Michel Leblanc

 *Nuclear Medicine Department Centre Hospitalier Régional de Trois-Rivières University of Montreal University of Sherbrooke Canada*

#### **1. Introduction**

140 Pulmonary Embolism

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the golden hour of hemodynamically significant pulmonary embolism. *Chest*,

Pulmonary embolism (PE) is a frequent and potentially lethal disease caused by the migration of a thrombus to the pulmonary circulation, typically from the venous system of the lower limbs. Unfortunately, there are no specific sets of symptoms which accurately predict or exclude the diagnosis. Therefore, in clinical practice, the diagnosis always strongly relies on imaging. On the other hand, clinical evaluation can predict the probability of embolism in a specific patient. This information can be used to select which patient can benefit most from imaging studies.

Historically, pulmonary angiography and planar ventilation perfusion (V/Q) scintigraphy were the main techniques available for identification of PE. Although traditionally viewed as the gold standard, pulmonary angiography is an invasive technique that suffers from significant limitations. It is not considered anymore as a suitable gold standard(Baile, King et al. 2000). V/Q scintigraphy was used extensively as a non-invasive alternative. It has a high sensitivity and a high negative predictive value. Unfortunately, the technique suffers from a large number of indeterminate studies in which the diagnosis of PE cannot be reliably confirmed or excluded. Indeed, in the PIOPED study, as much as 72% of cases were in that category. Although later studies substantially improved those numbers, the level of indeterminate findings remains high.

It is in that context that computed tomography pulmonary angiography (CTPA) emerged as an alternative non-invasive technique. CTPA carries the advantages of a much lower rate of indeterminate study and the ability to diagnose alternate conditions for the patient's symptoms. Also, the binary interpretation ("positive" vs "negative") was much more acceptable to physicians than the rather complex probabilistic system of V/Q scintigraphy. As such, it has become the principal imaging technique worldwide for the diagnosis of PE. In most centers, conventional planar V/Q scintigraphy is now a secondary technique used mainly when there are contraindications to CTPA or when CTPA is non-diagnostic or not available.

Nonetheless, CTPA also suffers from significant limitations. There are contraindications such as impaired renal function and allergies. The radiation dose is very high, especially to

Ventilation Perfusion Single Photon Emission

evaluation of true ventilation.

readily accomplished without artefacts.

**4. SPECT acquisition protocol** 

optimize their protocol.

then positioned under the camera for image acquisition.

Tomography (V/Q SPECT) in the Diagnosis of Pulmonary Embolism 143

particles that are generated at high temperature using a specialized oven. The particle sizes are typically 0,005 to 0,2 µm and have a high alveolar penetration index. Ventilation distribution is highly related to those obtained with Krypton 81m (Peltier, De Faucal et al. 1990; Cook and Clarke 1992). The term pseudogas has been used to describe the agent, a reflection of the fact that its behaviour during inspiration is close to that of a true gas. The superiority of Technegas to conventional DTPA aerosols has been demonstrated in COPD (Yogi et al. 2010). There is limited central deposition except in severe COPD. Underestimation of true ventilation is not a problem. The particles are cleared from the lungs with a biological half-life of about 5 1/2 days. The agent is thus ideal for SPECT

The perfusion technique has not changed significantly in last decades. It is accomplished by micro-embolization with radio-labelled particles injected into a peripheral vein. The particles are labelled with technetium-99m. Particle size is about 15 to 100µm. For a typical exam, about 400,000 labelled particles are injected. However, since there are about 300 million pre-capillary arterioles and 280 billion pulmonary capillaries, a very small percentage of the pulmonary circulation will be occluded. SPECT technique for perfusion is

In a clinical setting, ventilation is usually performed first with a smaller dose of radioactivity. Typically, the patient is asked to inhale Technegas through a tube set until the desired quantity of radioactivity is present in the lungs, typically 20-50 mega Becquerels (MBq). Usually, 2 to 5 breaths are required. The activity can be standardized in each department either through counting directly under the scintillation camera or with a portable Geiger counter. Patients are

The perfusion study is then performed with a higher dose of radioactivity. In most centers, a ratio of perfusion to ventilation activity of 4 to 1 is considered adequate. The injected dose should be tailored to insure such a ratio. Administered intravenous dose of labelled particles will typically be in the range of 100 to 250 MBq for most patients. Both ventilation and perfusion should be performed in the supine position to minimize regional gradients.

The protocol can be tailored to a certain point to the preference of the different centers. The number of tomographic steps should be at least 64 while 128 are considered optimal. Higher radiation doses will permit either higher-quality images or faster acquisition times. If a lower dose range is preferred, a general-purpose collimator which has a higher sensitivity (but a lower resolution) can be used. With such a collimator, using a 64 X 64 matrix, acquisition time can be as low as 5 second per step with perfusion and 10 seconds per step in ventilation in a 128 step protocol with 20-25 MBq in ventilation and 100-120 MBq in perfusion (Palmer, Bitzen et al. 2001). Using a high-resolution collimator and a matrix of 128 X 128 will produce higher-quality images at the expense of a higher radiation dose and longer acquisition times. Depending on the number of steps, the activity will be more in the range of 35-40 MBq in ventilation and 180-200 MBq in perfusion and the time per step will be 15-20 seconds in ventilation and 7-10 seconds in perfusion. Reconstruction of the data should be iterative using OSEM (ordered subset expectation maximization). Eight subsets and two iterations are recommended. Using a higher number of subsets and iterations may produce sharper images but noise will also be increased. However, every center can

the female breast. Also, the performance of CTPA in terms of sensitivity and specificity is far from optimal, especially when judged according to the results of the PIOPED II study, which showed significant inaccuracies when the CTPA result was not in line with the clinical probability.

Therefore, there is still a need for other techniques. In that context, Ventilation Perfusion Single Photon Emission Computed Tomography (V/Q SPECT) is rapidly emerging as an interesting alternative. V/Q SPECT is a natural 3D tomographic extension of the conventional V/Q planar technique. It is used in many centers in Europe, Australia and Canada as well as in Asia. Its use in the United States has unfortunately been limited by the absence of FDA approval of Technegas, a superior ventilation imaging agent which is essential for the implementation of V/Q SPECT.

## **2. Basis of emboli detection by nuclear techniques**

The major physiological consequence of PE is occlusion of a part of the pulmonary circulation. Usually, ventilation is preserved, resulting in increased dead space. Therefore, altered perfusion with normal ventilation is the usual consequence of PE. There are situations in which ventilation can be altered such as secondary lung infarct or atelectasis. In those cases, the chest x-ray is usually abnormal.

Nuclear techniques for the evaluation of regional ventilation and perfusion have existed for several decades. Ventilation is usually studied by inhalation of a radioactive gas or radioactive nebulised particles. Perfusion is studied by intravenous injection of radioactive particles (typically macroaggregates of albumin) which are trapped in the pulmonary circulation. In both cases, the distribution of radioactivity on the images is absolutely proportional to ventilation and perfusion. By comparing regional perfusion and ventilation, PE can be diagnosed as areas of absent perfusion with normal ventilation.

#### **3. Technical aspects of V/Q SPECT**

SPECT technique requires a ventilation agent which will distribute proportionately to true ventilation in the lungs. Also, once distributed, the agent has to remain fixed for the full period of the acquisition. Therefore, SPECT technique with a gas (xenon-133 or Krypton-81m) is not feasible with current technology, except if a steady state method is used which is complex and not practical in disease situations since it requires a high degree of patient collaboration with ventilation during the whole acquisition period. Therefore, evaluation of ventilation with gaseous agents is always done with a very limited number of planar views (often 1 or 2) and modern tomographic techniques (SPECT) are not clinically available.

SPECT is possible with radio-aerosols, such as DTPA-Tc99m, since these particles become impacted in the lung and their position remains relatively stable during the acquisition time. However, these aerosols, created by nebulisation, produce particles that are rather large (0,5 to 2,0 µm), that tend to deposit in the central airways to a certain degree, especially in chronic obstructive pulmonary disease (COPD). This leads to artefacts in the SPECT reconstruction and poor peripheral lung penetration. Images of suboptimal quality are produced, particularly in diseased lungs, in which mismatches can be missed or underestimated using these conventional aerosols.

Therefore, the use of newer generation ventilation agents such as Technegas is highly preferable. Technegas is an aerosol with very small technetium labelled solid graphite

the female breast. Also, the performance of CTPA in terms of sensitivity and specificity is far from optimal, especially when judged according to the results of the PIOPED II study, which showed significant inaccuracies when the CTPA result was not in line with the

Therefore, there is still a need for other techniques. In that context, Ventilation Perfusion Single Photon Emission Computed Tomography (V/Q SPECT) is rapidly emerging as an interesting alternative. V/Q SPECT is a natural 3D tomographic extension of the conventional V/Q planar technique. It is used in many centers in Europe, Australia and Canada as well as in Asia. Its use in the United States has unfortunately been limited by the absence of FDA approval of Technegas, a superior ventilation imaging agent which is

The major physiological consequence of PE is occlusion of a part of the pulmonary circulation. Usually, ventilation is preserved, resulting in increased dead space. Therefore, altered perfusion with normal ventilation is the usual consequence of PE. There are situations in which ventilation can be altered such as secondary lung infarct or atelectasis. In

Nuclear techniques for the evaluation of regional ventilation and perfusion have existed for several decades. Ventilation is usually studied by inhalation of a radioactive gas or radioactive nebulised particles. Perfusion is studied by intravenous injection of radioactive particles (typically macroaggregates of albumin) which are trapped in the pulmonary circulation. In both cases, the distribution of radioactivity on the images is absolutely proportional to ventilation and perfusion. By comparing regional perfusion and ventilation,

SPECT technique requires a ventilation agent which will distribute proportionately to true ventilation in the lungs. Also, once distributed, the agent has to remain fixed for the full period of the acquisition. Therefore, SPECT technique with a gas (xenon-133 or Krypton-81m) is not feasible with current technology, except if a steady state method is used which is complex and not practical in disease situations since it requires a high degree of patient collaboration with ventilation during the whole acquisition period. Therefore, evaluation of ventilation with gaseous agents is always done with a very limited number of planar views (often 1 or 2) and modern tomographic techniques (SPECT) are not clinically available. SPECT is possible with radio-aerosols, such as DTPA-Tc99m, since these particles become impacted in the lung and their position remains relatively stable during the acquisition time. However, these aerosols, created by nebulisation, produce particles that are rather large (0,5 to 2,0 µm), that tend to deposit in the central airways to a certain degree, especially in chronic obstructive pulmonary disease (COPD). This leads to artefacts in the SPECT reconstruction and poor peripheral lung penetration. Images of suboptimal quality are produced, particularly in diseased lungs, in which mismatches can be missed or

Therefore, the use of newer generation ventilation agents such as Technegas is highly preferable. Technegas is an aerosol with very small technetium labelled solid graphite

PE can be diagnosed as areas of absent perfusion with normal ventilation.

clinical probability.

essential for the implementation of V/Q SPECT.

those cases, the chest x-ray is usually abnormal.

**3. Technical aspects of V/Q SPECT** 

underestimated using these conventional aerosols.

**2. Basis of emboli detection by nuclear techniques** 

particles that are generated at high temperature using a specialized oven. The particle sizes are typically 0,005 to 0,2 µm and have a high alveolar penetration index. Ventilation distribution is highly related to those obtained with Krypton 81m (Peltier, De Faucal et al. 1990; Cook and Clarke 1992). The term pseudogas has been used to describe the agent, a reflection of the fact that its behaviour during inspiration is close to that of a true gas. The superiority of Technegas to conventional DTPA aerosols has been demonstrated in COPD (Yogi et al. 2010). There is limited central deposition except in severe COPD. Underestimation of true ventilation is not a problem. The particles are cleared from the lungs with a biological half-life of about 5 1/2 days. The agent is thus ideal for SPECT evaluation of true ventilation.

The perfusion technique has not changed significantly in last decades. It is accomplished by micro-embolization with radio-labelled particles injected into a peripheral vein. The particles are labelled with technetium-99m. Particle size is about 15 to 100µm. For a typical exam, about 400,000 labelled particles are injected. However, since there are about 300 million pre-capillary arterioles and 280 billion pulmonary capillaries, a very small percentage of the pulmonary circulation will be occluded. SPECT technique for perfusion is readily accomplished without artefacts.

In a clinical setting, ventilation is usually performed first with a smaller dose of radioactivity. Typically, the patient is asked to inhale Technegas through a tube set until the desired quantity of radioactivity is present in the lungs, typically 20-50 mega Becquerels (MBq). Usually, 2 to 5 breaths are required. The activity can be standardized in each department either through counting directly under the scintillation camera or with a portable Geiger counter. Patients are then positioned under the camera for image acquisition.

The perfusion study is then performed with a higher dose of radioactivity. In most centers, a ratio of perfusion to ventilation activity of 4 to 1 is considered adequate. The injected dose should be tailored to insure such a ratio. Administered intravenous dose of labelled particles will typically be in the range of 100 to 250 MBq for most patients. Both ventilation and perfusion should be performed in the supine position to minimize regional gradients.
