Vascular ARDS Recruitment After Inhaled Nitric Oxide

Purpose

Acute respiratory distress syndrome (ARDS) is when a person's lungs become inflamed, which can be caused by infection, trauma, surgery, blood transfusion, or burn. ARDS often leads to a situation where the person cannot breathe independently and needs machines' help. Once the lungs are inflamed, the small air sacs responsible for exchanging gases (i.e., ventilation) and the blood flow in the lungs (i.e., perfusion) can be affected. In the past, most research focused on studying ventilation physiology and how to help people breathe with machines. Less was done on perfusion because it requires imaging techniques such as computed tomography with intravenous contrast and radiation. One treatment option for low oxygen levels is inhaled nitric oxide (iNO), a gas that can dilate the lung blood vessels and improve oxygenation; however, it is not always clear whether this treatment will work. Prone position has been used for several years in the care of ARDS patients and has been demonstrated to improve survival in more severe patients. It is not known how iNO and prone positioning interact in determining the distribution of pulmonary perfusion and whether their combine use can benefit ARDS patients. Electrical Impedance Tomography (EIT) is a bedside and accessible imaging technique that is radiation-free and non-invasive and can potentially detect changes in lung perfusion. EIT can perform multiple measurements; it is portable and accessible. This prospective interventional study aims to assess changes in regional blood perfusion in the lungs of patients with ARDS in response to iNO and to prone positioning utilizing EIT. The main questions it aims to answer are: 1. If EIT can measure lung regional perfusion response to an iNO challenge of 20ppm for 15 minutes. 2. If EIT can measure the lung regional perfusion responses to prone position, applied alone and in combination with iNO. 3. If EIT is comparable to dual-energy computed tomography (DECT), the gold-standard method, in the detection of changes in regional lung perfusion due to iNO. 4. If EIT can be an imaging marker to identify ARDS severity Participants will be divided into three cohorts: 1. Sub-Cohort 1 (n=60): Participants will be asked to be monitored by EIT before, during, and after the administration of iNO (20 ppm) for 15 minutes (OFF-ON-OFF) in the supine position 2. Sub-Cohort 2 (N=10): Participants will be asked to be monitored by EIT before and during the administration of iNO (20 ppm) for 15 minutes (OFF-ON) in both the supine and in the prone position. The same subjects will be monitored also with DECT in the supine position and then after 30 minutes in the prone position (without NO administration). 3. Sub-Cohort 3 (N=10): In this subset of Sub-Cohort 1, subjects will be asked to be monitored also with DECT (in addition to EIT) in the supine body position before iNO and after 15 minutes while receiving iNO.

Conditions

  • Acute Respiratory Distress Syndrome
  • Ventilation Perfusion Mismatch

Eligibility

Eligible Ages
Between 18 Years and 80 Years
Eligible Sex
All
Accepts Healthy Volunteers
No

Inclusion Criteria

  • Adult intubated and mechanically ventilated patients (≥ 18 years old) admitted to the intensive care unit (ICU) - ARDS diagnosis with mild to moderate severity by Berlin criteria1 (100 mmHg < PaO2/FiO2 <= 300 mmHg) - Presence of an arterial line for blood gas measurement and blood pressure monitoring and of a central line for hypertonic saline injection

Exclusion Criteria

  • Suspected pregnancy, pregnancy or less than six weeks postpartum - Younger than 18 years or older than 80 years - Baseline methemoglobin ≥ 5% - Subjects enrolled in another interventional research study - Presence of pneumothorax - Usage of any devices with electric current generation, such as a pacemaker or internal cardiac defibrillator - Preexisting chronic lung disease or pulmonary hypertension - Past medical history of lung malignancy or pneumonectomy, or lung transplant - Left ventricle ejection fraction <20% - Hemodynamic instability is defined as: - Persistent systolic blood pressure <90 mmHg and/or >180 mmHg despite the use of vasopressor or vasodilators, or - Requiring an increment in inotropic vasopressors over the past two hours just before enrollment: more than 15 mcg/min for norepinephrine and dopamine, more than 10 mcg/min in epinephrine, and more than 50 mcg/ min for phenylephrine. - Hypernatremia (serum sodium > 150 mEq/L) - Patients cannot be enrolled for DECT if they have: - History of allergic reaction to intravenous contrast - Renal dysfunction on the day of the study (serum creatinine > 1.5 mg/dL)

Study Design

Phase
N/A
Study Type
Interventional
Allocation
Non-Randomized
Intervention Model
Parallel Assignment
Intervention Model Description
In a prospective, single-center, physiological, crossover study, the investigators will recruit 70 adults meeting the ARDS criteria based on the Berlin definition who have not previously received inhaled vasodilators.
Primary Purpose
Diagnostic
Masking
None (Open Label)

Arm Groups

ArmDescriptionAssigned Intervention
Experimental
Electrical Impedance Tomography 		A total of 60 subjects (Sub-Cohort 1) will receive an inhaled nitric oxide (iNO) challenge (20 ppm) for 15 min. The investigators will measure ventilation and perfusion distributions using EIT before iNO ("OFF1"), after 15 min on iNO ("ON"), and after 15 min washout ("OFF2") to confirm baseline stability.
  • Device: Nitric Oxide
    20ppm for 15 minutes delivered by INO max(Nitric Oxide) Company : INO therapeutics, Inc.
    Other names:
    • inhaled nitric oxide (iNO)
Experimental
Electrical Impedance Tomography and Dual-Energy Computed Tomography in the Supine and Prone position 		In a subset of 10 subjects (Sub-Cohort 2), EIT will be performed without and with iNO (OFF-ON) both in the supine and in the prone position. The OFF-ON fashion for EIT imaging is to minimize the subject's exposure to hypertonic saline solution. Sub-cohort 2 patient will be imaged also with DECT in the supine and after 30 minutes in the prone position. iNO will not be administered during DECT.
  • Device: Nitric Oxide
    20ppm for 15 minutes delivered by INO max(Nitric Oxide) Company : INO therapeutics, Inc.
    Other names:
    • inhaled nitric oxide (iNO)
Experimental
Electrical Impedance Tomography with and without Inhaled Nitric Oxide in the Supine Position 		10 subjects (Sub-Cohort 3) from Sub-Cohort 1 will be monitored without iNO, with iNO, and without iNO (OFF-ON-OFF) in the supine position. Sub-Cohort 3 subjects will be imaged also with DECT. Imaging will be performed in the supine position without iNO and following iNO administration for 15 minutes (OFF-ON) .
  • Device: Nitric Oxide
    20ppm for 15 minutes delivered by INO max(Nitric Oxide) Company : INO therapeutics, Inc.
    Other names:
    • inhaled nitric oxide (iNO)

Recruiting Locations

Massachusetts General Hospital
Boston, Massachusetts 02114
Contact:
Maurizio Cereda
6177263030
MCEREDA@mgh.harvard.edu

More Details

Status
Recruiting
Sponsor
Massachusetts General Hospital

Study Contact

Maurizio F Cereda, MD
6177263030
mcereda@mgh.harvard.edu

Detailed Description

The investigators will screen patients with ARDS diagnosis daily at MGH intensive care units and work in the consenting process with the ICU team and surrogates. The enrollment period will be limited to the time subjects will undergo the study procedures. Subjects will exit the study as soon as the study procedures are completed. No further procedures are planned; therefore, subjects will not be asked to return to the hospital exclusively for research-related purposes. The enrolled subjects (n=70) will be divided into three sub-cohorts. Sub-Cohort 1 (n=60) will be monitored with EIT before, during, and after the administration of iNO (OFF-ON-OFF). Sub-Cohort 2 (n=10) will be monitored with EIT before and during the administration of iNO (OFF-ON) in the supine and in the prone position, and with DECT in the supine and in the prone position (without iNO). Sub-Cohort 3 (n=10) will be a subset of Cohort 1 and will be monitored with DECT before and during the administration of iNO, in addition to EIT monitoring before, during and after iNO administration (OFF-ON-OFF). Methods to answer question 1 (To measure the topographic perfusion response to an iNO challenge with EIT): - The EIT monitoring will be composed of ventilation and perfusion distributions. First, the ventilation is recorded; at this point, no additional maneuver is needed; the subjects need to wear the electrode belt connected to the device, and their ventilation will be recorded. Secondly, for the perfusion distribution, after a pause in the ventilation, EIT measures the distribution of blood perfusion in the lungs during the injection of a 10 mL bolus of 11.7% hypertonic saline solution through a central venous catheter. Cohort 1 (n=60) will receive 20ppm of iNO for 15 minutes. Cohort 1 will be monitored with EIT before, during, and after the iNO delivery in an OFF-ON-OFF fashion. Methods to answer question 2 (To measure the topographic perfusion response to prone position, applied alone and in combination with iNO): - Sub-Cohort 2 (n=10) will be monitored with EIT before and after 15 minutes receiving 20ppm iNO in an OFF-ON fashion, both in the supine and in the prone position. A second EIT measurement off iNO will not be obtained to minimize the total dose of hypertonic saline solution. The subjects will be transported to the computed tomography (CT) room, and DECT will be performed first in the supine position. A second DECT will be obtained after 30 minutes in the prone position. No iNO will be given during DECT. Methods to answer question 3 (To compare changes of regional lung perfusion due to iNO detected by EIT against the changes detected by gold standard DECT): - 10 subjects in Sub-Cohort 1 will receive DECT in addition to EIT monitoring in the supine position. DECT will be obtained before the iNO delivery. Then, the iNO delivery will start, and after 15 minutes, DECT will be repeated. Methods to answer question 4 (to define correlations between EIT-derived perfusion changes during an iNO challenge and clinical characteristics and outcomes. ): - The investigators will explore the vascular response measured by EIT from all 70 subjects and categorize subjects accordingly. The investigators plan to apply EIT patterns as an image marker and use them in conjunction with other markers (demographical, radiological, clinical, biochemical, and inflammatory) to identify ARDS severity. Finally, - Blood MetHb levels will be continuously monitored before, during, and after each iNO administration of the day. At the end of each iNO administration, MetHb will continue to be monitored until values return to the level recorded before the current treatment and - The NO, nitrogen dioxide (NO2) will be continuously monitored by INOmax DSIR (Mallinckrodt) deliver system.