TY  - JOUR
AB  - Recent studies show that nasal high flow (NHF) therapy can support ventilation in patients with acute or chronic respiratory disorders. Clearance of dead-space has been suggested as being the key mechanisms of respiratory support with NHF therapy. The hypothesis of this study was that NHF in a dose-dependent manner can clear dead space of the upper airways from expired air and decrease re-breathing. The randomized cross-over study involved 10 volunteers using scintigraphy with 81mKrypton-gas (81mKr-gas) during a breath-holding maneuver with closed mouth and in three nasally breathing tracheotomized patients by volumetric capnography and oximetry through sampling CO2 and O2 in the trachea and measuring the inspired volume with inductance plethysmography following NHF rates of 15, 30 and 45 L/min. The scintigraphy revealed a decrease in 81mKr-gas clearance half-time with an increase of NHF in the nasal cavities (cc = -0.55, p < 0.01), pharynx (cc = -0.41, p < 0.01) and the trachea (cc = -0.51, p < 0.01). Clearance rates in nasal cavities derived from time constants and MRI-measured volumes were 40.6 (SD 12.3), 52.5 (SD 17.7) and 72.9 (SD 21.3) mL/s during NHF (15-30-45L/min). Measurement of inspired gases in the trachea showed an NHF-dependent decrease of inspired CO2 that correlated with an increase of inspired O2 (cc = -0.77, p < 0.05). NHF clears the upper airways from expired air, which reduces dead space by a decrease of re-breathing making ventilation more efficient. The dead-space clearance is flow and time-dependent and it may extend below the soft palate.
AU  - Möller, W.
AU  - Sheng Feng, M.S.*
AU  - Domanski, U.*
AU  - Franke, K.-J.*
AU  - Celik, G.
AU  - Bartenstein, P.*
AU  - Becker, S.*
AU  - Meyer, G.*
AU  - Schmid, O.
AU  - Eickelberg, O.
AU  - Tatkov, S.*
AU  - Nilius, G.*
C1  - 50307
C2  - 42084
CY  - Bethesda
SP  - 191-197
TI  - Nasal high flow reduces dead space.
JO  - J. Appl. Physiol.
VL  - 122
IS  - 1
PB  - Amer Physiological Soc
PY  - 2017
SN  - 8750-7587
ER  - 

TY  - JOUR
AB  - Recent studies showed that Nasal High Flow (NHF) with or without supplemental oxygen can assist ventilation of patients with chronic respiratory and sleep disorders. The hypothesis of this study was to test whether NHF can clear dead-space in two different models of the upper nasal airways. The first was a simple tube model consisting of a nozzle to simulate the nasal valve area, connected to a cylindrical tube to simulate the nasal cavity. The second was a more complex anatomically representative upper airway model, constructed from segmented CT-scan images of a healthy volunteer. After filling the models with tracer-gases, NHF was delivered at rates of 15, 30 and 45 L/min. The tracer gas clearance was determined using dynamic infrared CO2 spectroscopy and (81m)Kr-gas radioactive gamma camera imaging. There was a similar tracer-gas clearance characteristic in the tube model and the upper airway model: clearance half-times were below 1.0 s and decreased with increasing NHF rates. For both models, the anterior compartments demonstrated faster clearance levels (half-times < 0.5 s) and the posterior sections showed slower clearance (half-times < 1.0 s). Both imaging methods showed similar flow-dependent tracer-gas clearance in the models. For the anatomically-based model, there was complete tracer-gas removal from the nasal cavities within 1.0 s. The level of clearance in the nasal cavities increased by 1.8 mL/s for every 1.0 L/min increase in the rate of NHF. The study has demonstrated the fast-occurring clearance of nasal cavities by NHF therapy, which is capable of reducing of dead-space re-breathing.
AU  - Möller, W.
AU  - Celik, G.
AU  - Feng, S.*
AU  - Bartenstein, P.*
AU  - Meyer, G.*
AU  - Eickelberg, O.
AU  - Schmid, O.
AU  - Tatkov, S.*
C1  - 44432
C2  - 36838
CY  - Bethesda
SP  - 1525-1532
TI  - Nasal high flow clears anatomical dead space in upper airway models.
JO  - J. Appl. Physiol.
VL  - 118
IS  - 12
PB  - Amer Physiological Soc
PY  - 2015
SN  - 8750-7587
ER  - 

TY  - JOUR
AB  - Little is known about the effects of postnatal developmental changes in lung architecture and breathing patterns on intrapulmonary particle deposition. We measured deposition in the developing Wistar-Kyoto rat, whose lung development largely parallels that of humans. Deposition of 2-μm sebacate particles was determined in anesthetized, intubated, spontaneously breathing rats on postnatal days (P) 7 to 90 by aerosol photometry (Karrasch S, Eder G, Bolle I, Tsuda A, Schulz H. J Appl Physiol 107: 1293-1299, 2009). Respiratory parameters were determined by body plethysmography. Tidal volume increased substantially from P7 (0.19 ml) to P90 (2.1 ml) while respiratory rate declined from 182 to 107/min. Breath-specific deposition was lowest (9%) at P7 and P90 and markedly higher at P35 (almost 16%). Structural changes of the alveolar region include a ninefold increase in surface area (Bolle I, Eder G, Takenaka S, Ganguly K, Karrasch S, Zeller C, Neuner M, Kreyling WG, Tsuda A, Schulz H. J Appl Physiol 104: 1167-1176, 2008). Particle deposition per unit of time and surface area peaked at P35 and showed a minimum at P90. At an inhaled particle number concentration of 10(5)/cm(3), there was an estimated 450, 690, and 330 particles/(min × cm(2)) at P7, P35, and P90, respectively. Multiple regression models showed that deposition depends on the mean linear intercept as structural component and the breathing parameters, tidal volume, and respiratory rate (r(2) > 0.9). In conclusion, micron-sized particle deposition was dependent on the stage of postnatal lung development. A maximum was observed during late alveolarization (P35), which corresponds to human lungs of about eight years of age. Children at this age may therefore be more susceptible to micron-sized airborne environmental health hazards.
AU  - Schulz, H.
AU  - Eder, G.
AU  - Bolle, I.
AU  - Tsuda, A.*
AU  - Karrasch, S.
C1  - 7499
C2  - 29759
SP  - 759-765
TI  - Micron-sized intrapulmonary particle deposition in the developing rat lung.
JO  - J. Appl. Physiol.
VL  - 112
IS  - 5
PB  - American Physiological Society
PY  - 2012
SN  - 8750-7587
ER  - 

TY  - JOUR
AB  - Dickie R, Cormack M, Semmler-Behnke M, Kreyling WG, Tsuda A. Deep pulmonary lymphatics in immature lungs. J Appl Physiol 107: 859-863, 2009. First published June 25, 2008; doi:10.1152/japplphysiol.90665.2008.-Recently, we found that the translocation of inhaled nanoparticles from the air space to secondary organs is age dependent and substantially greater in neonates than in adults (J Respir Crit Care Med 177: A48, 2008). One reason for this difference might be age-dependent differences in alveolar barrier integrity. Because the neonate lung is undergoing morphogenetic and fluid balance changes, we hypothesize that the alveolar barrier of developing lungs is more easily compromised and susceptible to foreign material influx than that of adult lungs. On the basis of these hypotheses, we predict that the postnatally developing lung is also more likely to allow the translocation of some materials from the air space to the lymphatic lumens. To test this idea, we intratracheally instilled methyl methacrylate into immature and adult lungs and compared lymphatic filling between these two age groups. Scanning electron microscopy of the resultant corrosion casts revealed peribronchial saccular and conduit lymphatic architecture. Deep pulmonary lymphatic casts were present on the majority (58.5%) of airways in immature lungs, but lymphatic casting in adult lungs, as anticipated, was much more infrequent (21.6%). Thus the neonate lung appears to be more susceptible than the adult lung to the passage of instilled methyl methacrylate from the air space into the lymphatics. We speculate that this could imply greater probability of translocation of other materials, such as nanoparticles, from the immature lung as well.
AU  - Dickie, R.*
AU  - Cormack, M.*
AU  - Semmler-Behnke, M.
AU  - Kreyling, W.G.
AU  - Tsuda, A.*
C1  - 599
C2  - 26420
CY  - Bethesda
SP  - 859-863
TI  - Deep pulmonary lymphatics in immature lungs.
JO  - J. Appl. Physiol.
VL  - 107
IS  - 3
PB  - Amer Physiological Soc
PY  - 2009
SN  - 8750-7587
ER  - 

TY  - JOUR
AB  - A number of deposition models for humans, as well as experimental animals, have been described. However, no breath-by-breath deposition measurement in rats has been reported to date. The objective of this study is to determine lung deposition of micrometer-sized particles as a function of breathing parameters in the adult rat lung. A new aerosol photometry system was designed to measure deposition of nonhygroscopic, 2-µm sebacate particles in anesthetized, intubated, and spontaneously breathing 90-day-old Wistar-Kyoto rats placed in a size-adjusted body plethysmograph box. Instrumental dead space of the system was minimized down to 310 µl (i.e., ~20% of respiratory dead space). The system allows continuous monitoring of particle concentration in the respired volume. Breathing parameters, such as respiratory rate (f), tidal volume (VT), as well as inspiration/expiration times, were also monitored at different levels of anesthesia. The results showed that VT typically varied between 1.5 and 4.0 ml for regular breathing and between 4.0 and 10.0 ml for single-sigh breaths; f ranged from 40 to 200 breaths/min. Corresponding deposition values varied between 5 and 50%, depending on breath-by-breath breathing patterns. The best fit of deposition (D) was achieved by a bilinear function of VT and f and found to be D = 11.0 – 0.09·f + 3.75·VT. We conclude that our approach provides more realistic conditions for the measurement of deposition than conventional models using ventilated animals and allows us to analyze the correlation between breath-specific deposition and spontaneous breathing patterns.
AU  - Karrasch, S.
AU  - Eder, G.
AU  - Bolle, I.
AU  - Tsuda, A.*
AU  - Schulz, S.
C1  - 2079
C2  - 26467
CY  - Bethesda, MD
SP  - 1293-1299
TI  - Breath-by-breath measurement of particle deposition in the lung of spontaneously breathing rats.
JO  - J. Appl. Physiol.
VL  - 107
IS  - 4
PB  - American Physiological Society
PY  - 2009
SN  - 8750-7587
ER  - 

TY  - JOUR
AB  - Little is known about lung function during early stages of postnatal maturation, although the complex structural changes associated with developing rat lung are well studied. We therefore analyzed corresponding functional (lung volume, respiratory mechanics, intrapulmonary gas mixing, and gas exchange) and structural (alveolar surface area, mean linear intercept length, and alveolar septal thickness) changes of the developing rat lung at 7-90 days. Total lung capacity (TLC) increased from 1.54 +/- 0.07 to 16.7 +/- 2.46 (SD) ml in proportion to body weight, but an increase in body weight exceeded an increase in lung volume by almost twofold. Series dead space volume increased from 0.21 +/- 0.03 to 1.38 +/- 0.08 ml but decreased relative to TLC from 14% to 8%, indicating that parenchymal growth exceeded growth of conducting airways. Diffusing capacity of CO (D(CO)) increased from 8.1 +/- 0.8 to 214.1 +/- 23.5 micromol min(-1) hPa(-1), corresponding to a substantial increase in surface area from 744 +/- 20 to 6,536 +/- 488 cm(2). D(CO) per unit of lung volume is considerably lower in the immature lung, inasmuch as D(CO)/TLC in 7-day-old rats was only 42% of that in adult (90 day-old) rats. In humans, however, infants and adults show comparable specific D(CO). Our functional and structural analysis shows that gas exchange is limited in the immature rat lung. The pivotal step for improvement of gas exchange occurs with the transition from bulk alveolarization to the phase of expansion of air spaces with septal reconstruction and microvascular maturation.
AU  - Bolle, I.
AU  - Eder, G.
AU  - Takenaka, S.
AU  - Ganguly, K.
AU  - Karrasch, S.
AU  - Zeller, C.
AU  - Neuner, M.
AU  - Kreyling, W.G.
AU  - Tsuda, A.*
AU  - Schulz, S.
C1  - 2362
C2  - 25498
SP  - 1167-1176
TI  - Postnatal lung function in the developing rat.
JO  - J. Appl. Physiol.
VL  - 104
IS  - 4
PB  - American Physiological Society
PY  - 2008
SN  - 8750-7587
ER  - 

TY  - JOUR
AB  - The ability to visualize molecular processes and cellular regulators of complex pulmonary diseases such as asthma, chronic obstructive pulmonary disease (COPD), or adult respiratory distress syndrome (ARDS), would aid in the diagnosis, differentiation, therapy assessment and in small animal-based drug-discovery processes. Herein we report the application of normalized transillumination and fluorescence molecular tomography (FMT) for the noninvasive quantitative imaging of the mouse lung in vivo. We demonstrate the ability to visualize and quantitate pulmonary response in a murine model of LPS-induced airway inflammation. Twenty-four hours prior to imaging, BALB/c female mice were injected via tail vein with 2 nmol of a cathepsin-sensitive activatable fluorescent probe (excitation: 750 nm; emission: 780 nm) and 2 nmol of accompanying intravascular agent (excitation: 674 nm; emission: 694 nm). Six hours later, the mice were anesthetized with isoflurane and administered intranasal LPS in sterile 0.9% saline in 25 µl aliquots (one per nostril). Fluorescence molecular imaging revealed the in vivo profile of cysteine protease activation and vascular distribution within the lung typifying the inflammatory response to LPS insult. Results were correlated with standard in vitro laboratory tests (Western blot, bronchoalveolar lavage or BAL analysis, immunohistochemistry) and revealed good correlation with the underlying activity. We demonstrated the capacity of fluorescence tomography to noninvasively and longitudinally characterize physiological, cellular, and subcellular processes associated with inflammatory disease burden in the lung. The data presented herein serve to further evince fluorescence molecular imaging as a technology highly appropriate for the biomedical laboratory.
AU  - Haller, J.*
AU  - Hyde, D.*
AU  - Deliolanis, N.*
AU  - de Kleine, R.*
AU  - Niedre, M.*
AU  - Ntziachristos, V.
C1  - 3259
C2  - 25537
SP  - 795-802
TI  - Visualization of pulmonary inflammation using noninvasive fluorescence molecular imaging.
JO  - J. Appl. Physiol.
VL  - 104
IS  - 3
PB  - American Physiological Society
PY  - 2008
SN  - 8750-7587
ER  - 

TY  - JOUR
AB  - Spherical monodisperse ferromagnetic iron oxide particles of 1.9-microm geometric and 4.2-microm aerodynamic diameter were inhaled by 13 healthy nonsmoking subjects using the shallow bolus technique. The bolus width was 100 ml, and the penetration front depth was 150 +/- 27 ml. The mean flow rate during inhalation and exhalation was 250 ml/s. The Fowler dead space and the phase 1 dead space of the airways were 282 +/- 49 and 164 +/- 34 ml, respectively. Deposition was below 20% without breath holding and 51 +/- 8% after an 8-s breath-holding time. We attempted to confine the bolus deposition to the bronchial airways by limiting the bolus front depth to the phase 1 dead space volume. Particle retention was measured by the magnetopneumographic method over a period of 9 mo. Particle clearance from the airways showed a fast and a slow phase; 49 +/- 9% followed the fast phase with a mean half-time of 3.0 +/- 1.6 h and characterized the mucociliary clearance. The remaining fraction was cleared slowly with a half-time of 109 +/- 78 days. The slow clearance phase was comparable to clearance measurements from the lung periphery of healthy nonsmokers, which allowed macrophage-dependent clearance mechanisms of the slow cleared fraction to be taken into account. Despite the fact that part of the slowly cleared particles may originate from peripheral deposition, the data demonstrate that mucociliary clearance does not remove all particles deposited in the airways and that a significant fraction undergoes long-term retention mechanisms, the origin of which is still under discussion
AU  - Möller, W.
AU  - Häußinger, K.*
AU  - Winkler-Heil, R.*
AU  - Stahlhofen, W.
AU  - Meyer, T.*
AU  - Hofmann, W.*
AU  - Heyder, J.
C1  - 3588
C2  - 22487
SP  - 2200-2206
TI  - Mucociliary and long-term particle clearance in the airways of healthy nonsmoker subjects.
JO  - J. Appl. Physiol.
VL  - 97
PY  - 2004
SN  - 8750-7587
ER  - 

TY  - JOUR
AU  - Schulz, S.
AU  - Schulz, A.
AU  - Eder, G.
AU  - Heyder, J.
C1  - 3595
C2  - 22067
SP  - 1755-1762
TI  - Labelled carbon dioxide (C18O2 : An indicator gas for phase II in expirograms.
JO  - J. Appl. Physiol.
VL  - 97
PY  - 2004
SN  - 8750-7587
ER  - 

TY  - JOUR
AB  - The significance of convective and diffusive gas transport in the respiratory system was assessed from the response of combined inert gas and particle boluses inhaled into the conducting airways. Particles, considered as 'nondiffusing gas,' served as tracers for convection and two inert gases with widely different diffusive characteristics (He and SF6) as tracers for convection and diffusion. Six-milliliter boluses labeled with monodisperse di-2-ethylhexyl sebacate droplets of 0.86-μm aerodynamic diameter, 2% He, and 2% SF6 were inspired by three anesthetized mechanically ventilated beagle dogs to volumetric lung depths up to 170 ml. Mixing between inspired and residual air caused dispersion of the inspired bolus, which was quantified in terms of the bolus half-width. Dispersion of particles increased with increasing lung depth to which the boluses were inhaled. The increase followed a power law with exponents < 0.5 (mean 0.39), indicating that the effect of convective mixing per unit volume was reduced with depth. Within the pulmonary dead space, the behavior of the inert gases He and SF6 was similar to that of the particles, suggesting that gas transport was almost solely due to convection. Beyond the dead space, dispersion of He and SF6 increased more rapidly than dispersion of particles, indicating that diffusion became significant. The gas and particle bolus technique offers a suitable approach to differential analysis of gas transport in intrapulmonary airways of lungs.
AU  - Schulz, H.
AU  - Heilmann, P.
AU  - Hillebrecht, A.
AU  - Gebhart, J.
AU  - Meyer, M.R.
AU  - Piiper, J.
AU  - Heyder, J.
C1  - 40600
C2  - 0
SP  - 1557-1562
TI  - Convective and diffusive gas transport in canine intrapulmonary airways.
JO  - J. Appl. Physiol.
VL  - 72
IS  - 4
PY  - 1992
SN  - 8750-7587
ER  - 

TY  - JOUR
AB  - Single-breath inhalations of monodisperse aerosols were performed with a group of normal subjects to determine aerosol recovery from the human lung after periods of breath holding. Aerosols of monodisperse nonhygroscopic droplets of bis(2-ethylhexyl) sebacate of between 0.5 and about 2.5 μm diam were used for the inhalation. The inhalation apparatus allows continuous monitoring of particle number concentration and flow rate close to the mouth. Experiments were designed to find the optimum experimental conditions for the principal concept of Palmes et al. (In: Inhaled Particles and Vapours. London: Pergamon, 1976, vol. II, p. 339-347) to evaluate pulmonary airspace dimensions by means of aerosols. The experimental results obtained for various respiratory flow rates (125, 250, and 500 cm 3.s -1), settling velocities of the particles (10 -3 to 1.5 x 10 -2 cm.s -1), and volumes of inspired aerosols (500, 1,000, and 2,000 cm 3) are compared with the results derived from a mathematical model for the particle deposition during respiratory pauses. Monodisperse aerosols with particles between 1 and about 1.5 μm diam, inspired for breath holding into the lung region of interest, may provide optimum conditions for the sizing of air spaces by means of aerosols.
AU  - Gebhart, J.
AU  - Heyder, J.
AU  - Stahlhofen, W.
C1  - 33159
C2  - 35528
SP  - 465-476
TI  - Use of aerosols to estimate pulmonary air-space dimensions.
JO  - J. Appl. Physiol.
VL  - 51
IS  - 2
PY  - 1981
SN  - 8750-7587
ER  -