Topical antimicrobial treatment of mesh for the reduction of surgical site infections after hernia repair: a systematic review and meta-analysis.

PURPOSE: Use of mesh is essential in hernia repair. A common complication after hernia repair is surgical site infection (SSI), which poses a risk in spreading to the mesh, possibly causing mesh infection. Topical antimicrobial pretreatment of mesh may potentially reduce SSI risk in hernia repair and has shown promising results in in vitro and in vivo studies. Clinical evidence, however, is more important. This systematic review aims to provide an overview of available clinical evidence for antimicrobial pretreated mesh in hernia repair surgery to reduce SSI. METHODS: We report in accordance with PRISMA guidelines. CENTRAL, EMBASE, CINAHL and PubMed were searched up to October 2023 for studies that investigated the use of antimicrobial pretreated mesh on SSI incidence in adults undergoing hernia repair. The primary outcome was SSI incidence. We also collected data on pathogen involvement, hernia recurrence, and mesh infection. A meta-analysis on SSI risk and GRADE-assessment was performed of eligible studies. RESULTS: We identified 11 eligible studies (n = 2660 patients); 5 randomized trials and 6 cohort studies. Investigated interventions included pre-coated mesh, antibiotic carriers, mesh soaked or irrigated with antibiotic or antiseptic solution. Meta-analysis showed no significant reduction in SSI for antibiotic pretreated polypropylene mesh (RR 0.76 [95% CI 0.27; 2.09]; I2 50%). CONCLUSION: Data on topical mesh pretreatment to reduce SSI risk after hernia repair is limited. Very low certainty evidence from randomized trials in hernia repair surgery shows no significant benefit for antibiotic mesh pretreatment for SSI reduction, but data are imprecise due to optimal information size not being met.

Incisional Wound Irrigation for the Prevention of Surgical Site Infection: A Systematic Review and Network Meta-Analysis.

Importance: Surgical site infections (SSIs) are common postoperative complications and associated with significant morbidity, mortality, and costs. Prophylactic intraoperative incisional wound irrigation is used to reduce the risk of SSIs, and there is great variation in the type of irrigation solutions and their use. Objective: To compare the outcomes of different types of incisional prophylactic intraoperative incisional wound irrigation for the prevention of SSIs in all types of surgery. Data Sources: PubMed, Embase, CENTRAL, and CINAHL databases were searched up to June 12, 2023. Study Selection: Included in this study were randomized clinical trials (RCTs) comparing incisional prophylactic intraoperative incisional wound irrigation with no irrigation or comparing irrigation using different types of solutions, with SSI as a reported outcome. Studies investigating intracavity lavage were excluded. Data Extraction and Synthesis: This systematic review and network meta-analysis is reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis statement. Two reviewers independently extracted the data and assessed the risk of bias within individual RCTs using the Cochrane Risk of Bias 2 tool and the certainty of evidence using the Grading of Recommendations, Assessment, Development, and Evaluation framework. A frequentist network meta-analysis was conducted, and relative risks (RRs) with corresponding 95% CIs were reported. Main Outcome and Measure: The primary study outcome was SSI. Results: A total of 1587 articles were identified, of which 41 RCTs were included in the systematic review, with 17 188 patients reporting 1328 SSIs, resulting in an overall incidence of 7.7%. Compared with no irrigation, antiseptic solutions (RR, 0.60; 95% CI, 0.44-0.81; high level of certainty) and antibiotic solutions (RR, 0.46; 95% CI, 0.29-0.73; low level of certainty) were associated with a beneficial reduction in SSIs. Saline irrigation showed no statistically significant difference compared with no irrigation (RR, 0.83; 95% CI, 0.63-1.09; moderate level of certainty). Conclusions and Relevance: This systematic review and network meta-analysis found high-certainty evidence that prophylactic intraoperative incisional wound irrigation with antiseptic solutions was associated with a reduction in SSIs. It is suggested that the use of antibiotic wound irrigation be avoided due to the inferior certainty of evidence for its outcome and global antimicrobial resistance concerns.

Benefits and harms of perioperative high fraction inspired oxygen for surgical site infection prevention: a protocol for a systematic review and meta-analysis of individual patient data of randomised controlled trials.

INTRODUCTION: The use of high fraction of inspired oxygen (FiO2) intraoperatively for the prevention of surgical site infection (SSI) remains controversial. Promising results of early randomised controlled trials (RCT) have been replicated with varying success and subsequent meta-analysis are equivocal. Recent advancements in perioperative care, including the increased use of laparoscopic surgery and pneumoperitoneum and shifts in fluid and temperature management, can affect peripheral oxygen delivery and may explain the inconsistency in reproducibility. However, the published data provides insufficient detail on the participant level to test these hypotheses. The purpose of this individual participant data meta-analysis is to assess the described benefits and harms of intraoperative high FiO2compared with regular (0.21-0.40) FiO2 and its potential effect modifiers. METHODS AND ANALYSIS: Two reviewers will search medical databases and online trial registries, including MEDLINE, Embase, CENTRAL, CINAHL, ClinicalTrials.gov and WHO regional databases, for randomised and quasi-RCT comparing the effect of intraoperative high FiO2 (0.60-1.00) to regular FiO2 (0.21-0.40) on SSI within 90 days after surgery in adult patients. Secondary outcome will be all-cause mortality within the longest available follow-up. Investigators of the identified trials will be invited to collaborate. Data will be analysed with the one-step approach using the generalised linear mixed model framework and the statistical model appropriate for the type of outcome being analysed (logistic and cox regression, respectively), with a random treatment effect term to account for the clustering of patients within studies. The bias will be assessed using the Cochrane risk-of-bias tool for randomised trials V.2 and the certainty of evidence using Grading of Recommendations, Assessment, Development and Evaluation methodology. Prespecified subgroup analyses include use of mechanical ventilation, nitrous oxide, preoperative antibiotic prophylaxis, temperature (<35°C), fluid supplementation (<15 mL/kg/hour) and procedure duration (>2.5 hour). ETHICS AND DISSEMINATION: Ethics approval is not required. Investigators will deidentify individual participant data before it is shared. The results will be submitted to a peer-review journal. PROSPERO REGISTRATION NUMBER: CRD42018090261.

Incisional negative pressure wound therapy for the prevention of surgical site infection: an up-to-date meta-analysis and trial sequential analysis.

Background: The evidence on prophylactic use of negative pressure wound therapy on primary closed incisional wounds (iNPWT) for the prevention of surgical site infections (SSI) is confusing and ambiguous. Implementation in daily practice is impaired by inconsistent recommendations in current international guidelines and published meta-analyses. More recently, multiple new randomised controlled trials (RCTs) have been published. We aimed to provide an overview of all meta-analyses and their characteristics; to conduct a new and up-to-date systematic review and meta-analysis and Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessment; and to explore the additive value of new RCTs with a trial sequential analysis (TSA). Methods: PubMed, Embase and Cochrane CENTRAL databases were searched from database inception to October 24, 2022. We identified existing meta-analyses covering all surgical specialties and RCTs studying the effect of iNPWT compared with standard dressings in all types of surgery on the incidence of SSI, wound dehiscence, reoperation, seroma, hematoma, mortality, readmission rate, skin blistering, skin necrosis, pain, and adverse effects of the intervention. We calculated relative risks (RR) with corresponding 95% confidence intervals (CI) using a Mantel-Haenszel random-effects model. We assessed publication bias with a comparison-adjusted funnel plot. TSA was used to assess the risk of random error. The certainty of evidence was evaluated using the Cochrane Risk of Bias-2 (RoB2) tool and GRADE approach. This study is registered with PROSPERO, CRD42022312995. Findings: We identified eight previously published general meta-analyses investigating iNPWT and compared their results to present meta-analysis. For the updated systematic review, 57 RCTs with 13,744 patients were included in the quantitative analysis for SSI, yielding a RR of 0.67 (95% CI: 0.59-0.76, I2 = 21%) for iNPWT compared with standard dressing. Certainty of evidence was high. Compared with previous meta-analyses, the RR stabilised, and the confidence interval narrowed. In the TSA, the cumulative Z-curve crossed the trial sequential monitoring boundary for benefit, confirming the robustness of the summary effect estimate from the meta-analysis. Interpretation: In this up-to-date meta-analysis, GRADE assessment shows high-certainty evidence that iNPWT is effective in reducing SSI, and uncertainty is less than in previous meta-analyses. TSA indicated that further trials are unlikely to change the effect estimate for the outcome SSI; therefore, if future research is to be conducted on iNPWT, it is crucial to consider what the findings will contribute to the existing robust evidence. Funding: Dutch Association for Quality Funds Medical Specialists.

Six Long-Standing Questions about Antibiotic Prophylaxis in Surgery.

Surgical site infections (SSIs) are the most common adverse event occurring in surgical patients. Optimal prevention of SSIs requires the bundled integration of a variety of measures before, during, and after surgery. Surgical antibiotic prophylaxis (SAP) is an effective measure for preventing SSIs. It aims to counteract the inevitable introduction of bacteria that colonize skin or mucosa into the surgical site during the intervention. This document aims to guide surgeons in appropriate administration of SAP by addressing six key questions. The expert panel identifies a list of principles in response to these questions that every surgeon around the world should always respect in administering SAP.

Practical Guide to Statistical Considerations in Clinical Trials in Surgery.

This Guide to Statistics and Methods discusses key statistical considerations in the conduct of randomized clinical trials in surgery.

Perioperative care bundles for the prevention of surgical-site infections: meta-analysis.

BACKGROUND: Care bundles are used widely to prevent surgical-site infections (SSIs). Recent systematic reviews suggested larger effects from bundles with more interventions. These reviews were largely based on uncontrolled before-after studies and did not consider their biases. The aim of this meta-analysis was to determine the effectiveness of care bundles to prevent SSIs and explore characteristics of effective care bundles. METHODS: A systematic review, reanalysis, and meta-analysis of available evidence were undertaken. RCTs, controlled before-after studies, and uncontrolled before-after studies with sufficient data for reanalysis as interrupted time series studies (ITS) were eligible. Studies investigating the use of a care bundle, with at least one intraoperative intervention, compared with standard care were included. RESULTS: Four RCTs, 1 controlled before-after study, and 13 ITS were included. Pooled data from RCTs were heterogeneous. Meta-analysis of ITS resulted in a level change of -1.16 (95 per cent c.i.-1.78 to -0.53), indicating a reduction in SSI. The effect was larger when the care bundle comprised a higher proportion of evidence-based interventions. Meta-regression analyses did not show statistically significant associations between effect estimates and number of interventions, number of evidence-based interventions, or proportion of evidence-based interventions. CONCLUSION: Meta-analysis of ITS indicated that perioperative care bundles prevent SSI. This effect is inconsistent across RCTs. Larger bundles were not associated with a larger effect, but the effect may be larger if the care bundle contains a high proportion of evidence-based interventions. No strong evidence for characteristics of effective care bundles was identified.

Intraoperative Redosing of Surgical Antibiotic Prophylaxis in Addition to Preoperative Prophylaxis Versus Single-dose Prophylaxis for the Prevention of Surgical Site Infection: A Meta-analysis and GRADE Recommendation.

OBJECTIVE: The aim of this study was to determine the effect of preoperative surgical antibiotic prophylaxis (SAP) with additional intraoperative redosing compared to single-dose preoperative surgical antibiotic prophylaxis on the incidence of surgical site infections (SSI). SUMMARY BACKGROUND DATA: Preoperative SAP is standard care for the prevention of SSI. During long surgical procedures, additional intraoperative redosing of SAP is advised, but there is great variability in redosing strategies and compliance rates. METHODS: We performed a systematic search of MEDLINE (PubMed), Embase, CINAHL and CENTRAL on June 25th, 2021 according to PROSPERO registration CRD42021229035. We included studies that compared the effect of preoperative SAP with additional intraoperative redosing to single dose preoperative SAP (no redosing) on SSI incidence in patients undergoing any type of surgery. Two researchers performed data appraisal and extraction of summary data independently. Meta-analyses were stratified per study type. We used a generic inverse variance random-effects model to estimate a pooled odds ratio with corresponding 95% confidence intervals (CIs). RESULTS: We included 2 randomized controlled trials (RCT) and 8 cohort studies comprising of 9470 patients. Pooled odds ratios for SSI in patients receiving intraoperative redosing compared to those without redosing were 0.47 (95% CI: 0.19-1.16. I2 = 36%) for RCTs and 0.55 (95% CI: 0.38-0.79, I2 = 56%) for observational cohorts. There was considerable clinical heterogeneity among antibiotics used and redosing protocols. GRADE-assessment showed overall low certainty of evidence. CONCLUSION: Intraoperative redosing of SAP may reduce incidence of SSI compared to a single dose preoperative SAP in any type of surgery, based on studies with considerable heterogeneity of antibiotic regimens and redosing protocols.

The Effect of Hyperbaric Oxygen Therapy on Markers of Oxidative Stress and the Immune Response in Healthy Volunteers.

Hyperbaric oxygen therapy (HBOT) consists of breathing 100% oxygen under increased ambient pressure. There are indications that HBOT induces oxidative stress and activates immune pathways. However, previous research on immunological effects of HBOT has mainly been established in in vitro experiments and selected patient populations, limiting generalizability and increasing the chances of confounding by comorbidities and specific patient-related factors. More insight into the immunological effects of HBOT would aid investigation and comprehension of potentially novel treatment applications. Therefore, in this study, we investigated the effects of three 110-min HBOT-sessions with 24-h intervals on immunological parameters in healthy, young, male volunteers. Blood samples were obtained before and after the first and third HBOT sessions. We assessed neutrophilic reactive oxygen species (ROS) production, systemic oxidative stress [plasma malondialdehyde (MDA) concentrations] as well as neutrophil phagocytic activity, plasma concentrations of tumor necrosis factor (TNF), interleukin (IL)-6, IL-8, and IL-10, and production of TNF, IL-6, and IL-10 by leukocytes ex vivo stimulated with the Toll-like receptor (TLR) ligands lipopolysaccharide (TLR4) and Pam3Cys (TLR2). We observed decreased neutrophilic ROS production and phagocytosis following the second HBOT session, which persisted after the third session, but no alterations in MDA concentrations. Furthermore, plasma concentrations of the investigated cytokines were unaltered at all-time points, and ex vivo cytokine production was largely unaltered over time as well. These results indicate no induction of systemic oxidative stress or a systemic inflammatory response after repeated HBOT in healthy volunteers but may suggest exhaustion of ROS generation capacity and phagocytosis.

Effect of triclosan-coated sutures for abdominal wound closure on the incidence of abdominal wound dehiscence: a protocol for an individual participant data meta-analysis.

INTRODUCTION: Acute abdominal wound dehiscence (AWD) or burst abdomen is a severe complication after abdominal surgery with an incidence up to 3.8%. Surgical site infection (SSI) is the biggest risk factor for the development of AWD. It is strongly suggested that the use of triclosan-coated sutures (TCS) for wound closure reduces the risk of SSI. We hypothesise that the use of TCS for abdominal wound closure may reduce the risk of AWD. Current randomised controlled trials (RCTs) lack power to investigate this. Therefore, the purpose of this individual participant data meta-analysis is to evaluate the effect of TCS for abdominal wound closure on the incidence of AWD. METHODS AND ANALYSIS: We will conduct a systematic review of Medline, Embase and Cochrane Central Register of Controlled Trials for RCTs investigating the effect of TCS compared with non-coated sutures for abdominal wound closure in adult participants scheduled for open abdominal surgery. Two independent reviewers will assess eligible studies for inclusion and methodological quality. Authors of eligible studies will be invited to collaborate and share individual participant data. The primary outcome will be AWD within 30 days after surgery requiring reoperation. Secondary outcomes include SSI, all-cause reoperations, length of hospital stay and all-cause mortality within 30 days after surgery. Data will be analysed with a one-step approach, followed by a two-step approach. In the one-step approach, treatment effects will be estimated as a risk ratio with corresponding 95% CI in a generalised linear mixed model framework with a log link and binomial distribution assumption. The quality of evidence will be judged using the Grading of Recommendations Assessment Development and Evaluation approach. ETHICS AND DISSEMINATION: The medical ethics committee of the Amsterdam UMC, location AMC in the Netherlands waived the necessity for a formal approval of this study, as this research does not fall under the Medical Research involving Human Subjects Act. Collaborating investigators will deidentify data before sharing. The results will be submitted to a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42019121173.

WSES/GAIS/WSIS/SIS-E/AAST global clinical pathways for patients with skin and soft tissue infections.

Skin and soft-tissue infections (SSTIs) encompass a variety of pathological conditions that involve the skin and underlying subcutaneous tissue, fascia, or muscle, ranging from simple superficial infections to severe necrotizing infections.Together, the World Society of Emergency Surgery, the Global Alliance for Infections in Surgery, the Surgical Infection Society-Europe, The World Surgical Infection Society, and the American Association for the Surgery of Trauma have jointly completed an international multi-society document to promote global standards of care in SSTIs guiding clinicians by describing reasonable approaches to the management of SSTIs.An extensive non-systematic review was conducted using the PubMed and MEDLINE databases, limited to the English language. The resulting evidence was shared by an international task force with different clinical backgrounds.

WSES/GAIS/SIS-E/WSIS/AAST global clinical pathways for patients with intra-abdominal infections.

Intra-abdominal infections (IAIs) are common surgical emergencies and have been reported as major contributors to non-trauma deaths in hospitals worldwide. The cornerstones of effective treatment of IAIs include early recognition, adequate source control, appropriate antimicrobial therapy, and prompt physiologic stabilization using a critical care environment, combined with an optimal surgical approach. Together, the World Society of Emergency Surgery (WSES), the Global Alliance for Infections in Surgery (GAIS), the Surgical Infection Society-Europe (SIS-E), the World Surgical Infection Society (WSIS), and the American Association for the Surgery of Trauma (AAST) have jointly completed an international multi-society document in order to facilitate clinical management of patients with IAIs worldwide building evidence-based clinical pathways for the most common IAIs. An extensive non-systematic review was conducted using the PubMed and MEDLINE databases, limited to the English language. The resulting information was shared by an international task force from 46 countries with different clinical backgrounds. The aim of the document is to promote global standards of care in IAIs providing guidance to clinicians by describing reasonable approaches to the management of IAIs.

The Impact of Quality Improvement Interventions in Improving Surgical Infections and Mortality in Low and Middle-Income Countries: A Systematic Review and Meta-Analysis.

BACKGROUND: Morbidity and mortality in surgical systems in low- and middle-income countries (LMICs) remain high compared to high-income countries. Quality improvement processes, interventions, and structure are essential in the effort to improve peri-operative outcomes. METHODS: A systematic review and meta-analysis of interventional studies assessing quality improvement processes, interventions, and structure in developing country surgical systems was conducted according to the Preferred Reporting Items of Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Studies were included if they were conducted in an LMIC, occurred in a surgical setting, and measured the effect of an implementation and its impact. The primary outcome was mortality, and secondary outcomes were rates of rates of hospital-acquired infection (HAI) and surgical site infections (SSI). Prospero Registration: CRD42020171542. RESULT: Of 38,273 search results, 31 studies were included in a qualitative synthesis, and 28 articles were included in a meta-analysis. Implementation of multimodal bundled interventions reduced the incidence of HAI by a relative risk (RR) of 0.39 (95%CI 0.26 to 0.59), the effect of hand hygiene interventions on HAIs showed a non-significant effect of RR of 0.69 (0.46-1.05). The WHO Safe Surgery Checklist reduced mortality by RR 0.68 (0.49 to 0.95) and SSI by RR 0.50 (0.33 to 0.63) and antimicrobial stewardship interventions reduced SSI by RR 0.67 (0.48-0.93). CONCLUSION: There is evidence that a number of quality improvement processes, interventions and structural changes can improve mortality, HAI and SSI outcomes in the peri-operative setting in LMICs.

Effectiveness of Quality Improvement Processes, Interventions, and Structure in Trauma Systems in Low- and Middle-Income Countries: A Systematic Review and Meta-analysis.

BACKGROUND: Trauma mortality in low- and middle-income countries (LMICs) remains high compared to high-income countries. Quality improvement processes, interventions, and structure are essential in the effort to decrease trauma mortality. METHODS: A systematic review and meta-analysis of interventional studies assessing quality improvement processes, interventions, and structure in developing country trauma systems was conducted from November 1989 to August 2020 according to the Preferred Reporting Items of Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Studies were included if they were conducted in an LMIC population according to World Bank Income Classification, occurred in a trauma setting, and measured the effect of implementation and its impact. The primary outcome was trauma mortality. RESULTS: Of 37,575 search results, 30 studies were included from 15 LMICs covering five WHO regions in a qualitative synthesis. Twenty-seven articles were included in a meta-analysis. Implementing a pre-hospital trauma system reduced overall trauma mortality by 45% (risk ratio (RR) 0.55, 95% CI 0.4 to 0.75). Training first responders resulted in an overall decrease in mortality (RR 0.47, 95% CI 0.28 to 0.78). In-hospital trauma training with certified courses resulted in a reduction of mortality (RR 0.71, 95% CI 0.62 to 0.78). Trauma audits and trauma protocols resulted in varying improvements in trauma mortality. CONCLUSION: There is evidence that quality improvement processes, interventions, and structure can improve mortality in the trauma systems in LMICs.

Timing of Preoperative Antibiotic Prophylaxis and Surgical Site Infection: TAPAS, An Observational Cohort Study.

OBJECTIVE: To test the hypothesis that surgical site infection (SSI) risk differs, after administration of surgical antibiotic prophylaxis (SAP) within 60-30 or 30-0 minutes before incision. BACKGROUND: The importance of appropriate timing of SAP before surgery has long been recognized. However, available evidence is contradictive on the best timing within a 60-0 minutes time interval before incision. Here, we aim to evaluate previous contradictions with a carefully designed observational cohort. METHODS: An observational cohort study was conducted in a Dutch tertiary referral center. For 2 years, consecutive patients with SAP indication undergoing general, orthopedic, or gynecologic surgery were followed for the occurrence of superficial and deep SSI as defined by the Center of Disease Control and Prevention. The association between timing of SAP and SSI was assessed using multivariable logistic regression. RESULTS: After 3001 surgical procedures, 161 SSIs were detected. In 87% of the procedures, SAP was administered within 60 minutes before incision. Only antibiotics with short infusion time were used. Multivariable logistic regression indicated there was no conclusive evidence of a difference in SSI risk after SAP administration 60-30 minutes or 30-0 minutes before incision [odds ratio: 0.82; 95% confidence interval (0.57-1.19)]. CONCLUSIONS: For SAP with short infusion time no clear superior timing interval within the 60-minute interval before incision could be identified in this cohort. We were unable to reproduce differences in SSI risk found in earlier studies.

Enhanced PeriOperative Care and Health protection programme for the prevention of surgical site infections after elective abdominal surgery (EPOCH): study protocol of a randomised controlled, multicentre, superiority trial.

INTRODUCTION: Surgical site infections (SSI) are a common postoperative complication. During the development of the new WHO guidelines on SSI prevention, also in the Netherlands was concluded that perioperative care could be optimised beyond the current standard practice. We selected a limited set of readily available, cheap and evidence-based interventions from these new guidelines that are not part of standard practice in the Netherlands and formulated an Enhanced PeriOperative Care and Health bundle (EPOCH). Here, we describe the protocol for an open-label, randomised controlled, parallel-group, superiority trial to test the effect of the EPOCH bundle added to (national) standard care in comparison to standard care alone on the incidence of SSI. METHODS AND ANALYSIS: EPOCH consists of intraoperative high fractional inspired oxygen (0.80); goal-directed fluid therapy; active preoperative, intraoperative and postoperative warming; perioperative glucose control and treatment of severe hyperglycaemia (>10 mmoll-1) and standardised surgical site handling. Patients scheduled for elective abdominal surgery with an incision larger than 5 cm are eligible for inclusion. Participants are randomised daily, 1:1 according to variable block sizes, and stratified per participating centre to either EPOCH added to standard care or standard care only. The primary endpoint will be SSI incidence according to the Centers for Disease Control and Prevention (CDC) definition within 30 days as part of routine clinical follow-up. Four additional questionnaires will be sent out over the course of 90 days to capture disability and costs. Other secondary endpoints include anastomotic leakage, incidence of incisional hernia, serious adverse events, hospital readmissions, length of stay and cost effectiveness. Analysis of the primary endpoint will be on an intention-to-treat basis. ETHICS AND DISSEMINATION: Ethics approval is granted by the Amsterdam UMC Medical Ethics Committee (reference 2015_121). Results will be disseminated through peer-reviewed journals and summaries shared with stakeholders. This protocol is published before analysis of the results. TRIAL REGISTRATION NUMBER: Registered in the Dutch Trial Register: NL5572.