Standard abdominal wound edge protection with surgical dressings vs coverage with a sterile circular polyethylene drape for prevention of surgical site infections (BaFO): study protocol for a randomized controlled trial

Postoperative surgical site infections (SSIs) are one of the most frequent surgical complications and a major cause of postoperative morbidity, prolongation of hospital stay, healthcare costs and even mortality. An estimated 300,000 to 500,000 SSIs occur in the USA annually [1‐4]. In Germany SSIs are the third most frequent cause of nosocomial infections and account for approximately 15% of the 400,000 to 600,000 nosocomial infections per year (60,000 to 90,000 cases) according to data from the Robert-Koch Institute (RKI) and the German Nationales Referenzzentrum für Surveillance von Nosokomialen Infektionen (NRZ) [5, 6]. Data from the German Krankenhaus Infektions-Surveillance-System (KISS) estimate an even higher number of approximately 128,000 SSIs annually [6]. Furthermore, an estimated 7,500 to 15,000 patients die every year in Germany due to nosocomial infections [7, 8].

Despite the implementation of preventive measures such as preoperative antibiotic prophylaxis [9‐12] and antiseptic skin cleansing [9, 13], SSI rates in prospective trials with adequate follow-up and standardized SSI definition in abdominal surgical patients remain high and vary from 14% to 32% [14‐17]. Applying the SSI criteria of the Center for Disease Control (CDC) [9], which differentiate between superficial, deep and organ-space SSIs at postoperative day 30, Darouiche et al. reported an overall SSI rate of 16.1% in the control group (povidone-iodine skin preparation) of their randomized controlled trial (RCT) in patients with clean-contaminated abdominal surgery [18]. Seiler et al. reported similar numbers in a randomized multicenter trial comparing three different techniques of abdominal wall closure in abdominal surgical patients with SSI rates varying from 13% to 19% [19]. SSI rates following colorectal surgery seem to be even higher as was shown by Bennett-Guerrero and colleagues, who reported an overall SSI rate of 21% in the control group (and 30% in the intervention group) of their prospective multicenter RCT comparing the application of a gentamicin-collagen sponge versus no intervention in colorectal patients [20]. National data from the USA support these numbers [21].

Multiple studies have shown an increase in the mean length of hospital stay by 6 to 24 days if SSIs occur [4, 22‐25]. The resulting direct costs have to be added to the indirect costs such as loss of workforce or insurance payments resulting in substantial expenses for the healthcare system [26‐28].

The most frequent pathogens causing postoperative SSIs in general and abdominal surgical patients are endogenous pathogens from the skin or gastrointestinal tract (KISS data 2005 to 2008, [29]). This implies that adequate protection of the surgical site by wound edge protectors might reduce the rate of postoperative SSIs.

Several previous trials have investigated the effect of wound edge protectors on SSI rates in abdominal surgery and report mixed results. While some found beneficial effects [30‐33] others reported no benefit [34‐36]. Similarly, a randomized trial in 2011 in which wound protectors were introduced together with other measures as a bundle to reduce SSIs did not show a benefit [37]. The diverging results may be explained by trial design, since the mentioned trials were either performed in a single institution setting, had small sample sizes, lacked adequate blinding, standardization or used varying definitions of outcome variables (SSI definitions). Large multicenter randomized trials comparing the use of a wound edge protector with standard intervention (sterile towels) under standardized conditions and with defined outcome variable (CDC definition of SSIs) are lacking.

It is important to point out that BaFO will apply a circular plastic wound edge protector covering the whole width of the wound (skin, subcutaneous tissue, fascia and muscle; Figure 1) not other forms of surgical draping such as adhesive incise drapes for which beneficial [38, 39] as well as non-beneficial results [40, 41] have been reported. A Cochrane meta analysis of the latter intervention compared to no adhesive drapes found no evidence that iodine impregnated adhesive drapes reduce the SSI rate (relative risk 1.03, 95% confidence interval 0.064 to 1.66, P = 0.89) [42]. Interestingly, when the authors of the same meta analysis compared the use of non-impregnated adhesive drapes to no drape usage, they found the SSI rate significantly increased in the drape group (relative risk 1.23, 95% confidence interval 1.02 to 1.48, P = 0.03).

BaFO aims to investigate whether the application of a circular plastic wound edge protector (Figure 1) reduces the rate of SSIs (within 45 days postoperatively) in abdominal surgical patients that undergo elective midline or transverse laparotomy by 50% (from 16% to 8%). As a secondary endpoint the difference in intraoperative core body temperature between the two study groups will be evaluated.

The BaFO trial will be performed at 15 sites of the Trial Network (CHIR-Net) of the German Surgical Society (Deutsche Gesellschaft für Chirurgie (DGCH)). Most of these sites have participated in previous randomized controlled trials and all centers were adequately trained and prepared according to International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)-good clinical practice (GCP) rules for participation in this trial. CHIR-Net is funded by the German Ministry of Research and Education (Bundesministerium für Bildung und Forschung (BMBF); see funding information below).

All general and abdominal surgical patients scheduled for elective open abdominal surgery requiring a median or transverse laparotomy will be eligible, given their ability to understand the extent and nature of the BaFO trial as well as their written informed consent. Patients participating in the BaFO trial must be 18 years of age or older, and the planned operation should be classified as clean or clean-contaminated as per the CDC definition [9]. Exclusion criteria are listed in Figure 1.

A total of 258 patients will be analyzed per group. Given an estimated drop out rate of approximately 15%, 600 patients will be randomized to 1 of the 2 treatment arms.

Randomized, controlled, observer and patient blinded multicenter surgical trial with two parallel comparison groups.

A total of 15 centers of general and abdominal surgery in Germany will participate in this trial. The centers vary from university hospitals to community hospitals and include certified centers for colorectal surgery (Darmzentren). All centers are members of the Trial Network (CHIR-Net) of the German Surgical Society. Physicians or nurses involved in the trial have been trained in ICH-GCP prior to initiation of the trial. Furthermore, all centers and participants were specifically instructed in study-specific procedures prior to the start of the trial. The centers will be supported by an ICH-GCP qualified flying study nurse from the CHIR-Net Surgical Regional Centre Munich to ensure protocol conforming data acquisition and trial interventions. Stratification according to center will be performed and all centers must recruit a minimum of 15 patients.

The duration of the recruitment phase is expected to be 30 months. The last follow-up will be performed a maximum of 45 days after the last patient underwent the trial intervention. Hence, the total duration of the trial is expected to be no longer than 32 months. The study flow is outlined in Figure 2.

Randomization and blinding will be performed with the help of sealed, opaque, individually numbered envelopes, restricted to choosing one at a time. The envelopes contain data sheets with information regarding the group allocation and the randomization number. Both will be prefabricated by a biostatistician of the Technische Universität München (TUM; Munich, Germany). Randomization (visit 2, see Figure 2) will be performed after inclusion of the patient in the trial (informed consent, visit 1) or in the period between inclusion and the trial intervention (day of surgery) or at the day of surgery (visit 3). Randomization will be performed stratified by center. To assure balanced group sizes in the course of the accrual, a blockwise randomization is applied. Basic characteristics of the patient and day of randomization must be documented on the randomization sheets. Subsequently, randomization sheets must be dated, signed and stored away from the patient records, the trial documents and the investigator site file to ensure blinding. Patients, outcome assessors and the trial statistician will be blinded for the trial intervention. The outcome assessor (postoperative SSIs) will therefore neither be part of the surgical team that performs the trial intervention nor have access to the randomization sheets. Patients will be blinded since they are under general anesthesia during the operation and therefore will not be aware which intervention is used during the operation.

Experimental intervention: all elective general or abdominal surgical patients undergoing a midline or transverse laparotomy for any cause will have their surgical incisions covered with a circular sterile plastic wound edge protector during the operation (see Figure 1).

Control intervention: draping of the surgical incision will be performed with standard sterile surgical dressings.

The schedule of trial interventions is presented in Figure 2.

No additional risks for study patients are anticipated, since the application of a circular sterile plastic wound edge protector represents a clinically established standard method. The wound edge protector used in BaFO is CE certified (3 M Steri-Drape Wound Edge Protector, 3 M, St. Paul, MN, USA). All surgical procedures carried out within BaFO are not affected by the trial.

Primary efficacy endpoint of the BaFO trial is the rate of SSIs according to Center for Disease Control (CDC) criteria, which constitutes the internationally accepted standard definition within 45 days postoperatively [9]. Secondary outcome measure is the intraoperative core body temperature measured at the beginning, in the middle and at the end of the operation via nasal, rectal, transurethral or central venous probes. Temperature as well as the modality of measurement will be recorded.

All required information collected during the trial is entered in the case record form (CRF) by the investigator or a designated representative. Documentation is expected to be completed as soon as possible after the information has been collected. The investigator is responsible for the accuracy of the documentation and must ensure that all entries can be verified by source data. An explanation must be given for all missing data. Corrections in the CRF must be signed, dated and leave the corrected entry visible. The completed CRF must be reviewed, signed and dated by the investigator named in the trial protocol or by a designated subinvestigator. After keeping a copy at the trial center, the original CRF is sent in a sealed envelope by certified mail to the Centre for Data Management at the Münchner Studienzentrum (MSZ; member of the Network of Coordinating Centres for Clinical Trials (KKS Network) at the Technische Universität München, Munich, Germany). Double data entry is performed by data management according to standard operating procedures predefined in the data management plan to ensure correct transfer of data from the CRF to the database (hardware: Windows Server NT 2003 (Microsoft, Redmond, WA, USA); software: MACRO™ V.3, Microsoft SQL Database (Microsoft, Redmond, WA, USA); browser: Microsoft Internet Explorer V.6 or higher (Microsoft, Redmond, WA, USA)). Completeness, validity and plausibility of data are examined by validating programs as well as individual inspection and queries are generated accordingly which need to be clarified by the investigator or designated subinvestigator. At the end of the trial the principal investigator will retain the original CRFs.

Monitoring of the trial data will be performed by an independent institution experienced in the monitoring of surgical trials (KKS Network) at the TUM (Münchner Studienzentrum). Monitoring will be carried out in accordance with ICH-GCP guidelines [44] and standard operating procedures of the MSZ to ensure patients´ safety and integrity of the clinical data, for example, primary outcome measure in adherence to study protocol. All trial sites are activated with an initiation visit by the monitor or CHIR-Net coordinator, who will hand out and explain the investigator site file, discuss relevant issues and train trial personnel in study-specific interventions. Regular contact by phone or email with all participating centers will enable the CHIR-Net Coordinator and the monitor to control the study progression, adherence to the study protocol, and to discuss problems related to the study. Regular on-site monitoring visits are planned for all sites. Investigators must allow the monitor to look at all essential documents, support the monitor during visits and answer queries. All monitoring procedures will be predefined in a trial-specific monitoring manual. In addition, a GCP-trained flying study nurse employed by the CHIR-Net regional center Munich will assist the trial sites with documentation and data collection if needed. Furthermore, close-out visits are planned for each center.

Occurrence of the primary endpoint is assessed as endpoint only (not as adverse event).

The following conditions are expected after the initial operation and will therefore not be classified as adverse events: pain, nausea, vomiting, urinary tract infection, hyper/hypotension, imbalances of blood sugar or electrolytes and other lab values out of range, if they do not exceed grade 3 to 4 in the Common Terminology Criteria for Adverse Events version 3.0 [45]. Assessment will be performed by the investigator or the designated subinvestigator.

From the day the patient has signed informed consent until the regular end of the trial (visit 9) or until premature withdrawal of the patient, all serious adverse events (SAEs) will be documented on a ‘serious adverse events form’ available in the investigator site file. An SAE will be defined as an event, that results in death, is immediately life threatening, requires or prolongs hospitalization or results in persistent or clinically important disability or incapacity as judged by the investigator or designated subinvestigator. SAEs will be classified to intensity (mild, moderate, severe), outcome (ongoing, recovered completely, recovered with sequelae, death, unknown) and causality (unrelated; possibly, probably or definitely related to trial intervention; not assessable). The assessment is based on clinical findings and needs to be performed by the investigator or designated subinvestigator in the participating trial centers. SAEs will have to be reported within 7 days after becoming known.

Patients are free to withdraw trial participation at their own request at any time and without giving reasons for their decision. Withdrawals will be documented in the CRF and in the patient´s medical record. Furthermore, all ongoing SAEs have to be followed-up and documented until their final outcome can be determined.

The trial can be prematurely closed by the coordinating investigator in consultation with the responsible biostatistician for the following reasons: the planned interim analysis indicates that rate or severity of SAE/morbidity in this trial poses a potential health hazard caused by the trial treatment in one or both of the trial groups; it appears that patients' enrolment is unsatisfactory with respect to quality or quantity or data recording is severely inaccurate or incomplete; external evidence demanding a termination of the trial.

In case of premature closure, the ethics committee has to be informed.