Ciara M. Shaver

Pseudomonas aeruginosa Induces Localized Immunosuppression During Pneumonia

ABSTRACT Hospital-acquired bacterial pneumonia is a common and serious complication of modern medical care. Many aspects of such infections remain unclear, including the mechanisms by which invading pathogens resist clearance by the innate immune response and the tendency of the infections to be polymicrobial. Here, we used a mouse model of infection to show that Pseudomonas aeruginosa, a leading cause of hospital-acquired pneumonia, interferes with the ability of recruited phagocytic cells to eradicate bacteria from the lung. Early in infection, phagocytic cells, predominantly neutrophils, are recruited to the lungs but are incapacitated when they enter the airways by the P. aeruginosa toxin ExoU. The resulting paucity of functioning phagocytes allows P. aeruginosa to persist within the lungs and results in local immunosuppression that facilitates superinfection with less-pathogenic bacteria. Together, our results provide explanations for previous reports linking ExoU-secreting P. aeruginosa with more severe pulmonary infections and for the tendency of hospital-acquired pneumonia to be polymicrobial.

Atrial Fibrillation Is an Independent Predictor of Mortality in Critically Ill Patients.

Objectives:Atrial fibrillation has been associated with increased mortality in critically ill patients. We sought to determine whether atrial fibrillation in the ICU is an independent risk factor for death. A secondary objective was to determine if patients with new-onset atrial fibrillation have different risk factors or outcomes compared with patients with a previous history of atrial fibrillation. Design:Prospective observational cohort study. Setting:Medical and general surgical ICUs in a tertiary academic medical center. Patients:One thousand seven hundred seventy critically ill patients requiring at least 2 days in the ICU. Interventions:None. Measurements and Main Results:Demographics, medical history, development of atrial fibrillation, fluid balance, echocardiographic findings, medication administration, and hospital mortality were collected during the first 4 days of ICU admission. Atrial fibrillation occurred in 236 patients (13%) (Any AF). Of these, 123 patients (7%) had no prior atrial fibrillation (New-onset AF) while the remaining 113 (6%) had recurrent atrial fibrillation (Recurrent AF). Any AF was associated with male gender, Caucasian race, increased age, cardiac disease, organ failures, and disease severity. Patients with Any AF had increased mortality compared with those without atrial fibrillation (31% vs 17%; p < 0.001), and Any AF was independently associated with death (odds ratio, 1.62; 95% CI, 1.14–2.29; p = 0.007) in multivariable analysis controlling for severity of illness and other confounders. The association of atrial fibrillation with death was magnified in patients without sepsis (odds ratio, 2.92; 95% CI, 1.52–5.60; p = 0.001). Treatment for atrial fibrillation had no effect on hospital mortality. New-onset AF and Recurrent AF were each associated with increased mortality. New-onset AF, but not Recurrent AF, was associated with increased diastolic dysfunction and vasopressor use and a greater cumulative positive fluid balance. Conclusions:Atrial fibrillation in critical illness, whether new-onset or recurrent, is independently associated with increased hospital mortality, especially in patients without sepsis.

Randomized Trial of Video Laryngoscopy for Endotracheal Intubation of Critically Ill Adults.

Objective:To evaluate the effect of video laryngoscopy on the rate of endotracheal intubation on first laryngoscopy attempt among critically ill adults. Design:A randomized, parallel-group, pragmatic trial of video compared with direct laryngoscopy for 150 adults undergoing endotracheal intubation by Pulmonary and Critical Care Medicine fellows. Setting:Medical ICU in a tertiary, academic medical center. Patients:Critically ill patients 18 years old or older. Interventions:Patients were randomized 1:1 to video or direct laryngoscopy for the first attempt at endotracheal intubation. Measurements and Main Results:Patients assigned to video (n = 74) and direct (n = 76) laryngoscopy were similar at baseline. Despite better glottic visualization with video laryngoscopy, there was no difference in the primary outcome of intubation on the first laryngoscopy attempt (video 68.9% vs direct 65.8%; p = 0.68) in unadjusted analyses or after adjustment for the operator’s previous experience with the assigned device (odds ratio for video laryngoscopy on intubation on first attempt 2.02; 95% CI, 0.82–5.02, p = 0.12). Secondary outcomes of time to intubation, lowest arterial oxygen saturation, complications, and in-hospital mortality were not different between video and direct laryngoscopy. Conclusions:In critically ill adults undergoing endotracheal intubation, video laryngoscopy improves glottic visualization but does not appear to increase procedural success or decrease complications.

Clinical Characteristics and Outcomes Are Similar in ARDS Diagnosed by Oxygen Saturation/Fio2 Ratio Compared With Pao2/Fio2 Ratio

BACKGROUND Oxygen saturation as measured by pulse oximetry/Fio2 (SF) ratio is highly correlated with the Pao2/Fio2 (PF) ratio in patients with ARDS. However, it remains uncertain whether SF ratio can be substituted for PF ratio for diagnosis of ARDS and whether SF ratio might identify patients who are systemically different from patients diagnosed by PF ratio. METHODS We conducted a secondary analysis of a large observational prospective cohort study. Patients were eligible if they were admitted to the medical ICU and fulfilled the Berlin definition of ARDS with hypoxemia criteria using either the standard PF threshold (PF ratio ≤ 300) or a previously published SF threshold (SF ratio ≤ 315). RESULTS Of 362 patients with ARDS, 238 (66%) received a diagnosis by PF ratio and 124 (34%) by SF ratio. In a small group of patients who received diagnoses of ARDS by SF ratio who had arterial blood gas measurements on the same day (n = 10), the PF ratio did not meet ARDS criteria. There were no major differences in clinical characteristics or comorbidities between groups with the exception of APACHE (Acute Physiology and Chronic Health Evaluation) II scores, which were higher in the group diagnosed by PF ratio. However, this difference was no longer apparent when arterial blood gas-dependent variables (pH, Pao2) were removed from the APACHE II score. There were also no differences in clinical outcomes including duration of mechanical ventilation (mean, 7 days in both groups; P = .25), duration of ICU stay (mean, 10 days vs 9 days in PF ratio vs SF ratio; P = .26), or hospital mortality (36% in both groups, P = .9). CONCLUSIONS Patients with ARDS diagnosed by SF ratio have very similar clinical characteristics and outcomes compared with patients diagnosed by PF ratio. These findings suggest that SF ratio could be considered as a diagnostic tool for early enrollment into clinical trials.

Clinical Predictors of Hospital Mortality Differ Between Direct and Indirect ARDS

Background Direct (pulmonary) and indirect (extrapulmonary) ARDS are distinct syndromes with important pathophysiologic differences. The goal of this study was to determine whether clinical characteristics and predictors of mortality differ between direct or indirect ARDS. Methods This retrospective observational cohort study included 417 patients with ARDS. Each patient was classified as having direct (pneumonia or aspiration, n = 250) or indirect (nonpulmonary sepsis or pancreatitis, n = 167) ARDS. Results Patients with direct ARDS had higher lung injury scores (3.0 vs 2.8; P < .001), lower Simplified Acute Physiology Score II scores (51 vs 62; P < .001), lower Acute Physiology and Chronic Health Evaluation II scores (27 vs 30; P < .001), and fewer nonpulmonary organ failures (1 vs 2; P < .001) compared with patients with indirect ARDS. Hospital mortality was similar (28% vs 31%). In patients with direct ARDS, age (OR, 1.29 per 10 years; P = .01; test for interaction, P = .03), lung injury scores (OR, 2.29 per point; P = .001; test for interaction, P = .058), and number of nonpulmonary organ failures (OR, 1.67; P = .01) were independent risk factors for increased hospital mortality. Preexisting diabetes mellitus was an independent risk factor for reduced hospital mortality (OR, 0.47; P = .04; test for interaction, P = .02). In indirect ARDS, only the number of organ failures was an independent predictor of mortality (OR, 2.08; P < .001). Conclusions Despite lower severity of illness and fewer organ failures, patients with direct ARDS had mortality rates similar to patients with indirect ARDS. Factors previously associated with mortality during ARDS were only associated with mortality in direct ARDS. These findings suggest that direct and indirect ARDS have distinct features that may differentially affect risk prediction and clinical outcomes.

Clinical and Biological Heterogeneity in Acute Respiratory Distress Syndrome Direct Versus Indirect Lung Injury

The acute respiratory distress syndrome (ARDS) is a heterogeneous group of illnesses affecting the pulmonary parenchyma with acute onset bilateral inflammatory pulmonary infiltrates with associated hypoxemia. ARDS occurs after 2 major types of pulmonary injury: direct lung injury affecting the lung epithelium or indirect lung injury disrupting the vascular endothelium. Greater understanding of the differences between direct and indirect lung injury may refine the classification of patients with ARDS and lead to development of new therapeutics targeted at specific subpopulations of patients with ARDS.

Regulation of Alveolar Procoagulant Activity and Permeability in Direct Acute Lung Injury by Lung Epithelial Tissue Factor

Tissue factor (TF) initiates the extrinsic coagulation cascade in response to tissue injury, leading to local fibrin deposition. Low levels of TF in mice are associated with increased severity of acute lung injury (ALI) after intratracheal LPS administration. However, the cellular sources of the TF required for protection from LPS-induced ALI remain unknown. In the current study, transgenic mice with cell-specific deletions of TF in the lung epithelium or myeloid cells were treated with intratracheal LPS to determine the cellular sources of TF important in direct ALI. Cell-specific deletion of TF in the lung epithelium reduced total lung TF expression to 39% of wild-type (WT) levels at baseline and to 29% of WT levels after intratracheal LPS. In contrast, there was no reduction of TF with myeloid cell TF deletion. Mice lacking myeloid cell TF did not differ from WT mice in coagulation, inflammation, permeability, or hemorrhage. However, mice lacking lung epithelial TF had increased tissue injury, impaired activation of coagulation in the airspace, disrupted alveolar permeability, and increased alveolar hemorrhage after intratracheal LPS. Deletion of epithelial TF did not affect alveolar permeability in an indirect model of ALI caused by systemic LPS infusion. These studies demonstrate that the lung epithelium is the primary source of TF in the lung, contributing 60-70% of total lung TF, and that lung epithelial, but not myeloid, TF may be protective in direct ALI.

Cell-free hemoglobin: a novel mediator of acute lung injury

Patients with the acute respiratory distress syndrome (ARDS) have elevated levels of cell-free hemoglobin (CFH) in the air space, but the contribution of CFH to the pathogenesis of acute lung injury is unknown. In the present study, we demonstrate that levels of CFH in the air space correlate with measures of alveolar-capillary barrier dysfunction in humans with ARDS (r = 0.89, P < 0.001) and in mice with ventilator-induced acute lung injury (r = 0.89, P < 0.001). To investigate the specific contribution of CFH to ARDS, we studied the impact of purified CFH in the mouse lung and on cultured mouse lung epithelial (MLE-12) cells. Intratracheal delivery of CFH in mice causes acute lung injury with air space inflammation and alveolar-capillary barrier disruption. Similarly, in MLE-12 cells, CFH increases proinflammatory cytokine expression and increases paracellular permeability as measured by electrical cell-substrate impedance sensing. Next, to determine whether these effects are mediated by the iron-containing heme moiety of CFH, we treated mice with intratracheal hemin, the chloride salt of heme, and found that hemin was sufficient to increase alveolar permeability but failed to induce proinflammatory cytokine expression or epithelial cell injury. Together, these data identify CFH in the air space as a previously unrecognized driver of lung epithelial injury in human and experimental ARDS and suggest that CFH and hemin may contribute to ARDS through different mechanisms. Interventions targeting CFH and heme in the air space could provide a new therapeutic approach for ARDS.

Fatal Scopulariopsis infection in a lung transplant recipient: lessons of organ procurement.

Seventeen days after double lung transplantation, a 56‐year‐old patient with idiopathic pulmonary fibrosis developed respiratory distress. Imaging revealed bilateral pulmonary infiltrates with pleural effusions and physical examination demonstrated sternal instability. Broad‐spectrum antibacterial and antifungal therapy was initiated and bilateral thoracotomy tubes were placed. Both right and left pleural cultures grew a mold subsequently identified as Scopulariopsis brumptii. The patient underwent pleural irrigation and sternal debridement three times but pleural and wound cultures continued to grow S. brumptii. Despite treatment with five antifungal agents, the patient succumbed to his illness 67 days after transplantation. Autopsy confirmed the presence of markedly invasive fungal disease and pleural rind formation. The patients organ donor had received bilateral thoracostomy tubes during resuscitation in a wilderness location. There were no visible pleural abnormalities at the time of transplantation. However, the patients clinical course and the location of the infection, in addition to the lack of similar infection in other organ recipients, strongly suggest that Scopulariopsis was introduced into the pleural space during prehospital placement of thoracostomy tubes. This case of lethal infection transmitted through transplantation highlights the unique risk of using organs from donors who are resuscitated in an outdoor location.

Tissue factor deficiency increases alveolar hemorrhage and death in influenza A virus-infected mice

Essentials H1N1 Influenza A virus (IAV) infection is a hemostatic challenge for the lung. Tissue factor (TF) on lung epithelial cells maintains lung hemostasis after IAV infection. Reduced TF‐dependent activation of coagulation leads to alveolar hemorrhage. Anticoagulation might increase the risk for hemorrhages into the lung during severe IAV infection.