Negative Pressure Wound Therapy versus Gauze Dressings in Managing Open Fracture Wound of Lower Limbs: An Update Meta-Analysis of Randomized Controlled Trials

Whether the negative pressure wound therapy (NPWT) is superior to standard gauze dressings in managing open fracture wounds of lower limbs still remains a controversy. Herein, we updated a meta-analysis only including RCTs to comprehensively compare the clinical ecacy of the two dressings. Materials and methods We searched various databases including PubMed, Web of Science, Medline, Clinicaltrial.gov and Cochrane Library to screen eligible RCTs. Data extraction was performed by two reviewers independently. The data analysis was carried out using the Review Manager 5.3 software. Results There were 10 RCTs, along with 2780 patients, eligible for meta-analysis. We found patients in the NPWT group showed lower overall infection rate (MD = 0.70, 95% CI: 0.54 − 0.90, P = 0.005), acute wound infection rate (MD = 0.35, 95% CI: 0.16 − 0.77, P = 0.009) and shorter hospital stay (MD = 24.00, 95% CI: 6.82– 84.46, P < 0.00001) as compared with the control group. And the NPWT group showed higher proportion of patients with wound coverage than the control group. While no signicant difference was found between the two groups in terms of function score and other complications including deep infection rate, amputation and bone nonunion. Conclusion Based on the pooled results, we suggested that NPWT could be an alternative choice over traditional gauze dressings in managing the wound of open fracture of lower limbs.

Vacuum-assisted closure) AND (Fracture OR Open fracture). There is no limitation on the study design, publication status and publication years when searching databases. The reviewers also screened the reference list of included studies for additionally eligible studies.

Inclusion and Exclusion Criteria
Only prospective randomized controlled trials (RCTs) directly comparing the clinical outcomes between NPWT and standard gauze dressings for the wound management of open fracture of lower limbs were included. Inclusion criteria: (1) RCTs in English (published or unpublished); (2) Studies reporting that all patients suffering from open fracture of lower limbs were managed with NPWT (any systems) or traditional gauze dressings; (3) Studies reporting the following clinical outcomes: Overall infection rate, deep infection rate, acute wound infection rate, time for wound healing, disability rating index (DRI), positive rate for culturing, length of hospital stay and complications. et. al; (4) Studies available for full-text. Exclusion criteria: (1) Non-RCTs; (2) Only one study should be included for repeated studies involving the same patients; (3) Studies only reporting the cost-effectiveness analysis of NPWT; (4) Studies including patients treated with other management; (5) Studies reporting more than 20% patients were lost to follow-up.

Study selection
A total of 967 records were identi ed through originally searching in various databases and screening the reference lists. After 296 duplicates were removed by EndNote™ automatically and manually, the title and abstract of the remaining 671 records were screened for eligibility. Two reviewers conducted full-text review in 23 studies for potentially eligible studies, and 13 studies were excluded (3 systematic review, 2 content irrelevant, 8 non-RCTs). Finally, 10 RCTs were included in the present meta-analysis. Any disagreements were settled by a third author (Y.H.). The ow diagram of study selection was shown in Figure. 1.

Study Quality Assessment
Two reviewers assessed the quality of the included studies independently according to the Cochrane Collaboration's tool for assessing risk of bias in RCTs [19]. The study quality assessment comprised 7 items including random sequence generation, allocation concealment, blinding of participants and personnel, incomplete outcome data, selective reporting, and other bias. All of these items were rated as high risk, low risk and unclear risk. Any disagreement about the study quality assessment was addressed by discussion and consultation.

Data Extraction
Data extraction was performed by two independent reviewers. All relevant data in included RCTs was collected in a prepared form, and data presented as mean and 95 % con dence interval (CI) was transformed to the form of mean ± SD according to the Cochrane Handbook [20]. The baseline data comprised of the rst author, study design, publication years, country, number of patients, mean age, sex and duration of following up. The clinical characteristics of included patients contained Gustilo and Anderson classi cation, preoperative diagnosis of diabetics, smoking and method of wound closure. The data of clinical outcomes included overall infection rate, deep infection rate, acute wound infection rate, time for wound healing, DRI, the quality-of-life EuroQol-5 Dimensions (EQ-5D), positive rate for culturing, length of hospital stay and complications. A discussion was conducted to reach agreement if any disagreements between reviewers occurred.

Statistical Analysis
Data analysis was completed using Review Manager (RevMan, Version 5.4, USA). Dichotomous data was analyzed and presented with Odd Ratio (ORs) and 95% con dence intervals (95% CI), and continuous data was presented with Mean difference (MD) and 95% CI. Heterogeneity was assessed by the I 2 test, and signi cant heterogeneity existed if P < 0.10 and I 2 > 50%. If the heterogeneity was signi cant, a random-effect model was applied, otherwise, a xed-effect model was used. A P value < 0.05 was considered as statistically signi cant.

Characteristics of included RCTs
Eventually, a total of 10 RCTs involving 2780 patients, comprising of 1394 patients managed with NPWT and 1386 patients managed with traditional gauze dressings, were included in this meta-analysis [3,7,9,12,17,[21][22][23][24][25]. The baseline data of included RCTs was presented in Table 1. Each included study was prospective randomized controlled trial, and the publication years ranged from 2009 to 2021. Most studies were completed in Asia (seven studies), two in Europe and another one in America. The follow-up period ranged from 1 to 36 months and the mean age ranged from 31.9 to 49.8 years. Overall, there was no signi cant difference in patient number, mean age, BMI, follow-up period and sex proportions between the two groups. The clinical characters of included RCTs were summarized in Table 2. All patients were Type II or III fracture according to the Gustilo and Anderson classi cation. Similarly, there were no signi cant difference between the NPWT and control groups in terms of fracture type, diagnosis of diabetics, smoking and method of wound closure. Figure. 2 showed the quality evaluation of included RCTs. As a whole, the risk of bias of included studies was minor, but three studies were rated to high risk in blinding of participants and personnel [3,12,17]. Most studies were judged as unclear risk because the authors did not state the random sequence generation, allocation concealment, blinding of outcome assessment and incomplete outcome data clearly.   Figure. 3b, a xed-effect model was applied for analysis due to the absence of signi cant heterogeneity (P = 0.45, I 2 = 0%), and no signi cant difference was detected between the two groups (MD = 0.76, 95% CI: 0.58 − 1.00, P = 0.05). Regarding the rate of acute wound infection, 5 RCTs containing 315 patients were included for meta-analysis [7,9,22,23,25]. Data analysis was performed with a xed-effect model because the heterogeneity was not signi cant (P = 0.29, I 2 = 20%), and the pooled results suggested that the rate of acute wound infection in the NPWT group was signi cantly reduced (MD = 0.35, 95% CI: 0.16 − 0.77, P = 0.009) (Figure. 3c). The positive rate for culturing was provided in 3 studies (185 patients) [7,24,25]. As shown in Figure. 3d, without signi cant heterogeneity (P = 0.67, I 2 = 0%), we conducted the data analysis using a xed-effect model. The merged result showed that NPWT was effective in reducing the positive rate for culturing (MD = 0.19, 95% CI: 0.08 − 0.45, P = 0.0001) compared with traditional gauze dressings. Likewise, we collected data about the rate of clinical infection from positive culturing in 2 RCTs [7,25]. After merging with a xedeffect model, no signi cant difference was identi ed between the two groups (MD = 1.21, 95% CI: 0.29 − 5.06, P = 0.80) ( Figure. 3e).

E cacy evaluation of promoting wound healing
Time for wound ready for closure Regarding the time for wound ready for closure, data from 152 patients in 2 RCTs was available for data analysis [7,9]. As presented in Figure. 4a, because no signi cant heterogeneity was found (P = 0.42, I 2 = 0%), a xed-effect model was utilized to nish the meta-analysis, demonstrating that NPWT signi cantly shortening the time for wound ready for closure (MD =-1.19, 95% CI: -2.03 − 0.35, P = 0.006).

Time for the wound coverage
Regarding the Time for the wound coverage, data was provided in 2 RCTs involving 70 patients [22,23]. Because of the absence of signi cant heterogeneity (P = 0.92, I 2 = 0%), we used a xed-effect model to perform the data synthesis and detected that more wound coverage was completed within 3 weeks in the NPWT group (MD = 24.00, 95% CI: 6.82-84.46, P < 0.00001), as depicted in Figure.

Length of hospital stay
In terms of length of hospital stay, 2 RCTs were included for data analysis [22,23]. For length of hospital stay < 1 month, as shown in Figure. 5c, the heterogeneity was not signi cant (P = 0.92, I 2 = 0%) and a xed-effect model was used for data analysis, showing that more patients in the NPWT group discharged within 1 month postoperatively (OR = 24.00, 95% CI: 6.82-84.46, P < 0.00001). On the contrary, more patients in the ST group discharged beyond 1 month postoperatively (OR = 0.04, 95% CI: 0.01-0.15, P < 0.00001) (Figure. 5d). In short, NPWT shortened the length of hospital stay signi cantly.

Complications
Due to the data availability, we selected 2 complications containing amputation and bone nonunion for meta-analysis, which were reported in 2 RCTs at least. We merged each complication with a xed-effect model because the heterogeneity was not signi cant. The pooled results were summarized in Figure. 6. The difference between NPWT and ST regarding each complication was not statistically signi cant.

Discussion
Open fracture of lower extremities, especially for Gustilo type tibia fracture, is a challenging problem for orthopedists, which is usually companied with severe soft tissue injuries and wound contamination [12]. The wound management is a critical part in the treatment of open fracture of lower extremity. Different from standard gauze dressings, the NPWT is a special dressing with negative pressure exerted on the wound area, and the negative pressure on the wound was reported to promote the healing of various wound [7]. Currently, NPWT has been a conventionally used dressing for managing the wound of open fracture of lower extremities in some medicine institutions. However, recent publications including systematic reviews and RCTs could not reach an agreement with respect to the clinical superiority of NPWT over traditional dressings [2,3,15,17]. In this study, we updated such a meta-analysis only including RCTs to comprehensively compare the clinical e cacy of traditional gauze dressings and NPWT. Postoperative infection is a severe complication for open fracture of lower extremities, the incidence of which was signi cantly higher than that of closed fracture [26,27]. Therefore, the postoperative infection rate was a prominent indicator for evaluating the treatment choice of open fracture. After pooling and analysing the available data, we found that patients receiving NPWT showed lower total infection rate and acute wound infection rate than patients receiving traditional gauze dressings, which was consistent with the previous systematic reviews [2,15]. The two published reviews suggested that the reduced acute wound infection rate may be due to the promoting-healing effect of the negative pressure on the wound area, since there were su cient evidence suggesting that NPWT could promote wound healing through reducing oedema, increasing tissue granulation and angiogenesis [16,28]. We also found that the proportion of patients with suture conditions in the NPWT group was higher within three weeks, and the proportion of patients with wound healing in the NPWT group was higher than that in the control group within six weeks. This founding suggested that the use of NPWT could accelerate wound healing of open fracture of lower limbs. In addition, we also found that the positive rate of bacterial culture in the NPWT group was lower than the control group, but no signi cant difference was detected in the clinical infection rate of culturepositive patients in both groups. This founding suggested that the use of NPWT had a bacterial-removal effect, which was consistent with previous experimental researches and proved the clinical effect of NPWT on reducing the acute wound infection rate to a certain degree [14,29].
However, it was worth noting that we found no signi cant difference between the two groups with respect to the deep infection rate in our study. For open fracture of lower extremities, deep site infection is a more serious and complex complication than the acute wound infection. And whether the application of NPWT could reduce the deep infection rate still remained a controversy. Stannard JP et al reported a lower deep infection rate in the NPWT group (5.4%) than the control group (20%) receiving traditional gauze dressings [7]. However, this RCTs only included 59 patients and the small ample size limited its evidence level. Meanwhile, some large multicenter RCTs recently reported no signi cant difference between the NPWT and control groups regarding the deep infection rate, which was consistent with the pooled results in this study [3,17]. In fact, the occurrence of deep infection is associated with many factors, such as fracture type and antibiotic intervention. Dedmond [30]. Therefore, the choice of wound dressings is not the critical determinant for reducing the deep infection incidence of open fracture of lower limbs. As for other complications, we found no signi cant difference between the two groups in term of amputations and bone nonunion rate, the occurrence of which was also multifactorial and not determined by the choice of dressings [2]. There were two RCTs evaluating the function restoration of lower limbs after receiving NPWT or traditional dressings therapies. We found that patients in the NPWT group showed higher DRI score than the control group at 3 months (mean difference: 0.49, 95% CI: 0.23-0.76) and 6 months (mean difference: 0.41, 95% CI: 0.10-0.72). Although a statistically signi cant difference was detected between the two groups in the DRI score, this subtle difference made no clinical signi cance. Meanwhile, we found no signi cant difference between the two groups in EQ-5D score. The pooled results of function score suggested no superiority of NPWT over traditional gauze dressings in terms of lower extremity function recovery. However, we found that the proportion of patients hospitalized less than 1 month in the NPWT was signi cantly higher than the control group. The reduced hospitalization of the NPWT group may be contributed to the promoting wound-healing and bacterial clearance effect of NPWT. Overall, based on the pooled results of our analysis, we suggested that NPWT could be an alternative choice over traditional gauze dressings in managing the wound of open fracture of lower limbs, since we found that NPWT could reduce the acute wound infection rate and promote wound healing, thereby reducing the hospitalization of patients.

Study strengths and limitations
This updated meta-analysis included 10 RCTs, with a total of 2780 patients included. The inclusion of RCTs and the large sample size improved the evidence level of this study. To our best knowledge, this is the rst meta-analysis including all the RCTs to compare the clinical e cacy of NPWT and traditional gauze dressings on treating open fracture of lower limbs. Nevertheless, some limitations should be noti ed when generalizing the conclusion of this study. Firstly, due to the data availability, we cannot perform a subgroup analysis to compare the clinical effects of the two dressings on different types of open fracture wounds of lower limbs, which could result in the production of heterogeneity. Secondly, the longest follow-up period of these included RCTs was 1 year and the lack of long-term follow-up data impaired the evidence level in this study. Finally, the language bias should be noti ed since we only included studies published in English.

Conclusion
The present study found that the application of NPWT for treating open fracture of lower limbs could reduce the acute wound infection rate and total infection rate, promote wound healing and shorten hospital stay, as compared with traditional gauze dressings. Meanwhile, no signi cant difference was found between the two groups in term of deep infection rate, DRI and EQ-5D score. Herein, we suggested that NPWT could be an alternative choice over traditional gauze dressings for managing the wound of open fracture of lower limbs.