Interstitial lung disease is an umbrella term for more than two hundred disorders in which the delicate tissue between the air sacs becomes inflamed and scarred. As fibrosis accumulates, the lungs stiffen, oxygen transfer falters, and breathlessness deepens. Some patients remain stable for years while others slide rapidly toward respiratory failure, and distinguishing these trajectories early is one of the most urgent unsolved problems in pulmonary medicine. The concept of progressive pulmonary fibrosis was introduced to describe the non-idiopathic pulmonary fibrosis patients whose disease advances despite treatment, and international guidelines now define progression through three domains: worsening respiratory symptoms, declining lung function, and advancing scarring on high-resolution computed tomography.

Because the Xuzhou cohort included both idiopathic pulmonary fibrosis and other fibrotic ILD subtypes, the research team used the term fibrotic disease progression for a progression-like composite outcome adapted from those criteria. Patients were considered progressors if at least two of the three domains worsened within a nine-to-fifteen-month window around the twelve-month follow-up point. Two interstitial lung disease specialists who were blinded to the baseline oscillometry results adjudicated each outcome, and a thoracic radiologist blinded to all physiological data assessed the CT scans. Independent blinding of outcome assessors is a methodological detail that matters enormously in studies like this one, because expectations can otherwise quietly shape how ambiguous changes are judged.

The study was ambispective, meaning it combined retrospectively assembled routine clinical data with prospective follow-up after formal enrollment. Of 348 screened patients, 93 were excluded for reasons including airway-dominant diseases such as COPD and asthma, acute severe illness, malignancy, missing records, or absence of definite fibrosis on baseline CT. The final 255 patients underwent spirometry, diffusing capacity testing and impulse oscillometry at baseline. The technique itself is elegantly simple: while the patient breathes tidally through a mouthpiece, a loudspeaker superimposes small mult-frequency pressure pulses, and the device separates how much of each wave the respiratory system resists, captured as resistance measures R5 and R20, from how elastically it stores and returns energy, captured as reactance X5, resonant frequency Fres and the reactance area AX.

Over the follow-up window, 41 of the 255 patients — 16.1 percent — met the criteria for fibrotic disease progression. At baseline, the progressors already looked mechanically different: their X5 values were more negative, their AX values larger, and their resonant frequencies higher than those of patients who remained stable. By contrast, differences in R20, the resistance measured in larger central airways, were negligible, hinting that the informative signal lives in the lung periphery rather than the conducting airways. When the team modeled each parameter continuously using Firth penalized logistic regression — a method chosen because the number of events was limited and X5 showed near-complete statistical separation — a one-standard-deviation worsening in X5 carried an adjusted odds ratio of 8.89 for subsequent progression, with a confidence interval of 4.66 to 19.47.

AX, a composite measure integrating abnormal reactance across the breathing frequency spectrum, was associated with progression at an adjusted odds ratio of 1.67 per standard deviation, and resonant frequency at 1.61. The resistance measures R5, R20 and the device-reported mean R5–R20 did not survive adjustment and false-discovery-rate correction. Scaled differently, each 0.01 kilopascal-second-per-liter increase in X5, representing a less negative and therefore healthier reactance, was associated with 33 percent lower odds of progression. Yet the story is not a straight line: restricted cubic spline analysis revealed significant nonlinearity, meaning the relationship between X5 and risk changes shape across its range and cannot be compressed into a single constant effect.

The association survived a series of robustness checks. When the 87 patients with idiopathic pulmonary fibrosis were excluded, leaving 168 patients with 28 progression events, X5 remained strongly associated with progression at an adjusted odds ratio of 8.55, and AX stayed significant at 1.47. A sensitivity analysis restricted to patients assessed within a narrower ten-to-fourteen-month window reproduced the same directional pattern. This resilience matters because the formal progressive pulmonary fibrosis construct applies to non-IPF disease, so the signal is not merely an artifact of the most notoriously aggressive fibrotic subtype.

What makes the result scientifically interesting is what X5 and AX actually represent. Although oscillometry is often described as a small-airway test, in fibrotic lung disease the reactance parameters are influenced not only by the caliber of peripheral airways but also by parenchymal stiffness, elastic recoil and the mechanical load of scarred, heterogeneous tissue. In other words, a more negative X5 may reflect the lung as a whole becoming a less compliant, less elastic organ — a direct mechanical signature of fibrosis tightening its grip. Spirometry, the workhorse of pulmonary function testing, requires forceful maximal efforts and mainly indexes larger airways, while oscillometry requires only quiet tidal breathing, which could eventually make it valuable for patients unable to perform demanding maneuvers.

The predictive performance analyses, though explicitly exploratory, were eye-catching. A clinical base model containing age, sex, height and baseline forced vital capacity percent predicted achieved an optimism-corrected area under the curve of only 0.585 — barely better than a coin flip. Adding AX raised it to 0.703, and adding X5, whether modeled linearly or with a spline, lifted it to roughly 0.92, an incremental gain of about 0.34 with confidence intervals comfortably above zero. Brier scores, which penalize prediction error, improved correspondingly. With the internally derived X5 cutoff, no progression events occurred among patients classified as having normal reactance, a complete-separation pattern the authors interpret cautiously as cohort-specific rather than as proof of zero risk.

That caution is warranted, and the researchers are candid about the limitations. The study was conducted at a single center, progression events numbered only 41, and the receiver-operating-characteristic thresholds derived from the data shifted substantially across 500 bootstrap resamples — X5 cutoffs ranged from minus 0.130 to minus 0.050 kilopascal-second per liter — so no clinically applicable cutoff can yet be recommended. Follow-up CT was not uniformly available and was more often obtained in progressors, potentially biasing ascertainment, and treatment changes during follow-up were not modeled. Healthy controls were substantially younger than the patient cohort and served only as a descriptive reference. The authors accordingly frame their conclusions carefully: continuous oscillometric abnormalities, particularly X5 and AX, were associated with subsequent fibrotic progression and merit evaluation in larger, externally validated cohorts, but these results do not yet establish bedside predictive thresholds. If independent teams reproduce the signal, a test that takes minutes and asks nothing more of the patient than relaxed breathing could become a quiet early-warning system for one of medicine’s most relentless disease processes.

Subject of Research: Impulse oscillometry-derived respiratory mechanics as predictors of fibrotic progression in interstitial lung disease

Article Title: Impulse oscillometry-derived respiratory mechanical abnormalities and fibrotic disease progression in interstitial lung disease: a single-center cohort study

Article References: Zhang, C., Wang, Y., Feng, Z., Sun, Y., Zhang, M., Liu, Y., & Chen, B. (2026). Impulse oscillometry-derived respiratory mechanical abnormalities and fibrotic disease progression in interstitial lung disease: a single-center cohort study. Frontiers in Physiology, 17, Article 1962001. https://doi.org/10.3389/fphys.2026.1962001

Image Credits: AI Generated

DOI: 10.3389/fphys.2026.1962001

Keywords: interstitial lung disease, pulmonary fibrosis, impulse oscillometry, X5 reactance, reactance area, respiratory mechanics, progressive pulmonary fibrosis, spirometry, disease progression, lung function testing, Firth penalized regression, predictive modeling

The device, described in a recent paper in Frontiers in Medical Engineering, is the brainchild of Victoria Ribeiro Rodrigues, Lizuannette Mejia, Rafael G. Zucchi, Paul W. Davenport, and Nicholas J. Napoli, working across the university’s Human Informatics and Predictive Performance Optimization (HIPPO) Lab and the Department of Physiological Sciences. Their goal was ambitious: to create a single apparatus capable of applying both static and dynamic loads to the chest wall and abdomen, with precise, reproducible, and independently adjustable force levels. Existing methods, they argue, have fallen short on all these fronts, forcing researchers to choose between crude approximations that lack quantitative feedback or elaborate setups that cannot transition between restriction types.

At the heart of the problem is a fundamental distinction between two kinds of restriction. Static restriction immobilizes the chest wall entirely, regardless of how hard a person tries to breathe, mimicking conditions such as external bracing or severe mechanical constraint. Dynamic restriction, by contrast, applies a constant resistive load that allows movement only when the breathing muscles generate sufficient force to overcome it, a scenario that better reflects the challenges faced by people with chronic obstructive pulmonary disease (COPD), jet pilots enduring high g-forces, or race car drivers under sustained acceleration. Prior devices have typically addressed one or the other, but never both within a single, instrumented platform.

The University of Florida team’s solution is a wooden frame structure, roughly 48 inches tall and 33 inches wide, that surrounds a seated participant. Two middle boards, one positioned over the chest and one over the abdomen, slide along four rods connecting a padded front compression surface to a rear support board. Each middle board carries a vinyl strapping band, three feet long and eight inches wide, that wraps around the participant’s torso and secures with Velcro. A ratchet gear mechanism tightens the bands, pulling them snug against the body, while an adjustable width system of sliding wooden blocks ensures the bands conform to participants of different sizes. The vinyl material is deliberately non-stretchable, preventing any unintended give that could confound measurements.

What elevates the device beyond its predecessors is its instrumentation. Two Linear Variable Differential Transducers, or LVDTs, supplied by Omega, measure the horizontal displacement of the chest wall and abdomen during breathing, capturing even subtle changes in movement patterns. Pressure sensors, built around Millar Mikro-Cath pressure catheters inserted into air bladders filled with exactly 60 milliliters of air, monitor the force exerted by the bands on the chest and abdomen. Before each trial, the catheters are calibrated according to manufacturer guidelines, and a live data feed allows researchers to verify that the applied load matches the target pressure, tightening the bands further if the baseline falls short.

The transition between static and dynamic modes is elegantly simple. In static mode, four shaft collars are positioned and tightened on the rods, locking the middle boards in place and preventing any forward movement regardless of the participant’s effort. In dynamic mode, the collars are removed and constant force springs, flat strips of spring material coiled into cylinders, are mounted on the backboard and connected to the middle boards via carabiners. Unlike conventional compression springs, these provide a steady force throughout their range of motion, reaching full strength after being stretched to 1.25 times their diameter. This allows the participant to move the boards slightly while maintaining a consistent resistive load, simulating the kind of graded restriction encountered in real-world scenarios.

To validate the device, the team recruited six healthy, non-smoking volunteers, four males and two females, with a mean age of 24 years and a mean body mass index of 25.56 kilograms per square meter. Participants underwent pulmonary function testing under three conditions: baseline without restriction, static restriction, and dynamic restriction with a load of 45 kilograms. The tests measured forced expiratory volume in one second (FEV1) and forced vital capacity (FVC), following American Thoracic Society and European Respiratory Society acceptability criteria. Respiratory data, including airflow and mouth pressure, were recorded using a pneumotach connected to a mouthpiece and a two-way non-rebreathing valve.

The results were striking. Under both static and dynamic restriction, FEV1 and FVC dropped significantly compared to baseline, confirming that the device successfully induces physiologically meaningful restriction. FVC declined by 20.8 percent under dynamic loading and 28.2 percent under static loading, while FEV1 fell by 21.6 percent and 28.2 percent respectively. These reductions align closely with average decreases reported in prior chest wall strapping studies, which typically report FVC reductions of around 25.1 percent and FEV1 reductions of 24.9 percent. Additional metrics, including inspiratory volume, inspiratory time, peak inspiratory airflow, and peak inspiratory pressure, also showed significant differences across conditions, with participants adapting their breathing patterns under load by taking shallower, longer breaths that reduce the instantaneous work of breathing.

Displacement data from the LVDTs provided further confirmation of the device’s capabilities. During static trials, chest and abdominal movement was virtually zero, validating the rigid, non-yielding nature of the restriction. In dynamic trials, displacement reached approximately 0.5 centimeters, demonstrating that the device permits measurable movement under load. Pressure variability tests, conducted across three repeated trials for each condition, showed consistent mean pressures: in the static condition, minimum chest pressures ranged from 3.18 to 3.41 kilopascals with standard deviations between 0.17 and 0.22, while minimum abdominal pressures ranged from 2.70 to 2.96 kilopascals. In the dynamic condition, pressures were similarly reproducible, confirming that the device can deliver adjustable and repeatable loads across participants and sessions.

The implications extend well beyond the laboratory. The researchers envision applications in studying respiratory diseases such as asthma and cystic fibrosis, where chest wall mechanics play a critical role in disease progression. The device could also illuminate the physiological challenges faced by military personnel wearing body armor, firefighters in heavy gear, or astronauts and deep-sea divers operating under unusual pressure conditions. Because the apparatus allows independent restriction of the chest and abdomen, it opens new avenues for understanding how each region contributes to breathing patterns and how the body adapts when one or both are compromised. The team also suggests the platform could be extended to investigate cognitive function, muscle fatigue, and blood circulation under restricted breathing, domains where the interplay between respiratory mechanics and broader physiology remains poorly understood.

Looking ahead, the researchers acknowledge that their validation was conducted in a young adult sample, and that the effects of chest wall restriction may be amplified in older individuals, whose chest walls are stiffer due to calcified cartilage and vertebral deformities, and whose lungs have lost elastic recoil. Future studies, they argue, should include broader age ranges and populations with respiratory diseases, with careful attention to load levels that avoid triggering bronchoconstriction in vulnerable participants. Refinements to accommodate extreme body types and adjustable spring resistance for those with compromised pulmonary function could further expand the device’s reach. For now, the device stands as a versatile new tool in the growing effort to understand, model, and ultimately mitigate the respiratory challenges that arise when the simple act of breathing becomes a battle against constraint.

Subject of Research: Respiratory mechanics and biomedical engineering

Article Title: Chest wall restriction device for modeling respiratory challenges and dysfunction

Article References: Ribeiro Rodrigues, V., Mejia, L., Zucchi, R. G., Davenport, P. W., & Napoli, N. J. (2025). Chest wall restriction device for modeling respiratory challenges and dysfunction. Frontiers in Medical Engineering, 3, Article 1560136. https://doi.org/10.3389/fmede.2025.1560136

Image Credits: AI Generated

DOI: 10.3389/fmede.2025.1560136

Keywords: chest wall restriction, respiratory mechanics, breathing dysfunction, pulmonary function testing, biomedical engineering, static and dynamic loads, COPD, extreme environments, Chest, wall, restriction, device

The study, conducted by researchers at the University of Augsburg in collaboration with Friedrich Schiller University Jena and the University of Stuttgart, and published in Frontiers in Musculoskeletal Disorders, addresses a stubborn gap in musculoskeletal imaging. Conventional tools such as ultrasound, computed tomography, and electromyography have provided valuable clinical insights into chest wall function, but none of them can reliably distinguish individual intercostal muscle fascicles or separate the internal and external intercostal muscle groups from one another. Ultrasound, for instance, is widely used to measure parasternal intercostal muscle thickness in intensive care settings, but it cannot resolve the fine internal architecture needed for biomechanical modeling. Computed tomography, despite its ability to visualize small structures, lacks the soft-tissue contrast to differentiate between muscle layers that run in nearly opposite directions across the same intercostal space.

The research team set out to determine whether magnetic resonance imaging could succeed where these modalities fall short. They analyzed eleven high-resolution thoracic MRI datasets obtained from young male patients who had undergone chest imaging for unrelated clinical reasons. The cohort was deliberately homogeneous: all participants were around 25 years old on average, with a mean height of 1.82 meters, a mean weight of 78.18 kilograms, and a mean body mass index of 23.62. Exclusion criteria removed anyone with lung disease, major thoracic injuries, scoliosis, age over 60, or professional athletic training, ensuring that the measured muscles represented a healthy baseline rather than a pathological or highly trained variant.

Scanning was performed on a 3.0 Tesla Philips Ingenia system with patients lying supine and a receiver coil placed directly on the chest. Breath-holding commands were used to minimize motion artifacts from respiration and heartbeat, a critical consideration when the structures of interest are only millimeters thick and sit within a moving thorax. Three patients were imaged with T2-weighted turbo spin echo sequences in coronal, sagittal, axial, and specially oriented para-axial planes, while eight additional patients received T1-weighted coronal sequences of the sternal region, the protocol typically used for evaluating sternal fractures. Slice thicknesses ranged from 2 to 3 millimeters, with voxel dimensions as fine as 0.40 by 0.40 by 2.0 millimeters in the T1-weighted group.

The segmentation itself was carried out in 3D Slicer, an open-source image computing platform, using DICOM-format data transferred directly from the scanner. Rather than relying on automated tools—which a pilot attempt by the team had already shown to be inadequate for tracing the winding course of intercostal fascicles and their attachment points—the researchers marked each voxel of muscle tissue by hand. The costosternal region, where the parasternal and ventral rib segments meet, was chosen for quantification because it offered the clearest single-fascicle contours. For each patient, three fascicles per intercostal muscle group were defined in intercostal spaces 2, 3, and 4, and experienced radiologists with more than a decade of practice reviewed and finalized every annotation.

Measuring fascicle length required defining the insertion points of each muscle fiber bundle on two adjacent ribs and calculating the distance between them. The para-axial images, which were tilted 90 degrees relative to the coronal plane at the midpoint of each intercostal space, proved especially valuable because they displayed the muscle tissue in cross-section along its entire course from origin to insertion. Coronal images complemented this view by showing the fascicle trajectory and length in a single plane, while sagittal images, when available, served as a final verification. The results showed that internal intercostal muscle fascicles measured approximately 30 millimeters in length across all three intercostal spaces, with mean values of 30.02, 29.74, and 29.23 millimeters in spaces 2, 3, and 4 respectively, and no statistically significant differences between them.

Interestingly, the T2-weighted subgroup tended to yield slightly longer fascicle measurements than the T1-weighted subgroup, with significant differences appearing in intercostal spaces 2 and 4. The researchers attribute this to technical parameters such as voxel size, slice thickness, and subtle movements between imaging sequences rather than to any true anatomical difference. External intercostal muscles told a different story: their fascicle lengths varied considerably, ranging from about 21.7 millimeters in intercostal space 4 to a striking 41.7 millimeters in intercostal space 3, underscoring the greater architectural complexity of the outer muscle layer and the necessity of multidimensional image analysis to capture it accurately.

Beyond length, the team quantified the topographical orientation of each fascicle using an intercostal-insertion angle, defined between the muscle’s course and the rib surface bordering the intercostal space. For internal intercostal muscles, these angles increased progressively from roughly 120 degrees in intercostal space 2 to nearly 145 degrees in space 4, revealing that fascicles run at progressively steeper courses toward the lower chest. A notable finding emerged when the researchers compared the crossing angles of internal and external fascicles: rather than meeting at the textbook-perpendicular 90 degrees, the two muscle groups intersect at a sharper angle, a detail that could reshape how biomechanical models represent the force vectors generated during breathing.

Volumetric analysis and the calculation of physiological cross-sectional area—a key determinant of a muscle’s force-generating capacity—were only feasible when coronal and para-axial imaging were combined. Mean fascicle volumes for internal intercostal muscles in intercostal space 3 averaged 0.75 cubic millimeters, with calculated PCSA values clustering around 0.20 square millimeters. External intercostal fascicles showed volumes ranging from 0.55 to 0.97 cubic millimeters across spaces 2 through 4, with correspondingly small PCSA values. The data confirmed that fascicle volume and length scale proportionally with PCSA, providing a coherent internal check on the measurements. The team also measured interfascicular distance—the spacing between adjacent fascicles—finding an average of approximately 3.31 millimeters for parasternal internal intercostal muscles, with para-axial measurements yielding slightly higher values than coronal ones but without statistical significance.

The implications reach well beyond anatomy. Because the study cohort was young and presumably free of the intramuscular fat infiltration that accompanies aging and chronic disease, the resulting morphometric parameters can serve as a reference dataset for future comparative investigations. Patients with neuromuscular dysfunction, chronic obstructive pulmonary disease, or traumatic chest wall injuries could be scanned with the same protocol and compared against this healthy baseline, potentially revealing how intercostal muscle architecture deteriorates or adapts in disease. The researchers also emphasize that their manual segmentation data provide the anatomical ground truth needed before semiautomated or automated segmentation methods—such as transverse mask propagation, graph-based random walk algorithms, or atlas-based registration—can be reliably applied to these small and closely apposed muscle layers.

Limitations remain. Para-axial sequences were available for only three of the eleven patients, restricting the volumetric analysis to a small subgroup, and these specialized planes are not part of standard sternal MRI protocols because they add scanning time without routine diagnostic value. The small cohort, while homogeneous, limits generalizability, and the researchers acknowledge that a fully randomized fascicle selection was not feasible with the available data. Total PCSA for an entire intercostal space would also require knowledge of fascicle parameters in the lateral, dorsal, and paravertebral regions of the thorax, which remain unmapped. Nevertheless, the study establishes a practical imaging protocol for thoracic musculoskeletal assessment and lays the groundwork for biomechanical modeling of respiratory motion, surgical planning for rib fracture stabilization, and ultimately individualized therapeutic approaches for patients whose breathing depends on the quiet, tireless work of these hidden muscles.

Subject of Research: MRI-based manual segmentation and morphological analysis of human intercostal muscle fascicles

Article Title: Feasibility of magnetic resonance imaging manual segmentation of human intercostal muscles: a morphological analysis approach

Article References: Steingruber, L., Ruess, P., Hammer, M., Moll, P., Raab, S., & Koch, M. (2026). Feasibility of magnetic resonance imaging manual segmentation of human intercostal muscles: a morphological analysis approach. Frontiers in Musculoskeletal Disorders, 3, Article 1677352. https://doi.org/10.3389/fmscd.2025.1677352

Image Credits: AI Generated

DOI: 10.3389/fmscd.2025.1677352

Keywords: intercostal muscles, MRI, manual segmentation, 3D Slicer, fascicle length, muscle volume, physiological cross-sectional area, respiratory mechanics, thoracic stability, para-axial imaging, biomechanical modeling, musculoskeletal imaging

The core of the debate lies in a trade-off that every intensivist performs at the bedside, often several times a day. When lung-protective limits cap the tidal volume, the ventilator must increase the respiratory rate to sustain adequate minute ventilation, the total volume of air moved in and out of the lungs each minute. Minute ventilation is simply the product of tidal volume and respiratory rate, so mathematically the two settings can be traded against one another while the total remains constant. In theory, halving the tidal volume and doubling the rate should deliver the same gas exchange. In practice, the lungs and the body do not obey such neat arithmetic, and the consequences of shifting the balance in one direction or the other have remained surprisingly difficult to pin down.

The reason the trade-off is not neutral lies in the architecture of the respiratory system. Not all inhaled air reaches the alveoli, the tiny sacs where oxygen and carbon dioxide are actually exchanged. A substantial fraction of each breath fills the conducting airways, the trachea, bronchi and bronchioles, where no gas exchange takes place. This volume is known as anatomical dead space. When tidal volume is reduced, each breath carries a proportionally larger burden of dead space gas, air that is inhaled and exhaled without ever contributing to gas exchange. To compensate, the respiratory rate must rise even further than simple minute ventilation calculations would suggest, because the effective, alveolar ventilation falls faster than the total ventilation. Higher rates, in turn, shorten the time available for exhalation, raising the risk of air trapping and the build-up of intrinsic positive end-expiratory pressure, a phenomenon that can quietly strain the lungs and the right side of the heart.

Jung and her colleagues frame this problem through the lens of ventilatory efficiency, a concept that captures how much of the work of breathing actually translates into useful gas exchange. Ventilatory efficiency is commonly assessed by relating ventilation to carbon dioxide elimination, and it deteriorates when dead space fraction rises or when the matching between ventilation and perfusion within the lung worsens. The Hannover group contends that when clinicians and researchers trade tidal volume against respiratory rate, they typically track pressures, volumes and driving pressure, but rarely ask whether the resulting pattern of breathing is actually efficient. Two ventilator configurations that look equivalent on a monitor, delivering identical minute ventilation and similar airway pressures, can differ substantially in how much carbon dioxide they clear per liter of air moved, and that difference carries metabolic and mechanical consequences for the patient.

The correspondence appears alongside and responds to a study by Grieco and colleagues, also published in Intensive Care Medicine, which examined how respiratory mechanics modify the impact of ventilator settings on clinical outcomes in patients with acute brain injury. That work adds an important dimension to the debate, because patients with injured brains are exquisitely sensitive to changes in carbon dioxide levels, intrathoracic pressure and the hemodynamic effects of ventilation. In this population, the choice between a low tidal volume with a high rate and a slightly larger tidal volume with a lower rate is not merely a question of lung protection. It can influence cerebral blood flow, intracranial pressure and brain tissue oxygenation, making the trade-off a matter of neurological as well as pulmonary consequence.

To probe the physiological side of the question directly, the Hannover authors point to their own prospective physiological pilot study, published in Annals of Intensive Care, in which they systematically increased respiratory rate during low tidal volume ventilation and measured what happened to ventilatory efficiency and to the mechanical costs of breathing. The study, led by Jung with colleagues including Markou and Storch, was designed to isolate the effect of rate under controlled conditions, allowing the researchers to observe how the efficiency of carbon dioxide elimination and the energetic burden on the respiratory system changed as breaths became faster and smaller. Although pilot studies of this kind involve limited numbers of patients and are intended to generate hypotheses rather than definitive answers, they provide the kind of granular physiological data that large outcome trials often cannot capture.

The significance of this line of research extends beyond the physiology laboratory. Mechanical ventilation is one of the most common interventions in critical care, and the energy cost of breathing, whether performed by the patient’s own muscles or by a machine, is a real metabolic burden for patients whose reserves are already depleted. Inefficient ventilation means that the body, or the ventilator, must move more air to achieve the same gas exchange, and every liter of air moved imposes stress on the lung tissue, on the airways and on the circulation. If a high rate strategy systematically degrades ventilatory efficiency, then the apparent safety of very low tidal volumes may come with a hidden price that current protective ventilation protocols do not account for. Conversely, if efficiency is preserved across a wide range of rate settings, clinicians would gain welcome flexibility in tailoring ventilation to individual patients.

The Hannover authors also emphasize that respiratory mechanics, the elastic and resistive properties of the individual patient’s respiratory system, modify how these trade-offs play out. A stiff, poorly compliant lung in acute respiratory distress syndrome behaves very differently from a more compliant one, and the same ventilator settings can impose very different stresses depending on the underlying disease, the body size and the geometry of the airways. This is precisely the message reinforced by the Grieco study in brain-injured patients, where the impact of ventilator settings on outcomes depended on respiratory mechanics. The implication is uncomfortable but important: there may be no universal answer to the question of how to distribute ventilation between volume and rate, and the optimal balance may need to be determined for each patient rather than dictated by a single protocol.

What the correspondence ultimately calls for is a change in perspective rather than a change in practice. The authors do not dispute the value of low tidal volume ventilation, which remains one of the most robustly supported interventions in critical care. Instead, they argue that ventilatory efficiency deserves a place at the table when ventilator settings are chosen and when clinical trials are designed. Modern ventilators already measure many of the variables needed to estimate dead space and efficiency at the bedside, and incorporating these measurements into routine monitoring could allow clinicians to see not just how much air they are moving, but how effectively that air is working. As the field moves toward increasingly personalized ventilation strategies, the question posed by Jung, Gillmann and Stueber is likely to shape both research agendas and bedside decision-making in the years ahead.

For now, the message for the intensive care community is one of measured caution and renewed curiosity. The trade between tidal volume and respiratory rate is not a zero-sum game played out on the ventilator display; it is a physiological negotiation with consequences for gas exchange, energy expenditure, hemodynamics and, in vulnerable populations such as patients with brain injury, the injured organ itself. By insisting that ventilatory efficiency be considered in that negotiation, the Hannover group has added a compelling voice to a growing conversation about what protective ventilation truly means. The answer to their title question, on the evidence they marshal, appears to be a qualified yes, and the next generation of studies will need to determine exactly how that consideration should change the numbers entered on the ventilator each morning.

Subject of Research: Ventilatory efficiency in the trade-off between tidal volume and respiratory rate during protective mechanical ventilation

Article Title: Should ventilatory efficiency be considered when trading tidal volume against respiratory rate?

Article References: Jung, C., Gillmann, H.-J., & Stueber, T. (2026). Should ventilatory efficiency be considered when trading tidal volume against respiratory rate?. Intensive Care Medicine. https://doi.org/10.1007/s00134-026-08627-8

Image Credits: AI Generated

DOI: 10.1007/s00134-026-08627-8

Keywords: mechanical ventilation, tidal volume, respiratory rate, ventilatory efficiency, dead space, acute respiratory distress syndrome, intensive care medicine, respiratory mechanics, carbon dioxide elimination, acute brain injury, lung protection, minute ventilation

Total liquid ventilation is not science fiction. The concept dates back to the early 1970s, when researchers demonstrated that the alveoli of fluorocarbon-filled lungs could exchange gases across a liquid interface. Perfluorocarbons, the synthetic liquids used in TLV, possess two remarkable properties: they dissolve large quantities of oxygen and carbon dioxide, and they have extremely low surface tension. Because a premature infant’s lungs are deficient in surfactant—the body’s own surface-tension-lowering substance—filling them with a perfluorocarbon can, in principle, recruit collapsed alveoli uniformly, reduce the sheer forces that injure delicate tissue, and permit gentle ventilation at pressures that would be dangerous with gas. In TLV, a specialized ventilator with independent piston pumps fills the lungs with oxygenated liquid and then drains it, cycle after cycle, in a rhythm that mimics breathing.

Yet the technique has an Achilles’ heel that has shadowed its development for decades: airway collapse during expiration. As the liquid ventilator drains fluid from the lungs, the pressure inside the trachea and bronchi falls, and in a newborn—whose airway cartilage is soft and immature—the walls of these tubes can buckle inward under the pressure difference between the inside and outside of the airway. Previous work, including computational models and experiments in lambs and rabbits, had identified expiratory flow limitation and airway deformation as hazards of liquid-filled lungs. What has been missing is a direct, quantitative, in vivo picture of how much the airways actually deform during real TLV cycles, and what determines whether that deformation becomes dangerous. The new study set out to fill that gap.

The research team, led by Kevin Le Duc and Étienne Fortin-Pellerin of the Université de Sherbrooke, together with colleagues in mechanical engineering and molecular imaging, worked with nine piglets aged five to seven days and weighing around two kilograms. Piglets at this age are a well-established model for the neonatal airway, sharing key anatomical and mechanical features with human infants. The animals were placed on total liquid ventilation using perfluorooctyl bromide, a dense, radiopaque perfluorocarbon whose visibility on X-ray-based imaging makes it an ideal tracer for lung volume studies. When signs of tracheobronchial collapse appeared, additional perfluorocarbon was added to restore a normal expiratory pressure, and this baseline state was designated V0, corresponding to a median end-expiratory lung volume of 37 milliliters per kilogram.

From that baseline, the researchers then deliberately manipulated lung volume in a randomized sequence. Additional perfluorocarbon was administered in increments of one, three, and five milliliters per kilogram, creating ventilation levels labeled V1, V3, and V5. At each level, the team performed two kinds of computed tomography imaging. Static CT scans measured the end-expiratory lung volume itself, while dynamic CT scans captured something that had never before been quantified in a living neonatal model during TLV: the cross-sectional area of the trachea continuously throughout the expiratory phase of each breath. This dynamic imaging approach, adapted from techniques used to evaluate airway function in adult patients, allowed the investigators to watch the airway walls move in real time as liquid was withdrawn from the lungs.

The results were striking. At the baseline volume V0, the tracheal cross-sectional area varied by a median of 35 percent between the beginning and the end of expiration—a degree of deformation that, in a clinical setting, would occur entirely invisibly to the bedside team. The ventilator’s pressure readings gave no warning: the study found that severe expiratory tracheobronchial deformation can take place without any detectable drop in airway opening pressure, challenging the very safety markers that clinicians and engineers currently rely on to detect trouble during liquid ventilation. In other words, an infant’s airway could be collapsing substantially with every breath while the monitoring equipment reported that everything was normal.

When the researchers raised the end-expiratory lung volume by adding perfluorocarbon, the picture changed dramatically. At ventilation level V3, corresponding to a median end-expiratory lung volume of 42 milliliters per kilogram, tracheal deformation fell to a median of 18 percent, a statistically significant reduction. The mechanism is physically intuitive: a larger residual liquid volume at end-expiration maintains higher pressure within the airways throughout the expiratory phase, providing internal structural support that resists the compressive forces trying to collapse the soft-walled tubes. The liquid acts, in effect, as a hydraulic stent, splinting the trachea and bronchi open from the inside. This finding establishes, for the first time in vivo, a direct causal link between lung volume and airway stability during total liquid ventilation.

But the therapeutic window proved to be narrow, and the upper boundary of that window carries its own risks. When the team pushed lung volume to the highest level, V5, they observed a significant decrease in mean arterial pressure between the baseline and the highest volume condition. This hemodynamic consequence is consistent with a long-recognized principle in mechanical ventilation: overdistending the lungs raises intrathoracic pressure, which impedes venous return to the heart and reduces cardiac output. In a premature infant with limited cardiovascular reserve, such a drop in blood pressure could compromise perfusion of the brain, the heart, and other vital organs. Notably, blood gas values remained unchanged across all ventilation levels, meaning that the conventional measures of ventilation adequacy—oxygenation and carbon dioxide removal—gave no indication of either the airway deformation at low volumes or the circulatory compromise at high volumes.

The implications of this study extend well beyond the laboratory. For engineers designing the next generation of liquid ventilators, the message is that volume control, not merely pressure control, must be at the heart of the machine’s regulation strategy. The expiratory volume profile—the precise way liquid is withdrawn and how much is deliberately left behind at end-expiration—emerges as a critical, tunable parameter that can be optimized to keep airways open. For clinicians and translational researchers hoping to bring TLV to human neonates, the study defines a target range for end-expiratory lung volume, roughly between the levels that caused dangerous deformation and those that depressed blood pressure, and it warns that the currently used safety indicators are insufficient on their own. Complementary monitoring strategies, potentially including imaging or airway mechanics measurements, may be needed to detect occult collapse.

The road to clinical application remains long, and the authors are careful to frame their work as mechanistic evidence from an animal model rather than a recipe for the bedside. Piglets are not human infants, and the specific volume thresholds identified here cannot be transplanted directly into the neonatal intensive care unit. Nevertheless, the study delivers essential data for the safer translational development of a technique that could one day rescue babies whose lungs are too immature for any conventional approach. It also reinforces a broader lesson in respiratory medicine: the most dangerous events are sometimes the ones that leave no trace on the monitors. By making the invisible visible through dynamic CT imaging, this research has turned a hidden hazard into a measurable, and therefore manageable, quantity—bringing the dream of letting newborns breathe liquid one careful step closer to reality.

Subject of Research: The effect of end-expiratory lung volume on tracheal deformation and hemodynamic stability during total liquid ventilation in neonatal piglets

Article Title: Lung volume determines airway stability during total liquid ventilation: evidence from neonatal piglets

Article References: Le Duc, K., Bouchard, C., Samson, N., Taillandier-Pensarini, S.-G., Richard, G., Lavallée, É., Croteau, E., Espinosa-Bentacourt, O.-E., Poncet, S., Praud, J.-P., Micheau, P., & Fortin-Pellerin, É. (2026). Lung volume determines airway stability during total liquid ventilation: evidence from neonatal piglets. Pediatric Research. https://doi.org/10.1038/s41390-026-05423-4

Image Credits: AI Generated

DOI: 10.1038/s41390-026-05423-4

Keywords: total liquid ventilation, perfluorocarbon, neonatal piglets, airway collapse, end-expiratory lung volume, dynamic CT imaging, tracheal deformation, premature infants, hemodynamics, pediatric research, respiratory mechanics, liquid ventilator

ARDS is a life-threatening form of acute lung injury in which the air sacs of the lungs become inflamed and filled with fluid, dramatically reducing the tissue available for gas exchange. The stiffness of the respiratory system, measured as elastance, reflects how much pressure is required to deliver a given volume of air. Crucially, this total elastance is the sum of two distinct components: the lung itself and the chest wall, which includes the rib cage, the diaphragm and the abdomen. Standard ventilator management in ARDS has historically treated the respiratory system as a single unit, adjusting tidal volumes and pressures according to predicted body weight and plateau pressure thresholds. This approach implicitly assumes that the contribution of the chest wall remains relatively uniform across patients, an assumption that severe obesity decisively violates.

In patients with severe obesity, the massive accumulation of adipose tissue around the thorax and abdomen, together with the upward displacement of the diaphragm by intra-abdominal fat, substantially increases chest wall elastance. The chest wall becomes stiffer and resists expansion more strongly, which means that a larger fraction of the pressure generated by the ventilator is consumed in deforming the chest wall rather than in aerating the lung. As a consequence, clinically measured pressures at the airway opening can appear alarmingly high even when the lung itself is only mildly injured, or conversely, the true stress borne by the lung parenchyma may be underestimated if the clinician assumes that all measured pressure reflects lung injury. This partitioning problem lies at the heart of the argument advanced by the Marseille team.

The physiological consequences of elevated chest wall elastance in obese patients with ARDS are far-reaching. Transpulmonary pressure, the pressure difference across the lung that actually determines lung stress and strain, cannot be directly measured at the airway. It must be inferred by subtracting an estimate of pleural pressure, typically obtained with an esophageal balloon catheter, from the airway pressure. When chest wall elastance is high, pleural pressure rises, and the airway pressure needed to achieve adequate oxygenation and alveolar recruitment increases accordingly. A ventilator strategy calibrated to airway pressures alone may therefore deliver insufficient tidal volumes and inadequate positive end-expiratory pressure to an obese patient whose lungs are, in fact, recruitable, leading to derecruitment, atelectasis and worsening hypoxemia.

The Marseille authors situate their commentary within an ongoing discussion prompted by a recent debate in the same journal on whether the esophageal balloon catheter should be deployed to personalize ventilation of ARDS. Esophageal manometry is not a new technique; it has been used in respiratory physiology for decades. Yet its adoption in routine intensive care remains limited, partly because of concerns about technical complexity, the expertise required for correct placement and interpretation, and the absence until recently of large randomized trials demonstrating outcome benefits. The correspondence by Barrau and colleagues underscores that in specific patient populations, severe obesity chief among them, the assumptions underlying conventional ventilator titration break down in ways that esophageal measurements can reveal.

Supporting evidence for the physiological argument comes from earlier work cited by the authors. A study by Behazin and colleagues published in the Journal of Applied Physiology demonstrated that morbid obesity is associated with respiratory restriction and elevated pleural and esophageal pressures, providing direct experimental confirmation that the chest wall, rather than the lung, accounts for much of the measured stiffness in this population. In parallel, a multicenter study by Coudroy and colleagues published in Anesthesiology investigated the prevalence of complete airway closure according to body mass index in patients with ARDS, documenting that higher body mass index is associated with a greater frequency of complete airway closure, a phenomenon that further complicates pressure interpretation and ventilator management at the bedside.

Complete airway closure deserves particular attention because it illustrates how obesity transforms the mechanical behavior of the respiratory system in ARDS. When the airways close completely at a certain lung volume, the pressure measured at the airway no longer communicates with the alveoli until the closing pressure is exceeded. In obese patients, the elevated pleural pressures generated by the heavy chest wall and abdomen can promote such closure, meaning that a substantial portion of each delivered breath may initially serve simply to reopen collapsed airway segments. Clinicians unaware of this mechanism may misinterpret high measured pressures as evidence of overdistension or severe lung injury and may inappropriately reduce ventilatory support, when in fact the underlying problem is the mechanical load imposed by the chest wall.

The clinical stakes of these considerations are considerable. Obesity is a rapidly growing condition worldwide, and patients with severe obesity constitute an increasing share of intensive care admissions, including admissions for ARDS triggered by pneumonia, sepsis and other causes. If ventilator protocols designed around average chest wall mechanics systematically misjudge the lung stress experienced by obese patients, then a large and expanding group of critically ill individuals may receive suboptimal care. Personalized ventilation guided by esophageal manometry offers a way to partition respiratory system elastance into its lung and chest wall components, allowing clinicians to titrate positive end-expiratory pressure and tidal volume according to transpulmonary pressures that reflect what the lung tissue itself is actually experiencing.

The correspondence does not claim that esophageal manometry is a panacea. Interpreting esophageal pressure requires attention to the position of the catheter, the effects of patient positioning and the influence of abdominal pressure, and measurements obtained in the supine, sedated and paralyzed patient differ from those in upright spontaneous breathing. Nevertheless, the authors’ central message is that ignoring chest wall elastance in severe obesity risks systematic error, whereas measuring it offers the possibility of tailoring ventilator settings to the individual patient’s physiology. In their view, the question is no longer whether chest wall mechanics matter in obese patients with ARDS, but whether the tools to measure them should be deployed more widely to translate that understanding into practice.

As the debate over personalized ventilation continues, the contribution from the Marseille intensive care team adds a clear physiological anchor. Severe obesity elevates chest wall elastance, redistributes the pressure generated by the ventilator away from the lung and toward the chest wall, and thereby distorts the conventional interpretation of airway pressures in ARDS. Whether esophageal balloon catheters become a routine part of ARDS management will depend on ongoing research, training and the accumulation of clinical evidence, but for patients with severe obesity the case for looking beyond the airway pressure gauge has rarely been more compelling.

Subject of Research: The effect of severe obesity on chest wall elastance and personalized mechanical ventilation in ARDS

Article Title: Severe obesity and chest wall elastance in ARDS

Article References: Barrau, D., Hraiech, S., & Guervilly, C. (2026). Severe obesity and chest wall elastance in ARDS. Intensive Care Medicine. https://doi.org/10.1007/s00134-026-08624-x

Image Credits: AI Generated

DOI: 10.1007/s00134-026-08624-x

Keywords: ARDS, severe obesity, chest wall elastance, mechanical ventilation, esophageal manometry, transpulmonary pressure, pleural pressure, airway closure, critical care, respiratory mechanics, positive end-expiratory pressure, intensive care medicine

The study drew on the COmPLETE cohort, a cross-sectional investigation conducted at the University of Basel in Switzerland in collaboration with the Royal Brompton Hospital in London. All participants were free from cardiopulmonary disease, screened for active respiratory infection, and assessed with spirometry interpreted according to European Respiratory Society and American Thoracic Society guidelines using race-neutral Global Lung Initiative reference values. Each volunteer then completed a maximal cardiopulmonary exercise test on a cycle ergometer, with ventilation measured on a breath-by-breath basis and averaged over 10-second intervals. The cohort was remarkably balanced: women made up 52 percent of participants, body mass index averaged 23.7 kilograms per square meter, and lung function sat comfortably within normal limits, with predicted forced expiratory volume in one second at 107 percent and predicted forced vital capacity at 110 percent. In other words, these were genuinely healthy adults, not patients, which makes the age-related changes all the more telling.

The researchers framed their investigation around a growing appreciation in physiology that the irregularity, or complexity, of a biological signal can itself be a marker of health. In cardiology, reduced heart rate variability is a well-established signal of autonomic dysfunction and disease risk. But the application of entropy analysis to breathing during exercise has been far more limited. Sample entropy works by asking how predictable a time series is: a highly repetitive, regular pattern scores low, while a complex, irregular pattern scores high. The team calculated sample entropy for minute ventilation, breathing frequency, and tidal volume in every participant, using an embedding dimension of two and a tolerance coefficient of 0.2. Their initial hypothesis, modeled on the heart rate variability literature, was that aging would reduce ventilatory irregularity, constraining the breathing pattern in older adults. The data told a different story.

First, the conventional measures. As expected, exercise capacity declined steadily with age. Peak power output, peak oxygen uptake, peak minute ventilation, peak tidal volume, and peak breathing frequency all fell progressively across the decades, with correlations ranging from modest to strong. Peak oxygen uptake dropped from roughly 45 milliliters per kilogram per minute in the twenties to under 23 in the oldest group. But the striking finding was the shape of the change in breathing strategy. At the first ventilatory threshold, breathing frequency remained essentially flat across the entire age range, hovering around 20 to 22 breaths per minute regardless of whether a participant was 25 or 85. Yet the ratio of breathing frequency to minute ventilation traced a non-linear curve: stable from age 20 to about 55, then inflecting sharply upward. At peak exercise the same pattern emerged, with the frequency-to-ventilation ratio rising markedly in the 70-to-79 and 80-plus decades, indicating a shift toward a tachypneic, or rapid-and-shallow, breathing strategy.

This shift makes mechanical sense. Healthy aging is associated with loss of lung elastic recoil, stiffening of the chest wall, reduced respiratory muscle strength, and declining tidal volumes relative to lung capacity. As the lungs lose their spring, breathing deep becomes expensive. Older adults compensate by breathing more often rather than more deeply, achieving the required ventilation through frequency rather than depth. The study found that the tidal volume to forced vital capacity ratio rose with age at both threshold and peak exercise, confirming that older breathers were working closer to their volumetric limits. Age and peak breathing frequency emerged as independent predictors of ventilatory reserve utilization, the percentage of estimated maximal voluntary ventilation consumed during exercise. Meanwhile ventilatory efficiency deteriorated, with the ventilatory equivalent for carbon dioxide nadir climbing from 24 in the youngest group to 32 in those over 80, meaning older adults had to move substantially more air to eliminate the same amount of carbon dioxide.

Then came the entropy results, which overturned the researchers’ expectations. After adjusting for sex, body mass index, peak oxygen uptake, forced expiratory volume in one second, and exercise duration, generalized additive models revealed a non-linear relationship between age and ventilatory sample entropy across all three signals. Entropy values held steady through early and middle adulthood, then climbed progressively from approximately age 60 onward. The pattern appeared in minute ventilation entropy, tidal volume entropy, and breathing frequency entropy, with the models for minute ventilation explaining just over a quarter of the deviance. Far from becoming more rigid and predictable, the breathing of older adults became demonstrably more chaotic during exercise. The team had hypothesized a decline in irregularity with age, mirroring the well-documented decline in heart rate variability, and the opposite occurred.

The authors offer several plausible mechanisms, while cautioning that the observational design cannot settle the question definitively. One possibility is altered central respiratory drive or impaired integration of afferent feedback within the brainstem, a form of neural dedifferentiation consistent with the broader concept of loss of physiological complexity in aging. Elevated entropy has previously been documented in dysfunctional breathing and in post-COVID unexplained breathlessness, conditions where patients report exertional breathlessness without any underlying cardiorespiratory pathology. Intriguingly, the age-related rise in entropy coincides with the period when around a quarter of people over 65 report breathlessness in the absence of diagnosed disease. The stability of breathing frequency at the first ventilatory threshold suggests that at submaximal intensities, age-related mechanical constraints have not yet compromised ventilation; the irregularity and tachypneic shift become evident only as exercise intensity climbs into higher domains. Sex differences added another layer: males showed higher minute ventilation entropy than females, possibly because larger lung volumes and airway dimensions in males produce a broader, less constrained ventilatory response that registers as a more irregular time series.

The study also connected ventilatory irregularity to fitness. In secondary analyses, higher peak oxygen uptake was associated with lower sample entropy across all three ventilatory signals, and peak oxygen uptake was the primary determinant of minute ventilation and frequency entropy in models adjusted for age and body mass index. The authors are careful to note that this may reflect shared age-related influences rather than a direct mechanistic relationship, since cardiorespiratory fitness declines steadily after the fifth decade, roughly the same point at which entropy begins its ascent. Still, the possibility that fitness protects the fine-grained organization of breathing control is a tantalizing lead. The findings also fit into a developmental arc suggested by prior work in children and adolescents, where entropy values decline during maturation, indicating increasing refinement of respiratory control. Taken together, these studies sketch a lifespan trajectory in which breathing control is refined through childhood and adolescence, stabilizes through adulthood, and then de-differentiates in later life, echoing patterns observed in frailty research across multiple physiological systems.

Limitations are candidly acknowledged. The analysis was retrospective and cross-sectional, so longitudinal data would be needed to track how individual breathing patterns evolve with age. All testing occurred at a single Swiss center in a predominantly Caucasian cohort, which limits generalizability, and no perceptual breathlessness ratings such as Borg scale scores were collected, preventing a direct link between entropy and symptom intensity in this cohort. The use of estimated rather than directly measured maximal voluntary ventilation is a further caveat, though the two are strongly correlated in healthy people. Crucially, the proportion of the exercise test spent above the first ventilatory threshold was comparable across all age decades, between 52 and 54 percent, suggesting that differences in relative exercise intensity did not confound the entropy findings. The authors also provide normative entropy values across the age span, a reference standard intended to anchor future studies of breathlessness in older adults.

The bigger picture is compelling: the study demonstrates that the aged respiratory system is forced into a mechanically inefficient, frequency-dominant pattern accompanied by rising signal irregularity, a kind of neuromechanical dissociation that may underpin the heightened perception of breathlessness so commonly reported with healthy aging. Because breathing frequency tracks perceived exertion closely, the tachypneic shift documented here provides a physiological bridge between the aging lung and the everyday experience of getting winded. Future prospective studies correlating entropy with breathlessness scores, and longitudinal designs tracking entropy within individuals over time, will be needed to convert these cross-sectional patterns into clinical insight. But the message already resonates: aging does not simply dim the respiratory system, it rewires its control, and the mathematical fingerprint of that rewiring becomes visible somewhere around our sixtieth birthday.

Subject of Research: Age-related changes in ventilatory pattern and irregularity during exercise in healthy adults

Article Title: The ventilatory response pattern to exercise across the age‐span in healthy adults

Article References: Williams, Z. J., Cenerini, G., Schwendinger, F., Knaier, R., Wagner, J., Hull, J. H., & Schmidt‐Trucksäss, A. (2026). The ventilatory response pattern to exercise across the age‐span in healthy adults. Physiological Reports, 14(17), Article e71065. https://doi.org/10.14814/phy2.71065

Image Credits: AI Generated

DOI: 10.14814/phy2.71065

Keywords: healthy aging, ventilatory response, sample entropy, cardiopulmonary exercise testing, breathing frequency, tidal volume, exertional breathlessness, respiratory mechanics, physiological complexity, cardiorespiratory fitness, ventilatory threshold, COmPLETE study