Critical Illness, Pneumonia
Conditions
Keywords
High dose inhaled nitric oxide, Pneumonia, Critical care, Methemoglobin
Brief summary
The goal of this clinical trial is to learn the formation and recovery rate of methemoglobin (MetHb) in severely sick patients with pneumonia who receive high doses of inhaled nitric oxide (iNO) therapy at 250 parts per million (ppm), not exceeding 300 ppm. Meanwhile, the benefits of the therapy to treat severely sick patients with pneumonia will be explored. Patients who are 18 years or older, newly diagnosed with pneumonia, and severely sick with requirement of a breathing machine could be included. The main questions it aims to answer are: How does methemoglobin change through the iNO treatment? Does iNO therapy increase the number of patients recovering from pneumonia? Researchers will compare iNO treatment to placebo, which means using the same device as the treatment group without delivering the study drug. Participants will: * Receive iNO treatment starting at 250 ppm, not exceeding 300 ppm, 40 min, every 6 hours, from day 1 to day 5 * Be followed up for 60 days
Detailed description
This study is designed as a pilot, double-blinded, randomized controlled trial to investigate levels of methemoglobin in the treatment group versus the control group and efficacy of high dose inhaled NO among critically ill patients with pneumonia. We will enroll 34 adult patients with newly diagnosed pneumonia and invasive mechanical ventilation who are admitted to the ICUs at Massachusetts General Hospital. After enrollment, participants will be randomized in 1:1 ratio to intervention group or control group. Baseline characteristics will be collected. During treatment period, patients allocated to the intervention group will receive high dose inhaled NO starting at 250 ppm (not exceeding 300 ppm), 40min, 4 times daily, for 5 days. The control group will receive sham intervention. Both groups will receive standard therapy. During follow-up period, we will follow participants for a total duration of 60 days. Methemoglobin kinetic levels and efficacy outcomes will be collected.
Interventions
DRUGHigh dose inhaled nitric oxide
Inhaled nitric oxide starting at 250-300 ppm, 40min, every 6 hours, from day 1 to day 5. Nitric oxide is delivered using a gas cylinder containing nitric oxide and nitrogen.
OTHERSham treatment
Sham intervention with the nitric oxide gas cylinder replaced by that containing only nitrogen and all other delivery procedures identical to the intervention group
OTHERstandard therapy
Standard therapy pneumonia and critical illness
Sponsors
Massachusetts General Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 18 years or older * Intubated and mechanically ventilated * Within 72h of diagnosis of community- or hospital-acquired pneumonia * Written informed consent obtained from patients or legally authorized representatives
Exclusion criteria
* Baseline methemoglobin 3% or higher * Genetic diseases including glucose-6-phosphate dehydrogenase deficiency, cytochrome b5 reductase deficiency, sickle cell disease * Oxygen saturation \< 88% on 100% inspired fraction of oxygen * Anemia with hemoglobin \< 7.0 g/dl * Acute cardiogenic shock requiring inotropic or mechanical support with an ejection fraction less than 20% * Receiving inhaled NO therapy or decision to initiate inhaled NO therapy within 24 hours post randomization * A decision to do-not-resuscitate (DNR) * Enrollment in another experimental antimicrobial treatment protocol * Patients for whom follow-up is expected to be impossible
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Peaks of methomoglobin | From Day 1 to Day 5 | Continuous recording of MetHb and peaks of MetHb will be determined. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Nitrogen dioxide level | From Day 1 to Day 5 | Continuous measurement of nitrogen dioxide concentration in the inspiratory limb of breathing circuit |
| Feasibility | From enrollment to Day 60 | Referral, recruitment, retention, compliance and follow-up completion rates of the study |
| Clinical cure rate of pneumonia | From enrollment to test of cure day (4 -11 days post end of treatment) | Clinical cure is assessed at test of cure (4 -11 days post end of treatment) and defined as resolution of clinical signs and symptoms of pneumonia compared with baseline, including a reduction in SOFA and CPIS scores, improvement or lack of progression in chest imaging, and no requirement for additional antibacterial treatment. |
| Clinical improvement rate of pneumonia | Day 5 | Clinical improvement is assessed at end of treatment and defined as improvement in 2 or more clinical signs and symptoms of pneumonia compared with baseline, improvement or lack of progression of chest x-ray abnormalities, and no requirement for additional antibacterial treatment. Clinical signs and symptoms of pneumonia include new onset or worsening cough, purulent sputum or increased suction requirements, auscultation findings of pneumonia, dyspnea, tachypnea, or respiratory rate ≥ 30/min, hypoxemia, worsening gas exchange. |
| Microbiologic eradication rate | From enrollment to test of cure day (4 -11 days post end of treatment) | Absence of the baseline pathogen from tracheal aspiration or bronchoalveolar lavage fluid will be confirmed. If it is not possible to obtain an appropriate clinical specimen for culture and the patient has a successful clinical outcome, the response was presumed to be eradication. |
| 28-day all cause mortality | From enrollment to Day 28 | All cause mortality from enrollment to Day 28 |
| 60-day all cause mortality | From enrollment to Day 60 | All cause mortality from enrollment to Day 60 |
| 28-day ventilator free days | From enrollment to Day 28 | Successful liberation from mechanical ventilation should last more than 48 h without re-intubation in patients who have survived 28 days after randomization (extubation was counted from the last successful attempt in patients who have survived 28 days since randomization) and for patients ventilated for 28 days or more or who died before 28 days (irrespective of intubation status), the number of ventilator-free days was recorded at zero. |
| Days free from organ support in 28 days | From enrollment to Day 28 | Organ support includes mechanical ventilation, vasopressors and renal replacement therapy. |
| Blood stream infection | From enrollment to Day 28 | Positive blood culture with a pathogenic bacterium |
| Days free from antibiotics during hospitalization | From enrollment to the day of hospital discharge or death, whichever comes earlier, assessed up to 60 days | Days free from antibiotics during hospitalization |
| Acquisition of multidrug-resistant (MDR) infection or colonization | From enrollment to Day 28 | Multidrug-resistant infection is defined as pathogen acquiring non-susceptibility to at least one agent in three or more antibiotic categories |
| Hospital stay | From enrollment to the day of hospital discharge or death, whichever comes earlier, assessed up to 60 days | Days from enrollment to the end of hospitalization |
| ICU length of stay | From enrollment to the day of ICU discharge or death, whichever comes earlier, assessed up to 60 days | ICU length of stay |
| Inflammatory markers | From enrollment to test of cure (4-11 days post end of treatment) | The test includes C reactive protein (CRP), procalcitonin (PCT), monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor α (TNF α), interleukin 6 (IL-6), interleukin 8 (IL-8), interleukin 10 (IL-10). |
| Relapse rate | From enrollment to Day 28 | Relapse is assessed for patients with hospital-acquired pneumonia at 28-day follow-up after test of cure and defined as recurrence or new appearance of at least two of the three symptoms and signs (fever greater than 38 °C, leukocytosis or leukopenia, and purulent tracheobronchial secretions), along with a new or persistent infiltrate on chest radiography in a patient assessed as clinical cure at TOC. |
Countries
United States
Contacts
CONTACTLorenzo Berra, MD
CONTACTRun Dong, MD
PRINCIPAL_INVESTIGATORLorenzo Berra, MD
Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital
Outcome results
None listed