Exponential dosing to standardize myocardial perfusion image quality with rubidium-82 PET

To our knowledge, this is the first report of a patient-centered approach using exponential dosing to standardize image quality for 82Rb PET perfusion imaging. In the control group, when 82Rb activity was administered in proportion to patient weight (9 MBq·kg−1) image quality was observed to decrease significantly with increasing body weight (β values < 0). For each 10 kg increase in patient weight, the ECG-gated CNR decreased by approximately 10%. This is equivalent to 50% reduction in CNR when the patient weight is doubled from 50 kg (110 lbs) to 100 kg (220 lbs), similar to the reduction shown in the patient examples of Figure 6A and B. Conversely, in the experimental group (Figure 6C and D) using exponential dosing (0.1 MBq·kg−2) the image quality was more consistent (β values ≈ 0) with less than 10% variation on average across a wide range of patient weights ranging from approximately 50 to 120 kg. The biggest changes in activity occurred at the extremes of patient weight, essentially redistributing the population dose from the smaller to the larger patients as needed to standardize image quality.

Comparison to Guidelines and Previous Studies

The current ASNC guidelines advise either a constant dose for all patients or a proportional weight-based dose of 82Rb for PET perfusion studies,12 both of which have the limitation of producing lower quality images in obese patients. In the field of oncology PET, de Groot et al. found that 18FDG activity administered as a squared function of patient weight provided whole-body PET images of consistent quality, i.e., liver SNR no longer varied with patient weight.23 This exponential relation between 18FDG dose and body weight was also verified by Koopman24 for general implementation and independently by Musarudin et al.26 to provide constant liver image quality on a BGO PET-CT scanner. As a result of these studies, exponential or ‘quadratic’ dosing is now recommended for 18FDG PET-CT imaging in the most recent EANM procedure guidelines for tumor imaging.15 In the present study, the effects of exponential vs proportional 82Rb PET dosing on liver SNR were consistent with these previous studies of whole-body 18FDG PET.13,23,24,26,27 The de Groot model of image quality shown in Eq. 1 predicts that SNRLIVER will decrease inversely as the square of patient weight (β =  − 0.5) which is consistent with the mean value of − 0.48 observed in our control cohort (Table 3). This weight-dependence was effectively eliminated in the exponential dosing cohort with an average β < 0.01, reproducing the results demonstrated previously using 18FDG PET.

The effects of proportional dosing to produce constant LVMAX activity values in the heart (Figure 4) are partially consistent with results presented in the recent 82Rb PET study by van Dijk et al. who reported that the number of recorded ‘net’ coincidences (prompts–randoms) was constant over a wide range of patient weights.28 However, unlike this previous study which found no differences in body weight among the different categories of visual image quality with proportional dosing, the present study demonstrated statistically significant decreases in image quality (assessed visually and quantitatively) as a function of body weight, consistent with the model that was developed and validated previously for 18FDG whole-body PET.20,24 The pattern of decreasing image quality (despite constant tissue activity and ‘net’ coincidence counts) is likely due to the degrading effects of tissue attenuation on image quality. Our results suggest that the increasing noise effects of PET attenuation are approximately linear with patient weight, and these can be corrected with the exponential dosing protocol, to produce organ activity values that increase linearly with weight. It is surprising to us that van Dijk et al.28 did not find a significant weight-effect of image quality using their proportional dosing protocol, however there are some methodological factors in their study which may have contributed: 1. Indirect evaluation of the weight distribution of patients across different image quality scores, 2. PMT-based PET scanner with lower sensitivity and resolution, 3. Visual evaluation of static images only where noise effects are less apparent vs ECG-gated, 4. Use of a 82Rb generator system designed for single (constant) dose imaging.29

In contrast to our findings of improved standardization using exponential dosing with rubidium PET, a previous study with technetium SPECT perfusion imaging found that image noise in the LV myocardium could be standardized using the product of injected activity and scan-time adjusted as a proportional function of patient weight.30 While image quality using both these modalities is affected by the Poisson distribution of counting statistics, the noise effects and correction methods for the physical effects of scatter and attenuation (as well as random and prompt-gamma coincidences in PET) are quite different, which may explain the different results in SPECT vs PET.

Our results have important implications for pediatric imaging studies such as Kawasaki Disease where PET imaging has been used to guide clinical management.31 In children, the effective dose constant (radiation risk) is typically higher per unit activity injected (e.g., 4.9 vs 1.1 mSv·GBq−1 in a 5-year-old vs adult patient) reflecting the higher organ activity concentrations and smaller distances between organs.32 Our results suggest that the injected activity (and radiation effective dose) can be substantially reduced in the smallest patients while still maintaining diagnostic image quality.

Clinical implementation

The exponential dosing protocol for 82Rb was easy to implement clinically by the PET technologists as a simple calculation, i.e., activity = weight (kg) × weight (kg)/10. For example, an 85 kg patient would be prescribed the 82Rb dose of 85 × 8.5 = 722.5 MBq (19.5 mCi). Patients of 149 kg would be given the maximum dose of 2220 MBq (60 mCi) listed in the U.S. package insert25 or 3700 MBq (100 mCi) for a 193 kg (425 lbs) patient as listed in the Canadian monograph.33 The activity available from the 82Rb generator decreases over time according to the half-life of the parent 82Sr, from 3700 MBq on day 0 to 700 MBq on day 60. Therefore, to implement exponential 82Rb dosing in practice, patient scheduling needs to be adjusted accordingly, with maximum patient weights up to 193 kg on day 0 and up to 84 kg on day 60.

The present study results may be adapted to other PET perfusion imaging protocols, taking into account the differences in tracer retention fraction, isotope half-life, scan-time, and PET scanner sensitivity. 82Rb has approximately 30% tracer retention in the heart at a peak stress blood flow value of 3 mL·min−1·g−1, whereas other PET tracers such as 13N-ammonia or 18F-flurpiridaz have approximately 60% retention at peak stress, resulting in higher myocardial activity and image quality for the same injected dose.34 These longer half-life tracers typically require lower injected activity and scan-time that can be optimized for the desired image quality. These changes in imaging protocol should only affect the selected value of ε in Eq. 2, whereas the weight-dependence of cardiac PET image quality (β) is expected to remain the same regardless of these tracer and protocol changes. The present study value of ε = 0.1 MBq·kg−1 was selected to maintain the same 82Rb image quality as our previous clinical standard dosing protocol (9 MBq·kg−1) for our historical average patient weight of 90 kg. This value is higher than those reported previously (0.023 to 0.053 MBq·kg−2) to standardize 18FDG PET image quality, likely due to the ultra-short half-life of 82Rb resulting in much lower count-rate and image quality recorded per unit activity (MBq) injected. Exponential dosing for 13N-ammonia would likely use a value of ε closer to those used in prior 18FDG studies, as the typical scan times are close to the isotope half-life of 10 min.

Study limitations

The effects of exponential versus proportional dosing were evaluated only on stress perfusion image quality, however similar results are expected for perfusion imaging at rest. Only weight-based dosing was investigated in the present study, whereas other measures of patient body habitus such as body mass index, body surface area, chest circumference, etc. could be considered as the patient-specific factor used to prescribe the injected activity. Many of these factors were investigated in the original 18FDG study by de Groot which found that patient body weight was the best predictor of changes in image quality,23 therefore we followed the same approach and observed similar dosing protocol-dependent results for 82Rb PET.

Most of the patients evaluated in this study were in the range of 50 to 120 kg, however many patients at highest risk for CAD may be heavier than 120 kg. The maximum activity of 3700 MBq (100 mCi) available from the 82Rb generator33 enables exponential dosing in patients up to ≈ 190 kg (420 lbs), but further studies are needed to confirm effectiveness in this obese population, and to evaluate the trend toward improved image quality in the largest patients. The small reduction of injected activity in the exponential- vs proportional-dosing cohort was a by-product of our average cohort weight < 90 kg. Conversely, for patient populations > 90 kg the average injected activity is expected to increase if the same exponential dosing factor is used, i.e., ε = 0.1 MBq/kg2.

SNR in the LV myocardium could not be measured using the same method as the liver, i.e., SNRLV = LVMEAN/LVSD as the values of LVSD were not available in the Corridor-4DM analysis software, but could be the subject of future investigations. The values of LVSD would also be affected by variations in tracer uptake due to CAD, therefore any future studies of SNRLV would be recommended in subjects without CAD to ensure homogeneous tracer uptake.

We did not investigate the effects of exponential dosing on the quantification of myocardial blood flow (MBF). In a previous study, we have shown that PET detector saturation due to dead-time effects can bias the measurements of MBF when the bolus first-pass count-rate exceeds the scanner’s dynamic range.18 In centers performing MBF quantification, the injected activity must be kept below some maximum value which maintains accuracy of the bolus first-pass dynamic images, and this may limit the implementation of exponential dosing in larger patients. Saturation bias is PET scanner-specific and can be characterized easily as a function of the dynamic prompt coincidence count-rate.16,35 Unfortunately, these values are not saved currently in the reconstructed image DICOM headers by the PET vendor used in this study; this may limit the ability to perform routine quality assurance of MBF accuracy in clinical practice when using the exponential dosing protocol. In these patients there remains a trade-off between standardization of perfusion image quality versus accurate quantification MBF. The study of Moody et al. suggested that BMI-based dosing may be used to lower the incidence of PET saturation compared to proportional weight-based dosing.36 Patient BMI (kg/m2) is also proportional to weight therefore an exponential function of BMI may help to minimize saturation effects and maintain MBF accuracy while also standardizing 82Rb PET image quality.

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