technetium-tc-99m-sulfur-colloid and Cystic-Fibrosis

New measures are needed to rapidly assess emerging treatments for cystic fibrosis (CF) lung disease. Using an imaging approach, we evaluated the absorptive clearance of the radiolabeled small molecule probe diethylene triamine penta-acetic acid (DTPA) as an in vivo indicator of changes in airway liquid absorption. DTPA absorption and mucociliary clearance rates were measured in 21 patients with CF (12 adults and nine children) and nine adult controls using nuclear imaging. The effect of hypertonic saline on DTPA absorption was also studied. In addition, in vitro studies were conducted to identify the determinants of transepithelial DTPA absorption. CF patients had significantly increased rates of DTPA absorption compared with control subjects but had similar mucociliary clearance rates. Treatment with hypertonic saline resulted in a decrease in DTPA absorption and an increase in mucociliary clearance in 11 out of 11 adult CF patients compared with treatment with isotonic saline. In vitro studies revealed that ∼ 50% of DTPA absorption can be attributed to transepithelial fluid transport. Apically applied mucus impedes liquid and DTPA absorption. However, mucus effects become negligible in the presence of an osmotic stimulus. Functional imaging of DTPA absorption provides a quantifiable marker of immediate response to treatments that promote airway surface liquid hydration.

Topics: Adult; Aerosols; Case-Control Studies; Cells, Cultured; Child; Cystic Fibrosis; Female; Humans; Image Processing, Computer-Assisted; Male; Middle Aged; Mutation; Osmosis; Pentetic Acid; Radionuclide Imaging; Radiopharmaceuticals; Spirometry; Technetium Tc 99m Sulfur Colloid; Treatment Outcome; Young Adult

Aerodynamic forces provide the primary means of distributing aerosol medications within the lungs. Partial airway obstructions can limit both air flow and aerosol penetration into diseased zones. We hypothesize that low surface tension additives may help to disperse aerosol medications after deposition in the airways, improving dose uniformity and drug delivery to underventilated regions. To test this, we performed a pilot scintigraphy study of surfactant and saline deposition and postdeposition dispersion.. Because inhaled antibiotics for cystic fibrosis provide an example of where self-dispersing medications may be useful, we administered calfactant and saline aerosols with added Technetium 99m sulfur colloid (Tc-SC; 100 nm filtered) on different days in randomized order to eight cystic fibrosis (CF) subjects (average FEV(1)%, p=85 ± 12%). Nebulized delivery was matched (similar aerosol sizes and volume delivery rates, fixed breathing patterns). Tc-SC distribution in the lungs was imaged continuously for 30 min after delivery.. Both aerosols were well tolerated. Aerosol distribution was mostly peripheral (58/42%) and initially similar for saline and surfactant. Changes in whole lung counts after 30 min were also similar. Peripheral lung activity decreased more rapidly on average with calfactant though the difference versus saline was not statistically significant. Central to peripheral count ratio decreased with saline and increased with calfactant and c/p changes approached significance (-0.05 ± 0.16 vs. 0.10 ± 0.10; p=0.07 Wilcoxon).. Our results lack statistical significance, but suggest that inhaled calfactant increased peripheral clearance, due to either surfactant-based dispersion or mucociliary effects. Further studies are needed to define the potential for low surface tension carriers to improve drug delivery.

Topics: Administration, Inhalation; Adult; Aerosols; Airway Obstruction; Biological Products; Cystic Fibrosis; Drug Delivery Systems; Female; Humans; Lung; Male; Middle Aged; Nebulizers and Vaporizers; Particle Size; Pilot Projects; Pulmonary Surfactants; Radionuclide Imaging; Technetium Tc 99m Sulfur Colloid; Time Factors; Young Adult

Heterogeneity of inhaled particle deposition in airways disease may be a sensitive indicator of physiologic changes in the lungs. Using planar gamma scintigraphy, we developed new methods to locate and quantify regions of high (hot) and low (cold) particle deposition in the lungs.. Initial deposition and 24 hour retention images were obtained from healthy (n=31) adult subjects and patients with mild cystic fibrosis lung disease (CF) (n=14) following inhalation of radiolabeled particles (Tc99m-sulfur colloid, 5.4 μm MMAD) under controlled breathing conditions. The initial deposition image of the right lung was normalized to (i.e., same median pixel value), and then divided by, a transmission (Tc99m) image in the same individual to obtain a pixel-by-pixel ratio image. Hot spots were defined where pixel values in the deposition image were greater than 2X those of the transmission, and cold spots as pixels where the deposition image was less than 0.5X of the transmission. The number ratio (NR) of the hot and cold pixels to total lung pixels, and the sum ratio (SR) of total counts in hot pixels to total lung counts were compared between healthy and CF subjects. Other traditional measures of regional particle deposition, nC/P and skew of the pixel count histogram distribution, were also compared.. The NR of cold spots was greater in mild CF, 0.221±0.047(CF) vs. 0.186±0.038 (healthy) (p<0.005) and was significantly correlated with FEV1 %pred in the patients (R=-0.70). nC/P (central to peripheral count ratio), skew of the count histogram, and hot NR or SR were not different between the healthy and mild CF patients.. These methods may provide more sensitive measures of airway function and localization of deposition that might be useful for assessing treatment efficacy in these patients.

Topics: Administration, Inhalation; Adult; Case-Control Studies; Cystic Fibrosis; Female; Forced Expiratory Volume; Humans; Image Interpretation, Computer-Assisted; Lung; Male; Particle Size; Predictive Value of Tests; Radionuclide Imaging; Radiopharmaceuticals; Respiratory Mechanics; Severity of Illness Index; Technetium Tc 99m Sulfur Colloid

Gastrointestinal disturbances are common in people with cystic fibrosis (CF); however, motility studies in this population have yielded inconsistent results. This study examined gastric emptying (GE) and small bowel transit (SBT) time in children with CF and pancreatic insufficiency compared with a healthy adult reference group.. Participants consumed an 8-ounce liquid test meal (approximately 550 calories, 32 g of fat) labeled with 300 μCi 99m technetium (Tc) sulfur colloid. Subjects with CF received a standard dose of pancreatic enzymes before consuming the test meal. GE and SBT were measured using a standard nuclear medicine scan. GE was determined after correcting for 99mTc decay in both anterior and posterior images. SBT was determined by following the movement of the tracer from the stomach to the cecum. The percentage arrival of total small bowel activity at the terminal ileum and cecum/ascending colon at 6 hours was used as an index of SBT. A 1-way analysis of covariance was performed for comparisons between groups after adjustment for age, sex, and body mass index.. Subjects with CF (n = 16) had similar GE compared with the healthy reference group (n = 12); however, subjects with CF had significantly prolonged SBT time. At 6 hours, 37.2% ± 25.4% (95% CI 23.7-50.7) of the tracer reached the terminal ileum and colon compared with 68.6% ± 13.1% (95% CI 60.2-76.9) for the reference group (P < 0.001). After controlling for sex, age, and body mass index, this difference remained statistically significant (F = 12.06, adjusted R = 0.44, P < 0.002).. Children with CF and pancreatic insufficiency had unaltered GE but delayed SBT time when taking pancreatic enzymes.

Topics: Adolescent; Adult; Cystic Fibrosis; Dietary Supplements; Enzyme Replacement Therapy; Exocrine Pancreatic Insufficiency; Female; Gastrointestinal Motility; Gastrointestinal Transit; Humans; Intestinal Diseases; Intestine, Small; Male; Pancrelipase; Postprandial Period; Radiopharmaceuticals; Technetium Tc 99m Sulfur Colloid; Young Adult

Targeting adenoviral vectors for cystic fibrosis gene therapy to the human airways with minimal exposure to alveoli would avoid adverse reactions and maximize response. At present, to deliver gene therapy vectors, large volumes of fluid are instilled or nebulized as aerosols. Either approach would likely cause alveolar exposure and increases the potential for side effects. We describe a coarse spray delivery device that precisely and reproducibly delivers the viral vector to the human airways to treat a small region of the airways for clinical trials. An endoscopic washing pipe (Olympus) that can be inserted into the channel of a bronchoscope was used. To minimize the escape of the therapeutic material downstream from the site of administration, we restricted the volume delivered to <150 microl (to prevent bulk flow), and used large droplets. Their high velocity further enhanced the probability of impaction in the vicinity of the nozzle. A pneumatic dosing system (Kahnetics) was used to reproducibly deliver the spray. The droplet size distribution was determined by laser diffraction and confirmed by cascade impaction: 190-microm volume median diameter with 1% mass <10 microm. The localization of the spray was studied in hollow cast models of human airways. 99mTc-sulfur colloid was used as a radiolabeled marker for these studies. Localization of the deposited spray was determined by scintigraphy and by measuring the radioactivity exiting the terminal airways. In the lung casts the spray was localized to one or two generations over an approximately 2-cm2 area. We conclude that delivery of large droplet sprays limits exposure to a few generations and may be useful in topical gene delivery clinical trials.

Topics: Adenoviridae; Administration, Inhalation; Aerosols; Cell Line; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Dose-Response Relationship, Drug; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Humans; Lung; Models, Anatomic; Particle Size; Technetium Tc 99m Sulfur Colloid

This paper reports on a large retrospective analysis of mucociliary clearance (MCC) studies in a group of 59 patients with cystic fibrosis (CF) and 17 age-matched healthy subjects. As many of the CF patients were studied on multiple occasions, a total of 184 patient studies are presented. MCC was measured using a radioaerosol and gamma camera technique. In addition to whole lung clearance, MCC was measured from the central, intermediate, peripheral, basal, mid and apical regions of the lung. MCC was markedly decreased in the CF patient group. Not only was whole lung clearance (14.2 +/- 1.4% vs. 28.0 +/- 3.7%) impaired, but also clearance from the central (19.1 +/- 1.9% vs. 35.6 +/- 4.3%), intermediate (10.7 +/- 1.6% vs. 25.5 +/- 3.7%), apical (12.4 +/- 2.6% vs. 31.6 +/- 4.6%) and mid (14.0 +/- 1.9% vs. 30.4 +/- 4.0%) regions. Attempts were made to identify factors that may have influenced MCC in both the normal subjects and CF patients. Age, gender, body mass index, patient genotype, penetration index, spontaneous cough, and various lung function parameters were entered into a stepwise multiple regression model, but none of the factors proved to be statistically important in determining MCC. Both intrasubject repeatability and intersubject variability estimates are presented for the patients and normal subjects that had multiple studies. The values were found to be remarkably similar for both CF patients and normal subjects and for both intra- and intersubject repeatability. With marked deviation from normal ranges and good repeatability, the measurement of MCC in CF patients would seem to be a valuable outcome measure for clinical trials involving new pharmaceuticals and physical therapy designed to improve removal of secretions from the airways.

Topics: Adolescent; Adult; Aerosols; Analysis of Variance; Case-Control Studies; Cystic Fibrosis; Female; Gamma Cameras; Humans; Image Processing, Computer-Assisted; Male; Mucociliary Clearance; Radionuclide Imaging; Regression Analysis; Reproducibility of Results; Respiratory Function Tests; Retrospective Studies; Technetium Tc 99m Sulfur Colloid

In patients with cystic fibrosis (CF), dehydration of airway secretions leads to a decrease in mucociliary clearance (MCC). We examined the acute effect of MCC of a single administration by aerosolization of hypertonic saline (7%) (HS), amiloride (0.3% in 0.12% NaCl) (AML) and a combination of AML and HS (AML + HS) in 12 patients with CF using a radioaerosol technique. Isotonic saline [0.9%] (IS) was used as a control solution. As both the AML and HS solutions induced cough in some patients, the last nine patients studied also underwent a cough clearance day. This was to eliminate the possible confounding effect of cough on MCC measurement. Patients ranged from 18 to 28 yr (mean +/- SD, 22 +/- 3) with an FEV1 of 27 to 112% predicted (61 +/- 30%). Following deposition of the radioaerosol, baseline clearance was assessed for 30 min. This was followed by a 30-min intervention period. Assessment of post-intervention clearance for a further 30 min was then performed. Comparison of the amount of radioaerosol cleared from the right lung was made at 60 min (%C60) and 90 min (%C90) using repeated measures ANOVA. The percent cleared at 60 and 90 min was significantly increased with HS (%C60 = 26.5%, %C90 = 29.4%) and the combination of AML + HS (%C60 = 23.1%, %C90 = 27.4%) compared with both IS (%C60 = 14.7%, %C90 = 17.5%) and COUGH (%C60 = 18.0%, %C90 = 19.5%), p < 0.01. Inhalation of hypertonic saline is a potentially useful treatment in patients with cystic fibrosis.

Topics: Adolescent; Adult; Aerosols; Amiloride; Analysis of Variance; Confounding Factors, Epidemiologic; Cough; Cystic Fibrosis; Drug Combinations; Expectorants; Female; Forced Expiratory Volume; Humans; Isotonic Solutions; Lung; Male; Mucociliary Clearance; Saline Solution, Hypertonic; Technetium Tc 99m Sulfur Colloid

We compared bronchopulmonary distribution homogeneity of a radioaerosol before and after hospitalization in 20 patients with cystic fibrosis (CF) with pulmonary exacerbations in order to assess lung improvement. Deposition homogeneity was quantified in terms of skew (an index of distribution symmetry), derived from frequency distribution histograms generated from gamma camera images of the lungs following radioaerosol inhalation. Lower skew values indicate enhanced distribution homogeneity. Right lung skew (RLS) was significantly reduced following therapy (1.00 +/- 0.49 to 0.84 +/- 0.47), whereas skew in the left lung was unchanged (0.95 +/- 0.38 to 0.87 +/- 0.40). The reduction in RLS was significant in patients with Shwachman-Kulczycki (SK) clinical scores less than 50 (1.27 +/- 0.53 to 0.90 +/- 0.42), but not in patients with scores greater than 50 (0.81 +/- 0.38 to 0.80 +/- 0.52). These results indicate that treatment affected the right lung more than the left lung, particularly in patients with SK scores less than 50, and suggests that radioaerosol lung imaging may be valuable in identifying sites of impairment to be targeted during treatment. Statistically, skew was less sensitive an indicator of acute change than several other clinical indices that improved following hospital treatment.

Topics: Acute Disease; Adolescent; Adult; Aerosols; Child; Cystic Fibrosis; Female; Humans; Lung; Male; Radiography; Radionuclide Imaging; Respiratory Mechanics; Technetium Tc 99m Sulfur Colloid

We characterized the bronchopulmonary distribution of a 0.9 percent saline aerosol (1.12 microM) labelled with 99mTc sulfur colloid in nine normal subjects and five patients with CF. Homogeneity of distribution was quantified using indices derived from computerized analysis of Anger camera pulmonary images including skew (a measure of distribution asymmetry) and kurtosis (a measure of distribution range). Aerosol clearance in 97 minutes (a measure of large, central airway deposition) was also assessed. Values of skew and kurtosis were reproducible for the patients with CF and were significantly elevated compared to the normal subjects. Reproducibility of skew and kurtosis were not studied in the normal subjects. Clearance was not significantly different in the two groups. We conclude that the bronchopulmonary distribution of this radioaerosol is nonuniform in patients with CF, compared to normal subjects, and clearance may be impaired in patients with CF who are severely ill.

Topics: Adult; Aerosols; Cystic Fibrosis; Female; Forced Expiratory Volume; Humans; Lung; Male; Mucociliary Clearance; Radionuclide Imaging; Reproducibility of Results; Technetium Tc 99m Sulfur Colloid; Vital Capacity