Acute Lung Injury, Sepsis
Conditions
Keywords
ALI, Sepsis, statin
Brief summary
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.
Detailed 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.
Interventions
DRUGRosuvastatin
Subjects received an initial 40mg loading dose followed by 20 mg of study drug daily by mouth or feeding tube for 28 days or until discharged from the study hospital.
DRUGPlacebo
Subjects received placebo by mouth or feeding tube daily for 28 days or until discharged from study hospital.
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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 \>38 degrees Celsius (C) (any route) or \<36 degrees C (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 * 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Hospital Mortality to Day 60. | 60 days after randomization | The percentage of subjects alive at study day 60. Those subjects discharged home prior to day 60 were counted as alive at day 60. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Ventilator Free Days at Study Day 28 | time of initiating unassisted breathing to day 28 after study randomization | Ventilator Free Days (VFDs) to day 28 were defined as the number of days from the time of initiating unassisted breathing to day 28 after randomization, assuming survival for at least two consecutive calendar days after initiating unassisted breathing and continued unassisted breathing to day 28. If a subject received assisted breathing at day 27 or died prior to day 28, a value of zero VFDs was given. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Organ Failure Free Days at Day 14 | 14 days after randomization | The number of days from randomization to day 14 without an organ failure. Four main organ systems were measured: cardiovascular, coagulation, hepatic function, and renal function. |
| ICU Free Days to Day 28 | 28 days after randomization | — |
| Other Secondary Out-comes | 28 days after randomization | Percentage of subjects with Arrhythmia's, Bowel Ischemia, Myocardial Infarction, Ischemic Stroke, and Thromboembolism were measured. |
| Changes in Plasma Concentrations of C-reactive Protein (CRP) From Baseline to Day 6 and Day 14 | 6 and 14 days after randomization | CRP levels were collected on subjects at baseline and on-study. The change in concentration from baseline levels to levels on study days 6 and 14 was analyzed. Those subjects that were still alive and on study at day 6 and 14 with a measured CRP level were included in the analysis. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Rosuvastatin Half of the subjects will receive the active drug, Rosuvastatin.
Rosuvastatin: Patients will receive 20 mg of study drug daily by mouth or feeding tube for 28 days or until discharged from the study hospital. | 379 |
| Placebo Half of the patients will be randomized to the placebo.
Placebo: Patients will receive one placebo by mouth or feeding tube daily for 28 days or until discharged form study hospital. | 366 |
| Total | 745 |
Baseline characteristics
| Characteristic | Total | Rosuvastatin | Placebo |
|---|---|---|---|
| Age, Categorical <=18 years | 5 Participants | 3 Participants | 2 Participants |
| Age, Categorical >=65 years | 206 Participants | 114 Participants | 92 Participants |
| Age, Categorical Between 18 and 65 years | 534 Participants | 262 Participants | 272 Participants |
| Age, Continuous | 54.1 years STANDARD_DEVIATION 16.3 | 54.2 years STANDARD_DEVIATION 17.1 | 54.1 years STANDARD_DEVIATION 15.6 |
| APACHE III Score | 93.4 units on a scale STANDARD_DEVIATION 28.2 | 92.1 units on a scale STANDARD_DEVIATION 28.4 | 94.8 units on a scale STANDARD_DEVIATION 27.9 |
| Baseline Shock | 339 participants | 173 participants | 166 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 86 Participants | 46 Participants | 40 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 659 Participants | 333 Participants | 326 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Hours from intubation to randomization 24 hours or less | 253 participants | 124 participants | 129 participants |
| Hours from intubation to randomization between 24 and 48 hours | 396 participants | 204 participants | 192 participants |
| Hours from intubation to randomization between 48 and 72 hours | 72 participants | 41 participants | 31 participants |
| Hours from intubation to randomization more than 72 hours | 23 participants | 10 participants | 13 participants |
| Hours from intubation to randomization Unknown | 1 participants | 0 participants | 1 participants |
| PaFiO2:FiO2 ratio less than or equal to 200 mm Hg | 520 participants | 267 participants | 253 participants |
| Primary cause of lung injury Aspiration | 49 participants | 26 participants | 23 participants |
| Primary cause of lung injury Multiple Transfusion | 4 participants | 3 participants | 1 participants |
| Primary cause of lung injury Other | 11 participants | 7 participants | 4 participants |
| Primary cause of lung injury Pneumonia | 527 participants | 267 participants | 260 participants |
| Primary cause of lung injury Sepsis | 145 participants | 72 participants | 73 participants |
| Primary cause of lung injury Trauma | 6 participants | 2 participants | 4 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 6 participants | 1 participants | 5 participants |
| Race (NIH/OMB) Asian | 16 participants | 9 participants | 7 participants |
| Race (NIH/OMB) Black or African American | 105 participants | 52 participants | 53 participants |
| Race (NIH/OMB) More than one race | NA participants | NA participants | NA participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 5 participants | 2 participants | 3 participants |
| Race (NIH/OMB) Unknown or Not Reported | 24 participants | 14 participants | 10 participants |
| Race (NIH/OMB) White | 590 participants | 289 participants | 301 participants |
| Region of Enrollment United States | 745 participants | 379 participants | 366 participants |
| Sex: Female, Male Female | 380 Participants | 195 Participants | 185 Participants |
| Sex: Female, Male Male | 365 Participants | 184 Participants | 181 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 379 | 0 / 366 |
| serious Total, serious adverse events | 34 / 379 | 32 / 366 |
Outcome results
Primary
Hospital Mortality to Day 60.
The percentage of subjects alive at study day 60. Those subjects discharged home prior to day 60 were counted as alive at day 60.
Time frame: 60 days after randomization
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rosuvastatin | Hospital Mortality to Day 60. | 28.5 percentage of participants |
| Placebo | Hospital Mortality to Day 60. | 24.9 percentage of participants |
Comparison: Hospital mortality to day 60 was estimated using the Kaplan Meier estimate, with patients discharged home before day 60 considered alive at day 60. The analysis was stratified by co-enrolled treatment assignments for 81 patients also enrolled in a randomized clinical trial of two different nutritional strategies. A maximum of 1000 patients were to be enrolled, providing a 92% probability of rejecting the null hypothesis for the effect on mortality if a true difference in mortality was 9%.p-value: 0.2195% CI: [-2.3, 10.2]Proc lifetest
Secondary
Ventilator Free Days at Study Day 28
Ventilator Free Days (VFDs) to day 28 were defined as the number of days from the time of initiating unassisted breathing to day 28 after randomization, assuming survival for at least two consecutive calendar days after initiating unassisted breathing and continued unassisted breathing to day 28. If a subject received assisted breathing at day 27 or died prior to day 28, a value of zero VFDs was given.
Time frame: time of initiating unassisted breathing to day 28 after study randomization
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rosuvastatin | Ventilator Free Days at Study Day 28 | 15.1 days | Standard Deviation 10.8 |
| Placebo | Ventilator Free Days at Study Day 28 | 15.1 days | Standard Deviation 11 |
Comparison: Ventilator, ICU free, and organ failure free days were analyzed by analysis of variance, utilizing treatment assignment where applicable.p-value: 0.9695% CI: [-1.6, 1.5]ANCOVA
Other Pre-specified
Changes in Plasma Concentrations of C-reactive Protein (CRP) From Baseline to Day 6 and Day 14
CRP levels were collected on subjects at baseline and on-study. The change in concentration from baseline levels to levels on study days 6 and 14 was analyzed. Those subjects that were still alive and on study at day 6 and 14 with a measured CRP level were included in the analysis.
Time frame: 6 and 14 days after randomization
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rosuvastatin | Changes in Plasma Concentrations of C-reactive Protein (CRP) From Baseline to Day 6 and Day 14 | Day 6 | -12.9 mg/dL | Standard Deviation 27.79 |
| Rosuvastatin | Changes in Plasma Concentrations of C-reactive Protein (CRP) From Baseline to Day 6 and Day 14 | Day 14 | -19.8 mg/dL | Standard Deviation 31.23 |
| Placebo | Changes in Plasma Concentrations of C-reactive Protein (CRP) From Baseline to Day 6 and Day 14 | Day 6 | -15.1 mg/dL | Standard Deviation 23.26 |
| Placebo | Changes in Plasma Concentrations of C-reactive Protein (CRP) From Baseline to Day 6 and Day 14 | Day 14 | -14.8 mg/dL | Standard Deviation 26.28 |
Other Pre-specified
ICU Free Days to Day 28
Time frame: 28 days after randomization
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rosuvastatin | ICU Free Days to Day 28 | 14.3 days | Standard Deviation 10.1 |
| Placebo | ICU Free Days to Day 28 | 14.4 days | Standard Deviation 10.3 |
Other Pre-specified
Organ Failure Free Days at Day 14
The number of days from randomization to day 14 without an organ failure. Four main organ systems were measured: cardiovascular, coagulation, hepatic function, and renal function.
Time frame: 14 days after randomization
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rosuvastatin | Organ Failure Free Days at Day 14 | Cardiovascular | 8.5 days | Standard Deviation 4.8 |
| Rosuvastatin | Organ Failure Free Days at Day 14 | Coagulation | 10.7 days | Standard Deviation 5.1 |
| Rosuvastatin | Organ Failure Free Days at Day 14 | Hepatic | 10.8 days | Standard Deviation 5 |
| Rosuvastatin | Organ Failure Free Days at Day 14 | Renal | 10.1 days | Standard Deviation 5.3 |
| Placebo | Organ Failure Free Days at Day 14 | Renal | 11.0 days | Standard Deviation 4.7 |
| Placebo | Organ Failure Free Days at Day 14 | Cardiovascular | 8.7 days | Standard Deviation 4.9 |
| Placebo | Organ Failure Free Days at Day 14 | Hepatic | 11.8 days | Standard Deviation 4.3 |
| Placebo | Organ Failure Free Days at Day 14 | Coagulation | 11.1 days | Standard Deviation 4.8 |
Other Pre-specified
Other Secondary Out-comes
Percentage of subjects with Arrhythmia's, Bowel Ischemia, Myocardial Infarction, Ischemic Stroke, and Thromboembolism were measured.
Time frame: 28 days after randomization
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Rosuvastatin | Other Secondary Out-comes | Arrhythmias | 9.0 percentage of participants |
| Rosuvastatin | Other Secondary Out-comes | Bowel Ischemia | 1.4 percentage of participants |
| Rosuvastatin | Other Secondary Out-comes | Myocardial Infarction | 0.5 percentage of participants |
| Rosuvastatin | Other Secondary Out-comes | Thromboembolism | 6.3 percentage of participants |
| Rosuvastatin | Other Secondary Out-comes | Ischemic Stroke | 0.3 percentage of participants |
| Placebo | Other Secondary Out-comes | Myocardial Infarction | 0.6 percentage of participants |
| Placebo | Other Secondary Out-comes | Arrhythmias | 8.4 percentage of participants |
| Placebo | Other Secondary Out-comes | Ischemic Stroke | 0.3 percentage of participants |
| Placebo | Other Secondary Out-comes | Bowel Ischemia | 1.9 percentage of participants |
| Placebo | Other Secondary Out-comes | Thromboembolism | 6.9 percentage of participants |