Pulmonary clearance of 99mTc-HMPAO aerosol

The clearance rate of inhaled aerosols of a lipophilic substance, 99mTc-HMPAO (Hexamethyl propylene amine oxime) was studied and compared to that of hydrophilic substances in 6 normal volunteers and 18 patients with lung diseases. The subject in sitting position inhaled a single deep breath of 99mTc-HMPAO aerosols, and held his breath about 30 sec. Then he continued to breath aerosols again for about 3 min. Radioactivity rapidly falls down during breath holding, to about 60% of the peak value (fast phase), with T 1/2 of 3.75 +/- 2.22 sec in 6 normal volunteers. This rapid phase was not appeared in hydrophilic aerosols with 99mTc-DTPA and 99mTc-pertechnetate and in lipophilic aerosol with 123I-IMP aerosol. The clearance of residual activity of 99mTc-HMPAO was slow with T 1/2 of 17.4 +/- 4.0 min. The T 1/2 of 99mTc-DTPA, 99mTc-pertechnetate and 123I-IMP were 50.2 +/- 20.9 min, 11.4 +/- 4.3, and 62.5 +/- 20.8 min respectively. 99mTc-HMPAO may cross transcellularly using the whole alveolar surface. The clearance of aerosols in the fast phase is rapid and depend on the regional perfusion. On the other hand, hydrophilic aerosol pass by an intercellular pathway and the clearance will be diffusion limited. As conclusion, inhalation study of 99mTc-HMPAO might be a new method to evaluate perfusion following ventilation study.     

A combined procedure for 99mTc aerosol ventilation and perfusion imaging

For several years, radioaerosols have been successfully used to provide detailed images of regional ventilation to aid in the differential diagnosis of pulmonary embolism. It has been widely advocated that the ventilation images should follow the perfusion scan and that the amount of aerosol deposited in the patient's lungs should be three times greater than the perfusion dose. We employed an alternative approach which avoided the deposition of an unpredictable amount of aerosol in individual patients. The aerosol study was performed first, and the activity of the microspheres used for the perfusion images was then tailored to the actual amount of aerosol which the patient had retained. This allowed a microsphere/aerosol activity ratio of 10:1 to be readily achieved, thus successfully masking the ventilation pattern by the perfusion activity. The faster biological clearance of 99mTc-DTPA aerosol from the lung fields, as compared to 99mTc-sulphur-colloid aerosol, allowed higher initial activities to be deposited in the lungs, thus enabling a high-resolution collimator to be used. When the perfusion study was delayed by 1 h (one effective half-life for the 99mTc-DTPA aerosol), it was not necessary to increase the perfusion activity required to mask the ventilation image.     

Investigation of pulmonary epithelial permeability in patients after hyperbaric oxygen therapy by 99mTc diethylenetriaminepentaacetic acid aerosol inhalation lung scintigraphy

The aim of this study was to evaluate the possibility of pulmonary epithelial permeability damage in patients after hyperbaric oxygen therapy (HBOT) by 99mTc diethylenetriaminepentaacetic acid (99mTc-DTPA) aerosol inhalation lung scintigraphy. Twenty-five controls and 21 patients with normal chest X-rays and no cigarette smoking for at least 1 year were recruited for the study. 99mTc-DTPA aerosol inhalation lung scans were performed after 20 HBOT sessions in 21 patients with refractory osteomyelitis or diabetic foot. The HBOT with 100% oxygen at 2.5 atm absolute for 100 min was performed five times a week. Clearance rates (%/min) of 99mTc-DTPA aerosol in each lung field were calculated from the dynamic images for 30 min. Clearance rates of 99mTc-DTPA aerosol were compared between patients and controls by the unpaired t test. Thirteen patients who had 99mTc-DTPA aerosol lung scans before and after HBOT therapy studies were tested for statistical significance by using the paired t test. There was no statistically significant difference (P>0.05, unpaired t test) between patients and controls in every lung field. For the 13 patients who had 99mTc-DTPA aerosol studies both before and after 20 HBOT sessions, the results also showed no statistically significant difference (P>0.05, paired t test). It is concluded that there was no demonstrable pulmonary epithelial permeability change under current clinical HBOT protocol.     

Detection of alveolar epithelial injury by<Superscript>99m</Superscript>Tc-DTPA radioaerosol inhalation lung scan following blunt chest trauma

DTPA clearance rate is a reliable index of alveolar epithelial permeability, and is a highly sensitive marker of pulmonary epithelial damage, even of mild degree. In this study, 99mTc-DTPA aerosol inhalation scintigraphy was used to assesss the pulmonary epithelial membrane permeability and to investigate the possible application of this permeability value as an indicator of early alveolar or interstitial changes in patients with blunt chest trauma. A total of 26 patients was chest trauma (4 female, 22 male, 31-80 yrs, mean age; 53+/-13 yrs) who were referred to the emergency department in our hospital participated in this tsudy. Technetium-99m diethylene triamine pentaacetic acid (DTPA) aerosol inhalation scintigraphy was performed on the first and thirtieth days after trauma. Clearance half times (T1/2) were calculated by placing a mono-exponential fit on the curves. Penetration index (PI) was calculated on the first-minute image. On the first day, mean T1/2 value of the whole lung was 63+/-19 minutes (min), and thirtieth day mean T1/2 value was 67+/-21 min. On the first day, mean PI values of the lung and 30th day mean PI value were 0.60+/-0.05, and 0.63+/-0.05, respectively. Significant changes were observed in radioaerosol clearance and penetration indices. Following chest trauma, clearance of 99mTc-DTPA increased owing to breakdown of the alveolar-capillary barrier. This increase in the epithelial permeability of the lung appears to be an early manifestation of lung disease that may lead to efficient therapy in the early phase.     

Pulmonary clearance of 99mTc-DTPA aerosol in patients with progressive systemic scleroderma]

Alveolar epithelial permeability was assessed in 32 patients with progressive systemic scleroderma (PSS), using 99mTc-DTPA aerosol. Immediately after the inhalation of 99mTc-DTPA aerosol for 3 to 6 minutes under normal tidal breathing, lung was imaged sequentially for 30 minutes from the posterior by a gamma camera and exponential fitting was processed on the time activity curve. T1/2 (min) was used as a parameter for the evaluation of permeability of alveolar epithelium. Patients with collagen disease showed shorter T1/2 (T1/2 = 43.7 +/- 23.8 min) than the normal volunteers (T1/2 = 76.8 +/- 8.7 min). No significant difference was observed between patients with or without interstitial changes on the chest CT. Significant correlation was not observed between T1/2 and %VC or %DLco. In 8 cases, studies were repeated in the interval of 3 to 19 months. Improvement of T1/2 was seen in 4 cases, independent of CT findings. These results suggest that 99mTc-DTPA aerosol clearance study provides information independent from other lung examinations, and may be useful for the assessment of lung interstitial changes in patients with PSS.     

Evaluation of the alveolar-capillary membrane permeability using 99mTc-HMPAO aerosols in severe diffuse interstitial fibrosis

Local information on permeability of the alveolar-capillary barrier (PACB) can be ascertained by parametric images, after inhalation of radioarosols and computer processing. Our aim is to compare the results of 99mTc-HMPAO aerosols on PACB studies with those of 99mTc-DTPA aerosols, a standard technique. We compared the two techniques in separate samples: normal controls and patients with severe lung interstitial pathologies. Perfusion studies using 99mTc-MAA have also been performed in all patients. The aerosols were produced using ultrasound and lowered surface tension solution of 99mTc-HMPAO and 99mTc-DTPA. The time-activity curves (TACs) for every pixel on the lung area were used to calculate the half-disappearance times (T1/2). Parametric images were then generated with those times. The comparison of the results obtained with 99mTc-HMPAO and 99mTc-DTPA aerosols suggests that the first ones are more specific for local alterations of the lung epithelial transport in the pathologies studied. This method distinguishes between permeability deficiency due to local perfusion decrease and ACB deterioration.     

Measurement of pulmonary epithelial permeability with Tc-DTPA aerosol

The rate at which inhaled aerosol of 99mTc-diethylenetriamine pentaacetate (DTPA) leaves the lung by diffusion into the vascular space can be measured with a gamma camera or simple probe. In normal humans, 99mTc-DTPA clears from the lung with a half time of about 80 minutes. Many acute and chronic conditions that alter the integrity of the pulmonary epithelium cause an increased clearance rate. Thus cigarette smoking, alveolitis from a variety of causes, adult respiratory distress syndrome (ARDS), and hyaline membrane disease (HMD) in the infant have all been shown to be associated with rapid pulmonary clearance of 99mTc-DTPA. Rapid clearance is also promoted by increased lung volume and decreased surfactant activity. Although the mechanism of increased clearance in pathological states is not known, the 99mTc-DTPA lung-clearance technique has great potential clinically, particularly in patients at risk from ARDS and HMD and in the diagnosis and follow-up of alveolitis.     

Impaired lung epithelial permeability in hepatitis C virus antibody positive patients detected by 99mTc-DTPA aerosol scintigraphy

Chronic hepatitis C virus (HCV) infection has been recently identified as an aetiological agent in idiopathic pulmonary fibrosis. The present study was designed to determine the pulmonary clearance rate of 99mTc-diethylenetriaminepentaacetic acid (99mTc-DTPA) in asymptomatic HCV antibody positive (HCV Ab+) patients and the role of 99mTc-DTPA aerosol scintigraphy in the early detection of lung involvement. Twenty-six non-smoker HCV Ab+ and HCV-RNA (+) patients (20 female, six male; aged 43+/-11 years), with no clinical pulmonary symptoms, and normal radiological findings, were studied. Thirty-one healthy non-smoker volunteers (24 female, seven male; aged 40+/-10 years) were taken as a control group. 99mTc-DTPA aerosol inhalation scintigraphy and pulmonary function tests were performed in all patients and in controls. On the basis of the scintigrams the percentage decline in activity per minute (Kep) was evaluated, which represented an accurate parameter of lung membrane permeability. The mean Kep values of healthy controls (0.78+/-0.13 for left lung, 0.79+/-0.14 for right lung) were significantly lower than HCV Ab+ patients (1.10+/-0.31 for left lung, 1.11+/-0.34 for right lung, P<0.001). But no significant change was observed in PFT (P>0.05). We conclude that subclinical alveolitis and/or interstitial lung disease may be present in patients with HCV Ab+, since it is known that an increase in the epithelial permeability of the lung is an early manifestation of interstitial disease.     

Characterization of the generation of radiolabeled monodisperse albuterol particles using the spinning-top aerosol generator.

Inhaled radiolabeled aerosols provide invaluable information about in vivo drug deposition. Here, we report our methodology for radiolabeling and imaging monodisperse pharmacologic aerosols in order to study basic aerosol science concepts of drug delivery within the human airways. METHODS: We used a spinning-top aerosol generator to produce (99m)Tc-labeled monodisperse albuterol sulfate aerosols of 1.5-, 3-, and 6- micro m mass median aerodynamic diameter. RESULTS: In vitro Andersen cascade validation data showed that technetium and albuterol were coassociated on each impactor stage for all 3 aerosols, and the radiolabeling process itself did not affect their particle size distributions. Good-quality gamma-camera scintigraphic images of lung and extrathoracic deposition were obtained within an asthmatic patient. CONCLUSION: We have successfully radiolabeled and imaged monodisperse albuterol aerosols within the human lungs. This novel technique provides an important tool to relate fundamental concepts of aerosol particle behavior, in vivo deposition, and therapeutic clinical response.     

Dynamic pulmonary scintigraphy with Tc99m radioaerosol for the evaluation of the permeability of the alveolo-capillary barrier

Pulmonary clearance of small droplet 99mTc-DTPA radioaerosol was studied in 100 patients (12 normal subjects, N; 10 asymptomatic healthy smokers, FA; 31 patients with interstitial lung diseases, IP; 47 patients with chronic obstructive lung disease, BPCO). The first seven minutes of clearance were described with the function At = Ao*exp (-K*t) and the time constant K was considered representative of the 99mTc-DTPA clearance rate and hence of the alveolar-capillary barrier permeability. Groups FA, IP and BPCO showed a significant (p less than 0.05) or a highly significant (p less than 0.01) increase in permeability when compared to group N. No correlation was found between permeability and bronchial obstruction tests. The following conclusions were drawn: --99mTc-DTPA dynamic lung scanning is an easy, non-invasive method to assess derangements of alveolar-capillary barrier permeability secondary to epithelial damage; --permeability increase is a very early effect of cigarette smoke damage to the epithelium; --other mechanisms of epithelial injury are present in diffuse lung disease; --while the clinical role of this new pathophysiological test is not yet clear, it is likely that it may become a very early marker of pulmonary epithelial damage in diffuse lung disease.     

Difference in inhaled aerosol deposition patterns in the lungs due to three different sized aerosols.

Deposition patterns of inhaled aerosol in the lungs were studied in five normal subjects and 20 patients with lung disease by inhaling radioaerosols with three different particle size distributions. These aerosols were generated from BARC, UltraVent, and Mistogen-EN-142. Particle size distributions generated by these three nebulizers were 0.84, 1.04 and 1.93 microns in activity median aerodynamic diameter (AMAD) with its geometric standard deviation (sigma g) of 1.73, 1.71 and 1.52, respectively. Deposition patterns of inhaled aerosols were compared qualitatively and quantitatively by studying six different parameters: alveolar deposition ratio (ALDR), Xmax, Xmean, standard deviation (S.D.), skewness and kurtosis of the radioactive distribution in the lungs following inhalation. It has been found that aerosol deposition patterns varied with particle size. The unevenness of aerosol deposition, Xmax, Xmean and the number of 'hot spots' became more prominent with the increase in particle size, whereas values of ALDR and S.D. decreased as particle size increased. Knowing these deposition characteristics would facilitate a judicious application of aerosol inhalation to medical use.     

The APE nebuliser--a new delivery system for the alveolar targeting of particulate technetium 99m diethylene triamine penta-acetic acid

We report the validation of a new delivery system--aerosol production equipment (known by the acronym APE), which generates a particulate aerosol of technetium 99m diethylene triamine penta-acetic acid (DTPA) with a mass-median aerodynamic diameter of 0.35 microns and a geometric standard deviation of 1.8 Twenty subjects were studied; in group 1 were 12 healthy men with normal spirometry; in group 2 were 8 men with AIDS who had mildly abnormal lung function following an episode of pneumocystis pneumonia-spirometry FEV1 3.08 (0.73) L, FVC 4.83 (0.82) L [mean (SD)]. The APE nebulizer was used to form a particulate aerosol with 200 MBq of 99mTc DTPA, which was collected in a 35 1 reservoir of air, which was subsequently inhaled. The mean (SD) inhalation time was 4.7 (0.44) min. The output of the nebulizer (% of activity inhaled) was 82%. Using planar imaging, the penetration index (right lung) in group 1 was 0.93 (0.18), mean (SD), and in group 2 it was 0.91 (0.12). There was virtually no tracheal deposition and extrapulmonary deposition (oropharynx and stomach) was less than 5% of the aerosol delivered. Single-photon emission tomography (SPET) studies carried out in five patients from group 1 confirmed homogeneous intrapulmonary deposition of 99mTc-DTPA. In view of the excellent intrapulmonary deposition of 99mTc-DTPA produced by the APE nebulizer, it may provide an alternative to conventional ventilation studies using radioactive gases.     

Ventilation scintigraphy with lipophilic cationic compounds

OBJECTIVE: On the basis of our hypothesis that lipophilic cations may be more suitable for ventilation lung scintigraphy than the conventional technetium-99m diethylenetriamine penta-acetic acid (Tc-DTPA), comparative studies were carried out. BASIC METHODS: The nebulization potential of nine routine radiopharmaceuticals was compared on medical and scintigraphy-specific nebulizers. This was followed by ventilation scintigraphy in 14 patients with chronic obstructive airway disease (n=13) or pulmonary embolism (n=1) where either 99mTc-methoxyisobutylisonitrile (n=10) or Tc-tetrofosmin (n=4) was used. Same-patient comparison with 99mTc-DTPA ventilation scan was available in six patients using the same acquisition protocol. Comparison with 99mTc-DTPA was made with respect to the nebulization rates, radioactivity delivered per unit of radioactivity available for inhalation, and regional distribution of inhaled counts. RESULTS: Lipophilic cation solutions had a significantly higher nebulization rate compared with 99mTc-DTPA using the medical nebulizer (235%, P<0.01) and 370% on scintigraphy-specific nebulizer (P<0.01). More than three times the counts of 99mTc-methoxyisobutylisonitrile or 99mTc-tetrofosmin was deposited in the body compared with Tc-DTPA aerosol per megabecquerel activity inhaled (1.5 vs. 0.4 kcounts/MBq) (P<0.001), preferentially in the lungs (75.2 vs. 65.2%), at the expense of oropharynx and stomach. Within the lungs, about 50% more counts were deposited in the outer one-third lung with lipophilic cations. Overall, therefore, more than 12 times the radioactivity deposition was achieved in the peripheral one-third of the lungs with the lipophilic cations. CONCLUSION: Ventilation lung scanning with lipophilic cations is a viable substitute of nanoparticle scintigraphy (technegas and pertechnegas, which are expensive and technically far more demanding).     

Mismatch between 99mTc-DTPA aerosol and 81mKr lung ventilation scintigraphy: a pitfall of radionuclide imaging

Pulmonary ventilation and perfusion scintigraphies were performed using 99mTc-MAA, 81mKr, and 99mTc-DTPA aerosol in a patient with asthma. Lung perfusion scintigraphy and 99mTc-DTPA aerosol scintigraphy showed multiple matching defects, however, 81mKr ventilation scintigraphy showed mismatch with lung perfusion scintigraphy. A pitfall of this examination was discussed.     

Chemical breakdown of technetium-99m DTPA during nebulization

Aerosols of 99mTc diethylenetriaminepentaacetic acid ([99mTc]DTPA) used for measuring lung permeability and lung ventilation require a radioaerosol delivery system to produce an aerosol with reproducible size and radiochemical purity. To test how well nebulizers meet this requirement, radiochemical purity of aerosols produced with a jet and an ultrasonic nebulizer was evaluated. The activity median aerodynamic diameter (AMAD) and geometric standard deviation (sigma g) of radioaerosols were 0.46 micron (sigma g = 1.6) for the jet nebulizer and 0.70 micron (sigma g = 1.7) for the ultrasonic nebulizer. Paper and liquid chromatographic assays were obtained on the [99mTc]DTPA aerosol solute produced with each nebulizer. The results of these tests showed major differences in radiochemical purity. Aerosols produced in the jet nebulizer consistently showed greater than 90% of the radioactivity bound to the DTPA ligand whereas aerosols produced in the ultrasonic nebulizer showed less than 10% of the radioactivity bound to DTPA. The results support the need to test radiochemical purity of aerosols before using an aerosol nebulizer for pulmonary imaging and clearance studies.     

Aerosol deposition and clearance measurement: a novel technique using dynamic SPET

Planar gamma camera scintigraphy is a well-established technique for characterising the deposition and clearance of radiolabelled aerosols. While single-photon emission tomography (SPET) can offer superior assessment of radioaerosol deposition and better differentiation between peripheral and central deposition, the long acquisition times of single-headed SPET have largely prevented its use for measuring clearance or deposition of fast-clearing radioaerosols. This study investigated the feasibility of fast dynamic SPET imaging (1 min/frame) using a three-headed gamma camera to assess the regional and total deposition and clearance of different radioaerosols over a period of 26 min. Six subjects inhaled nebulised technetium-99m diethylene triamine penta-acetic acid radiolabelled aerosols with small and large droplet sizes [mass median aerodynamic diameter (MMAD) 3.2 +/- 0.2 and 6.5 +/- 0.2 microm, span 1.8 and 1.7, respectively] and in normal (0.9%) or hypertonic (7%) saline with controlled breathing on four separate occasions. The penetration indices (PIs) calculated from the SPET data for normal saline were 0.50 +/- 0.04 and 0.36 +/- 0.02 for the small and large droplet sizes, respectively. Consistent with the hygroscopic growth of the hypertonic aerosols, the PIs for hypertonic saline were lower, at 0.43 +/- 0.02 and 0.34 +/- 0.02 for the small and large droplet sizes, respectively. PIs calculated from the planar data showed similar trends, but failed to detect the significant difference seen with SPET between small normal and small hypertonic saline radioaerosols. In conclusion, the feasibility of using fast dynamic SPET for imaging radioaerosol deposition and associated radiolabel clearance in the lung has been successfully demonstrated. The fast SPET was able to reveal important differences in aerosol deposition that were not detected by planar imaging.     

Kit preparation of technetium-99m-mercaptoacetyltriglycine: analysis, biodistribution and comparison with technetium-99m-DTPA in patients with impaired renal function

Technetium-99m-mercaptoacetyltriglycine (99mTc-MAG3) was prepared by a frozen solution method, enabling the preparation of kits yielding a product substantially free of lipophilic impurities (96% 99mTc-MAG3). However, biliary activity was not completely eliminated as HPLC-purified 99mTc-MAG3 was also excreted by that route. Sequential 99mTc-DTPA and 99mTc-MAG3 renal scans were performed in 15 patients with renal dysfunction, including renal transplant recipients. In all cases, the 99mTc-MAG3 kit preparation provided superior images to 99mTc-DTPA at all levels of renal function due to a higher target-to-background ratio and a plasma clearance twice as fast as 99mTc-DTPA. Interpretation of delayed 99mTc-MAG3 images, however, was complicated by biliary excretion which will limit quantitative estimates of renal clearance. A 99mTc-MAG3 kit is likely to be of value in renal transplant assessment and in cases of significant renal impairment but would not appear to offer major advantages over 99mTc-DTPA in routine renal imaging.     

Determining the influence of biocompatible oxygenators during cardiopulmonary bypass by 99m Tc-DTPA aerosol assessment of pulmonary permeability

Changes in pulmonary permeability provide a partial measure of the clinical impact of biocompatible oxygenator use during cardiopulmonary bypass surgery. Previous research has shown that the clearance rate of 99mTc-labelled diethylene triamine penta-acetic acid (99mTc-DTPA) aerosol from the lungs is increased following cardiopulmonary bypass, resulting from an increase in pulmonary permeability. The aerosol clearance rate has been shown to return to normal after a period of 7 days. A blind trial was set up to assess the clinical impact of a biocompatible, Trillium-coated oxygenator compared with a standard oxygenator. In a group of 25 patients 99mTc-DTPA aerosol studies were carried out prior to cardiopulmonary bypass surgery for mitral valve surgery. Repeat studies were undertaken 3-4 h and 24-28 h after surgery. Analysis of the rates of pulmonary clearance reproduced the trends seen in earlier research. There was however no statistically significant difference in the variation of serial clearance times between the groups of patients undergoing surgery using the Trillium-coated oxygenators and those using the standard oxygenators.     

Technegas and Pertechnegas particle size distribution

Technegas and Pertechnegas are radioactive aerosols produced in a commercial generator and used for lung scintigraphy. The aerosols are produced by first evaporating to dryness standard technetium-99m generator eluate (^99m-TcO₄ in normal saline) in a graphite crucible (thesimmer stage) and then heating this to 2500° C (the burn stage). The aim of this work was to measure the particle size distributions of these agents and relate this to regional lung deposition. Factors that may vary during production of the aerosol in routine use were investigated to determine whether they influenced the particle size. Activity size distributions were measured using a serial wire-screen diffusion battery. The Technegas size distribution was approximately log-normal with an activity median diameter of 158 nm and a geometric standard deviation of 1.5. The results for Pertechnegas were similar. The median size increased with the number of simmers and with the time from generation. The increase in size with the number of simmers is thought to be due to the increased salt content in the crucible prior to the burn. The predicted lung deposition is 37% in the alveolar region and 5% in the bronchial region. Significant changes in deposition are not predicted over the range of particle sizes measured.