Eur Surg Res 2014;53:43–60 DOI: 10.1159/000363233 Received: December 17, 2013 Accepted: April 28, 2014 Published online: July 23, 2014

© 2014 S. Karger AG, Basel 0014–312X/14/0534–0043$39.50/0 www.karger.com/esr

Original Paper

Ropivacaine for Continuous Wound Infusion for Postoperative Pain Management: A Systematic Review and Meta-Analysis of Randomized Controlled Trials Shane Raines a Glen Kelleher d

Cecilia Hedlund b Kjell Ahlén c

Malin Franzon b

Stefan Lillieborg b

a Department of Biometrics and Information Science, AstraZeneca R&D, Wilmington, Del., USA; Departments of b Biometrics and Information Science and c Medical Science, AstraZeneca R&D, Södertälje, Sweden; d Medical Department, AstraZeneca, North Ryde, N.S.W., Australia

Key Words Continuous wound infusion · Postoperative analgesia · Ropivacaine · Systematic review Abstract Background: The use of continuous wound infusion (CWI) of local anaesthetics has been suggested as a safe and effective alternative technique to epidural anaesthesia/analgesia that allows surgeons to provide postoperative pain relief while reducing opioid consumption and associated adverse events. A previous meta-analysis by Liu et al. [Am Coll Surg 2006; 203: 914–932] reported results mainly from studies of bupivacaine. Subsequently, several new randomized controlled trials (RCTs) of ropivacaine have been published. This systematic review and quantitative meta-analysis evaluates the efficacy of ropivacaine for CWI. Methods: Systematic literature searches (EMBASE, MEDLINE) were performed to retrieve studies which met the following criteria: double-blind RCT of ropivacaine versus either placebo or an active comparator; use of ropivacaine solution without added active agents, and prohibition of other routine analgesics during the study period except rescue patient-controlled analgesia. For each included study, standardized effect sizes for ropivacaine versus placebo were calculated for opioid rescue use, pain score at rest, and pain score at mobilization. Meta-analyses were conducted for each endpoint. Results: Fourteen RCTs comparing ropivacaine (n = 376) versus placebo (n = 380) were identified. Effect size estimates revealed significantly less opioid rescue use for ropivacaine patients (–1.3; 95% CI –1.5 to –1.1) and significantly less pain for ropivacaine patients both at rest (–1.1; 95% CI –1.3 to –0.9) and on mobilization (–1.5; 95% CI –1.7 Shane Raines Department of Biometrics and Information Science Room C4B-104, PO Box 15437 Wilmington, DE 19850-5437 (USA) E-Mail Shane.Raines @ AstraZeneca.com

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Eur Surg Res 2014;53:43–60 DOI: 10.1159/000363233

© 2014 S. Karger AG, Basel www.karger.com/esr

Raines et al.: Ropivacaine for Continuous Wound Infusion for Postoperative Pain Management: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

to –1.3). The weighted mean reduction in opioid rescue use was 22.4 mg. Conclusion: This systematic review and meta-analysis presents substantial evidence that ropivacaine provides clinically meaningful reductions in opioid use and pain outcomes. Ropivacaine CWI is effective for postoperative pain management in a wide range of surgical procedures. © 2014 S. Karger AG, Basel

Introduction

In recent years, alternative postoperative analgesic techniques have been increasingly used, whereby a continuous or intermittent infusion of local anaesthetic solution is directed into the surgical wound via a catheter. These techniques, hereafter referred to as continuous wound infusion (CWI) and intermittent wound infusion (IWI), are utilized for a variety of surgical procedures, including cardiothoracic, general, gynaecological-urological, and orthopaedic surgeries. The CWI technique provides several significant benefits over other currently practised postoperative pain control techniques such as intravenous opioids and continuous nerve blocks. Advantages of the wound infusion technique are that the infusion affects only the surgical area and eliminates the risk of vascular, pleural, or neural placement of needles, thereby allowing its use in patients where an epidural technique cannot safely be used (e.g., due to coagulopathy, use of thrombolytics, or anatomic anomalies). While the use of continuous peripheral nerve block techniques has been suggested as a safe and effective alternative to epidural anaesthesia/analgesia, wound infusion provides another option for anaesthetists and surgeons who prefer to provide effective postoperative pain relief by means of a less complicated technique. Liu et al. [1] performed a systematic review of wound infusion studies which included a total of 2,407 patients from 51 randomized controlled trials (RCTs) in a qualitative analysis and a total of 2,141 patients from 44 RCTs in a quantitative analysis. The results of the quantitative analysis showed that postoperative wound infusion with a long-acting local anaesthetic via catheters improved analgesia and reduced opioid use, increased patient satisfaction, and in some cases reduced the length of hospital stay. As 34 of the 44 studies included in the quantitative analysis of Liu et al. [1] reported results of bupivacaine CWI, the current review aims to expand on those results by conducting a similar systematic review and metaanalysis including only results from wound infusion studies of ropivacaine. Methods Information Sources EMBASE was initially searched for studies evaluating ropivacaine in CWI and IWI for the period 1980 up to 28 February 2011. The search strategy combined ‘postoperative analgesia’, ‘analgesic activity’, ‘analgesia’ or ‘postoperative pain’ and ‘ropivacaine’. A second search combined ‘catheter’, ‘continuous infusion’, ‘infusion pump’, ‘drug instillation’ or ‘surgical wound’. These two searches were then combined (and) and refined by excluding (not) ‘epidural anesthesia’ or ‘epidural drug administration’. Thereafter, an Ovid Medline search was constructed on the basis of the EMBASE search, restricted to the time period 1997 to 28 February 2011 because the EMBASE search revealed no clinical trials earlier than 1998. The MEDLINE search was limited to human data and firstly combined ‘infusion pumps’, ‘pain’, ‘instillation, drug’, ‘pain, postoperative’, or ‘catheterization’ and ‘ropivacaine’. From this search result, an exclusion (not) was made of the combined terms ‘anesthesia, epidural’, ‘nerve block’ or ‘anesthesia, spinal’. The two searches identified a total of 736 potential publications (with partial overlap) for systematic review. The search results were reviewed for the specific inclusion and exclusion criteria by a scientist (G.K.). Potentially relevant clinical trials were scrutinized for the appropriate drug administration technique/

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Eur Surg Res 2014;53:43–60 DOI: 10.1159/000363233

© 2014 S. Karger AG, Basel www.karger.com/esr

Raines et al.: Ropivacaine for Continuous Wound Infusion for Postoperative Pain Management: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

wound catheter placement and study design by a board-certified anaesthesiologist (K.A.). As a further test of the comprehensiveness of the search, the list of references at the end of each RCT selected was reviewed. Searches were also conducted to find relevant unpublished data using the Google internet search engine and the US National Institute of Health ClinTrials.gov website. Study Selection Studies of postoperative analgesia were selected, without predefined criteria on the extent of surgery or specific types of surgical procedures. Inclusion criteria required that studies be double-blind RCTs of ropivacaine CWI or IWI with either placebo (saline) or an active comparator as the control group. Additional inclusion criteria required the use of ropivacaine as a single-agent test solution and the prohibition of other confounding routine analgesics during the study period. The use of rescue analgesia [often patient-controlled analgesia (PCA), usually morphine] was permitted and formed part of the efficacy evaluation. Exclusion criteria were local anaesthetic administration via epidural, spinal, or peripheral nerve block, intravenous, discrete injections by needle (field block), and intra-articular, topical, or infusion not into surgical wound (i.e., subacromial space, intraperitoneal, submuscular, extrapleural, and subtenon). Data Extraction Three efficacy variables were identified as common to the majority of studies: pain score at rest, pain score at mobilization, and opioid rescue use. For each study, pain scores at 24 h (or the time point closest to 24 h for those studies without a 24-hour assessment) were extracted using the various scoring methods reported (i.e., visual analogue scale 0–100 mm, visual analogue scale 0–10 cm, verbal numerical rating scale 0–10). For opioid rescue use, total morphine rescue use at either 48 or 72 h was extracted. For two studies reporting piritramide rescue use, total morphine rescue use was derived by multiplying the piritramide dose by the potency of piritramide relative to morphine (i.e., 0.65) (see table 1 for details of the extracted endpoints by study). For each efficacy variable, the number of patients, mean and standard deviation were extracted by treatment group for each study. In some instances, it was necessary to estimate the mean from the reported median or the standard deviation from the reported confidence interval (CI), standard error of the mean, or interquartile range. All efficacy variables were extracted from each study by one statistician (C.H. or M.F.) with 2 different statisticians checking for accuracy (S.R. and C.H. or M.F.). Safety events extracted from each study were the reported incidences of postoperative nausea and vomiting (PONV; either as one event or as two separate events), incidences of adverse events, and signs of wound infection. PONV results were extracted by the statisticians as described for efficacy variables; adverse events and signs of wound infection were extracted by a scientist (G.K.) and verified by the anaesthesiologist (K.A.). Statistical Analysis Separate meta-analyses were performed for the variables pain score at rest, pain score during mobilization, and opioid rescue use. For each publication, the effect size between ropivacaine and placebo was estimated using Hedges’ gu statistic [2]. This statistic was selected as it provides an unbiased estimate of the effect size [2, 3]. The gu statistic was calculated as the standardized mean difference (i.e., the difference between the experimental and control group means divided by the pooled standard deviation) multiplied by a correction factor (see equation 37 of Hedges and Olkin [2] for the formula). The standard error (se) of Hedges’ gu was calculated as:

se(gu) 

nr nc nr nc



gu2 , 2 nr nc

where nr and nc are the number of patients in the ropivacaine and control groups, respectively. Hedges’ weights were calculated as the reciprocal of the estimated variance (i.e., 1/se2). The overall estimate of the effect size was calculated as the weighted mean of the gu statistics using the Hedges weights. The standard error of this estimate was calculated as the reciprocal of the square root of the sum of the weights [2]. CIs for Hedges’ gu and overall effect size estimates were calculated using the normal approximation (i.e., estimate ± z(0.975) times the standard error). Study specific and overall effect size estimates and CIs were summarized using forest plots. Effect sizes were considered statistically significant if the 95% CI did not include zero. No adjustments were made to account for multiple comparisons. Hedges’

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Eur Surg Res 2014;53:43–60 DOI: 10.1159/000363233

© 2014 S. Karger AG, Basel www.karger.com/esr

Raines et al.: Ropivacaine for Continuous Wound Infusion for Postoperative Pain Management: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Table 1. Efficacy endpoints extracted by study

First author, year

Opioid rescue use

Pain at rest

Pain on mobilization

Bianconi [24], 2003

NA (diclofenac and tramadol used for rescue)

Pain at rest score (VAS 0 – 100) at 24 h

Pain on passive mobilization score (VAS 0 – 100) at 24 h

Dowling [33], 2003

Total morphine equivalent dose during the first 72 h

Mean overall pain score (VAS 0 – 10) from 0 to 72 h

NA

Gottschalk [22], 2003

Total piritramide dose during the first 48 h

Pain at rest score (VAS 0 – 100) at 24 h

Pain on mobilization score (VAS 0–100) at 24 h

Bianconi [25], 2004

NA (diclofenac and tramadol used for rescue)

Pain at rest score (VAS 0 – 100) at 24 h

Pain on passive mobilization score (VAS 0 – 100) at 24 h

Stewart [20], 2004

Total morphine required over entire admission

NA (no variability estimates reported)

NA (no variability estimates reported)

Blumenthal [34], 2005

Total morphine consumption during the first 48 h

Pain at rest score (VAS 0 – 100) at 24 h

Pain on motion score (VAS 0 – 100) at 24 h

Ansaloni [23], 2007

NA (keterolac used for rescue)

Pain at rest score (VAS 0 – 100) at 24 h

Pain on coughing score (VAS 0 – 100) at 24 h

Beaussier [39], 2007

Total morphine consumption during the first 72 h

Pain at rest score (verbal NRS 0 – 10) at 24 h

Pain on coughing score (verbal NRS 0 – 10) at 24 h

Forastiere [21], 2008

Total morphine consumption during the first 48 h

Pain at rest score (VAS 0 – 10) at 24 h

Pain on coughing score (VAS 0 – 10) at 24 h

Dagtekin [35], 2009

Cumulative piritramide consumption during the first 48 h

Pain at rest score (VAS 0 – 100) at 16 h

Pain on coughing score (VAS 0 – 100) at 16 h

Chan [28], 2010

Total morphine consumption during the first 72 h

Pain at rest score (VAS 0 – 100) at 24 h

Pain after spirometry score (VAS 0 – 100) at 24 h

Iyer [26], 2010

NA (no results reported by treatment group)

NA (no variability estimates reported)

NA (no variability estimates reported)

Wang [19], 2010

Total morphine consumption during the first 48 h

Average pain at rest score (NRS 0 – 10) on day 1

Average pain on movement score (NRS 0 – 10) on day 1

Aguirre [17], 2012

Total morphine consumption during the first 48 h

Pain at rest score (VAS 0 – 100) at 24 h

Pain with motion score (VAS 0 – 100) at 24 h

NA = Not available or no opioid equivalent conversion available; VAS = visual analogue scale; NRS = numerical rating scale.

weights were also used to calculate weighted mean differences for each variable. To assess the heterogeneity of results, Cochran’s Q and the I2 statistics were calculated for each efficacy variable. No meta-analyses were performed for the incidence of nausea and vomiting as this information was not presented consistently across studies. To summarize the nausea and vomiting results, extracted data by study were compiled into a tabular display.

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Eur Surg Res 2014;53:43–60 DOI: 10.1159/000363233

© 2014 S. Karger AG, Basel www.karger.com/esr

Raines et al.: Ropivacaine for Continuous Wound Infusion for Postoperative Pain Management: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Potentially relevant articles identified and screened for retrieval (EMBASE n = 386, MEDLINE n = 350) Publications excluded (n = 702) Not CWI or IWI route of drug administration No original clinical trial (review, letters, case reports), duplicates Potentially appropriate studies to be included in the meta-analysis (n = 34) Excluded from meta-analysis (n = 20) Mixture of analgesics (n = 5) Analgesic comedication (n = 4) Non-randomized (n = 1) Uncontrolled (n = 7) Intermittent infusion (n = 3)

RCTs included in meta-analysis (n = 14)

RCTs withdrawn Rescue medication (n = 4) Pain at rest (n = 2) Pain on mobilization (n = 3) (All due to lack of estimates useful for meta-analysis) RCTs with usable information Rescue medication (n = 10) Pain at rest (n = 12) Pain on mobilization (n = 11)

Fig. 1. Study selection for meta-analysis.

Results

Thirty-four clinical trials using the CWI or IWI techniques were identified (see fig. 1 for the study selection diagram). Eight studies were excluded as 7 were uncontrolled and 1 [4] was not randomized. Of the remaining 26 RCTs, 9 were excluded due to the infusion of analgesic mixtures [5–8] or the use of analgesic comedication [9–13]. While 3 RCTs using intermittent infusion technique [14–16] were identified, these 3 studies were considered insufficient in number to justify a separate meta-analysis for the IWI route of administration. The remaining 14 RCTs studied continuous infusion and were included in the systematic review and meta-analysis. Of these 14 RCTs, 5 were published in journals of surgery and 9 in journals of anaesthesiology. For 1 study initially retrieved as an abstract, the complete data were later published and contributed to the systematic review and meta-analysis [17]. Only 1 unpublished study entitled ‘A phase II/III study of continuous local anesthetic infusion in median sternotomy following cardiac surgery’ was identified. The ClinTrials.gov website noted that this study had been suspended due to an ‘increased wound infection rate’. Despite various

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Eur Surg Res 2014;53:43–60 DOI: 10.1159/000363233

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Raines et al.: Ropivacaine for Continuous Wound Infusion for Postoperative Pain Management: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Table 2. Characteristics of included RCTs; wound infusion regimens First author, year

Ropivacaine, n

Con- Procedure trol, n

Bianconi [24], 2003

18

19

Dowling [33], 2003

16

Gottschalk [22], 2003

Wound catheter placement

Ropivacaine concentration (bolus; infusion rate)

Duration of wound infusion, h

Total hip or knee replacement

Between muscle fascia and subcutis

Bolus 40 ml at 5 mg/ml; infusion 2 mg/ml at 5 ml/h

55

19

Coronary artery bypass

2 catheters anterior to sternum

Bolus 20 ml at 2 mg/ml; infusion 2 mg/ml at 4 ml/h

48

12

14

Open shoulder surgery

SC

Bolus 20 + 10 ml at 2 mg/ml, infusion 2 mg/ml at 5 ml/h

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Bianconi [25], 2004

18

19

Spine fusion

Between muscle fascia and subcutis

Bolus 40 ml at 5 mg/ml; infusion 2 mg/ml at 5 ml/h

55

Stewart [20], 2004

23

24

Inguinal hernia repair

On external inguinal ring

No bolus; infusion 7.5 mg/ml at 4 ml/h

24

Blumenthal [34], 2005

18

18

Iliac crest bone graft for shoulder surgery

Over iliac crest harvest site

Bolus 30 ml at 5 mg/ml; infusion 2 mg/ml at 5 ml/h

48

Ansaloni [23], 2007

48

48

Appendectomy

Above parietal peritoneum

Bolus 10 ml at 2 mg/ml; infusion 2 mg/ml at 5 ml/h

48

Beaussier [39], 2007

21

21

Open resection of malignant colorectal tumours

Between parietal peritoneum and transversalis fascia

Bolus 10 ml at 2 mg/mL; infusion 2 mg/ml at 10 ml/h

48

Forastiere [21], 2008

84

84

Open nephrectomy

Two catheters: (1) superior to transverse muscle and below internal and external oblique muscles, (2) SC

Bolus 10 ml at 10 mg/ml; infusion 5 mg/ml at 4 ml/h

48

Dagtekin [35], 2009

8

8

Transverse rectus abdominis musculocutaneous flap reconstruction

Two catheters: (1) SC in abdominal wound in loop over the fascial sheath, (2) loop over m. pectoralis major under the autologous flap extending into the axilla

Bolus 10 ml at 2 mg/ml; infusion 2 mg/ml at 10 ml/h in each catheter (total 20 ml/h)

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Chan [28], 2010

22

22

Open hepatic surgery

Within the musculofascial layer

Bolus 20 ml at 2.5 mg/ml; infusion 2.5 mg/ml at 4 ml/h

68

Iyer [26], 2010

24

21

Bariatric surgery

Subfascial space and SC

Bolus 30 ml at 5 mg/ml; infusion 2 mg/ml at 2 ml/h in each catheter (total 4 ml/h)

72

Wang [19], 2010

28

27

Laparotomy

Two catheters placed at the level of the musculofascial closure

No bolus; infusion 2 mg/ml at 2 ml/h in each catheter (total 4 ml/h)

67.5

Aguirre [17], 2012

36

36

Minimal invasive hip replacement

Epicapsular

Bolus 20 ml at 3 mg/ml; infusion 3 mg/ml at 8 ml/h

48

376

380

Total

Control patients received saline. SC = Subcutaneous.

attempts to obtain information from the study sponsor [18], no additional information was obtained before the meta-analysis was completed. The 14 included RCT’s employed postoperative CWI of ropivacaine or saline into the surgical wound via a catheter in abdominal, cardiothoracic, ilioinguinal, orthopaedic, and general surgery, and major plastic reconstructions (see table 2 for additional characteristics of each included study). Two studies involved the minor procedures of appendectomy and inguinal hernia repair. Apart from the appendectomy study, all surgical procedures were elective. The overall evaluation included a total of 376 patients (20–81 years old) administered continuous infusion of ropivacaine in concentrations from 2 to 7.5 mg/ml. Except for 2 studies [19, 20], an active ropivacaine bolus dose was provided prior to initiation of the ropivacaine infusion. In 1 study [21], this ropivacaine bolus dose was given to both treatment groups prior

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DOI: 10.1159/000363233

Raines et al.: Ropivacaine for Continuous Wound Infusion for Postoperative Pain Management: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Table 3. Pain at rest scores and effect size estimates by study and overall

First author, year

Bianconi [24], 2003 Dowling [33], 2003 Gottschalk [22], 2003 Bianconi [25], 2004 Blumenthal [34], 2005 Ansaloni [23], 2007 Beaussier [39], 2007 Forastiere [21], 2008 Dagtekin [35], 2009 Chan [28], 2010 Wang [19], 2010 Aguirre [17], 2012 Overall

Scale

Ropivacaine

Placebo

mean

SD

VAS 0 – 100

20.0

VAS 0 – 10

Weightb

Pooled SD

Effect size

mean SD

Mean difference

13.15

50.0

40.10

–30.0

30.18

–1.0

–1.7 to –0.3

8.27

1.6

0.84

2.6

1.04

– 1.0

0.95

–1.0

–1.7 to –0.3

7.69

VAS 0 – 100

30.0

1.70

40.0

7.41

–10.0

5.58

–1.7

–2.6 to –0.8

4.70

VAS 0 – 100

23.3

20.36

52.3

35.31

–29.0

29.03

–1.0

–1.7 to –0.3

8.26

VAS 0 – 100

4.0

5.60

7.8

15.50

– 3.8

11.65

–0.3

–1.0 to 0.3

8.89

VAS 0 – 100

15.0

11.00

26.1

22.50

–11.1

17.71

–0.6

–1.0 to –0.2 22.89

Verbal NRS 0 – 10

1.7

1.80

3.4

1.70

– 1.7

1.75

–1.0

–1.6 to –0.3

VAS 0 – 10

0.0

–

1.7

–

– 1.7

0.66

–2.6

–3.0 to –2.2 22.94

VAS 0 – 100 VAS 0 – 100 NRS 0 – 10

10.6 18.4 2.4

12.90 10.80 –

12.9 34.6 3.0

11.90 15.10 –

– 2.3 –16.2 – 0.6

12.41 13.13 2.03

–0.2 –1.2 –0.3

–1.2 to 0.8 3.98 –1.9 to –0.6 9.29 –0.8 to 0.2 13.60

VAS 0 – 100

18.0

6.00

25.0

7.20

– 7.0

6.63

–1.0

–1.5 to –0.6 15.84

–

–

–

–1.1

–1.3 to –0.9

–

–

–

esti95% CI matea

9.43

A negative effect size indicates reduced pain score in ropivacaine-treated patients as compared to placebo-treated patients. NRS = Numerical rating scale; VAS = visual analogue scale. a Estimate calculated as Hedges’ gu statistic. b Weight calculated as the reciprocal of the estimated variance (1/se2) of each Hedges’ gu statistic.

to initiation of the randomized wound infusion [21]. Patients were administered ropivacaine at dose rates of 4–20 ml/h for 24–72 h, corresponding to 24-hour doses of 192–1,000 mg (including bolus). The majority of studies used the 2 mg/ml concentration and a dose rate of 8–20 mg/h for up to 48 h. One study [22] included both 2 and 3.75 mg/ml ropivacaine groups; however, only results from the 2 mg/ml group were extracted as this dose reflects the more commonly used ropivacaine dose for CWI and provided a more conservative estimate of treatment effects. Placebo control groups included a total of 380 patients. Of the 14 studies included, pain at rest and pain on mobilization data were available for 12 studies and 11 studies, respectively, and opioid rescue use data were available for 10 studies (table 1). Three studies contributing to pain analyses did not give opioid rescue use data [23–25], whereas 2 other studies not contributing pain data were analysed for opioid use [12, 20]. One study [26] did not provide sufficient information to contribute to any efficacy analysis. Pain at Rest and on Mobilization Effect size estimates for each study and overall are displayed in tables 3 and 4. The overall effect size estimates reveal significantly less pain for ropivacaine patients both at rest (effect

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Eur Surg Res 2014;53:43–60 © 2014 S. Karger AG, Basel www.karger.com/esr

DOI: 10.1159/000363233

Raines et al.: Ropivacaine for Continuous Wound Infusion for Postoperative Pain Management: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Table 4. Pain during mobilization scores and effect size estimates by study and overall

First author, year

Bianconi [24], 2003 Gottschalk [22], 2003 Bianconi [25], 2004 Blumenthal [34], 2005 Ansaloni [23], 2007 Beaussier [39], 2007 Forastiere [21], 2008 Dagtekin [35], 2009 Chan [28], 2010 Wang [19], 2010 Aguirre [17], 2012 Overall

Scale

Ropivacaine

Placebo

mean

mean

SD

Mean SD

difference

Pooled SD

Effect size esti-

Weightb

95% CI

matea

VAS 0 – 100

27.7

19.52

77.8

33.56

–50.1

27.65

–1.8

–2.5 to –1.0

6.64

VAS 0 – 100

50.0

14.83

80.0

7.41

–30.0

11.42

–2.5

–3.6 to –1.5

3.58

VAS 0 – 100

30.1

29.70

74.9

32.69

–44.8

31.27

–1.4

–2.1 to –0.7

7.42

VAS 0 – 100

8.6

8.30

30.7

20.00

–22.1

15.31

–1.4

–2.1 to –0.7

7.21

VAS 0 – 100

41.1

20.90

51.5

27.80

–10.4

24.59

–0.4

–0.8 to –0.0

23.48

Verbal NRS 0 – 10

4.0

1.90

6.5

1.90

– 2.5

1.90

–1.3

–2.0 to –0.6

8.69

VAS 0 – 10

2.6

–

5.1

–

– 2.5

0.82

–3.0

–3.5 to –2.6

19.54

VAS 0 – 100 VAS 0 – 100 NRS 0 – 10 VAS 0 – 100

50.1 26.3 5.2 20.0

– 4.8 –23.3 – 0.2 –25.0

23.21 13.21 2.13 8.74

–0.2 –1.7 –0.1 –2.8

–1.2 to 0.8 –2.4 to –1.0 –0.6 to 0.4 –3.5 to –2.2

3.98 8.00 13.73 9.00

–1.5

–1.7 to –1.3

–

20.80 11.40 – 7.40 –

54.9 49.6 5.4 45.0 –

25.40 14.80 – 9.90 –

–

–

A negative effect size indicates reduced pain score in ropivacaine-treated patients as compared to placebo-treated patients. NRS = Numerical rating scale; VAS = visual analogue scale. a Estimate calculated as Hedges’ gu statistic. b Weight calculated as the reciprocal of the estimated variance (1/se2) of each Hedges’ gu statistic.

size of –1.1; 95% CI –1.3 to –0.9; fig. 2) and on mobilization (effect size of –1.5; 95% CI –1.7 to –1.3; fig. 3). The weighted mean differences between ropivacaine- and placebo-treated patients in pain at rest and on mobilization were –13.3 and –20.0 mm, respectively. There was evidence of heterogeneity across studies for both pain at rest (Q = 87, p < 0.001; I2 = 87.0) and pain on mobilization (Q = 372, p < 0.001; I2 = 97.1). Opioid Rescue Use Table 5 displays effect size estimates for each study and the overall effect size estimate. The overall estimate reveals significantly less opioid rescue use for ropivacaine patients (effect size of –1.3; 95% CI –1.5 to –1.1; fig. 4). The weighted mean reduction between ropivacaine- and placebo-treated patients in opioid rescue use was 22.4 mg. There was evidence of heterogeneity in opioid rescue use results across studies (Q = 83.5, p < 0.001; I2 = 89.2). PONV and Other Adverse Events The incidence of PONV was reported for 8 studies. The PONV results extracted from each study are displayed in table 6. Overall, the incidences of PONV appear similar between the ropivacaine and placebo groups. Only 1 of the 8 studies reported a marked reduction in PONV for ropivacaine-treated patients [21]. While not reporting incidences by treatment group, Aguirre et al. [17] also described a reduction of PONV in the ropivacaine group.

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Bianconi (2003) Dowling (2003) Gottschalk (2003) Bianconi (2004) Blumenthal (2005) Ansaloni (2007) Beaussier (2007) Forastiere (2008) Dagtekin (2009) Chan (2010) Wang (2010) Aguirre (2012) Overall

–4.5

–4.0

–3.5

–3.0

–2.5

–2.0 –1.5 –1.0 Effect size

–0.5

0

0.5

1.0

Fig. 2. Forest plot of pain at rest effect size estimates from published CWI studies of ropivacaine versus placebo [17, 19, 21–25, 28, 33–35, 39]. A negative effect size indicates reduced pain in ropivacaine-treated patients as compared to placebo-treated patients. Error bars denote 95% CIs.

Bianconi (2003) Gottschalk (2003) Bianconi (2004) Blumenthal (2005) Ansaloni (2007) Beaussier (2007) Forastiere (2008) Dagtekin (2009) Chan (2010) Wang (2010) Aguirre (2012) Overall

–4.5

–4.0

–3.5

–3.0

–2.5

–2.0 –1.5 –1.0 Effect size

–0.5

0

0.5

1.0

Fig. 3. Forest plot of pain during mobilization effect size estimates from published CWI studies of ropivacaine versus placebo [17, 19, 21–25, 28, 34, 35, 39]. A negative effect size indicates reduced pain in ropivacainetreated patients as compared to placebo-treated patients. Error bars denote 95% CIs.

No increase in wound infection rate as compared to placebo was reported in any of the included RCTs. Signs of wound infection were reported in 6 ropivacaine-treated and 5 placebo-treated patients (table 7). One study [17] of minimal invasive hip replacement reported no delays in wound healing and no wound infections at the 3-month follow-up visit. During the preparation of the manuscript, the previously unpublished sternotomy study suspended due to an increased wound infection rate [18] was published; this study by Agarwal

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Table 5. Total opioid rescue medication use and effect size estimates by study and overall

First author, year

Dowling [33], 2003 Gottschalk [22], 2003 Stewart [20], 2004 Blumenthal [34], 2005 Beaussier [39], 2007 Forastiere [21], 2008 Dagtekin [35], 2009 Chan [28], 2010 Wang [19], 2010 Aguirre [17], 2012 Overall

Ropivacaine

Placebo

mean

SD

mean

47.3 31.7 2.1 20.5 48.0 11.5 23.6 58.0 78.7 45.4

30.59 12.50 3.36 19.90 23.00 2.47 16.80 30.00 – 9.50

78.7 62.5 5.4 47.8 84.0 21.8 30.6 86.0 110.6 69.7

–

–

Weightb

SD

Mean difference

Pooled SD

estimatea 95% CI

57.26 31.70 6.86 20.20 37.00 3.39 12.30 44.00 – 9.60

–31.4 –30.8 – 3.3 –27.3 –36.0 –10.3 – 7.0 –28.0 –31.9 –24.3

47.05 24.82 5.44 20.05 30.81 2.97 14.72 37.66 45.66 9.55

–0.7 –1.2 –0.6 –1.3 –1.1 –3.5 –0.4 –0.7 –0.7 –2.5

–1.3 to 0.0 –2.0 to –0.4 –1.2 to –0.0 –2.1 to –0.6 –1.8 to –0.5 –3.9 to –3.0 –1.4 to 0.5 –1.3 to –0.1 –1.2 to –0.1 –3.1 to –1.9

–1.5

–1.7 to –1.3

–

–

–

Effect size

–

8.25 5.48 11.24 7.37 9.02 16.86 3.90 10.31 12.98 10.04 –

A negative effect size indicates reduced opioid rescue use in ropivacaine-treated patients as compared to placebo-treated patients. a Estimate calculated as Hedges’ gu statistic. b Weight calculated as the reciprocal of the estimated variance (1/se2) of each Hedges’ gu statistic.

Dowling (2003) Gottschak (2003) Stewart (2004) Blumenthal (2005) Beaussier (2007) Forastiere (2008) Dagtekin (2009) Chan (2010) Wang (2010) Aguirre (2012) Overall

–4.5

–4.0

–3.5

–3.0

–2.5

–2.0 –1.5 –1.0 Effect size

–0.5

0

0.5

1.0

Fig. 4. Forest plot of total opioid rescue medication effect size estimates from published CWI studies of ropivacaine versus placebo [17, 19–22, 28, 33–35, 39]. A negative effect size indicates reduced use of opioids in ropivacaine-treated patients as compared to placebo-treated patients. Error bars denote 95% CIs.

et al. [27] reported wound infection rates of 9.1% (4/44) for ropivacaine and 0% (0/41) for placebo. While the ropivacaine rate was not statistically different from placebo, it was significantly higher than the clinic’s historical control rate and therefore resulted in premature discontinuation of the study.

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Table 6. Incidence of nausea and/or vomiting

First author, year Bianconi [24], 2003 Bianconi [25], 2004 Gottschalk [22], 2003 Blumenthal [34], 2005 Ansaloni [23], 2007

Adverse reaction

Time point, h

PONV

NA

8

10

PONV Nausea Vomiting

NA NA NA

5 5 3

7 4 1

PONV Nausea

NA 12 24 48 12 24 48 0 6 12 18 24 30 36 42 48 0 8 16 32 48 0 8 16 32 48 NA NA

Vomiting Forastiere [21], 2008

PONV

Dagtekin [35], 2009

Nausea

Vomiting

Wang [19], 2010

Nausea Vomiting

Ropivacaine, n (%)

2 6 4 2 2 0 0 12 (14.3) 13 (15.5) 21 (25.0) 7 (8.3) 7 (8.3) 0 0 7 (8.3) 7 (8.3) 1 1 3 0 1 0 0 1 0 0 11 2

Placebo, n (%)

3 5 2 1 1 0 0 8 (9.5) 42 (50.0) 42 (50.0) 49 (58.3) 49 (58.3) 34 (40.5) 39 (46.4) 15 (17.9) 24 (28.6) 0 1 1 3 2 0 1 0 1 1 7 1

NA = Not available.

Only 3 safety events requiring discontinuation of the wound infusion were reported across all studies. In 1 ropivacaine-treated patient undergoing spine fusion [25], wound infusion was discontinued 4 h after surgery due to respiratory difficulties, chest pain, and T-wave abnormality as a result of an acutely low haemoglobin level. Another patient developed a transient ischaemic attack about 48 h after open hepatic surgery [28]. In another study [19], 1 control group patient had her morphine PCA terminated around 24 h after surgery due to excessive confusion and sedation. Across all included studies, there were no reports or signs of local anaesthetic systemic toxicity with all reported ropivacaine plasma concentrations below toxic levels. Catheter leakage was reported for 1 patient each in the ropivacaine and placebo groups in one study using elastomeric pumps [23]; none of the other RCTs reported any cases of leakage or catheter dislocation.

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Table 7. Wound infection rate by study versus control groups

First author, year

Ropivacaine, n

Wound Placebo, Wound infection ropi- infection n vacaine, n placebo, n

Bianconi [24], 2003 Dowling [33], 2003 Gottschalk [22], 2003 Bianconi [25], 2004 Stewart [20], 2004 Blumenthal [34], 2005 Ansaloni [23], 2007 Beaussier [39], 2007 Forastiere [21], 2008 Dagtekin [35], 2009 Chan [28], 2010 Iyer [26], 2010 Wang [19], 2010 Aguirre [17], 2012

18 16 12 18 23 18 48 21 84 8 22 24 28 36

19 19 14 19 24 18 48 21 84 8 22 21 27 36

376

380

Total

0 ND 0 0 0 NR 4 NR NR NR NR NR 2 0

0 ND 0 0 0 NR 2 NR NR NR NR NR 3 0

6

5

ND = Authors state ‘no difference’ in wound infection or healing between treatment groups; NR = presence or absence of wound infection not reported or discussed.

Discussion

As the number of controlled studies conducted with ropivacaine CWI to date is relatively small, the results of the 14 identified studies were combined using meta-analysis methods to provide more robust estimates of the effect size of ropivacaine compared to placebo. Three efficacy variables common to the majority of studies were pain score at rest, pain score at mobilization, and opioid rescue use. Estimates of the effect size for ropivacaine versus placebo were calculated using Hedges’ gu statistic, which provides a standardized estimate of the treatment effect allowing results across studies to be combined regardless of the scale or unit of measure. The meta-analysis of these three variables demonstrated that postoperative pain scores at rest and on mobilization are significantly lower, and that the need for intravenous opioids is significantly reduced with ropivacaine CWI compared to control groups given placebo. The weighted mean reductions of 13 and 20 mm in pain at rest and on mobilization scores, respectively, are considered to be clinically meaningful as demonstrated in studies of acute pain in the emergency department setting where the minimum clinically significant difference is reported to be 9–13 mm [29, 30]. The magnitude of the reduction for pain at rest is similar to that from an observational study by Tilleul et al. [31] which also reported significant reductions of approximately 1.5 cm (or 15 mm) for ropivacaine CWI as compared to intravenous morphine. For all three variables included in the meta-analyses, the overall effect size estimates of ropivacaine versus placebo were greater than 0.8 and thus considered to be large in magnitude [32]. A more clinician-friendly interpretation of the overall effect size estimate for opioid rescue use is that an average ropivacaine-treated patient will use less opioid rescue medication than 90.3% of those treated with placebo. Similar interpretations for pain endpoints suggest that an average ropivacaine-treated patient will experience less pain at rest than 86.4% and less pain on mobilization than 92.9% of patients treated with placebo.

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While 4 studies did not provide results sufficient for inclusion in the meta-analysis of opioid rescue use, the overall results of these studies were supportive of the meta-analysis finding that ropivacaine CWI reduces the need for rescue medication. Iyer et al. [26] reported no significant difference in morphine rescue use between ropivacaine and placebo but also noted potentially confounding differences in morphine use by day of surgery. While this study reported no significant difference in morphine rescue use, the authors did report significant improvements in mobility endpoints including time to sit up and time to walk. The other 3 studies not contributing to the opioid rescue analysis used either keterolac [23] or a combination of diclofenac and tramadol as rescue medication [24, 25]. All 3 studies reported significant reductions in rescue medication use with ropivacaine compared to placebo. Ansaloni et al. [23] reported that ropivacaine patients used approximately 1/3 of the keterolac used by placebo-treated patients. In addition, the 2 studies by Bianconi et al. [24, 25] reported significant reductions for both diclofenac and tramadol use. Conversion of the tramadol reductions reported in the Bianconi studies to morphine equivalents suggests reductions in opioid rescue of 17–33 mg for ropivacaine-treated patients consistent with the 20-mg estimate from the meta-analysis. The meta-analysis indicated heterogeneity in the results of the efficacy variables across studies. This heterogeneity might be expected given the various types of surgeries studied and differences in the pain associated with each surgery type. In addition, the type and amount of rescue medication allowed after treatment and doses of ropivacaine varied across studies. It is interesting to note that the studies by Forastiere et al. [21] and Aguirre et al. [17] which showed the largest effect sizes for the pain during mobilization and total opioid rescue variables also had two of the highest ropivacaine exposures over the first 24 h (580 and 636 mg, respectively). Contrasting these exposures with those from the studies of Ansaloni et al. [23] and Wang et al. [19] (260 and 192 mg, respectively) may suggest that the efficacy can be improved for some procedures by using higher ropivacaine exposures. This suggested dose-response relationship is further supported by the results of the study by Gottschalk et al. [22], which demonstrated that an infusion rate of 18.75 mg/h significantly reduced pain at rest and during mobilization compared to a rate of 10 mg/h. Additional studies are required to adequately examine the impact of ropivacaine infusion rate and/or bolus dose on efficacy. The results of Liu et al. [1] in their systematic review, including the use of both ropivacaine and bupivacaine for wound infusion, showed that postoperative wound infusion of long-acting local anaesthetics via catheters improved analgesia and reduced opioid use, increased patient satisfaction, and perhaps reduced length of hospital stay. They noted consistent evidence of these benefits for the infusion technique across a wide range of surgical procedures, location of wound catheters, and dosing regimens of bupivacaine and ropivacaine, and a low incidence of catheter-related complications. Five of the studies [22, 24, 25, 33, 34] included in the current meta-analysis were also included by Liu et al. [1]. In addition, the current meta-analysis includes data from 8 new studies [12, 17, 19, 21, 23, 26, 28, 35] published after 2006 and the study by Stewart et al. [20] that was omitted by Liu et al. While Liu et al. did not perform separate meta-analyses for ropivacaine and bupivacaine, our results confirm that ropivacaine CWI is an effective postoperative analgesic regimen, with clinically meaningful reductions in opioid use and pain outcomes. Safety Considerations While the methodologies for evaluating PONV differed substantially between studies in the current systematic review and did not allow for meta-analysis, the study employing the largest sample size and a dose rate of 20 mg/h ropivacaine demonstrated a significant reduction in PONV after gastrointestinal surgery from a highest incidence over the first 24 h

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of 50–58% for control patients as compared to 8–15% for ropivacaine-treated patients [21]. The difference was maintained up to 48 h (table 6). Also time to bowel recovery (21.8 vs. 33.6 h, p < 0.001) and time to patient discharge from hospital (2.1 vs. 3.2 days; p < 0.001) were significantly reduced in patients in the ropivacaine group. In this study [21], overall morphine use was significantly reduced from a mean of 21.8 mg in control patients to 11.5 mg with ropivacaine CWI suggesting that 10 mg morphine-sparing is a meaningful reduction for patients. Using published meta-analyses, Tilleul et al. [31] estimated the incidences of PONV for intravenous morphine, CWI, and epidural as 36, 24, and 18%, respectively. The use of intravenous opioids as the major component of the postoperative analgesic regimen is likely to be common in a number of postoperative wards. A potential serious complication of intravenous opioids is respiratory depression which, depending on the methods used for detection, has been observed in 1.2–11.5% of patients. Intravenous opioids are also associated with incidences of pruritus ranging from 10.7 to 17.5% and with urinary retention in 6.6–25% of patients [36]. CWI involves a potential risk of reaching high local anaesthetic plasma concentrations that may cause systemic toxicity. A major difference between long-acting local anaesthetics is the lower potential of ropivacaine in causing central nervous system and cardiovascular toxicity at high systemic blood concentrations [37]. In a study of cardiac resuscitation after incremental overdosage of 4 local anaesthetics, open-chest dogs were randomized to receive incremental escalating infusions to the point of cardiovascular collapse (mean arterial pressure ≤45 mm Hg). Hypotension and arrhythmias were treated with epinephrine, openchest massage, and advanced cardiac life support protocols, respectively. Mortality from bupivacaine and ropivacaine was 50 and 10%, respectively [38]. A threshold for central nervous system toxicity was defined during intravenous infusion in healthy volunteers [37] as a mean (range) of pharmacologically active unbound ropivacaine of 0.56 (0.34–0.85) mg/l as compared to 0.30 (0.13–0.51) mg/l bupivacaine (p < 0.001). Muscular twitching occurred more frequently after bupivacaine. Bupivacaine increased QRS width during sinus rhythm compared with placebo (p < 0.001) and ropivacaine (p < 0.01). The minimum concentration where central nervous system symptoms were observed is referred to as the toxicity threshold, i.e. 0.34 mg/l unbound ropivacaine. In the absence of measurements of unbound concentrations, total concentrations below 3.4 mg/l ropivacaine are considered to be below this toxicity threshold. Plasma concentrations of ropivacaine were assessed in more than 180 patients in 9 of the 14 CWI studies using infusion rates up to 40 mg/h. The majority of the studies employed a CWI dose rate of 8–20 mg/h ropivacaine for up to 48 h after end of surgery. There was no report of ropivacaine plasma concentrations exceeding the toxic threshold or adverse events indicative of systemic toxicity in the RCTs. There was also no report of systemic toxicity from bupivacaine or ropivacine in the retrospective study infusing 7.5 mg/h of either agent [13]. In 1 RCT infusing ropivacaine 40 mg/h, duplicate wound catheters were employed in connection with reconstructive flap surgery into a large wound site. The individual maximum plasma concentrations of unbound ropivacaine remained below the threshold for systemic toxicity (0.34 mg/l) and ranged from 0.026 to 0.24 mg/l at 24 h and from 0.043 to 0.20 at 48 h after the start of infusion. Dagtekin et al. [35] concluded that a dose of 960 mg of ropivacaine daily did not result in toxic plasma concentrations. In 4 studies [17, 22, 34, 39] assessing unbound plasma concentrations, values were well below the threshold for systemic toxicity after CWI of ropivacaine 10–24 mg/h for 48 h after an initial bolus infusion of ropivacaine 20–150 mg. Additionally, in a pharmacokinetic study [40], 5 patients were given ropivacaine CWI for 96 h after colon cancer resection. A loading dose of ropivacaine 225 mg (30 ml, 7.5 mg/ml) was injected around the surgical site before CWI at a rate of 10 mg/h (5 ml/h, 2 mg/ml) for 96 h. Individual unbound plasma

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ropivacaine concentrations were low (≤0.087 mg/l) and decreased during the time of infusion. With regard to the systemic safety of ropivacaine CWI, the results of our meta-analysis therefore are similar to those of Liu et al. [1] who reported no case of systemic toxicity from bupivacaine or ropivacaine among 2,141 patients. The placement of the wound catheter by the surgeon under direct vision before wound closure minimizes the risk of overdose from inadvertent intravascular injection that is associated with nerve block techniques. The use of adequate rates of infusion will prevent overdose, and a rate of up to 20 mg/h of ropivacaine is well documented with no overdose reports in the RCTs. The only study [14] where plasma concentrations were reported to approach the tolerability ceiling employed ropivacaine IWI self-administered by patients. Although no symptom of local anaesthetic toxicity was observed, IWI is considered less well studied than CWI. Possible adverse events that might be related to local toxicity of high local concentrations of local anaesthetics are peripheral nerve damage and damage to the surrounding tissue (dermis, subcutis, muscles). Peripheral nerve damage can result in sensibility disturbances and/or impairment/loss of motor function. Damage to the surrounding tissue may be observed as impaired wound healing, inflammatory reaction or necrosis. None of these adverse events were reported in the RCTs. In the study by Dagtekin et al. [35], the perfusion of the transverse rectus abdominis musculocutaneous flap was assessed pre-, intra- and postoperatively by measuring the oxygen saturation of haemoglobin, the relative concentration of haemoglobin in the illuminated tissue, the relative blood flow, and the blood flow velocity being measured on several occasions. No negative effect or difference from placebo was found. Aguirre et al. [17] in their study of minimal invasive hip replacement reported a significant decrease in wound discomfort to touch and pressure pain in ropivacaine-treated patients 3 months after surgery (p < 0.0001), suggesting that effective local anaesthesia of the surgical wound for 48 h may have long-term benefits. In addition, patients were asked about the presence of any new onset of sensory and motor deficits during their normal daily activities, with no difference between ropivacaine and control patients 3 months after surgery. The study using a mixture of ropivacaine and ketoprofen [6] for elective caesarean delivery also included evaluation of complications at 1 and 6 months after surgery. No undesirable side effects or residual pain at 1 and 6 months requiring treatment were recorded in either group. Limitations of the Meta-Analysis The selection criteria for the meta-analysis involved RCTs using ropivacaine single-agent CWI solution and no other confounding routine analgesics during the study period, apart from rescue analgesia. Therefore, our results do not inform about the incremental effect of ropivacaine when infused together with analgesic mixtures of intravenous or oral opioids and/or NSAIDs or other analgesic comedications [5–13]. In an abdominal colorectal surgery study, Polglase et al. [5] found no decrease in PCA morphine use nor pain intensities for ropivacaine CWI (21.6 mg/h) patients as compared to saline patients when combined with a routine battery of intravenous tramadol 50 mg and paracetamol 1 g every 6 h, plus ketorolac 15 or 30 mg intramuscularly every 12 h. While some included studies report a decrease in the length of hospital stay, this metaanalysis does not provide any evidence of shorter hospitalizations or cost-effectiveness for ropivacaine CWI. After open nephrectomy, Forastiere et al. [21] estimated savings of approximately 1 hospital day and approximately EUR 300 for ropivacaine CWI versus opioid PCA alone. In addition, an observational study by Tilleul et al. [31] comparing intravenous morphine PCA, CWI, or epidural analgesia for postoperative analgesia after abdominal surgery reported mean durations of hospitalization of 9.3, 7.9, and 9.8 days, respectively. In addition

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to the reduction of at least 1 day for CWI patients, Tilleul et al. [31] reported cost savings of EUR 750–1,000 in comparison to either morphine PCA or epidural analgesia. We retrieved no comparative RCT of ropivacaine CWI versus bupivacaine CWI. A retrospective study comparing 0.15% ropivacaine and 0.15% bupivacaine as continuous intercostal block in the incisional thoracotomy wound after port access heart surgery [13] reported no significant differences in the number of bolus infusions (2.1 vs. 2.1) or piritramide rescue dose (1.6 vs. 2.1) for ropivacaine versus bupivacaine. The results of the meta-analysis by Liu et al. [1] also support similar efficacy between ropivacaine and bupivacaine as CWI as the weighted mean reductions of 10 mm, 22 mm, and 11 mg for pain at rest, pain with activity, and opioid rescue use, respectively, are comparable to those reported here. In conclusion, this systematic review and meta-analysis of 14 RCTs provides substantial evidence that CWI of ropivacaine is effective for postoperative pain management for a wide range of surgical procedures. Overall, ropivacaine demonstrated robust and clinically meaningful reductions in opioid use and pain outcomes with no major adverse effects. Infusion rates of 8–20 mg/h for up to 48 h were associated with plasma concentrations of ropivacaine well below the toxicity threshold. While this meta-analysis establishes the efficacy of ropivacaine CWI as compared to placebo, additional studies are required to provide efficacy and cost-effectiveness comparisons to bupivacaine CWI and other postsurgical analgesic procedures. Disclosure Statement Shane Raines, Stefan Lillieborg, and Glen Kelleher are employees of AstraZeneca. Cecilia Hedlund, Malin Franzon, and Kjell Ahlén were employees of AstraZeneca during the time this work was performed. AstraZeneca holds the original innovator marketing authorization for ropivacaine (NaropinTM).

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Eur Surg Res 2014;53:43–60 DOI: 10.1159/000363233

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