Variability in uptake efficiency for pulsed versus constant concentration delivery of inhaled nitric oxide

BACKGROUND: Nitric oxide (NO) is currently administered using devices that maintain constant inspired NO concentrations. Alternatively, devices that deliver a pulse of NO during the early phase of inspiration may have use in optimizing NO dosing efficiency and in extending application of NO to long-term use by ambulatory, spontaneously breathing patients. The extent to which the amount of NO delivered for a given pulse sequence determines alveolar concentrations and uptake, and the extent to which this relationship varies with breathing pattern, physiological, and pathophysiological parameters, warrants investigation. METHODS: A mathematical model was used to analyze inhaled nitric oxide (NO) transport through the conducting airways, and to predict uptake from the alveolar region of the lung. Pulsed delivery was compared with delivery of a constant concentration of NO in the inhaled gas. RESULTS: Pulsed delivery was predicted to offer significant improvement in uptake efficiency compared with constant concentration delivery. Uptake from the alveolar region depended on pulse timing, tidal volume, respiratory rate, lung and dead space volume, and the diffusing capacity of the lung for NO (D(L)NO). It was predicted that variation in uptake efficiency with breathing pattern can be limited using a pulse time of less than 100 ms, with a delay of less than 50 ms between the onset of inhalation and pulse delivery. Nonlinear variation in uptake efficiency with D(L)NO was predicted, with uptake efficiency falling off sharply as D(L)NO decreased below ~50-60 ml/min/mm Hg. Gas mixing in the conducting airways played an important role in determining uptake, such that consideration of bulk convection alone would lead to errors in assessing efficiency of pulsed delivery systems. CONCLUSIONS: Pulsed NO delivery improves uptake efficiency compared with constant concentration delivery. Optimization of pulse timing is critical in limiting intra- and inter-subject variability in dosing

Bench and mathematical modeling of the effects of breathing a helium/oxygen mixture on expiratory time constants in the presence of heterogeneous airway obstructions

Abstract Background Expiratory time constants are used to quantify emptying of the lung as a whole, and emptying of individual lung compartments. Breathing low-density helium/oxygen mixtures may modify regional time constants so as to redistribute ventilation, potentially reducing gas trapping and hyperinflation for patients with obstructive lung disease. In the present work, bench and mathematical models of the lung were used to study the influence of heterogeneous patterns of obstruction on compartmental and whole-lung time constants. Methods A two-compartment mechanical test lung was used with the resistance in one compartment held constant, and a series of increasing resistances placed in the opposite compartment. Measurements were made over a range of lung compliances during ventilation with air or with a 78/22% mixture of helium/oxygen. The resistance imposed by the breathing circuit was assessed for both gases. Experimental results were compared with predictions of a mathematical model applied to the test lung and breathing circuit. In addition, compartmental and whole-lung time constants were compared with those reported by the ventilator. Results Time constants were greater for larger minute ventilation, and were reduced by substituting helium/oxygen in place of air. Notably, where time constants were long due to high lung compliance (i.e. low elasticity), helium/oxygen improved expiratory flow even for a low level of resistance representative of healthy, adult airways. In such circumstances, the resistance imposed by the external breathing circuit was significant. Mathematical predictions were in agreement with experimental results. Time constants reported by the ventilator were well-correlated with those determined for the whole-lung and for the low-resistance compartment, but poorly correlated with time constants determined for the high-resistance compartment. Conclusions It was concluded that breathing a low-density gas mixture, such as helium/oxygen, can improve expiratory flow from an obstructed lung compartment, but that such improvements will not necessarily affect time constants measured by the ventilator. Further research is required to determine if alternative measurements made at the ventilator level are predictive of regional changes in ventilation. It is anticipated that such efforts will be aided by continued development of mathematical models to include pertinent physiological and pathophysiological phenomena that are difficult to reproduce in mechanical test systems.</p

Methods for evaluation of helium/oxygen delivery through non-rebreather facemasks

Abstract Background Inhalation of low-density helium/oxygen mixtures has been used both to lower the airway resistance and work of breathing of patients with obstructive lung disease and to transport pharmaceutical aerosols to obstructed lung regions. However, recent clinical investigations have highlighted the potential for entrainment of room air to dilute helium/oxygen mixtures delivered through non-rebreather facemasks, thereby increasing the density of the inhaled gas mixture and limiting intended therapeutic effects. This article describes the development of benchtop methods using face models for evaluating delivery of helium/oxygen mixtures through facemasks. Methods Four face models were used: a flat plate, a glass head manikin, and two face manikins normally used in life support training. A mechanical test lung and ventilator were employed to simulate spontaneous breathing during delivery of 78/22 %vol helium/oxygen through non-rebreather facemasks. Based on comparison of inhaled helium concentrations with available clinical data, one face model was selected for measurements made during delivery of 78/22 or 65/35 %vol helium/oxygen through three different masks as tidal volume varied between 500 and 750 ml, respiratory rate between 14 and 30 breaths/min, the inspiratory/expiratory ratio between 1/2 and 1/1, and the supply gas flow rate between 4 and 15 l/min. Inhaled helium concentrations were measured both with a thermal conductivity analyzer and using a novel flow resistance method. Results Face models borrowed from life support training provided reasonably good agreement with available clinical data. After normalizing for the concentration of helium in the supply gas, no difference was noted in the extent of room air entrainment when delivering 78/22 versus 65/35 %vol helium/oxygen. For a given mask fitted to the face in a reproducible manner, delivered helium concentrations were primarily determined by the ratio of supply gas flow rate to simulated patient minute ventilation, with the inspiratory/expiratory ratio playing a secondary role. However, the functional dependence of helium concentration on these two ratios depended on the mask design. Conclusions Large differences in mask performance were identified. With continued refinement, the availability of reliable benchtop methods is expected to assist in the development and selection of patient interfaces for delivery of helium/oxygen and other medical gases

Bench experiments comparing simulated inspiratory effort when breathing helium-oxygen mixtures to that during positive pressure support with air

Abstract Background Inhalation of helium-oxygen (He/O2) mixtures has been explored as a means to lower the work of breathing of patients with obstructive lung disease. Non-invasive ventilation (NIV) with positive pressure support is also used for this purpose. The bench experiments presented herein were conducted in order to compare simulated patient inspiratory effort breathing He/O2 with that breathing medical air, with or without pressure support, across a range of adult, obstructive disease patterns. Methods Patient breathing was simulated using a dual-chamber mechanical test lung, with the breathing compartment connected to an ICU ventilator operated in NIV mode with medical air or He/O2 (78/22 or 65/35%). Parabolic or linear resistances were inserted at the inlet to the breathing chamber. Breathing chamber compliance was also varied. The inspiratory effort was assessed for the different gas mixtures, for three breathing patterns, with zero pressure support (simulating unassisted spontaneous breathing), and with varying levels of pressure support. Results Inspiratory effort increased with increasing resistance and decreasing compliance. At a fixed resistance and compliance, inspiratory effort increased with increasing minute ventilation, and decreased with increasing pressure support. For parabolic resistors, inspiratory effort was lower for He/O2 mixtures than for air, whereas little difference was measured for nominally linear resistance. Relatively small differences in inspiratory effort were measured between the two He/O2 mixtures. Used in combination, reductions in inspiratory effort provided by He/O2 and pressure support were additive. Conclusions The reduction in inspiratory effort afforded by breathing He/O2 is strongly dependent on the severity and type of airway obstruction. Varying helium concentration between 78% and 65% has small impact on inspiratory effort, while combining He/O2 with pressure support provides an additive reduction in inspiratory effort. In addition, breathing He/O2 alone may provide an alternative to pressure support in circumstances where NIV is not available or poorly tolerated.</p

Impact of oysters as top predators on microbial food web dynamics: a modelling approach with parameter optimisation. Running page head: Modelling oyster impact on MFW

International audienceAquaculture is becoming a relevant and productive source of seafood, and production is expected to double in the near future. However, bivalve activities can significantly impact coastal ecosystem functioning. To study the direct and indirect impacts of oysters on the microbial food web, a 0D biogeochemical modelling approach was adopted. The model was adjusted by parameter optimisation, assimilating data from several mesocosm observations of concentrations of nitrate, phosphate, silicate, dissolved organic carbon, chlorophyll, and bacterial biomass. The optimisation method provided a set of optimal parameters to fit the experimental observations of ‘control’ (i.e. natural water without oysters) and ‘oyster’ (i.e. natural water with oysters) mesocosms. The modelling results showed good accordance with the experimental observations, suggesting that the oysters directly reduced phytoplankton community biomass, thus constraining the ecosystem to a more heterotrophic state. Oysters also reduced competition between bacteria and phytoplankton for nutrient uptake, favouring higher bacterial biomass than in the control experiment. Additionally, the presence of oysters strongly increased large micro-zooplankton biomass (50-200 µm; mainly ciliates and large flagellates). This was a consequence of bacterivory by small zooplankton (5-50 µm; mostly flagellates and small ciliates), providing a trophic link between bacteria and larger zooplankton. In conclusion, parameter optimisation showed good capacity to manage experimental data in order to build a more realistic model. Such models, in connection with future developments in aquaculture and global change scenarios, could be a promising tool for exploited ecosystem management and testing different environmental scenarios

An in silico analysis of oxygen uptake of a mild COPD patient during rest and exercise using a portable oxygen concentrator

Ira Katz,1,2 Marine Pichelin,1 Spyridon Montesantos,1 Min-Yeong Kang,3 Bernard Sapoval,3,4 Kaixian Zhu,5 Charles-Philippe Thevenin,5 Robert McCoy,6 Andrew R Martin,7 Georges Caillibotte1 1Medical R&amp;D, Air Liquide Sant&eacute; International, Centre de Recherche Paris-Saclay, Les Loges-en-Josas, France; 2Department of Mechanical Engineering, Lafayette College, Easton, PA, USA; 3Physique de la Mati&egrave;re Condens&eacute;e, CNRS, Ecole Polytechnique, Palaiseau, 4Centre de Math&eacute;matiques et de leurs Applications, CNRS, UniverSud, Cachan, 5Centre Explor!, Air Liquide Healthcare, Gentilly, France; 6Valley Inspired Products, Inc, Apple Valley, MN, USA; 7Department of Mechanical Engineering, University of Alberta, Edmonton, AB, Canada Abstract: Oxygen treatment based on intermittent-flow devices with pulse delivery modes available from portable oxygen concentrators (POCs) depends on the characteristics of the delivered pulse such as volume, pulse width (the time of the pulse to be delivered), and pulse delay (the time for the pulse to be initiated from the start of inhalation) as well as a patient&rsquo;s breathing characteristics, disease state, and respiratory morphology. This article presents a physiological-based analysis of the performance, in terms of blood oxygenation, of a commercial POC at different settings using an in silico model of a COPD patient at rest and during exercise. The analysis encompasses experimental measurements of pulse volume, width, and time delay of the POC at three different settings and two breathing rates related to rest and exercise. These experimental data of device performance are inputs to a physiological-based model of oxygen uptake that takes into account the real dynamic nature of gas exchange to illustrate how device- and patient-specific factors can affect patient oxygenation. This type of physiological analysis that considers the true effectiveness of oxygen transfer to the blood, as opposed to delivery to the nose (or mouth), can be instructive in applying therapies and designing new devices. Keywords: efficiency, respiratory physiology, respiratory disease, pulsed deliver

What Causes Uneven Aerosol Deposition in the Bronchoconstricted Lung? A Quantitative Imaging Study

BACKGROUND: A previous PET-CT imaging study of 14 bronchoconstricted asthmatic subjects showed that peripheral aerosol deposition was highly variable among subjects and lobes. The aim of this work was to identify and quantify factors responsible for this variability. METHODS: A theoretical framework was formulated to integrate four factors affecting aerosol deposition: differences in ventilation, in how air vs. aerosol distribute at each bifurcation, in the fraction of aerosol escaping feeding airways, and in the fraction of aerosol reaching the periphery that is exhaled. These factors were quantified in 12 of the subjects using PET-CT measurements of relative specific deposition sD*, relative specific ventilation sV* (measured with dynamic PET or estimated as change in expansion between two static HRCTs), average lobar expansion FVOL, and breathing frequency measured during aerosol inhalation fN. RESULTS: The fraction of the variance of sD* explained by sV* (0.38), by bifurcation effects (0.38), and by differences in deposition along feeding airways (0.31) were similar in magnitude. We could not directly estimate the contribution of aerosol that was exhaled. Differences in expansion did not explain any fraction of the variability in sD* among lobes. The dependence of sD* on sV* was high in subjects breathing with low fN, but weakened among those breathing faster. Finally, sD*/sV* showed positive dependence on FVOL among low fN subjects, while the dependence was negative among high fN subjects. CONCLUSION: The theoretical framework allowed us to analyze experimentally measured aerosol deposition imaging data. When considering bronchoconstricted asthmatic subjects, a dynamic measurement of ventilation is required to evaluate its effect on aerosol transport. The mechanisms behind the identified effects of fN and FVOL on aerosol deposition need further study and may have important implications for aerosol therapy in subjects with heterogeneous ventilation. Keywords: aerosol deposition; asthma; bronchoconstriction; escape fractions; sedimentation; ventilationNational Institutes of Health (U.S.) (Award R01HL68011

Regional Ventilation and Aerosol Deposition with Helium-Oxygen in Bronchoconstricted Asthmatic Lungs

Background: Theoretical models suggest that He-O₂ as carrier gas may lead to more homogeneous ventilation and aerosol deposition than air. However, these effects have not been clinically consistent and it is unclear why subjects may or may not respond to the therapy. Here we present 3D-imaging data of aerosol deposition and ventilation distributions from subjects with asthma inhaling He-O₂ as carrier gas. The data are compared with those that we previously obtained from a similar group of subjects inhaling air. Methods: Subjects with mild-to-moderate asthma were bronchoconstricted with methacholine and imaged with PET-CT while inhaling aerosol carried with He-O₂. Mean-normalized-values of lobar specific ventilation sV∗ and deposition sD∗ were derived and the factors affecting the distribution of sD∗ were evaluated along with the effects of breathing frequency (f) and regional expansion (FVOL). Results: Lobar distributions of sD∗ and sV∗ with He-O₂ were not statistically different from those previously measured with air. However, with He-O₂ there was a larger number of lobes having sV∗ and sD∗ closer to unity and, in those subjects with uneven deposition distributions, the correlation of sD∗ with sV∗ was on average higher (p < 0.05) in He-O₂ (0.84 ± 0.8) compared with air (0.55 ± 0.28). In contrast with air, where the frequency of breathing during nebulization was associated with the degree of sD∗-sV∗ correlation, with He-O₂ there was no association. Also, the modulation of f on the correlation between FVOL and sD∗/sV∗ in air, was not observed in He-O₂. Conclusion: There were no differences in the inter-lobar heterogeneity of sD∗ or sV∗ in this group of mild asthmatic subjects breathing He-O₂ compared with patients previously breathing air. Future studies, using these personalized 3D data sets as input to CFD models, are needed to understand if, and for whom, breathing He-O₂ during aerosol inhalation may be beneficial.National Institutes of Health (U.S.) (Award R01HL68011