The influence of flowrate and gas density on positive airway pressure for high flow nasal cannula applied to infant airway replicas.

High flow nasal cannula (HFNC) therapy has been previously shown to produce positive upper airway pressures in adult and child patients. This work aimed to evaluate and quantify the effects of HFNC flowrate and gas type on airway pressures measured in vitro in infant airway replicas. Ten realistic infant airway replicas, extending from nares to trachea, were connected in turn to a lung simulator and were supplied gas flows through HFNC. Air and heliox were each provided at two weight-indexed flowrates, 1 l/min/kg and 2 l/min/kg. Pressure and lung volume were continuously measured during simulated breathing. For constant simulated patient effort, no statistically significant change in tidal volume was measured between baseline and lower or higher HFNC flowrates, nor was there any significant difference in tidal volume between air and heliox. Tracheal pressure increased with increasing HFNC flow rate, and was highly variable between airway replicas. Higher pressures were measured for air versus heliox. For air supplied at 2 l/min/kg, average airway pressures in excess of 4 cm H2O were generated, with positive end-expiratory pressure (PEEP) ranging from 2.5 to nearly 12 cm H2O across the replicas. A predictive correlation for PEEP was proposed based on supplied gas density and flow velocities exiting the cannula and nares, and was able to account for a portion of variability between airway replicas (R2 = 0.913). Additionally, PEEP was well correlated with, and predictive of, expiratory peak pressure (R2 = 0.939) and average inspiratory pressure (R2 = 0.944).

In Vitro-In Silico Comparison of Pulsed Oxygen Delivery From Portable Oxygen Concentrators Versus Continuous Flow Oxygen Delivery.

BACKGROUND: Portable oxygen concentrators (POCs) deliver oxygen in intermittent pulses. The challenge of establishing equivalence between continuous flow oxygen and nominal pulse flow settings on different POCs is well known. In vitro bench measurements and in silico mathematical modeling were used to compare the performance of 4 POCs versus continuous flow oxygen by predicting the FIO2 at the trachea and entering the acini. METHODS: Each of the 4 POCs was connected to a 3-dimensional printed replica of a human adult nasal airway via nasal cannula. A test lung simulated 3 breathing patterns representative of a patient with COPD at rest, during exercise, and while asleep. POCs were tested for each breathing pattern at all integer pulse flow settings. Volume-averaged FIO2 was calculated by analyzing oxygen concentrations and inhalation flow over time. In vitro oxygen waveforms were then combined with a single-path mathematical model of the lungs to assess oxygen transport through the conducting airways. In vitro experiments and mathematical modeling were repeated for continuous flow oxygen. RESULTS: Continuous flow oxygen consistently delivered more (>2% absolute) oxygen in terms of volume-averaged FIO2 for all nominally equivalent pulse flow settings of >2. Differences were also observed when comparing performances between different POCs, particularly at high device settings (5 and 6). Simulations showed that efficiency of delivery to the acinar region of the lungs was higher in pulse flow than in continuous flow oxygen but that continuous flow oxygen generally delivered a higher absolute volume of oxygen. Differences in absolute oxygen delivery per breath between continuous flow oxygen and pulse flow were smaller for acinar delivery than for tracheal delivery. CONCLUSIONS: Significant differences in POC performance based on volume-averaged FIO2 were found between pulse flow and continuous flow oxygen, and among pulse flow modes in different POCs. Although pulse flow was a more efficient mode of delivery than continuous flow oxygen, continuous flow oxygen delivered a greater absolute volume of oxygen per breath.

Correlation of high flow nasal cannula outlet area with gas clearance and pressure in adult upper airway replicas.

BACKGROUND: Primary benefits of high flow nasal cannula therapy include washout of carbon dioxide rich exhaled gas and increased airway pressures during tidal breathing. This work reports on the influence of high flow nasal cannula outlet area on upper airways gas clearance and tracheal pressures using measurements in five realistic adult nose-throat airway replicas. METHODS: Two commercial high flow nasal cannulas and one generic nasal cannula of varying size were compared. 100% oxygen was supplied via cannulas at flow rates ranging from 30 to 90l/min to replicas originally filled with air, and oxygen concentrations at the larynx and trachea were compared over time. Additionally, and separately, replicas were connected to a mechanical lung simulator to simulate tidal breathing while undergoing high flow nasal cannula therapy, with tracheal pressure-time waveforms recorded. FINDINGS: Faster gas clearance corresponded with higher flow rates (P<0.001), and with smaller cannula outlet area (P<0.001). Observed pressures were in approximate agreement with limited available in-vivo data in the literature. Between 0 and 60L/min cannula flow rates, tracheal positive end expiratory pressures increase was greater with the smallest cannula (∆PPEEP=785SD(185) Pa) compared to the largest cannula (∆PPEEP=380SD(120)Pa). Regression analysis indicates that positive end expiratory pressure is proportional to the square of flow velocities exiting the cannula and nares (R2=0.906). INTERPRETATION: Since increased pressure and clearance rate have been associated with improved clinical outcomes in previous studies, our results suggest that smaller cannula outlet area may be preferable.

Comparison of pulsed versus continuous oxygen delivery using realistic adult nasal airway replicas.

BACKGROUND: Portable oxygen concentrators (POCs) typically include pulse flow (PF) modes to conserve oxygen. The primary aims of this study were to develop a predictive in vitro model for inhaled oxygen delivery using a set of realistic airway replicas, and to compare PF for a commercial POC with steady flow (SF) from a compressed oxygen cylinder. METHODS: Experiments were carried out using a stationary compressed oxygen cylinder, a POC, and 15 adult nasal airway replicas based on airway geometries derived from medical images. Oxygen delivery via nasal cannula was tested at PF settings of 2.0 and 6.0, and SF rates of 2.0 and 6.0 L/min. A test lung simulated three breathing patterns representative of a chronic obstructive pulmonary disease patient at rest, during exercise, and while asleep. Volume-averaged fraction of inhaled oxygen (FiO2) was calculated by analyzing oxygen concentrations sampled at the exit of each replica and inhalation flow rates over time. POC pulse volumes were also measured using a commercial O2 conserver test system to attempt to predict FiO2 for PF. RESULTS: Relative volume-averaged FiO2 using PF ranged from 68% to 94% of SF values, increasing with breathing frequency and tidal volume. Three of 15 replicas failed to trigger the POC when used with the sleep breathing pattern at the 2.0 setting, and four of 15 replicas failed to trigger at the 6.0 setting. FiO2 values estimated from POC pulse characteristics followed similar trends but were lower than those derived from airway replica experiments. CONCLUSION: For the POC tested, PF delivered similar, though consistently lower, volume-averaged FiO2 than SF rates equivalent to nominal PF settings. Assessment of PF oxygen delivery using POC pulse characteristics alone may be insufficient; testing using airway replicas is useful in identifying possible cases of failure and may provide a better assessment of FiO2.

An injection and mixing element for delivery and monitoring of inhaled nitric oxide.

BACKGROUND: Inhaled nitric oxide (NO) is a selective pulmonary vasodilator used primarily in the critical care setting for patients concurrently supported by invasive or noninvasive positive pressure ventilation. NO delivery devices interface with ventilator breathing circuits to inject NO in proportion with the flow of air/oxygen through the circuit, in order to maintain a constant, target concentration of inhaled NO. METHODS: In the present article, a NO injection and mixing element is presented. The device borrows from the design of static elements to promote rapid mixing of injected NO-containing gas with breathing circuit gases. Bench experiments are reported to demonstrate the improved mixing afforded by the injection and mixing element, as compared with conventional breathing circuit adapters, for NO injection into breathing circuits. Computational fluid dynamics simulations are also presented to illustrate mixing patterns and nitrogen dioxide production within the element. RESULTS: Over the range of air flow rates and target NO concentrations investigated, mixing length, defined as the downstream distance required for NO concentration to reach within ±5 % of the target concentration, was as high as 47 cm for the conventional breathing circuit adapters, but did not exceed 7.8 cm for the injection and mixing element. CONCLUSION: The injection and mixing element has potential to improve ease of use, compatibility and safety of inhaled NO administration with mechanical ventilators and gas delivery devices.

Effects of a helium/oxygen mixture on individuals' lung function and metabolic cost during submaximal exercise for participants with obstructive lung diseases.

BACKGROUND: Helium/oxygen therapies have been studied as a means to reduce the symptoms of obstructive lung diseases with inconclusive results in clinical trials. To better understand this variability in results, an exploratory physiological study was performed comparing the effects of helium/oxygen mixture (78%/22%) to that of medical air. METHODS: The gas mixtures were administered to healthy, asthmatic, and chronic obstructive pulmonary disease (COPD) participants, both moderate and severe (6 participants in each disease group, a total of 30); at rest and during submaximal cycling exercise with equivalent work rates. Measurements of ventilatory parameters, forced spirometry, and ergospirometry were obtained. RESULTS: There was no statistical difference in ventilatory and cardiac responses to breathing helium/oxygen during submaximal exercise. For asthmatics, but not for the COPD participants, there was a statistically significant benefit in reduced metabolic cost, determined through measurement of oxygen uptake, for the same exercise work rate. However, the individual data show that there were a mixture of responders and nonresponders to helium/oxygen in all of the groups. CONCLUSION: The inconsistent response to helium/oxygen between individuals is perhaps the key drawback to the more effective and widespread use of helium/oxygen to increase exercise capacity and for other therapeutic applications.

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 (DLNO). 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 DLNO was predicted, with uptake efficiency falling off sharply as DLNO 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.

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

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.

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.

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

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.

An in vitro assessment of aerosol delivery through patient breathing circuits used with medical air or a helium-oxygen mixture.

BACKGROUND: The bench experiments presented herein were conducted in order to investigate the influence of carrier gas, either medical air or a helium-oxygen mixture (78% He, 22% O2), on the droplet size distribution and aerosol mass delivered from a vibrating mesh nebulizer through a patient breathing circuit. METHODS: Droplet size distributions at the exit of the nebulizer T-piece and at the patient end of the breathing circuit were determined by laser diffraction. Additional experiments were performed to determine the effects on measured size distributions of gas humidity and of the droplet residence time during transport from the nebulizer to the laser diffraction measurement volume. Aerosol deposition in the nebulizer, breathing circuit, and on expiratory and patient filters was determined by photometry following nebulization of sodium fluoride solutions into the breathing circuit during simulated patient breathing. RESULTS: With no humidification of the carrier gas, droplet volume median diameter (VMD) at the exit of the nebulizer T-piece was 5.5±0.1 µm for medical air, and 4.3±0.1 µm for helium-oxygen. Varying the aerosol residence time between the nebulizer and the measurement volume did not affect the measured size distributions; however, humidification of the carrier gases reduced differences in VMD at the nebulizer exit between medical air and helium-oxygen. At the patient end of the breathing circuit, droplet VMDs were 1.8±0.1 µm for medical air and 2.2±0.1 µm for helium-oxygen. The percentages of sodium fluoride recovered from the nebulizer, breathing circuit, patient filter, and expiratory filter were, respectively, 29.9±8.3, 40.4±5.6, 8.3±1.5, and 21.5±2.1% for air, and 32.6±2.2, 36.3±0.7, 12.0±1.4, and 19.1±1.1% for helium-oxygen. CONCLUSIONS: Ventilation with helium-oxygen in place of air-oxygen mixtures can influence both the droplet size distribution and mass of nebulized aerosol delivered through patient breathing circuits. Assessment of these effects on aerosol delivery is important when incorporating helium-oxygen into patient ventilation strategies.

The ventilation distribution of helium-oxygen mixtures and the role of inertial losses in the presence of heterogeneous airway obstructions.

The regional distribution of inhaled gas within the lung is affected in part by normal variations in airway geometry or by obstructions resulting from disease. In the present work, the effects of heterogeneous airway obstructions on the distribution of air and helium-oxygen were examined using an in vitro model, the two compartments of a dual adult test lung. Breathing helium-oxygen resulted in a consistently more uniform distribution, with the gas volume delivered to a severely obstructed compartment increased by almost 80%. An engineering approach to pipe flow was used to analyze the test lung and was extrapolated to a human lung model to show that the in vitro experimental parameters are relevant to the observed in vivo conditions. The engineering analysis also showed that helium-oxygen can decrease the relative weight of the flow resistance due to obstructions if they are inertial in nature (i.e., density dependent) due to either turbulence or laminar convective losses.

The effects of simulated airway diseases and affected flow distributions on aerosol deposition.

BACKGROUND: Experimental and theoretical aspects of targeted drug delivery have been addressed several times in this journal. Herein, a computational study of particle deposition patterns within healthy and diseased lungs has been performed, using a validated aerosol dosimetry model and a flow-resistance model. OBJECTIVE: To evaluate to what extent the uneven flow distributions produced by the physical manifestations of respiratory diseases affect the deposition patterns of inhaled aerosolized drugs. METHODS: Diseases were simulated by constrictions and blockages, which caused uneven flow distributions. Respiratory conditions of sedentary and pronounced activities, and of particle sizes ranging from 0.1 microm to 10 microm, were used as the basis for the calculated deposition patterns. RESULTS: Findings are presented that describe flow as a function of airway disease state (eg, flow redistribution). Data on the effects of lung morphologies, healthy and diseased, on compartmental (tracheobronchial and pulmonary) and local (airway generation) aerosol deposition are also given. By formulating these related factors, modeling results show that aerosolized drugs can be effectively targeted to appropriate sites within lungs to elicit positive therapeutic effects. CONCLUSIONS: We have addressed the complexities involved when taking into account interactive effects between diseased airway morphologies and redistributed air flows on the transport and deposition of inhaled particles. Our results demonstrate that respiratory diseases may influence the deposition of inhaled drugs used in their treatment in a systematic and predictable manner. We submit this work as a first step in establishing the use of mathematical modeling techniques as a sound scientific basis to relate airway diseases and aerosolized drug delivery protocols.