INTRODUCTION: Open fractures with significant soft tissue injury are associated with high rates of complications, such as non-union, infection, chronic pain and disability. Complications often require further inpatient care, and in many cases, multiple operations and prolonged rehabilitation. Use of hyperbaric oxygen therapy as an adjunct to standard orthopaedic trauma care has the potential to reduce the complications of musculoskeletal injury and thus improve outcomes. Two previous randomised trials have suggested some positive effect, but neither functional measures nor long-term outcomes were reported. METHODS AND ANALYSIS: An international, multicentre, randomised, open-label, clinical trial. Patients with trauma with an acute open fracture of the tibia with severe soft tissue injury (Gustilo grade 3) and high risk of injury-related complications were recruited from participating major trauma hospitals with hyperbaric facilities. Patients were enrolled with the expectation of commencing 12 sessions of hyperbaric oxygen therapy within 48 h of injury. The primary outcome measure is the incidence of acute complications of the open fracture wound at 14 days. Other short-term outcome measures include amputation, need for fasciotomy, time until wound closure, breakdown of closed wounds, time until definitive orthopaedic fixation, number of operative procedures, intensive care stay and hospital stay. Long-term follow-up will continue for 2 years postinjury. ETHICS AND DISSEMINATION: Ethics approval was given by The Alfred Health Human Ethics Committee (206/04) and the Monash University Human Research Ethics Committee (CF07/4208). Approval was also obtained from the institutional research ethics committee at each participating site. This study will make a significant contribution to the trauma literature and should answer the question of whether hyperbaric oxygen therapy can significantly improve outcomes in severe lower limb trauma. Collective study results will be published in international journals and presented at relevant conferences. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov: NCT00264511; Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12607000559415.

Department of Anaesthesia and Perioperative Medicine The Alfred Hospital and Monash University Melbourne Victoria Australia

Department of Epidemiology and Preventive Medicine School of Public Health and Preventive Medicine Monash University Melbourne Victoria Australia

Department of Molecular Medicine and Surgery Karolinska Institutet at Karolinska University Hospital Stockholm Sweden

Department of Orthopaedic Surgery The Alfred Hospital Melbourne Victoria Australia

Department of Physiology and Pharmacology Section for Anesthesiology and Intensive Care Medicine Karolinska Institutet at Karolinska University Hospital Stockholm Sweden

Hospital Pedro Hispano Rua Dr Eduardo Torres Matosinhos Portugal

Hyperbaric Service Department of Intensive Care and Hyperbaric Medicine The Alfred Hospital Melbourne Victoria Australia Department of Epidemiology and Preventive Medicine School of Public Health and Preventive Medicine Monash University Melbourne Victoria Australia

Ostrava City Hospital Ostrava Czech Republic University of Ostrava Ostrava Zabreh Czech Republic

Royal Hobart Hospital Hobart Tasmania Australia

See more in PubMed

Bondurant FJ, Cotler HB, Buckle R et al. . The medical and economic impact of severely injured lower extremities. J Traumatol 1988;28:1270–3. PubMed

Urquhart DM, Edwards ER, Graves SE et al. . Characterisation of orthopaedic trauma admitted to adult Level 1 Trauma Centres. Injury 2006;37:120–7. 10.1016/j.injury.2005.10.016 PubMed DOI

Bradley C, Harrison J. Descriptive epidemiology of traumatic fractures in Australia. Injury research and statistics series. Adelaide: Australian Institute of Health and Welfare, 2004.

Court-Brown CM, Rimmer S, Prakash U et al. . The epidemiology of open long bone fractures. Injury 1998;29:529–34. 10.1016/S0020-1383(98)00125-9 PubMed DOI

Gibbons CL. Tibial shaft fractures. In: Fairbank JCT, Pynsent PB, Carr A, eds. Classification of musculoskeletal trauma. Oxford: Butterworth-Heinemann, 1999, pp 241–53.

Weiss RJ, Montgomery SM, Ehlin A et al. . Decreasing incidence of tibial shaft fractures between 1998 and 2004: information based on 10,627 Swedish inpatients. Acta Orthop 2008;79:526–33. 10.1080/17453670710015535 PubMed DOI

Court-Brown CM, Caesar B. The Epidemiology of Fractures. In: Rockwood CA, Green DP, Bucholz RW, eds. Rockwood and Green's fractures in adults. 7th edn. Lippincott Williams & Wilkins, 2010:53–8.

Breugem CC, Strackee SD. Is there evidence-based guidance for timing of soft tissue coverage of grade III B tibia fractures? Int J Low Extrem Wounds 2006;5:261–70. 10.1177/1534734606295030 PubMed DOI

Harris AM, Althausen PL, Kellam J et al. . Complications following limb-threatening lower extremity trauma. J Orthop Trauma 2009;23:1–6. 10.1097/BOT.0b013e31818e43dd PubMed DOI

MacKenzie EJ, Jones AS, Bosse MJ et al. . Health-care costs associated with amputation or reconstruction of a limb-threatening injury. J Bone Joint Surg Am 2007;89:1685–92. 10.2106/JBJS.F.01350 PubMed DOI

Butcher JL, MacKenzie EJ, Cushing B et al. . Long-term outcomes after lower extremity trauma. J Trauma 1996;41:4–9. 10.1097/00005373-199607000-00002 PubMed DOI

MacKenzie EJ, Burgess AR, McAndrew MP et al. . Patient-oriented functional outcome after unilateral lower extremity fracture. J Orthop Trauma 1993;7:393–401. 10.1097/00005131-199310000-00001 PubMed DOI

MacKenzie EJ, Cushing BM, Jurkovich GJ et al. . Physical impairment and functional outcomes six months after severe lower extremity fractures. J Trauma 1993;34:528–38; discussion 538–529 10.1097/00005373-199304000-00009 PubMed DOI

Urquhart DM, Williamson OD, Gabbe BJ et al. . Outcomes of patients with orthopaedic trauma admitted to level 1 trauma centres. Aust N Z J Surg 2006;76:600–6. 10.1111/j.1445-2197.2006.03785.x PubMed DOI

Niinikoski J. Which role for HBOT to improve tissue salvage after acute muscul-skeletal trauma? International joint meeting on hyperbaric and underwater medicine. Bologna: Grafica Victoria, 1996.

Strauss M. Crush injury, compartment syndrome and other acute traumatic ischaemias. In: Whelan K. ed. Hyperbaric medicine practice. Flagstaff: Best Publishing, 2004:753–78.

Kemmer A. Crush injury and other acute ischaemias. In: Mathieu D, ed. Handbook on hyperbaric medicine. Dordecht: Springer, 2006:305–28.

Garcia-Covarrubias L, McSwain NEJ, Van Meter K et al. . Adjuvant hyperbaric oxygen therapy in the management of crush injury and traumatic ischemia: an evidence-based approach. Am Surg 2005;71:144–51. PubMed

Friedman HI, Fitzmaurice M, Lefaivre JF et al. . An evidence-based appraisal of the use of hyperbaric oxygen on flaps and grafts. Plast Reconstr Surg 2006;117(7 Suppl):175S–90S; discussion 191S–192S 10.1097/01.prs.0000222555.84962.86 PubMed DOI

Goldman RJ. Hyperbaric oxygen therapy for wound healing and limb salvage: a systematic review. PM R 2009;1:471–89. 10.1016/j.pmrj.2009.03.012 PubMed DOI

Wang C, Schwaitzberg S, Berliner E et al. . Hyperbaric oxygen for treating wounds: a systematic review of the literature. Arch Surg 2003;138:272–9; discussion 280 10.1001/archsurg.138.3.272 PubMed DOI

Dauwe PB, Pulikkottil BJ, Lavery L et al. . Does hyperbaric oxygen therapy work in facilitating acute wound healing: a systematic review. Plast Reconstr Surg 2014;133:208e–15e. 10.1097/01.prs.0000436849.79161.a4 PubMed DOI

Hsu RW, Hsu WH, Tai CL et al. . Effect of hyperbaric oxygen therapy on patellar tendinopathy in a rabbit model. J Trauma 2004;57:1060–4. 10.1097/01.TA.0000149247.63934.12 PubMed DOI

Ishii Y, Miyanaga Y, Shimojo H et al. . Effects of hyperbaric oxygen on procollagen messenger RNA levels and collagen synthesis in the healing of rat tendon laceration. Tissue Eng 1999;5:279–86. 10.1089/ten.1999.5.279 PubMed DOI

Ishii Y, Ushida T, Tateishi T et al. . Effects of different exposures of hyperbaric oxygen on ligament healing in rats. J Orthop Res 2002;20:353–6. 10.1016/S0736-0266(01)00094-8 PubMed DOI

Kawashima M, Tamura H, Nagayoshi I et al. . Hyperbaric oxygen therapy in orthopedic conditions. Undersea Hyperb Med 2004;31:155–62. PubMed

Yablon IG, Cruess RL. The effect of hyperbaric oxygen on fracture healing in rats. J Trauma 1968;8:186–202. 10.1097/00005373-196803000-00007 PubMed DOI

Zamboni WA, Brown RE, Roth AC et al. . Functional evaluation of peripheral-nerve repair and the effect of hyperbaric oxygen. J Reconstr Microsurg 1995;11:27–9; discussion 29–30 10.1055/s-2007-1006507 PubMed DOI

Zhao DW. Therapeutic effect of hyperbaric oxygen on recovery of surgically repaired peripheral nerve injury. Zhonghua Wai Ke Za Zhi 1991;29:118–20, 143. PubMed

Zamboni WA. The microcirculation and ischaemia-reperfusion: basic mechanism of hyperbaric oxygen. In: Whelan K. ed. Hyperbaric medicine practice. Flagstaff: Best Publishing, 2004:779–94.

Strauss M. Crush injuries and skeletal compartment muscle compartment syndrome. Feldmeier JJ, ed. In: Hyperbaric oxygen committee report. Undersea and Hyperbaric Medicine Society, 2003:27–34.

Lindstrom T, Gullichsen E, Lertola K et al. . Effects of hyperbaric oxygen therapy on perfusion parameters and transcutaneous oxygen measurements in patients with intramedullary nailed tibial shaft fractures. Undersea Hyperb Med 1998;25:87–91. PubMed

Bouachour G, Cronier P, Gouello JP et al. . Hyperbaric oxygen therapy in the management of crush injuries: a randomized double-blind placebo-controlled clinical trial. J Trauma 1996;41:333–9. 10.1097/00005373-199608000-00023 PubMed DOI

Fischer MD, Gustilo RB, Varecka TF. The timing of flap coverage, bone-grafting, and intramedullary nailing in patients who have a fracture of the tibial shaft with extensive soft-tissue injury. J Bone Joint Surg Am 1991;73:1316–22. PubMed

Gustilo RB, Anderson JT. Prevention of infection in the treatment of one thousand and twenty-five open fractures of long bones: retrospective and prospective analyses. J Bone Joint Surg Am 1976;58:453–8. PubMed

Whittle AP, Russell TA, Taylor JC et al. . Treatment of open fractures of the tibial shaft with the use of interlocking nailing without reaming. J Bone Joint Surg Am 1992;74:1162–71. PubMed

Bosse MJ, MacKenzie EJ, Kellam JF et al. . A prospective evaluation of the clinical utility of the lower-extremity injury-severity scores. J Bone Joint Surg Am 2001;83-A:3–14. PubMed

Caudle RJ, Stern PJ. Severe open fractures of the tibia. J Bone Joint Surg Am 1987;69:801–7. PubMed

Gustilo RB, Mendoza RM, Williams DN. Problems in the management of type III (severe) open fractures: a new classification of type III open fractures. J Trauma 1984;24:742–6. 10.1097/00005373-198408000-00009 PubMed DOI

Lange RH. Limb reconstruction versus amputation decision making in massive lower extremity trauma. Clin Orthop Relat Res 1989:92–9. PubMed

MacKenzie EJ, Bosse MJ, Kellam JF et al. . Characterization of patients with high-energy lower extremity trauma. J Orthop Trauma 2000;14:455–66. 10.1097/00005131-200009000-00001 PubMed DOI

Tarkin IS, Clare MP, Marcantonio HC et al. . An update on the management of high-energy pilon fractures. Injury 2008;39:142–54. 10.1016/j.injury.2007.07.024 PubMed DOI

CDC. Surgical site infection manual. National Healthcare Safety Network, 2014:11–12.

National Health and Medical Research Council (Australia). Australian Research Council. Australian vice-chancellors’ committee: national statement on ethical conduct in human research. Canberra: National Health and Medical Research Council, 2007.

TGA. Note for guidance on good clinical practice (CPMP/ICH/135/95)—annotated with TGA comments. DSEB, 2000.

Freedman B. Equipoise and the ethics of clinical research. N Engl J Med 1987;317:141–5. 10.1056/NEJM198707163170304 PubMed DOI

Bennett MH, Stanford RE, Turner R. Hyperbaric oxygen therapy for promoting fracture healing and treating fracture nonunion. Cochrane Database Syst Rev 2012;11:CD004712. PubMed PMC

Eskes A, Vermeulen H, Lucas C et al. . Hyperbaric oxygen therapy for treating acute surgical and traumatic wounds. Cochrane Database Syst Rev 2013;12:CD008059. PubMed

Pape HC, Grimme K, Van Griensven M et al. . Impact of intramedullary instrumentation versus damage control for femoral fractures on immunoinflammatory parameters: prospective randomized analysis by the EPOFF Study Group. J Trauma 2003;55:7–13. 10.1097/01.TA.0000075787.69695.4E PubMed DOI

Weitz-Marshall AD, Bosse MJ. Timing of closure of open fractures. J Am Acad Orthop Surg 2002;10:379–84. PubMed

Knopp W, Kugler J, Reckert P et al. . The determinants of the quality of life after a type-III open tibial fracture. The results of a multicenter study. Chirurg 1997;68:1156–61; discussion 1162 10.1007/s001040050337 PubMed DOI

Bosse MJ, MacKenzie EJ, Kellam JF et al. . An analysis of outcomes of reconstruction or amputation after leg-threatening injuries. N Engl J Med 2002;347:1924–31. 10.1056/NEJMoa012604 PubMed DOI

McCarthy ML, MacKenzie EJ, Edwin D et al. . Psychological distress associated with severe lower-limb injury. J Bone Joint Surg Am 2003;85-A:1689–97. PubMed

Godina M. Early microsurgical reconstruction of complex trauma of the extremities. Plast Reconstr Surg 1986;78:285–92. 10.1097/00006534-198609000-00001 PubMed DOI

Gopal S, Majumder S, Batchelor AG et al. . Fix and flap: the radical orthopaedic and plastic treatment of severe open fractures of the tibia. J Bone Joint Surg Br 2000;82:959–66. 10.1302/0301-620X.82B7.10482 PubMed DOI

Parrett BM, Matros E, Pribaz JJ et al. . Lower extremity trauma: trends in the management of soft-tissue reconstruction of open tibia-fibula fractures. Plast Reconstr Surg 2006;117:1315–22; discussion 1323–1314 10.1097/01.prs.0000204959.18136.36 PubMed DOI

Verhelle N, Vranckx J, Van den Hof B et al. . Bone exposure in the leg: is a free muscle flap mandatory? Plast Reconstr Surg 2005;116:170–7; discussion 178–181 10.1097/01.PRS.0000169698.89331.0B PubMed DOI

Garg AX, Greene T, Levin NW. A well-conducted randomized trial that establishes no benefit of therapy is an important medical advance. Nephrol Dial Transplant 2008;23:52–5. 10.1093/ndt/gfm712 PubMed DOI

Hyperbaric Oxygen for Lower Limb Trauma (HOLLT): an international multi-centre randomised clinical trial

See more in PubMed

ANZCTR
ACTRN12607000559415

ClinicalTrials.gov
NCT00264511