Effect of iNO in Patients With Submassive and Massive PE

Study to Evaluate the Role of Inhaled Nitric Oxide (iNO) on Pulmonary Hemodynamics in Patients With Intermediate/Submassive and Massive Pulmonary Embolism (PE)

A single center study to evaluate the effect of inhaled nitric oxide (iNO) on pulmonary dynamics in patients presenting with imaging confirmed intermediate/submassive or massive pulmonary embolism (PE). The target enrollment is 20 subjects at Ronald Reagan UCLA Medical Center. PE patients undergoing catheter-based intervention will be administered iNO during their intervention and pulmonary hemodynamic measurement will be measured before, during, and after iNO administration (Invasive Cohort). Patients who are not undergoing catheter-based intervention will also be administered iNO and will have pulmonary hemodynamics, blood pressure, and heart rate measured non-invasively (Non-Invasive Cohort).

Study Overview

• Status: Withdrawn
• Conditions: Pulmonary Embolism; Pulmonary Embolism Subacute Massive
• Intervention / Treatment: Drug: inhaled nitric oxide (iNO)

Detailed Description

This is a single center study to evaluate patients presenting with imaging confirmed intermediate/submassive or massive pulmonary embolism (PE). The investigators anticipate to enroll a total of 20-25 subjects at Ronald Reagan UCLA Medical Center.

After informed consent is obtained, the subject will proceed under one of two study intervention arms depending on his or her treatment plan. If the patient requires invasive treatment such as interventional thrombectomy or catheter-directed thrombolysis (CDT), the participant will be enrolled in the interventional radiology arm (invasive cohort). If the patient requires non-invasive treatment such as anticoagulation therapy, deep vein thrombosis (DVT) thrombectomy, or inferior vena cava (IVC) filter, the participant will be enrolled in the non-intervention arm (non-invasive cohort).

Interventional Radiology Arm (Invasive Cohort):

The following procedure will be performed:

Interventional radiology (IR) will perform a right heart catheterization (RHC) as part of a planned IR procedure. Patient arrives in the IR suite and is positioned flat with head of bed between flat and 45 degrees. O2 amount and modality, blood pressure, pressor name, dose, and rate will be recorded. If the patient is intubated, the sedation/analgesia drug name(s), dose(s), and rate(s) will be recorded. If the patient is not intubated, name and dose amount of sedation will be recorded. Arterial blood gas will be obtained if an A-line is placed.

Bedside apical 4 chamber view (RV:LV ratio) will be recorded using an ultrasound device, and noninvasive RV data will be obtained with Edwards ClearSight system and Edwards EV1000 clinical platform.

Edwards ClearSight system and Edwards EV1000 clinical platform is a finger probe worn with a supportive forearm strap. Hemodynamic measurements from the finger cuff will be recorded at intervals.

Novel non-invasive methods of estimating stroke volume and associated cardiac output have the potential to revolutionize PE risk stratification and care. Non-invasive blood pressure (NIBP) monitors can even measure stroke volume beat to beat, allowing for continuous evaluation of cardiac function. NIBP systems are typically composed of a finger cuff with an inflatable bladder, pressure sensors, and light sensors. An arterial pulse contour is formed using the volume clamp method of blood pressure measurement combined with calibration and brachial pressure reconstruction algorithms. The stroke volume with each heart beat can be estimated as the area under the systolic portion of the blood pressure curve divided by the afterload. A limitation of using NIBP monitors to measure stroke volume is their relative inaccuracy, as they are calculations of an indirect measurement. However, NIBP monitors¬ may improve clinical care of PE because they allow for assessment of dynamic cardiac changes in real time. Detection of worsening stroke volume in acute PE could inform providers of impending cardiac collapse, and improvement of stroke volume may function as a positive prognostic factor or marker of therapeutic success. Use of NIBP monitors during acute PE to identify clinically significant changes in cardiac function may advance both PE prognostication and management.

The Butterfly iQ+ (one possible ultrasound device which may be used) is a single-probe, whole-body ultrasound device.

After initial measurements, inhaled nitric oxide (iNO) will be administered at 30 ppm for 3 minutes. The same measurements will be obtained/calculated before, during iNO administration, and after iNO has been withheld for 2 minutes.

All major changes in pressures, sedation, vital signs, and major events will be recorded throughout the RHC procedure.

iNO is scheduled to be weaned off post RHC but the IR/anesthesia team may choose to keep the patient on iNO at their clinical discretion. The patient will then proceed to their standard of care IR procedures with planned intervention.

Non-intervention Arm (Non-invasive Cohort):

Vitals including O2 amount and modality, blood pressure, pressor name, dose, and rate will be recorded. If the patient is intubated, the name, dose, and rate of sedation and analgesia will be recorded. If the patient is not intubated, name and dose amount of sedation will be recorded. Arterial blood gas will be obtained if an A-line is placed. Bedside apical 4 chamber view will be recorded (RV:LV ratio) with an ultrasound device, and noninvasive RV data will be obtained with Edwards ClearSight system and Edwards EV1000 clinical platform. This data will be obtained before, during iNO administration, and after iNO has been withheld for 2 minutes.

If a subject initially enrolled in the Non-intervention Arm (Non-invasive Cohort) needs an invasive procedure, they will be removed from the study.

• Study Type: Interventional
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90095
      • Ronald Reagan UCLA Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patient ≥ 18 years of age.
• The patient or patient's surrogate decision maker must understand and sign the informed consent form (ICF).
• Hospitalized (Emergency Room (ER) or inpatient) with:
• Imaging (computed tomography pulmonary angiography (CTPA) or ventilation/perfusion (VQ) lung scan) proven acute pulmonary embolism (PE)
• PE meets the following intermediate risk PE criteria (or massive, see below):
• Troponin > .1 AND
• Imaging (computed tomography (CT) or transthoracic echocardiogram (TTE)) signs of RV compromise (at least 1 of the following):
• RV:LV>1 on TTE or CTPA OR RV dilation (TTE or CTPA OR RV dysfunction on TTE.
• Massive PE
• Intensive care unit (ICU) level of care (Patient moving to ICU, ICU level of care in ER, or currently in ICU)
• Ability to comply with study protocol in investigator's judgement

Exclusion Criteria:

• Pregnancy or breastfeeding
• Inability to administer iNO through current mode of O2 delivery (i.e. BiPAP)
• Active hemoptysis
• Known allergy to iNO.
• Any serious medical condition of lab abnormality that, in the investigator's judgement, precludes the patient's safe participation in the study.
• Methemoglobin reductase deficiency
• Unable to obtain consent or patient or patient surrogate decision maker declines
• Patients already on iNO prior to study enrollment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Interventional Radiology Arm (Invasive Cohort); Interventional radiology (IR) will perform a right heart catheterization (RHC) as part of a planned IR procedure. Bedside apical 4 chamber view (RV:LV ratio) will be recorded using an ultrasound device, and noninvasive RV data will be obtained with Edwards ClearSight system and Edwards EV1000 clinical platform. The Butterfly iQ+ (one possible ultrasound device which may be used) is a single-probe, whole-body ultrasound device. After initial measurements, inhaled nitric oxide (iNO) will be administered at 30 ppm for 3 minutes. The same measurements will be obtained/calculated before, during iNO administration, and after iNO has been withheld for 2 minutes.	Drug: inhaled nitric oxide (iNO); Inhaled nitric oxide (iNO), which is known mainly from the pulmonary hypertension literature for its therapeutic role in pulmonary arterial hypertension, has been proposed as a potential pharmacologic adjunct to standard anticoagulation in acute PE. Inhaled nitric oxide (iNO) will be administered at 30 ppm for 3 minutes. The measurements will be obtained/calculated before, during iNO administration, and after iNO has been withheld for 2 minutes.; Other Names: INOmax
ACTIVE_COMPARATOR: Non-intervention Arm (Non-invasive Cohort); Vitals including O2 amount and modality, blood pressure, pressor name, dose, and rate will be recorded. If the patient is intubated, the name, dose, and rate of sedation and analgesia will be recorded. If the patient is not intubated, name and dose amount of sedation will be recorded. Arterial blood gas will be obtained if an A-line is placed. Bedside apical 4 chamber view will be recorded (RV:LV ratio) with an ultrasound device, and noninvasive RV data will be obtained with Edwards ClearSight system and Edwards EV1000 clinical platform. This data will be obtained before, during iNO administration, and after iNO has been withheld for 2 minutes.	Drug: inhaled nitric oxide (iNO); Inhaled nitric oxide (iNO), which is known mainly from the pulmonary hypertension literature for its therapeutic role in pulmonary arterial hypertension, has been proposed as a potential pharmacologic adjunct to standard anticoagulation in acute PE. Inhaled nitric oxide (iNO) will be administered at 30 ppm for 3 minutes. The measurements will be obtained/calculated before, during iNO administration, and after iNO has been withheld for 2 minutes.; Other Names: INOmax

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
right atrial pressure (RAP)	right atrial pressure (RAP) in mmHg	measured invasively during a right heart catheterization (RHC) before administration of iNO
right atrial pressure (RAP)	right atrial pressure (RAP) in mmHg	measured invasively during a right heart catheterization (RHC) during administration of iNO
right atrial pressure (RAP)	right atrial pressure (RAP) in mmHg	measured invasively during a right heart catheterization (RHC) after administration of iNO
right ventricular pressure (RVP)	right ventricular pressure (RVP) in mmHg	measured invasively during a right heart catheterization (RHC) before administration of iNO
right ventricular pressure (RVP)	right ventricular pressure (RVP) in mmHg	measured invasively during a right heart catheterization (RHC) during administration of iNO
right ventricular pressure (RVP)	right ventricular pressure (RVP) in mmHg	measured invasively during a right heart catheterization (RHC) after administration of iNO
pulmonary arterial pressure (PAP)	pulmonary arterial pressure (PAP) in mmHg	measured invasively during a right heart catheterization (RHC) before administration of iNO
pulmonary arterial pressure (PAP)	pulmonary arterial pressure (PAP) in mmHg	measured invasively during a right heart catheterization (RHC) during administration of iNO
pulmonary arterial pressure (PAP)	pulmonary arterial pressure (PAP) in mmHg	measured invasively during a right heart catheterization (RHC) after administration of iNO
pulmonary capillary wedge pressure (PCWP)	pulmonary capillary wedge pressure (PCWP) in mmHg	measured invasively during a right heart catheterization (RHC) before administration of iNO
pulmonary capillary wedge pressure (PCWP)	pulmonary capillary wedge pressure (PCWP) in mmHg	measured invasively during a right heart catheterization (RHC) during administration of iNO
pulmonary capillary wedge pressure (PCWP)	pulmonary capillary wedge pressure (PCWP) in mmHg	measured invasively during a right heart catheterization (RHC) after administration of iNO
cardiac output (CO) (by Fick and Thermodilution)	Cardiac Output (CO) is the amount of blood the heart pumps from each ventricle per minute. It is usually expressed in litres per minute (L/min).	measured invasively during a right heart catheterization (RHC) before administration of iNO
cardiac output (CO) (by Fick and Thermodilution)	Cardiac Output (CO) is the amount of blood the heart pumps from each ventricle per minute. It is usually expressed in litres per minute (L/min).	measured invasively during a right heart catheterization (RHC) during administration of iNO
cardiac output (CO) (by Fick and Thermodilution)	Cardiac Output (CO) is the amount of blood the heart pumps from each ventricle per minute. It is usually expressed in litres per minute (L/min).	measured invasively during a right heart catheterization (RHC) after administration of iNO
cardiac index (CI) (by Fick and Thermodilution)	Cardiac index (CI) is the cardiac output proportional to the body surface area (BSA). The unit of measurement is litres per minute per square metre (L/min/m2).	measured invasively during a right heart catheterization (RHC) before administration of iNO
cardiac index (CI) (by Fick and Thermodilution)	Cardiac index (CI) is the cardiac output proportional to the body surface area (BSA). The unit of measurement is litres per minute per square metre (L/min/m2).	measured invasively during a right heart catheterization (RHC) during administration of iNO
cardiac index (CI) (by Fick and Thermodilution)	Cardiac index (CI) is the cardiac output proportional to the body surface area (BSA). The unit of measurement is litres per minute per square metre (L/min/m2).	measured invasively during a right heart catheterization (RHC) after administration of iNO
mixed venous O2	mixed venous O2 in %	measured invasively during a right heart catheterization (RHC) before administration of iNO
mixed venous O2	mixed venous O2 in %	measured invasively during a right heart catheterization (RHC) during administration of iNO
mixed venous O2	mixed venous O2 in %	measured invasively during a right heart catheterization (RHC) after administration of iNO
central venous O2	central venous O2 in %	measured invasively during a right heart catheterization (RHC) before administration of iNO
central venous O2	central venous O2 in %	measured invasively during a right heart catheterization (RHC) during administration of iNO
central venous O2	central venous O2 in %	measured invasively during a right heart catheterization (RHC) after administration of iNO
systemic PaO2	systemic PaO2 in mmHg	measured invasively during a right heart catheterization (RHC) before administration of iNO
systemic PaO2	systemic PaO2 in mmHg	measured invasively during a right heart catheterization (RHC) during administration of iNO
systemic PaO2	systemic PaO2 in mmHg	measured invasively during a right heart catheterization (RHC) after administration of iNO
systolic blood pressure (SBP)	Systolic Blood Pressure in mmHg	measured invasively during a right heart catheterization (RHC) before administration of iNO
systolic blood pressure (SBP)	Systolic Blood Pressure in mmHg	measured invasively during a right heart catheterization (RHC) during administration of iNO
systolic blood pressure (SBP)	Systolic Blood Pressure in mmHg	measured invasively during a right heart catheterization (RHC) after administration of iNO
diastolic blood pressure (DBP)	Diastolic Blood Pressure in mmHg	measured invasively during a right heart catheterization (RHC) before administration of iNO
diastolic blood pressure (DBP)	Diastolic Blood Pressure in mmHg	measured invasively during a right heart catheterization (RHC) during administration of iNO
diastolic blood pressure (DBP)	Diastolic Blood Pressure in mmHg	measured invasively during a right heart catheterization (RHC) after administration of iNO
mean arterial pressure (MAP)	mean arterial pressure (MAP) in mmHg	measured invasively during a right heart catheterization (RHC) before administration of iNO
mean arterial pressure (MAP)	mean arterial pressure (MAP) in mmHg	measured invasively during a right heart catheterization (RHC) during administration of iNO
mean arterial pressure (MAP)	mean arterial pressure (MAP) in mmHg	measured invasively during a right heart catheterization (RHC) after administration of iNO
blood pressure (BP) (measured noninvasively)	The pressure of the blood in the circulatory system, often measured for diagnosis since it is closely related to the force and rate of the heartbeat and the diameter and elasticity of the arterial walls. Systolic Blood Pressure in mmHg Diastolic Blood Pressure in mmHg	measured noninvasively before administration of inhaled nitric oxide (iNO)
blood pressure (BP) (measured noninvasively)	The pressure of the blood in the circulatory system, often measured for diagnosis since it is closely related to the force and rate of the heartbeat and the diameter and elasticity of the arterial walls. Systolic Blood Pressure in mmHg Diastolic Blood Pressure in mmHg	measured noninvasively during administration of inhaled nitric oxide (iNO)
blood pressure (BP) (measured noninvasively)	The pressure of the blood in the circulatory system, often measured for diagnosis since it is closely related to the force and rate of the heartbeat and the diameter and elasticity of the arterial walls. Systolic Blood Pressure in mmHg Diastolic Blood Pressure in mmHg	measured noninvasively after administration of inhaled nitric oxide (iNO)
heart rate (HR) (measured noninvasively)	The number of heartbeats per unit of time, usually per minute. Measured in beats per minute (BPM)	measured noninvasively before administration of inhaled nitric oxide (iNO)
heart rate (HR) (measured noninvasively)	The number of heartbeats per unit of time, usually per minute. Measured in beats per minute (BPM)	measured noninvasively during administration of inhaled nitric oxide (iNO)
heart rate (HR) (measured noninvasively)	The number of heartbeats per unit of time, usually per minute. Measured in beats per minute (BPM)	measured noninvasively after administration of inhaled nitric oxide (iNO)
cardiac index (CI) (measured noninvasively)	Cardiac index (CI) is the cardiac output proportional to the body surface area (BSA). The unit of measurement is litres per minute per square metre (L/min/m2).	measured noninvasively before administration of inhaled nitric oxide (iNO)
cardiac index (CI) (measured noninvasively)	Cardiac index (CI) is the cardiac output proportional to the body surface area (BSA). The unit of measurement is litres per minute per square metre (L/min/m2).	measured noninvasively during administration of inhaled nitric oxide (iNO)
cardiac index (CI) (measured noninvasively)	Cardiac index (CI) is the cardiac output proportional to the body surface area (BSA). The unit of measurement is litres per minute per square metre (L/min/m2).	measured noninvasively after administration of inhaled nitric oxide (iNO)

Collaborators and Investigators

• Sponsor: University of California, Los Angeles
• Collaborators: Mallinckrodt
• Investigators: Principal Investigator: Rajan Saggar, M.D., University of California, Los Angeles

Publications and helpful links

General Publications

• Summerfield DT, Desai H, Levitov A, Grooms DA, Marik PE. Inhaled nitric oxide as salvage therapy in massive pulmonary embolism: a case series. Respir Care. 2012 Mar;57(3):444-8. doi: 10.4187/respcare.01373. Epub 2011 Oct 12.
• Capellier G, Jacques T, Balvay P, Blasco G, Belle E, Barale F. Inhaled nitric oxide in patients with pulmonary embolism. Intensive Care Med. 1997 Oct;23(10):1089-92. doi: 10.1007/s001340050461.
• Szold O, Khoury W, Biderman P, Klausner JM, Halpern P, Weinbroum AA. Inhaled nitric oxide improves pulmonary functions following massive pulmonary embolism: a report of four patients and review of the literature. Lung. 2006 Jan-Feb;184(1):1-5. doi: 10.1007/s00408-005-2550-7.
• Kline JA, Puskarich MA, Jones AE, Mastouri RA, Hall CL, Perkins A, Gundert EE, Lahm T. Inhaled nitric oxide to treat intermediate risk pulmonary embolism: A multicenter randomized controlled trial. Nitric Oxide. 2019 Mar 1;84:60-68. doi: 10.1016/j.niox.2019.01.006. Epub 2019 Jan 8.

Helpful Links

• Edwards ClearSight system

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): June 1, 2021
• Primary Completion (ANTICIPATED): December 31, 2022
• Study Completion (ANTICIPATED): June 30, 2023

Study Registration Dates

• First Submitted: July 21, 2021
• First Submitted That Met QC Criteria: July 30, 2021
• First Posted (ACTUAL): August 9, 2021

Study Record Updates

• Last Update Posted (ACTUAL): May 18, 2022
• Last Update Submitted That Met QC Criteria: May 11, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Embolism and Thrombosis; Embolism; Pulmonary Embolism; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Autonomic Agents; Peripheral Nervous System Agents; Protective Agents; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Antioxidants; Free Radical Scavengers; Endothelium-Dependent Relaxing Factors; Gasotransmitters; Nitric Oxide
• Other Study ID Numbers: 21-000569

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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