Inhaled Nitric Oxide in Severe Obesity

The Effect of Inhaled Nitric Oxide on Intrapulmonary Shunt in Acutely Hypoxemic Patients With Severe Obesity

The goal of this clinical trial is to learn about the effects of inhaled nitric oxide on oxygenation and lung perfusion in participants with severe obesity who have acute hypoxemic respiratory failure and are on mechanical ventilation

The main questions it aims to answer are:

1. In acute hypoxemic respiratory failure, what are the effects of inhaled nitric oxide on oxygenation in participants with severe obesity compared to participants with normal body weight.
2. In acute hypoxemic respiratory failure, what are the effects of inhaled nitric oxide on lung perfusion and heart function in participants with severe obesity compared to participants with normal body weight.
3. In acute hypoxemic respiratory failure, does severe obesity impact nitric oxide signaling pathways?

Participants with acute hypoxemic respiratory failure will be exposed to inhaled nitric oxide (20 ppm) while being clinically monitored.

Study Overview

• Status: Not yet recruiting
• Conditions: Obesity; Respiratory Insufficiency; Nitric Oxide; Hypoxemic Respiratory Failure
• Intervention / Treatment: Device: Nitric oxide

Detailed Description

The study is a single-center, open-label clinical trial in mechanically ventilated participants with acute hypoxemic respiratory failure. The primary aim is to assess changes in intrapulmonary shunt (primary study outcome) to inhaled nitric oxide in participants with severe obesity and those with normal body weight. The secondary aims are to determine differences in regional lung perfusion (measured by electrical impedance tomography), right ventricular pressure (measured by transthoracic echocardiography), and biomarkers of nitric oxide signaling dysfunction (nitric oxide activity, pro-inflammatory cytokines, endothelial glycocalyx fragments)

The primary study intervention involves inhaled nitric oxide at 20 ppm for 15 minutes. The investigators will compare inhaled nitric oxide response in participants with severe obesity (defined by body mass index greater than or equal to 40) to participants with normal body weight (defined by body mass index 18.5-24.9). 40 participants with acute hypoxemic respiratory failure will be enrolled (20 with severe obesity and 20 with normal body weight). The investigators will enroll a separate cohort of mechanically ventilated participants who do not have acute hypoxemic respiratory failure (10 with severe obesity and 10 with normal body weight). In this cohort, investigators will collect additional blood at a single time point to compare levels of nitric oxide signaling pathways between patients with and without acute hypoxemia across body weight.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Timothy Gaulton, MD, Msc; Phone Number: 6177263030; Email: tgaulton@mgh.harvard.edu
• Study Contact Backup: Name: Maurizio Cereda, MD; Phone Number: 6177263030; Email: mcereda@mgh.harvard.edu

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
      • Contact: Timothy Gaulton, MD, Msc; Phone Number: 6177263030; Email: tgaulton@mgh.harvard.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

For participants with acute hypoxemic respiratory failure

Inclusion Criteria:

• Acute hypoxemic respiratory failure, defined as persistent hypoxemia (PaO2/FiO2 ≤ 300 mmHg or SpO2/FiO2 ≤ 315) and on invasive mechanical ventilation for < 72 hours
• Presence of an arterial and central venous catheter (for blood gas measurement)
• Admitted to a participating MGH ICU

Exclusion Criteria:

• Age < 18 years
• Pregnancy or known active breastfeeding
• Prisoner or Incarceration
• Inability or unwillingness of subject or legal surrogate/representative to give written informed consent
• Use of inhaled or oral pulmonary vasodilatory therapy within the 24 hours preceding study enrollment

• Contraindication to inhaled NO

  • Baseline Methemoglobin ≥ 3%
  • Known left ventricle ejection fraction < 20%
  • Known history of G6PD deficiency or cytochrome issues
  • Prior adverse reaction to inhaled nitric oxide
• Presence of pneumothorax or acute pulmonary embolism
• Chronic hypoxemia requiring home supplemental non-invasive oxygen (nasal cannula or positive pressure ventilation) or home mechanical ventilation
• Chronic pulmonary vascular disease on home chemical vasodilator support (e.g., sildenafil)
• History of lung resection or transplant

• Hemodynamic instability at the time of potential study enrollment defined as:

  • Persistent systolic blood pressure < 90 mmHg 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.

EIT assessments of lung perfusion will only be performed in participants who are already receiving neuromuscular blocking agents (e.g., cisatracurium) at the time of study enrollment. EIT assessments of lung perfusion will not be performed in participants who have the following contraindications to EIT perfusion monitoring:

• Hypernatremia (serum sodium > 150 mEq/L)
• Usage of any devices with electric current generation such as pacemaker or internal cardiac defibrillator

For controls without acute hypoxemic respiratory failure

Inclusion Criteria:

• Receiving invasive mechanical ventilation and do not have a diagnosis of acute hypoxemic respiratory failure (PaO2/FiO2 > 300 mmHg or SpO2/FiO2> 315)
• Presence of an arterial catheter
• Admitted to a participating MGH ICU

Exclusion Criteria:

• Age < 18 years
• Pregnancy or known active breastfeeding
• Prisoner or Incarceration
• Inability or unwillingness of subject or legal surrogate/representative to give written informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Acute hypoxemic respiratory failure; Participants (n = 40) with acute hypoxemic respiratory failure will receive inhaled nitric oxide (20 ppm) for 15 min.	Device: Nitric oxide; 20ppm for 15 minutes delivered by INO max(Nitric Oxide) Company : INO therapeutics, Inc.
No Intervention: Participants without acute hypoxemic respiratory failure; Participants (n = 20) without acute hypoxemic respiratory failure will not receive inhaled nitric oxide

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intrapulmonary shunt	Intrapulmonary shunt will be defined as the difference in intrapulmonary shunt (%) to inhaled nitric oxide. Intrapulmonary shunt will be defined using the modified Berggren equation based on central venous and arterial oxygen concentrations from a central venous and peripheral arterial catheter.	Intrapulmonary shunt will be assessed before inhaled nitric oxide, at 15 minutes after inhaled nitric oxide, and at 15 minutes after inhaled nitric oxide discontinuation.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Gas exchange	Measures of gas exchange be defined by Pa02/Fi02 and dead space fraction in response to inhaled nitric oxide	Gas exchange will be assessed before inhaled nitric oxide, at 15 minutes after inhaled nitric oxide, and at 15 minutes after inhaled nitric oxide discontinuation.
Regional pulmonary perfusion	In participants who are already receiving neuromuscular blocking agents, regional pulmonary perfusion will be measured and defined as the % change to inhaled nitric oxide in 4 lung regions of interest (right upper, right lower, left upper, left lower)	Regional pulmonary perfusion will be assessed before inhaled nitric oxide, at 15 minutes after inhaled nitric oxide, and at 15 minutes after inhaled nitric oxide discontinuation.
Right ventricular systolic pressure	The investigators will measure right ventricular systolic pressure, an ultrasound surrogate of pulmonary arterial pressure, in response to inhaled nitric oxide	Right ventricular systolic pressure will be assessed before inhaled nitric oxide, at 15 minutes after inhaled nitric oxide, and at 15 minutes after inhaled nitric oxide discontinuation.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Nitric oxide activity	Nitric oxide activity will be measured by nitrate, nitrite, nitrosyl-hemoglobin using chemiluminescence in response to inhaled nitric oxide	Nitric oxide activity will be assessed before inhaled nitric oxide, at 15 minutes after inhaled nitric oxide, and at 15 minutes after inhaled nitric oxide discontinuation. Nitric oxide activity will be measured in control participants (single timepoint).
Nitric oxide signaling pathways	The investigators will measure pro-inflammatory cytokines (INF-α, IL-6, IL-8, IL-10, IL-1β, TNF-α, MCP-1) using multiplex enzyme-linked immunosorbent assays and endothelial glycocalyx fragments (heparan sulfate, chondroitin sulfate, hyaluronic acid) using Liquid Chromatography (UPLC)-tandem mass spectrometry.	Biomarkers will be measured after enrollment in participants with and without acute hypoxemic respiratory failure (single time point)

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital

Publications and helpful links

General Publications

• Borges JB, Suarez-Sipmann F, Bohm SH, Tusman G, Melo A, Maripuu E, Sandstrom M, Park M, Costa EL, Hedenstierna G, Amato M. Regional lung perfusion estimated by electrical impedance tomography in a piglet model of lung collapse. J Appl Physiol (1985). 2012 Jan;112(1):225-36. doi: 10.1152/japplphysiol.01090.2010. Epub 2011 Sep 29.
• Spina S, Marrazzo F, Morais CCA, Victor M, Forlini C, Guarnieri M, Bastia L, Giudici R, Bassi G, Xin Y, Cereda M, Amato M, Langer T, Berra L, Fumagalli R. Modulation of pulmonary blood flow in patients with acute respiratory failure. Nitric Oxide. 2023 Jul 1;136-137:1-7. doi: 10.1016/j.niox.2023.05.001. Epub 2023 May 10.

Study record dates

Study Major Dates

• Study Start (Estimated): October 1, 2026
• Primary Completion (Estimated): October 1, 2028
• Study Completion (Estimated): December 1, 2028

Study Registration Dates

• First Submitted: November 4, 2024
• First Submitted That Met QC Criteria: November 4, 2024
• First Posted (Actual): November 5, 2024

Study Record Updates

• Last Update Posted (Actual): May 20, 2026
• Last Update Submitted That Met QC Criteria: May 19, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: inhaled nitric oxide; acute hypoxemic respiratory failure; severe obesity; intrapulmonary shunt
• Additional Relevant MeSH Terms: Nutrition Disorders; Overnutrition; Body Weight; Respiratory Tract Diseases; Respiration Disorders; Overweight; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Signs and Symptoms; Obesity; Respiratory Insufficiency; Obesity, Morbid; Diagnostic Techniques and Procedures; Diagnosis; Breath Tests; Fractional Exhaled Nitric Oxide Testing
• Other Study ID Numbers: 2024p003089

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: IPD will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a Data Use Agreement (DUA). For more information or to submit a request, please contact the study investigators
• IPD Sharing Time Frame: Data requests can be submitted starting 9 months after article publication and the data will be made accessible for up to 24 months. Extensions will be considered on a case-by-case basis.
• IPD Sharing Access Criteria: Access to trial IPD can be requested by qualified researchers engaging in independent scientific research.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ANALYTIC_CODE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: No