In this project we will investigate lung mechanics in humans with ARDS in order to develop therapies to improve gas exchange, patient comfort, and ventilatory muscle function. Subproject 1 will describe abnormalities in lung mechanics over time in patients with ARDS and examine correlations among abnormalities of mechanics and gas exchange. Airway resistance, lung and chest wall compliance, mechanical impedance, and work of breathing will be monitored from airflow, volume, airway and esophageal pressure measurements. Respired gases, and arterial blood will be sampled to monitor gas exchange. We will examine similar measures of lung mechanics before and after bronchodilating drugs to test the clinical importance of reversible bronchoconstriction to disordered mechanics, blood oxygenation, and CO2 elimination. Subproject 2 will assess interactions of expiratory effort and PEEP in changing lung volume and gas exchange. While triggering mechanical ventilation, normal subjects will be CO2-driven to hyperventilate as lung volume is tracked by inductance plethysmography. Intra-thoracic pressure and muscle activity will be monitored. The lung volume increments resulting from PEEP will be measured and evidence of attenuation during hyperpnea sought. In patients with acute hypoxemia, lung volume, intra-thoracic pressure and muscle activity will be recorded, as in normals. Hemodynamics and gas exchange will also be monitored before and after sedation and muscle paralysis to determine the mechanisms by which gas exchange is altered by muscle relaxation. Subproject 3 will examine patient- ventilator interactions during ARDS in order: (1) to develop practical bedside measures of the ventilatory capability and workload of spontaneous breathing, thus facilitating ventilator withdrawal, (2) to determine the influence of ventilator mode, machine settings and ventilatory drive on the patient's workload during machine-assisted breathing, and (3) to define the determinants of asynchrony between machine cycling and patient effort. Airway and esophageal pressure-volume plots will be obtained during controlled, assisted, and spontaneous breathing, and work of breathing will be calculated. Pressure-volume and flow information and electromyography will be used to indicate timing differences in patient and ventilator cycles. Apart from its physiologic interest, such data will provide guidelines for selecting the optimal mode and machine settings for patient management.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Specialized Center (P50)
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Vanderbilt University Medical Center
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Brigham, K L; Lane, K B; Meyrick, B et al. (2000) Transfection of nasal mucosa with a normal alpha1-antitrypsin gene in alpha1-antitrypsin-deficient subjects: comparison with protein therapy. Hum Gene Ther 11:1023-32
Conner, B D; Bernard, G R (2000) Acute respiratory distress syndrome. Potential pharmacologic interventions. Clin Chest Med 21:563-87
Mangialardi, R J; Martin, G S; Bernard, G R et al. (2000) Hypoproteinemia predicts acute respiratory distress syndrome development, weight gain, and death in patients with sepsis. Ibuprofen in Sepsis Study Group. Crit Care Med 28:3137-45
Brigham, K L; Stecenko, A A (2000) Gene therapy for acute lung injury. Intensive Care Med 26 Suppl 1:S119-23
Arons, M M; Wheeler, A P; Bernard, G R et al. (1999) Effects of ibuprofen on the physiology and survival of hypothermic sepsis. Ibuprofen in Sepsis Study Group. Crit Care Med 27:699-707
Peters, M T; Brigham, K L; King, G A et al. (1999) Optimization of cationic liposome-mediated gene transfer to human bronchial epithelial cells expressing wild-type or abnormal cystic fibrosis transmembrane conductance regulator (CFTR). Exp Lung Res 25:183-97
Wheeler, A P; Bernard, G R (1999) Treating patients with severe sepsis. N Engl J Med 340:207-14
Snapper, J R; Trochtenberg, D S; Hwang, Y S et al. (1999) Effect of pulmonary edema on tracheal diameter. Respiration 66:522-7
Dupont, W D; Plummer Jr, W D (1998) Power and sample size calculations for studies involving linear regression. Control Clin Trials 19:589-601
Clark, M P; Chow, C W; Rinaldo, J E et al. (1998) Multiple domains for initiator binding proteins TFII-I and YY-1 are present in the initiator and upstream regions of the rat XDH/XO TATA-less promoter. Nucleic Acids Res 26:2813-20

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