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NCT Number: NCT05801224

Vascular ARDS Recruitment After Inhaled Nitric Oxide

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.

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Key information

Conditions

Acute Respiratory Distress Syndrome Lung Diseases Pathologic Processes Pathological Conditions, Signs and Symptoms Respiration Disorders Respiratory Aspiration Respiratory Distress Syndrome Respiratory Tract Diseases Ventilation Perfusion Mismatch

Age range

18 year–80 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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)

Treatment and study plan

Nitric oxide

Device

20ppm for 15 minutes delivered by INO max(Nitric Oxide) Company : INO therapeutics, Inc.

Other names: inhaled nitric oxide (iNO)

Primary outcomes

  1. Change in regional lung perfusion after the delivery of inhaled nitric oxide

    Time frame: Day 1

    The primary outcome is to detect changes in regional perfusion distribution with the administration of inhaled nitric oxide with electrical impedance tomography by measuring changes in impedance.

Secondary outcomes

  1. Compare methods to detect change in regional lung perfusion after the delivery of inhaled nitric oxide

    Time frame: Day 1

    The secondary outcome is to To compare electrical impedance tomography measurements against the gold standard dual-energy computed tomography (DECT)

Other outcomes

  1. Age

    Time frame: Day 1

    This exploratory outcome plans to utilize electrical impedance tomography as an image marker and combine them with other markers (demographical, radiological, clinical, biochemical, and inflammatory) to identify ARDS sub-phenotypes.

    Age (years)

  2. Gender

    Time frame: Day 1

    This exploratory outcome plans to utilize electrical impedance tomography as an image marker and combine them with other markers (demographical, radiological, clinical, biochemical, and inflammatory) to identify ARDS sub-phenotypes.

  3. Height

    Time frame: Day 1

    This exploratory outcome plans to utilize electrical impedance tomography as an image marker and combine them with other markers (demographical, radiological, clinical, biochemical, and inflammatory) to identify ARDS sub-phenotypes.

  4. Weight

    Time frame: Day 1

    This exploratory outcome plans to utilize electrical impedance tomography as an image marker and combine them with other markers (demographical, radiological, clinical, biochemical, and inflammatory) to identify ARDS sub-phenotypes.

  5. Race

    Time frame: Day 1

    This exploratory outcome plans to utilize electrical impedance tomography as an image marker and combine them with other markers (demographical, radiological, clinical, biochemical, and inflammatory) to identify ARDS sub-phenotypes.

  6. Ethnicity

    Time frame: Day 1

    This exploratory outcome plans to utilize electrical impedance tomography as an image marker and combine them with other markers (demographical, radiological, clinical, biochemical, and inflammatory) to identify ARDS sub-phenotypes.

  7. Comorbidities

    Time frame: Day 1

    Presence in the past medical history of conditions such as hypertension, diabetes,obesity, COPD, liver disease, and heart failure, among others.

    This exploratory outcome plans to utilize electrical impedance tomography as an image marker and combine them with other markers (demographical, radiological, clinical, biochemical, and inflammatory) to identify ARDS sub-phenotypes.

  8. Hours Elapsed since intubation

    Time frame: Day 1

    This exploratory outcome plans to utilize electrical impedance tomography as an image marker and combine them with other markers (demographical, radiological, clinical, biochemical, and inflammatory) to identify ARDS sub-phenotypes.

  9. Apache II score

    Time frame: Within 24 hours of intensive care admission

    This exploratory outcome plans to utilize electrical impedance tomography as an image marker and combine them with other markers (demographical, radiological, clinical, biochemical, and inflammatory) to identify ARDS sub-phenotypes.

  10. Intensive care unit survival at 28 days

    Time frame: Day 28

    This exploratory outcome plans to utilize electrical impedance tomography as an image marker and combine them with other markers (demographical, radiological, clinical, biochemical, and inflammatory) to identify ARDS sub-phenotypes.

  11. Hospital survival at 28 days

    Time frame: Day 28

    This exploratory outcome plans to utilize electrical impedance tomography as an image marker and combine them with other markers (demographical, radiological, clinical, biochemical, and inflammatory) to identify ARDS sub-phenotypes.

  12. Ventilation-free days

    Time frame: From day 1 to day 28

    This exploratory outcome plans to utilize electrical impedance tomography as an image marker and combine them with other markers (demographical, radiological, clinical, biochemical, and inflammatory) to identify ARDS sub-phenotypes.

  13. PaO2

    Time frame: Day 1, arterial blood gas samples will be taken at two time points: before and 1 hour after iNO. Subsequent days up to 28 days will be determined by the critical care staff

    The PaO2 will be measured with an arterial blood sample. This exploratory outcome plans to utilize electrical impedance tomography as an image marker and combine them with other markers (demographical, radiological, clinical, biochemical, and inflammatory) to identify ARDS sub-phenotypes.

  14. PaCO2

    Time frame: Day 1, arterial blood gas samples will be taken at two time points: before and 1 hour after iNO. Subsequent days up to 28 days will be determined by the critical care staff

    The PaCO2 will be measured with an arterial blood sample. This exploratory outcome plans to utilize electrical impedance tomography as an image marker and combine them with other markers (demographical, radiological, clinical, biochemical, and inflammatory) to identify ARDS sub-phenotypes.

  15. Ph

    Time frame: Day 1, arterial blood gas samples will be taken at two time points: before and 1 hour after iNO. Subsequent days up to 28 days will be determined by the critical care staff

    The Ph will be measured with an arterial blood sample. This exploratory outcome plans to utilize electrical impedance tomography as an image marker and combine them with other markers (demographical, radiological, clinical, biochemical, and inflammatory) to identify ARDS sub-phenotypes.

  16. Methemoglobin (MetHb)

    Time frame: Day 1, arterial blood gas samples will be taken at two time points: before and 1 hour after iNO. Subsequent days up to 28 days will be determined by the critical care staff

    The MetHb will be measured with an arterial blood sample. This exploratory outcome plans to utilize electrical impedance tomography as an image marker and combine them with other markers (demographical, radiological, clinical, biochemical, and inflammatory) to identify ARDS sub-phenotypes.

  17. HCO3 (bicarbonate)

    Time frame: Day 1, arterial blood gas samples will be taken at two time points: before and 1 hour after iNO. Subsequent days up to 28 days will be determined by the critical care staff

    The HCO3 will be measured with an arterial blood sample. This exploratory outcome plans to utilize electrical impedance tomography as an image marker and combine them with other markers (demographical, radiological, clinical, biochemical, and inflammatory) to identify ARDS sub-phenotypes.

  18. Tidal Volume

    Time frame: From day 1 to day 28

    Ventilator Parameter. This exploratory outcome plans to utilize electrical impedance tomography as an image marker and combine them with other markers (demographical, radiological, clinical, biochemical, and inflammatory) to identify ARDS sub-phenotypes.

  19. Plateau, peak and positive end-expiratory pressures

    Time frame: From day 1 to day 28

    Ventilator Parameters are measured during tidal ventilation, inspiratory and expiratory holds.

    This exploratory outcome plans to utilize electrical impedance tomography as an image marker and combine them with other markers (demographical, radiological, clinical, biochemical, and inflammatory) to identify ARDS sub-phenotypes.

  20. Respiratory rate

    Time frame: From day 1 to day 28

    Ventilator Parameters are measured during tidal ventilation, inspiratory and expiratory holds.

    This exploratory outcome plans to utilize electrical impedance tomography as an image marker and combine them with other markers (demographical, radiological, clinical, biochemical, and inflammatory) to identify ARDS sub-phenotypes.

  21. Flow

    Time frame: From day 1 to day 28

    Ventilator Parameters are measured during tidal ventilation, inspiratory and expiratory holds.

    This exploratory outcome plans to utilize electrical impedance tomography as an image marker and combine them with other markers (demographical, radiological, clinical, biochemical, and inflammatory) to identify ARDS sub-phenotypes.

  22. Vasopressors requirements (dopamine, dobutamine, epinephrine, levosimendan, milrinone, vasopressin, norepinephrine)

    Time frame: From day 1 to day 28

    We will calculate the Vasoactive-inotropic score (VIS). The VIS compares different vasoactive-inotropic drugs and doses among the patients.

    VIS = dopamine dose (mg/kg/min)+ dobutamine [mg/kg/min) +100 x epinephrine dose (mg/ kg/min) +50 x levosimendan dose [mg/kg/min) + 10 x milrinone dose [mg/kg/min)+ 10,000 x vasopressin [units/kg/min) + 100x norepinephrine dose [mg/kg/min) using the maximum dosing rates of vasoactive and inotropic medications.

    Ref: Koponen et al. British Journal of Anaesthesia, 122 (4): 428e436 (2019).

    This exploratory outcome plans to utilize electrical impedance tomography as an image marker and combine them with other markers (demographical, radiological, clinical, biochemical, and inflammatory) to identify ARDS sub-phenotypes.

  23. Arterial blood pressure, central venous pressure, pulmonary artery pressure

    Time frame: From day 1 to day 28

    Hemodynamic parameters. The pulmonary artery pressure will be measured if the subject have a pulmonary artery pressure placed by the ICU staff with clinical purposes.

    This exploratory outcome plans to utilize electrical impedance tomography as an image marker and combine them with other markers (demographical, radiological, clinical, biochemical, and inflammatory) to identify ARDS sub-phenotypes.

  24. Life sustaining therapies

    Time frame: From day 1 to day 28

    Other life-sustaining therapies than mechanical ventilation and vasopressors administration: Antibiotics, Renal replacement therapy (RRT), extracorporeal membrane oxygenation (ECMO), chemotherapy, and artificial nutrition.

    This exploratory outcome plans to utilize electrical impedance tomography as an image marker and combine them with other markers (demographical, radiological, clinical, biochemical, and inflammatory) to identify ARDS sub-phenotypes.

  25. CRP, MCP-1, TNF-alpha, IL-6, IL-8, IL-10, Ang-2, VEGF

    Time frame: From day 1 to day 28

    Blood samples will be collected and Systemic markers of inflammation and plasma cytokines: CRP, MCP-1, TNF-alpha, IL-6, IL-8, IL-10, Ang-2, VEGF will be measured.

    This exploratory outcome plans to utilize electrical impedance tomography as an image marker and combine them with other markers (demographical, radiological, clinical, biochemical, and inflammatory) to identify ARDS sub-phenotypes.

Study contacts

Contact information is provided by the study sponsor or research team.

Maurizio F Cereda, MD

CONTACT

[email protected]

6177263030

Roberta Ribeiro De Santis Santiago, MD, PhD

CONTACT

[email protected]

6176437733

Sponsors and collaborators

Lead sponsor

Massachusetts General Hospital

Other

Registry information

Official study title

Regional Vascular Recruitment With Inhaled Nitric Oxide in Patients With ARDS

Important dates

Study start
2026
Primary completion
2028
Study completion
2028
First posted
Apr 6, 2023
Registry last updated
Aug 18, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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