Michael A. Benvenuti

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 patients 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 patients risk of postoperative dysregulation of the APR and complications.

Double-Edged Sword: Musculoskeletal Infection Provoked Acute Phase Response in Children

The acute phase response has a crucial role in mounting the bodys response to tissue injury. Excessive activation of the acute phase response is responsible for many complications that occur in orthopedic patients. Given that infection may be considered continuous tissue injury that persistently activates the acute phase response, children with musculoskeletal infections are at markedly increased risk for serious complications. Future strategies that modulate the acute phase response have the potential to improve treatment and prevent complications associated with musculoskeletal infection.

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.

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.

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

Abstract 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.

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 childrens 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.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 childrens 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.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 childrens 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 childrens 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.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 childrens 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.

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.

Abstract 113: The Total Acute Phase Response Predicts Complications in Children with Musculoskeletal Infection

PURPOSE: Survey-based research has emerged as a primary method of evaluating the impact and outcomes of breast reconstruction in an era of patient centered care. Despite increased utilization of patient reported outcomes measures, such as the BREAST-Q surveys, there are few studies assessing non-response among study participants. Differential non-response to surveys threatens the generalizability and validity of studies evaluating patient reported outcomes. The objectives of this study were to identify independent variables associated with non-response to surveys following breast reconstruction to aid in the design and improvement of future patient-reported outcomes research.