Carolyn M. Hendrickson

Viral pathogens and acute lung injury: investigations inspired by the SARS epidemic and the 2009 H1N1 influenza pandemic.

Acute viral pneumonia is an important cause of acute lung injury (ALI), although not enough is known about the exact incidence of viral infection in ALI. Polymerase chain reaction-based assays, direct fluorescent antigen (DFA) assays, and viral cultures can detect viruses in samples from the human respiratory tract, but the presence of the virus does not prove it to be a pathogen, nor does it give information regarding the interaction of viruses with the host immune response and bacterial flora of the respiratory tract. The severe acute respiratory syndrome (SARS) epidemic and the 2009 H1N1 influenza pandemic provided a better understanding of how viral pathogens mediate lung injury. Although the viruses initially infect the respiratory epithelium, the relative role of epithelial damage and endothelial dysfunction has not been well defined. The inflammatory host immune response to H1N1 infection is a major contributor to lung injury. The SARS coronavirus causes lung injury and inflammation in part through actions on the nonclassical renin angiotensin pathway. The lessons learned from the pandemic outbreaks of SARS coronavirus and H1N1 capture key principles of virally mediated ALI. There are pathogen-specific pathways underlying virally mediated ALI that converge onto a common end pathway resulting in diffuse alveolar damage. In terms of therapy, lung protective ventilation is the cornerstone of supportive care. There is little evidence that corticosteroids are beneficial, and they might be harmful. Future therapeutic strategies may be targeted to specific pathogens, the pathogenetic pathways in the host immune response, or enhancing repair and regeneration of tissue damage.

Lifetime trauma exposure and prospective cardiovascular events and all-cause mortality: Findings from the Heart and Soul Study

Objective Little is known about the effect of cumulative psychological trauma on health outcomes in patients with cardiovascular disease. The objective of this study was to prospectively examine the association between lifetime trauma exposure and recurrent cardiovascular events or all-cause mortality in patients with existing cardiovascular disease. Methods A total of 1021 men and women with cardiovascular disease were recruited in 2000 to 2002 and followed annually. Trauma history and psychiatric comorbidities were assessed at baseline using the Computerized Diagnostic Interview Schedule for DSM-IV. Health behaviors were assessed using standardized questionnaires. Outcome data were collected annually, and all medical records were reviewed by two independent, blinded physician adjudicators. We used Cox proportional hazards models to evaluate the association between lifetime trauma exposure and the composite outcome of cardiovascular events and all-cause mortality. Results During an average of 7.5 years of follow-up, there were 503 cardiovascular events and deaths. Compared with the 251 participants in the lowest trauma exposure quartile, the 256 participants in the highest exposure quartile had a 38% greater risk of adverse outcomes (hazard ratio = 1.38, 95% confidence interval = 1.06–1.81), adjusted for age, sex, race, income, education, depression, posttraumatic stress disorder, generalized anxiety disorder, smoking, physical inactivity, and illicit drug abuse. Conclusions Cumulative exposure to psychological trauma was associated with an increased risk of recurrent cardiovascular events and mortality, independent of psychiatric comorbidities and health behaviors. These data add to a growing literature showing enduring effects of repeated trauma exposure on health that are independent of trauma-related psychiatric disorders such as depression and posttraumatic stress disorder.

Differences in degree, differences in kind: characterizing lung injury in trauma

BACKGROUND Acute lung injury following trauma remains a significant source of morbidity and mortality. Although multiple trauma studies have used hypoxemia without radiographic adjudication as a surrogate for identifying adult respiratory distress syndrome (ARDS) cases, the differences between patients with hypoxemia alone and those with radiographically confirmed ARDS are not well described in the literature. We hypothesized that nonhypoxemic, hypoxemic, and ARDS patients represent distinct groups with unique characteristics and predictors. METHODS Laboratory, demographic, clinical, and outcomes data were prospectively collected from 621 intubated, critically injured patients at an urban Level 1 trauma center from 2005 to 2013. Hypoxemia was defined as PaO2/FIO2 ratio of 300 or lower. ARDS was adjudicated using Berlin criteria, with blinded two-physician consensus review of chest radiographs. Group comparisons were performed by hypoxemia and ARDS status. Logistic regression analyses were performed to separately assess predictors of hypoxemia and ARDS. RESULTS Of the 621 intubated patients, 64% developed hypoxemia; 46% of these hypoxemic patients developed ARDS by chest radiograph. Across the three groups (no hypoxemia, hypoxemia, ARDS), there were no significant differences in age, sex, or comorbidities. However, there was an increase in severity of shock, injury, and chest injury by group, with corresponding trends in transfusion requirements and volume of early fluid administration. Outcomes followed a similar stepwise pattern, with pneumonia, multiorgan failure, length of intensive care unit stay, number of ventilator days, and overall mortality highest in ARDS patients. In multiple logistic regression, early plasma transfusion, delayed crystalloid administration, body mass index, and head and chest injury were independent predictors of hypoxemia, while head and chest injury, early crystalloid infusion, and delayed platelet transfusion were independent predictors of ARDS. CONCLUSION Hypoxemia and ARDS exist on a spectrum of respiratory dysfunction following trauma, with increasing injury severity profiles and resuscitation requirements. However, they also represent distinct clinical states with unique predictors, which require directed research approaches and targeted therapeutic strategies. LEVEL OF EVIDENCE Prognostic and epidemiologic study, level III.

The acute respiratory distress syndrome following isolated severe traumatic brain injury.

BACKGROUND Acute respiratory distress syndrome (ARDS) is common after traumatic brain injury (TBI) and is associated with worse neurologic outcomes and longer hospitalization. However, the incidence and associated causes of ARDS in isolated TBI have not been well studied. METHODS We performed a subgroup analysis of 210 consecutive patients with isolated severe TBI enrolled in a prospective observational cohort at a Level 1 trauma center between 2005 and 2014. Subjects required endotracheal intubation and had isolated severe TBI defined by a head Abbreviated Injury Scale (AIS) score of 3 or greater and AIS score lower than 3 in all other categories. ARDS within the first 8 days of admission was rigorously adjudicated using Berlin criteria. Regression analyses were used to test the association between predictors of interest and ARDS. RESULTS The incidence of ARDS in the first 8 days after severe isolated TBI was 30%. Patients who developed ARDS were administered more crystalloids (4.3 L vs. 3.5 L, p = 0.005) and blood products in the first 12 hours of admission. Patients with ARDS had significantly worse clinical outcomes measured at 28 days, including longer median intensive care unit and hospital stays (4 days vs. 13 days, p < 0.001, and 7.5 days vs. 14.5 days, p < 0.001, respectively). In unadjusted logistic regression analyses, the odds of developing ARDS were significantly associated with head AIS score (odds ratio [OR], 1.8; p = 0.018), male sex (OR, 2.9; p = 0.012), and early transfusion of platelets (OR, 2.8; p = 0.003). These associations were similar in a multivariate logistic regression model. CONCLUSION In the era of balanced hemostatic resuscitation practices, severity of head injury, male sex, early crystalloids, and early transfusion of platelets are associated with a higher risk of ARDS after severe isolated TBI. Early transfusion of platelets after severe TBI may be a modifiable risk factor for ARDS, and these findings invite further investigation into causal mechanisms driving this observed association. LEVEL OF EVIDENCE Prognostic/epidemiologic study, level III.

Misclassification of acute respiratory distress syndrome after traumatic injury: The cost of less rigorous approaches.

BACKGROUND Adherence to rigorous research protocols for identifying adult respiratory distress syndrome (ARDS) after trauma is variable. To examine how misclassification of ARDS may bias observational studies in trauma populations, we evaluated the agreement of two methods for adjudicating ARDS after trauma: the current gold standard, direct review of chest radiographs and review of dictated radiology reports, a commonly used alternative. METHODS This nested cohort study included 123 mechanically ventilated patients between 2005 and 2008, with at least one PaO2/FIO2 less than 300 within the first 8 days of admission. Two blinded physician investigators adjudicated ARDS by two methods. The investigators directly reviewed all chest radiographs to evaluate for bilateral infiltrates. Several months later, blinded to their previous assessments, they adjudicated ARDS using a standardized rubric to classify radiology reports. A &kgr; statistics was calculated. Regression analyses quantified the association between established risk factors as well as important clinical outcomes and ARDS determined by the aforementioned methods as well as hypoxemia as a surrogate marker. RESULTS The &kgr; was 0.47 for the observed agreement between ARDS adjudicated by direct review of chest radiographs and ARDS adjudicated by review of radiology reports. Both the magnitude and direction of bias on the estimates of association between ARDS and established risk factors as well as clinical outcomes varied by method of adjudication. CONCLUSION Classification of ARDS by review of dictated radiology reports had only moderate agreement with the current gold standard, ARDS adjudicated by direct review of chest radiographs. While the misclassification of ARDS had varied effects on the estimates of associations with established risk factors, it tended to weaken the association of ARDS with important clinical outcomes. A standardized approach to ARDS adjudication after trauma by direct review of chest radiographs will minimize misclassification bias in future observational studies. LEVEL OF EVIDENCE Diagnostic study, level II.

Biology and pathology of fibroproliferation following the acute respiratory distress syndrome

The landmark study of low-tidal volume ventilation (LTVV) in acute respiratory distress syndrome (ARDS) demonstrated treatment benefit across a broad patient population [1]. In the era of LTVV, researchers studying ARDS must identify both preventative strategies for ARDS as well as effective treatments for a heterogenous population with a lower mortality rate. Distinguishing among ARDS subphenotypes would improve efficiency in clinical trial design and help clinicians tailor supportive and therapeutic treatments. To this end, there is considerable interest in the use of biomarkers in ARDS to define specific biological phenotypes, describe factors driving resolution of disease and, most importantly, identify patients at highest risk for poor outcomes [2, 3]. This approach to targeted therapy has revolutionized care for breast cancer patients and may facilitate innovative therapies for ARDS [4]. Endotypes have been established by a variety of methods. Some studies rely on measuring specific proteins of interest to establish thresholds that correlate with hard clinical outcomes [3, 5]. Others use sophisticated biostatistical models such as latent class analysis to identify patterns within a dataset that predict response to therapy or outcomes of interest [2]. In an article recently published in Intensive Care Medicine, Forel et al. [6] describe the findings from their biomarker study, “Type III procollagen is a reliable marker of ARDS-associated lung fibroproliferation.” The authors identified and validated a threshold level for bronchoalveolar lavage (BAL) concentration of the N-terminal of procollagen peptide III (NT-PCP-III) that correlates with histopathologic fibrosis confirmed on open lung biopsy (OLB), a surrogate outcome presumed to be on the same causal pathway as mortality and prolonged mechanical ventilation, in a subgroup of patients with ARDS who could potentially benefit from therapies that mitigate fibrosis. While irreversible fibrosis due to ARDS was a common clinical problem before LTVV became the standard of care, the incidence of permanent scarring of lung tissue appears to have declined over the past 15 years. The strongest evidence for the lower incidence is the enrollment difficulty encountered by ARDS Network Researches conducting the Late Steroid Rescue Study (LaSRS) study. Based on earlier disease incidence, the study group anticipated enrolling 400 patients over 3 years. However this plan was revised due to low enrollment, and it ultimately took 7 years to enroll 180 patients from 12 US university medical centers. Furthermore, a large cohort study compared subjects who died between 1991 and 2000 to those who died between 2001 and 2010, and found that among patients at risk for ARDS, the proportion of patients with diffuse alveolar damage (DAD) on autopsy was higher in the first decade of the study [7]. Higher tidal volume ventilation strategies may have driven the incidence of persistent ARDS with fibroproliferative features before 2000. Patients who progress to fibrosis after ARDS have prolonged requirements for mechanical ventilation, low lung compliance, and high dead space measurements. However, it is difficult to accurately identify this subgroup of patients using early clinical and demographic characteristics. Even among patients with non-resolving ARDS after 7 days of mechanical ventilation, it is not clear which individuals have irreversible fibrosis without invasive testing with OLB [8]. In the spirit of defining specific ARDS subphenotypes, et al. describe an approach using a biomarker in BAL to identify patients with fibrosis in non-resolving ARDS through a minimally invasive diagnostic test. NT-PCP-III is the product of protease activity in the extracellular space and a marker of collagen synthesis by pulmonary fibroblasts. Plasma and BAL concentrations of NT-PCP-III in patients with ARDS are elevated in the first 24 h and correlate with death and ventilator-free days [9–11]. NT-PCP-III is elevated in BAL samples taken 24 h after ARDS onset, suggesting that fibroblasts are active soon after injury [10]. Furthermore, the concentration of NT-PCP-III in BAL at 24 h is higher in patients who die after ARDS, indicating a shift towards fibrosis after inflammation that sets the stage for a severe pathologic response to injury. Forel et al. [6] show for the first time that the BAL concentration of NT-PCP-III reliably correlates with fibrosis on histopathology specimens from OLB. BAL NT-PCP-III in ARDS is higher in patients who die and have fewer ventilator-free days, despite adherence to LTVV protocols. Overall, the authors present strong evidence that NT-PCP-III may be an important biomarker of fibrosis and might serve as a screening measurement for enrollment in trials of therapies targeted at mitigating fibrosis in patients with non-resolving ARDS. The data presented by Forel et al. [6] have some limitations. Fibrosis is not strictly defined in the discussion of many of the clinical and translational studies in ARDS. Lung fibrosis is marked by irreversible structural damage to the alveoli and the accumulation of fibroblasts. Fibrosis is preceded by a fibroproliferative or organizing phase characterized by the accumulation of myofibroblastas in a loose extracellular matrix in the alveolar septa and distal air spaces [12]. This fibroproliferative phase is a potentially reversible state and may be the optimal target for corticosteroids in persistent ARDS [13]. A more precise definition of lung abnormalities in lung biopsies is needed in future studies to differentiate earlier fibroproliferation from later fibrosis as sensitivity to glucocorticoid therapy may differ along this spectrum. The inclusion of ten patients from the determination cohort in the validation cohort of 51 subjects is a potential source of bias and may limit the generalizability of the threshold defined by this study. Lastly, the most important limitation of this study is one that is common to many biomarker studies: the authors have only examined one protein from one physiologic compartment at one point in time during a complex and heterogeneous disease process. To fully grasp the enormity of the problem that Forel et al. [6] are tackling, it is important to briefly review what is more generally known about fibroproliferation in ARDS. Autopsy and histopathological studies in ARDS show an early inflammatory phase followed by a fibroproliferative repair phase, with deposition of matrix proteins, including collagen. Some patients progress to effective tissue repair and resolution of ARDS while others develop irreversible lung fibrosis and have higher mortality rates. As illustrated in Fig. 1, this balance between resolution of injury and ineffective or inappropriate tissue repair is complex and modulated by proinflammatory cytokines, the extracellular matrix, and the effects of aging on host responses [14]. Alveolar fibroblasts are central players in the fibrotic and inflammatory response in ARDS and can be cultured from BAL in 25 % of patients with ARDS, but not from ventilated controls [15]. These cultured fibroblasts behave similarly to fibroblasts isolated from subjects with idiopathic pulmonary fibrosis, exhibiting a blunted response to stimulation with an anti-fibrotic mediators and increased collagen 1 secretion. Not only are the forces driving collagen deposition complex, but for a complete understanding of the physiology and pathology of fibrotic changes in the lung it is important to consider the pathways for degradation of matrix proteins that occur in both normal physiology and disease states [16]. Fig. 1 The spectrum of response to the fibroproliferative phase of acute respiratory distress syndrome (ARDS). The fibroproliferative phase of ARDS is followed by a spectrum of host responses that range from resolution of injury and restoration of normal alveolar ... BAL NT-PCP-III may be a valuable biomarker for a subphenotype of ARDS patients with fibroproliferation in the LTVV era. It remains to be established if this biomarker can identify patients who may have a differential response to glucocorticoids or other treatments designed to reduce the lung fibrosis that develops in some patients after ARDS.

Endothelial biomarkers in human sepsis: pathogenesis and prognosis for ARDS:

Experimental models of sepsis in small and large animals and a variety of in vitro preparations have established several basic mechanisms that drive endothelial injury. This review is focused on what can be learned from the results of clinical studies of plasma biomarkers of endothelial injury and inflammation in patients with sepsis. There is excellent evidence that elevated plasma levels of several biomarkers of endothelial injury, including von Willebrand factor antigen (VWF), angiopoietin-2 (Ang-2), and soluble fms-like tyrosine kinase 1 (sFLT-1), and biomarkers of inflammation, especially interleukin-8 (IL-8) and soluble tumor necrosis factor receptor (sTNFr), identify sepsis patients with a higher mortality. There are also some data that elevated levels of endothelial biomarkers can identify which patients with non-pulmonary sepsis will develop acute respiratory distress syndrome (ARDS). If ARDS patients are divided among those with indirect versus direct lung injury, then there is an association of elevated levels of endothelial biomarkers in indirect injury and markers of inflammation and alveolar epithelial injury in patients with direct lung injury. New research suggests that the combination of biologic and clinical markers may make it possible to segregate patients with ARDS into hypo- versus hyper-inflammatory phenotypes that may have implications for therapeutic responses to fluid therapy. Taken together, the studies reviewed here support a primary role of the microcirculation in the pathogenesis and prognosis of ARDS after sepsis. Biological differences identified by molecular patterns could explain heterogeneity of treatment effects that are not explained by clinical factors alone.

Characterization of distinct coagulopathic phenotypes in injury: Pathway-specific drivers and implications for individualized treatment.

BACKGROUND International normalized ratio (INR) and partial thromboplastin time (PTT) are used interchangeably to diagnose acute traumatic coagulopathy but reflect disparate activation pathways. In this study, we identified injury/patient characteristics and coagulation factors that drive contact pathway, tissue factor pathway (TF), and common pathway dysfunction by examining injured patients with discordant coagulopathies. We hypothesized that patients with INR/PTT discordance reflect differing phenotypes representing contact versus tissue factor pathway perturbations and that characterization will provide targets to guide individualized resuscitation. METHODS Plasma samples were prospectively collected from 1,262 critically injured patients at a single Level I trauma center. Standard coagulation measures and an extensive panel of procoagulant and anticoagulant factors were assayed and analyzed with demographic and outcome data. RESULTS Fourteen percent of patients were coagulopathic on admission. Among these, 48% had abnormal INR and PTT (BOTH), 43% had isolated prolonged PTT (PTT-CONTACT), and 9% had isolated elevated INR (INR-TF). PTT-CONTACT and BOTH had lower Glasgow Coma Scale score than INR-TF (p < 0.001). INR-TF had decreased factor VII activity compared with PTT-CONTACT, whereas PTT-CONTACT had decreased factor VIII activity compared with INR-TF. All coagulopathic patients had factor V deficits, but activity was lowest in BOTH, suggesting an additive downstream effect of disordered activation pathways. Patients with PTT-CONTACT received half as much packed red blood cell and fresh frozen plasma as did the other groups (p < 0.001). Despite resuscitation, mortality was higher for coagulopathic patients; mortality was highest in BOTH and higher in PTT-CONTACT than in INR-TF (71%, 60%, 41%; p = 0.04). CONCLUSIONS Discordant phenotypes demonstrate differential factor deficiencies consistent with dysfunction of contact versus tissue factor pathways with additive effects from common pathway dysfunction. Recognition and treatment of pathway-specific factor deficiencies driving different coagulopathic phenotypes in injured patients may individualize resuscitation and improve outcomes. LEVEL OF EVIDENCE Prognostic/epidemiological study, level II.

Higher mini-BAL total protein concentration in early ARDS predicts faster resolution of lung injury measured by more ventilator-free days

The protein concentration of alveolar edema fluid in acute respiratory distress syndrome (ARDS) is dynamic. It reflects alveolar flooding during acute injury, as well as fluid and protein clearance over time. We hypothesized that among ARDS patients treated with low tidal volume ventilation, higher concentrations of protein in mini-bronchoalveolar lavage (mBAL) samples would predict slower resolution of lung injury and worse clinical outcomes. Total protein and IgM concentrations in day 0 mBAL samples from 79 subjects enrolled in the aerosolized albuterol (ALTA) ARDS Network Albuterol Trial were measured by colorimetric assay and ELISA, respectively. Linear regression models were used to test the association of mBAL proteins with clinical outcomes and measures of length of illness, including ventilator-free days (VFDs). Median mBAL total protein concentration was 1,740 μg/ml [interquartile range (IQR): 890-3,170]. Each 500 μg/ml increase in day 0 mBAL total protein was associated with an additional 0.8 VFDs [95% confidence interval (CI): 0.05-1.6, P value = 0.038]. Median mBAL IgM concentration was 410 ng/ml (IQR: 340-500). Each 50 ng/ml increase in mBAL IgM was associated with an additional 1.1 VFDs (95% CI 0.2-2.1, P value = 0.022). These associations remained significant and were not attenuated in multivariate models adjusted for age, serum protein concentration, and vasopressor use in the 24 h before enrollment. Thus, higher mBAL total protein and IgM concentrations at day 0 are associated with more VFDs in patients with ARDS and may identify patients with preserved alveolar epithelial mechanisms for net alveolar fluid clearance.

Elevated plasma levels of TIMP-3 are associated with a higher risk of acute respiratory distress syndrome and death following severe isolated traumatic brain injury

Background Complications after injury, such as acute respiratory distress syndrome (ARDS), are common after traumatic brain injury (TBI) and associated with poor clinical outcomes. The mechanisms driving non-neurologic organ dysfunction after TBI are not well understood. Tissue inhibitor of matrix metalloproteinase-3 (TIMP-3) is a regulator of matrix metalloproteinase activity, inflammation, and vascular permeability, and hence has plausibility as a biomarker for the systemic response to TBI. Methods In a retrospective study of 182 patients with severe isolated TBI, we measured TIMP-3 in plasma obtained on emergency department arrival. We used non-parametric tests and logistic regression analyses to test the association of TIMP-3 with the incidence of ARDS within 8 days of admission and in-hospital mortality. Results TIMP-3 was significantly higher among subjects who developed ARDS compared with those who did not (median 2810 pg/mL vs.2260 pg/mL, p=0.008), and significantly higher among subjects who died than among those who survived to discharge (median 2960 pg/mL vs.2080 pg/mL, p<0.001). In an unadjusted logistic regression model, for each SD increase in plasma TIMP-3, the odds of ARDS increased significantly, OR 1.5 (95% CI 1.1 to 2.1). This association was only attenuated in multivariate models, OR 1.4 (95% CI 1.0 to 2.0). In an unadjusted logistic regression model, for each SD increase in plasma TIMP-3, the odds of death increased significantly, OR 1.7 (95% CI 1.2 to 2.3). The magnitude of this association was greater in a multivariate model adjusted for markers of injury severity, OR 1.9 (95% CI 1.2 to 2.8). Discussion TIMP-3 may play an important role in the biology of the systemic response to brain injury in humans. Along with clinical and demographic data, early measurements of plasma biomarkers such as TIMP-3 may help identify patients at higher risk of ARDS and death after severe isolated TBI. Level of evidence III.