Interpretation of experimental results
The experiments presented above were conducted using a mechanical test lung with the goal of comparing the effects of He/O2 breathing and positive pressure support on simulated inspiratory effort across a range of obstructive phenotypes. The test lung provides a physical, conceptual model of the human respiratory tract. Clearly, some salient features of the respiratory system are not present in the test lung, so that potential effects on inspiratory effort of, for example, changes in ventilation distribution, dynamic airway closure, or respiratory muscle recruitment were not modeled in the present work. That said, the use of a mechanical test system has enabled us to perform controlled, parametric experiments which we’ve found useful in examining the manner in which He/O2 and pressure support affect inspiratory effort. While it should be noted that increased resistance in obstructive lung diseases may also markedly impact expiration, the work presented primarily addresses effects on inspiratory effort, as reduction of a patient’s inspiratory effort and work of breathing is a main goal of ventilatory support.
Positive pressure support was supplied to the breathing chamber using an ICU ventilator operated in NIV mode. While leaks at patient interfaces clearly influence ventilator performance during NIV
, these particular experiments were performed under the ideal condition of no leak, in order to eliminate effects of ventilator-specific leak compensation algorithms and patient-ventilator asynchrony to focus instead on the more fundamental influence of gas properties on lung mechanics.
The mechanical work spent during inhalation consists of an elastic component required to expand the lung and chest wall, and a resistive component required to move gas through the airways. Additional components of work resulting from non-elastic deformation of tissues are comparably small
. In the present experiments, elastic work was performed as the breathing chamber of the test lung expanded against the force of its spring, the position of which was adjusted in order to simulate varying levels of compliance. Resistive work was associated with the passage of gas through the airway resistors. Such resistors are used to represent pressure losses at varying flow rates through the complex network of airways making up the respiratory tract. The pressure loss across the parabolic resistors predominantly used in this study is dominated by inertial effects, so that it varies with gas density and with the square of gas velocity. In contrast, the nearly linear resistance presented by the breathing filters (Figure
2a) arises mainly due to effects of gas viscosity during passage through the porous filter medium, with gas density playing only a minor role due to the persistence of small inertial effects. In general, parabolic resistors may be thought to represent pressure losses that arise from obstructions occurring in upper airways and the larger airways of the lung, where pressure losses are also inertial in nature, whereas linear resistors are representative of the smaller, peripheral airways, in which flow is sufficiently slow that viscous pressure losses dominate. The density-dependence of inertial pressure losses has been widely attributed to the presence of turbulence in the upper airways and bronchi; however, several authors have noted that even under laminar flow conditions pressure losses may maintain an inertial dependence due to convective acceleration occurring as flow changes direction, for example, at airway bifurcations
[12–14, 22, 23]. The latter point is important in understanding the manner in which breathing He/O2 influences airway resistance and work of breathing, given that the magnitude of inertial pressure losses decreases with decreasing gas density. Indeed, a recent numerical analysis demonstrated that at elevated inspiratory flow rates He/O2 is expected to reduce pressure losses (i.e. airway resistance) down to approximately the 10th lung generation, where flow is laminar
With the above in mind, it should be no surprise that the reduction in inspiratory effort observed in the present experiments for He/O2 compared to air depended strongly on the magnitude and type of simulated airway obstruction. As observed in Figure
2b, the effect of He/O2 on inspiratory effort was considerably smaller for the breathing filters than for the parabolic resistors. During these experiments, the inspiratory flow waveform observed at the support ventilator rose sharply to approximately 35 L/min (~0.6 L/s) at the start of inhalation, and then flattened to a value of approaching 20 L/min (~0.33 L/s). Referring to Figure
2a, over these flow rates there is a considerable reduction in the pressure drop across the parabolic resistors for He/O2 compared to air, whereas the pressure drop across the filters is essentially equal for the two gases. Accordingly, the contrasting influence of He/O2 on inspiratory effort seen in Figure
2b can primarily be attributed to the different flow-pressure drop relationship for the two types of resistance.
3, inspiratory effort is plotted against the resistive loss coefficient defined earlier (see Table
1) for parabolic resistors. For air, the application of pressure support of either 10 or 15 cm H2O decreased inspiratory effort in a consistent manner, independent of the resistive loss coefficient, below that measured for zero support. When no pressure support was provided, the simulated inspiratory effort was equivalent to the total work required for inspiration. With the application of pressure support, this total work was partitioned between the inspiratory effort and work done by the ventilator providing support. That is to say, pressure support lowered inspiratory effort by performing a portion, or in some cases nearly all, of the total work of inspiration. In contrast, substituting He/O2 for air decreased the resistive component of the total work of inspiration. As a consequence, even without pressure support, the inspiratory effort was reduced. Only small differences in inspiratory effort were measured between the two He/O2 mixtures (78/22 and 65/35), consistent with the relatively minor differences in gas properties between these two mixture concentrations
, and suggesting that varying the O2 concentration within this range would have little influence on the clinical efficacy of He/O2 mixtures.
Whereas the compliance of the breathing chamber was fixed throughout the experiments summarized in Figure
5 demonstrates the influence of varying compliance on inspiratory effort. The inspiratory effort rose sharply as compliance decreased, regardless of whether air or He/O2 was inhaled. The reduction in inspiratory effort between air and He/O2 was constant for a given breathing pattern because in conducting this set of experiments only two Rp5 resistors were used (so that the resistive loss coefficient was held constant). Accordingly, it can be concluded that, in the present experiments, He/O2 affected only the resistive component of the inspiratory work. It is important to note that although He/O2 has no effect on the elastic work of breathing for the mechanical test lung, significant effects might be expected for patients experiencing expiratory flow limitations and associated dynamic hyperinflation. For these patients, the elastic work of breathing is elevated because lung compliance decreases as lung volume increases towards total lung capacity (TLC)
. He/O2 can improve expiratory flow by lowering airway resistance
[26–28], so as to reduce end-expiratory lung volumes and improve compliance, which in turn will decrease the elastic work of breathing upon inhalation. In the present experiments, replacing air with He/O2 allowed the breathing chamber to empty faster (Figure
4); however, this did not translate to reduced elastic work because the volume to which the test lung chamber was inflated had little influence on its compliance. Moreover, while the expiratory flow curves in Figure
4 indicate that ventilation with He/O2 eliminated end-expiratory gas trapping that occurred with air for the case shown, in the majority of cases studied, no end-expiratory gas trapping developed, neither for air nor He/O2.
In addition to lowering end-expiratory lung volumes as described above, improved expiratory flow when breathing He/O2 may also lower the corresponding intrinsic PEEP in the lung. When the intrinsic PEEP within the lung is greater than the PEEP supplied at the level of the ventilator, the patient must do added work to lower the pressure at the ventilator by an amount sufficient to trigger inspiratory pressure support. In such circumstances, breathing He/O2 may be expected to reduce the triggering work by decreasing or eliminating intrinsic PEEP. In the present work, such effects likely occurred for the most obstructive cases; however, as intrinsic PEEP was not directly measured, this component of the work of breathing was not quantified explicitly.
5 do not include data for the combination of He/O2 with pressure support, as in the majority of cases studied this resulted in near zero inspiratory effort. Experiments at low breathing chamber compliance, for which significant amounts of inspiratory effort were measured for He/O2 combined with pressure support, are summarized in Table
2. As these experiments were conducted with a fixed level of resistance, the absolute difference in inspiratory effort between air and He/O2 was the same (within experimental error) for each level of pressure support. Concurrent to this difference in resistive work, the effect of pressure support on inspiratory effort was the same for He/O2 as for air: a portion of the total work required for inspiration was performed by the support ventilator, leaving less work for the driving ventilator (the patient) to perform. It is not surprising that experimental values of the ventilator work were below the theoretical values, given that the latter were calculated assuming an instantaneous rise in pressure at the start of inhalation, whereas in the experiments there was a small lag between the initiation of a new breath and ramp-up of pressure support. The results presented in Table
2 provide strong evidence that He/O2 and pressure support may be used in a complementary, additive manner to lower the work of breathing for patients with severe airway obstruction. This conclusion is well aligned with the results of Jaber and colleagues
 for a small group of patients suffering acute exacerbations of COPD, where use of He/O2 during pressure support NIV enhanced the reduction in patient effort provided by NIV with air/O2 mixtures.
Implications for clinical investigation of helium/oxygen mixtures
The experiments presented above were conducted in part to gain insight into variation in patient response to He/O2. Though the use of He/O2 in respiratory medicine has been a subject of considerable research for many decades, widespread clinical use has yet to follow. Previously, the lack of delivery devices specifically designed for use with He/O2 has impeded its adoption
[29–31]. The recent development of He/O2-compatable devices, including the ventilator employed in the present study, aims to remove this obstacle. However, the fact remains that patient response to breathing He/O2 is highly variable
[3, 12, 13]. It is clear that the direct effects of He/O2 on reducing airway resistance and the resistive work of breathing, and indirect effects on elastic work due to improved expiratory flow, depend strongly on the severity and location of airway obstruction
[12, 32]. The latter, the location of obstruction, is especially important in determining the manner in which pressure loss through an obstructed airway varies with gas flow rate and density. More than fifty years ago, building on foundational work on airway resistance by Rohrer
, Arthur Otis and colleagues
[21, 23, 34, 35] were careful to separate airway resistance into two components: a viscous resistance for which pressure loss varies linearly with flow rate, and a second component, resulting from convective acceleration of flow (e.g. at bifurcations)
 and/or turbulence
[21, 23], for which the pressure loss varies with the square of the flow rate, and also with gas density. Further, these researchers described experimental procedures through which the magnitude of each of these components could be estimated for a specific individual
[21, 23, 34]. Today, the relationship between pressure loss and flow through airways is commonly approximated as linear, so that resistance may be described by a single parameter (expressed in cm H2O L-1 sec). Though convenient in many applications, airway resistance measured under such an approximation does not provide a useful parameter in predicting patient response to He/O2, as viscous and density-dependent resistances are lumped into the same term. The resistive loss coefficient used to quantify density-dependent airway resistance in the present study was a strong predictor of the reduction in inspiratory effort afforded by He/O2. It is our hope that such results will encourage clinicians working with He/O2 to re-examine and improve upon early techniques used to separate and quantify the different components of airway resistance, towards a goal of better identifying those patients that will respond to He/O2 therapy.