Safety Study of Inhaled Carbon Monoxide to Treat Pneumonia and Sepsis-Induced Acute Respiratory Distress Syndrome (ARDS)

Inclusion Criteria:

All patients (age 18 and older) will be eligible for inclusion if they meet all of the following consensus criteria for sepsis and ARDS3,4 or if they meet the criteria for pneumonia as described below.

• Patients with sepsis are defined as those with life-threatening organ dysfunctioncaused by a dysregulated host response to infection:

1. Suspected or proven infection: Sites of infection include thorax, urinarytract, abdomen, skin, sinuses, central venous catheters, and central nervoussystem

2. Increase in Sequential Organ Failure Assessment (SOFA) Score ≥ 2 over baseline

• ARDS is defined when all four of the following criteria are met:

1. A PaO2/FiO2 ratio ≤ 300 with at least 5 cm H2O positive end-expiratory airwaypressure (PEEP)

2. Bilateral opacities on frontal chest radiograph (not fully explained byeffusions, lobar/lung collapse, or nodules) within 1 week of a known clinicalinsult or new or worsening respiratory symptoms

3. A need for positive pressure ventilation by an endotracheal or tracheal tube

4. Respiratory failure not fully explained by cardiac failure or fluid overload;need objective assessment (e.g., echocardiography) to exclude hydrostatic edemaif no risk factor is present

• Pneumonia (without ARDS or sepsis) will be defined as a unilateral or bilateral lunginfiltrate on chest X-ray or chest CT (not fully explained by effusions, lobar/lungcollapse or nodules) in the setting of receiving mechanical ventilation, a newsuspected respiratory infection, an increase in SOFA score less than 2 at the timeof randomization (baseline).

• Pneumonia (with sepsis, without ARDS) will be defined as a unilateral or bilaterallung infiltrate on chest X-ray or chest CT (not fully explained by effusions,lobar/lung collapse or nodules) in the setting of receiving mechanical ventilationand a new suspected respiratory infection with an increase in SOFA score of ≥ 2 overbaseline at the time of randomization. Pneumonia with bilateral opacities, PaO2/FiO2ratio ≤ 300, or an increase in SOFA score greater than or equal to 2 over baselinewill continue to be considered ARDS and sepsis.

Exclusion Criteria:

An individual who meets any of the following criteria will be excluded from participation in this study:

1. Age less than 18 years

2. Greater than 168 hours since ARDS onset

3. Pregnant or breastfeeding

4. Prisoner

5. Patient, surrogate, or physician not committed to full support (exception: a patientwill not be excluded if he/she would receive all supportive care except for attemptsat resuscitation from cardiac arrest)

6. No consent/inability to obtain consent or appropriate legal representative notavailable

7. Physician refusal to allow enrollment in the trial

8. Moribund patient not expected to survive 24 hours

9. No arterial line or central line/no intent to place an arterial or central line

10. No intent/unwillingness to follow lung protective ventilation strategy

11. Severe hypoxemia defined as SpO2 < 95 or PaO2 < 90 on FiO2 ≥ 0.9

12. Hemoglobin < 7.0 g/dL

13. Subjects who are Jehovah's Witnesses or are otherwise unable or unwilling to receiveblood transfusions during hospitalization

14. Acute myocardial infarction (MI) or acute coronary syndrome (ACS) within the last 90days

15. Coronary artery bypass graft (CABG) surgery within 30 days

16. Angina pectoris or use of nitrates with activities of daily living

17. Severe cardiopulmonary disease classified as New York Heart Association (NYHA) classIV

18. Stroke (ischemic or hemorrhagic) within the prior 1 month, cardiac arrest requiringCPR within the prior 72 hours, or inability to assess mental status followingcardiac arrest

19. Burns > 40% total body surface area

20. Severe airway inhalational injury

21. Use of high frequency oscillatory ventilation

22. Use of extracorporeal membrane oxygenation (ECMO)

23. Use of inhaled pulmonary vasodilator therapy (eg. nitric oxide [NO] orprostaglandins)

24. Diffuse alveolar hemorrhage from vasculitis

25. Concurrent participation in other investigational drug study