B. T. Thompson

Severity of Hypoxemia and Effect of High Frequency Oscillatory Ventilation in ARDS.

Rationale: High‐frequency oscillatory ventilation (HFOV) is theoretically beneficial for lung protection, but the results of clinical trials are inconsistent, with study‐level meta‐analyses suggesting no significant effect on mortality. Objectives: The aim of this individual patient data meta‐analysis was to identify acute respiratory distress syndrome (ARDS) patient subgroups with differential outcomes from HFOV. Methods: After a comprehensive search for trials, two reviewers independently identified randomized trials comparing HFOV with conventional ventilation for adults with ARDS. Prespecified effect modifiers were tested using multivariable hierarchical logistic regression models, adjusting for important prognostic factors and clustering effects. Measurements and Main Results: Data from 1,552 patients in four trials were analyzed, applying uniform definitions for study variables and outcomes. Patients had a mean baseline PaO2/FiO2 of 114 ± 39 mm Hg; 40% had severe ARDS (PaO2/FiO2 <100 mm Hg). Mortality at 30 days was 321 of 785 (40.9%) for HFOV patients versus 288 of 767 (37.6%) for control subjects (adjusted odds ratio, 1.17; 95% confidence interval, 0.94‐1.46; P = 0.16). This treatment effect varied, however, depending on baseline severity of hypoxemia (P = 0.0003), with harm increasing with PaO2/FiO2 among patients with mild‐moderate ARDS, and the possibility of decreased mortality in patients with very severe ARDS. Compliance and body mass index did not modify the treatment effect. HFOV increased barotrauma risk compared with conventional ventilation (adjusted odds ratio, 1.75; 95% confidence interval, 1.04‐2.96; P = 0.04). Conclusions: HFOV increases mortality for most patients with ARDS but may improve survival among patients with severe hypoxemia on conventional mechanical ventilation.

Volume Delivered During Recruitment Maneuver Predicts Lung Stress in Acute Respiratory Distress Syndrome

Objective:Global lung stress varies considerably with low tidal volume ventilation for acute respiratory distress syndrome. High stress despite low tidal volumes may worsen lung injury and increase risk of death. No widely available parameter exists to assess global lung stress. We aimed to determine whether the volume delivered during a recruitment maneuver (VRM) is inversely associated with lung stress and mortality in acute respiratory distress syndrome. Design:Substudy of an acute respiratory distress syndrome clinical trial on esophageal pressure-guided positive end-expiratory pressure titration. Setting:U.S. academic medical center. Patients:Forty-two patients with acute respiratory distress syndrome in whom airflow, airway pressure, and esophageal pressure were recorded during the recruitment maneuver. Interventions:A single recruitment maneuver was performed before initiating protocol-directed ventilator management. Recruitment maneuvers consisted of a 30-second breath hold at 40u2009cm H2O airway pressure under heavy sedation or paralysis. VRM was calculated by integrating the flow-time waveform during the maneuver. End-inspiratory stress was defined as the transpulmonary (airway minus esophageal) pressure during end-inspiratory pause of a tidal breath and tidal stress as the transpulmonary pressure difference between end-inspiratory and end-expiratory pauses. Measurements and Main Results:VRM ranged between 7.4 and 34.7u2009mL/kg predicted body weight. Lower VRM predicted high end-inspiratory and tidal lung stress (end-inspiratory: &bgr; = –0.449; 95% CI, –0.664 to –0.234; p < 0.001; tidal: &bgr; = –0.267; 95% CI, –0.423 to –0.111; p = 0.001). After adjusting for PaO2/FIO2 and either driving pressure, tidal volume, or plateau pressure and positive end-expiratory pressure, VRM remained independently associated with both end-inspiratory and tidal stress. In unadjusted analysis, low VRM predicted increased risk of death (odds ratio, 0.85; 95% CI, 0.72–1.00; p = 0.026). VRM remained significantly associated with mortality after adjusting for study arm (odds ratio, 0.84; 95% CI, 0.71–1.00; p = 0.022). Conclusions:Low VRM independently predicts high lung stress and may predict risk of death in patients with acute respiratory distress syndrome.

Effects of inhaled CO administration on acute lung injury in baboons with pneumococcal pneumonia.

Inhaled carbon monoxide (CO) gas has therapeutic potential for patients with acute respiratory distress syndrome if a safe, evidence-based dosing strategy and a ventilator-compatible CO delivery system can be developed. In this study, we used a clinically relevant baboon model of Streptococcus pneumoniae pneumonia to 1) test a novel, ventilator-compatible CO delivery system; 2) establish a safe and effective CO dosing regimen; and 3) investigate the local and systemic effects of CO therapy on inflammation and acute lung injury (ALI). Animals were inoculated with S. pneumoniae (10(8)-10(9) CFU) (n = 14) or saline vehicle (n = 5); in a subset with pneumonia (n = 5), we administered low-dose, inhaled CO gas (100-300 ppm × 60-90 min) at 0, 6, 24, and/or 48 h postinoculation and serially measured blood carboxyhemoglobin (COHb) levels. We found that CO inhalation at 200 ppm for 60 min is well tolerated and achieves a COHb of 6-8% with ambient CO levels ≤ 1 ppm. The COHb level measured at 20 min predicted the 60-min COHb level by the Coburn-Forster-Kane equation with high accuracy. Animals given inhaled CO + antibiotics displayed significantly less ALI at 8 days postinoculation compared with antibiotics alone. Inhaled CO was associated with activation of mitochondrial biogenesis in the lung and with augmentation of renal antioxidative programs. These data support the feasibility of safely delivering inhaled CO gas during mechanical ventilation and provide preliminary evidence that CO may accelerate the resolution of ALI in a clinically relevant nonhuman primate pneumonia model.

S5.8 Chemical composition of two commercial heparins with differing antiproliferative effect on smooth muscle cells

aggregation of cells from the marine sponge Microciona prolifera. Homophilic binding of an extracellular adhesion proteoglycan mediates aggregation in the presence of Ca 2÷. Aggregation-inhibiting monoclonal antibodies produced against the purified proteoglycan recognize carbohydrate epitopes (JBC 262 (1987) 5870-5877). In addition to uronic acid and N-acetylglucosamine these glycans also contain neutral sugars, including fucose. The glycans have been postulated to mediate polyvalent carbohydrate-carbohydrate interactions (JBC 261 (1986) 2853-2859). In order to elucidate the molecular mechanism of these interactions we have purified and characterized carbohydrate epitopes from the proteoglycan. One of the oligosaccharides isolated after fragmentation of the glycans was identified as the pyruvylated trisaccharide