Multiply injured patients with orthopaedic injuries are at increased risk of local (fracture-related) and systemic complications including nonunion, osteomyelitis, nosocomial infection (NI), multiple organ failure (MOF), and death. These patients typically present with complex injury patterns and compromised hemodynamics, leading to challenging decisions pertaining to titration of orthopaedic care. Hemodynamic status, markers of anaerobic metabolism [pH, base deficit (BD), and lactate], concomitant injury (eg, chest and head), and physiologic status (eg, presence or absence of coagulopathy) typically guide timing and choices of initial and staged fracture fixation in polytrauma patients.
Evidence continues to accumulate that injury-associated inflammation and immunologic response have also significant effects on acute clinical outcomes.1–5 However, the patient-specific immunologic response has not been incorporated in intervention decision-making algorithms. Various studies have demonstrated associations between elevated levels of proinflammatory and anti-inflammatory cytokines, chemokines, and damage-associated molecular pattern molecules and adverse outcomes following traumatic injury and fracture intervention, yet immunologic diagnostic testing is not routinely used in the clinical arena.6–8 This lack of clinical application of immunologic biomarkers likely reflects the complexity of the immune/inflammatory response to injury. Advancements in bioinformatics, computational modeling, and systems biology have allowed researchers and clinicians to better understand the marked complexities of injury-associated immunologic response and its impact on clinical outcomes.9,10 For example, investigators have recently identified distinct immunologic biomarker networks that occur within hours of injury that correlate with adverse outcomes such as NI and MOF.3,5,11–15 These methods offer new opportunities to better understand a more composite, patient-specific response to injury that accounts for hemodynamics, anaerobic metabolism, and the immediate immunologic response to injury.
The purpose of the study was to quantify the acute immunologic biomarker response in polytraumatized patients with major skeletal trauma. This investigation sought to identify temporal associations of an expanded panel of immunologic mediators with short-term complications, including NI and the magnitude of organ dysfunction, in a prospective cohort of multiply injured patients with major axial and lower extremity orthopaedic injuries. We hypothesized that patients with complicated clinical courses, defined by higher levels of organ dysfunction, would exhibit marked differences in their postinjury immunologic response compared to patients without complicated clinical courses.
PATIENTS AND METHODS
Consecutive multiply injured patients, 18-55 years of age, with major orthopaedic injuries that presented to our institution as a trauma activation and admitted to the intensive care unit (ICU) were eligible for enrollment into this prospective, observational study. Orthopaedic injuries included all pelvic and acetabular fractures, operative femur fractures, and operative tibia fractures. Institutional review board approval was previously obtained. Patients were enrolled from April 29, 2015, through October 5, 2016. Consent was obtained within 48 hours of injury and before the fourth blood draw from the patient or legal authorized health care representative. Exclusion criteria were presentation to our institution greater than 6 hours after injury, severe traumatic brain injury, pre-existing immunologic dysfunction, history of organ failure, and pregnancy. Severe traumatic brain injury was defined as an initial Glasgow Coma Scale (GCS) of 7 or less without significant improvement within 48 hours.
Blood was collected upon presentation to the emergency department (time 0), at 8, 24, and 48 hours after injury. Blood samples were all processed within 2 hours of collection. Samples were centrifuged at room temperature at 1500 rpm for 10 minutes. 1.0 mL of plasma was aliquoted into separate cryovial tubes and immediately frozen at −80°C.
Plasma analyses were performed using a Luminex panel Bioassay of 20 protein-level immunologic mediators. The following inflammatory mediators were measured: IL-1β, IL-1 receptor antagonist (IL-1RA), soluble IL-2 receptor-α (sIL-2Rα), IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-17A, IL-17E/IL-25, IL-21, IL-22, IL-23, IL-33, interferon gamma-induced protein 10 (IP-10), monokine induced by interferon gamma (MIG), monocyte chemoattractant protein-1 (MCP-1), and high mobility group box 1 (HMGB1). Cytokine values are represented by serum concentrations of pg/mL. HMGB1 concentrations are represented in ng/mL.
Patient demographics (age, sex, and body mass index), comorbidities, injury characteristics [Abbreviated Injury Score (AIS), Injury Severity Score (ISS), blood transfusions, ICU length of stay (LOS), hospital LOS, and number of days on mechanical ventilation], and short-term clinical data (vital signs, electrolytes, hematologic values, and markers of resuscitation) were obtained from the electronic medical record. Massive transfusion was defined as 10 units of packed red blood cells (PRBCs) in 24 hours. Critical administration threshold transfusion refers to 3 units of PRBCs given within 1 hour. The initial pH and BD upon admission to the trauma center were recorded, as well as the worst pH and BD in the first 24 hours.
Measurement of Organ Dysfunction
Organ dysfunction was calculated according to the Marshall Multiple Organ Dysfunction score (MODScore) on a daily basis.16,17 The Marshall MODScore is a validated measure of organ dysfunction in a trauma population (Table 1).16,17 It consists of a 0–4 point grading scale for each of the following systems: cardiovascular, respiratory, hepatic, hematologic, renal, and neurologic.
The Marshall MODScore has been shown to correlate well with in-hospital adverse outcomes such as MOF, NI, and prolonged ICU and hospital LOS.3,16–18 We investigated daily MODScore (MODSD2, MODSD3, MODSD4, and MODSD5) and all possible combinations of MODScore between days 2 and 5 including daily maximum MODScore and average MODScore (aMODSD2–D3; aMODSD2–D4; aMODSD2–D5; aMODSD3–D4; aMODSD3–D5; and aMODSD4–D5) as nearly all orthopaedic interventions occurred in this time frame. In addition, the majority of patients either resolved their organ dysfunction or progressed into longer-term organ dysfunction by day 5 after injury. MODScore on day 1 reflects the injury magnitude and early resuscitative efforts, as opposed to development of organ dysfunction, and thus was not used in organ dysfunction assessment.19 Combining MODScore from D2 through D5 (aMODSD2–D5) provided the most comprehensive information and exhibited the best correspondence to ICU LOS, hospital LOS, and days on mechanical ventilation compared with any other iteration of daily MODScore or average MODScore on days 2 through 5. This is consistent with previous studies in which circulating biomarker networks have been shown to effectively stratify trauma patients into high and low organ dysfunction cohorts, and correspond with in-hospital complication profiles including NI, LOS, days of mechanical ventilation, and survival.3,5,13 The severity of organ dysfunction, measured by MODScore on days 2 through 5, has been shown to correlate with the magnitude and duration of hemorrhagic shock following injury.20 Accordingly, aMODSD2–D5 was chosen as the primary clinical outcome to which early injury-specific immunologic data were compared.
Scatterplots were used to investigate different possibilities of aMODD2–D5 scoring to establish a threshold that would serve as a moderate-term outcome measure of patient recovery. It was found that aMODD2–D5 value of 4 was the most effective at simultaneously discriminating between patients with higher ICU LOS, hospital LOS, and days on mechanical ventilation. Biomarkers were then compared in a group of patients with low organ dysfunction (aMODSD2–D5 of ≤4) to a group of patients with high organ dysfunction (aMODS2–5 > 4) at multiple time points including initial presentation to the emergency department (time 0), 8, 24, and 48 hours after injury.
Using SDs outlined by the Center for Disease Control, diagnoses of NI (which included pneumonia, urinary tract infection, bloodstream infection, Clostridium difficile infection, and wound infection) were established.21–25 As an exploratory analysis, immunologic mediator concentrations were also compared between patients who did and did not develop NI.
The Student t test was used to compare biomarkers at each individual time point after injury as well as between patients who did and did not develop NI. A multivariate logistic regression model was used to assess the effect of biomarkers and injury severity measures simultaneously. Mann–Whitney U tests and Fisher exact tests were used to compare patient demographics and hospital stay characteristics between patients grouped by aMODSD2-D5 scores. A P value of <0.05 was considered to be statistically significant.
Sixty-one multiply injured patients with major orthopaedic injuries were enrolled prospectively. Forty-four patients had pelvis and acetabular fractures (18 operative and 26 nonoperative), 22 had operative femur fractures, and 20 had operative tibia fractures.
There were 34 patients in the aMODS D2–D5 ≤ 4 (low organ dysfunction) group and 27 patients in the aMODSD2–D5 >4 (high organ dysfunction) group. There were no demographic differences between the aMODSD2–D5 ≤4 and aMODSD2–D5 >4 groups (Table 2). The aMODSD2–D5 ≤ 4 group had a significantly lower ISS, spent fewer days in the ICU, hospital, and on mechanical ventilation, and required fewer blood transfusions than the MODS >4 group (Table 2).
Patients with aMODSD2–D5 >4 had significantly higher serum concentrations of IL-6, IL-8, IL-10, MCP-1, IL-1RA, and MIG than aMODSD2–D5 ≤4 at nearly all time points (Figs. 1A–F). Lower concentrations of IL-21 and IL-22 were measured in aMODSD2–D5 >4 compared with aMODSD2–D5 ≤4 (Figs. 1G, H). Box and whisker plots illustrate median differences between the high and low organ dysfunction group and quartile distribution of biomarker data (Figs. 2A–D). Although most biomarker protein concentrations were greatest upon presentation (0 hours), marked increases in circulating levels of IL-6 and IL-8 were observed at the 8-hour time point resulting in larger differences between the groups (Figs. 1A, B). Few differences were observed between aMODSD2–D5 ≤4 versus aMODSD2–D5 >4 with respect to the other inflammatory mediator proteins measured.
A multivariate analysis was used to explore the independent association of select biomarkers on aMODSD2–D5, after adjusting for the following measures of injury severity: (1) ISS; (2) admission BD; and (3) number of units of blood transfused in the first 24 hours. Many of the baseline biomarker values were highly correlated with the measures of injury severity making independent associations undetectable after the adjustments.
Patients who developed NI (n = 24) had significantly elevated circulating levels of IL-10, MIG, and HMGB1 compared with patients who did not develop NI (n = 37) (Figs. 3A–D). Several additional mediators demonstrated a trend toward higher circulating levels in patients who developed NI but did not achieve significance (Figs. 3A–D).
The immunologic response following injury has been shown to influence short-term outcomes in trauma patients.1–5 This study sought to explore the dynamic progression of immunologic biomarkers in multiply injured patients with major pelvic and/or lower extremity fractures. Temporal quantification of trauma-relevant immune mediator proteins identified 8 biomarkers, from a panel of 20, that were consistently elevated (IL-6, IL-8, IL-10, MCP-1, IL-1RA, and MIG) or depressed (IL-21 and IL-22) during the initial injury and resuscitative time frame in patients who subsequently developed higher levels of organ dysfunction. Although our data demonstrate differences in immunoactive mediators between low and high organ dysfunction patients, causation of any of the biomarkers and organ dysfunction is not known.
Several factors impact the outcome of polytraumatized patients, including severity of injury, immunologic and physiologic response to injury, comorbidities, and genetics.26–28 Severe trauma incites an inflammatory response that can become both severe and prolonged, leading to systemic inflammatory response syndrome. Further immune dysregulation has been associated closely with NI, organ dysfunction, and other relevant complications such as wound infections.28 Although significant strides have been made over the past decade in characterizing the complexities of the immunologic response after trauma, patient-specific and injury-specific factors that result in immune dysregulation are only partially understood.1–5,11,13–15,28–30
The postinjury immune response is a highly complex process characterized by a progression of cell-mediated events orchestrated by cytokine and chemokine signaling. Measurement of isolated inflammatory mediators fails to reflect the dynamic nature and orchestration of the immune response and has proven to be largely ineffective in predicting clinical phenotypes. By contrast, computational analyses of inflammatory networks and mediator interconnectivity may offer a more intricate approach to short-term outcome prediction.3,14,15 The complexity of the immunologic response has largely mitigated development of meaningful immunologically based diagnostic modalities to guide clinical decisions. Likewise, the vast majority of clinical trials using reductionist interventions directed at modulating individual immunologic mediators have failed to improve clinical outcomes.31 It is likely that successful future immunologic-based interventions will have to affect the coordination of the immunologic orchestration in contrast to mitigating changes in isolated mediators.
The primary objective of this investigation was to compare biomarker responses in patient groups with different levels of organ dysfunction. Therefore, it was important to quantify organ dysfunction using methods that were clinically relevant. There are multiple organ dysfunction scoring systems that are notably similar. Therefore, instead of investigating how biomarker changes compared with phenotypic differences of the various organ scoring systems, we adopted an alternative approach that integrated a temporally expanded signature of organ dysfunction to include MODS scores from days 2 to 5 after injury. This corresponded to a timeframe in which nearly all patients either resolved their injuries or developed longer-term illness with prolonged admission to ICU, consistent with previous investigations.3,10,13,20 A similar approach could have clearly been used with SOFA scores of Denver scores. This approach identified a stark cutoff value of aMODSD2–D5 of 4, which delineated patients into groups of benign or complicated outcomes based on hospital LOS, ICU LOS, and duration of mechanical ventilation. We anticipate that the findings in this study would not have been affected by stratifying patients by other organ scoring systems.
Decisions surrounding timing and magnitude of fracture surgery in multiply injured patients currently rely on measures of hemodynamic stability, resuscitation, injury severity, and injury distribution. The concept of “Damage Control Orthopaedics (DCO)” was introduced over 20 years ago.32,33 Studies demonstrated improved survival rates in physiologically unstable patients who were treated with temporizing measures as opposed to immediate definitive fracture fixation.33,34 Vallier et al., have demonstrated that “Early Appropriate Care (EAC),” defined as early definitive fixation of spine, pelvis, acetabular, and femur fractures minimized systemic complications and reduced hospital LOS in appropriately resuscitated patients.35–38 Trauma patients with major orthopaedic injuries were treated with early definitive fracture stabilization if they met the following criteria: (1) appropriately resuscitated (pH > 7.25, lactate <2.5, and BD less than 4–6 trending positive); (2) hemodynamically stable (systolic blood pressure >90 mm Hg); (3) normothermic; (4) absence of trauma-induced coagulopathy; (5) absence of brain injury causing elevated intracranial pressure; (6) absence of severe chest injury resulting in impaired oxygenation despite high ventilatory requirements; and (7) clear by the trauma service. Although EAC criteria were commonly applied from a resuscitation standpoint, overall physiologic status (coagulation, core temperature, and regional organ injury) was considered before deciding on early definitive fracture fixation. At our institution, the general trauma surgery service is primarily responsible for the initial care of trauma patients. However, the trauma service and orthopaedic trauma service generally establish very early communication and work collaboratively to develop a treatment plan that facilitates an ideal sequence of interventions.
Regional organ injury also affects outcomes in trauma patients with orthopaedic injuries.34,39–41 Specifically, patients with severe head injuries benefit from initial damage control measures.39 Severe chest injury causing impaired oxygenation is associated with systemic inflammation and the development of acute respiratory distress syndrome.34,40 Hypothermia, coagulopathy, and acidosis have been termed the “lethal triad” of trauma, and patients presenting with this pathologic constellation of physiologic parameters are typically treated initially with “damage control” measures.42 Using current treatment algorithms, physiologically unstable and underresuscitated patients, or those with severe concomitant organ injury (head and chest) are typically triaged into DCO. Likewise, patients with severe extremity soft-tissue injuries, who are at greater risk of local and systemic complications, are triaged into damage control algorithms.40 Understanding how early changes in both magnitude and orchestration of the immunologic response to injury potentially offers patient-specific information to further inform treatment triage decisions.
To date, there are few orthopaedic-related studies that have described associations between inflammatory biomarkers [eg, interleukin (IL)-6, IL-8, TNF-α, and mitochondrial DNA] and the timing and magnitude of fracture interventions.6–8,43,44 In addition, it is likely that computational analyses of changes in mediator concentrations will be necessary to inform individual treatment triage decisions with immunologic response data.3,5,13,45
This investigation corroborated the findings of other trauma-related studies in that we observed a distinct progression of an exaggerated immunologic response during the initial 48 hours following injury in patients who developed adverse short-term outcomes. As anticipated, increases in circulating levels of protein-level immunologic mediators were significantly affected by injury severity. However, it is likely that differences in mediator concentrations in patients with high or low organ dysfunction also reflect individualized response to injury. Therefore, quantifying temporal progression of immunologic mediator concentrations has potential to provide insight on patient-specific response to injury. Currently, the clinical significance of these findings is unknown, although it is notable that cytokines such as IL-21, IL-22, and IL-23, which play key roles in suppressing type 17 immune/inflammatory responses, are considered tissue-protective; in this regard, recent studies have implicated type 17 immunity in progression toward death in human blunt trauma.15,45,46 In addition, future studies also need to continue to gravitate toward computational analyses that characterize temporal and spatial networks of immunologic mediators and how these networks are affected by injury and interventions.
Several of the mediators that were elevated in the higher organ dysfunction group of patients in this experiment (IL-6, IL-8, IL-10, and MCP-1) have been described in multiple studies as being associated with adverse short-term clinical outcomes, including acute respiratory distress syndrome, NI, sepsis, multiple organ dysfunction syndrome, MOF, and death.3,5,11,12,30 IL-6, IL-8, and MCP-1 function as proinflammatory cytokines that are liberated following tissue injury and/or infection. IL-10 is an anti-inflammatory cytokine and is responsible for impeding cytokine production. IL-21 and IL-22 play a role in immune suppression and were found to have lower circulating levels in the high organ dysfunction group. Although this investigation focuses on proteomics and the sample size is small, our findings support the genomic storm model proposed by the Glue Grant researchers that describes a simultaneous and rapid upregulation of the innate immune response and downregulation of the adaptive immune response.5,30
This study has numerous limitations. Only 20 trauma-related cytokines/chemokines were studied, although dozens of biomarkers have been described to be associated with the immunologic response after trauma. Methodology was limited by the number of biomarker panels commercially available and also by resources. Second, this investigation merely measured magnitudes of biomarker elevation after injury. More sophisticated biomarker dynamic network analyses have been described and may better describe postinjury immunologic activity through quantification and description of biomarker orchestration.3,5,13–15 In addition, associations described in this study were based on a limited number of orthopaedic trauma patients with considerable injury heterogeneity. Future investigations should compare temporal change in biomarker concentrations in multiply injured patients with fractures to trauma patients without substantial extremity injuries.
Both the transcriptome and proteome are known to quickly change within hours of injury.5,30 Another shortcoming of this study is related to reporting on a limited proteomic analysis. A larger scale transcriptomic and proteomic analysis may provide a more accurate and comprehensive picture of the immunologic response following injury.
The revised Berlin Definition of polytrauma provides a more uniform definition across trauma centers: AIS >2 in at least 2 regions and the presence of one of the following 5 physiologic variables: systolic blood pressure ≤90 mm Hg, GCS ≤8, base excess ≤ −6, international normalized ratio (INR) ≥1.4, and age ≥70 years.47 Inherent weaknesses of the AIS and ISS relate to their typical estimation and calculation days to weeks after hospital admission making utilization in prospective studies less attractive. Enrollment into the current investigation was determined within minutes of presentation. Thus, the diagnosis of polytrauma had to be established very early, and the inclusion criteria were crafted to capture a severely injured group of trauma patients. 93% of the patients in the current study met the Berlin Definition of polytrauma.
Finally, injury severity was clearly different between the 2 groups, which invariably accounted for the majority of differences in biomarker concentrations. Previous work has demonstrated that early concentrations of inflammatory cytokines (ie, IL-6, IL-8, and MCP-1) are predictably higher in patients with greater injury severity.5 Accordingly, clinical outcomes invariably demonstrate association with injury severity. However, there are many patients who resolve severe injuries without complications and other patients who develop severe short-term and longer-term complications with seemingly low injury magnitude. Understanding individual immunotyping of trauma patients would allow clinicians to anticipate outcomes and better titrate interventions. This is particularly pertinent to multiply injured patients with multiple fractures who would benefit from an optimized approach to the timing and choices of orthopaedic interventions. Clinician-investigators have advocated for an individualized, comprehensive, and coordinated approach as necessary means to deliver precision medicine to trauma patients.48 Integration of an individual's immunologic response with injury metrics and the subsequent physiologic response (upon which treatment algorithms are currently based) will improve a clinician's ability to stratify a trauma patient's clinical trajectory. Future investigations pertaining to biomarker progression after injury should aim to match patient groups based on initial injury severity.
Trauma patients with major orthopaedic injuries that developed higher levels of organ dysfunction were observed to have 2–3 times greater initial circulating levels (<24 hours) of specific immunologic biomarkers (IL-6, IL-8, IL-10, MCP-1, IL-1RA, and MIG) compared with patients who had lower levels of organ dysfunction (Figs. 1A–F). Similarly, initial diminished circulating levels of 2 mediators (IL-21, 1.5x; IL-22, 2x) were detected in the high organ dysfunction group compared with the low organ dysfunction group (Figs. 1G, H). Precision medicine approaches to trauma patients rely on individualized quantification of injury metrics, underlying host factors, and will increasingly be informed by the patient-specific immunologic response.48 Incorporation of immunologic biomarkers with established measures of acidosis, regional injury, and evolving postinjury physiology can aid in identification of orthopaedic trauma patients at risk of complications. Immunologic biomarker patterns measured immediately after injury may offer important information to titrate both initial and staged orthopaedic surgical interventions.
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