Introduction

Pulmonary embolism (PE) is a treatable disease caused by thrombus formation in the lung vasculature, commonly from the lower extremity's deep veins compromising the blood flow to the lungs. Undiagnosed massive PE can be fatal if not diagnosed and treated in a timely fashion. The diagnosis of PE is based on imaging. Computed tomography of pulmonary arteries (CTPA) and ventilation-perfusion (V/Q) scan are the two most common and widely practiced testing modalities to diagnose pulmonary embolism. Pulmonary ventilation (V) and Perfusion (Q) scan, also known as lung V/Q scan, is a nuclear test that uses the perfusion scan to delineate the blood flow distribution and the ventilation scan to measure airflow distribution in the lungs. The primary utilization of the V/Q scan is to help diagnose lung clots called pulmonary embolisms. V/Q scan provides help in clinical decision-making by evaluating scans showing ventilation and perfusion in all areas of the lungs using radioactive tracers. PIOPED I study by Vreim CE et al. showed that 65% of the V/Q scans were non-diagnostic for pulmonary embolism.[1] 

V/Q scan faced a setback because of this study since 1990 until later studies and EANM guidelines based upon holistic principles and modern imaging techniques for V/Q scintigraphy showed a rate of non-diagnostic PE equal to or less than 3% with excellent sensitivity and specificity.[2] In the V/Q lung scan, an aerosol and injectable radioactive tracer are used to assess lung ventilation (V) and perfusion (Q) to identify V/Q mismatch areas. The most common clinical indication for a V/Q lung scan is to assess the likelihood of pulmonary embolism (PE) when contrast or radiation exposure is contraindicated. A subset of the patient population who can not tolerate the intravenous contrast, the radiation of the definitive diagnostic test (CT pulmonary angiography), have severe renal insufficiency (stage IV), or had a severe allergic reaction to contrast material then V/Q scan is the test of choice to diagnose PE. Usually, ventilation imaging is conducted before perfusion imaging.

In conventional scintigraphy, a radiolabeled agent like technetium 99m-diethylenetriamine pentaacetic acid (99mTc-DTPA) in aerosol form and gamma-emitting 99mTc-macro aggregated albumin (MAA) in the intravenous form are given to the patient to assess ventilation and perfusion, respectively. Then gamma camera is used to register their distribution into the alveoli and pulmonary arteries. One segmental or two sub-segmental perfusion defects with a normally ventilated area (V/Q mismatch) is the definition of a high-probability scan for PE.

Procedures

The patient is supposed to lie still on the table, breathing normally while the technician takes scans from different angles. The procedure is discussed in detail with the patient as the patient's cooperation is a key element during the whole scanning because the patient's movement can blur the images. The duration of the whole scanning takes about 30-45 minutes though it may take longer. The procedure involves two phases, which can be done simultaneously or one after another. One phase is ventilation, and the other is perfusion. For ventilation scans, radioactive xenon or technetium is breathed through the nebulizer via mouthpiece for a few minutes. A gamma camera is placed close to the patient, and scans at different angles are taken. Similarly, for the perfusion scan, radioactive contrast-containing technetium is given intravenously to the patient, and images are taken. V/Q scan utilizes the novel pulmonary arterial segmental anatomy as a single end-artery perfuses each segment. Each conical bronchopulmonary segment has its base towards pleural surfaces. Classically, thrombi occlude the pulmonary arteries and create characteristic wedge-shaped lobar, segmental, or subsegment defects based on the level of occlusion. According to the Society of Nuclear Medicine (SNM), before a nuclear medicine study [3], the pre-test probability of PE must be evaluated by using assessment tools (Well criteria, D-dimer test result).[4] A posterior-anterior and lateral chest radiograph must be done one hour before the study. However, chest radiographs obtained 24 hours before the V/Q scans are acceptable in patients without worsening signs and symptoms. Different products, including inert gases (81mKr, 133Xe) and radiolabelled aerosols 99mTc-DTPA and 99mTc-labelled ultra-fine dispersion of technetium-labeled carbon, are used in mapping regional ventilation.

1) Radiolabelled Aerosols (for Ventilation Scan)

• 99Tc: 99Tc-DTPA is the most widely used radionuclide with a dosage of 900 to 1,300 MBq (25 to 35 mCi) with a photopeak of 140 keV.[5] 99mTc-Technegas is preferably used in SPECT, especially in COPD patients.[6][7]
• 81mKr: with a dosage of 40 to 400 MBq (1 to 10 mCi) and with a photopeak of 190
• keV.
• 133Xe: with a dosage of 200 to 750 MBq (5 to 20 mCi) and a photopeak of 81 keV.[3]

The pulmonary clearance of 99Tc-DTPA can be used to estimate the alveolar epithelial membrane integrity. In alveolar inflammatory conditions such as allergic or toxic alveolitis (smoking), the clearance rate would increase, therefore shortening 99Tc-DTPA half-life.[8]

2) Injectable Radionuclides (for Perfusion Scan)

•  99mTc-MAA: with a dosage of 40 to 150 MBq (1 to 4 mCi).[3]

The procedure is done in two phases first, the ventilation, then perfusion imaging. A disposable nebulizer is used to deliver the 99Tc-DTPA aerosol to the lung via a mouthpiece to perform the ventilation image. The patient should be upright or in a supine position with the nose occluded. 133Xe is preferred in assessing patients with obstructive airway disease.[3] To perform the perfusion image, the patient is instructed to cough and to take multiple deep breaths necessary before introducing the IV 99mTc-MAA. The vial containing 99mTc-MAA must be agitated, and the syringe must be inverted on withdrawal. Blood retraction into the syringe should be avoided to prevent imaging artifacts. 99mTc-MAA must be slowly delivered while the patient is breathing at their normal tidal volume and lying in a supine position.

Imaging Protocols: Different imaging protocols are utilized; V/Q imaging with SPECT (V/Q) is a widely accepted and practiced protocol or, in rare situations, planar scintigraphy (V/Q). Sometimes, perfusion-only scanning is performed. Many institutions during the COVID-19 pandemic opted to perform perfusion only scanning to minimize the dispersion/spread of SARS-CoV-2. V/Q may also be combined with CTPA or computed tomography. A systemic review performed on 23 prospective studies concluded that among 7000 patients in whom D-dimer assessment combined with clinical probability was inconclusive, a normal perfusion scan (Q scan) safely excluded pulmonary embolism.

1. V/Q SPECT Imaging Technique

Single-photon emission computed tomography (SPECT) obtains the image through multidetector gamma-cameras to generate three-dimensional images. SPECT showed higher sensitivity than the planar technique.[9] If the CTPA contrast and radiation exposure are contraindicated or must be avoided, the V/Q SPECT is considered the second-line diagnostic test.[10][11] Advantages of the V/Q SPECT technique:

• Low indetermination rate and more reproducibility [12][13]
• Greater sensitivity (97%) and specificity (91%) [14]
• New and advanced analytic data processing, such as V/Q ratio qualification [15]

2. V/Q Planar Imaging Technique

Planar imaging acquisition is a two-dimensional technique obtained through a dual-head gamma camera for ventilation and perfusion scans, respectively. Limited patient movement between the two scans is crucial.[9] This technique is used with at least four views when the V/Q SPECT is not feasible.[16]

Disadvantages of the V/Q planar technique:

• Two-dimensional images are compared with the advancing three-dimensional V/Q SPECT.
• Inaccurate determination of lung segmental involvement after the embolic event.[17]
• Inexact determination of the degree of perfusion defects.[18]

3. V/Q SPECT/CT Imaging Technique

In this technique, a low-dose CT scan is integrated with the functional SPECT to provide more detailed anatomic information. In practice, the CT image (without contrast) is usually taken after the perfusion scan.[10] Radiation exposure is the main disadvantage.

Advantages of SPECT/CT:

• More reliable detection of V/Q mismatch conditions than PE, such as in obstructive lung disease, external vascular compression, or neoplasm.[16]
• Better V/Q matching information due to non-embolic causes (pneumonia, pleural, or pericardial effusion). 
• Detection of PE cases in which V/Q is unusually matched, like PE, with an area of pulmonary infarction.[16]
• Carries the highest diagnostic accuracy.[19]

4. Combined V/Q SPECT with CTPA

It enables the radiologist to localize the clot site reported in the CT pulmonary angiography (CTPA).[10]

Indications

Ventilation-perfusion V/Q scanning is mostly indicated for a patient population in whom CTPA is contraindicated (pregnancy, renal insufficiency, chronic kidney disease stage 4 or more, or severe contrast allergy) or relatively inconclusive. The data are conflicting regarding the superiority of one modality (CTPA) over the other (V/Q) to diagnose PE in pregnant patients; however, V/Q is the test of choice in pregnant females with suspected PE who have a normal chest radiograph. V/Q scan can provide additional information to determine PE resolution, measure pulmonary functions before surgical intervention in lung cancer, may provide evidence of COPD, left heart failure, pneumonia, evaluation of congenital cardiac and pulmonary disorders (arteriovenous fistula), pulmonary arterial stenosis, cardiac shunts, evaluation of pulmonary hypertension, cystic fibrosis, and the diagnosis of bronchopleural fistulas.[18][20][21]

Potential Diagnosis

V/Q ratio is the ratio between air getting into the alveoli and the blood flow to the lungs. Ventilation, perfusion, and V/Q vary in different lung regions because of the effect of gravity and the differences in the sub-atmospheric intrapleural pressure. Both ventilation (V) and perfusion (Q) are higher at the lungs' bases than at the apex. However, the perfusion is proportionally higher than the ventilation at the base and vice versa at the apex. As a result, the V/Q ratio is low at the base and higher at the apex. Considering that ventilation equals approximately 4 L per minute and the perfusion equals 5 L/min, a normal V/Q level is 0.8.

Potential Differential Diagnosis Based on Mismatched V/Q Ratio

1. High V/Q ratio (>0.8)

It develops when ventilation exceeds perfusion.

Causes are:

• Lung regions with pulmonary blood flow obstruction, e.g., pulmonary embolism or non-embolic obstruction by tumor and/or radiation therapy 
• Cardiovascular shock
• Emphysema

2. Low V/Q ratio (<0.8)

It develops when perfusion exceeds ventilation. This can occur by either decreasing ventilation or increasing the perfusion without a change in ventilation.

Causes are:

• Pulmonary infections such as pneumonia
• Pulmonary edema
• Acute respiratory distress syndrome
• Alveolar collapse
• Asthma
• Eisenmenger syndrome
• Pulmonary AV communication
• Extrinsic compression of alveoli due to compression atelectasis
• In PE, over perfusion can occur in the normally ventilated regions where blood flow is diverted from the impaired blood flow region

Normal and Critical Findings

During the interpretation of ventilation-perfusion scintigraphy studies, ventilation and perfusion imaging are used in conjunction.

Three types of defects can be found:

1. Matched- ventilation and perfusion defects are concordant with each other. This occurs when the perfusion defect is in correspondence with the ventilatory abnormality. 
2. Mismatched- defect in perfusion with either normal or near-normal ventilation. Mismatched defects can be seen in pulmonary embolism, veno-occlusive disease, tumor obstructing an artery, or radiation therapy.
3. Reverse mismatched- defect in ventilation with either normal or less severe corresponding perfusion defect.

Defect size can be calculated as:

1. Large more than 75% of the segment 

2. Moderate 25 to 75% of the segment

3. Small less than 25% of the segment

Various criteria have been proposed to categorize the likelihood of PE.

• Original PIOPED criteria
• Modified PIOPED II criteria
• Perfusion-only modified PIOPED criteria
• Perfusion-only PISAPED criteria

Currently, the most commonly used criteria are:

1. Modified PIOPED II (prospective investigation of pulmonary embolism diagnosis)
2. PISAPED (the prospective investigative study of acute pulmonary embolism diagnosis)

The original PIOPED (prospective investigation of pulmonary embolism diagnosis) study classifies V/Q scan into high probability, intermediate probability, low probability, and indeterminate scan.

1. High Probability Scan:

• More than two large mismatched V/Q segmental defects.

2. Intermediate Probability Scan: 

• Two moderate or one large mismatched V/Q defect - difficult to categorize as high or low.

3. Low Probability Scan: 

• Non-segmental perfusion defects.
• Perfusion defect is substantially less than a chest X-ray defect.
• Matched V/Q defects, negative chest X-ray, and any number of small perfusion defects.

Modified PIOPED II criteria- Classifies V/Q scan as non-diagnostic, normal, very low probability, and high probability.

High Probability

• Two or more large mismatched segmental or segmental equivalent defects are present. 
• One segmental equivalent means a defect of more than 75% of a segment, and half segmental equivalent means a defect of 25 to 75%

Very Low Probability

• 1-3 small segmental defects
• Non-segmental perfusion defect
• Perfusion defect smaller than X-ray chest lesion
• Two or more matched defects with normal chest X-Ray
• Single matched defect in the mid or upper lung
• Solitary large pleural effusion
• Stripe sign (presence of peripheral perfusion in a defect)

Non-diagnostic

• All other findings

Normal: Diffuse homogeneous radiotracer activity on both perfusion and ventilation scans

PISAPED criteria are classified based on the following scan findings:

It is simple and eliminates nondiagnostic readings. It combines only the perfusion part of the V/Q scan with Chest X-Ray

PE Present

• One or more wedge-shaped perfusion defects

PE Absent

• No perfusion defects
• Non-wedge shaped perfusion defect
• Shape defects caused by the mediastinum, diaphragm, or an enlarged heart

Right-to-Left Shunt Study Interpretation

Presence of quantum mottling (QM), a randomly distributed clump of radioactivity present in soft tissues of the brain, trunk, or limbs. In addition to that, the fraction of the right-left shunt is calculated using (extra-pulmonary/total body ratio) of the injectable agent.[20]

Rule of V/Q scan in chronic obstructive pulmonary disease (COPD)- It is used to assess both early ventilation and perfusion defect in COPD in addition to the extent of the disease.[21] Preoperative lung scintigraphy- it provides more anatomical information. Additionally, ventilation and perfusion status are reported on each one of the six lung regions.[3] Interpretation of post-transplantation lung scintigraphy- it delineates the patency of pulmonary vascular anastomoses immediately after the transplantation. In addition to functional report for V/Q matching regionally.

Risk stratification of PE should be performed using a combination of pre-test probability by Well score and V/Q scan results. Data is suggestive that in the case of high clinical suspicion and high probability V/Q scan - the risk of PE increases to 96%. In low/intermediate or high clinical suspicion and normal or near-normal probability V/Q scan- the risk of PE is less than 10%. In low to intermediate clinical probability and high probability V/Q scans - the risk of PE is still more than 50%.

Interfering Factors

Few factors interfere with the quality of imaging and hence make interpretation challenging. These are:

• The decubitus position negatively affects the outcome and can show a picture of a mismatch. 
• The change in the position from upright in the ventilation scan to supine during the perfusion scan. 
• Inadequate distribution of the injectable agent when administered through a central line.
• Blood clotting during the injectable administration, which appears as a hot spot on the scan. 
• The presence of obstructive lung disease interferes with scan accuracy; thus, a bronchodilator should be used before the procedure. 
• Heart failure decreases scan accuracy.[3]

Complications

Ventilation-perfusion V/Q scan is a safe procedure and is generally well tolerated by patients. However, a few complications can occur.

1. Pain, redness, swelling, and bruising at the injection site.
2. Treatable allergic reaction to a radioactive isotope.
3. Exposure of radiation to the fetus, especially during the first trimester.

Patient Safety and Education

• The scan involves the risk of radiation exposure. However, the risk of radiation exposure is relatively lower than in other modalities like CTPE.
• The total duration of the procedure is about 30 minutes to an hour.
• Patients should be informed about the steps of the procedure. This involves inhalation of radioactive gas in the first part to look at the airways, followed by intravenous injection of a different radioactive material to see the blood flow in the lungs. Laying still in the scanner will enhance the quality of the images. 
• Overall, the test is safely tolerated by most patients. Redness and swelling might develop at the injection site. Allergic reaction to the radioactive material is a rare complication and can be treated as needed.
• There is no special preparation except for breastfeeding females.
• Lung scintigraphy is a nuclear medicine modality with low radiation exposure, and dose reduction is considered in the pregnant and pediatric groups.[22]
• The patient must be instructed about the procedure's steps, duration, and the negative impact of repeated movements. Pregnant women should be told about the fetus's minor risk due to radiation exposure, especially during the first trimester. Interruption of breastfeeding is recommended twelve hours before 99mTc-MAA administration only.

Clinical Significance

CTPA is the current standard of care; V/Q scan is preferred in patients where CTPA is not possible or is contraindicated. These include pregnant females, patients with renal failure, allergy to iodinated radiocontrast material, patients who cannot fit into a CT scanner, or in patients with low probability. It has 50-fold lower radiation dose exposure to breasts. A systemic review performed on 23 prospective studies concluded that among 7000 patients in whom D-dimer assessment combined with clinical probability was inconclusive, a normal perfusion scan safely excluded PE. The V/Q scan's specificity and sensitivity are 93% and 85%, respectively, using PIOPED II criteria and 97% and 80%, respectively, using PISAPED criteria, comparable to CTPA, that has specificity and sensitivity of 98% and 86%, respectively.