Breathing freely during nitrogen washout

Current protocols for multiple breath nitrogen washout (MBNW) in adult and pediatric patients aim at constant breathing frequency and tidal volume during the maneuver. Yet, it is unclear if the controlled breathing frequency has any significant effect on the regional distribution of specific ventilation. The requirement for controlled breathing in MBNW protocols arises from multiple sources including classical modeling of alveolar gas washout (9), the need for consistent identification of the phases of within-breath changes in exhaled gas concentration (2), and the necessity of synchronization with imaging acquisition during magnetic resonance (MRI) MBNW or computed tomography Xe washout (5, 12). Understanding what effects controlled breathing and an imposed breathing frequency have on ventilation heterogeneity in comparison to free-breathing is highly relevant for the correct interpretation of MBNW measurements. Also, patients may find it difficult to follow instructions for controlled breathing. The liberation from such constraints without sacrificing the quality of the results could be an important contribution to increasing the use of MBNW.

Prisk and collaborators, a group with advanced expertise in both MBNW and MRI imaging of specific ventilation (9, 12), compared, in a new imaging study published in this issue of the Journal of Applied Physiology, the distributions of ventilation from MBNW during free-breathing with a controlled breathing protocol (10). Regional specific ventilation of eight subjects with healthy lungs was imaged when they were asked to either breathe in synchrony with the noise generated by the MRI machine (12 breaths/min) without changing the functional residual capacity, or at their free will. MRI synchronized breathing is the group’s original technique, which was previously compared with classic exhaled gas MBNW analysis (12). The free-breathing during ventilation imaging is a newly proposed alternative with post-acquisition synchronization between image and breathing cycles using plethysmography signals and pulses from the scanner. The results show individual changes in full-width at half-maximum of a log-normal distribution fitted to the experimental data of both breathing conditions, yet no difference in average among subjects. Importantly, regional specific ventilation during free or controlled breathing was well correlated and showed only a small bias.

Regional distribution of ventilation has structural and functional causes following regional differences primarily in airway resistance and tissue compliance. Together with regional differences in end-expiratory lung volumes, heterogeneous regional ventilation results in inhomogeneous washout rates for a tracer gas (e.g., nitrogen within the lungs after the patient started breathing 100% oxygen). These washout rates are proportional to the regional specific ventilation and its heterogeneity is affected by convective gas flows as well as by the diffusive gas transport in the lung periphery (2). MBNW tests aim at quantifying the heterogeneity of washout rate from dynamic changes in the end-expiratory or mean expired gas concentration using summarizing indices (6), estimation of continuous distributions (9), or direct regional imaging (12). Healthy subjects are expected to breathe with a fairly stable functional residual capacity (11) and with the majority of the regional tissue expansion within the linear segment of the pressure-volume curve (4). Thus, small differences in tidal volume between controlled and free-breathing measurements should not cause major differences in the regional washout rates as long as metabolic rate and minute ventilation are the same. By using information from the nitrogen concentration profile during expiration, MBNW can separate diffusion and convection heterogeneity (2), which is not possible with the MRI imaging method used in the study by Prisk et al. (10).

Prisk et al. (10) estimated also the lung clearance index (LCI) corresponding to their measured distributions of specific ventilation. LCI measures the number of times a volume equal to the functional residual capacity (FRC) must be exhaled to decrease the concentration of tracer gas below a prespecified threshold. An increase in LCI is a measure of decreased washout rates indicating a global impairment of the specific ventilation or an increased heterogeneity in regional ventilation. LCI is known to change due to variations in dead space-to-tidal volume ratio (Vd/Vt) or FRC to end-inspiratory volume ratio [FRC/(FRC + Vt)] with inverse and partially compensating effects (6, 11). In healthy subjects, MBNW at three respiratory frequencies 5 breaths/min apart and with similar tidal volumes resulted in no statistically significant differences in LCI (11). The new results from Prisk et al. (10) suggest that this preserved LCI corresponds to minor or no changes in the regional distributions of specific ventilation. Imaging provides here insights into regional changes beyond the global parameters, which could be relevant to understand the underlying mechanisms of changes in heterogeneity.

The results from Prisk et al. (10) show that breathing requirements for MBNW can be relaxed in healthy patients or subjects. But, additional studies are needed to determine if free-breathing during MBNW is justified in patients with lung diseases causing a heterogeneous distribution of ventilation in the lungs (7). In principle, ventilation heterogeneity in lung diseases involves regional changes in ventilation mechanics leading to regional differences in time constants and asynchronous airflows within the bronchial tree (3). Any changes in breathing frequency affect the distribution of airflows and, thus, the heterogeneity in ventilation. However, these changes can be relatively small (3) and, in the light of previous MBNW measurements at multiple controlled frequencies (7) and the new findings from Prisk et al., it seems possible that they may be too small relative to the magnitude of heterogeneity in regional ventilation to be clinically relevant for MBNW measurements.

The difference in body position between supine imaging and the upright seated posture during MBNW is expected to result in different distributions of regional ventilation in the lungs. However, it is unclear if that redistribution of ventilation between different regions of the lungs could result in a substantial effect of free-breathing on ventilation heterogeneity compared with controlled breathing. The redistribution of ventilation to different regions is not necessarily linked to changes in the effects of breathing pattern on ventilation heterogeneity. Also, it may be necessary to establish some limitations for variations during free-breathing, e.g., defining an acceptable maximum for the variation of the tidal volume since large fluctuations such as deep breaths would eventually have an impact on ventilation heterogeneity.

In conclusion, if the results from Prisk et al. are confirmed in patients with lung disease, it could allow liberation from the current requirements for a controlled breathing pattern during the assessment of ventilation heterogeneity using MBNW. The technical limitations can be addressed with new techniques, such as the post-acquisition breath and imaging synchronization, and the development of alternative models of the alveolar gas washout that have fewer assumptions about breathing patterns (1, 8). MBNW with free-breathing is easier for both the subject and the operator, and results in the study by Prisk et al. (10) should be an incentive for expanding the application of MBNW.

GRANTS

This publication was supported by National Heart, Lung, and Blood Institute Grant R01-HL-141900.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

G.C.M.R. and T.W. drafted manuscript, edited and revised, and approved final version of manuscript.