Negative pressure wound therapy for surgical site infections: a systematic review and meta-analysis of randomized controlled trials

Clinical Microbiology and Infection 25 (2019) 1328e1338

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Systematic review

Negative pressure wound therapy for surgical site infections: a systematic review and meta-analysis of randomized controlled trials Hui-Zi Li y, Xiang-He Xu y, Da-Wei Wang y, Yi-Ming Lin, Nan Lin, Hua-Ding Lu* Department of Orthopaedics, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai 519000, Guangdong, China

a r t i c l e i n f o

a b s t r a c t

Article history: Received 15 February 2019 Received in revised form 2 June 2019 Accepted 3 June 2019 Available online 17 June 2019

Objectives: Previous studies showed the effectiveness of negative pressure wound therapy (NPWT) in preventing surgical site infections (SSIs), but current guidelines do not recommend its routine use for surgical wounds. The aim was to compare the effectiveness and safety of NPWT with standard surgical dressing or conventional therapy for preventing SSIs. Methods: Pubmed, Embase and the Cochrane Library were systematically searched on 10 April 2019. Also, we searched clinicaltrials.gov and references of relevant studies. Eligibility criteria were randomized controlled trials (RCTs) and adult surgical patients were included. The effectiveness of NPWT versus standard surgical dressing or conventional therapy was investigated. Relative risks (RRs) and mean differences (MDs) with 95% confidence intervals (CIs) were used to estimate the pooled effect of dichotomous outcomes and continuous outcomes respectively. The primary outcome was surgical site infections. The quality of included studies and the certainty of the evidence were assessed using the risk of bias tool and the GRADE approach. Results: A total of 45 RCTs with 6624 surgical patients were included. NPWT reduced SSIs (RR 0.58; 95% CI 0.49e0.69) and wound dehiscence(17 RCTs; RR 0.80; 95% CI 0.65e1.00). NPWT did not increase the risk of hematoma (9 RCTs; RR 0.91; 95% CI 0.40e2.07) and hospital readmission(9 RCTs; RR 0.77; 95% CI 0.52e1.12) or prolong length of hospital stay(15 RCTs; MD e0.38; 95% CI, e0.78 to 0.02). NPWT significantly increased the risk of all adverse event-related outcomes (10 RCTs; RR 3.21; 95% CI, 1.17e8.78). The level of certainty was identified as low for the primary outcome and very low for all the secondary outcomes. Conclusions: Compared with standard wound care, NPWT may reduce the risk of SSIs. We are uncertain whether NPWT reduces or increases the risk of wound dehiscence, haematoma, hospital readmission and all adverse event-related outcomes or if it shortens or prolongs length of hospital stay. Hui-Zi Li, Clin Microbiol Infect 2019;25:1328 © 2019 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Editor: M. Paul Keywords: Meta-analysis Negative-pressure wound therapy Randomized controlled trials Surgical wound infection Systematic review

Introduction Surgical site infection (SSI), a frequent postoperative complication with an approximate incidence rate of 5.4% is associated with increased mortality, morbidity, unplanned readmission and impaired quality of life [1e3]. Several perioperative risk factors have been identified as underlying predictors for SSIs, including contaminated or dirty wounds, high body mass index (BMI),

* Corresponding author. H.-d. Lu, Department of Orthopaedics, Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, China. E-mail address: [email protected] (H.-D. Lu). y These authors contributed equally to this work.

smoking status, intraoperative fraction of inspired oxygen and hypoalbuminaemia [4e8]. The potential mechanisms behind the association between these high-risk factors and increased SSIs are mainly attributed to direct contamination, dead space formation, malnutrition and insufficient oxygen supply in affected surgical wounds [8e10]. Accordingly, some preventive strategies are recommended to reduce postoperative SSIs, such as wound protector devices, antimicrobial-coated sutures, intraoperative skin preparation, oxygenation and maintaining normal body temperature [11,12]. Regardless of a potential decreasing trend lately, SSIs still impose a large clinical and societal burden, especially in some lowincome and developing countries [13e15]. Therefore, it is of great

https://doi.org/10.1016/j.cmi.2019.06.005 1198-743X/© 2019 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

H.-Z. Li et al. / Clinical Microbiology and Infection 25 (2019) 1328e1338

significance to further seek for new promising strategies for preventing SSIs, particularly in high-risk surgical patients. Negative pressure wound therapy (NPWT), a relatively new wound management method, has been verified to be effective to promote wound healing of open wounds and chronic wounds [16,17]. Apart from drawing wound edges together, the beneficial effect of NPWT involve multiple dimensions including reducing tissue oedema and bacterial bioburden, removing exudate in wounds and promoting angiogenesis and granulation tissue formation [18]. Mechanistically, these advantages of NPWT seem to be helpful in eliminating some of the aforementioned risk factors associated with SSIs. Actually, several systematic reviews with meta-analysis have suggested that NPWT can act as an effective measure to reduce SSIs following caesarean delivery, general surgery and orthopaedic surgery [19e21]. However, the 2016 WHO recommendations suggested that the quality of evidence was ranked as relatively low owing to weak statistical power, risk of bias and imprecision, resulting in a conditional recommendation [11]. Furthermore, the results of previous meta-analyses were challenged by many recently published randomized controlled trials (RCTs). Wihbey et al. [22] found that NPWT did not reduce the risk of SSIs in obese women undergoing caesarean delivery. Murphy et al. [23] claimed that prophylactic use of NPWT was not associated with a lower incidence of SSIs after open colorectal surgery. Additionally, some vagueness associated with NPWT still existed as to whether the effectiveness of NPWT can extend to some special subpopulations (e.g. patients with contaminated/dirty or clean contaminated wounds and patients undergoing clean surgeries with high-risk factors, including obesity). Also, the safety of NPWT and the influence of the implementation methods (e.g. types of negative pressure and duration of NPWT) on SSIs were largely unclear. Considering these aforementioned controversies and uncertainties, an updated meta-analysis of RCTs was performed to clarify the effectiveness and safety of NPWT for preventing SSIs. We focused on the effect of NPWT on SSIs in high-risk surgical patients, including obese patients. Moreover, trial sequential analysis (TSA) was employed to explore the robustness and creditability of the pooled effect. Materials and methods The systematic review and meta-analysis was performed following the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines and the Cochrane Handbook for Systematic Reviews of Interventions (Version 5.1.0) [24]. The protocol was pre-registered in the PROSPERO database (CRD42019119276). The processes of literature search, study selection, data extraction, quality assessment, and statistical analyses were independently undertaken by two reviewers, with inconsistencies resolved by a third reviewer. Search strategy and selection criteria Only RCTs comparing the effectiveness and safety of NPWT with standard surgical dressing or conventional therapy for preventing SSIs in adults surgical patients were included. We did not impose any restrictions with respect to surgery types, NPWT device types, the definition of SSIs, sample size and publication types. For studies with double publications or potential overlapping patients, we only included the final publications or studies with bigger sample size. Studies were excluded if they involved (1) paediatric surgery; (2) operations for infected or chronic non-healing wounds including diabetic, venous and arterial ulcers; and (3) if SSIs were not reported.

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Pubmed, Embase and the Cochrane library were systematically searched from inception until 10 April 2019 for eligible studies without limitations in language, publication status and date. In addition, we checked references of previous systematic reviews, meta-analyses and relevant reviews. We searched clinicaltrials.gov for any unpublished RCTs with available results. The full searching strategy of three databases are detailed in Table S1. Outcomes The primary outcome was surgical site infection at the longest follow-up reported, irrespective of the grading systems for SSIs. The secondary outcomes included wound dehiscence, wound haematoma, all adverse event-related outcomes, hospital readmission, hospital length of stay and hospital costs. All adverse event-related outcomes involved wound blisters, allergic skin reactions, mechanical skin damage or other adverse events associated with € rk et al. [25]. All NPWTs according to the definition by Svensson-Bjo the dichotomous outcomes were defined as the ones with the longest follow-up established in the individual included studies, irrespective of the definition and duration. Data extraction and quality assessment Baseline data including demographic characteristics, inclusion and exclusion criteria of candidate patients, risk factors for SSIs, types of surgical procedures and wounds, intervention details of NPWT and control group, definition of outcomes of interest and follow-ups were extracted from included studies. The quality of included studies was assessed using the Cochrane Collaboration risk of bias tool, including random-sequence generation, allocation sequence concealment, blinding of participants and personnel, blinding of outcome assessment, completeness of outcome data, selective reporting, and other sources of bias [26]. Furthermore, we performed quality of evidence assessment for quantitative pooled outcomes using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach (GRADEpro software) [27]. The certainty of the evidence based on RCTs was identified as default ‘high’ and could be downgraded owing to methodological limitations [28], inconsistency [29], imprecision of pooled estimates [30], indirectness of evidence [31] and evidence of reporting bias [32]. The certainty of evidence was categorized as high, moderate, low and very low. Data analysis Relative risks (RRs) and mean differences (MDs) with 95% confidence intervals (CIs) were used to calculate the pooled effect of NPWT for dichotomous outcomes and continuous outcomes respectively. The pooled estimates for dichotomous outcomes (ManteleHaenszel method) were based on the intention-to-treat (ITT) principle. For continuous outcomes (inverse variance method), we extracted the actual number of patients who completed the follow-up when considering the difficulty to calculate MDs and standard deviation (SDs) in an ITT model. For studies which provided medians with interquartile ranges (IQR), means with p values or medians with ranges we used approximation methods to estimate means and SDs [33,34]. Owing to substantial clinical and methodological heterogeneity across included studies, random-effects models were used for all the pooled analyses. Statistical heterogeneity was identified using forest plots, the chisquare test and the I2 statistic. I2 of more than 50% was deemed to represent significant statistical heterogeneity [35]. To clarify potential sources of statistical heterogeneity, we performed metaregression analyses for year of publication and sample size.

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Potential publication bias for the primary outcome was assessed using funnel plot inspection and the Egger test [36]. All the above analyses were performed using RevMan5.3.3 (Cochrane Collaboration) and STATA12.0 (Stata Corporation, College Station, TX, USA). To explore the robustness and creditability of the pooled estimate for the primary outcome, we conducted trial sequential analysis (TSA) to estimate the required information size (RIS) and monitor possible risk of random error and false positive [37]. The RIS and trial sequential monitoring boundary were calculated using two-sided 5% risk of a type I error, a power of 80%, an anticipated relative risk reduction of 15% and a control event rate of 17.7% (the pooled SSI rate in control group). TSA was undertaken using TSA software 0.9.5.10 (http://www.ctu.dk/tsa/).

contaminated operations and clean operations with highrisk factors as defined in the individual included studies. (3) Including only obese surgical patients (BMI 30). We also conducted subgroup analyses for the primary outcome according to (1) wound types (clean, clean contaminated and contaminated/dirty); (2) negative pressure (e125 mmHg and e80 mmHg); (3) NPWT duration(1e4 days, 5e7 days and >7 days). Tests for subgroups difference with p <0.05 were statistically significant. Results Study selection

Sensitivity analysis and subgroup analysis The following sensitivity analyses were performed to clarify the effect of NPWT on SSIs in some special subpopulations. (1) Including only high-quality studies defined as low risk of bias for ‘allocation concealment’ or for both the ‘allocation concealment’ and the ‘outcome assessor blinding’ domains. (2) Including high-risk patients for SSIs, defined as patients undergoing contaminated or dirty operations, clean

A total of 15 593 publications were obtained following systematic searching from three databases. After removing duplicates and irrelevant studies, 112 studies were identified for further fulltext assessment. Three studies investigating the effect of NPWT for SSIs in high-risk traumatic wounds were performed in the same institution (University of Alabama at Birmingham) and initiated at the same time (June 2001) [38e40]. Two studies [41,42] exploring the effect of NPWT on pelvic fractures, acetabular fractures and hip fractures were conducted by Crist and colleagues in the same

Fig. 1. PRISMA flow chart of studies selection. aClinicaltrials.gov and references of previous systematic reviews, meta-analyses, relevant reviews and included studies.

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institution and initiated at the same time (March 2008), both of which were included in a recent Cochrane review [43]. To avoid potential duplicated eligible patients in these studies, we only included the two latest publications after excluding the two with a smaller sample size and one preliminary abstract publication [40,42]. Of these studies, 41 trials met our inclusion criteria [22,23,40,42,44e80]. Additionally, we identified four eligible trials through the clinicaltrials.gov search and references of relevant studies [81e84]. Finally, we included 45 RCTs totalling 6624 surgical patients (39 full texts and six conference abstracts) in the meta-analyses [22,23,40,42,44e80] The detailed process of studies selection is shown in Fig. 1. Study characteristics All the included studies were published from 2006 to 2019 and sample sizes ranged from 30 to 876. Six studies were multicentre [22,40,47,53,55,72] and the others were single centre. Patients in included studies underwent different surgical procedures including fractures, joint arthroplasty, cardiovascular surgery, general surgery and caesarean delivery. Eleven studies involved contaminated/dirty surgical wounds [40,55,57,63,64,69,70,74,81,83,84], nine involved clean contaminated wounds [23,45,48,56,59,65,72,78,79], 24 involved clean wounds [22,42,44,46,47,49e54,58,60,61,66e68, 71,73,75e77,80,82] and one involved mixed wounds [62]. NPWT devices, definition of SSIs and follow-ups were varied among included studies (Table 1). Thirty-two trials included patients at high risk for SSIs [22,23,40,44,45,47,48,50,51,55e61,63e65,67e 70,72,74,77e81,83,84] and, of these, eight involved obese patients [22,47,51,58,60,68,77,80]. The detailed inclusion criteria and exclusion criteria of patients in included studies are shown in Table S2. Risk of bias assessment of the included studies is presented in Fig. S1. None of the included studies were deemed at low risk of bias in all the seven domains. Twenty-four studies [22,23,44,47,48,50,52e55,57,59,60,62,64,65,67,69,73,76e79,82] were identified as low risk of bias in ‘random-sequence generation’ domain and 23 as [22,23,44,47e49,52e55,57,59,62,65e68, 70,73,76,77,80,82] low risk of bias in the ‘allocation concealment’ domain. None of the trials were double-blinded owing to the fact that it was impossible to blind medical workers and surgical patients to NPWT and control group treatment. Fourteen studies [23,44,48e50,52,55,65e68,76,77,79] conducted ‘blinding of outcomes assessment’ and only one [62] study was classified as high risk of bias for this domain owing to the fact that the study assessor was not blinded to the treatment group and the outcome assessor was a senior member of the operating surgical team. Manufacturers of the negative pressure device played an important role in the funding of these studies and 18 studies [22,23,40,44,47,48,52,53,55,62,67,68,73,79e81,83,84] were considered as high risk of ‘other bias’ for this reason. The detailed judgment reasons for those domains rated as high risk of bias are detailed in Table S3. The primary outcome: SSIs All the included studies reported on SSIs, per eligibility and NPWT was associated with a 40% lower risk of SSIs than the control group, with moderate heterogeneity (RR 0.58; 95% CI 0.49e0.69; I2 ¼ 19%; Fig. 2). There was no obvious evidence of publication bias through visualization of the funnel plot and statistical tests (Egger test: p 0.125; Fig. 3a). NPWT significantly reduced the risk of SSIs in high-risk surgical patients (32 RCTs; RR 0.60; 95% CI 0.50e0.73; I2 ¼ 23%; Table 2), obese surgical patients (eight RCTs; RR 0.73; 95% CI 0.55e0.98; I2 ¼ 0; Table 2), and studies with low risk of bias for allocation

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concealment (23 RCTs; RR 0.62; 95% CI 0.50e0.79; I2¼26%; Table 2), or for allocation concealment and outcome assessor blinding (12 RCTs; RR 0.58; 95% CI, 0.41e0.82; I2 ¼ 38%; Table 2). Furthermore, we conducted TSA for the primary outcome. The cumulative Zcurve in the TSA crossed the trial sequential monitoring for benefit, but did not reach the RIS boundary (n ¼ 9185), establishing that the evidence for the effect is firm (Fig. 3b). NPWT was associated with reduced risk of SSIs in nearly all the subgroups, except for the subgroup of any wound type including a single unpowered trial and in the subgroup of NPWT duration >7 days (Table 2). No significant subgroup interactions were identified among the predefined subgroups (Table 2). There was no significant association between SSIs and year of publication (p 0.262) or sample size (p 0.194) on meta-regression (Fig. S2). Secondary outcomes Compared with the control group, NPWT led to a lower risk of wound dehiscence (17 RCTs; RR 0.80; 95% CI 0.65e1.00; I2 ¼ 4%; Table 3). There was no significant effect of NPWT on haematoma occurrence (nine RCTs; RR 0.91; 95% CI 0.40e2.07; I2 ¼ 11%; Table 3), hospital readmission (nine RCTs; RR 0.77; 95% CI 0.52e1.12; I2 ¼ 5%; Table 3) and length of hospital stay (15 RCTs; MD e0.38; 95% CI e0.78 to 0.02; I2 ¼ 73%; Table 3). The detailed description of all adverse event-related outcomes is shown in Table S4. NPWT significantly increased the risk of all adverse eventrelated outcomes (10 RCTs; RR 3.21; 95% CI 1.17e8.78; I2 ¼ 78%; Table 3). Blister formations were the most frequently reported adverse events and acted as the leading contributor to the significant increased risk of all adverse events in NPWT group. Only two studies reported hospital costs, but with conflicting results [50,76]. Gillespie et al. [76] found that patients in the NPWT group had higher per-day hospital cost than those in the control group. However, the study by Kwon et al. [50] suggested that the average variable hospital costs in the high-risk NPWT group were lower than those in the high-risk control group. Certainty of the evidence based on GRADE The certainty of the pooled effect estimate for SSIs was graded as ‘low’ owing to very serious risk of bias. Evidence for the pooled estimates of the secondary outcomes including wound dehiscence, haematoma, all adverse event-related outcomes, hospital readmission and hospital length of stay were graded as ‘very low’ (Table 3 and Table S5). Discussion Main findings The current study indicates that NPWT may be associated with a lower incidence of SSIs than the control group. Furthermore, the effectiveness of NPWT may extend to some high-risk surgical subpopulations including obese patients. The level of certainty was identified as ‘very low’ for all the secondary outcomes, so we are uncertain whether NPWT reduces or increases the risk of wound dehiscence, hematoma, hospital readmission, and all adverse event-related outcomes or if it shortens or prolongs length of hospital stay. Compared with previous studies Many reviews with meta-analysis have been performed to assess the effectiveness of NPWT for SSIs, but their results were inconclusive and restricted by small sample size, weak statistical

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Table 1 Characteristics of included studies Fist author year

Clinical settings No. randomized Type of procedure (intervention/ control)

Wound categories (closure or not)

Details of NPWT* (setting/ status/duration)

Control group

Definition of SSIs

Follow-up

Article type

Howell 2011 [80]

Single-centre

24/36

Total knee arthroplasty

Clean (closed)

Sterile gauze dressing

Self-definition

12 months

Full text

Masden 2012 [79]

Single centre

50/43

Lower extremity or abdominal wounds

Clean contaminated (closed)

VAC (e125 mmHg/continuous pressure/48 hr) VAC (e125 mmHg/continuous pressure/3 d)

Stannard 2012 [40] Multicentre

130/119

Lower extremity fractures

Contaminated/dirty (closed)

Jayakumar 2013 [83] Biter 2014 [78]

Single centre

20/20

Severe open fractures

Single centre

24/25

Chaboyer 2014 [77] Single centre

46/46

Gupta 2014 [84]

Single centre

15/15

Open musculoskeletal injuries

Contaminated/ dirty(open)

Gillespie 2015 [76] Single centre

35/35

Primary hip arthroplasty

Clean (closed)

Hasselmann 2015 [82] Witt-Majchrzak 2015 [75] Arti 2016 [74]

Single centre

64/63

Vascular surgical procedure Clean(closed)

Single centre

40/40

Single centre

45/45

Off-pump coronary artery bypass grafting procedure Open fracture

Karlakki 2016 [73]

Single centre

110/110

Leon 2016 [72]

Multi-centre

47/34

Total hip and knee arthroplasties Colorectal surgery

Sabat 2016 [71] Uchino 2016 [70]

Single centre Single centre

30/33 28/31

Vascular surgery Ileostomy closure

Virani 2016 [69]

Single centre

43/50

Open fracture

Crist 2017 [42]

Single centre

33/33#

Acetabular fracture

Clean-contaminated (closed) Clean(closed) Contaminated/dirty (closed) Contaminated/dirty (open) Clean(closed)

Gunatilake 2017 [68] Lee 2017a [66]

Single centre

46/46

Caesarean delivery

Clean(closed)

Single centre

53/49

Revascularization procedures

Clean(closed)

Lee 2017b [67]

Single centre

33/27

Cardiac surgery

Clean(closed)

Li 2017 [65]

Single centre

33/38

Open abdominal surgery

Lozano-Balderas 2017 [64]

Single centre

25/29

Laparotomy

Clean-contaminated (closed) Contaminated/dirty (open)

Clean(closed) Contaminated/ dirty(open) Clean(closed)

Standard dry dressings Self-definition

Conventional sterile dressing VAC (e125 mmHg/continuous Silicone wound pressure/14 d) dressing PICO(NA/NA/4 d) Comfeel Plus standard dressing VAC (e125 mmHg /intermittent Sterile dressing pressure /changing on 3e4 d depending upon the amount of drain) PICO (e80 mmHg/continuous Hydrocolloid and pressure/5 d or maintain until standard Dressing discharge) PICO (e80/continuous Standard wound pressure/7 d) dressing PICO (e80 mmHg/continuous Conventional dressings pressure/6 d) VAC(e125 mmHg /intermittent Conventional dressings pressure/10e14 d) PICO (NA/NA/7 d) OPSITE post-op visible dressing NA Usual dressing Prevena (NA/NA/5 d) PICO (NA/NA/2 w)

Average follow- Full text up was 113 days 6 yeas Full text

Self-definition

3 years

Full text

Self-definition

6 months

Full text

CDC criteria

28 days

Full text

Self-definition

6 weeks

Full text

CDC criteria

6 weeks

Full text

CDC criteria and Szilagyi classification ECDC criteria

90 days

Abstract

6 weeks

Full text

Self-definition

1 months

Full text

Self-definition

6 weeks

Full text

NA

30 days

Abstract

12 months 30 days

Abstract Full text

(17-29) weeks

Full text

12 weeks

Full text

(32-52) days

Full text

90 days

Full text

6 weeks

Full text

30 days

Full text

6 months

Full text

Conventional dressings NA Adhesive wound Self-definition dressing VAC (e125 mmHg/intermittent Cleaning dressing Self-definition pressure /NA) VAC (e125 mmHg/continuous Standard dry dressings Self-definition pressure/at least 48 h) Prevena (e125 mmHg/ Sterile gauze dressings Self-definition continuous pressure/5e7 d) CDC criteria Standard surgical Prevena (NA/continuous pressure/8 d or maintain until dressing discharge) Conventional dry gauze ASEPSIS score Prevena (e125 mmHg/ continuous pressure/maintain dressings until discharged or to a maximum of 7 d) VSD (e125 mmHg/continuous Traditional gauze CDC criteria pressure/3 d) dressing Standard surgical CDC criteria VAC(NA/NA/maintain until dressing healthy granulation tissue development)

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Contaminated/dirty (open) Surgical excision for Clean pilonidal sinus contaminated(open) Elective caesarean sections Clean (closed)

VAC (e125 mmHg/continuous pressure/maintain until discharge) VAC(NA/NA/NA)

Standard dry dressings Self-definition

Single centre

17/34

Perforator flap

Single centre

25/25

Laparotomy

Pleger 2017 [61]

Single centre

43/57

Vascular surgery

Contaminated/dirty (closed) Clean, cleancontaminated, and contaminated (closed) Clean(closed)

Ruhstaller 2017 [60] Shen 2017 [59]

Single centre

67/69

Caesarean section

Clean(closed)

Single centre

132/133

Sibin 2017 [81]

Single centre

15/15

Tuuli 2017 [58] Bobkiewicz 2018 [56] Costa 2018 [55]

Single centre Single centre

60/60 15/15

Multicentre

226/234

Engelhardt 2018 [54] Galiano 2018 [53]

Single centre

67/74

Laparotomy for neoplasms Clean-contaminated (closed) Open tibia fractures Contaminated/dirty (open) Caesarean delivery Clean(closed) Stoma reversal procedure Cleancontaminated(closed) Open Fracture of the lower Contaminated/dirty limb (open) Vascular surgery Clean(closed)

Multicentre

200/200

Clean(closed)

VSD (e125 mmHg/continuous pressure/5e7 d) PICO(e80 mmHg /NA/4 day)

Conventional wound dressing Standard dressing

Prevena (e125 mmHg/NA/5 e7 d) Prevena (NA/NA/3 d) VAC (e125 mmHg/continuous pressure/4 d) VAC(NA/Intermittent pressure/ NA) PICO(e80 mmHg /NA/4 d) NPWT was applied every 3 days Openecell solid foam and sealed dressing(NA/NA/NA) Prevena (e125 mmHg/ continuous pressure/5 d) PICO(e80 mmHg/NA/7 d)

Gombert 2018 [52] Single centre

98/90

Bilateral reduction mammoplasty Vascular surgery

Hussamy 2018 [51] Single centre

222/219

Caesarean delivery

Clean(closed)

Hyldig 2018 [47] Javed 2018 [48]

Multi-centre Single centre

432/444 62/61

Caesarean section Pancreaticoduodenectomy

Kwon 2018 [50]

Single centre

61/62

Vascular surgery

Clean(closed) Cleancontaminated(closed) Clean(closed)

Muller-Sloof 2018 [49] Murphy 2018 [23]

Single centre

25/26

Single centre

144/140

Elective breast reconstruction Colorectal surgery

Newman 2018 [44] Single centre

80/80

Revision arthroplasty

Clean(closed)

Shim 2018 [57]

Single centre

30/21

Multitissue hand injuries

Keeney 2018 [46]

Single centre

263/263

Wihbey 2018 [22]

Multi-centre

80/81

Total knee or hip arthroplasty Caesarean delivery

Contaminated/dirty (closed) Clean (closed)

Prevena (e125 mmHg/ continuous pressure/5e7 d) Prevena (e125 mmHg/ continuous pressure/2e7 d) PICO(NA/NA/5 d) Prevena (e125 mmHg/ continuous pressure/4 d) Prevena (e125 mmHg/ continuous pressure/5 d) Prevena (e125 mmHg/NA/5 e7 d) Prevena (e125 mmHg/ continuous pressure/5 d or maintain until discharge) Prevena (NA/continuous pressure/at least 2 d or maintain until discharge) CuraVAC (e75 mmHg /Continuous pressure/2 w) PICO (e80 mmHg /NA/7 d)

Clean (closed)

Prevena (NA/NA/5e7 d)

Ker 2019 [45]

Single centre

28/21

Clean(closed)

Clean(closed) Clean contaminated(closed)

Split-Skin Grafting for Skin Clean Cancer contaminated(closed)

Acti-vacuumeassisted closure dressing (e125 mmHg /continuous pressure/5e7 d)

Self-definition

Short-term

Full text

CDC criteria

30 days

Full text

Conventional adhesive Szilagyi classification plaster Standard dressings Self-definition

30 days

Full text

4 weeks

Full text

Standard sterile dressing Sterile dressings

CDC criteria

30 days

Full text

Self-definition

At least 6 weeks Full text

Standard dressings Standard dressing

CDC criteria NA

30 days NA

Abstract Abstract

Standard dressings

CDC criteria

12 months

Full text

6 weeks

Full text

90 days

Full text

Szilagyi classification

30 days

Full text

NA

18 months

Abstract

Self-definition CDC criteria

30 days 30 days

Full text Full text

Szilagyi classification

30 days

Full text

Self-definition

4 weeks

Full text

Standard gauze dressing

CDC criteria

30 days

Full text

Silver-impregnated wound dressing

Self-definition

12 weeks

Full text

Conventional dressing

Self-definition

1 year

Full text

Standard postsurgical dressings Sterile slim adhesive strips Traditional bolster dressing

Self-definition

2 years

Full text

CDC criteria

6 weeks

Full text

Self-definition

3 months

Full text

Absorbent adhesive Szilagyi classification dressing Standard care dressings Self-definition Standard wound dressings Standard surgical dressing Standard dressing Standard dressing Standard gauze dressing Adhesive strips

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Mendame-Ehya 2017 [63] Oleary 2017 [62]

d, days; w, weeks; NPWT, negative pressure wound therapy; CDC criteria, Center for Disease Control criteria; ECDC criteria, European Centre for Disease Prevention and Control; ASEPSIS, Additional treatment, the presence of Serous discharge, Erythema, Purulent exudate, and Separation of the deep tissues, the Isolation of bacteria, and the duration of inpatient Stay; NA, not available. *Only the actual NPWT details available in included studies were extracted.

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Fig. 2. Effect of NPWT on preventing SSIs in all included trials. The current pooled estimate was based on random effect model and intention-to-treat (ITT) principle. NPWT, negative pressure wound therapy; SSI, surgical site infection; CI, confidence interval; M-H, ManteleHaenszel.

power, risk of bias, imprecision and methodological pitfalls. A recent systematic review by Sahebally et al. [19] also found that the incidence of SSIs was lower in the NPWT group. However, RCTs and observational studies were inappropriately incorporated to estimate the overall pooled effect, which introduced into substantial statistical heterogeneity (I2 ¼ 66%) and degraded the quality of evidence. On the contrary, a review published in 2017 found that NPWT did not provide a significant advantage in preventing SSIs among obese women undergoing caesarean delivery [85].

However, the limited included number of studies (four RCTs) with a small sample size (408 women) led to imprecision. A recent updated Cochrane review also verified the effectiveness of NPWT in reducing the risk of SSIs [43]. However, the review only included 23 RCTs with 2533 surgical patients undergoing surgical wounds healing by primary closure and the reviewers did not further explore the robustness and creditability of the pooled estimate for SSIs and the potential effect of NPWT on SSIs in high-risk surgical patients.

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Fig. 3. Funnel plot and trial sequential analysis for NPWT on preventing SSIs in all included trials. (a) Funnel plot comparing NPWT with control group for SSIs(Egger test: p 0.125). Pink circles denote individual included studies. (b) The accumulative Z-curve crossed the trial sequential monitoring for benefit, but not reached the RIS boundary (n ¼ 9185), which suggested the evidence level of the current pooled estimate was sufficient powerful and robust. The RIS and trial sequential monitoring boundary were calculated using 2-sided 5% risk of a type I error, a power of 80%, an anticipated relative risk reduction of 15%, and a control event rate of 17.7% (the pooled SSI rate in control group). NPWT, negative pressure wound therapy; SSI, surgical site infection; RIS, required information size. Table 2 Sensitivity and subgroup analysis of NPWT for SSIs Outcomes

Number of trials (references)

NPWT (n/N) Control (n/N) Risk ratio (95% CI) p for overall effect I2 (%) p for interaction

Primary analysis (random effect model, ITT) Sensitivity analyses for SSIs Studies with low risk of bias for allocation concealment Studies with low risk of bias for allocation and concealment and outcome assessor blinding High-risk patients

45[22,23,40,42,44e80]

280/3285

474/3339

0.58 (0.49e0.69)

＜0.00001

19

23 [22,23,44,47e49,52e55,57,59, 62,65e68,70,73,76,77,80,82]

185/2070

292/2088

0.62 (0.50e0.79)

＜0.0001

26

12 [23,44,48,49,52,55,65e68,76,77]

108/881

169/872

0.58 (0.41e0.82)

0.002

38

32 [22,23,40,44,45,47,48,50,51,55e61, 63e65,67e70,72,74,77e81,83,84] 8 [22,47,51,58,60,68,77,80]

230/2343

370/2372

0.60 (0.50e0.73)

＜0.00001

23

71/977

101/1001

0.73 (0.55e0.98)

0.03

0

Obese patients(BMI30) Subgroup analyses based on wound types Clean Clean-contaminated Contaminated/dirty Any wound types Subgroup analyses based on NPWT negative pressure* Negative pressure (e125 mmHg) Negative pressure (e80 mmHg) Subgroup analyses based on NPWT duration* 1e4 d 5e7 d 7d

NA

0.5 24 [22,42,44,46,47,49e54,58,60,61,66e68, 71,73,75e77,80,82] 9 [23,45,48,56,59,65,72,78,79] 11 [40,55,57,63,64,69,70,74,81,83,84] 1 [62]

135/2131

238/2191

0.60 (0.49e0.74)

＜0.00001

0

88/535 55/594 2/25

118/510 110/613 8/25

0.63 (0.41e0.97) 0.50 (0.36e0.69) 0.25 (0.06e1.06)

0.04 ＜0.0001 0.06

43 9 NA 0.98

22 [23,40,42,45,48e52,54,59,61,63,65, 66,68,69,74,78,79,84,85] 7 [46,53,58,62,75,76,82]

161/1375

259/1394

0.59 (0.45e0.77)

0.0001

33

22/609

41/636

0.59 (0.35e1.00)

0.05

0 0.83

9 [48,58e60,62,65,77,79,85] 19 [22,23,45e47,49,50,52e54,61, 63,66,68,73,75,76,82,85] 5 [57,67,70,74,78]

49/499 132/1735

81/511 223/1794

0.60 (0.38e0.95) 0.59 (0.45e0.78)

0.03 0.0001

31 22

15/180

19/171

0.74 (0.39e1.40)

0.35

0

d, days; NPWT, negative pressure wound therapy; NA, not available; SSIs, surgical site infection. * Only the actual NPWT details available in individual included studies were analysed.

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Table 3 The GRADE evidence quality for main outcomes Outcomes

Number of trials (references)

NPWT (n/N)

Control (n/N)

RRs or MDs with 95% CIs

p for overall effect

I2 (%)

Quality

SSIs Wound dehiscence

45 [22,23,40,42,44e80] 17 [22,40,44,47,49e51,53,57e59,61, 68,75,76,79,85] 9 [22,44,45,50,57,59,61,75,76] 10 [22,44,58,60,66,73,75,77,78,85]

280/3285 159/1696

474/3339 199/1699

0.58 (0.49e0.69) 0.80 (0.65e1.00)

＜0.00001 0.05

19 4

Low a Very lowa,b

14/529 73/561

20/530 32/572

0.91 (0.40e2.07) 3.21 (1.17e8.78)

0.82 0.02

11 78

Very lowa,c Very lowa,c,d

9 [22,44,48,50,51,59,67,76,77] 15 [22,23,44,48,50,52,60e62,66,67,73,74,76,77]

51/771 954

64/766 953

0.77 (0.52e1.12) e0.38 (e0.78 to 0.02)

0.17 0.06

5 73

Very lowa,b,c Very lowa,e

Haematoma All adverse event-related outcomes Hospital readmission Hospital length of stay

GRADE, Grading of Recommendations, Assessment, Development, and Evaluations (GRADE); SSIs, surgical site infection; RR, relative risk; MD, mean difference. a At least one domain was identified as high risk of bias in all included studies. b The funnel plot seems to be asymmetric. c Wide confidence interval. d Significant statistical heterogeneity(I2 ¼ 78%). e Significant statistical heterogeneity(I2 ¼ 73%).

Compared with previous studies, our systematic review included more studies (45 RCTs) with a larger sample size (6624 surgical patients). Moreover, TSA confirmed that the current evidence was basically conclusive and further studies are unlikely to reverse the results. Additionally, sensitivity analyses confirmed that the advantage of NPWT consistently existed in high-risk subpopulations, which may facilitate the generalizability of NPWT for surgical wounds management. Potential implications for clinical practice Many clinical practice guidelines recommended that NPWT can be used for closed surgical wounds in high-risk patients or highrisk surgical procedures. However, the evidence for routine use of NPWT was limited by low quality of evidence from the small number of RCTs [11,86,87]. Another reason hampering the prioritized use of NPWT is the high hospital costs and poor availability of the devices, especially in some low-resource settings [11]. The current study indicated that NPWT may lead to a lower incidence of SSIs when compared with standard care in high-risk surgical wounds. Few RCTs included studies investigated the costeffectiveness of NPWT for preventing SSIs in our systematic review. However, the advantage of cost-effectiveness for NPWT was supported by many previous studies involving in high-risk surgical incisions, including coronary artery bypass grafting surgery, highrisk abdominal incisions, joint replacements and caesarean section in obese women [88e91]. It is noteworthy that the risk of adverse events overall in NPWT group was about 3.2 times higher than that in control group. Non-optimal NPWT deployment might have been responsible for the occurrence of these adverse events. Our study analysed the effects of NPWT on SSIs using different negative pressures and NPWT duration. However, the optimal strategy (e.g. negative pressure target, duration and dressings change frequency) for surgical wound management remains largely unclear. Therefore, further studies assessing the optimal NPWT strategy are warranted. Limitations Our study has many limitations. Firstly, all the included studies had at least one domain identified as high risk of bias. The relative low quality of included studies seriously degraded the quality of evidence and impaired the credibility of the overall pooled effect estimate. Nonetheless, the results of subgroup analyses, sensitivity analyses, and TSA are basically consistent with the overall pooled effect, which supports that the benefit of NPWT for preventing SSIs is robust and reliable.

Secondly, it is hard to ignore the potential clinical and methodological heterogeneity across included studies owing to the broad inclusion criteria in our systematic review, although the statistical heterogeneity was low. Random effect model was employed to conservatively estimate the effect of NPWT on SSIs. Furthermore, we undertook subgroup analyses and metaregression analyses to explore the underlying heterogeneity. However, no significant factors were identified. A possible interpretation is that the statistical heterogeneity may not be attributable to an individual factor, but multiple clinical and methodological factors within or between included studies. For length of hospital stay, some included studies reported skewed distributed data. There are no generally accepted methods to deal with skewed distributed data in meta-analyses. We used two established approximation methods to estimate means with standard deviations. The methods can perform very well for both normal data and skewed data by taking the sample size into consideration. However, it may still be inappropriate to use means to estimate the pooled effect of skewed continuous outcomes. Conclusions NPWT may be associated with less SSIs as compared with standard wound care. Further studies are warranted to explore the optimal methodology of using NPWT. Transparency declaration This study was supported by grants from the National Natural Science Foundation of China (nos. 81772384 and 81572174). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. All the authors do not have conflict of interests to declare. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.cmi.2019.06.005. References [1] Sax H, Uckay I, Balmelli C, Bernasconi E, Boubaker K, Muhlemann K, et al. Overall burden of healthcare-associated infections among surgical patients. Results of a national study. Ann Surg 2011;253:365e70. [2] Merkow RP, Ju MH, Chung JW, Hall BL, Cohen ME, Williams MV, et al. Underlying reasons associated with hospital readmission following surgery in the United States. JAMA 2015;313:483e95.

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