Statins for Acutely Injured Lungs From Sepsis (SAILS)

National Institutes of Health (NIH)

Status and phase: Terminated; Phase 3

Conditions: Acute Lung Injury; Sepsis

Treatments: Drug: Placebo; Drug: Rosuvastatin

Study type: Interventional

Funder types: NIH

Identifiers

NCT00979121

670

N01HR056179 (Other Grant/Funding Number)

Details and patient eligibility

About

Objective: assess the efficacy and safety of oral rosuvastatin in patients with sepsis-induced Acute Lung Injury (ALI).

Hypothesis: Rosuvastatin therapy will improve mortality in patients with sepsis-induced ALI.

Full description

Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (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 was administered through an enteral feeding tube or administered orally following extubation when patients were 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 was determined by the patient's primary team. Study drug was blinded with an identical appearing placebo. The first study drug dose (rosuvastatin or placebo) was administered within 4 hours of randomization as a loading dose of 40 mg.

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

Enrollment: 745 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

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

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

  3. Body temperature >38 degrees Celsius (C) (any route) or <36 degrees C (accepting core temperatures only; indwelling catheter, esophageal, rectal)

  4. 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:
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  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
   • Creatine Kinase (CK) , alanine aminotransferase (ALT) or aspartate aminotransferase (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 (Continuous Positive Airway Pressure/BiLevel Positive Airway Pressure) 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 Predicted Body Weight (PBW) ventilation protocol

16. Cardiac disease classified as NYHA (New York Heart Association) 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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Triple Blind

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745 participants in 2 patient groups, including a placebo group

Rosuvastatin

Active Comparator group

Description:

Half of the subjects were randomized to the active drug (Rosuvastatin). Dosage, Form, and Frequency: drug was provided as 10mg tablets and administered through an enteral feeding tube or orally (following extubation when patients were able to safely take oral medications). An initial 40mg loading dose was administered followed by a daily 20 mg maintenance dose. Maintenance dosing was adjusted for renal failure not compensated by renal replacement therapy. Duration: drug was administered daily until: 1. 28 days after randomization or 3 days after ICU discharge (whichever comes first), 2. Discharge from study hospital, 3. Death

Treatment:

Drug: Rosuvastatin

Placebo

Placebo Comparator group

Description:

Half of the subjects were randomized to placebo. 10mg tablets identical to active drug were administered through an enteral feeding tube or orally (following extubation when patients were able to safely take oral medications). Dosage, frequency, and duration was provided in the same manner as the active drug.

Treatment:

Drug: Placebo