303

ORIGINAL
Postoperative nausea and vomiting following lower limb surgery :a comparison between single-injection intraarticularanesthesia and continuous epidural anesthesia
Yuta Uemura1, Yoko Sakai1, Yasuo M. Tsutsumi2, Nami Kakuta1, Chiaki Murakami1, Shiho Satomi1, Takuro Oyama1,
Naohiro Ohshita3, Tomoya Takasago4, Daisuke Hamada4, Koichi Sairyo4, and Katsuya Tanaka1
1
Department of Anesthesiology, Tokushima University, Tokushima JAPAN, 2Department of Anesthesiology and Critical Care, Graduate Schoolof Biomedical and Health Sciences, Hiroshima University, Hiroshima JAPAN, 3Department of Anesthesiology, Osaka Dental University,
Osaka JAPAN, 4Department of Orthopedics, Institute of Biomedical Sciences, University of Tokushima Graduate School, Tokushima, JAPAN

Abstract : Study Objective : the incidence of postoperative nausea and vomiting (PONV) following single-injection intraarticular anesthesia was compared to that following continuous epidural anesthesia. Design : Prospective, double-blind, randomized study. Setting : University-affiliated teaching hospital. Patients : Forty-eightpatients finally participated in this study, and each group contained twenty-four patients. Interventions : Patients scheduled to undergo lower limb surgery under general anesthesia were randomly allocated into twogroups, to receive either single-injection intraarticular or continuous epidural anesthesia for postoperative
analgesia. Measurements : The incidence and severity of PONV, complete response rates (i.e., no vomiting or
rescue antiemetic use), and pain scores were recorded 2, 24, and 48 h postoperatively. Main results : No significant differences between groups were observed in the incidence and severity of PONV, rescue antiemetic use, orcomplete response rate at any of the time points, but only the use of rescue analgesics was significantly less incontinuous epidural anesthesia group during the 2-24h postoperative period (P=0.04). Conclusion : While the useof single-injection intraarticular anesthesia following lower limb surgery did not prevent PONV more than continuous epidural anesthesia in this study, the intraarticular technique still provides greater simplicity, safety,
and cost-effectiveness. J. Med. Invest. 66 : 303-307, August, 2019
Keywords : PONV, intraarticular injections, epidural anesthesia

INTRODUCTION
Postoperative nausea and vomiting (PONV) is a distressing
complication that can adversely affect patient recovery ; it frequently delays patient discharge from the post-anesthesia careunit and is the leading cause of unexpected hospital admission
following planned ambulatory surgery (1). PONV is consideredby many patients to be more distressing than postoperative pain(2). The general incidence of PONV is approximately 50% andin a subset of high-risk patients, PONV rates can be as high as
70% (3, 4, 5, 6). The four main risk factors of PONV include thefemale sex, a history of PONV or motion sickness, being a nonsmoker, and the use of postoperative opioids (7).
Immediate postoperative pain following lower limb surgery
can be severe and sometimes difficult to manage. Postoperative
pain relief can be achieved using a variety of techniques, suchas intravenous analgesia, epidural analgesia, peripheral nerve
blocks, and local anesthetic infiltration. Effective treatment of
postoperative pain and controlling side effects are important
to enable early rehabilitation and hospital discharge following
lower limb surgery (8). Continuous epidural analgesia has beenshown to provide better pain relief than systemic opioid administration, but is associated with significant side effects, including
nausea, urinary retention, hypotension, and delayed mobilization.
Received for publication February 26, 2019 ; accepted June 27, 2019.
Uemura and Sakai contributed equally to this work.
Address correspondence and reprint requests to Nami Kakuta, MD,
PhD, Department of Anesthesiology, Tokushima University, 3-18-15,
Kuramoto, Tokushima 770-8503, JAPAN and Fax : +81-88-633-7182.

Furthermore, use of epidural analgesia may delay initiation of
anticoagulant thromboprophylaxis due to the potential risk of
epidural hematoma (8, 9). Local infiltration of analgesics combined with a single-injection or continuous infusion of local anesthetics at the surgical site has been reported as an alternative
method for achieving effective postoperative pain relief (10, 11).
Additionally, various combinations of drugs and local infiltration
techniques (i.e., drug mixture, and the use of a wound catheter)
have been evaluated (11,12,13). Among them, use of the intraarticular analgesic method has been shown to potentially reduce
the occurrence of side effects while maintaining adequate pain
relief and maximum muscle control. However, these studies
have provided conflicting results owing to their differing study
designs (14, 15, 16,17,18).
Since intraarticular anesthesia is administered by the surgeon intraoperatively and acts locally, we predicted that therate of complications following intraarticular anesthesia may beless than that of other methods. Therefore, the purpose of thisstudy was to compare the incidence of PONV following the useof intraarticular local anesthesia to that following continuous
epidural anesthesia, after lower limb surgery.

PATIENTS AND METHODS
The current prospective study was approved by the Human
Research Ethics Committee of Tokushima University Hospitaland registered in the clinical trials database (UMIN000019978).
Informed consent was obtained from all patients, and the study
was conducted in accordance with the principles outlined in the
Declaration of Helsinki.

The Journal of Medical Investigation Vol. 66 2019

304

Y. Uemura, et al. PONV after intraarticular anesthesia

Patients aged 30–85 years, with an American Society of Anesthesiologists (ASA) physical status of Ⅰ–Ⅲ, that were scheduled
to undergo lower limb surgery (total knee arthroplasty, total hip
arthroplasty, or rotational acetabular osteotomy) under generalanesthesia were enrolled in this prospective study between November 2015 and July 2016. The patients’ information, including
their sex, history of PONV and/or motion sickness, and smoking
status, was recorded. The exclusion criteria were as follows : an
ASA physical status of Ⅳ, abnormal liver and/or renal function,or use of antiemetics.
No preanesthetic medication was administered. All patientswere monitored using electrocardiography, noninvasive arterial
blood pressure, pulse oximetry, and capnography. General anesthesia was induced with remifentanil, propofol, and rocuronium
to facilitate endotracheal intubation, and was maintained using
volatile anesthetics (sevoflurane 1–2% and desflurane 4–6%)
in oxygen, with a mixture of remifentanil 0.1–0.5 μg/kg/min
and fentanyl 0–100 μg. Incremental doses of rocuronium wereadministered, as necessary, for neuromuscular blockade, theeffects of which were reversed using sugammadex 2 mg/kg uponsurgery completion.
Prior to undergoing surgery, the patients were randomly allocated into one of two groups according to which postoperative
analgesia method they were to receive : single-injection intraarticular anesthesia or continuous epidural anesthesia. The patients that received intraarticular anesthesia (i.e., Group I) wereadministered ropivacaine 200 mg and dexamethasone 6.6 mg,
mixed with sterile normal saline to comprise a combined volumeof 40 mL. Patients that were to receive continuous epidural anesthesia (i.e., Group E) underwent epidural catheter placement
at either L2–3 or L3–4, followed by epidural administration offentanyl 0.1 μg/kg/ml, total 10ug/kg and local anesthetic (0.125%
levobupivacaine, 2–4 ml/h) ; this was maintained for > 48 h. A
rescue analgesic (dicrofenac sodium 25mg sup. or loxoprofen sodium 60mg p.o.) was administered upon patient request for bothgroups. Intravenous metoclopramide (10 mg) was administeredas a rescue antiemetic when necessary.

The incidence and severity of PONV, complete response rate,
and the patients’ pain scores (using a visual analog scale [VAS])
were recorded 2, 24, and 48 h after surgery by blinded observers.
The severity of nausea was recorded using the following scale : 0,absence of nausea ; 1, mild nausea ; 2, moderate nausea ; or 3,
severe nausea. The complete response rate was defined as no occurrence of vomiting and no rescue antiemetic use. The patients’
analgesic demands were also recorded.

Statistical analysis
Statistical analyses were performed using SPSS software,version 22 (SPSS Inc., Chicago, IL, USA). The data are expressed as the mean ± standard deviation (SD). P values < 0.05
were considered statistically significant without any adjustment
for multiplicity of testing.
The t-test, χ2 test, and Fisher’s exact test were used to analyze the patient demographics, cumulative incidence of vomitingat each time point, rescue antiemetic use, complete response
rate, and VAS pain scores. The Mann-Whitney U test was used
to analyze the nausea severity scores.

RESULTSOf 53 patients considered eligible for the study, 3 refused and50 agreed to participate. One patient was excluded due to the operation being called off and one patient was excluded to occlusionof the epidural catheter (Figure 1). Twenty-four patients received
intraarticular anesthesia (Group I), and 24 received continuous
epidural anesthesia (Group E). The demographic data weresimilar for both groups with respect to age, sex, weight, ASA
physical status, smoking status, and history of motion sickness
and PONV. Similarly, there were no differences in the durationsof anesthesia or surgery, or the amount of blood loss (Table 1).
There were no significant differences observed in the incidence of PONV, nausea severity scores, rescue antiemetic use, orcomplete response rate between the two groups at any time point

Figure 1. CONSORT flow chart showing the selection process for patients.

305

The Journal of Medical Investigation Vol. 66 August 2019
(Table 2). The VAS pain scores were also not significantly different between the groups ; however, the use of rescue analgesics
was significantly less in Group E during the 2–24-h postoperative period (Table 3).
Table 1. Patient demographic and perioperative data
Group I(n = 24)

Group E(n = 24)

67.1 ± 9.6

60.5 ± 13.9

8:16

7:17

Patients
Age (years)
Sex (Male : Female)
Height (cm)154.0 ± 7.1

157.6 ± 7.2

Weight (kg)58.6 ± 11.0

60.7 ± 13.3

3/19/2

7/16/1

Smoker1

1

History of motion sickness

2

3

History of PONV

3

4

Duration of anesthesia (min)248.5 ± 57.8

256.3 ± 49.8

Duration of surgery (min)180.1 ± 59.4

189 ± 66.0

Blood loss (ml)429.5 ± 393.6

487.0 ± 442.8

Type of surgery (Hip : Knee)

18 : 6

22 : 2

Total hip arthroplasty

17

20

Rotational acetabular osteotomy

1

2

Total knee arthroplasty

6

2

ASA physical status (I/II/III)
Risk factors

Table 3. Postoperative pain data
Group I(n = 24)

Group E(n = 24)

Rescue analgesic use (%)

9 (38%)

10 (42%)

VAS pain score

4.4 ± 3.5

4.5 ± 4.1

P = 0.91

Rescue analgesic use (%)

13 (54%)6 (25%)

P = 0.04#

VAS pain score

2.3 ± 2.0

2.3 ± 2.7

P-value

0–2-h Postoperative period
P = 0.5

2–24-h Postoperative period
P = 0.9

24–48-h Postoperative period
Rescue analgesic use (%)

9 (38%)

7 (29%)

VAS pain score

1.4 ± 1.9

2.5 ± 2.6

P = 0.38

P = 0.10

Data are presented as the number of patients (percentile) or themean ± standard deviation.
Group I, intraarticular anesthesia group ; Group E, continuous epidural anesthesia group ; VAS, visual analog scale (0, no pain ; to 10,
the worst pain imaginable).

Surgery-/anesthesia-related parameters

Data are presented as the mean ± standard deviation, or number(n).
Group I, intraarticular anesthesia group ; Group E, continuous
epidural anesthesia group ; ASA, American Society of Anesthesiologists ; PONV, postoperative nausea and vomiting.

Table 2. Postoperative parameters
Group I(n = 24)

Group E(n = 24)

P-value
P = 0.36

0–2-h Postoperative period
PONV

5

6

Vomiting (no. of episodes)

48

Nausea scores (0/1/2/3)

19/1/0/4

18/0/1/5

Rescue antiemetic use

42Complete response (%)

20 (83%)19 (79%)P = 0.5

P = 0.12

P = 0.37
P = 0.71

P = 0.33

2–24-h Postoperative period
PONV

2

6

Vomiting (no. of episodes)

04

Nausea scores (0/1/2/3)

22/0/1/1

18/1/3/2

Rescue antiemetic use

12

Complete response (%)

23 (96%)21 (88%)

PONV

1

4

Vomiting (no. of episodes)

02

Nausea scores (0/1/2/3)

23/0/1/0

20/2/0/2

Rescue antiemetic use

11

Complete response (%)

23 (96%)22 (92%)

P = 0.10
P = 0.14
P = 0.5

P = 0.3

24–48-h Postoperative period
P = 0.17

P = 0.16

P = 0.16
P = 0.76
P = 0.5

Data are presented as the number of patients (percentile), unlessotherwise stated.
Group I, intraarticular anesthesia group ; Group E, continuous epidural anesthesia group ; PONV, postoperative nausea and vomiting.
Nausea scores : 0, absence of nausea ; 1, mild nausea ; 2, moderatenausea ; or 3, severe nausea.

DISCUSSION
In this study, we compared the intraarticular injection technique with continuous epidural infusion for postoperative analgesia, and found no significant differences in the incidence orseverity of PONV, complete response rate, or the use of rescue
antiemetics between the two methods. The benefits of intraarticular analgesia have been evaluated previously, primarily withpatients having underwent knee surgery ; a systematic review ofprevious studies demonstrated evidence of reduced pain during
the immediate and early postoperative periods following intraarticular local anesthesia after knee surgery (15, 18). However,some studies have demonstrated the effectiveness of intraarticular analgesia following hip surgery (11,12). In the current study,
we included patients undergoing knee or hip surgery, and foundthat intraarticular analgesia was effective for pain management
following both types of surgery.
We noted that there was a significant difference between thetwo study groups regarding the use of rescue analgesics during
the 2–24-h postoperative period. Since single-injection intraarticular analgesia only remains effective short period (19,20), it
is reasonable that patients in Group I required rescue analgesia
more often than those in Group E. However surgical site, kneeor hip, and the invasiveness, i.e. total knee arthroplasty > total
hip arthroplasty, may influence on the results for the use of
rescue analgesics. Although, there was no statistically significant difference, Group I tended to have more knee surgery thanGroup E. Use of continuous wound catheters may reduce theneed for rescue analgesics ; however, we chose not to utilize themin the present study owing to concerns regarding the possible
increased risks of infection and delayed wound healing (8, 21).
Previous studies investigating the efficacy of local infiltration
analgesia after knee surgery did not demonstrate an increased
frequency of infections, but the follow-up periods in these studies
were very limited (10, 22, 23). Therefore, it should be further investigated whether combining intraarticular injections and continuous infusion of local anesthesia to surgical sites can provide
more effective pain control than traditional methods.
Ropivacaine is a relatively new, long-acting, aminoamide local
anesthetic agent (24) that is chemically homologous to bupivacaine and mepivacaine (25). It demonstrates similar clinical efficacy to racemic bupivacaine, but is less cardio- and neurotoxic,
and induces less vasodilation. The peak plasma concentrationof ropivacaine following intraarticular administration has been306

Y. Uemura, et al. PONV after intraarticular anesthesia

shown to be proportional to the dose administered, and remains
below the recognized toxicity level after administration of 200
mg (19,20). Therefore, we chose to administer 200 mg of ropivacaine for intraarticular anesthesia in our study.
A few previous studies have quantified the incidence of PONV
after intraarticular analgesia ; Lykoudi et al. (26) found no significant difference between ropivacaine and a placebo, and Rautoma et al. (27) reported that the incidence PONV for patients thatreceived ropivacaine was lower than that of those who received
a placebo. However, intraarticular ropivacaine and morphine
administration has been associated with a higher incidence of
PONV (16), but these study participants were only observed for ashort period (24-h). In the present study, we did not observe any
significant reduction in PONV during the 48-h postoperative
period.
This study had several limitations. First, we did not define thedose of fentanyl for continuous epidural anesthesia, which may
have affected the study’s results. Second, dexamethasone wasused as an adjuvant drug in the intraarticular analgesia group.
Dexamethasone is a potent and highly selective glucocorticoidwith minimal mineralocorticoid effects. It inhibits nociceptive
impulse transmission along myelinated C-fibers, and whencombined with local anesthetics, it increases the duration of regional blocks (28, 29). Intraarticular ropivacaine has only beenshown to be effective when it is administered with other drugs,
not when used alone (15) ; therefore, dexamethasone was usedin this study to increase analgesic efficacy. The corticosteroid
dexamethasone effectively prevents nausea and vomiting inpostoperative patients. However, in this study, it may have acted
locally via steroid receptors, it could not have acted systemically ; therefore, it could not prevent PONV. Finally, antiemetic use
was restricted to only metoclopramide in this study ; however,use of other antiemetics may have reduced PONV.
In conclusion, the use of single-injection intraarticular anesthesia following lower limb surgery did not prevent PONV morethan continuous epidural anesthesia in this study. However, thegreater simplicity, safety, and cost effectiveness of the intraarticular technique is apparent. Therefore, further studies areneeded to further decrease the incidence of PONV.

CONFLICTS OF INTEREST
Each author declares that they have no conflicts of interest
associated with this study or manuscript.

ACKNOWLEDGEMENTS
This study was supported entirely by JSPS KAKENHI (Grant
Number 18K16483).

REFERENCES
1.

2.

3.

Parra-Sanchez I, Abdallah R, You J, Fu AZ, Grady M,
Cummings K 3rd, Apfel C, Sessler DI : A-time motion economic analysis of postoperative nausea and vomiting inambulatory surgery. Can J Anaesth 59 : 366-375, 2012
Macario A, Weinger M, Carney S, Kim A : Which clinicalanesthesia outcomes are important to avoid? The perspective of patients. Anesth Analg 89 : 652-658, 1999
Kakuta N, Tsutsumi YM, Horikawa YT, Kawano H,
Kinoshita M, Tanaka K, Oshita S : Neurokinin-1 receptor
antagonism, aprepitant, effectively post-operative nausea and vomiting while increasing analgesic tolerance

in laparoscopic gynecological procedures. J Med Invest
58 : 246-251, 2011.
4. Tsutsumi YM, Kakuta N, Soga T, Kume K, Hamaguchi E,
Tsutsumi R, Tanaka K : The effects of intravenous fosaprepitant and ondansetron for the prevention of postoperative
nausea and vomiting in neurosurgery patients : a prospective, randomized, double-blinded study. Biomed Res Int
2014 : 307025(1-6), 2014.
5. Soga T, Kume K, Kakuta N, Hamaguchi E, Tsutsumi R,
Kawanishi R, Fukuta K, Tanaka K, Tsutsumi YM : Fosaprepitant versus ondansetron for the prevention of postoperative nausea and vomiting in patients who undergo
gynecologic abdominal surgery with patient-controlled
epidural analgesia : a prospective, randomized, double-blind
study. J Anesth 29 : 696-701, 2015.
6. Kakuta N, Kume K, Hamaguchi E, Tsutsumi R, Mita N,
Tanaka K, Tsutsumi YM : The effects of intravenous fosaprepitant and ondansetron for the prevention of postoperative
nausea and vomiting in patients who undergo lower limb
surgery. –A prospective, randomized, double-blind study– J
Anesth 29 : 836-841, 2015.
7. Apfel CC, Läärä E, Koivuranta M, Greim CA, Roewer N : A
simplified risk score for predicting postoperative nausea
and vomiting : conclusions from cross-validations between
two centers. Anesthesiology 91 : 693-700, 1999
8. Anderson KV, Bak M, Christensen BV, Harazuk J, Pedersen
NA, Soballe K : A randomized, controlled trial comparing
local infiltration analgesia with epidural infusion for total
knee arthroplasty. Acta Orthop 81 : 606-610, 2010
9. Choi PT, Bhandari M, Scott J, Douketis J : Epidural anesthesia for pain relief following hip or knee replacement.
Cochrane Database Syst Rev : CD003071, 2003
10. Vendittoli PA, Makinen P, Drolet P, Lavigne M, Fallaha M,
Guertin MC, Varin F : A multimodal analgesia protocol for
total knee arthroplasty. A randomized, controlled study. J
Bone Joint Surg Am 88 : 282-289, 2006
11. Anderson LØ, Kehlet H : Analgesic efficacy of local infiltration analgesia in hip and knee arthroplasty : a systematic
review. Br J Anaesth 113 : 360-374, 2014
12. Anderson KV, Pfeiffer-Jensen M, Haraldstad V, Søballe
K : Reduced hospital stay and narcotic consumption, andimproved mobilization with local and intraarticular infiltration after hip arthroplasty : a randomized clinical trial of
an intraarticular technique versus epidural infusion in 80
patients. Acta Orthop 78 : 180-186, 2007
13. Kerr DR, Kohan L : Local infiltration analgesia : a technique for the control of acute postoperative pain following
knee and hip surgery : a case study of 325 patients. Acta
Orthop 79 : 174-182, 2008
14. Browne C, Copp S, Reden L, Pulido P, Colwell C Jr : Bupivacaine bolus injection versus placebo for pain management
following total knee arthroplasty. J Arthroplasty 19 : 377380, 2004
15. Rosen AS, Colwell CW, Pulido PA, Chaffee TL, Copp SN : A
randomized controlled trial of intraarticular ropivacaine forpain management immediately following total knee arthroplasty. HSS J 6 : 155-159, 2010
16. Tanaka N, Sakahashi H, Sato E, Hirose K, Ishii S : The
efficacy of intra-articular analgesia after total knee arthroplasty in patients with rheumatoid arthritis and in patientswith osteoarthritis. J Arthroplasty 16 : 306-311, 2001
17. Zhou Y, Yang TB, Wei J, Zeng C, Li H, Yang T, Lei GH : Single-dose intra-articular ropivacaine after arthroscopic knee
surgery decreases post-operative pain without increasingside effects : a systematic review and meta-analysis. Knee
Surg Sports Traumatol Arthrosc 24 : 1651-1659, 2016

The Journal of Medical Investigation Vol. 66 August 201918. Møiniche S, Mikkelesen S, Wetterslev J, Dahl JB : A systematic review of intra-articular local anesthesia for postoperative pain relief after arthroscopic knee surgery. Reg
Anesth Pain Med 24 : 430-437, 1999
19. Convery PN, Milligan KR, Quinn P, Sjövall J, Gustafsson
U : Efficacy and uptake of ropivacaine and bupivacaine
after single intra-articular injection in the knee joint. Br J
Anaesth 87 : 570-576, 2001
20. Chen S,Chen Z, Jin Y, Tian Z, Lin X, Zhu M, Xu S, Lin J, Xu
J : Pharmacokinetics and efficacy of ropivacaine in Chinesepatients following intra-articular administration. Int J Clin
Pharmacol Ther 51 : 393-400, 2013
21. Liu SS, Richman JM, Thirlby RC, Wu CL : Efficacy ofcontinuous wound catheters delivering local anesthetic for
postoperative analgesia : A quantitative and qualitative
systematic review of randomized controlled trials. J Am
Coll Surg 203 : 914-932, 2006
22. Bianconi M, Ferrano L, Traina GC, Zanoli G, Antonelli T,
Guberti A, Ricci R, Massari L : Pharmacokinetics and efficacy of ropivacaine continuous wound instillation after joint
replacement surgery. Br J Anaesth 91 : 830-835, 2003
23. Dobrydnjov I, Anderberg C, Olsson C, Shapurova O, AngelK, Bergman S : Intraarticular vs.extraarticular ropivacaine

307

infusion following high-dose local infiltration analgesia after
total knee arthroplasty. Acta Orthop 82 : 692-698,2011
24. McClure JH : Ropivacaine. Br J Anaesth 76 : 300-307, 1996
25. Knudsen K, Beckman Suurküla M, Blomberg S, Sjövall J,
Edvardsson N : Central nervous and cardiovascular effectsof i.v. infusions of ropivacaine, bupivacaine and placebo involunteers. Br J Anaesth 78 : 507-514, 1997
26. Lykoudi I, Kottis G, Nikolaou VS, Setaki P, Fassoulaki
A, Efstathopoulos N : Intra-articular morphine enhances
analgesic efficacy of ropivacaine for knee arthroscopy inambulatory patients. Orthopedics 34 : 91, 2011
27. Rautoma P, Santanen U, Avela R, Luurila H, Perhoniemi V,
Erkola O : Diclofenac premedication but not intra-articularropivacaine alleviates pain following day-case knee arthroplasty. Can J Anaesth 47 : 220-224, 2000
28. Bhattacharjee DP, Biswas C, Haldar P, Ghosh S, Piplai G,
Rudra JS : Efficacy of intraarticular dexamethasone forpostoperative analgesia after arthroscopic knee surgery. J
Anaesthesiol Clin Pharmacol 30 : 387-390, 2014
29. Johansson A, Hao J, Sjölund B : Local corticosteroid application blocks transmission in normal nociceptive C-fibers.
Acta Anaesthesiol Scand 34 : 335-338, 1990