Clinical trial NCT03183063: Non-Contrast 4DCT to Detect Pulmonary Thromboembolic Events
Official title: A Novel Method to Detect Pulmonary Thromboembolic Events With Non-Contrast 4DCT
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Pulmonary Thromboembolisms
Pulmonary Embolism
Lead sponsor: William Beaumont Hospitals
Sponsor class: OTHER
First posted: 2017-06-09
Enrollment: 139
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Patients will be imaged with SPECT/CT and 4DCT to compare perfusion with the respiratory induced blood mass changed (RIBMC) defect. Each patient will have both imaging studies performed on the same day.

15 subjects will be enrolled into Cohort 1 and will receive SPECT/CT and 4DCT imaging as described. After those are enrolled another 5 subjects will be enrolled into Cohort 2 and will receive SPECT/CT and 4DCT imaging as previously described with the first 4DCT being obtained with normal breathing and the second scan being obtained with positive pressure breathing via BiPAP. Cohort 3 will enroll 124 participants with clinical suspicion of PE, who will be or have had CTA imaging. 4DCT imaging will be performed for these study participants.
Primary purpose: DIAGNOSTIC

Brief summary: Deep vein thrombosis (DVT) occurs when a blood clot forms in a deep vein, typically in the lower extremities. Pulmonary embolism (PE) occurs when a DVT clot (or fragment) breaks free and travels through the heart to the pulmonary arteries (having to do with the lungs) and lodges in an artery causing a partial or complete blockage. PE is difficult to diagnose due to the non-specific signs and symptoms patients have with this condition such as a cough, shortness of breath, increased heart rate, blood tinged sputum, low oxygen levels.

The standard test to diagnose PE is the Pulmonary Computed Tomography Angiogram (CTA). This can be prohibitive with some patients due to the amount of radiation exposure as well as the complications associated with the need to use intravenous (IV) contrast. In this study the investigators are looking at an alternative method of diagnosing PE's in the Emergency Department where the investigators look at the breathing and blood flow to the lungs thru respiratory gated non-contrast CT (commonly called 4DCT).

The investigators hypothesize that respiratory induced blood mass change in the lungs will allow the identification of under-perfused lung regions.

Cohort 1: An anticipated15 participants will be enrolled with a diagnosis of PE by CTA. Each will receive SPECT/CT and 4DCT imaging on the same day. Respiratory induced blood mass change images will be issued from the 4DCT and compared to the SPECT/CT images.

Cohort 2: An anticipated 5 participants will be enrolled under the same criteria and study procedures as Cohort 1. The participants in Cohort 2 will have the addition of Bilevel Positive Airway Pressure (BiPAP) during the 4DCT imaging. This cohort will be used to compare the effect of airway pressure on 4DCT image.

Cohort 3: An anticipated 124 participants will be enrolled. Study procedure will be 4DCT only. Participants must be having or have had a CTA to rule in/out PE. This cohort of the study will be using 4DCT to compare negative CTA to positive CTA findings.

Detailed description: The standard test to diagnose PE is the Pulmonary Computed Tomography Angiogram (CTA). This can be prohibitive with some patients due to the amount of radiation exposure as well as the complications associated with the need to use intravenous (IV) contrast. CTA can detect acute PE with a sensitivity of 99 percent and specificity of 95 percent when combined with CT venography. In patients not medically eligible for CTA, the other option for diagnosis is a ventilation-perfusion (V/Q) single photon emission computed tomography (SPECT) scan. Though this is often prohibitive due to transport to Nuclear Medicine dept., prolonged test time, no test during off hours, etc. In this study the investigators are looking at an alternative method of diagnosing PE's in the Emergency Department where the investigators look at ventilation and perfusion images thru respiratory gated non-contrast CT (commonly called 4DCT).

Technetium-99 m macroaggregated albumin (99mTc-MAA) imaged with single photon emission computed tomography (SPECT) is considered the standard method for the quantitative determination of pulmonary perfusion. Magnetic resonance imaging (MRI) with contrast agents have been utilized experimentally to image the pulmonary vasculature and tissue perfusion. Quantification of SPECT images requires correction of the acquired data for attenuation and attenuation correction, which has lead to the development of SPECT/CT scanners. The low-dose CT can be utilized to evaluate the lung airway architecture, lung parenchyma, and pleural space in conjunction with the registered perfusion images rivaling CTA in sensitivity and specificity.

In a study comparing CT attenuation with SPECT perfusion defects, patients were found to have hypo-attenuated pulmonary regions corresponding to regions with decreased perfusion in 57 percent of acute pulmonary emboli and 88 percent of chronic emboli cases. In the same study, hyper-attenuated regions were found to correspond to regions with hyperperfusion. A method to measure pulmonary perfusion based on subtraction digital fluoroscopy without contrast has been reported. In that study, subtraction images were generated between chest projection images at systole and diastole generating an image representing the perfusion difference. These perfusion projection images were correlate with 99mTc-MAA scintigraphy. Thus, changes in the amount and distribution of pulmonary perfusion throughout the respiratory cycle can be expected and these changes may be apparent on dynamic CT.

Simon described a technique to calculate the change in fractional content of air within pulmonary tissue between anatomically matched CT regions based on a simple model that assumes the density changes were solely due to air content. The investigators successfully applied that model to inhale and exhale breath-hold CT image pairs as well as 4DCT images to create ventilation images. However, the amount of blood in the thorax and lungs varies with the respiratory cycle, thus violating the assumption of this model. The investigators found a cyclic variation in the apparent weight of the lung on 4DCT and others have reported respiratory induced variations in pulmonary perfusion of the lung on MRI. The pulmonary density changes found on 4DCT thus result from both changes in air and blood content.

4DCT derived ventilation images can also be inferred from the respiratory motion induced local tissue volume changes independent of the 4DCT density values. The Jacobian determinant of the deformation field, calculated from the result of images depicting different respiratory phases of the lungs, is used to estimate the local volume changes or ventilation. There is a discrepancy between the density based and the Jacobian based ventilation images suggesting a method to extract respiratory induced blood mass change from 4DCT images. The investigators hypothesize the respiratory induced blood mass changed (RIBMC) will only occur within perfused lung regions. Each image set will contain information representing the density change resulting from both ventilation and RIBMC. Extracting both ventilation and perfusion-like image from the 4DCT image intensities, referred to as Hounsfield Units (HU) is our goal.

The investigators found a cyclic variation in the apparent mass of the pulmonary parenchyma. The investigators hypothesize this variation is due to changes in pulmonary perfusion from respiratory-induced variation in cardiac output. The investigators hypothesize this respiratory induced blood mass change (RIBMC) will allow the identification of hypoperfused lung regions. The investigators did a preliminary study by creating 4DCT RIBMC images from cases with hypoxia induced vasoconstriction, patients with malignant airway constriction. The resulting images compare well with 99mTc-MAA SPECT images. It is unknown, however, if this process works to detect perfusion defects due to PE where the perfusion is obstructed and breathing normal.

In this study patients found to have new segmental, lobar or greater perfusion defects, will be imaged with 99mTc-MAA SPECT/CT and 4DCT to compare perfusion with RIBMC defects. This is a prospective imaging trial of 20 subjects diagnosed by CTA.

An anticipated 15 subjects will be enrolled into Cohort 1 and each will receive 99mTc-MAA SPECT/CT and two (2) 4DCT imaging scans (back-to-back) on the same day. This data will be analyzed for objectives 1, 4 and 5.

An anticipated 5 subjects will be enrolled into Cohort 2 and they will also receive 99mTc-MAA SPECT/CT and two (2) 4DCT imaging scans (back-to-back) on the same day, with the first one being obtained with normal breathing as previously done and the second one being obtained with positive pressure breathing via BiPAP. Cohort 2 results will be analyzed for objective 6 only. Respiratory induced blood mass change (RIBMC) images will be derived from the 4DCT images and quantitatively compared with the SPECT perfusion images.

Cohort 3. The objective of this cohort of the study is to collect and process the image data necessary to assess the sensitivity and specificity of our 4DCT. We will conduct a prospective imaging study of an anticipated 124 patients who present with symptoms leading to a clinical concern for PE and who subsequently undergo chest CTA for further evaluation. One 4DCT before or after the CTA is the only study imaging in this cohort. Data from this cohort will be analyzed for objectives 2 and 3.

Subjects will be followed for a period of 48 hours after imaging for any adverse effects to the 99mTc-MAA.

The Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0) will be used to grade all treatment-related adverse events. All Adverse Event (AE) effects will be reported to the Principal Investigator, who will determine the course of action for the study participant and will determine whether the AE affects the study and requires changes to the protocol and/or informed consent form.

Eligibility criteria: Inclusion Criteria:

* Patients with segmental or lobar pulmonary emboli on CTA identified within the past 48 hours
* May have initiated anticoagulation therapy
* Patients must sign informed consent to enter this study
* Documented not pregnant if child-bearing age woman

Exclusion Criteria:

* Patients unable to tolerate two 15-minute (4DCT) and one 30-minute imaging sessions (SPECT/CT) in the same day
* Unable to sign informed consent due to cognitive impairment or health status
* Patients who are unstable from a respiratory status requiring ICU care
* Patients who receive tissue plasminogen activator
* Patients who are \<18 years old

Primary outcomes:
measure: Correlation of 4DCT Identified Perfusion With SPECT/CT Identified Perfusion
timeFrame: 1 hour
measure: Count of Participants With True Positive Detection of PE Using Contrast-free 4DCT Functional Imaging and SPECT/CT (Sensitivity)
timeFrame: 48 hours
measure: Count of Participants With True Negative Detection of PE Using Contrast-free 4DCT Functional Imaging (Specificity)
timeFrame: 48 hours
Secondary outcomes:
measure: Measure and Correlate the 4DCT Re-imaging Variance in Radiographic Tidal Volume of RIBMC Images
timeFrame: 1 hour
measure: Measure and Correlate the 4DCT Re-imaging Variance in Parenchymal Lung Mass of RIBMC Images
timeFrame: 1 hour
Other outcomes:
measure: Measure and Correlate the Airway Pressure Variance of RIBMC Images
timeFrame: 1 hour
Locations:
city: Royal Oak
country: United States
facility: William Beaumont Hospital
state: Michigan
Study officials:
affiliation: Beaumont Health
name: Thomas Guerrero, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: