Safety Study of Inhaled Carbon Monoxide to Treat Acute Respiratory Distress Syndrome (ARDS)

The acute respiratory distress syndrome (ARDS) is a syndrome of severe acute lung
inflammation and hypoxemic respiratory failure with an incidence of 180,000 cases annually in
the U.S.Despite decades of research and recent advances in lung protective ventilator
strategies, morbidity and mortality remain unacceptably high. Furthermore, no specific
effective pharmacologic therapies currently exist. The lack of specific effective therapies
for sepsis-related ARDS indicates a need for new treatments that target novel pathways.
Carbon monoxide (CO) represents a novel therapeutic modality in ARDS based on data obtained
in experimental models of ARDS and sepsis over the past decade.

CO has been shown to be protective in experimental models of Acute Lung Injury (ALI),
including hyperoxia and endotoxin exposure, bleomycin, ischemia/reperfusion, and
ventilator-induced lung injury (VILI). At low doses, CO has been shown to confer tissue
protective effects in these ALI models. In addition, CO has been shown to decrease
inflammation, enhance phagocytosis, and improve mortality in models of sepsis including
endotoxemia, hemorrhagic shock, and cecal ligation and puncture (CLP). CO has also been shown
to have beneficial therapeutic effects in pre-clinical models of disease including pulmonary
hypertension, vascular injury, and transplantation. Furthermore, multiple human studies have
demonstrated that experimental administration of several different concentrations of CO is
well tolerated and that low dose inhaled CO can be safely administered to subjects in a
controlled research environment.

The purpose of this study is to assess the safety of inhaled CO therapy in mechanically
ventilated patients with sepsis-induced ARDS.

Inclusion Criteria:

1. Patients with sepsis are defined as those with suspected or documented infection:

Suspected or proven infection: Sites of infection include thorax, urinary tract,
abdomen, skin, sinuses, central venous catheters, and central nervous system

All eligible patients meet the new definition of sepsis (suspected or proven infection
and a SOFA ≥ 2) as PaO2/FiO2 ratio < 300 = 2 SOFA points.

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

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

- Bilateral infiltrates consistent with pulmonary edema on frontal chest radiograph

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

- No clinical evidence of left atrial hypertension for bilateral pulmonary
infiltrates.

3. ARDS onset is defined as the time the last of criteria 1-4 are met. ARDS must persist
through the enrollment time window of 120 hours.

4. Infiltrates considered "consistent with pulmonary edema" include any infiltrates not
fully explained by mass, atelectasis, or effusion or opacities known to be chronic
(greater than 1 week). Vascular redistribution, indistinct vessels, and indistinct
heart borders alone are not considered "consistent with pulmonary edema" and thus
would not count as qualifying opacities for this study.

Exclusion Criteria:

1. Age less than 18 years

2. Greater than 120 hours since ARDS onset

3. Pregnant or breast-feeding

4. Prisoner

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

6. No consent/inability to obtain consent

7. Physician refusal to allow enrollment in the trial

8. Moribund patient not expected to survive 24 hours

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

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

11. Severe hypoxemia defined as SpO2 <95 or PaO2 <80 on FiO2 ≥0.8

12. Hemoglobin < 7.5 g/dl or hemoglobin < 8 g/dl and actively bleeding

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

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

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

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

17. Cardiopulmonary disease classified as NYHA class IV

18. Stroke (ischemic or hemorrhagic) within the prior 3 months

19. Diffuse alveolar hemorrhage from vasculitis

20. Use of high frequency ventilation

21. Participation in other interventional studies involving investigational agents

22. Burns > 40% total body surface area

23. Use of inhaled pulmonary vasodilator therapy (eg. NO or prostaglandins)