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Abstract Background Approximately 1 in 10 patients with a surgically treated open fracture will develop a surgical site infection. The Aqueous-PREP trial will investigate the effect of 10% povidone-iodine versus 4% chlorhexidine in aqueous antiseptic solutions in reducing infections after open fracture surgery. The study protocol was published in April 2020. Methods and design The Aqueous-PREP trial is a pragmatic, multicenter, open-label, randomized multiple period cluster crossover trial. Each participating cluster is randomly assigned in a 1:1 ratio to provide 1 of the 2 study interventions on all eligible patients during a study period. The intervention periods are 2 months in length. After completing a 2-month period, the participating cluster crosses over to the alternative intervention. We plan to enroll a minimum of 1540 patients at 14 sites. Results The primary outcome is surgical site infection guided by the Centers for Disease Control and Prevention’s National Healthcare Safety Network reporting criteria (2017). All participants’ surgical site infection surveillance period will end 30 days after definitive fracture management surgery for superficial infections and 90 days after definitive fracture management surgery for deep incisional or organ/space infections [1]. The secondary outcome is an unplanned fracture-related reoperation within 12 months of the fracture. Conclusion This manuscript serves as the formal statistical analysis plan (version 1.0) for the Aqueous-PREP trial. The statistical analysis plan was completed on February 28, 2022.

Abstract Background Preoperative antiseptic skin solutions are used prior to most surgical procedures; however, there is no definitive research comparing infection-related outcomes following use of the various solutions available to orthopedic trauma surgeons. The objective of this pilot study was to test the feasibility of a cluster randomized crossover trial that assesses the comparative effectiveness of a 10% povidone-iodine solution versus a 4% chlorhexidine gluconate solution for the management of open fractures. Methods Two orthopedic trauma centers participated in this pilot study. Each of these clinical sites was randomized to a starting solution (povidone-iodine solution or chlorhexidine gluconate) then subsequently crossed over to the other treatment after 2 months. During the 4-month enrollment phase, we assessed compliance, enrollment rates, participant follow-up, and accurate documentation of the primary clinical outcome. Feasibility outcomes included (1) the implementation of the interventions during a run-in period; (2) enrollment of participants during two 2-month enrollment phases; (3) application of the trial interventions as per the cluster randomization crossover scheme; (4) participant follow-up; and (5) accurate documentation of the primary outcome (surgical site infection). Feasibility outcomes were summarized using descriptive statistics reported as means (standard deviation) or medians (first quartile, third quartile) for continuous variables depending on their distribution and counts (percentage) for categorical variables. Corresponding 95% confidence intervals (CIs) were also reported. Results All five of the criteria for feasibility were met. During the run-in phase, all 18 of the eligible patients identified at the two clinical sites received the correct cluster-assigned treatment. A total of 135 patients were enrolled across both sites during the 4-month recruitment phase, which equates to 92% (95% CI 85.9 to 96.4%) of eligible patients being enrolled. Compliance with the assigned treatment in the pilot study was 98% (95% CI 93.5 to 99.8%). Ninety-eight percent (95% CI 93.5 to 99.8%) of participants completed the 90-day post-surgery follow-up and the primary outcome (SSI) was accurately documented for 100% (95% CI 96.6 to 100.0%) of the participants. Conclusions These results confirm the feasibility of a definitive study comparing antiseptic solutions using a cluster randomized crossover trial design. Building upon the infrastructure established during the pilot phase, a definitive study has been successfully initiated. Trial registration ClincialTrials.gov , number NCT03385304 . Registered December 28, 2017.

Abstract Background In cluster randomized crossover (CRXO) trials, groups of participants (i.e., clusters) are randomly allocated to receive a sequence of interventions over time (i.e., cluster periods). CRXO trials are becoming more comment when they are feasible, as they require fewer clusters than parallel group cluster randomized trials. However, CRXO trials have not been frequently used in orthopedic fracture trials and represent a novel methodological application within the field. To disseminate the early knowledge gained from our experience initiating two cluster randomized crossover trials, we describe our process for the identification and selection of the orthopedic practices (i.e., clusters) participating in the PREP-IT program and present data to describe their key characteristics. Methods The PREP-IT program comprises two ongoing pragmatic cluster randomized crossover trials (Aqueous-PREP and PREPARE) which compare the effect of iodophor versus chlorhexidine solutions on surgical site infection and unplanned fracture-related reoperations in patients undergoing operative fracture management. We describe the process we used to identify and select orthopedic practices (clusters) for the PREP-IT trials, along with their characteristics. Results We identified 58 potential orthopedic practices for inclusion in the PREP-IT trials. After screening each practice for eligibility, we selected 30 practices for participation and randomized each to a sequence of interventions (15 for Aqueous-PREP and 20 for PREPARE). The majority of orthopedic practices included in the Aqueous-PREP and PREPARE trials were situated in level I trauma centers (100% and 87%, respectively). Orthopedic practices in the Aqueous-PREP trial operatively treated a median of 149 open fracture patients per year, included a median of 11 orthopedic surgeons, and had access to a median of 5 infection preventionists. Orthopedic practices in the PREPARE trial treated a median of 142 open fracture and 1090 closed fracture patients per year, included a median of 7.5 orthopedic surgeons, and had access to a median of 6 infection preventionists. Conclusions The PREP-IT trials provide an example of how to follow the reporting standards for cluster randomized crossover trials by providing a clear definition of the cluster unit, a thorough description of the cluster identification and selection process, and sufficient description of key cluster characteristics. Trial registration Both trials are registered at ClinicalTrials.gov (A-PREP: NCT03385304 December 28, 2017, and PREPARE: NCT03523962 May 14, 2018).

Abstract Background This study aimed to address the current limitations of the use of composite endpoints in orthopaedic trauma research by quantifying the relative importance of clinical outcomes common to orthopaedic trauma patients and use those values to develop a patient-centered composite endpoint weighting technique. Methods A Best-Worst Scaling choice experiment was administered to 396 adult surgically-treated fracture patients. Respondents were presented with ten choice sets, each consisting of three out of ten plausible clinical outcomes. Hierarchical Bayesian modeling was used to determine the utilities associated with the outcomes. Results Death was the outcome of greatest importance (mean utility = − 8.91), followed by above knee amputation (− 7.66), below knee amputation (− 6.97), severe pain (− 5.90), deep surgical site infection (SSI) (− 5.69), bone healing complications (− 5.20), and moderate pain (− 4.59). Mild pain (− 3.30) and superficial SSI (− 3.29), on the other hand, were the outcomes of least importance to respondents. Conclusion This study revealed that patients’ relative importance towards clinical outcomes followed a logical gradient, with distinct and quantifiable preferences for each possible component outcome. These findings were incorporated into a novel composite endpoint weighting technique.

Abstract Background Observational studies have found that 75% of healthy adult fracture patients (ages 18–50) have serum 25-hydroxyvitamin D (25(OH)D) levels

Abstract Background Femoral neck fractures in patients ≤ 60 years of age are often very different injuries compared to low-energy, hip fractures in elderly patients and are difficult to manage because of inherent problems associated with high-energy trauma mechanisms and increased functional demands for recovery. Internal fixation, with multiple cancellous screws or a sliding hip screw (SHS), is the most common treatment for this injury in young patients. However, there is no clinical consensus regarding which surgical technique is optimal. Additionally, there is compelling rationale to use vitamin D supplementation to nutritionally optimize bone healing in young patients. This pilot trial will determine feasibility and provide preliminary clinical data for a larger definitive trial. Methods We will conduct a multicenter, concealed randomized controlled pilot study, using a 2 × 2 factorial design in 60 patients aged 18–60 years with a femoral neck fracture. Eligible patients will be randomized in equal proportions to one of four groups: 1) SHS and vitamin D supplementation (4000 international units (IU) daily dose) for 6 months, 2) cancellous screws and vitamin D supplementation (4000 IU daily dose) for 6 months, 3) SHS and placebo, and 4) cancellous screws and placebo. Participants will be followed for 12 months post-fracture. Feasibility outcomes include initiation of clinical sites, recruitment, follow-up, data quality, and protocol adherence. Clinical outcomes, for both the pilot and planned definitive trials, include a composite of patient-important outcomes (re-operation, femoral head osteonecrosis, severe femoral neck malunion, and nonunion), health-related quality of life and patient-reported function, fracture healing complications, and radiographic fracture healing. A priori success criteria have been established. If the pilot study is deemed successful, study participants will be included in the definitive trial and clinical outcomes for the pilot will not be analyzed. If the pilot study is not deemed successful, clinical outcome data will be analyzed. Discussion Results of this study will inform the feasibility of a definitive trial. If clinical outcome data are analyzed, they will be disseminated through a publication and presentations. Trial registration The FAITH-2 trial, described as a definitive trial, was registered at ClinicalTrials.gov (NCT01908751) prior to enrollment of the first participant.

Abstract Background Given its role in treating musculoskeletal conditions, rehabilitation medicine may be an important factor in decreasing the use of opioids among injured workers. The primary objective was to determine if increased utilization of rehabilitation services was associated with decreased persistent opioid use among workers’ compensation claimants. The secondary objective was to determine the combined association of rehabilitation service utilization and persistent opioid use with days of work lost due to injury. Methods Using Chesapeake Employers’ Insurance Company claims data from 2008 to 2016, claimants with at least one filled opioid prescription within 90 days of injury were eligible for inclusion. The primary outcome was persistent opioid use, defined as at least one filled opioid prescription more than 90 days from injury. The secondary outcome was days lost due to injury. The primary variable of interest, rehabilitation service utilization, was quantified based on the number of rehabilitation service claims and grouped into five levels (no utilization, and four quartiles - low, medium, high, very high). Results Of the 9596 claimants included, 29% were persistent opioid users. Compared to claimants that did not utilize rehabilitation services, patients with very high rehabilitation utilization were nearly three times more likely (OR: 2.71, 95% CI: 2.28–3.23, p

Abstract Background Surgically-managed fractures, particularly open fractures, are associated with high rates of surgical site infections (SSIs). To reduce the risk of an SSI, orthopaedic surgeons routinely clean open fracture wounds in the emergency department (ED) and then apply a bandage to the open wound. Prior to the surgical incision, it is standard practice to prepare the fracture region with an antiseptic skin solution as an additional SSI prevention strategy. Multiple antiseptic solutions are available. Objectives To explore the variation in practice patterns among orthopaedic surgeons regarding antiseptic solution use in the ED and antiseptic preparatory techniques for fracture surgery. Methods We developed a 27-item survey and surveyed members of several orthopaedic associations. Results Two hundred and-ten surveys were completed. 71.0% of respondents irrigate the open wound and skin in the ED, primarily with saline alone (59.7%) or iodine-based solutions (32.9%). 90.5% of responders indicated that they dress the open wound in the ED, with 41.0% applying a saline-soaked bandage and 33.7% applying an iodine-soaked dressing (33.7%). In their surgical preparation of open fractures, 41.0% of respondents used an iodine-based solution, 26.7% used a chlorhexidine gluconate (CHG)-based solution, and 31.4% used a combination of the two. In closed fractures, 43.8% of respondents used a CHG-based solution, 28.1% used an iodine-based solution, and 27.1% used a combination. Despite theoretical concerns about the use of alcohol in open wounds, 51.4% used alcohol-based solutions or alcohol alone during skin preparation of open fractures. Conclusions A lack of consensus exists regarding use of antiseptic surgical preparation solutions for fractures. High-quality clinical research is needed to assess the effectiveness of different surgical antiseptic preparation solutions on patient outcomes in fracture populations.

Abstract Background The objective of this analysis is to evaluate the necessity of large clinical trials using FLOW trial data. Methods The FLOW pilot study and definitive trial were factorial trials evaluating the effect of different irrigation solutions and pressures on re-operation. To explore treatment effects over time, we analyzed data from the pilot and definitive trial in increments of 250 patients until the final sample size of 2447 patients was reached. At each increment we calculated the relative risk (RR) and associated 95% confidence interval (CI) for the treatment effect, and compared the results that would have been reported at the smaller enrolments with those seen in the final, adequately powered study. Results The pilot study analysis of 89 patients and initial incremental enrolments in the FLOW definitive trial favored low pressure compared to high pressure (RR: 1.50, 95% CI: 0.75–3.04; RR: 1.39, 95% CI: 0.60–3.23, respectively), which is in contradiction to the final enrolment, which found no difference between high and low pressure (RR: 1.04, 95% CI: 0.81–1.33). In the soap versus saline comparison, the FLOW pilot study suggested that re-operation rate was similar in both the soap and saline groups (RR: 0.98, 95% CI: 0.50–1.92), whereas the FLOW definitive trial found that the re-operation rate was higher in the soap treatment arm (RR: 1.28, 95% CI: 1.04–1.57). Conclusions Our findings suggest that studies with smaller sample sizes would have led to erroneous conclusions in the management of open fracture wounds. Trial registration NCT01069315 (FLOW Pilot Study) Date of Registration: February 17, 2010, NCT00788398 (FLOW Definitive Trial) Date of Registration: November 10, 2008.

An amendment to this paper has been published and can be accessed via the original article.