Albumin and the fibrinogen-to-albumin ratio: Biomarkers for the acute phase response following total knee arthroplasty.

PURPOSE: Complications following total knee arthroplasty (TKA) lead to patient morbidity and cost. While acute phase reactants, such as c-reactive protein (CRP) and fibrinogen, have been used to predict complications following TKA, the extent and duration of changes in albumin levels following TKA are unknown. It is hypothesized that like CRP and fibrinogen, albumin, and the fibrinogen/albumin ratio (FAR) represent useful measures of the acute phase response (APR) following TKA. The purpose of this study was to describe the longitudinal course of albumin and FAR in healthy patients following TKA, relative to established biomarkers, and examine if the variance in albumin or FAR correlates with patient comorbidities. METHODS: This retrospective cohort study of patients undergoing TKA at a tertiary medical center. CRP, fibrinogen, and albumin values were collected pre- and post-operatively. An age-adjusted Charlson comorbidity index (CCI) was utilized as a measure of patient comorbidity status. RESULTS: The median preoperative albumin value was 4.3 g/dL, which dropped to 3.6 g/dL on postoperative day 1 following TKA. The albumin value returned to 93% of the baseline by postoperative week 2. The course of albumin inversely mirrored the course of CRP (r = -0.41). Median preoperative FAR was 0.087 g/L, which rose to 0.130 g/L by postoperative week 2 and returned to baseline by postoperative week 6. While preoperative FAR strongly correlated with postoperative week 2 values (r = 0.74), there was a weak positive correlation between age-adjusted CCI and pre-operative FAR (r = 0.24) in patients undergoing primary TKA. CONCLUSION: Albumin levels follow a predictable postoperative decline that inversely correlates with CRP in healthy patients following TKA. Given the low cost and abundance of laboratories offering albumin levels, direct albumin levels and/or albumin ratios such as FAR may be underutilized biomarkers for monitoring the APR following TKA.

A Clinical Prediction Algorithm to Stratify Pediatric Musculoskeletal Infection by Severity.

OBJECTIVE: There are currently no algorithms for early stratification of pediatric musculoskeletal infection (MSKI) severity that are applicable to all types of tissue involvement. In this study, the authors sought to develop a clinical prediction algorithm that accurately stratifies infection severity based on clinical and laboratory data at presentation to the emergency department. METHODS: An IRB-approved retrospective review was conducted to identify patients aged 0 to 18 who presented to the pediatric emergency department at a tertiary care children's hospital with concern for acute MSKI over a 5-year period (2008 to 2013). Qualifying records were reviewed to obtain clinical and laboratory data and to classify in-hospital outcomes using a 3-tiered severity stratification system. Ordinal regression was used to estimate risk for each outcome. Candidate predictors included age, temperature, respiratory rate, heart rate, C-reactive protein (CRP), and peripheral white blood cell count. We fit fully specified (all predictors) and reduced models (retaining predictors with a P-value ≤0.2). Discriminatory power of the models was assessed using the concordance (c)-index. RESULTS: Of the 273 identified children, 191 (70%) met inclusion criteria. Median age was 5.8 years. Outcomes included 47 (25%) children with inflammation only, 41 (21%) with local infection, and 103 (54%) with disseminated infection. Both the full and reduced models accurately demonstrated excellent performance (full model c-index 0.83; 95% confidence interval, 0.79-0.88; reduced model 0.83; 95% confidence interval, 0.78-0.87). Model fit was also similar, indicating preference for the reduced model. Variables in this model included CRP, pulse, temperature, and an interaction term for pulse and temperature. The odds of a more severe outcome increased by 30% for every 10 U increase in CRP. CONCLUSIONS: Clinical and laboratory data obtained in the emergency department may be used to accurately differentiate pediatric MSKI severity. The predictive algorithm in this study stratifies pediatric MSKI severity at presentation irrespective of tissue involvement and anatomic diagnosis. Prospective studies are needed to validate model performance and clinical utility. LEVEL OF EVIDENCE: Level II-prognostic study.

Effects of Antibiotic Timing on Culture Results and Clinical Outcomes in Pediatric Musculoskeletal Infection.

INTRODUCTION: Musculoskeletal infection (MSI) is a common cause of morbidity and hospital resource utilization in the pediatric population. Many physicians prefer to withhold antibiotics until tissue cultures can be taken in an effort to improve culture yields. However, there is little evidence that this practice improves culture results or outcomes in pediatric MSI. Therefore, investigating the effects of antibiotic timing may lead to improved clinical practice guidelines for treating children with MSI. METHODS: An IRB-approved retrospective review was conducted that identified 113 patients aged 0 to 18 who presented to the pediatric emergency room at a tertiary care children's hospital with MSI from 2008 to 2013. Demographic data, culture results, severity markers, and intervention timing were obtained from the medical record. Logistic regression and Cox survival analysis were performed to determine the relationship of antibiotic timing with culture sensitivity and time to discharge. RESULTS: No difference was seen in culture sensitivity antibiotic administration in either the local (55% culture before antibiotics vs. 89% after antibiotics) or disseminated group (76% before vs. 79% after), which persisted when further accounting for disease severity with C-reactive protein. However, later administration of antibiotics in the local infection group correlated with a decreased likelihood of discharge (3.91 d when cultured before antibiotics vs. 2.93 d when cultured after antibiotics; hazard ratio, 0.53; P<0.05). In patients with disseminated infection, antibiotic administration was not shown to correlate with any difference in time to discharge (hazard ratio, 1.08). CONCLUSIONS: The authors were surprised to find that tissue culture sensitivities were not decreased by antibiotic administration in either local or disseminated MSI, suggesting that antibiotic administration should not be delayed to obtain tissue cultures. The correlation of earlier antibiotic administration with shorter length of stay in children with local MSI led the authors to conclude that antibiotics should be initiated as quickly as possible. Further study is necessary to confirm these findings and establish clinical practice guidelines. LEVEL OF EVIDENCE: Level III-retrospective cohort.

C-Reactive Protein Predicts Risk of Venous Thromboembolism in Pediatric Musculoskeletal Infection.

BACKGROUND: The rate of venous thromboembolism in children with musculoskeletal infections (MSKIs) is markedly elevated compared with hospitalized children in general. Predictive biomarkers to identify high-risk patients are needed to prevent the significant morbidity and rare mortality associated with thrombotic complications. We hypothesize that overactivation of the acute phase response is associated with the development of pathologic thrombi and we aim to determine whether elevations in C-reactive protein (CRP) are associated with increased rates of thrombosis in pediatric patients with MSKI. METHODS: A retrospective cohort study measuring CRP in pediatric MSKI patients with or without thrombotic complications. RESULTS: The magnitude and duration of elevation in CRP values correlated with the severity of infection and the development of pathologic thrombosis. In multivariable logistic regression, every 20 mg/L increase in peak CRP was associated with a 29% increased risk of thrombosis (P<0.001). Peak and total CRP were strong predictors of thrombosis with area under the receiver-operator curves of 0.90 and 0.92, respectively. CONCLUSIONS: Future prospective studies are warranted to further define the discriminatory power of CRP in predicting infection-provoked thrombosis. Pharmacologic prophylaxis and increased surveillance should be strongly considered in patients with MSKI, particularly those with disseminated disease and marked elevation of CRP. LEVEL OF EVIDENCE: Level III.

Unexpected timely fracture union in matrix metalloproteinase 9 deficient mice.

Immediately following a fracture, a fibrin laden hematoma is formed to prevent bleeding and infection. Subsequently, the organized removal of fibrin, via the protease plasmin, is essential to permit fracture repair through angiogenesis and ossification. Yet, when plasmin activity is lost, the depletion of fibrin alone is insufficient to fully restore fracture repair, suggesting the existence of additional plasmin targets important for fracture repair. Previously, activated matrix metalloproteinase 9 (MMP-9) was demonstrated to function in fracture repair by promoting angiogenesis. Given that MMP-9 is a defined plasmin target, it was hypothesized that pro-MMP-9, following plasmin activation, promotes fracture repair. This hypothesis was tested in a fixed murine femur fracture model with serial assessment of fracture healing. Contrary to previous findings, a complete loss of MMP-9 failed to affect fracture healing and union through 28 days post injury. Therefore, these results demonstrated that MMP-9 is dispensable for timely fracture union and cartilage transition to bone in fixed femur fractures. Pro-MMP-9 is therefore not a significant target of plasmin in fracture repair and future studies assessing additional plasmin targets associated with angiogenesis are warranted.

A Novel Classification System Based on Dissemination of Musculoskeletal Infection is Predictive of Hospital Outcomes.

BACKGROUND: Musculoskeletal infections (MSKIs) are a common cause of pediatric hospitalization. Children affected by MSKI have highly variable hospital courses, which seem to depend on infection severity. Early stratification of infection severity would therefore help to maximize resource utilization and improve patient care. Currently, MSKIs are classified according to primary diagnoses such as osteomyelitis, pyomyositis, etc. These diagnoses, however, do not often occur in isolation and may differ widely in severity. On the basis of this, the authors propose a severity classification system that differentiates patients based on total infection burden and degree of dissemination. METHODS: The authors developed a classification system with operational definitions for MSKI severity based on the degree of dissemination. The operational definitions were applied retrospectively to a cohort of 202 pediatric patients with MSKI from a tertiary care children's hospital over a 5-year period (2008 to 2013). Hospital outcomes data [length of stay (LOS), number of surgeries, positive blood cultures, duration of antibiotics, intensive care unit LOS, number of days with fever, and number of imaging studies] were collected from the electronic medical record and compared between groups. RESULTS: Patients with greater infection dissemination were more likely to have worse hospital outcomes for LOS, number of surgeries performed, number of positive blood cultures, duration of antibiotics, intensive care unit LOS, number of days with fever, and number of imaging studies performed. Peak C-reactive protein, erythrocyte sedimentation rate, white blood cell count, and temperature were also higher in patients with more disseminated infection. CONCLUSIONS: The severity classification system for pediatric MSKI defined in this study correlates with hospital outcomes and markers of inflammatory response. The advantage of this classification system is that it is applicable to different types of MSKI and represents a potentially complementary system to the previous practice of differentiating MSKI based on primary diagnosis. Early identification of disease severity in children with MSKI has the potential to enhance hospital outcomes through more efficient resource utilization and improved patient care. LEVEL OF EVIDENCE: Level II-prognostic study.

Bone Fracture Acute Phase Response-A Unifying Theory of Fracture Repair: Clinical and Scientific Implications.

Bone fractures create five problems that must be resolved: bleeding, risk of infection, hypoxia, disproportionate strain, and inability to bear weight. There have been enormous advancements in our understanding of the molecular mechanisms that resolve these problems after fractures, and in best clinical practices of repairing fractures. We put forth a modern, comprehensive model of fracture repair that synthesizes the literature on the biology and biomechanics of fracture repair to address the primary problems of fractures. This updated model is a framework for both fracture management and future studies aimed at understanding and treating this complex process. This model is based upon the fracture acute phase response (APR), which encompasses the molecular mechanisms that respond to injury. The APR is divided into sequential stages of "survival" and "repair." Early in convalescence, during "survival," bleeding and infection are resolved by collaborative efforts of the hemostatic and inflammatory pathways. Later, in "repair," avascular and biomechanically insufficient bone is replaced by a variable combination of intramembranous and endochondral ossification. Progression to repair cannot occur until survival has been ensured. A disproportionate APR-either insufficient or exuberant-leads to complications of survival (hemorrhage, thrombosis, systemic inflammatory response syndrome, infection, death) and/or repair (delayed- or non-union). The type of ossification utilized for fracture repair is dependent on the relative amounts of strain and vascularity in the fracture microenvironment, but any failure along this process can disrupt or delay fracture healing and result in a similar non-union. Therefore, incomplete understanding of the principles herein can result in mismanagement of fracture care or application of hardware that interferes with fracture repair. This unifying model of fracture repair not only informs clinicians how their interventions fit within the framework of normal biological healing but also instructs investigators about the critical variables and outputs to assess during a study of fracture repair.

Aligning In-Service Training Examinations in Plastic Surgery and Orthopaedic Surgery With Competency-Based Education.

BACKGROUND: In-service training examinations (ITEs) are used to assess residents across specialties. However, it is not clear how they are integrated with the Accreditation Council for Graduate Medical Education Milestones and competencies. OBJECTIVE: This study explored the distribution of specialty-specific milestones and competencies in ITEs for plastic surgery and orthopaedic surgery. METHODS: In-service training examinations were publicly available for plastic surgery (PSITE) and orthopaedics (OITE). Questions on the PSITE for 2014-2016 and the OITE for 2013-2015 were mapped to the specialty-specific milestones and the 6 competencies. RESULTS: There was an uneven distribution of milestones and competencies in ITE questions. Nine of the 36 Plastic Surgery Milestones represented 52% (341 of 650) of questions, and 3 were not included in the ITE. Of 41 Orthopaedic Surgery Milestones, 7 represented 51% (201 of 394) of questions, and 5 had no representation on the ITE. Among the competencies, patient care was the most common (PSITE = 62% [403 of 650]; OITE = 59% [233 of 394]), followed by medical knowledge (PSITE = 34% [222 of 650]; OITE = 31% [124 of 394]). Distribution of the remaining competencies differed between the 2 specialties (PSITE = 4% [25 of 650]; OITE = 9% [37 of 394]). CONCLUSIONS: The ITEs tested slightly more than half of the milestones for the 2 specialties, and focused predominantly on patient care and medical knowledge competencies.

Similar Clinical Severity and Outcomes for Methicillin-Resistant and Methicillin-Susceptible Staphylococcus aureus Pediatric Musculoskeletal Infections.

BACKGROUND: Prior studies of pediatric musculoskeletal infection have suggested that methicillin-resistant Staphylococcus aureus (MRSA) infections result in worse outcomes compared with infections with methicillin-susceptible S aureus (MSSA) strains. Based on these results, clinical prediction algorithms have been developed to differentiate between MRSA and MSSA early in a patient's clinical course. This study compares hospital outcomes for pediatric patients with MRSA and MSSA musculoskeletal infection presenting to the emergency department at a large tertiary care children's hospital. METHODS: A retrospective study identified pediatric patients with S aureus musculoskeletal infection over a 5-year period (2008-2013) by sequential review of all pediatric orthopedic consults. Relevant demographic information, laboratory values, and clinical outcomes were obtained from the electronic medical record. RESULTS: Of the 91 identified cases of S aureus pediatric musculoskeletal infection, there were 49 cases of MRSA infection (53%) and 42 cases of MSSA infection (47%). There were no significant differences between MRSA and MSSA infections in median hospital length of stay (4.8 vs 5.7 days, P = .50), febrile days (0.0 vs 1.5 days, P = .10), and antibiotic duration (28 vs 34 days, P = .18). Methicillin-resistant S aureus infections were more likely to require operative intervention than MSSA infection (85% vs 62%, P = .15). A logistic regression model based on C-reactive protein, temperature, white blood cell count, pulse, and respiratory rate at presentation demonstrated poor ability to differentiate between MRSA and MSSA infection. CONCLUSIONS: The results demonstrated no significant differences between MSSA and MRSA musculoskeletal infections for most hospital outcomes measured. However, MRSA infections required more operative interventions than MSSA infections. In addition, a predictive model based on severity markers obtained at presentation was unable to effectively differentiate between MRSA and MSSA infection. The clinical utility and capacity for early differentiation of MRSA and MSSA depends on virulence patterns that may vary temporally and geographically.

Characterizing the Acute Phase Response in Healthy Patients Following Total Joint Arthroplasty: Predictable and Consistent.

BACKGROUND: During surgery, trauma to musculoskeletal tissue induces a systemic reaction known as the acute phase response (APR). When excessive or prolonged, the APR has been implicated as an underlying cause of surgical complications. The purpose of this study was to determine the typical APR following total joint arthroplasty in a healthy population defined by the Charlson Comorbidity Index (CCI). METHODS: This retrospective study identified 180 healthy patients (CCI < 2) who underwent total joint arthroplasty by a single surgeon for primary osteoarthritis from 2013 to 2015. Serial measurements of C-reactive protein (CRP) and fibrinogen were obtained preoperative, perioperative, and at 2 and 6 weeks postoperative. RESULTS: Postoperative CRP peaked during the inpatient period and returned to baseline by 2 weeks. Fibrinogen peaked after CRP and returned to baseline by 6 weeks. Elevated preoperative CRP correlated with a more robust postoperative APR for both total hip arthroplasty and total knee arthroplasty, suggesting that a patient's preoperative inflammatory state correlates with the magnitude of the postoperative APR. CONCLUSION: Measurement of preoperative acute phase reactants may provide an objective means to predict a patient's risk of postoperative dysregulation of the APR and complications.

Pediatric Musculoskeletal Infection: Hijacking the Acute-Phase Response.

Tissue injury activates the acute-phase response mediated by the liver, which promotes coagulation, immunity, and tissue regeneration. To survive and disseminate, musculoskeletal pathogens express virulence factors that modulate and hijack this response. As the acute-phase reactants required by these pathogens are most abundant in damaged tissue, these infections are predisposed to occur in tissues following traumatic or surgical injury. Staphylococcus aureus expresses the virulence factors coagulase and von Willebrand binding protein to stimulate coagulation and to form a fibrin abscess that protects it from host immune-cell phagocytosis. After the staphylococcal abscess community reaches quorum, which is the colony density that enables cell-to-cell communication and coordinated gene expression, subsequent expression of staphylokinase stimulates activation of fibrinolysis, which ruptures the abscess wall and results in bacterial dissemination. Unlike Staphylococcus aureus, Streptococcus pyogenes expresses streptokinase and other virulence factors to activate fibrinolysis and to rapidly disseminate throughout the body, causing diseases such as necrotizing fasciitis. Understanding the virulence strategies of musculoskeletal pathogens will help to guide clinical diagnosis and decision-making through monitoring of acute-phase markers such as C-reactive protein, erythrocyte sedimentation rate, and fibrinogen.

Elevated d-Dimer Is Not Predictive of Symptomatic Deep Venous Thrombosis After Total Joint Arthroplasty.

BACKGROUND: Serum d-dimer is a common screening test for symptomatic deep venous thrombosis (DVT) after total joint arthroplasty. This study characterized the longitudinal resolution of d-dimer measurements after total hip and knee arthroplasty (THA/TKA) over a 6-week period. The authors hypothesized that serum d-dimer would not return to baseline or be below the institutional threshold for a positive test at 6 weeks after uncomplicated total joint arthroplasty, suggesting that quantitative d-dimer has limited clinical utility for postoperative DVT screening. METHODS: An institutional review board-approved retrospective cohort study was conducted with consecutive patients between January 2013 and June 2015. A total of 177 adult patients aged 40-88 years who underwent a primary hip or knee arthroplasty with a Charlson Comorbidity Index <3 were included in the study. Serum d-dimer was measured at preoperative, perioperative, and postoperative 2- and 6-week time points. RESULTS: d-dimer measurements peaked 2 weeks postoperatively for both TKA and THA. At the 6-week time point, the peak serum d-dimer measurement resolved by 54.3% and 76.6% for TKA and THA, respectively. At 6 weeks after operation, 92% of THA patient and 100% of TKA patients had serum d-dimer measurements higher than the institutional threshold (0.40 µg/mL) for a "positive" quantitative test. No symptomatic DVTs were reported for the THA and TKA cohorts during the study period. CONCLUSION: The results suggest that serum d-dimer is an ineffective screening test for the diagnosis of symptomatic DVT in the acute postoperative period. The authors propose that extravascular fibrinolysis, a process essential for wound healing, has a crucial role in the prolonged elevation of serum d-dimer in the postoperative period.