Effectiveness of Iodophor vs Chlorhexidine Solutions for Surgical Site Infections and Unplanned Reoperations for Patients Who Underwent Fracture Repair: The PREP-IT Master Protocol

Abstract

Importance: The risk of developing a surgical site infection after extremity fracture repair is nearly 5 times greater than in most elective orthopedic surgical procedures. For all surgical procedures, it is standard practice to prepare the operative site with an antiseptic solution; however, there is limited evidence to guide the choice of solution used for orthopedic fracture repair.

Objective: To compare the effectiveness of iodophor vs chlorhexidine solutions to reduce surgical site infections and unplanned fracture-related reoperations for patients who underwent fracture repair.

Design, setting, and participants: The PREP-IT (Program of Randomized Trials to Evaluate Pre-operative Antiseptic Skin Solutions in Orthopaedic Trauma) master protocol will be followed to conduct 2 multicenter pragmatic cluster randomized crossover trials, Aqueous-PREP (Pragmatic Randomized Trial Evaluating Pre-Operative Aqueous Antiseptic Skin Solution in Open Fractures) and PREPARE (Pragmatic Randomized Trial Evaluating Pre-Operative Alcohol Skin Solutions in Fractured Extremities). The Aqueous-PREP trial will compare 4% aqueous chlorhexidine vs 10% povidone-iodine for patients with open extremity fractures. The PREPARE trial will compare 2% chlorhexidine in 70% isopropyl alcohol vs 0.7% iodine povacrylex in 74% isopropyl alcohol for patients with open extremity fractures and patients with closed lower extremity or pelvic fractures. Both trials will share key aspects of study design and trial infrastructure. The studies will follow a pragmatic cluster randomized crossover design with alternating treatment periods of approximately 2 months. The primary outcome will be surgical site infection and the secondary outcome will be unplanned fracture-related reoperations within 12 months. The Aqueous-PREP trial will enroll a minimum of 1540 patients with open extremity fractures from at least 12 hospitals; PREPARE will enroll a minimum of 1540 patients with open extremity fractures and 6280 patients with closed lower extremity and pelvic fractures from at least 18 hospitals. The primary analyses will adhere to the intention-to-treat principle and account for potential between-cluster and between-period variability. The patient-centered design, implementation, and dissemination of results are guided by a multidisciplinary team that includes 3 patients and other relevant stakeholders.

Discussion: The PREP-IT master protocol increases efficiency through shared trial infrastructure and study design components. Because prophylactic skin antisepsis is used prior to all surgical procedures and the application, cost, and availability of all study solutions are similar, the results of the PREP-IT trials are poised to inform clinical guidelines and bring about an immediate change in clinical practice.

Trial registration: ClinicalTrials.gov Identifiers: NCT03385304 and NCT03523962.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Slobogean reported receiving grants from Patient-Centered Outcomes Research Institute and the US Department of Defense during the conduct of the study; personal fees from Zimmer Biomet and Smith & Nephew outside the submitted work. Dr Sprague reported receiving grants from Patient-Centered Outcomes Research Institute, Canadian Institutes of Health Research, the US Department of Defense, McMaster University Surgical Associates, and The Physicians Services Incorporated during the conduct of the study; personal fees from Global Research Solutions, University of Sherbrooke, Dartmouth University, and University of Maryland outside the submitted work. Dr Bhandari reported receiving grants from Patient-Centered Outcomes Research Institute, Canadian Institutes of Health Research, the US Department of Defense, and Physicians Services Incorporated during the conduct of the study; personal fees from Smith & Nephew, Stryker, Amgen, Zimmer, Moximed, Bioventus, Merck, Eli Lilly, Sanofi, Ferring, and Conmed outside the submitted work; and grants from Smith & Nephew, DePuy, Eli Lily, Bioventus, Stryker, Zimmer, and Amgen outside the submitted work. Dr Rojas reported receiving grants from Physicians Services Incorporated during the conduct of the study. Ms Wood reported receiving honoraria from University of Maryland during the conduct of the study; and receiving personal fees from Bush Ross outside the submitted work. Dr Harris reported serving as an advisory board member for Entasis; and serving as the infection control section editor for UptoDate outside the submitted work. Dr Petrisor reported receiving grants from Canadian Institutes of Health Research during the conduct of the study. Dr Mullins reported receiving grants from Patient-Centered Outcomes Research Institute during the conduct of the study; personal fees and nonfinancial support from AstraZeneca, Bayer, Boehringer-Ingelheim, Illumina, Janssen/J&J, Merck, Pfizer, Regeneron, and Sanofi outside the submitted work. Ms Heels-Ansdell reported receiving grants from Patient-Centered Outcomes Research Institute, the US Department of Defense, and Canadian Institutes of Health Research during the conduct of the study. Ms Del Fabbro reported receiving grants from Physicians’ Services Incorporated and McMaster Surgical Associates during the conduct of the study. Dr Della Rocca reported receiving personal fees from DePuy-Synthes; and having stock options from The Orthopaedic Implant Company, Mergenet Medical, and Intellectual Ventures outside the submitted work. Dr Gitajn reported receiving personal fees from Stryker outside the submitted work. Mr Friedrich reported receiving an honorarium from University of Maryland during the conduct of the study. Mr Rudnicki reported receiving grants from Patient-Centered Outcomes Research Institiute and the US Department of Defense during the conduct of the study. Dr Jeray reported receiving consulting fees from ZimmerBiomet; presentation fees from Radius; and research funding from AO North America outside the submitted work. Dr Joshi reported receiving grants from University of Maryland during the conduct of the study; and grants from the US Department of Defense and Patient-Centered Outcomes Research Institiute outside the submitted work. Ms Camara reported receiving grants from the US Department of Defense and Patient-Centered Outcomes Research Institute during the conduct of the study. Dr Szasz reported receiving grants from Physician’s Services Incorporated and McMaster Surgical Associates during the conduct of the study. Mr N. O’Hara reported receiving grants from Patient-Centered Outcomes Research Institute and the US Department of Defense during the conduct of the study; stock options from Arbutus Medical Inc; and grants from Osteosynthesis and Trauma Care Foundation outside the submitted work. Ms McKay reported receiving grants from University of Maryland during the conduct of the study; and personal fees from Global Resaarch Solutions outside the submitted work. Dr Devereaux reported receiving grants from Abbott Diagnostics, Boehringer Ingelheim, Philips Healthcare, and Roche Diagnostics; and grants and nonfinancial support from Siemens outside the submitted work. Dr O’Toole reported receiving grants from Patient-Centered Outcomes Research Institute and the US Department of Defense during the conduct of the study; personal fees from Smith & Nephew Consultant; consulting fees and stock from Imagen; and personal fees and personal fees and royalties from Coorstek outside the submitted work. Dr Zura reported receiving personal fees from Bioventus and Smith & Nephew and Osteocentric outside the submitted work. Dr Tanner reported receiving grants from the US Department of Defense and Patient-Centered Outcomes Research Institute during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.. Randomized Treatment Allocation, Cluster Crossover, and Recruitment

Figure 2.. PREP-IT (Program of Randomized Trials to Evaluate Pre-operative Antiseptic Skin Solutions in Orthopaedic Trauma) Organization