A study protocol for a Pilot Masked, Randomized Controlled Trial Evaluating Locally-applied Gentamicin versus Saline in Open Tibia Fractures (pGO-Tibia) in Dar es Salaam, Tanzania

Ericka P von Kaeppler, Claire Donnelley, Syed H Ali, Heather J Roberts, John M Ibrahim, Hao-Hua Wu, Edmund N Eliezer, Travis C Porco, Billy T Haonga, Saam Morshed, David W Shearer, Ericka P von Kaeppler, Claire Donnelley, Syed H Ali, Heather J Roberts, John M Ibrahim, Hao-Hua Wu, Edmund N Eliezer, Travis C Porco, Billy T Haonga, Saam Morshed, David W Shearer

Abstract

Background: Open tibia fractures are a major source of disability in low- and middle-income countries (LMICs) due to the high incidence of complications, particularly infection and chronic osteomyelitis. One proposed adjunctive measure to reduce infection is prophylactic local antibiotic delivery, which can achieve much higher concentrations at the surgical site than can safely be achieved with systemic administration. Animal studies and retrospective clinical studies support the use of gentamicin for this purpose, but no high-quality clinical trials have been conducted to date in high- or low-income settings.

Methods: We describe a protocol for a pilot study conducted in Dar es Salaam, Tanzania, to assess the feasibility of a single-center masked randomized controlled trial to compare the efficacy of locally applied gentamicin to placebo for the prevention of fracture-related infection in open tibial shaft fractures.

Discussion: The results of this study will inform the design and feasibility of a definitive trial to address the use of local gentamicin in open tibial fractures. If proven effective, local gentamicin would be a low-cost strategy to reduce complications and disability from open tibial fractures that could impact care in both high- and low-income countries.

Trial registration: ClinicalTrials.gov, Registration # NCT03559400 ; Registered June 18, 2018.

Keywords: Antibiotics; Fracture-related infection; Gentamicin; Global health; Open tibia fracture; Orthopaedic surgery.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Study Intervention Protocol. a The preparation and storage of 40 mL study solutions, either 2 mg/mL gentamicin (intervention) or normal saline (placebo control). b The process of intraoperative randomization. Following fracture debridement and bony stabilization with planned fixation, the surgeon confirms that the wound amenable to primary closure. If the wound is primarily closable, participants are randomized to receive intraoperative local injection of either intervention or placebo control, labeled either ‘Solution A’ or ‘Solution B’. Research coordinators retrieve the allocated syringe of study solution from the dedicated study refrigerator. c The process of solution administration. Following wound closure, the surgeon draws the study solution from a sterile basin into a sterile syringe and injects the study solution by inserting the needle down to bone through an anteromedial approach at the level of the fracture site. A minimum of 5 mL of study solution may be injected, and the injection is continued until either extravasation is seen through the traumatic wound or a maximum of 40 mL has been administered, whichever occurs first. d The process of solution administration. A full-video demonstration of injection procedure can be found in Additional file 1

References

    1. James SL, Abate D, Abate KH, Abay SM, Abbafati C, Abbasi N, et al. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. The Lancet. 2018;392(10159):1789–1858. doi: 10.1016/S0140-6736(18)32279-7.
    1. Kohlprath R, Assal M, Uçkay I, Holzer N, Hoffmeyer P, Suva D. Open fractures of the tibia in the adult: surgical treatment and complications. Rev Med Suisse. 2011;7(322):2484–2488.
    1. Harris AM, Althausen PL, Kellam J, Bosse MJ, Castillo R, Lower Extremity Assessment Project (LEAP) Study Group Complications following limb-threatening lower extremity trauma. J Orthop Trauma. 2009;23(1):1–6. doi: 10.1097/BOT.0b013e31818e43dd.
    1. Barei DP, Nork SE, Mills WJ, Henley MB, Benirschke SK. Complications associated with internal fixation of high-energy bicondylar tibial plateau fractures utilizing a two-incision technique. J Orthop Trauma. 2004;18(10):649–657. doi: 10.1097/00005131-200411000-00001.
    1. Clelland SJ, Chauhan P, Mandari FN. The epidemiology and management of tibia and fibula fractures at Kilimanjaro Christian Medical Centre (KCMC) in Northern Tanzania. Pan Afr Med J. 2016;25:51. doi: 10.11604/pamj.2016.25.51.10612.
    1. Lawing CR, Lin F-C, Dahners LE. Local injection of aminoglycosides for prophylaxis against infection in open fractures. J Bone Joint Surg Am. 2015;97(22):1844–1851. doi: 10.2106/JBJS.O.00072.
    1. Craig J, Fuchs T, Jenks M, Fleetwood K, Franz D, Iff J, et al. Systematic review and meta-analysis of the additional benefit of local prophylactic antibiotic therapy for infection rates in open tibia fractures treated with intramedullary nailing. Int Orthop. 2014;38(5):1025–1030. doi: 10.1007/s00264-014-2293-2.
    1. Carver DC, Kuehn SB, Weinlein JC. Role of systemic and local antibiotics in the treatment of open fractures. Orthop Clin North Am. 2017;48(2):137–153. doi: 10.1016/j.ocl.2016.12.005.
    1. Morgenstern M, Vallejo A, McNally MA, Moriarty TF, Ferguson JY, Nijs S, et al. The effect of local antibiotic prophylaxis when treating open limb fractures. Bone Joint Res. 2018;7(7):447–456. doi: 10.1302/2046-3758.77.BJR-2018-0043.R1.
    1. The FLOW Investigators A trial of wound irrigation in the initial management of open fracture wounds. New England J Med. 2015;373(27):2629–2641. doi: 10.1056/NEJMoa1508502.
    1. Bhandari M, Guyatt G, Walter SD, Tornetta P, Schemitsch EH, Swiontkowski M, et al. Randomized trial of reamed and unreamed intramedullary nailing of tibial shaft fractures: by the Study to Prospectively Evaluate Reamed Intramedullary Nails in Patients with Tibial Fractures (SPRINT) Investigators*. J Bone Joint Surg. 2008;90(12):2567–2578. doi: 10.2106/JBJS.G.01694.
    1. Haonga BT, Liu M, Albright P, Challa ST, Ali SH, Lazar AA, et al. Intramedullary nailing versus external fixation in the treatment of open tibial fractures in Tanzania: results of a randomized clinical trial. J Bone Joint Surg. 2020;102(10):896–905. doi: 10.2106/JBJS.19.00563.
    1. TRUST Investigators writing group, Busse JW, Bhandari M, Einhorn TA, Schemitsch E, Heckman JD, Tornetta P 3rd, Leung KS, Heels-Ansdell D, Makosso-Kallyth S, Della Rocca GJ, Jones CB, Guyatt GH. Re-evaluation of low intensity pulsed ultrasound in treatment of tibial fractures (TRUST): randomized clinical trial. BMJ. 2016;355:i5351. 10.1136/bmj.i5351. PMID: 27797787; PMCID: PMC5080447.
    1. Bosse MJ, MacKenzie EJ, Kellam JF, Burgess AR, Webb LX, Swiontkowski MF, et al. An analysis of outcomes of reconstruction or amputation after leg-threatening injuries. New England J Med. 2002;347(24):1924–1931. doi: 10.1056/NEJMoa012604.
    1. Doshi P, Gopalan H, Sprague S, Pradhan C, Kulkarni S, Bhandari M. Incidence of infection following internal fixation of open and closed tibia fractures in India (INFINITI): a multi-centre observational cohort study. BMC Musculoskelet Disord. 2017;18(1):156. doi: 10.1186/s12891-017-1506-4.
    1. Westgeest J, Weber D, Dulai SK, Bergman JW, Buckley R, Beaupre LA. Factors associated with development of nonunion or delayed healing after an open long bone fracture: a prospective cohort study of 736 subjects. J Orthop Trauma. 2016;30(3):149–155. doi: 10.1097/BOT.0000000000000488.
    1. Helbig L, Bechberger M, Aldeeri R, Ivanova A, Haubruck P, Miska M, et al. Initial peri- and postoperative antibiotic treatment of infected nonunions: results from 212 consecutive patients after mean follow-up of 34 months. Ther Clin Risk Manag. 2018;14:59–67. doi: 10.2147/TCRM.S152008.
    1. Peng J, Ren Y, He W, Li Z, Yang J, Liu Y, et al. Epidemiological, clinical and microbiological characteristics of patients with post-traumatic osteomyelitis of limb fractures in Southwest China: a hospital-based study. J Bone Jt Infect. 2017;2(3):149–153. doi: 10.7150/jbji.20002.
    1. Cavanaugh DL, Berry J, Yarboro SR, Dahners LE. Better prophylaxis against surgical site infection with local as well as systemic antibiotics. J Bone Joint Surg Am. 2009;91(8):1907–1912. doi: 10.2106/JBJS.G.01237.
    1. OʼToole RV, Joshi M, Carlini AR, Murray CK, Allen LE, Scharfstein DO, et al. Local antibiotic therapy to reduce infection after operative treatment of fractures at high risk of infection: a multicenter, randomized, controlled trial (VANCO Study) J Orthop Trauma. 2017;31(Suppl 1):S18–S24.
    1. Edson RS, Terrell CL. The aminoglycosides. Mayo Clin Proc. 1999;74(5):519–528. doi: 10.1016/S0025-6196(11)65134-3.
    1. Selby NM, Shaw S, Woodier N, Fluck RJ, Kolhe NV. Gentamicin-associated acute kidney injury. QJM. 2009;102(12):873–880. doi: 10.1093/qjmed/hcp143.
    1. Miclau T, Edin ML, Lester GE, Lindsey RW, Dahners LE. Bone toxicity of locally applied aminoglycosides. J Orthop Trauma. 1995;9(5):401–406. doi: 10.1097/00005131-199505000-00007.
    1. Fassbender M, Minkwitz S, Kronbach Z, Strobel C, Kadow-Romacker A, Schmidmaier G, et al. Local gentamicin application does not interfere with bone healing in a rat model. Bone. 2013;55(2):298–304. doi: 10.1016/j.bone.2013.04.018.
    1. Chan A-W, Tetzlaff JM, Altman DG, Laupacis A, Gøtzsche PC, Krleža-Jerić K, et al. SPIRIT 2013 statement: defining standard protocol items for clinical trials. Ann Intern Med. 2013;158(3):200–207. doi: 10.7326/0003-4819-158-3-201302050-00583.
    1. Eldridge SM, Chan CL, Campbell MJ, Bond CM, Hopewell S, Thabane L, et al. CONSORT 2010 statement: extension to randomised pilot and feasibility trials. BMJ. 2016;355:i5239. doi: 10.1136/bmj.i5239.
    1. Loudon K, Treweek S, Sullivan F, Donnan P, Thorpe KE, Zwarenstein M. The PRECIS-2 tool: designing trials that are fit for purpose. BMJ. 2015:350 [cited 2020 May 19]. Available from: .
    1. Hoff WS, Bonadies JA, Cachecho R, Dorlac WC. East Practice Management Guidelines Work Group: Update to practice management guidelines for prophylactic antibiotic use in open fractures. J Trauma. 2011;70(3):751–754. doi: 10.1097/TA.0b013e31820930e5.
    1. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)—a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009;42(2):377–381. doi: 10.1016/j.jbi.2008.08.010.
    1. Harris PA, Taylor R, Minor BL, Elliott V, Fernandez M, O’Neal L, et al. The REDCap consortium: building an international community of software platform partners. J Biomed Inform. 2019;95:103208. doi: 10.1016/j.jbi.2019.103208.
    1. Henry SL, Galloway KP. Local antibacterial therapy for the management of orthopaedic infections. Clin-Pharmacokinet. 1995;29(1):36–45. doi: 10.2165/00003088-199529010-00005.
    1. Mercado MG. Acute kidney injury: diagnosis and management. Acute kidney injury. 2019;100(11):8.
    1. Antoci V, Adams C, Hickok N, Shapiro I, Parvizi J. Antibiotics for local delivery systems cause skeletal cell toxicity in vitro. Clin Orthop Related Res. 2007;462:200–206. doi: 10.1097/BLO.0b013e31811ff866.
    1. Hanssen A. Local antibiotic delivery vehicles in the treatment of musculoskeletal infection. Clin Orthop Related Res. 2005;437:91–96. doi: 10.1097/01.blo.0000175713.30506.77.
    1. Arain M, Campbell MJ, Cooper CL, Lancaster GA. What is a pilot or feasibility study? A review of current practice and editorial policy. BMC Med Res Methodol. 2010;10(1):67. doi: 10.1186/1471-2288-10-67.
    1. Leon AC, Davis LL, Kraemer HC. The role and interpretation of pilot studies in clinical research. J Psychiatric Res. 2011;45(5):626–629. doi: 10.1016/j.jpsychires.2010.10.008.
    1. Thabane L, Lancaster G. A guide to the reporting of protocols of pilot and feasibility trials. Pilot Feasibility Stud. 2019;5(1):37. doi: 10.1186/s40814-019-0423-8.
    1. Lancaster GA, Dodd S, Williamson PR. Design and analysis of pilot studies: recommendations for good practice: design and analysis of pilot studies. J Eval Clin Pract. 2004;10(2):307–312. doi: 10.1111/j..2002.384.doc.x.
    1. Thabane L, Ma J, Chu R, Cheng J, Ismaila A, Rios LP, et al. A tutorial on pilot studies: the what, why and how. BMC Med Res Methodol. 2010;10(1):1. doi: 10.1186/1471-2288-10-1.
    1. Wj M, Morgenstern M, McNally MA, Moriarty TF, McFadyen I, Scarborough M, et al. Fracture-related infection: a consensus on definition from an international expert group. Injury. 2018;49(3):505–510. doi: 10.1016/j.injury.2017.08.040.
    1. Litrenta J, Iii PT, Mehta S, Jones C. Determination of radiographic healing: an assessment of consistency using RUST and Modified RUST in metadiaphyseal fractures. J Orthop Trauma. 2015;29(11):5. doi: 10.1097/BOT.0000000000000390.
    1. Bhandari M, Wasserman S, Yurgin N, Petrisor B, Sprague S, Dent R. Development and preliminary validation of a Function IndeX for Trauma (FIX-IT) Can J Surg. 2013;56(5):E114–E120. doi: 10.1503/cjs.004312.
    1. Dolan P. Modeling valuations for EuroQol Health States. Medical care. 1997;35(11):1095–1108. doi: 10.1097/00005650-199711000-00002.
    1. Lopetegui M, Yen P-Y, Lai A, Jeffries J, Embi P, Payne P. Time motion studies in healthcare: what are we talking about? J Biomed Inform. 2014;49:292–299. doi: 10.1016/j.jbi.2014.02.017.
    1. Reilly MC, Zbrozek AS, Dukes EM. The Validity and reproducibility of a work productivity and activity impairment instrument. Pharmacoeconomics. 1993;4(5):353–365. doi: 10.2165/00019053-199304050-00006.
    1. Teare MD, Dimairo M, Shephard N, Hayman A, Whitehead A, Walters SJ. Sample size requirements to estimate key design parameters from external pilot randomised controlled trials: a simulation study. Trials. 2014;15:264. doi: 10.1186/1745-6215-15-264.
    1. Friedman LM, Furberg CD, DeMets D, Reboussin DM, Granger CB. Fundamentals of Clinical Trials. 5th ed: Springer International Publishing; 2015. [cited 2020 Mar 12]. Available from:
    1. Weigmann K. The ethics of global clinical trials. EMBO Rep. 2015;16(5):566–570. doi: 10.15252/embr.201540398.
    1. Hunt A, Saenz C, Littler K. The global forum on bioethics in research meeting, “ethics of alternative clinical trial designs and methods in low- and middle-income country research”: emerging themes and outputs. Trials. 2019;20(Suppl 2):701. doi: 10.1186/s13063-019-3840-3.

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner