Shock volume: Patient-specific cumulative hypoperfusion predicts organ dysfunction in a prospective cohort of multiply injured patients

BACKGROUND: Multiply injured patients are at risk of developing hemorrhagic shock and organ dysfunction. We determined how cumulative hypoperfusion predicted organ dysfunction by integrating serial Shock Index measurements. METHODS: In this study, we calculated shock volume (SHVL) which is a patient-specific index that quantifies cumulative hypoperfusion by integrating abnormally elevated Shock Index (heart rate/systolic blood pressure ≥ 0.9) values acutely after injury. Shock volume was calculated at three hours (3 hr), six hours (6 hr), and twenty-four hours (24 hr) after injury. Organ dysfunction was quantified using Marshall Organ Dysfunction Scores averaged from days 2 through 5 after injury (aMODSD2–D5). Logistic regression was used to determine correspondence of 3hrSHVL, 6hrSHVL, and 24hrSHVL to organ dysfunction. We compared correspondence of SHVL to organ dysfunction with traditional indices of shock including the initial base deficit (BD) and the lowest pH measurement made in the first 24 hr after injury (minimum pH). RESULTS: SHVL at all three time intervals demonstrated higher correspondence to organ dysfunction (R2 = 0.48 to 0.52) compared to initial BD (R2 = 0.32) and minimum pH (R2 = 0.32). Additionally, we compared predictive capabilities of SHVL, initial BD and minimum pH to identify patients at risk of developing high-magnitude organ dysfunction by constructing receiver operator characteristic curves. SHVL at six hours and 24 hours had higher area under the curve compared to initial BD and minimum pH. CONCLUSION: SHVL is a non-invasive metric that can predict anticipated organ dysfunction and identify patients at risk for high-magnitude organ dysfunction after injury. LEVEL OF EVIDENCE: Prognostic study, level III

SHOCK VOLUME: A PRECISION MEDICINE BASED INDEX THAT PREDICTS TRANSFUSION REQUIREMENTS AND ORGAN DYSFUNCTION IN MULTIPLY INJURED PATIENTS

poster abstractIntroduction: Multiply injured patients (MIPs) in hemorrhagic shock develop oxygen debt, which causes organ dysfunction and can lead to death. Clinicians monitor hypoperfusion by interpreting progression of traditional hemodynamic measures along with serum markers of hypoperfusion, which reflect current hemodynamic and metabolic status. However, these indices are sampled at discrete time points and poorly reflect cumulative hypoperfusion. Shock Volume (SV) is a novel, non-invasive, patient-specific index developed to quantify cumulative hypoperfusion. SV integrates the time and magnitude of shock index (Heart Rate/Systolic Blood Pressure) values above 0.9 (known threshold of hypoperfusion) using serial individual vital sign data. SV can be monitored in real time to assess ongoing hypoperfusion. The goal of this study was to determine how SV corresponded to transfusion requirements and organ dysfunction. Methods: SV was measured in six hour increments for 48 hours after injury in a retrospective cohort of 74 MIPs (18-65; Injury Severity Score > 18). SV was compared to base deficit (BD) in predicting mass transfusions (MT) and critical administration transfusions (CATs). Presence of multiple organ failure (MOF) was determined using the Denver Organ Failure assessment score, while Sequential Organ Failure Assessment scores were used to determine magnitude of organ dysfunction. Results: Patients who had accumulated 40 units of SV within six hours of injury and 100 units of SV within twelve hours of injury were at high risk for requiring MT or multiple CATs. SV measurements were equally sensitive and specific as compared to BD values in predicting transfusions. SV measurements at six hours after injury stratified patients at risk for MOF and corresponded to the magnitude of organ failure. Conclusions: SV is a patient-specific index that can be quantified in real-time in critically injured patients. SV is a non-invasive surrogate for cumulative hypoperfusion and predicts high volume transfusions and organ dysfunction

Computational evidence for an early, amplified systemic inflammation program in polytrauma patients with severe extremity injuries

Extremity and soft tissue injuries contribute significantly to inflammation and adverse in-hospital outcomes for trauma survivors; accordingly, we examined the complex association between clinical outcomes inflammatory responses in this setting using in silico tools. Two stringently propensity-matched, moderately/severely injured (Injury Severity Score > 16) patient sub-cohorts of ~30 patients each were derived retrospectively from a cohort of 472 blunt trauma survivors and segregated based on their degree of extremity injury severity (above or below 3 on the Abbreviated Injury Scale). Serial blood samples were analyzed for 31 plasma inflammatory mediators. In addition to standard statistical analyses, Dynamic Network Analysis (DyNA) and Principal Component Analysis (PCA) were used to model systemic inflammation following trauma. Patients in the severe extremity injury sub-cohort experienced longer intensive care unit length of stay (LOS), total LOS, and days on a mechanical ventilator, with higher Marshall Multiple Organ Dysfunction (MOD) Scores over the first 7 days post-injury as compared to the mild/moderate extremity injury sub-cohort. The higher severity cohort had statistically significant elevated lactate, base deficit, and creatine phosphokinase on first blood draw, along with significant changes in multiple circulating inflammatory mediators. DyNA pointed to a sustained role for type 17 immunity in both sub-cohorts, along with IFN-γ in the severe extremity injury group. DyNA network complexity increased over 7 days post-injury in the severe injury group, while generally decreasing over this same time period in the mild/moderate injury group. PCA suggested a more robust activation of multiple pathways in the severe extremity injury group as compared to the mild/moderate injury group. These studies thus point to the possibility of self-sustaining inflammation following severe extremity injury vs. resolving inflammation following less severe extremity injury

Objective metric of energy absorbed in tibial plateau fractures corresponds well to clinician assessment of fracture severity

Objectives Determine the agreement between subjective assessments of fracture severity and an objective CT-based metric of fracture energy in tibial plateau fractures. Methods Six fellowship-trained orthopaedic trauma surgeons independently rank-ordered 20 tibial plateau fractures in terms of severity based upon AP and lateral knee radiographs. A CT-based image analysis methodology was used to quantify the fracture energy, and agreement between the surgeons’ severity rankings and the fracture energy metric was tested by computing their concordance, a statistical measure that estimates the probability that any two cases would be ranked with the same ordering by two different raters or methods. Results Concordance between the six orthopaedic surgeons ranged from 82% to 93%, and concordance between surgeon severity rankings and the computed fracture energy ranged from 73% to 78%. Conclusions There is a high level of agreement between experienced surgeons in their assessments of tibial plateau fracture severity, and a slightly lower agreement between the surgeon assessments and an objective CT-based metric of fracture energy. Taken together, these results suggest that experienced surgeons share a similar understanding of what makes a tibial plateau fracture more or less severe, and an objective CT-based metric of fracture energy captures much but not all of that information. Further research is ongoing to characterize the relationship between surgeon assessments of severity, fracture energy, and the eventual clinical outcomes for patients with fractures of the tibial plateau

Blood Purification by Non-Selective Hemoadsorption Prevents Death after Traumatic Brain Injury and Hemorrhagic Shock in Rats

Background Patients who sustain traumatic brain injury (TBI) and concomitant hemorrhagic shock (HS) are at high risk of high-magnitude inflammation which can lead to poor outcomes and death. Blood purification by hemoadsorption (HA) offers an alternative intervention to reduce inflammation after injury. We tested the hypothesis that HA would reduce mortality in a rat model of TBI and HS. Methods Male Sprague Dawley rats were subjected to a combined injury of a controlled cortical impact (CCI) to their brain and pressure-controlled hemorrhagic shock (HS). Animals were subsequently instrumented with an extracorporeal blood circuit that passed through a cartridge for sham or experimental treatment. In experimental animals, the treatment cartridge was filled with proprietary beads (Cytosorbents; Monmouth Junction, NJ) that removed circulating molecules between 5 KDa and 60 KDa. Sham rats had equivalent circulation but no blood purification. Serial blood samples were analyzed with multiplex technology to quantify changes in a trauma-relevant panel of immunologic mediators. The primary outcome was survival to 96hr post-injury. Results HA improved survival from 47% in sham treated rats to 86% in HA treated rats. There were no treatment-related changes in histologic appearance. HA affected biomarker concentrations both during the treatment and over the ensuing four days after injury. Distinct changes in biomarker concentrations were also measured in survivor and non-survivor rats from the entire cohort of rats indicating biomarker patterns associated with survival and death after injury. Conclusions Blood purification by non-selective HA is an effective intervention to prevent death in a combined TBI/HS rat model. HA changed circulating concentrations of multiple inmmunologically active mediators during the treatment time frame and after treatment. HA has been safely implemented in human patients with sepsis and may be a treatment option after injury

Dysfunctional stem and progenitor cells impair fracture healing with age

Successful fracture healing requires the simultaneous regeneration of both the bone and vasculature; mesenchymal stem cells (MSCs) are directed to replace the bone tissue, while endothelial progenitor cells (EPCs) form the new vasculature that supplies blood to the fracture site. In the elderly, the healing process is slowed, partly due to decreased regenerative function of these stem and progenitor cells. MSCs from older individuals are impaired with regard to cell number, proliferative capacity, ability to migrate, and osteochondrogenic differentiation potential. The proliferation, migration and function of EPCs are also compromised with advanced age. Although the reasons for cellular dysfunction with age are complex and multidimensional, reduced expression of growth factors, accumulation of oxidative damage from reactive oxygen species, and altered signaling of the Sirtuin-1 pathway are contributing factors to aging at the cellular level of both MSCs and EPCs. Because of these geriatric-specific issues, effective treatment for fracture repair may require new therapeutic techniques to restore cellular function. Some suggested directions for potential treatments include cellular therapies, pharmacological agents, treatments targeting age-related molecular mechanisms, and physical therapeutics. Advanced age is the primary risk factor for a fracture, due to the low bone mass and inferior bone quality associated with aging; a better understanding of the dysfunctional behavior of the aging cell will provide a foundation for new treatments to decrease healing time and reduce the development of complications during the extended recovery from fracture healing in the elderly

Severe muscle trauma triggers heightened and prolonged local musculoskeletal inflammation and impairs adjacent tibia fracture healing

Objectives: Complicated fracture healing is often associated with the severity of surrounding muscle tissue trauma. Since inflammation is a primary determinant of musculoskeletal health and regeneration, it is plausible that delayed healing and non-unions are partly caused by compounding local inflammation in response to concomitant muscle trauma. Methods and results: To investigate this possibility, a Lewis rat open fracture model [tibia osteotomy with adjacent tibialis anterior (TA) muscle volumetric muscle loss (VML) injury] was interrogated. We observed that VML injury impaired tibia healing, as indicated by diminished mechanical strength and decreased mineralized bone within the fracture callus, as well as continued presence of cartilage instead of woven bone 28 days post-injury. The VML injured muscle presented innate and adaptive immune responses that were atypical of canonical muscle injury healing. Additionally, the VML injury resulted in a perturbation of the inflammatory phase of fracture healing, as indicated by elevations of CD3+ lymphocytes and CD68+ macrophages in the fracture callus at 3 and 14d post-injury, respectively. Conclusions: These data indicate that heightened and sustained innate and adaptive immune responses to traumatized muscle are associated with impaired fracture healing and may be targeted for the prevention of delayed and non-union following musculoskeletal trauma

Predictors of Improved Early Clinical Outcomes After Elective Implant Removal

Objectives: To determine preoperative factors predictive of improvement in pain and function after elective implant removal. We hypothesized that patients undergoing orthopaedic implant removal to relieve pain would have significant improvements in both pain and function. Design: Prospective cohort study. Setting: Level I Trauma Center. Patients/Participants: One hundred eighty-nine patients were enrolled after consenting for orthopaedic implant removal to address residual pain. One hundred sixty-three were available for 3-month follow-up. Main Outcome Measurement: Preoperative and postoperative outcome measures including Patient Reported Outcomes Measurement Information System (PROMIS) scores were compared. Preoperative scores, surgeon prediction of pain improvement, and palpable implants were analyzed as predictors of outcomes. Results: Median PROMIS physical function and pain interference scores and visual analogue scale significantly improved by 6, 8, and 2 points, respectively (P < 0.001 for all). Worse preinjury scores predicted improvement in respective postoperative outcomes (P < 0.001 for all). Surgeon prediction of improvement was associated with improved PROMIS pain interference (P = 0.005), patient subjective assessment of pain improvement (P = 0.03), and subjective percent of pain remaining at 3 months (P = 0.02). Implant superficial palpability was not predictive for any postoperative outcomes. Conclusions: Although the primary indication for implant removal in this population was pain relief, many patients also had a clinically relevant improvement in physical function. In addition, patients who start with worse global indices of pain and function are more likely to improve after implant removal. This suggests that implant-related pain directly contributes to global dysfunction

A Comprehensive Review of Mouse Diaphyseal Femur Fracture Models

Complications related to treatment of long bone fractures still stand as a major challenge for orthopaedic surgeons. Elucidation of the mechanisms of bone healing and development, and the subsequent alteration of these mechanisms to improve outcomes, typically requires animal models as an intermediary between in vitro and human clinical studies. Murine models are some of the most commonly used in translational research, and mouse fracture models are particularly diverse, offering a wide variety of customization with distinct benefits and limitations depending on the study. This review critically examines three common femur fracture models in the mouse, namely cortical hole, 3-point fracture (Einhorn), and segmental bone defect. We lay out the general procedure for execution of each model, evaluate the practical implications and important advantages/disadvantages of each and describe recent innovations. Furthermore, we explore the applications that each model is best adapted for in the context of the current state of murine orthopaedic research

Impairment of early fracture healing by skeletal muscle trauma is restored by FK506

BACKGROUND: Heightened local inflammation due to muscle trauma or disease is associated with impaired bone regeneration. METHODS: We hypothesized that FK506, an FDA approved immunomodulatory compound with neurotrophic and osteogenic effects, will rescue the early phase of fracture healing which is impaired by concomitant muscle trauma in male (~4 months old) Lewis rats. FK506 (1 mg/kg; i.p.) or saline was administered systemically for 14 days after an endogenously healing tibia osteotomy was created and fixed with an intermedullary pin, and the overlying tibialis anterior (TA) muscle was either left uninjured or incurred volumetric muscle loss injury (6 mm full thickness biopsy from middle third of the muscle). RESULTS: The salient observations of this study were that 1) concomitant TA muscle trauma impaired recovery of tibia mechanical properties 28 days post-injury, 2) FK506 administration rescued the recovery of tibia mechanical properties in the presence of concomitant TA muscle trauma but did not augment mechanical recovery of an isolated osteotomy (no muscle trauma), 3) T lymphocytes and macrophage presence within the traumatized musculature were heightened by trauma and attenuated by FK506 3 days post-injury, and 4) T lymphocyte but not macrophage presence within the fracture callus were attenuated by FK506 at 14 days post-injury. FK506 did not improve TA muscle isometric torque production CONCLUSION: Collectively, these findings support the administration of FK506 to ameliorate healing of fractures with severe muscle trauma comorbidity. The results suggest one potential mechanism of action is a reduction in local T lymphocytes within the injured musculoskeletal tissue, though other mechanisms to include direct osteogenic effects of FK506 require further investigation