Prophylactic negative-pressure wound therapy prevents surgical site infection in abdominal surgery: an updated systematic review and

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Article

Reference

Prophylactic negative-pressure wound therapy prevents surgical site infection in abdominal surgery: an updated systematic review and

meta-analysis of randomized controlled trials and observational studies

MEYER, Jérémy, et al.

Abstract

Prevention of surgical site infection (SSI) is a public health challenge. Our objective was to determine if pNPWT allows preventing SSI after laparotomy.

MEYER, Jérémy, et al. Prophylactic negative-pressure wound therapy prevents surgical site infection in abdominal surgery: an updated systematic review and meta-analysis of randomized controlled trials and observational studies. Clinical Infectious Diseases, 2020

PMID : 32818259

DOI : 10.1093/cid/ciaa1203

Available at:

http://archive-ouverte.unige.ch/unige:142240

Disclaimer: layout of this document may differ from the published version.

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Title: Prophylactic negative-pressure wound therapy prevents surgical site infection in abdominal surgery: an updated systematic review and meta-analysis of randomized controlled trials and observational studies

Authors:

Jeremy Meyer, MD, MD-PhD^1,2 Elin Roos, MD³

Ziad Abbassi, MD^1,2 Nicolas C. Buchs, MD, PD^1,2 Frédéric Ris, MD, PD^1,2 Christian Toso, MD, PhD, PD^1,2

Affiliations: 1. Division of Digestive Surgery University Hospitals of Geneva Rue Gabrielle-Perret-Gentil 4 1211 Genève 14

Switzerland

2. Unit of Surgical Research University of Geneva Rue Michel-Servet 1 1206 Genève Switzerland

3. Department of Global Public Health

Downloaded from https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa1203/5895040 by University de Geneve user on 29 September 2020

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2 Karolinska Institutet

SE-17177 Stockholm Sweden

Corresponding author: Jeremy Meyer, MD, MD-PhD Division of Digestive Surgery University Hospitals of Geneva Rue Gabrielle-Perret-Gentil 4 1211 Genève 14

Switzerland

E-mail: [email protected] Phone: +41.22.379.52.52

Alternative contact: Dr. Elin Roos, e-mail: [email protected]

summary: Emerging evidence suggests that prophylactic negative-pressure wound therapy reduces the incidence of surgical site infection after laparotomy, but this finding needs confirmation by high quality studies.

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3 ABSTRACT

Background:

Prevention of surgical site infection (SSI) is a public health challenge. Our objective was to determine if pNPWT allows preventing SSI after laparotomy.

Methods:

MEDLINE, Embase and Web of Science were searched on the 06.10.2019 for original studies reporting the incidences of SSI in patients undergoing open abdominal surgery with and without pNPWT. Risk difference (RD) between control and pNPWT patients and risk ratios (RR) for SSI were obtained using random effects models.

Results:

Twenty-one studies (2’930 patients, five RCT, 16 observational studies) were retained for the analysis. Pooled RD between patients with and without pNPWT was -12% (95%CI: -17% to -8%, I2:

54%, p<0.00001) in favor of pNPWT. That risk difference was -12% (95% CI: -22 to -1%, I2 : 69%, p=0.03) when pooling only RCT (792 patients). pNPWT was protective against the incidence of SSI with a RR of 0.53 (95%CI: 0.40-0.71, I²: 56%, p<0.0001). The effect on pNPWT was more prononced in studies with an incidence of SSI≥20% in the control arm. The preventive effect of pNPWT on SSI remained after correction for potential publication bias. However, when pooling only high-quality observational studies (642 patients) or RCT (527 patients), significance was lost.

Conclusion :

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4 Existing studies suggest that pNPWT on closed wounds is protective against the occurrence of SSI in abdominal surgery, but these findings need to be confirmed by more high quality evidence, preferentially in subgroups of patients with an incidence of SSI≥20% in the control arm

KEYWORDS

Prevena, VAC, PICO, NPWT, SSI, surgical infection, pNPWT, prophylaxis, prevention, morbidity ABBREVIATIONS

NNT Number needed to treat

pNPWT Prophylactic negative-pressure wound therapy

RCT Randomized controlled trial

RD Risk difference

RR Risk ratio

SSI Surgical site infection

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5 Introduction

Surgical site infection (SSI) constitutes an infection related to a surgical procedure, as defined by the United States Centers for Disease Control and Prevention (CDC)¹. SSI increases patients’ morbidity and hampers healthcare budgets ^2-6. Further, SSI was identified as the next frontier in global surgery, especially after gastrointestinal resection in countries with low human development index ⁷. Therefore, aiming at reducing the incidence of SSI constitutes a public health challenge.

Recently, negative pressure wound therapy (NPWT) has been applied on closed surgical wounds for primary healing with the aim of preventing wound-related complications, notably SSI. This new technique, namely prophylactic NPWT (pNPWT) or closed incision NPWT (ciNPWT), consists in an adhesive wound protection connected to a pump, which applies a negative pressure on closed surgical incision. Several commercial devices are on the market, such as the PREVENA incision management system (KCI, Acelity) and the PICO single use negative pressure wound therapy system (Smith and Nephew), comprising or not a canister for fluid collection and applying different pressures, ranging from -75mmHg to -175mmHg. In some centers, the conventional V.A.C system (KCI, Acelity) or VSD system (Wuhan VSD Medical Science and Technology Co, Ltd) used for secondary healing is applied directly on closed surgical wounds to provide pNPWT.

Evidence in the field has emerged and aggregate data have shown efficiency of pNPWT in decreasing the incidence of SSI in plastic surgery, vascular surgery, orthopedic surgery and gynecologic surgery

8. To date, the National Institute for Health and Care Excellence (NICE) recommends the use of pPNWT on closed wounds in patients at risk for SSI ⁹ and the World Health Organization (WHO) emitted the same recommendation but formulated reserves due to the cost and availability of such therapy ¹⁰.

So far, however, pooled evidence in abdominal surgery reached conflicting conclusions. Existing systematic reviews and meta-analyses which showed an effect of pNPWT did not specifically investigate the effect of pNPWT in patients undergoing abdominal surgery, and pooled data from different surgical sites ^11-13 or were outdated ¹⁴. The existing systematic reviews and meta-analyses

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6 of randomized controlled trials (RCT) specifically investigating pNPWT in abdominal surgery showed an absence of effect of pNPWT in preventing SSI ¹⁵ (and the subgroup analysis by Zwanenburg et al.

11). However, these publications pooled the same RCT ^11,15 and reached similar conclusion. Further, subgroup analysis per surgical procedure or per pNPWT commercial device was not performed, whereas incidence of SSI per surgical procedure and efficiency of pNPWT devices might differ ¹³. Therefore, the primary objective of the present systematic review and meta-analysis was to finally determine if pNPWT allows decreasing the incidence of SSI after open abdominal surgery.

Secondary objectives were to determine the numbers of patients to treat (NNT) to avoid one case of SSI per surgical procedure and per commercial pNPWT device.

Materials and methods

The study protocol was registered in the International Prospective Register of Ongoing Systematic Reviews (PROSPERO). The study was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines ¹⁶ (Table S1). MEDLINE, Embase and Web of Science were searched on the 6^th of October 2019 without time limit for original studies written in English, Swedish or French including patients who benefited from pNPWT after open abdominal surgery with skin closure. Briefly, to be selected, articles had to contain terms related to SSI, pNPWT and laparotomy in the title, abstract or keywords. Search strategy is summarized in Table S2. Additional records were identified by manual search of the reference lists of the included publications. Case series, conference abstracts, letters to the editor and secondary analyses of previously published papers were excluded. Studies including patients <18 y.o., studies reporting use of pNPWT on perineal wounds, inguinal wounds, caesarean delivery, or studies with antibiotic wound irrigation, were excluded. Two independent reviewers (JM, ER) carried out the systematic review as first and second reviewers using the Covidence software ¹⁷. Discrepancies were solved by a third author (FR). Demographics, type of surgery performed, type of pNPWT device used (Prevena incision management system (KCI, Acelity, San Antonio, USA), PICO single use negative pressure

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7 wound therapy system (Smith & Nephew, Hertfordshire, UK), V.A.C. system (KCI, Acelity, San Antonio, USA)), as well as incidences of SSI in patients with and without pNPWT, were extracted from included publications. The term “conventional wound dressing” was used to identify control patients who did not benefit from pNPWT. Techniques for subcutaneous tissue and skin closure were not documented due to high heterogeneity among studies and within studies. The incidence of SSI was combined across studies using models with random effects (Der Simonina and Laird approach) on logit-transformed incidences. Risk ratios (RR) and risk differences (RD) were obtained using models with random effect (Mantel-Haenszel ¹⁸). NNT were calculated as 1/(-RD).

Heterogeneity was assessed using the Q-test and quantified using the I² value. Risk of bias was assessed by using the Newcastle-Ottawa scale ¹⁹ for observational studies and the Cochrane Collaboration’s tool for assessing risk of bias ²⁰ for randomized controlled trials (RCT). Subgroups analyses were performed according to the quality ranking of included studies, the sample size of studies, the type of surgery performed, the type of pNPWT device used and the design of included studies. An investigation of a potential publication bias has been added. To this end, we inspected the symmetry of funnel plots. We applied the trim and fill method to identify studies potentially missing because of a publication bias and to assess the pooled intervention’s effect corrected for a potential publication bias ²¹. The software Review Manager (RevMan 5, version 5.3, Copenhagen:

the Nordic Cochrane Centre, The Cochrane Collaboration, 2014) was used for the meta-analysis ²². Investigation of a potential publication bias was conducted with the software R version 4.0.2 (R Core Team (2013). R : A language and environment for statistical computing. R Foundation for Statistical Computing). All statistical analyses were reviewed by a statistician (CC).

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8 Results

Inclusion process

Fifty-seven publications were identified in MEDLINE, 46 in Embase and 25 in Web of Science. Six publications were retrieved from other sources. Thirty-two duplicates were removed. Of the 102 publications left, 73 were excluded after title and abstract screening and eight after full text screening, leaving 21 studies representing 2’930 patients for definitive inclusion ^23-43 (Figure 1).

Characteristics of included studies

Included studies were recent, with the first included study reporting the use of pNPWT being published in 2012 ⁴². Thirteen publications were retrospective studies 23-31,37,39,42,43

, three were prospective studies ^34,38,40 and five were RCT 32,33,35,36,41

. Eleven studies were observational studies with non-randomized controls 23-25,27,29-31,37,38,40,43

, and five studies had historical controls consecutive to change of practice 26,28,34,39,42

. SSI was mostly defined according to the CDC criteria

23,25,28,29,31,33,35,36,38-41

(Table S3).

The number of included patients ranged from 49 ³⁶ to 394 patients ²⁵. Four studies included patients who underwent general abdominal surgery 33,34,36,39

, six colorectal surgery 24,27,35,38,40,43

, six abdominal wall reconstruction 26,28-30,37,42

, three pancreaticoduodenectomy ^25,31,32, two abdominal oncologic surgery ^23,41. Devices used were regular VAC or VSD in seven studies 23-26,30,33,37

, PREVENA in six studies 27,29,32,35,39,43

and PICO in three studies ^36,38,40. Two studies used alternatively PREVENA or VAC

28,34

. The type of pNPWT device used was not described in 3 studies ^31,41,42. Negative pressure applied varied from -75mmHg ^24,37,42 to 125mmHg 23,25-27,29,30,32-35,41,43

. Duration of therapy ranged from three days ³³ to 10 days ^28,31 (Table S4).

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9 Quality assessment of included studies

According to the Newcastle-Ottawa scale, seven studies 28,34,37-40

were ranked as high quality for assessing the risk of SSI in pNPWT patients and in controls, and nine as medium quality 23-27,29-31,42

(Table S5). According to the Cochrane Collaboration’s tool, four RCT 32,33,35,36

were considered to be of high quality and one was considered to be of medium quality ⁴¹ (Table S6).

Pooled incidences of SSI in pNPWT and control patients

Incidence of SSI in pNPWT patients

Pooled incidence of SSI in pNPWT patients (21 studies ^23-43, 1'185 patients) was 13.2% (95%CI : 9.5% to 18.1%, I²: 75%). In patients undergoing colorectal surgery (six studies 24,27,35,38,40,43

, 372 patients), abdominal wall reconstruction (six studies 26,28-30,37,42

, 222 patients) or pancreaticoduodenectomy (three studies ^25,31,32, 207 patients), the incidence was of 9.5% (95%CI : 3.6% to 22.9%, I²: 85%), 19.5% (95%CI : 11.0% to 32.2%, I²: 65%) and 11.1% (95%CI : 3.6% to 22.9%, I²:0%), respectively. When pooling only RCT (five studies 32,33,35,36,41

, 395 patients), the incidence was of 13.8% (95%CI : 6.8% to 26.1%, I²: 83%) (Table 1). There was no statistical difference in terms of incidence of SSI between surgical procedures (p=0.2230), pNPWT devices (p=0.5284) or study designs (p= 0.9331).

Incidence of SSI in control patients

The pooled incidence of SSI in patients with conventionnal dressing (21 studies ^23-43, 1'745 patients) was 26.1% (95%CI : 22.1% to 30.5%, I²: 70%). When pooling patients undergoing colorectal surgery (six studies 24,27,35,38,40,43

, 762 patients), abdominal wall reconstruction (six studies 26,28-30,37,42

, 238 patients) or pancreaticoduodenectomy (three studies ^25,31,32, 371 patients), the incidence of SSI was 28.0% (95%CI : 20.1% to 32.5%, I²: 83%), 30.1% (95%CI : 19.6% to 43.3%, I²: 72%) and 26.5%

(95%CI : 21.3% to 32.5%, I²: 17%), respectively. When pooling only RCT (five studies 32,33,35,36,41

, 397

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10 patients), the incidence of SSI in patients with conventional wound dressing was of 26.6% (95% CI : 18.9% to 36.1%, I²: 69%) (Table 1). There was no statistical difference in terms of SSI between surgical procedures (p=0.85), devices (p=0.079) or designs (p= 0.74).

Pooled risk difference between control and pNPWT patients

The pooled RD for SSI between control patients and pNPWT patients (21 studies ^23-43, 2'930 patients) was -12% (95% CI : -17% to 8%, I² : 57%, p<0.00001) (Figure 2A), meaning that the incidence of SSI was lower by 12 points in pNPWT patients. When pooling only studies including

>100 patients (10 studies 23-25,27,29,32,35,37,41,43

, 2'230 patients), the pooled RD was -10% (95%CI : -15%

to -5%, I² : 54%, p<0.0001). In patients undergoing colorectal surgery (six studies 24,27,35,38,43

, 1'134 patients), abdominal wall reconstruction (six studies 26,28-30,37,42

, 460 patients) or pancreatectomy (three studies ^25,31,32, 578 patients), the RD were -16% (95% CI : -24% to -7%, I² : 67%, p=0.0002), - 11% (95% CI : -20% to -2%, I² : 42%, p=0.02) and -15% (95% CI : -22% to -8%, I² : 8%, p<0.0001), respectively. When pooling only studies reporting the use of PREVENA (six studies 27,29,32,35,39,43

, 1’103 patients), PICO (three studies ^36,38,40, 149 patients) or VAC/VSD (seven studies 23-26,30,33,37

, 1’075 patients), the RD were of -12% (95% CI : -19% to -5%, I² : 56%, p=0.0006), -30% (95% CI : -43% to - 18%, I² : 0%, p<0.00001) or -12% (95% CI : -17% to -7%, I² : 24%, p<0.0001), respectively. The RD was of +3% (95% CI : -9% to +18%, I² : 30%, p=0.23), -17% (95% CI : -21% to -12%, I² : 0%, p<0.00001) and -19% (95% CI : -29% to -9%, I² : 57%, p=0.0008), when pooling studies including patients at low risk, medium risk and high risk of SSI, respectively. When pooling only RCT (five studies 32,33,35,36,41

, 792 patients), the RD was -12% (95% CI : -22% to -1%, I2 : 69%, p=0.03). RD were of -16% (95% CI : -27%

to -5%, I2 : 70%, p=0.004) or -16% (95% CI : -27% to -4%, I2 : 60%, p=0.008) when pooling only high quality observational studies (seven studies 28,34,37-40

, 642 patients) or high quality RCT (four studies

32,33,35,36

, 527 patients), respectively. No statistical difference in terms of RD existed between surgical procedures (p=0.73) or study designs (p=0.95). However, the RD was the highest when using the

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11 PICO device (p=0.025) and when pooling studies including patients with an incidence of SSI≥30% in the control group (Table 2).

Pooled RR for SSI among pNPWT patients

By pooling all included studies reporting the incidence of SSI in intervention (pNPWT) and in control patients (21 studies ^23-43, 2'930 patients), we found that pNPWT was significantly protective against the occurrence of SSI with a pooled RR for SSI of 0.53 (95% CI : 0.40-0.71, I2 : 56%, p<0.0001) (Figure 2B). When pooling only studies with a sample size > 100 patients (ten studies ^23-

25,27,29,32,35,37,41,43

, 2'230 patients), pooled RR for SSI for pNPWT patients was 0.62 (95% CI : 0.45-0.86, I2 : 59%, p=0.004). When pooling patients undergoing colorectal surgery (6 studies 24,27,35,38,40,43

, 1’134 patients), abdominal wall reconstruction (six studies 26,28-30,37,42

, 460 patients) or pancreaticoduodenectomy (three studies ^25,31,32, 578 patients), pooled RR were 0.35 (95% CI : 0.16- 0.76, I2 : 74%, p=0.008), 0.65 (95% CI : 0.43-0.98, I2 : 26%, p=0.04) and 0.42 (95% CI : 0.28-0.65, I2 : 0%, p<0.0001). When pooling studies using the PREVENA (six studies 27,29,32,35,39,43

, 1’103 patients), the PICO (three studies ^36,38,40, 149 patients) or the VAC/VSD systems (seven studies 23-26,30,33,37

, 1’075 patients), pooled RR for SSI were of 0.50 (95% CI : 0.28-0.90, I2 : 73%, p=0.02), 0.21 (95% CI : 0.09- 0.48, I2 : 0%, p=0.0002) and 0.51 (95% CI : 0.38-0.69, I2 : 0%, p<0.0001), respectively. When pooling only RCT (five studies 32,33,35,36,41

, 792 patients), the protective effect of pNPWT against the occurrence of SSI had a RR of 0.56 but lost significance (95% CI : 0.30-1.03, I2 : 67%, p=0.06).

Similarly, when pooling only high quality observational studies (seven studies 28,34,37-40

, 642 patients) or high quality RCT (four studies 32,33,35,36

, 527 patients), the effect of pNPWT on the prevention of SSI was not significant with RR of, respectively, 0.50 (95% CI : 0.25-1.00, I2 : 67%, p=0.05) and 0.40 (95%

CI : 0.15-1.02, I2 : 74%, p=0.05). No statistical difference in terms of RR for SSI existed between surgical procedures (p=0.23), devices (p=0.14) or designs (p=0.96). However, RR were significantly lower when pooling studies including patients at high risk for SSI than in studies pooling patients at lower risk (p=0.0494). Results are reported in Table 2.

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12 Number needed to treat to prevent one occurrence of SSI

Among all studies (21 studies ^23-43, 2'930 patients), the NNT to prevent one occurrence of SSI was 9 patients (6 to 13 patients). When pooling only high quality observational studies (seven studies

28,34,37-40

, 642 patients), NNT was 7 (4 to 20), and when pooling only high quality RCT (four studies

32,33,35,36

, 527 patients), NNT was 7 (4 to 25) (Table 3).

Publication bias

The trim-and-fill approach identified various studies potentially missing corresponding to effects in favour of control (right part of the funnel plots) (Figure 3). After correcting for these missing studies, the intervention’s effect was reduced, but remained statistically significant in cohort studies and in all studies but not in RCT (Table 4).

Discussion

In the present meta-analysis, the incidence of SSI among 1’745 patients with conventional wound dressing was 26.1%. The average cost of a SSI ranging between 20'785 USD ⁴⁴ and 49’449 USD ⁴, we can consider that SSI constitutes a major public health issue hampering healthcare budgets.

Recent evidence in general surgery proposed pNPWT to prevent SSI ⁸, but pooled evidence was lacking regarding abdominal surgery. Noteworthy, the systematic review and meta-analysis by Sahebally et al. is outdated and did not include the latest publications in the field ¹⁴. Recently, Zwanenburg et al. showed that pNPWT allowed reducing the incidence of SSI when pooling observational studies (RR: 0.40, p<0.0001) but not when pooling RCT (RR: 0.56, p=0.06) ¹¹. This was further demonstrated by Kuper et al. who pooled the same RCT in their quantitative analysis ¹⁵. However, in these latest analyses, the difference between pNPWT and conventional wound therapy was close to significance, and heterogeneity in terms of surgical procedure, type of pNPWT device, pressure applied and duration of therapy might have altered the pooled analyses. Therefore, we

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13 believed that new evidence was needed assessing pNPWT among different surgical procedures and comparing the different existing commercial devices ¹³.

In patients undergoing laparotomy, we found that pNPWT allowed decreasing the risk for SSI by approximately 50%. The pooled RD (-12% for all studies, p<0.00001) was found to be significant for all pNPWT devices and surgical procedures, such as colorectal surgery, abdominal wall reconstruction and pancreaticoduodenectomy. That risk difference was also significant when pooling only RCT, high quality observational studies or high quality RCT. We determined that nine patients should benefit from pNPWT to avoid one case of SSI (NNT=9).

Further, pNPWT was protective against the occurrence of SSI with a pooled RR of 0.53. Similarly to the RD, the protective effect was conserved when using different pNPWT devices and performing different surgical procedures.

However, in opposition with the RD, the RR lost significance when pooling only RCT (p=0.06), high quality observational studies (p=0.05) or high quality RCT (p=0.05).

To exclude a potential contribution of publication bias in the observed results, we perfomred a trim- and-fill approach, which identified various studies potentially missing corresponding to effects in favour of control. After correcting for these missing studies, the intervention’s effect was reduced but remained statistically significant (RR 0.72, 95% CI: 0.53-0.96, p=0.026; RD -10.1%, 95% CI: -14.6 to -5.7%, p<0.001). Of note, the missing studies identified by the trim-and-fill approach are studies that should be added for the funnel plot to be symmetric. A publication bias may be the source of the asymmetry but heterogenity factors can also explain the asymmetry. For instance, studies using the PICO device showed a large effect (and a high incidence of SSI in control groups) and were located on the extreme left part of funnel plots. Therefore, these studies contributed to the asymmetry and their opposites were detected missing. Finally, the detected asymmetry in funnel plots is potentially not fully explained by a publication bias but might be the consequence of heterogeneity in patients’ populations.

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14 Noteworthy, by performing sensitivity analyses, we noted that the effect on pNPWT was more prononced in studies with an incidence of SSI≥20% in the control arm. We believe that the absence of effect in terms of RR observed by pooling RCT might be explained by greater heterogeneity (I² : 67%) than the heterogeneity obtained when pooling only observational studies (I² : 27%) or all studies (I² : 56%). Of note, we noticed that the RCT by Shen et al. (RR : 1.01, 95% CI : 0.58-1.75, weight : 27.5%) strongly pulled the aggregate measure towards the absence of effect (RR : 1), whereas the incidence of SSI in its control arm was only of 15.8% (21/133 patients). Therefore, we propose that new RCT investigate pNPWT in high-risk patients, such as those undergoing, for example, emergency laparotomy.

Based on our results, we believe that pNPWT should be recommended in abdominal surgery patients. Further, we consider that pNPWT can lead to an improved cost-effectiveness and sustainable economies for healthcare systems.

Further, we think that recommendation for pNPWT in low- and middle incomes countries, which are at higher risk for SSI after gastrointestinal resection ^7,45, should be investigated by cost-benefit analyses adapted to the cost of SSI in these settings. Regardless, pNPWT would allow reducing patients’ morbidity independently of potential financial benefits.

To our knowledge, the present systematic review and meta-analysis is the largest published specifically investigating the effect of pNPWT in abdominal surgery, pooling 1'185 patients with pNPWT and 1'745 with conventional wound dressing. Further, we performed sensitivity analyses to confirm similar effect according to the type of surgical procedure performed and the type of device used. The present meta-analysis is, however, limited by the high pooled incidence of SSI (26.1%) reported in patients with conventional dressing, which might lead to an overestimation of the effect of pNPWT, and which might be due to an overrepresentation of high risk patients in included studies. We note that, in comparison, the GlobalSurg Collaborative reported an incidence of SSI after gastrointestinal resection that was of 9.4% in countries with high human development index ⁴⁵. Further, as the magnitude of preoperative risk for SSI among included patients is not well

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15 documented, differs between studies and might be higher than in routine practice, we think that recommendation of use of pNPWT in low risk patients should probably wait for further studies.

Another limitation is the conflicting effect existing when pooling RCT. We confirm the previous observation showing an absence of effect (but close to significance) when calculating the RR ^11,15, whereas we have found a statistically significant preventive effect of pNPWT when determining the RD in all RCT and high quality RCT. We believe that the heterogeneity in terms of results among existing RCT might be explained by the diversity of surgical procedures performed, by variations in pNPWT and by heterogeneity in patients’ populations, and that new evidence is required to draw definitive conclusion based on RCT.

To conclude, we showed that pNPWT allows reducing the incidence of SSI by 12 points in patients undergoing abdominal surgery and has a protective effect against the occurrence of SSI with a RR of 0.53, even after correction for potential publication bias. pNPWT allowed to prevent one SSI per nine patients, which may contribute to a more efficient use of financial resources in healthcare systems.

Future confirmation of these results should however be performed by new RCT, preferentially in patients at higher risk for SSI. Further, economical analysis should be undertaken, especially in low- and middle income countries, where incidence of SSI might be underevaluated due to information bias, and costs of management of SSI might differ from high income countries. Also, we note that evidence is lacking in emergency surgery where application of pNPWT might be of great interest due to higher incidence of SSI.

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16 Acknowledgements: The authors thank Dr. Christophe Combescure, Msc, statistician from the Division of Epidemiology of the University Hospitals of Geneva, Switzerland, for reviewing the analyses.

Authors contribution: JM conceived and designed the study. JM and ER acquired the data.

JM and ER analysed the data. JM, ER, ZA, NCB, FR and CT interpreted the data. JM, ER, ZA, NCB, FR and CT contributed to the writing of the manuscript and to its critical revision. JM, ER, ZA, NCB, FR and CT approved the final version of the manuscript.

CONFLICT-OF-INTEREST DISCLOSURE

The authors disclose no conflict of interest.

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13. Roos E, Toso C, Meyer J. COMMENT ON: Meta-analysis, Meta-regression, and GRADE Assessment of Randomized and Nonrandomized Studies of Incisional Negative Pressure Wound Therapy Versus Control Dressings for the Prevention of Postoperative Wound Complications. Annals of Surgery; Accepted for publication.

14. Sahebally SM, McKevitt K, Stephens I, et al. Negative Pressure Wound Therapy for Closed Laparotomy Incisions in General and Colorectal Surgery: A Systematic Review and Meta-analysis.

JAMA Surg 2018; 153(11): e183467.

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271(1): 67-74.

16. Moher D, Liberati A, Tetzlaff J, Altman DG, Group P. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol 2009; 62(10): 1006-12.

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18 17. https://www.covidence.org/reviews/active.

18. https://handbook-5-1.cochrane.org/chapter_9/9_4_4_3_random_effects_method.htm.

19. Wells G, Shea B, O'Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses.

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22. https://community.cochrane.org/help/tools-and-software/revman-5.

23. Blackham AU, Farrah JP, McCoy TP, Schmidt BS, Shen P. Prevention of surgical site infections in high-risk patients with laparotomy incisions using negative-pressure therapy. Am J Surg 2013;

205(6): 647-54.

24. Bonds AM, Novick TK, Dietert JB, Araghizadeh FY, Olson CH. Incisional negative pressure wound therapy significantly reduces surgical site infection in open colorectal surgery. Dis Colon Rectum 2013; 56(12): 1403-8.

25. Burkhart RA, Javed AA, Ronnekleiv-Kelly S, et al. The use of negative pressure wound therapy to prevent post-operative surgical site infections following pancreaticoduodenectomy. HPB (Oxford) 2017; 19(9): 825-31.

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27. Curran T, Alvarez D, Pastrana Del Valle J, Cataldo TE, Poylin V, Nagle D. Prophylactic closed- incision negative-pressure wound therapy is associated with decreased surgical site infection in high- risk colorectal surgery laparotomy wounds. Colorectal Dis 2019; 21(1): 110-8.

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24(1): 49-55.

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19 37. Pauli EM, Krpata DM, Novitsky YW, Rosen MJ. Negative pressure therapy for high-risk

abdominal wall reconstruction incisions. Surg Infect (Larchmt) 2013; 14(3): 270-4.

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20 FIGURES/TABLES LEGENDS

Table 1. Pooled incidence of SSI between pNPWT and control patients

The incidence of SSI was combined across studies using models with random effects (Der Simonina and Laird approach) on logit-transformed incidences. Heterogeneity was assessed using the Q-test and quantified using the I² value. Subgroups analyses were performed according to the type of surgery performed, the type of pNPWT device used and the design of included studies.

Table 2. Pooled risk difference and risk ratio for SSI between pNPWT and control patients

Risk ratio (RR) and risk difference (RD) were obtained using models with random effect (Mantel-Haenszel). Heterogeneity was assessed using the Q-test and quantified using the I² value. Risk of bias was assessed by using the Newcastle-Ottawa scale for observational studies and the Cochrane Collaboration’s tool for assessing risk of bias for randomized controlled trials (RCT). Subgroups analyses were performed according to the quality ranking of included studies, the sample size of studies, the type of surgery performed, the type of pNPWT device used, the incidence of SSI in the control arm and the design of included studies.

Table 3. Pooled number needed to treat to avoid one occurrence of SSI

Number needed to treat (NNT) was calculated as 1/(-RD). Subgroups analyses were performed according to the quality ranking of included studies, the type of surgery performed and the type of pNPWT device used.

Table 4. Pooled measures of the intervention’s effect corrected for a potential publication bias

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21 To investigate for a potential publication bias, we inspected the symmetry of funnel plots. We applied the trim-and-fill method to identify studies potentially missing

because of a publication bias and to assess the pooled intervention’s effect corrected for a potential publication bias. The reported number of missing studies is the number of studies identified with the trim-and-fill approach that should be added for the funnel plot to symmetric. Risk difference (RD) and risk ratio (RR) corrected for publication bias were reported.

Figure 1. PRISMA flowchart for inclusion process

Figure 2. Meta-analysis assessing the risk of SSI in patients with and without pNPWT

A. Pooled risk difference (RD). B. Pooled Risk ratio (RR). Each horizontal bar summarizes a study. The bars represent 95% confidence intervals. The grey squares inform on each of the studies’ weight in the meta-analysis. The diamond in the lower part of the graph depicts the pooled estimate along with 95% confidence intervals. Events = patients with surgical site infection (SSI).

Figure 3. Funnel plots for the investigation of a potential publication bias.

A. For the risk ratio. B. For the risk difference. Grey full circles represent the studies included in the meta-analyses and the white circles the studies suspected to be unpublished (as identified by the trim-and-fill approach).

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22 Table 1

Subgroup analyses pNPWT Control

Studies, n Patients, n Pooled incidence (95% CI), I² Patients, n

Pooled incidence (95% CI), I² All studies 21 1185 13.2% (9.5 to 18.1), I²=75% 1745 26.1% (22.1 to 30.5), I²=70%

Surgery Colorectal 6 372 9.5% (3.6 to 22.9), I²=85% 762 28.0% (20.1 to 32.5), I²=83%

Abdominal wall reconstruction 6 222 19.5% (11.0 to 32.2), I²=65% 238 30.1% (19.6 to 43.3), I²=72%

Pancreaticoduodenectomy 3 207 11.1% (3.6 to 22.9), I²=0% 371 26.5% (21.3 to 32.5), I²=17%

Device PREVENA 6 462 12.4% (5.5 to 25.7), I²=89% 641 25.8% (18.3 to 35.0), I²=80%

PICO 3 74 8.1% (3.7 to 16.9), I²=0% 75 38.8% (28.4 to 50.3), I²=0%

VAC or VSD 7 390 12.9% (9.5 to 17.3), I²=13% 756 25.9% (21.1 to 31.3), I²=50%

Design Retrospective cohorts 13 697 12.3% (7.9 to 18.6), I²=72% 1255 24.9% (20.1 to 30.5), I²=72%

Prospective cohorts 3 93 14.6% (4.8 to 37.0), I²=70% 93 31.9% (16.6 to 52.5), I²=71%

Randomized controlled trials 5 395 13.8% (6.8 to 26.1), I²=83% 397 26.6% (18.9 to 36.1), I²=69%

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23 Table 2

Risk difference Risk ratio

Subgroup analyses Studies,

n

Patients, n

Pooled RD

(95% CI) I2 p-value p- value

Pooled RR

(95%CI) I2 p-value p- value All studies 21 2930 -12% (-17% to -

8%) 57% <0.00001 - 0.53 (0.40 to 0.71) 56% <0.0001 -

Sample size >100 patients 10 2230 -10% (-15% to -

5%) 54% <0.0001

0.23

0.62 (0.45 to 0.86) 59% 0.004

0.19 ≤100 patients 11 700 -16% (-25% to

-8%) 62% 0.0002

0.41 (0.24 to 0.70) 49% 0.001

Surgery Colorectal 6 1134 -16% (-24% to -

7%) 67% 0.0002

0.73

0.35 (0.16 to 0.76) 74% 0.008

0.23 Abdominal wall

reconstruction 6 460 -11% (-20% to -

2%) 42% 0.02

0.65 (0.43 to 0.98) 26% 0.04

Pancreaticoduodenectomy 3 578 -15% (-22% to -

8%) 8% <0.0001

0.42 (0.28 to 0.64) 0% <0.001

Device PREVENA 6 1103 -12% (-19% to -

5%) 56% 0.0006

0.025

0.50 (0.28 to 0.90) 73% 0.02

0.14 PICO 3 149 -30% (-43% to -

18%) 0% <0.00001

0.21 (0.09 to 0.48) 0% <0.0002

VAC or VSD 7 1075 -12% (-17% to -

7%) 24% <0.0001

0.51 (0.38 to 0.69) 0% <0.0001

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24

Design Retrospective cohorts 13 1952 -12% (-16% to -

8%) 23% <0.00001

0.95

0.53 (0.39 to 0.70)

27% <0.0001

0.96 Prospective cohorts 3 186 -17% (-51% to

+16%) 88% 0.31

0.44 (0.08 to 2.46) 84% 0.35

RCT 5 792 -12% (-22% to -

1%) 69% 0.03

0.56 (0.30 to 1.03) 67% 0.06 Incidence of SSI in the

control group < 20% 6 974 3% (-9% to

+2%) 30% 0.23

0.0002

0.84 (0.54 to 1.28) 30% 0.41

0.0494 20 - 29% 7 1175 -17% (-21% to

-12%) 0% <0.00001

0.37 (0.21 to 0.63) 43% 0.003

≥ 30% 8 781 -19% (-29% to

-9%) 57% 0.0008

0.48 (0.30 to 0.77) 64% 0.006

Quality ranking High quality observational

studies 7 642 -16% (-27% to -

5%) 70% 0.004

0.95

0.42 (0.20 to 0.87) 71% 0.05

0.93 High quality RCT 4 527 -16% (-27% to -

4%) 60% 0.008

0.40 (0.15 to 1.02) 74% 0.05

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25 Subgroup analyses Studies, n Patients, n NNT, n (95% CI)

All studies 21 2930 9 (6 to 13)

Surgery Colorectal 6 1134 7 (5 to 15)

Abdominal wall reconstruction 6 460 10 (5 to 50) Pancreaticoduodenectomy 3 578 7 (5 to 13)

Device PREVENA 6 1103 9 (6 to 20)

PICO 3 149 4 (3 to 6)

VAC or VSD 7 1075 9 (6 to 15)

Quality ranking High quality observational studies 7 642 7 (4 to 20) High quality RCT 4 527 7 (4 to 25)

Table 3

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26

Pooled risk difference Pooled risk ratio

Missing studies, n RD (95%CI) p Missing studies, n RR (95%CI) p

All studies (n=21) 4 -10.1% (-14.6% to -5.7%) <0.001 8 0.72 (0.53 to 0.96) 0.026 Observational studies (n=16) 2 -11.0% (-16.1% to -5.9%) <0.001 5 0.64 (0.46 to 0.90) 0.011 RCT (n=5) 2 -5.6% (-16.1% to 4.9%) 0.295 2 0.76 (0.41 to 1.38) 0.364

Table 4

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27 Figure 1

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28 Figure 2

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29 Figure 3