Carbon Monoxide to Prevent Lung Inflammation
Condition: Respiratory Distress Syndrome, Adult
MeSH terms: Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Acute Lung Injury
Study type: Interventional
Phase: Phase 1

Summary: 
      This study will examine in healthy volunteers how breathing carbon monoxide (CO) affects lung
      inflammation. Severe lung inflammation sometimes develops in patients with pneumonia or
      patients who develop serious blood stream infections. Studies in the laboratory and in
      animals show that CO can decrease lung inflammation.

      Healthy volunteers between 18 and 40 years of age who do not smoke, are not taking any
      medications, do not have asthma, are not allergic to sulfa- and penicillin-based drugs, and
      are not pregnant may be eligible for this study. Candidates are screened with a medical
      history and physical examination, blood and urine tests, electrocardiogram (EKG), and chest
      x-ray. Subjects are enrolled in either a pilot study or the main study.

      Participants undergo bronchoscopy and bronchoalveolar lavage to study the effects of
      endotoxin (a component of bacteria that causes inflammation similar to that in patients with
      lung infections) on lung function. Before the procedure, a small plastic tube (catheter) is
      placed in a vein to collect blood samples and another is placed in an artery to check blood
      pressure. For the bronchoscopy, the mouth and nasal airways are numbed with lidocaine, and a
      bronchoscope (thin flexible tube) is passed through the nose into the airways of the lung. A
      small amount of salt water is squirted through the bronchoscope into one lung and then salt
      water containing endotoxin is squirted into the other lung.

      Following the bronchoscopy, subjects are treated with either CO or room air (placebo) for 6
      hours. (Subjects in the pilot study receive treatment for only 3 hours). The gas is delivered
      through a cushioned mask placed over the nose and mouth. The amount of exhaled CO is measured
      before, during, and after inhalation of the gas. For this measurement, subjects take a deep
      breath to fill up their lungs and slowly exhale into a mouthpiece connected to a measuring
      device until they feel their lungs are empty.

      After the CO treatment, a second bronchoscopy is done to examine how the lung responded to
      the CO or room air. This is studied in two ways. To sample the air, a large needle is used to
      withdraw air through the bronchoscope over about 3 seconds. Then the areas of the lung that
      were squirted with salt water alone and with endotoxin and salt water and are rinsed (lavage)
      and cells and secretions are collected.

      ...
    

Detailed description: 
      Acute respiratory distress syndrome (ARDS) is a major cause of morbidity and mortality. Of
      the many potential predisposing factors, sepsis and pneumonia represent the two main causes
      of ARDS. In spite of an increase in survival in recent years mortality in patients with ARDS
      is still estimated around 30 to 40%. In this context, development of effective preventive
      strategies in patients at high risk of development of ARDS is of paramount importance.
      Unfortunately, the results of studies evaluating prophylactic regimens for ARDS have been
      mostly disappointing.

      The gaseous molecule carbon monoxide (CO) has been traditionally viewed as a toxic metabolic
      and industrial waste. However, recent studies have demonstrated an important physiologic role
      of CO in many biological systems. Specifically, strong anti-inflammatory, anti-oxidant and
      anti-thrombotic effects of CO gas administration and heme oxygenase activation (the enzyme
      that generates endogenous CO gas) have been demonstrated in several animal models.

      Previous studies conducted in our department have demonstrated that bronchoscopic
      instillation of endotoxin (LPS) in healthy volunteers elicits a compartmentalized pulmonary
      inflammatory response, serving as an excellent model to evaluate interventions directed
      towards suppression of lung inflammation at its earliest stages.

      In the current single blinded, randomized, placebo controlled study, we are planning to
      evaluate the effects of inhaled carbon monoxide on local pulmonary inflammatory responses
      following endotoxin administration. Healthy subjects will undergo local endotoxin
      instillation, breathe CO or room air through a mask for 6 hours, and then a repeat
      bronchoscopy with lavage will be done at 6 hours to assess the ability of CO to suppress
      local inflammation in the lung.
    

Intervention name(s): Bronchoscopy; Bronchoalveolar lavage; Endotoxin; Carbon Monoxide
Intervention type(s): Procedure; Procedure; Drug; Drug
Intervention MeSH terms: Dimercaprol; Carbon Monoxide
Allocation: Randomized
Primary purpose: Treatment
Keywords: Lung Permeability; Endotoxin Tolerance; Bronchoscopy; Carbon Monoxide Inhalation