Pathoanatomy and Clinical Correlates of the Immunoinflammatory Response Following Orthopaedic Trauma

Abstract

The natural inflammatory response to major trauma may be associated with the development of a systemic inflammatory state, remote multiorgan failure, and death. Although a controlled inflammatory response is beneficial, an exaggerated response can cause serious adverse systemic effects. Early identification of high-risk patients, based on inflammatory markers and genomic predisposition, should help direct intervention in terms of surgical stabilization and biologic response modification. Currently, two markers of immune reactivity, interleukin-6 and human leukocyte antigen-DR class II molecules, appear to have the most potential for regular use in predicting the clinical course and outcome in trauma patients; however, the ability to measure markers of inflammation is still limited at many hospitals. With improving technology and increasing research interest, understanding of the significance of the immunoinflammatory response system in injured patients will continue to evolve.Inflammation is not itself considered to be a disease but a salutary operation … but when it cannot accomplish that salutary purpose … it does mischief. John Hunter 1For decades, the inflammatory response has been recognized as a physiologic reaction to injury. This complex response arises from the interplay between various mediators produced at the site of injury, including cytokines, growth factors, nitric oxide, and platelet-activating factors, and the activation of local and systemic polymorphonuclear neutrophils (PMNs), lymphocytes, and macrophages. In the acute period following major trauma, this endogenous response system mobilizes to initiate healing and acts as a barrier to injury propagation. Cytokines operate as the main regulators of the postinjury immune response. These mediators, which are produced by diverse cell types, exert their effects by binding to specific cellular receptors, regulating gene transcription, and modifying intracellular signaling pathways 2 (Figure 1).Typically, the amplitude of the inflammatory response is related to the severity of injury. When injury is dramatic, the local inflammatory response may propagate systemically, resulting in serious systemic disease, including acute respiratory distress syndrome and multiorgan failure. 3 In addition to the initial injury, surgical reduction and fixation of fractures also stimulate the immunoinflammatory response. 4 This may result in a second-hit phenomenon, in which a

Cytokine Levels (IL-4, IL-6, IL-8 and TGFβ) as Potential Biomarkers of Systemic Inflammatory Response in Trauma Patients

“…Recently, an increasing research interest has been focused on the issue of cytokines and their role in immune activity in trauma patients [1][2][3][4][5]. Skeletal and tissue injuries may cause a hyper-inflammatory reaction of the immune system manifested by elevation in levels of pro-inflammatory cytokines and may lead to the development of systemic inflammatory reaction syndrome (SIRS).…”

“…The development of this hyper-inflammatory reaction is manifested by activation of the immune system which triggers increased secretion of pro-inflammatory cytokines, such as interleukin-6 (IL-6) and IL-8 [2,4]. The increase in pro-inflammatory cytokines is evident soon after injuries (six hours) and lasts usually for 24-48 hours in most cases.…”

Biomechanics of Musculoskeletal Injury

“…However, patients who are hemodynamically unstable, hypothermic, who have coagulation abnormalities or poor oxygenation due to traumatic lung injury have increased rates of acute lung injury after intermedullary reaming. If these conditions cannot be reversed with adequate resuscitation, these patients benefit from a protocol of damage control orthopaedics consisting of initial external fixation for transient stabilization followed by delayed definitive fracture fixation stabilization followed by delayed definitive fracture fixation (Bone & Giannoudis, 2011;Giannoudis et al, 2009;O'Toole et al, 2005, Hardwood et al, 2005Sears et al, 2009;Pape et al, 2009;. Although inflammation is potentially harmful, with the ability to induce both local and systemic responses, it is also necessary to initiate the healing process.…”

“…One study showed that combined fracture and soft tissue injury caused higher levels of systemic inflammatory mediators (IL-6 and IL-10) than either fracture of soft tissue injury alone. The literature on SIRS and orthopedic trauma is extensive (Hardwood et al, 2005;Seibel et al, 1985;Scalea 2000;Olson, 2004;Schroeder et al, 2009;Sears et al, 2009;Weninger et al, 2007) with the femoral fracture being the primary model since it is a long bone fracture and is often most related with systemic and pulmonary collapse secondary to injury and surgery. Concern about the timing of definitive intramedullary fixation, which includes intramedullary reaming and further release of marrow contents and inflammatory mediators, is an ongoing debate in the orthopedic trauma community.…”

“…Careful consideration of timing is critical in the care of the trauma patients since further surgical intervention can worsen the inflammatory response. In severe polytrauma patients, it is often preferable to perform limited fracture stabilization, rather than definitive orthopaedic repair immediately, since surgery can function as a second traumatic event with a second wave of inflammatory cytokine release, which can augment the initial systemic inflammatory response to the trauma with increased potential to cause systemic disease including SIRS and ARDS (Second hit theory) (Reikeras, 2010;Sears et al, 2009). Hauser et al reports that SIRS is universal after traumatic injury and that the clinical presentation differs only in intensity .…”