Richard J. Maunder

Local abnormalities in coagulation and fibrinolytic pathways predispose to alveolar fibrin deposition in the adult respiratory distress syndrome.

To determine the possible mechanism(s) promoting alveolar fibrin deposition in the adult respiratory distress syndrome (ARDS), we investigated the initiation and regulation of both fibrinolysis and coagulation from patients with ARDS (n = 14), at risk for ARDS (n = 5), and with interstitial lung diseases (ILD) (n = 8), and normal healthy individuals (n = 13). Bronchoalveolar lavage (BAL) extrinsic pathway inhibitor activity was increased in ARDS BAL compared with patients at risk for ARDS (P = 0.0146) or normal controls (P = 0.0013) but tissue factor-factor VII procoagulant activity was significantly increased in ARDS BAL compared with all other groups (P less than 0.001). Fibrinolytic activity was not detectable in BAL of 10 of the 14 patients with ARDS and low levels of activity were found in BAL of the other four ARDS patients. Depressed fibrinolysis in ARDS BAL was not due to local insufficiency of plasminogen; rather, there was inhibition of both plasmin and plasminogen activator. Plasminogen activator inhibitor 1 was variably detected and low levels of plasminogen activator inhibitor 2 were found in two ARDS BAL samples, but plasminogen activator inhibitor 2 was otherwise undetectable. ARDS BAL antiplasmin activity was, in part, due to alpha 2-antiplasmin. We conclude that abnormalities that result in enhanced coagulation and depressed fibrinolysis, thereby predisposing to alveolar fibrin deposition, occur in the alveolar lining fluids from patients with ARDS.

Adult Respiratory Distress Syndrome: Sequence and Importance of Development of Multiple Organ Failure

The adult respiratory distress syndrome (ARDS) represents a common denominator of acute lung injury leading to alveolar flooding, decreased lung compliance, and altered gas transport. In the absence of specific etiology and therapy, the management of ARDS remains largely supportive. Ubiquitous use of intermittent positive-pressure ventilation with positive end-expiratory pressure (PEEP) improves arterial oxygenation but with some risk of pulmonary barotrauma and decreased cardiac output. The recent understanding of lung inflation as a modulator of right heart afterload and the effect of the right ventricle on global cardiac performance continues to redefine optimal patterns of ventilatory and hemodynamic intervention in ARDS. ImagesFIG. 1

Clinical InvestigationsAdult Respiratory Distress Syndrome: Sequence and Importance of Development of Multiple Organ Failure

The adult respiratory distress syndrome (ARDS) represents a common denominator of acute lung injury leading to alveolar flooding, decreased lung compliance, and altered gas transport. In the absence of specific etiology and therapy, the management of ARDS remains largely supportive. Ubiquitous use of intermittent positive-pressure ventilation with positive end-expiratory pressure (PEEP) improves arterial oxygenation but with some risk of pulmonary barotrauma and decreased cardiac output. The recent understanding of lung inflation as a modulator of right heart afterload and the effect of the right ventricle on global cardiac performance continues to redefine optimal patterns of ventilatory and hemodynamic intervention in ARDS. ImagesFIG. 1

Changes in Plasma Fibronectin Isoform Levels Predict Distinct Clinical Outcomes in Critically Ill Patients

Introduction Concentrations of the total pool of fibronectin in plasma (TFN), and the subset of this pool that contains the alternatively spliced EDA segment (A+FN), are both affected by disease processes, and the latter pool has gained a reputation as a biomarker for vascular injury. We therefore wished to determine if changes in either FN pool correlate with clinical outcomes in critically ill individuals. Methods We analyzed a database for 57 patients with major trauma (n = 33) or sepsis syndrome (n = 24) in which plasma levels of TFN and A+FN had been measured at intervals, along with clinical parameters. Logistic regression analysis was performed to detect associations between predictive variables and three clinical outcomes: 1) the acute respiratory distress syndrome (ARDS), 2) milder acute lung injury designated acute hypoxemic respiratory failure (AHRF), and 3) survival to hospital discharge. Results An increase in plasma TFN during the first 24 hours of intensive care unit (ICU) observation was negatively associated with progression to ARDS (odds ratio 0.98 per 1 microgram (μg)/ml increase, 95% CI (0.97, 1.00)) and AHRF (OR 0.97 per 1 μg/ml increase, (0.95, 0.99)), whereas an increase in A+FN over the first 24 hours was positively associated with progression to AHRF (OR 1.65 per 1 μg/ml increase, (1.04, 2.62)). Additionally, the ratio of the partial pressure of oxygen in arterial blood (PaO2) to the percentage of oxygen in inspired air (FIO2) after 24 hours was positively associated with survival (OR 1.01 per 1 unit increase in ratio, (1.00, 1.03)), along with change in A+FN (OR 1.30 per 1 μg/ml increase, (0.90, 1.88)). Conclusions Different FN isoforms may constitute predictive covariate markers for distinct clinical outcomes in critically ill patients. The data also suggest that early TFN accumulation in the circulation may confer a clinical benefit to patients at risk for acute lung injury.

Bronchoalveolar lavage desmosine in bleomycin-induced lung injury in marmosets and patients with adult respiratory distress syndrome

Measurement of urinary desmosine in experimental models of emphysema has been used to demonstrate elastin catabolism. In order to evaluate the hypothesis that accelerated elastin degradation also occurs in association with acute lung injury characterized by fibrotic repair, we prepared acid hydrolysates of lung lavage (LL) and used a radioimmunoassay for desmosine to measure concentrations of this elastic-specific cross-link in LL. Lavage desmosine (pmol/100 microliter LL) was measured following bleomycin-induced lung injury in marmosets and was shown to be elevated at 1 week (median 6.0, range 5.1-7.8), 2 weeks (8.4, 6.2-8.7), and 4 weeks (7.6, 4.8-7.8) compared to control levels (1.8, 1.4-3.7). Elevations of lavage desmosine after bleomycin were temporarily associated with remodeling of the lung as indicated by increased total lung collagen, reduced diffusing capacity and lung compliance, and histologic evidence of pulmonary fibrosis. Bronchoalveolar lavage (BAL) desmosine was measured in patients with the Adult Respiratory Distress Syndrome (ARDS) and compared with patients at risk, patients with other interstitial lung diseases, and normal healthy controls. BAL desmosine (pmol/100 microliters) was not significantly different in patients with ARDS (3.2, 2.1-3.0), patients at risk for ARDS (2.8, 2.5-4.4), and those with interstitial lung disease (3.0, 1.7-5.3) compared to normal controls (2.9, 1.9-4.7). There were poor correlations of BAL desmosine with physiologic indices of severity of disease in patients with ARDS and those at risk. Accelerated elastolysis occurred in the lower respiratory tract during the evaluation of bleomycin-induced pulmonary fibrosis in marmosets but was undetectable in BAL of patients studied within the first 3 days of ARDS.