Statins for Acutely Injured Lungs From Sepsis

ALI/ARDS involves extensive inflammation in the lungs that can lead to rapid respiratory
failure. These conditions are most commonly caused by pneumonia, generalized infection, or
severe trauma to the lungs, but can also be less commonly caused by smoke or salt water
inhalation, drug overdose, or shock.

For some people, ALI/ARDS resolves without treatment, but many severe cases result in
hospitalization in the intensive care unit (ICU), where 30% to 40% of cases end in
mortality. Current treatments for ALI/ARDS include assisted breathing with a ventilator,
supportive care, and management of the underlying causes.

Upon admission to the ICU, Rosuvastatin or placebo will be administered through an enteral
feeding tube or administered orally following extubation when patients are able to safely
take oral medications. The type and placement of the enteral feeding tube (nasogastric,
nasoenteric, PEG, orogastric, oroenteric, etc.) and the ability to safely take oral
medications will be determined by the patient's primary team. Study drug will be blinded
with an identical appearing placebo. The first study drug dose (rosuvastatin or placebo)
will be administered within 4 hours of randomization as a loading dose of 40 mg.

Blood pressure, heart rate, ventilation settings, and various blood factors will be measured
during treatment. Phone-based follow-up assessments will occur at Months 6 and 12 after ICU
discharge and will include measurements of health-related quality of life; psychological,
neurocognitive, and physical activity outcomes; healthcare utilization; and mortality.

Inclusion Criteria:

- 1. Systemic inflammatory response syndrome (SIRS) defined as meeting at least
criteria (a) or (b)for a systemic inflammatory response:

1. White blood cell count >12,000 or <4,000 or >10% band forms

2. Body temperature >38oC (any route) or <36oC (accepting core temperatures only;
indwelling catheter, esophageal, rectal)

3. Heart rate (> 90 beats/min) or receiving medications that slow heart rate or
paced rhythm 2. Suspected or proven infection: Sites of infection include
thorax, urinary tract, abdomen, skin, sinuses, central venous catheters, and
bacterial meningitis (Appendix A).

3. ALI as defined by acute onset of:

1. PaO2 / FiO2 ≤ 300 (intubated). If altitude > 1000m, then PaO2 / FiO2 ≤ 300 x
(PB/760), and

2. Bilateral infiltrates consistent with pulmonary edema on frontal chest
radiograph, and

3. Requirement for positive pressure ventilation via an endotracheal tube, and

4. No clinical evidence of left atrial hypertension, or if measured, a Pulmonary
Arterial Wedge Pressure (PAOP) less than or equal to 18 mm Hg. If a patient
has a PAOP > 18 mmHg, then the other criteria must persist for more than 12
hours after the PAOP has declined to ≤ 18 mmHg, and still be within the 48-hour
enrollment window.

"Acute onset" is defined as follows: the duration of the hypoxemia criterion (#1) and the
chest radiograph criterion (#2) must be ≤ 28 days at the time of randomization. Opacities
considered "consistent with pulmonary edema" include any patchy or diffuse opacities not
fully explained by mass, atelectasis, or effusion or opacities known to be chronic (> 28
days). The findings of vascular redistribution, indistinct vessels, and indistinct cardiac
borders are not considered "consistent with pulmonary edema".

All ALI criteria (3a-d above) must occur within the same 24 hour period. The onset of ALI
is when the last ALI criterion is met. Patients must be enrolled within 48 hours of ALI
onset and no more than 7 days from the initiation of mechanical ventilation. SIRS
criteria must occur within the 72 hours before or the 24 hours after ALI onset.
Information for determining when these time window criteria were met may come from either
the Network hospital or a referring hospital reports.

Exclusion Criteria:

1. No consent/inability to obtain consent

2. Age less than 18 years

3. More than 7 days since initiation of mechanical ventilation

4. More than 48 hours since meeting ALI inclusion criteria

5. Patient, surrogate, or physician not committed to full support ).

6. Unable to receive or unlikely to absorb enteral study drug

7. Rosuvastatin specific exclusions

- Receiving a statin medication within 48 hours of randomization

- Allergy or intolerance to statins

- Physician insistence for the use or avoidance of statins during the current
hospitalization

- CK , ALT or AST > 5 times the upper limit of normal

- Diagnosis of hypothyroidism and not on thyroid replacement therapy

- Pregnancy or breast feeding

- Receiving niacin, fenofibrate or cyclosporine, gemfibrozil, atazanavir,
lopinavir, ritonavir, daptomycin

8. Severe chronic liver disease

9. Moribund patient not expected to survive 24 hours

10. Chronic respiratory failure defined as PaCO2 > 60 mm Hg in the outpatient setting

11. Home mechanical ventilation (noninvasive ventilation or via tracheotomy) except for
CPAP/BIPAP used solely for sleep-disordered breathing

12. Diffuse alveolar hemorrhage from vasculitis

13. Burns > 40% total body surface

14. Interstitial lung disease of severity sufficient to require continuous home oxygen
therapy

15. Unwillingness or inability to utilize the ARDS network 6 ml/kg PBW ventilation
protocol

16. Cardiac disease classified as NYHA class IV

17. Myocardial infarction within past 6 months

18. Intraparenchymal Central Nervous System (CNS) bleed within a month of randomization.

19. Temperature >40.3 C in the 6 hours before randomization