Analysis of maximal expiratory flow-volume curves in adult survivors of preterm birth.

Adult survivors of very preterm (≤32 wk gestational age) birth without (PRE) and with bronchopulmonary dysplasia (BPD) have variable degrees of airflow obstruction at rest. Assessment of the shape of the maximal expiratory flow-volume (MEFV) curve in PRE and BPD may provide information concerning their unique pattern of airflow obstruction. The purposes of the present study were to 1) quantitatively assess the shape of the MEFV curve in PRE, BPD, and healthy adults born at full-term (CON), 2) identify where along the MEFV curve differences in shape existed between groups, and 3) determine the association between an index of MEFV curve shape and characteristics of preterm birth (i.e., gestational age, mass at birth, duration of oxygen therapy) in PRE and BPD. To do so, we calculated the average slope ratio (SR) throughout the effort-independent portion of the MEFV curve and at increments of 5% of forced vital capacity (FVC) between 20 and 80% of FVC in PRE (n = 19), BPD (n = 25), and CON (n = 20). We found that average SR was significantly higher in PRE (1.34 ± 0.35) and BPD (1.33 ± 0.45) compared with CON (1.03 ± 0.22; both P < 0.05) but similar between PRE and BPD (P = 0.99). Differences in SR between groups occurred early in expiration (i.e., 20-30% of FVC). There was no association between SR and characteristics of preterm birth in PRE and BPD groups (all P > 0.05). The mechanism(s) of increased SR during early expiration in PRE/BPD relative to CON is unknown but may be due to differences in the structural and mechanical properties of the airways.

Alleviating mechanical constraints to ventilation with heliox improves exercise endurance in adult survivors of very preterm birth.

Adult survivors of very preterm birth (PRET) have significantly lower aerobic exercise capacities than their counterparts born at term (CONT), but the underlying cause is unknown. To test whether expiratory flow limitation (EFL) during exercise negatively affects exercise endurance in PRET, we had PRET and CONT exercise to exhaustion breathing air and again breathing heliox. In PRET, EFL decreased and time-to-exhaustion increased significantly while breathing heliox. Heliox had a minimal effect on EFL and had no effect on time-to-exhaustion in CONT. We conclude that aerobic exercise endurance in PRET is limited, in part, by mechanical ventilatory constraints, specifically EFL.

Premature birth affects the degree of airway dysanapsis and mechanical ventilatory constraints.

NEW FINDINGS: What is the central question of this study? Adult survivors of preterm birth without (PRE) and with bronchopulmonary dysplasia (BPD) have airflow obstruction at rest and significant mechanical ventilatory constraints during exercise compared with those born at full term (CON). Do PRE/BPD have smaller airways, indexed via the dysanapsis ratio, than CON? What is the main finding and its importance? The dysanapsis ratio was significantly smaller in BPD and PRE compared with CON, with BPD having the smallest dysanapsis ratio. These data suggest that airflow obstruction in PRE and BPD might be because of smaller airways than CON. Adult survivors of very preterm birth (≤32 weeks gestational age) without (PRE) and with bronchopulmonary dysplasia (BPD) have obstructive lung disease as evidenced by reduced expiratory airflow at rest and have significant mechanical ventilatory constraints during exercise. Airflow obstruction, in any conditions, could be attributable to several factors, including small airways. PRE and/or BPD could have smaller airways than their counterparts born at full term (CON) owing to a greater degree of dysanaptic airway development during the pre- and/or postnatal period. Thus, the purpose of the present study was to compare the dysanapsis ratio (DR), as an index of airway size, between PRE, BPD and CON. To do so, we calculated DR in PRE (n = 21), BPD (n = 14) and CON (n = 34) individuals and examined flow-volume loops at rest and during submaximal exercise. The DR, using multiple estimates of static recoil pressure, was significantly smaller in PRE and BPD (0.16 ± 0.05 and 0.10 ± 0.03 a.u.) compared with CON (0.22 ± 0.04 a.u.; both P < 0.001) and smallest in BPD (P < 0.001). The DR was significantly correlated with peak expiratory airflow at rest (r = 0.42; P < 0.001) and the extent of expiratory flow limitation during exercise (r = 0.60; P < 0.001). Our findings suggest that PRE/BPD might have anatomically smaller airways than CON, which might help to explain their lower expiratory airflow rate at rest and during exercise and further our understanding of the consequences of preterm birth and neonatal O2 therapy.

Bubble and macroaggregate methods differ in detection of blood flow through intrapulmonary arteriovenous anastomoses in upright and supine hypoxia in humans.

Blood flow through intrapulmonary arteriovenous anastomoses (Q̇IPAVA) increases in healthy humans breathing hypoxic gas and is potentially dependent on body position. Previous work in subjects breathing room air has shown an effect of body position when Q̇IPAVA is detected with transthoracic saline contrast echocardiography (TTSCE). However, the potential effect of body position on Q̇IPAVA has not been investigated when subjects are breathing hypoxic gas or with a technique capable of quantifying Q̇IPAVA. Thus the purpose of this study was to quantify the effect of body position on Q̇IPAVA when breathing normoxic and hypoxic gas at rest. We studied Q̇IPAVA with TTSCE and quantified Q̇IPAVA with filtered technetium-99m-labeled macroaggregates of albumin (99mTc-MAA) in seven healthy men breathing normoxic and hypoxic (12% O2) gas at rest while supine and upright. On the basis of previous work using TTSCE, we hypothesized that the quantified Q̇IPAVA would be greatest with hypoxia in the supine position. We found that Q̇IPAVA quantified with 99mTc-MAA significantly increased while subjects breathed hypoxic gas in both supine and upright body positions (ΔQ̇IPAVA = 0.7 ± 0.4 vs. 2.5 ± 1.1% of cardiac output, respectively). Q̇IPAVA detected with TTSCE increased from normoxia in supine hypoxia but not in upright hypoxia (median hypoxia bubble score of 2 vs. 0, respectively). Surprisingly, Q̇IPAVA magnitude was greatest in upright hypoxia, when Q̇IPAVA was undetectable with TTSCE. These findings suggest that the relationship between TTSCE and 99mTc-MAA is more complex than previously appreciated, perhaps because of the different physical properties of bubbles and MAA in solution. NEW & NOTEWORTHY Using saline contrast bubbles and radiolabeled macroaggregrates (MAA), we detected and quantified, respectively, hypoxia-induced blood flow through intrapulmonary arteriovenous anastomoses (Q̇IPAVA) in supine and upright body positions in healthy men. Upright hypoxia resulted in the largest magnitude of Q̇IPAVA quantified with MAA but the lowest Q̇IPAVA detected with saline contrast bubbles. These surprising results suggest that the differences in physical properties between saline contrast bubbles and MAA in blood may affect their behavior in vivo.

Relationship between quantitative and descriptive methods of studying blood flow through intrapulmonary arteriovenous anastomoses during exercise.

Several methods exist to study intrapulmonary arteriovenous anastomoses (IPAVA) in humans. Transthoracic saline contrast echocardiography (TTSCE), i.e., bubble scores, is minimally-invasive, but cannot be used to quantify the magnitude of blood flow through IPAVA (QIPAVA). Radiolabeled macroaggregates of albumin (99mTc-MAA) have been used to quantify QIPAVA in humans, but this requires injection of radioactive particles. Previous work has shown agreement between 99mTc-MAA and TTSCE, but this has not been tested simultaneously in the same group of subjects. Thus, the purpose of this study was to determine if there was a relationship between QIPAVA quantified with 99mTc-MAA and bubble scores obtained with TTSCE. To test this, we used 99mTc-MAA and TTSCE to quantify and detect QIPAVA at rest and during exercise in humans. QIPAVA significantly increased from rest to exercise using 99mTc-MAA and TTSCE and there was a moderately-strong, but significant relationship between methods. Our data suggest that high bubble scores generally correspond with large QIPAVA quantified with 99mTc-MAA during exercise.

Ventilatory and sensory responses in adult survivors of preterm birth and bronchopulmonary dysplasia with reduced exercise capacity.

RATIONALE: Adults born very to extremely preterm, with or without bronchopulmonary dysplasia (BPD), have obstructive lung disease, but it is unknown whether this results in respiratory limitations, such as mechanical constraints to Vt expansion during exercise leading to intolerable dyspnea and reduced exercise tolerance, as it does in patients with chronic obstructive pulmonary disease. OBJECTIVES: To test the hypothesis that adult survivors of preterm birth (≤32 wk gestational age) with (n = 20) and without BPD (n = 15) with reduced exercise capacity demonstrate clinically important respiratory limitations at near-maximal exercise compared with full-term control subjects (n = 20). METHODS: Detailed ventilatory and sensory measurements were made before and during exercise on all patients in the three study groups. MEASUREMENTS AND MAIN RESULTS: During exercise at 90% of peak [Formula: see text]o2 ([Formula: see text]o2peak), inspiratory reserve volume decreased to ∼0.5 L in all groups, but this occurred at significantly lower absolute workloads and [Formula: see text]e in ex-preterm subjects with and without BPD compared with full-term control subjects. Severe dyspnea was present and similar at comparable [Formula: see text]e between all groups, but leg discomfort at comparable workloads was greater in ex-preterm subjects with and without BPD compared with control subjects. At 50 to 90% of [Formula: see text]o2peak, exercise-induced expiratory flow limitation was significantly greater in ex-preterm subjects with BPD compared with ex-preterm subjects without BPD and control subjects. The degree of expiratory flow limitation in ex-preterm subjects with and without BPD was significantly related to neonatal O2 therapy duration. CONCLUSIONS: Severe dyspnea and leg discomfort associated with critical constraints on Vt expansion may lead to reduced exercise tolerance in adults born very or extremely preterm, whether or not their birth was complicated by BPD and despite differences in expiratory flow limitation. In this regard, adults born very or extremely preterm have respiratory limitations to exercise similar to patients with chronic obstructive pulmonary disease.

Pulmonary gas exchange efficiency during exercise breathing normoxic and hypoxic gas in adults born very preterm with low diffusion capacity.

Adults with a history of very preterm birth (<32 wk gestational age; PRET) have reduced lung function and significantly lower lung diffusion capacity for carbon monoxide (DLCO) relative to individuals born at term (CONT). Low DLCO may predispose PRET to diffusion limitation during exercise, particularly while breathing hypoxic gas because of a reduced O2 driving gradient and pulmonary capillary transit time. We hypothesized that PRET would have significantly worse pulmonary gas exchange efficiency [i.e., increased alveolar-to-arterial Po2 difference (AaDO2)] during exercise breathing room air or hypoxic gas (FiO2 = 0.12) compared with CONT. To test this hypothesis, we compared the AaDO2 in PRET (n = 13) with a clinically mild reduction in DLCO (72 ± 7% of predicted) and CONT (n = 14) with normal DLCO (105 ± 10% of predicted) pre- and during exercise breathing room air and hypoxic gas. Measurements of temperature-corrected arterial blood gases, and direct measure of O2 saturation (SaO2), were made prior to and during exercise at 25, 50, and 75% of peak oxygen consumption (V̇o2peak) while breathing room air and hypoxic gas. In addition to DLCO, pulmonary function and exercise capacity were significantly less in PRET. Despite PRET having low DLCO, no differences were observed in the AaDO2 or SaO2 pre- or during exercise breathing room air or hypoxic gas compared with CONT. Although our findings were unexpected, we conclude that reduced pulmonary function and low DLCO resulting from very preterm birth does not cause a measureable reduction in pulmonary gas exchange efficiency.

Normal pulmonary gas exchange efficiency and absence of exercise-induced arterial hypoxemia in adults with bronchopulmonary dysplasia.

Cardiopulmonary function is reduced in adults born very preterm, but it is unknown if this results in reduced pulmonary gas exchange efficiency during exercise and, consequently, leads to reduced aerobic capacity in subjects with and without bronchopulmonary dysplasia (BPD). We hypothesized that an excessively large alveolar to arterial oxygen difference (AaDO2) and resulting exercise-induced arterial hypoxemia (EIAH) would contribute to reduced aerobic fitness in adults born very preterm with and without BPD. Measurements of pulmonary function, lung volumes and diffusion capacity for carbon monoxide (DLco) were made at rest. Measurements of maximal oxygen consumption, peak workload, temperature- and tonometry-corrected arterial blood gases, and direct measure of hemoglobin saturation with oxygen (SaO2) were made preexercise and during cycle ergometer exercise in ex-preterm subjects ≤32-wk gestational age, with BPD (n = 12), without BPD (PRE; n = 12), and full term controls (CONT; n = 12) breathing room air. Both BPD and PRE had reduced pulmonary function and reduced DLco compared with CONT. The AaDO2 was not significantly different between groups, and there was no evidence of EIAH (SaO2 < 95% and/or AaDO2 ≥ 40 Torr) in any subject group preexercise or at any workload. Arterial O2 content was not significantly different between the groups preexercise or during exercise. However, peak power output was decreased in BPD and PRE subjects compared with CONT. We conclude that EIAH in adult subjects born very preterm with and without BPD does not likely contribute to the reduction in aerobic exercise capacity observed in these subjects.

Prevalence of left heart contrast in healthy, young, asymptomatic humans at rest breathing room air.

Our purpose was to report the prevalence of healthy, young, asymptomatic humans who demonstrate left heart contrast at rest, breathing room air. We evaluated 176 subjects (18-41 years old) using transthoracic saline contrast echocardiography. Left heart contrast appearing ≤3 cardiac cycles, consistent with a patent foramen ovale (PFO), was detected in 67 (38%) subjects. Left heart contrast appearing >3 cardiac cycles, consistent with the transpulmonary passage of contrast, was detected in 49 (28%) subjects. Of these 49 subjects, 31 were re-evaluated after breathing 100% O2 for 10-15min and 6 (19%) continued to demonstrate the transpulmonary passage of contrast. Additionally, 18 of these 49 subjects were re-evaluated in the upright position and 1 (5%) continued to demonstrate the transpulmonary passage of contrast. These data suggest that ~30% of healthy, young, asymptomatic subjects demonstrate the transpulmonary passage of contrast at rest which is reduced by breathing 100% O2 and assuming an upright body position.

Effect of initial gas bubble composition on detection of inducible intrapulmonary arteriovenous shunt during exercise in normoxia, hypoxia, or hyperoxia.

Concern has been raised that altering the fraction of inspired O2 (Fi(O2)) could accelerate or decelerate microbubble dissolution time within the pulmonary vasculature and thereby invalidate the ability of saline contrast echocardiography to detect intrapulmonary arteriovenous shunt in subjects breathing either a low or a high Fi(O2). The present study determined whether the gaseous component used for saline contrast echocardiography affects the detection of exercise-induced intrapulmonary arteriovenous shunt under varying Fi(O2). Twelve healthy human subjects (6 men, 6 women) performed three 11-min bouts of cycle ergometer exercise at 60% peak O2 consumption (Vo(2peak)) in normoxia, hypoxia (Fi(O2) = 0.14), and hyperoxia (Fi(O2) = 1.0). Five different gases were used to create saline contrast microbubbles by two separate methods and were injected intravenously in the following order at 2-min intervals: room air, 100% N2, 100% O2, 100% CO2, and 100% He. Breathing hyperoxia prevented exercise-induced intrapulmonary arteriovenous shunt, whereas breathing hypoxia and normoxia resulted in a significant level of exercise-induced intrapulmonary arteriovenous shunt. During exercise, for any Fi(O2) there was no significant difference in bubble score when the different microbubble gas compositions made with either method were used. The present results support our previous work using saline contrast echocardiography and validate the use of room air as an acceptable gaseous component for use with saline contrast echocardiography to detect intrapulmonary arteriovenous shunt during exercise or at rest with subjects breathing any Fi(O2). These results suggest that in vivo gas bubbles are less susceptible to changes in the ambient external environment than previously suspected.

The morbidity of the 34- to 35-week gestation: should we reexamine the paradigm?

Algorithms for the management of preterm labor avoid the use of tocolysis beyond 34 weeks' gestation, based in large part on low respiratory morbidity found at this gestational age. We sought to delineate the morbidities, not just respiratory, of this age group in a modern neonatal intensive care unit setting. We prospectively looked at hospital resource use and general morbidity in a consecutive 2-year cohort of 34-weekers at our hospital. The concurrent consecutive 35-week cohort was used as a control. Data were prospectively collected from obstetricians and bedside records. Compared with 35-weekers, the 34-week group had similar obstetric characteristics. Significant differences were seen in use of oxygen, nasal continuous positive airway pressure, methylxanthines, home apnea monitoring, antibiotics, and phototherapy. The 34-week group took longer to come off intravenous lines and were discharged later. Overall, they used approximately twice the resources of the 35-week group. To stop or not use tocolysis at 34 weeks' gestation based mainly on low respiratory morbidity ignores the significant other morbidities. These findings suggest a reconsideration of the paradigm regarding 34-week gestation as a cutoff point in decision making.