Respiratory and cardiopulmonary limitations to aerobic exercise capacity in adults born preterm

Abstract

Adults born preterm, regardless of whether they develop bronchopulmonary dysplasia, have underdeveloped respiratory and cardiopulmonary systems. The resulting impaired respiratory and cardiopulmonary systems are inadequate for the challenges imposed by aerobic exercise, which is exacerbated by the presence of bronchopulmonary dysplasia. Thus the respiratory and cardiopulmonary systems of these preterm individuals may be the most influential contributors to the significantly lower aerobic exercise capacity compared with their term born counterparts. The precise underlying cause(s) of the lower aerobic exercise capacity in adults born preterm is not entirely known but could be a number of interrelated parameters including mechanical ventilatory constraints, impaired pulmonary gas exchange efficiency, and excessive cardiopulmonary pressures. Likewise, additional aspects, such as impaired cardiovascular function and altered muscle bioenergetics, may play additional roles in limiting aerobic exercise capacity. Whether or not all or some of these aspects are present in adults born preterm and precisely how they may contribute to the lower aerobic exercise capacity are only beginning to be systematically explored. The purpose of this mini-review is to outline what is currently known about the respiratory and cardiopulmonary limitations during exercise in this population and to identify key areas where additional knowledge will help to advance this area. Additionally, where possible, we highlight the similarities and differences between obstructive lung disease resulting from preterm birth and chronic obstructive pulmonary disease (COPD) as the physiology and pathophysiology of these two forms of obstructive lung disease may not be identical.

INTRODUCTION

Preterm birth accounts for 10-12% of all live births (3a). In infants born “very” (8–12 wk early) to “extremely” (>12 wk early) preterm (49), there are significant challenges related to ventilation and pulmonary gas exchange (respiratory) and heart-lung hemodynamic interactions (cardiopulmonary). Postnatal lung development appears to be normal in individuals born preterm, but there does not appear to be any significant “catch-up” lung growth/development during early (27) or young adulthood (47). Similarly, cardiac structure and function also appear to be altered with preterm birth (26, 32, 33). Generally speaking, adults born preterm whether or not they develop bronchopulmonary dysplasia can be characterized as having impaired respiratory and cardiopulmonary function at rest (13, 15, 22, 28, 34, 35, 38, 44), varying degrees of pulmonary vascular disease (20, 31), and possibly early heart failure (6).

Aerobic exercise capacity is a known predictor of all causes of morbidity and mortality and is determined by the integrative responses of the cardiovascular and respiratory systems, as well as O₂ uptake and utilization at the muscle. Thus an impairment at any level of O₂ uptake, transport, and utilization would reduce exercise capacity. One consequence of impaired respiratory and cardiopulmonary function in adults born preterm is a lower aerobic exercise capacity compared with their term-born counterparts (8, 13, 15, 28, 34, 35, 38, 43, 48). In general, those born most preterm, with the greatest developmental immaturity, have the greatest degree of respiratory and cardiopulmonary impairment and, similarly, the greatest exercise impairment (Fig. 1). The precise underlying cause(s) of lower exercise capacity in adults born preterm is likely some combination of all possible factors, but at present, it is unknown whether or not peripheral O₂ diffusing/uptake kinetics and/or muscle bioenergetics differ from term-born individuals. However, lung pathophysiology is known to impair exercise ability; thus mechanical ventilatory constraints, pulmonary gas exchange efficiency, and cardiopulmonary hemodynamics have been characterized in adults born preterm.

Fig. 1.

V̇o_2max vs. gestational age is displayed for previous work in before/bronchopulmonary dysplasia (PRE/BPD; blue) and term-born individuals (7, 13–15, 34, 35, 48). Black line depicts the linear relationship between these parameters, but statistics were not performed given the bimodal data. The green shaded area between gestational age 32 and 36 wk represents the region where little or nothing is known about V̇o_2max.

Here, we provide working hypotheses outlining the existing work on the potential respiratory and cardiopulmonary limitations to exercise capacity identifying knowledge gaps and areas where additional work is needed (Fig. 2). Early life interventions to treat or mitigate the outlined limitations may increase longevity and quality of life for those who are otherwise impaired from a young age. Thus the importance of understanding the physiological mechanisms of exercise impairment in adults born preterm cannot be understated.

Fig. 2.

Schematic representation of working hypothesis(es) for the reduced aerobic exercise capacity in before/bronchopulmonary dysplasia (PRE/BPD) compared with term-born individuals. While this schematic is comprehensive, we refrained from making all possible connections to enhance clarity. Blue text represents what is known; red text represents what has been shown to not occur, on average; and green text represents what is not known or has not been tested. A solid arrow represents an established causal link and a dotted arrow represents an untested but presumed causal link. A-aDO₂, alveolar-to-arterial difference in Po₂; DH, dynamic hyperinflation; EFL, expiratory flow limitation; EIAH, exercise-induced arterial hypoxemia; P_PA, pulmonary artery pressure; PVR, pulmonary vascular resistance; Q_T, pulmonary blood flow (i.e., right heart output); RM, respiratory muscle; RV, residual volume; TLC, total lung capacity; Wb, work of breathing.

RESPIRATORY LIMITATIONS

Adults born preterm have impaired pulmonary function consistent with an obstructive airflow pattern. The underlying reasons for their impaired pulmonary function have not been adequately characterized but would undoubtedly play a role in impaired respiratory and cardiopulmonary responses to exercise. Lung function can be considered impaired due to having smaller lungs and/or having impaired expiratory airflow. Adults born preterm have normal lung volumes, when appropriately matched for sex and height (7, 8, 13–15, 17, 23, 31, 34, 35, 37, 38, 47, 48). Thus it appears that insufficient expiratory (and/or inspiratory) pressure generation and/or excessive airflow resistance are the likely cause(s) of their impaired respiratory function, specifically lower expiratory airflow.

Resting Pulmonary Function

Respiratory pressure generation.

Driving pressure, i.e., alveolar pressure, during a forced expiration is determined by the balance of expiratory muscle strength and elastic recoil of the lungs and chest wall (during the initial 20% of expiration) (36). None of these parameters have been quantified in adults born preterm. However, animal models of preterm birth demonstrate the presence of alveolar simplification (4, 9), which is physiologically similar to emphysema and, if pervasive enough, would decrease lung elastic recoil. Computed tomography in human adults born preterm, however, report little or no emphysema and suggest that any present alveolar simplification may be insufficient to be physiologically important (45). One study has assessed maximal expiratory pressure generation in child survivors of preterm birth, and they found it to be within the normal range for their age (28). Assuming that these findings extend into adulthood, then adults born preterm may also have normal respiratory muscle strength, but this remains unknown.

Airway resistance and responsiveness.

Previous work, primarily in children, supports the presumption that survivors of preterm birth have a greater airflow resistance (23, 48) and adults born preterm have a more pronounced “scoop” in the maximum expiratory flow-volume curve (37). The cause(s) of the greater airflow resistance in adults born preterm remain unknown but could be due to smaller airways and/or greater bronchial smooth muscle tone compared with term-born individuals. A recent study using computed tomography reported that children born preterm had smaller distal airways (e.g., third or fourth generation of airways) than those born at term (43). Similarly, a crude index of airway size can be determined using the dysanapsis ratio. This calculation relies on an estimate of lung recoil pressure, cannot distinguish where in the tracheobronchial tree differences exist or differentiate between morphologically small and constricted airways (15). Nevertheless, a significantly smaller dysanapsis ratio was found in adults born preterm compared with term-born individuals suggestive of smaller airways, even when using an emphysema model with decreased lung recoil (14). It is possible that abnormally high lung compliance exists in the adults born preterm due to inadequate lung connective tissue or impaired surfactant turnover, but this is entirely unknown. Surfactant turnover is slower in preterm children (39), and this may persist into adulthood. Thus direct measures of airway morphology and static recoil pressures will certainly help to illuminate this poorly studied area.

The presence of bronchoconstriction and/or airway hyperresponsiveness does not appear to be generalizable with only 30-50% of adults born preterm responsive to acute bronchodilator administration (5, 22, 23, 35). Some adults born preterm exhibit an asthma-like phenotype with responsiveness to bronchodilators, whereas others exhibit a chronic obstructive pulmonary disease (COPD)-like phenotype with little bronchodilator responsiveness. Accordingly, not all obstructive lung disease should be considered a uniform condition. This highlights the need for systematic studies examining potential roles of β2-adrenergic airway receptor expression and sensitization, chronic airway inflammation, and responsiveness to bronchial provocation challenges in adults born preterm.

Mechanical Ventilatory Constraints

A mechanical ventilatory constraint is any parameter that alters the breathing pattern or limits an increase in ventilation. These include expiratory airflow limitation, dynamic hyperinflation, and/or an excessive mechanical work of breathing. The presence of a mechanical ventilatory constraint reduces exercise capacity (11, 24, 25) via the metaboreflex and the respiratory muscles “stealing” blood flow from the exercising muscles (24, 25).

Expiratory flow limitation.

Once expiratory tidal airflow approaches or meets the maximal attainable airflow at a given lung volume, expiratory flow limitation is present (3) and is rare and minimal (≤20% of the tidal volume), if present, in healthy, nonsedentary individuals during exercise. Expiratory flow limitation, in general terms, results from either an excessive ventilatory demand (athletes) or reduced capacity (patients with lung disease). Adults born preterm have a reduced capacity due to having underdeveloped lungs, rather than from an obstructive lung disease caused by smoking or occupational exposure, and those who developed bronchopulmonary dysplasia from prolonged supplemental O₂ may have the greatest reductions in ventilatory capacity. Accordingly, the origin of their reduced ventilatory capacity differs from COPD patients.

Adults born preterm have a greater prevalence and magnitude of expiratory flow limitation compared with term-born controls during exercise (34). The magnitude of expiratory flow limitation appears to be related to gestational age and/or days on O₂ during the neonatal period for those individuals who developed bronchopulmonary dysplasia. Adults born preterm had a greater magnitude of expiratory flow limitation despite having a ventilation that was on average 20-30 L/min less than term-born individuals at near-peak exercise. Similar findings have been reported during submaximal through near maximal exercise in other adult cohorts (14, 15). Helium-oxygen mixtures (heliox) have been used to lessen airflow resistance (15) and decrease the magnitude of expiratory airflow limitation (12, 15). Compared with air, breathing heliox during exercise significantly decreased the magnitude of expiratory flow limitation with a concomitant increase in ventilation and exercise endurance to a duration comparable to the term-born controls (15). However, the change in exercise time and expiratory flow limitation was not equal, suggesting that mechanical ventilatory constraints, particularly expiratory flow limitation, play only a partial role in the lower exercise endurance observed in adults born preterm. Of interest, when heliox is used in COPD patients during exercise, there is an improvement in exercise endurance (16) and a reduction in fatigue but not a “normalization” of exercise time, highlighting another difference between these two obstructive lung diseases.

Dynamic hyperinflation.

Dynamic hyperinflation is a phenomenon occurring when end-expiratory lung volume increases to a volume greater than functional residual capacity and inspiratory reserve volume inappropriately decreases. In COPD (2, 16, 21), dynamic hyperinflation leads to a reduced inspiratory reserve volume, intolerable dyspnea, and exercise termination (21). Dynamic hyperinflation may be a strategy used, subconsciously, to avoid expiratory flow limitation, but is an energetically expensive breathing strategy because lung compliance is very low near total lung capacity (1) and is associated with a tachypneic respiratory pattern, likely requiring high respiratory muscle blood flow (41). Aliverti et al. (2) have reasoned that COPD patients “learn” to dynamically hyperinflate after years of excessive expiratory muscle recruitment yields no increased/improved airflow. Adults born preterm have had expiratory flow limitation their whole life, so they provide a good model to test this hypothesis. Out of 52 individuals in these combined studies (14, 15, 34) only 5 demonstrated a change in end-expiratory lung volume sufficient to be considered dynamic hyperinflation (21, 37), so previous work does not support this hypothesis in this population. Additionally, the degree of dyspnea for a given level of ventilation in adults born preterm was not different from term-born individuals, which suggests that dyspnea may not play a role in termination of exercise in these subjects. Accordingly, this phenotype of non-hyperinflation and normal sensation of dyspnea in adults born preterm highlights another difference from that observed in COPD (21).

Mechanical work of breathing.

One compelling area of exploration that has yet to be investigated in adults born preterm is the mechanical work of breathing. The presence of one or more mechanical ventilatory constraints would result in an excessive work of breathing at a given ventilation. Thus adults born preterm with significant expiratory flow limitation, presumably from smaller airways, would have an excessive work of breathing. Quantification of the mechanical work of breathing, as well as a thorough assessment of static and dynamic (i.e., exercise) respiratory mechanics, would be of significant physiological and clinical interest in this population.

As an interim summary, adults born preterm have mechanical ventilatory constraints during exercise that may contribute, at least in part, to the lower exercise capacity observed in this population. However, studies in larger more diverse cohorts of adults born preterm are needed for a more complete understanding of the respiratory mechanics, prevalence of expiratory flow limitation and dynamic hyperinflation, as well as the various dimensions of breathlessness. Unlike COPD patients, who presumably had normal lungs before the onset of disease, adults born preterm have had a lifetime of impaired respiratory function that began before they matured to adulthood. Thus identifying the differences and similarities between this population and COPD patients may allow for a better understanding of the respiratory limitations in both populations.

Pulmonary Gas Exchange Efficiency

Preterm infants have abnormal alveologenesis and vasculogenesis (46), leading to respiratory impairments, mentioned above and likely contribute to a decrease in resting gas transfer (or diffusing capacity) for carbon monoxide (13, 38). Pulmonary gas exchange efficiency, defined as the alveolar-to-arterial difference in Po₂ (A-aDO₂), can be negatively impacted by a mismatching of alveolar ventilation and pulmonary perfusion, diffusion limitation, and/or right-to-left shunt (10). An excessively large A-aDO₂ and/or significant exercise-induced arterial hypoxemia [EIAH; $\text{S}{\text{a}}_{{\text{O}}_2}$ ≤95% (10)] during exercise would decrease O₂ delivery and limit exercise capacity in adults born preterm. Accordingly, it is reasonable to hypothesize that adults born preterm would have impaired pulmonary gas exchange efficiency, particularly during exercise when ventilatory demand increases ~10 times and pulmonary blood flow (i.e., right heart cardiac output) increases approximately 4 to 5 times. Nevertheless, the A-aDO₂ appears to be similar between adults born preterm and term-born individuals at rest and during exercise (13, 17, 35). In both groups, the A-aDO₂ increased with increasing exercise intensity to a similar extent in both groups never exceeding 25 Torr in the 25 participants tested (13, 35). In another study, very few (3/14) had an A-aDO₂ >25 Torr with exercise (17), for an overall presence of excessive pulmonary gas exchange impairment in ~8% (3/39) of adults born preterm. Therefore, pulmonary gas exchange efficiency does not worsen with exercise more in adults born preterm than term-born controls, even with near maximal exercise (17, 35). This was also true when adults born preterm, with a clinically mild reduction in diffusing capacity for carbon monoxide, were further challenged with exercise while breathing hypoxic gas (12% O₂), and the A-aDO₂ increased equally between both groups (13). Importantly, in these studies, arterial Pco₂ did not differ between groups, demonstrating that adults born preterm had an appropriate ventilatory response to exercise (13, 35), which is different than that observed in COPD.

Even with a normal increase in the A-aDO₂ with exercise, it is possible that adults born preterm develop EIAH (10). However, adults born preterm do not develop EIAH, even during near-maximal exercise (13, 17, 35). Accordingly, it does not appear that either an excessive A-aDO₂ or EIAH contributes significantly to the lower exercise capacity observed in adults born preterm. This is surprising given they have abnormally developed airways and pulmonary vasculature and are, therefore, likely to have mismatched ventilation and perfusion even at rest. However, future work in larger cohorts, including individuals with more severe lung disease of prematurity, is needed to more definitively support this conclusion.

CARDIOPULMONARY LIMITATIONS

Pulmonary Hemodynamics

Impaired pulmonary vasculogenesis in adults born preterm may lead to fewer pulmonary vessels and, therefore, a reduced pulmonary vascular capacity available for recruitment and distention compared with term-born individuals (40). This may leave adults born preterm unable to accommodate the four to five times increase in pulmonary blood flow during near-maximal exercise, resulting in an excessive increase in pulmonary arterial pressure. This could lead to excessive right heart work and/or altered cardiopulmonary coupling, which may lead to early termination of exercise (18). Additionally, an excessive pulmonary arterial pressure would increase capillary pressure favoring fluid movement into the interstitial space and/or alveoli and possibly lowering diffusing capacity. Nevertheless, this appears to be negligible as there is no evidence for worse gas exchange than term-born controls, even during exercise in hypoxia, as outlined above.

In general, adults born preterm do not have resting pulmonary hypertension (20, 31), defined as mean pulmonary arterial pressure >25 mmHg (19), although some do have pulmonary hypertension (n = 2/11) (20). Nevertheless, the pulmonary arterial pressure increase with exercise appears to be exaggerated in adults born preterm (20, 31). Pulmonary arterial pressure at rest and during exercise is known to increase with age (29, 30), which means adults born preterm may have an increased risk of developing, and/or an earlier onset of developing, pulmonary hypertension. Interestingly, our previous work demonstrates that adults born preterm that did not develop bronchopulmonary dysplasia had the greatest pulmonary arterial pressures with exercise and suggested that the greatest increases were in women (31). This potential sex effect in adults born preterm needs to be further explored as it could have significant implications given that pulmonary hypertension affects women more frequently than men.

An exaggerated increase in pulmonary arterial pressure, impaired right ventricular function, and/or altered cardiopulmonary coupling could contribute to a reduced exercise capacity in adults born preterm by truncating the increase in pulmonary blood flow with exercise. A lower pulmonary blood flow would decrease O₂ delivery to the exercising skeletal muscle. In fact, recent work has demonstrated that altered cardiac function in adults born preterm is associated with a lower exercise capacity (26, 32, 33). Importantly, impaired left ventricular function may lead to a greater increase in left atrial pressure, which is the primary determinant of pulmonary arterial pressure during exercise (42). Likewise, we have highlighted the exaggerated increase in pulmonary arterial pressure with exercise. These factors, in isolation or combination, may contribute, at least in part, to the lower exercise capacity in adults born preterm. However, additional work in larger cohorts including those with severe bronchopulmonary dysplasia would be particularly valuable as they are the least well studied.

SUMMARY AND FUTURE DIRECTIONS

Respiratory and cardiopulmonary function is compromised in adults born preterm, but we are just beginning to understand the numerous possible mechanisms limiting exercise capacity in this population. The lower exercise capacity observed in adults born preterm is not likely due to either impaired pulmonary gas exchange efficiency or EIAH. Conversely, excessive mechanical ventilatory constraints appear to explain, in large part, the lower exercise capacity in this population. Additional contributions from an exaggerated increase in pulmonary arterial pressure with exercise and/or impaired ventricular function are also likely present. Opportunities for advancing this area include systematic studies of the respiratory and cardiopulmonary contributors highlighted in this mini-review and other non-respiratory contributors to impaired aerobic exercise capacity in adults born preterm with all severities of bronchopulmonary dysplasia. Importantly, the ventilatory constraints in these preterm individuals are not identical to COPD. Thus assuming that these two obstructive lung diseases are similar does not appear to be warranted and suggests that studies specific to adults born preterm are critical for understanding the long-term outcomes of this population. Understanding the integrative respiratory and cardiopulmonary responses to exercise may allow for the development of potential therapeutic targets early in life to slow an excessive, early decline in exercise capacity in adults born preterm thereby improving their longevity and quality of life.

GRANTS

The authors’ work reported in this article was funded in part by the American Heart Association Scientist Development Grant 2280238, Giles F. Filley Memorial Award for Excellence in Respiratory Physiology and Medicine, Medical Research Foundation of Oregon Early Clinical Investigatory Award, Ohio University Research Committee Award, and the National Heart, Lung, and Blood Institute Grant R15-HL-148850.

DISCLOSURES

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

AUTHOR CONTRIBUTIONS

J.W.D. and A.T.L. conceived and designed research; J.W.D. and A.T.L. analyzed data; J.W.D. and A.T.L. interpreted results of experiments; J.W.D. prepared figures; J.W.D. drafted manuscript; J.W.D. and A.T.L. edited and revised manuscript; J.W.D. and A.T.L. approved final version of manuscript.