-opioid analgesia use inthese patients decreases postoperative nausea and vomiting(PONV) and allows for a more rapid recovery [3]. One of thesimplest methods to limit opioid intake in the postoperative
period is to schedule narcotic alternatives including acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs),and gabapentin rather than administering them on an asneeded basis [4]. The scheduled use of selective or nonselective NSAIDs, cyclooxygenase (COX) 2 inhibitors, and acetaminophen (orally or intravenously [IV]) has been shown to
improve postoperative analgesia and reduce the consumptionof systemic opioids and their dose-dependent adverse effects

13

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Journal of Anesthesia[5, 6]. A meta-analysis of 30 randomized controlled trials(RCTs), which included 2364 patients, showed that administering acetaminophen IV either before surgery or before
arrival at the post-anesthesia care unit reduced the risk ofnausea and pain, both of which are known to delay surgicalrecovery [6].
As Japanese insurance processes restrict the use of perioperative antiemetic agents, the rate of PONV remains highin Japan, especially after gynecologic surgery. We hypothesize that opioid sparing using SIVA may be an effective
strategy to decrease the rate of PONV for patients undergoing laparoscopic gynecologic surgery (LGS) in Japan. In
2011, the accepted clinical dosage of IV acetaminophen in
Japan increased from a maximum of 1500 to 4000 mg per
day to allow for a more optimal analgesic effect. To date,however, there have been few clinical studies evaluating
this new maximum dosage of acetaminophen. Moreover,acetaminophen is often prescribed to patients only on an
as-needed basis depending on their pain levels, with few
studies or recommendations evaluating the use of scheduled
IV acetaminophen (SIVA) in postoperative patients.
The aim of this study was to assess the effect of SIVA
on the incidence of PONV and the efficacy of analgesia inpatients undergoing LGS according to our hospital’s management protocols. We included patients specifically undergoing LGS because these procedures allow us to assess theisolated effects of SIVA on PONV without potential confounding factors related to the use of epidural anesthesia or
IV opioids.

Methods
The present study was approved by the Institutional
Review Board of Saiseikai Yokohamashi Tobu Hospital(Approval no. 2016090), was registered with the Center for
Clinical Trials, Japan Medical Association (JMA) Clinical
Trials Registry (JMA registration no.: JMA-IIA00326),
and was conducted after disclosure of information. The
requirement for informed consent was waived because of
the retrospective nature of the study. We included patients
who had undergone elective LGS for benign diseases of
the uterus or ovaries and had been managed postoperatively using either our hospital’s old or new pain management protocols.
In our hospital’s old LGS pain management protocol,
tramadol (a weak opioid) and acetaminophen were used on
an as-needed basis (Table 1), and patients were discharged
in the morning of postoperative day 4. On June 1, 2017,
our hospital initiated a new pain management protocol thatused SIVA after LGS (Table 1, Fig 1). The switchoverto the new protocol took place during a transition period
between June 1, 2017 and June 30, 2017.
For this retrospective study, we reviewed medical
records to identify consecutive patients who underwent
LGS between January 1, 2017 and May 31, 2017 andwere managed using the old pain management protocol.
These patients were enrolled in our study and designatedas the historical group (Group H). Consecutive patients
who underwent LGS between July 1, 2017 and November

Table 1  Management protocol regarding laparoscopic gynecologic surgery
PeriodPreoperative

The old protocol (Group H)

The new protocol (Group S)a

Major ­components
Intake of oral rehydration s­ olutionb until 2 h before surgery
No laxative medication and premedication
Thorough oral cavity care
Intraoperative Use of short-acting anesthetics
Patient is kept w­ armcIntravenous acetaminophen injected 30 min before the end of surgery. Wound infiltration with local anesthetic is performed
Prevention of PONV during operation
Early ambulation and oral diet (postoperative day 1)
Postoperative Early ambulation and oral diet (postoperative day 1)
On the operative day, intravenous infusion of acetaminophen Tramadol is Scheduled intravenous acetaminophen and tramadol
administered on an as-needed b­ asisd
taken as needed ­repeatedlydabInformation sharing/patient education (before and after surgery)

500-ml plastic bottles (OS-1, classified as a type of food in Japan (Otsuka Pharmaceutical Factory, Inc., Tokushima, Japan). We provided
1500 ml of the solution to the patients at 20:00 h on the night before surgery and allowed them to drink at least 500 ml at any time until 2 h
before entering the operating roomc

While the body surface was covered with blankets or towels, the patient was kept warm with a Bair Hugger (3 M, St. Paul, MN) set at 38 °C.
The target body temperature was set at a bladder temperature of 36–37 °C. The fluids used were warmed to 35–36 °C with a warming device
before transfusiond

The maximum total amount of tramadol used (intravenous or/and oral)was up to 300 mg per day

13

Journal of Anesthesia

Time

POD 2 and 3

POD 1

POD 0
(operaon day)POD 4
(discharge day)<Intravenous acetaminophen>: 4:00 10:00 16:00 22:00
Scheduled intravenous acetaminophen(SIVA)

During operaon䐟 SIVA should start 30
min before skin closure.
䐠 Wound infiltraonwith a local anesthec

APS round of visits at 9:00

Prevenon of PONV
Injecon of dexamethasone anddroperidol during the operaon<Oral acetaminophen>: 4:00 10:00 16:00 22:00<Rescue medicine as need>
POD: Postoperave day, APS: acute pain service
SIVA: Scheduled intravenous acetaminophen
PONV: Postoperave nausea and voming
Rescue medicine: tramadol

Fig. 1  Pain management protocol for laparoscopic gynecologic surgery. IV acetaminophen was injected 30 min before the end of surgery, and every 6 h for 48 h, with a total of four doses of 1000 mg forpatients weighing ≥ 50 kg or 15 mg/kg for patients weighing < 50 kg.

Wounds were infiltrated with a local anesthetic (20–40 ml of 0.2%
ropivacaine). On postoperative day 1, patients transitioned to oral
acetaminophen

30, 2017 and who were managed following the new SIVA
protocol were enrolled and designated as the study group(Group S).
The inclusion criteria included patients aged 20 years orolder who were categorized as class I or II by the American Society of Anesthesiologists Physical Status (ASA-PS)
scale. The exclusion criteria included patients with renal
dysfunction (estimated creatinine clearance < 20 ml/min
or ongoing hemodialysis), liver dysfunction (AST or ALT> 100 U/l), prescribed NSAIDs on postoperative day 0 or
1, and/or deviation from our hospital’s standard LGS management protocols.
This study compared patients treated with two different pain management protocols (with and without SIVA)(Table 1). The primary outcomes were the incidences of
PONV during postoperative days 0 to 1 and the patient
requirement for an additional antiemetic in the postoperative period. The secondary outcomes included pain score
on postoperative day 1, the patient requirement for additional analgesic medications, and length of hospitalization(LOH).

Primary outcomes
The incidences of PONV from postoperative days 0 to 1
were the primary outcomes of this study and were assessedby reviewing the medical records. Patient requirement foran additional antiemetic was assessed by the frequency ofprescriptions for metoclopramide. We also carried out a subanalysis for the incidences of PONV stratified by risk of
PONV (based on the scoring system by Apfel et al.) [7].

Secondary outcomesA secondary outcome of the study was the postoperative
pain assessment as estimated by the Numerical Rating Scale(NRS) on postoperative day 1 at 9:00 during rest. Anesthesiologists informed the patients regarding NRS reporting
before surgery and then estimated their postoperative painusing it, during acute pain services (APS) rounds.
The postoperative use of analgesics was another secondary outcome and was assessed by calculating the frequency of prescribed analgesics, including tramadol and13

Journal of Anesthesia

acetaminophen. Data on sex, age, body mass index (BMI),
ASA-PS, disease type, maintenance of anesthesia, operation
time, LOH, and laboratory results were also collected fromthe database.

Maintenance of anesthesia
Patients were permitted to drink carbohydrate beverages up
to 2 h before administration of anesthesia. No pre-anesthetic
medications were administered. Anesthesia was inducedwith propofol and remifentanil. Following muscle relaxation with rocuronium, the trachea was intubated. Anesthesia
was maintained with an inhalation anesthetic (sevoflurane)
and remifentanil, and fentanyl and rocuronium were intermittently administered as needed. In both patient groups,
IV acetaminophen was injected 30 min before the end of
surgery at doses of 1000 mg for patients weighing ≥ 50 kg
and 15 mg/kg for patients weighing < 50 kg. Wounds werealso infiltrated with a local anesthetic (20–40 ml of 0.2%
ropivacaine). After completion of the surgical procedure,
remifentanil and inhalation anesthesia were stopped, andmuscle relaxation was reversed. Following confirmation of
the patient’s awakening by an anesthesiologist, the endotracheal tube was removed. Epidural or total IV anesthesia(continuous infusions of propofol and remifentanil) was not
utilized for any included surgeries.

SIVA occurred less than 120 min after surgery ended. On
postoperative day 1, patients were switched to scheduled oral
acetaminophen. When a patient’s pain at rest was over 4 on
the NRS, a nurse would administer tramadol at intervals of
4 h or more. Liver function panels were checked on postoperative days 1 and 3. When the levels of AST or ALT were
elevated by more than 100 U/L, SIVA was stopped.
Tramadol, a weak opioid, was selected, to relieve visceralpain. NSAIDs were not used in Group S.

Prevention of PONV
In both groups, patients with a high PONV risk (≧ 60% on
the scoring system by Apfel et al.) [7] were given antiemetics during the procedure. Dexamethasone (6.6 mg) was
injected following anesthetic induction and droperidol
administered (0.625–1.25 mg) at the end of surgery. When
PONV occurred, rescue antiemetic therapy with metoclopramide was provided.

Postoperative rehabilitation and nutrition

Postoperative pain management

On postoperative day 1, breathing exercises for 10 min per
day were recommended. On postoperative day 2, the patientswere advised to be out of bed for more than 2 h. They werepermitted to drink clear fluids, starting at 6 h after surgery,and to eat food, starting on the morning of postoperative
day 1.

Group H

Discharge criteria

In Group H, postoperative pain medications were administered as needed. When the patient’s pain at rest was morethan 4 on the NRS, the nurse administered one rescue drug
from the medications ordered by the physician. On the dayof the procedure, IV infusions of either acetaminophen(Acelio IV Injection; Terumo Corporation, Tokyo, Japan)
or tramadol (Tramal IV Injection; Nippon Shinyaku Co.,
Kyoto, Japan) were used. Starting on postoperative day 1,
oral acetaminophen or tramadol was provided as needed,
at intervals of 4 h or more. The total maximum tramadol(intravenous or/and oral) used was up to 300 mg per day.
NSAIDs were not used for any patients owing to the risk ofgastrointestinal complications.

Discharge typically occurred on the morning of postoperative day 4 based on the management protocol. Patients weredischarged when they met the following criteria: (a) had
good pain management with oral analgesia; (b) were able totolerate solid food without abdominal symptoms; (c) wereindependently mobile or had the same mobility level as that
before admission; and (d) met all of the above criteria andwere willing to go home.

Group SIn Group S, patients were given pain medications at timed
intervals, receiving SIVA every 6 h for 24 h postoperatively,
for a total of four doses (1000 mg/dose every 6 h for patientsweighing ≥ 50 kg and 15 mg/kg every 6 h for patients weighing < 50 kg). Every patient was administered SIVA at thesame time (4:00, 10:00, 16:00, and 22:00), unless the first13

Sample size
The sample size was calculated based on the result of aprevious study [8]. Based on this study, patients received
either acetaminophen 2 g (group A) or placebo (group C)
intravenously 30 min while under general anesthesia prior
to abdominal hysterectomy. According to the results of thisstudy, the incidence of PONV was lower in group A than ingroup C (36% vs 60%, P = 0.044). Therefore, we estimatedthat a minimum sample size of 88 patients (44 in each arm)
would be needed to obtain 80% power and an alpha levelof 0.05 to detect a difference in the incidence of PONV
between groups. We set the registration period to 5 months

Journal of Anesthesia

so that at least 100 patients (50 in each arm) could be registered after allowances for a drop-out of 10%.

Statistical analyses
Statistical analyses were performed using JMP10.0.2 (SASInstitute, Cary, NC, USA).
Group results were compared using Fisher’s exact test
for binary categorical variables. NRS values, LOH, andthe number of prescriptions for antiemetics or analgesics
were compared between the two groups using the Wilcoxon
rank-sum test and expressed as a median value (minimum
value, bottom quartile–top quartile, maximum value). For
continuous variables, the results are expressed as a meanvalue with standard deviation (SD) and compared between
groups using a two-sample t test. The two-tailed significancelevel (P value) was set at 5%.

Results
Patients who underwent elective LGS during the study
period and who met the inclusion and exclusion criteria wereselected based on their information in the medical records.
All patients were treated according to either the old or the
new management protocol during the investigation period.
A total of 84 patients were registered for this study, with 34
in Group H and 50 in Group S (Fig. 2). Eighteen patientswere dropped from group H: four required no preventionof PONV, eight presented an incomplete set of data, andsix were prescribed NSAIDs. Eleven patients were dropped
from group S, three did not require prevention of PONV,
four presented changes in surgical procedures, and four wereprescribed NSAIDs. Table 2 summarizes patient characteristics of both groups. There were no statistically significant differences between the groups regarding age, height,

weight, ASA-PS, surgery type, duration of anesthesia, duration of the operations, blood loss, urine volume, intraoperative amounts of administered fentanyl and remifentanil, theend of operation time (AM or PM), or high risk of PONV.

Primary outcomes
The incidences of PONV from postoperative days 0 to 1
were significantly lower in Group S than in Group H (GroupH = 58.8%, Group S = 30.0%, P = 0.0085) (Table 3). Furthermore, the frequency of metoclopramide prescriptions
from postoperative days 0 to 1 was significantly lower inGroup S than in Group H (Group S: 0 [0, 0–1.0, 2.0]; Group
H: 2.0 [0, 1.0–4.0, 7.0]; P = 0.0129) (Fig. 3). The incidenceof PONV was significantly higher in patients with a low
PONV risk (Apfel score = 0–2 points) in Group H than thosein group S (Group H: 60.0%; Group S: 17.4%; P = 0.0054)(Table 4).

Secondary outcomes
Figure 4a compares the NRS at rest on postoperative day 1
at 9:00 in both groups. The NRS did not significantly differ
between patients both groups (Group S: 2 [0, 0–3.0, 8.0];
Group H: 1.0 [0, 0–1.0, 4.0]; P = 0.1947). The number of
additional tramadol prescriptions from postoperative days
0 to 1 was significantly lower in Group S than in Group H(Group S: 0 [0, 0–1.0, 2.0]; Group H: 1.0 [0, 0–2.0, 4.0];
P = 0.0021) (Fig. 4b). LOH after surgery did not significantly differ between the groups (Group S: 4.0 [3.0, 4.0–4.0,
5.0] days; Group H: 4.0 [3.0, 4.0–4.0, 5.0] days; P = 0.0552)(Table 5). No patient in either group had an elevation of
more than 100 U/l in their AST or ALT levels on postoperative day 1.

<Group H><Group S>

Paents (n 52)

Paents (n 61)

18 dropouts:
4 with no prevenon of PONV
8 with an incomplete set of data
6 with prescribed NSAIDs

Eligible for analysis(n 34)
Fig. 2  Flowchart of eligible patients. In total, 84 patients were eligible for analysis, including 34 patients in Group H and 50 patientsin Group S. In Group H, 12 patients were excluded: four patients did
not receive PONV prophylaxis during surgery and eight patients had

11 dropouts:
3 with no prevenon of PONV
4 with changes in surgical procedures
4 with prescribed NSAIDs

Eligible for analysis(n 50)
incomplete datasets. In Group S, seven patients were excluded: threepatients did not receive PONV prophylaxis during surgery and four
patients had changes in their surgical procedures

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Journal of Anesthesia
Table 2  Patient characteristics
Age (years)
Height (cm)Weight (kg)
ASA-PS score
I (n)
II (n)III (n)Surgery type
Laparoscopic hysterectomy (n)Laparoscopic ovarian resection (n)During operation
Anesthetic duration (min)Operative duration (min)The end of operation time (AM(n)/PM(n))
Fentanyl (μg)
Remifentanil (mg)Blood loss (ml)Urine volume (ml)Patients with high PONV risk (n)Group H (n = 34)

Group S (n = 50)

P value

44.7 ± 11.2
157.8 ± 6.7
55.2 ± 7.3

42.7 ± 11.8
158.6 ± 5.4
57.6 ± 12.4

20
12
1

34
16
0

0.4464*0.5500*0.3001*0.407713 (38.2%)
21 (61.8%)

25 (50.0%)25 (50.0%)

166.4 ± 44.3
121.6 ± 42.6
20/14
341 ± 1080.84 ± 0.21
33 [0, 112.5]
135 [100, 300]
14 (41.2%)

175.2 ± 54.0
132.4 ± 54.4
33/17
354 ± 1030.86 ± 0.29
20 [0, 80.5]
200 [95, 400]
27 (54.0%)

0.2876††

0.4335*0.3362*0.5043††0.5847*0.8018*0.5578†0.6456†
0.2485††

Continuous variables: mean ± standard deviation; Group H: historical group; Group S: SIVA group;
Patients with a high PONV risk: ≧ 60% on scoring system by Apfel et al. [7]Mean value ± standard deviation, median value [first quartile, third quartile]*A two-sample t test: significant when P < 0.05
†Wilcoxon rank-sum test: significant when P < 0.05††

Fisher exact probability test: significant when P < 0.05

Table 3  Incidence of PONV

PONV (+): n (%)
PONV (−): n (%)

Group H (n = 34)

Group S (n = 50)

P value20 (58.8%)
14 (41.2%)

15 (30.0%)35 (70.0%)

0.0085*PONV postoperative nausea and vomiting*

Fisher’s exact probability test: significant when P < 0.05

Discussion
This study showed that postoperative SIVA in patients
undergoing LGS significantly reduced the incidences ofboth PONV. SIVA also significantly reduced the numberof required prescriptions for metoclopramide from postoperative days 0 to 1. When stratified according to initialrisk for PONV, the incidence of PONV was significantly
lower in patients with a low-PONV-risk in Group S thanin those in Group H. Furthermore, postoperative SIVA
significantly reduced the required number of rescue analgesic medications (i.e., tramadol). However, the NRS atrest on postoperative day 1 at 9:00 and the LOH did not
differ between the two groups.

13

PONV occurs in approximately 30% of patients undergoing general anesthesia [7, 9]. Female gender, nonsmoking status, a history of PONV and/or motion sickness, andanticipated use of postoperative opioids have previously
been identified as important risk factors for PONV [7, 9].
Apfel et al. have demonstrated that cholecystectomies, laparoscopic procedures, and gynecological surgeries are also
statistically significant independent predictors of PONV [7].
Furthermore, antiemetics such as 5-HT3 receptor antagonists and neurokinin-1 (NK1) receptor antagonists are still
unapproved for use in Japan. These factors may explain
the high incidence of PONV in both Group H (58.8%) andGroup S (30.0%) patients, which necessitated the use of the
weak opioid tramadol, especially in Group H.
It has been well documented that opioid analgesics areassociated with nausea, vomiting, sedation, dysphoria, pruritus, constipation, urinary hesitancy, and respiratory depression after surgery [10]. If our hospital’s protocol had allowed
physicians to use ondansetron in patients, then the incidenceof PONV identified in this study might have been decreased,
as observed in other studies of laparoscopic cholecystectomies [11, 12]. However, as physicians could not use ondansetron, the incidences of PONV were significantly decreasedby the administration of postoperative SIVA, allowing forJournal of Anesthesia

Fig. 3  The number of additional antiemetics required from postoperative days 0 to 1. The number of additional antiemetics required frompostoperative days 0 to 1 was significantly lower in Group S than inGroup H [Group S: 0 (0, 0–1.0, 2.0); Group H: 2.0 (0, 1.0–4.0, 7.0);

P = 0.0129]. The number of antiemetic prescriptions was compared
between groups using a Wilcoxon rank-sum test and expressed as amedian value (minimum value, bottom quartile to top quartile, maximum value)

Table 4  Incidence of PONV according to high or low risk for PONV
PONV (+)

PONV (−)

Total

Low PONV risk: Apfel score = 0–2 points
Group H: n (%)
Group S: n (%)

12 (60.0%)
4 (17.4%)*

8 (40.0%)
19 (82.6%)

20
23*P = 0.0054

High PONV risk: Apfel score = 3–4 points
Group H: n (%)
Group S: n (%)

8 (57.1%)
11 (40.7%)

6 (42.9%)
16 (59.3%)

1427
P = 0.3458

Patients with high PONV risk: ≧ 60%; scoring system by Apfel et al. [7]
PONV postoperative nausea and vomiting*Fisher’s exact probability test: significant when P < 0.05

scarce opioid administration and a decreased need for tramadol. Apfel et al. found similar results and concluded that
PONV prophylaxis is rarely warranted in low-risk patients,
while moderate-risk patients may benefit from a single intervention [6]. Additionally, Apfel et al. recommended thatmultiple interventions should be reserved only for high-riskpatients because antiemetics are highly effective, safe, andinexpensive. In contrast, our study shows that even patientswith a low risk of PONV can benefit from postoperative

SIVA, as the incidence of PONV was significantly lower inGroup S patients than in Group H patients [6]. Therefore,
we conclude that prophylaxis of PONV using antiemetics
should be prescribed according to PONV risk; however,
SIVA prophylaxis should be used regardless of the assessedrisk grade.
The postoperative pain management protocol utilized inGroup S was based on a number of historically importantstudies and guidelines. In 2002, Crews et al. showed that a13

Journal of Anesthesia

Fig. 4  a The NRS at rest on postoperative day 1 at 9:00. The NRS
did not significantly differ between groups (Group S: 2 [0, 0–3.0,8.0]; Group H: 1.0 [0, 0–1.0, 4.0]; P = 0.1947). The NRS was compared between groups using a Wilcoxon rank-sum test and expressed
as a median value (minimum value, bottom quartile to top quartile,
maximum value). b The number of prescriptions for tramadol frompostoperative days 0 to 1. The number of tramadol prescriptions frompostoperative days 0 to 1 were significantly lower in Group S than inGroup H [Group S: 0 (0, 0–1.0, 2.0); Group H: 1.0 (0, 0–2.0, 4.0);
P = 0.0021]. The number of tramadol prescriptions were compared
between the groups using the Wilcoxon rank-sum test and expressed
as a median value (minimum value, bottom quartile to top quartile,
maximum value)

Table 5  Length of
hospitalization after surgery

Group H (n = 34)

Group S (n = 50)

P

4.0 [3.0, 4.0–4.0, 5.0]

4.0 [3.0, 4.0–4.0, 5.0]

0.0552

LOH after surgery (days)

Wilcoxon rank-sum test: significant when P < 0.05
Median value [minimum value, bottom quartile to top quartile, maximum value]
LOH length of hospitalization

multimodal strategy for the management of postoperative
pain should be pursued in a stepwise manner [13], similar
to the ladder of therapy for cancer pain developed by theWorld Health Organization [14]. As a result, the postoperative pain management protocols in our hospital were
designed to incorporate that stepwise model. Further, the
ERAS protocol for pain management after gastrointestinal
surgeries recommends a multimodal analgesia (MMA) regimen, including the administration of opioids, non-opioids,

13

epidural anesthesia, and local anesthesia [15]. The MMA
regimen is based on the routine use of non-opioid analgesia(i.e., NSAIDs, COX-2 inhibitors, and acetaminophen) andis indicated in patients undergoing open and laparoscopic
abdominal procedures. This regimen is designed to reducethe consumption of opioids and their dose-dependent side
effects, which are known to delay recovery. As our study analyzed patients who underwent an LGS for benign diseases, acombination of treatment with non-opioid medications andJournal of Anesthesia

local anesthetic wound infiltration was selected for postoperative pain management. In this study, we evaluated the
NRS on a postoperative day 1 at 9:00 to assess the effects ofacetaminophen at minimum blood and cerebrospinal fluid(CSF) concentrations, as every patient received SIVA at thesame timepoints (4:00, 10:00, 16:00, 22:00) in our hospital. We believe that the reason the NRS and the number ofdoses of rescue medicines (i.e., tramadol) administered during the first 24 h after surgery were lower in Group S than inGroup H was that CSF concentration of acetaminophen wasmaintained by SIVA. Neil et al. demonstrated that earlier
and greater CSF penetration occurs as a result of the earlier
and higher plasma peak levels achieved with IV acetaminophen administration than with oral or rectal administration[16]. Other studies have confirmed that IV acetaminophen
reaches a higher and faster peak plasma concentration thanoral administration [17]. SIVA has repeatedly been shown
to be a safe and efficacious analgesic in major orthopedic
surgeries [18, 19]. Similarly, it has been found to be efficacious for gastrointestinal and gynecological surgeries [20,21]. Even if the number of rescue medicines administeredduring the first 24 h after surgery was significantly lower inGroup S, the NRS score did not significantly differ between
Groups H and S. We speculate that no significant differenceswere identified due to LGS being a less invasive procedure
with lower associated pain levels.
Santoso et al. demonstrated that multimodal pain control
is associated with a significant reduction in LOH following
open abdominal hysterectomy [22]. Similarly, Shaffer et al.
demonstrated that pairing SIVA with opioid use for postoperative pain management could potentially decrease LOH,
opioid-related complication rates, and hospital expenses[23]. The updated ERAS Society guidelines for gynecologic/
oncology surgery also support this point of view [3]. Our
results show, however, that LOH following surgery did not
differ between Group H and Group S patients. This discrepancy may result from a unique feature of the Japanese medical system, i.e., the Diagnosis Procedure Combination/PerDiem Payment System (DPC/PDPS). In Japan, the amountof a medical fee is the sum of a comprehensive evaluation
and a high evaluation component, which is predeterminedfor each DPC. Therefore, LOH is not an accurate index for
medical economic burdens. As the LOH of LGS is initiallyshorter, a significant difference may have been difficult to
identify, even with the use of a weak opioid versus a stronger
one.
This study had several limitations. First, because of thesmall sample size in the control group, the total quantity oftramadol used was significantly higher; therefore, it might
have seemed to contribute to PONV and bias the result.
However, we do not consider it excessive, as the amountof intravenous tramadol was administered in up to threedoses (100 mg per time) per day. We evaluated the generating frequency of PONV that occurs in the range of theusual amount used and concluded that the study involved
limited bias.
Second, because the evaluation of PONV was carriedout by different nurses, it is possible that the assessments
were inconsistent. Further, as evaluation of PONV cannot
be carried out quantitatively, there is a limit to its utility,
especially in a retrospective study. In contrast, we could
have quantitatively evaluated the number of additionalantiemetics used and thereby assessed for PONV and theeffect of SIVA appropriately. Third, we used only one
evaluation time-point for the NRS instead of an averageof scores at several times, which would have been ideal.
Furthermore, the NRS was evaluated only during rest,
when ideally; it should have been evaluated also while thepatients were mobile. However, as the NRS was directly
evaluated by the same anesthesiologist, the accuracy of its
evaluation was considered high.

Conclusion
Introduction of SIVA into the postoperative pain management protocol of LGS reduced the incidences of PONV,
and the number of prescriptions for adjunctive antiemetics
from postoperative days 0 to 1. The incidence of PONV
in patients who were considered to have a low risk of
PONV was significantly lower in Group S than in Group
H. Furthermore, postoperative SIVA reduced the numberof times rescue analgesic medications were required. The
NRS at rest on postoperative day 1 at 9:00 and the LOH
did not differ between the groups. In patients undergoing
LGS, PONV prophylaxis using antiemetic medications
should be prescribed according to the PONV risk assessment; however, PONV prophylaxis using SIVA can beused regardless of an individual’s risk assessment. Our
results suggest that SIVA can be introduced into the management protocols of multiple procedures in Japan.
Acknowledgements All authors contributed equally to the study
design, data collection, data interpretation, figure creation, and writingof the manuscript. We would like to thank Editage (https​://www.edita​
ge.jp) for English language editing and Biostatistical Research Corporation (https​://www.biost​ar.co.jp/) for assistance with the research
protocol and statistical analyses.
Author contribution TS and TU contributed to the study conception
and the designing and drafting of the manuscript. MN and TK contributed to acquisition and interpretation of the data. TY was responsible
for the revision of important intellectual content and final approval ofthe version to be published. All authors read and approved the final
manuscript.

13

Journal of Anesthesia

Compliance with ethical standards
Conflict of interest The authors report no conflicts of interest in thiswork.

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