Clinical trial NCT04996667: Effect of INO in Patients with Submassive and Massive PE
Official title: Study to Evaluate the Role of Inhaled Nitric Oxide (iNO) on Pulmonary Hemodynamics in Patients with Intermediate/submassive and Massive Pulmonary Embolism (PE)
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE2
Conditions: Pulmonary Embolism
Pulmonary Embolism Subacute Massive
Lead sponsor: University of California, Los Angeles
Sponsor class: OTHER
Collaborators: name: Mallinckrodt
First posted: 2021-08-09
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: right atrial pressure (RAP)
timeFrame: measured invasively during a right heart catheterization (RHC) before administration of iNO
measure: right atrial pressure (RAP)
timeFrame: measured invasively during a right heart catheterization (RHC) during administration of iNO
measure: right atrial pressure (RAP)
timeFrame: measured invasively during a right heart catheterization (RHC) after administration of iNO
measure: right ventricular pressure (RVP)
timeFrame: measured invasively during a right heart catheterization (RHC) before administration of iNO
measure: right ventricular pressure (RVP)
timeFrame: measured invasively during a right heart catheterization (RHC) during administration of iNO
measure: right ventricular pressure (RVP)
timeFrame: measured invasively during a right heart catheterization (RHC) after administration of iNO
measure: pulmonary arterial pressure (PAP)
timeFrame: measured invasively during a right heart catheterization (RHC) before administration of iNO
measure: pulmonary arterial pressure (PAP)
timeFrame: measured invasively during a right heart catheterization (RHC) during administration of iNO
measure: pulmonary arterial pressure (PAP)
timeFrame: measured invasively during a right heart catheterization (RHC) after administration of iNO
measure: pulmonary capillary wedge pressure (PCWP)
timeFrame: measured invasively during a right heart catheterization (RHC) before administration of iNO
measure: pulmonary capillary wedge pressure (PCWP)
timeFrame: measured invasively during a right heart catheterization (RHC) during administration of iNO
measure: pulmonary capillary wedge pressure (PCWP)
timeFrame: measured invasively during a right heart catheterization (RHC) after administration of iNO
measure: cardiac output (CO) (by Fick and Thermodilution)
timeFrame: measured invasively during a right heart catheterization (RHC) before administration of iNO
measure: cardiac output (CO) (by Fick and Thermodilution)
timeFrame: measured invasively during a right heart catheterization (RHC) during administration of iNO
measure: cardiac output (CO) (by Fick and Thermodilution)
timeFrame: measured invasively during a right heart catheterization (RHC) after administration of iNO
measure: cardiac index (CI) (by Fick and Thermodilution)
timeFrame: measured invasively during a right heart catheterization (RHC) before administration of iNO
measure: cardiac index (CI) (by Fick and Thermodilution)
timeFrame: measured invasively during a right heart catheterization (RHC) during administration of iNO
measure: cardiac index (CI) (by Fick and Thermodilution)
timeFrame: measured invasively during a right heart catheterization (RHC) after administration of iNO
measure: mixed venous O2
timeFrame: measured invasively during a right heart catheterization (RHC) before administration of iNO
measure: mixed venous O2
timeFrame: measured invasively during a right heart catheterization (RHC) during administration of iNO
measure: mixed venous O2
timeFrame: measured invasively during a right heart catheterization (RHC) after administration of iNO
measure: central venous O2
timeFrame: measured invasively during a right heart catheterization (RHC) before administration of iNO
measure: central venous O2
timeFrame: measured invasively during a right heart catheterization (RHC) during administration of iNO
measure: central venous O2
timeFrame: measured invasively during a right heart catheterization (RHC) after administration of iNO
measure: systemic PaO2
timeFrame: measured invasively during a right heart catheterization (RHC) before administration of iNO
measure: systemic PaO2
timeFrame: measured invasively during a right heart catheterization (RHC) during administration of iNO
measure: systemic PaO2
timeFrame: measured invasively during a right heart catheterization (RHC) after administration of iNO
measure: systolic blood pressure (SBP)
timeFrame: measured invasively during a right heart catheterization (RHC) before administration of iNO
measure: systolic blood pressure (SBP)
timeFrame: measured invasively during a right heart catheterization (RHC) during administration of iNO
measure: systolic blood pressure (SBP)
timeFrame: measured invasively during a right heart catheterization (RHC) after administration of iNO
measure: diastolic blood pressure (DBP)
timeFrame: measured invasively during a right heart catheterization (RHC) before administration of iNO
measure: diastolic blood pressure (DBP)
timeFrame: measured invasively during a right heart catheterization (RHC) during administration of iNO
measure: diastolic blood pressure (DBP)
timeFrame: measured invasively during a right heart catheterization (RHC) after administration of iNO
measure: mean arterial pressure (MAP)
timeFrame: measured invasively during a right heart catheterization (RHC) before administration of iNO
measure: mean arterial pressure (MAP)
timeFrame: measured invasively during a right heart catheterization (RHC) during administration of iNO
measure: mean arterial pressure (MAP)
timeFrame: measured invasively during a right heart catheterization (RHC) after administration of iNO
measure: blood pressure (BP) (measured noninvasively)
timeFrame: measured noninvasively before administration of inhaled nitric oxide (iNO)
measure: blood pressure (BP) (measured noninvasively)
timeFrame: measured noninvasively during administration of inhaled nitric oxide (iNO)
measure: blood pressure (BP) (measured noninvasively)
timeFrame: measured noninvasively after administration of inhaled nitric oxide (iNO)
measure: heart rate (HR) (measured noninvasively)
timeFrame: measured noninvasively before administration of inhaled nitric oxide (iNO)
measure: heart rate (HR) (measured noninvasively)
timeFrame: measured noninvasively during administration of inhaled nitric oxide (iNO)
measure: heart rate (HR) (measured noninvasively)
timeFrame: measured noninvasively after administration of inhaled nitric oxide (iNO)
measure: cardiac index (CI) (measured noninvasively)
timeFrame: measured noninvasively before administration of inhaled nitric oxide (iNO)
measure: cardiac index (CI) (measured noninvasively)
timeFrame: measured noninvasively during administration of inhaled nitric oxide (iNO)
measure: cardiac index (CI) (measured noninvasively)
timeFrame: measured noninvasively after administration of inhaled nitric oxide (iNO)
Secondary outcomes:
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Ronald Reagan UCLA Medical Center
state: California
Study officials:
affiliation: University of California, Los Angeles
name: Rajan Saggar, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.