Effect of iNO in Patients With Submassive and Massive PE

Study Overview
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Brief Summary
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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).

Detailed Description
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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.

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

Conditions
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Pulmonary Embolism, Pulmonary Embolism Subacute Massive

Intervention / Treatment
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* Drug: inhaled nitric oxide (iNO)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Interventional Radiology Arm (Invasive Cohort)<br>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)<br>* 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.<br>* Other names: INOmax;|
| Active Comparator: Non-intervention Arm (Non-invasive Cohort)<br>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)<br>* 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.<br>* Other names: INOmax;|

What is the study measuring?
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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) |