Alex R. Carlson

Exercise-induced interstitial pulmonary edema at sea-level in young and old healthy humans

We asked whether aged adults are more susceptible to exercise-induced pulmonary edema relative to younger individuals. Lung diffusing capacity for carbon monoxide (DLCO), alveolar-capillary membrane conductance (Dm) and pulmonary-capillary blood volume (Vc) were measured before and after exhaustive discontinuous incremental exercise in 10 young (YNG; 27±3 years) and 10 old (OLD; 69±5 years) males. In YNG subjects, Dm increased (11±7%, P=0.031), Vc decreased (-10±9%, P=0.01) and DLCO was unchanged (30.5±4.1 vs. 29.7±2.9mL/min/mmHg, P=0.44) pre- to post-exercise. In OLD subjects, DLCO and Dm increased (11±14%, P=0.042; 16±14%, P=0.025) but Vc was unchanged (58±23 vs. 56±23mL, P=0.570) pre- to post-exercise. Group-mean Dm/Vc was greater after vs. before exercise in the YNG and OLD subjects. However, Dm/Vc was lower post-exercise in 2 of the 10 YNG (-7±4%) and 2 of the 10 OLD subjects (-10±5%). These data suggest that exercise decreases interstitial lung fluid in most YNG and OLD subjects, with a small number exhibiting evidence for exercise-induced pulmonary edema.

The effect of aging and cardiorespiratory fitness on the lung diffusing capacity response to exercise in healthy humans

Aging is associated with deterioration in the structure and function of the pulmonary circulation. We characterized the lung diffusing capacity for carbon monoxide (DLCO), alveolar-capillary membrane conductance (DmCO), and pulmonary-capillary blood volume (Vc) response to discontinuous incremental exercise at 25, 50, 75, and 90% of peak work (Wpeak) in four groups: 1) Young [27 ± 3 yr, maximal oxygen consumption (V̇o2max): 110 ± 18% age predicted]; 2) Young Highly Fit (27 ± 3 yr, V̇o2max: 147 ± 8% age predicted); 3) Old (69 ± 5 yr, V̇o2max: 116 ± 13% age predicted); and 4) Old Highly Fit (65 ± 5 yr, V̇o2max: 162 ± 18% age predicted). At rest and at 90% Wpeak, DLCO, DmCO, and Vc were decreased with age. At 90% Wpeak, DLCO, DmCO, and Vc were greater in Old Highly Fit vs. Old adults. The slope of the DLCO-cardiac output (Q̇) relationship from rest to end exercise at 90% Wpeak was not different between Young, Young Highly Fit, Old, and Old Highly Fit (1.35 vs. 1.44 vs. 1.10 vs. 1.35 mlCO·mmHg-1·liter blood-1, P = 0.388), with no evidence of a plateau in this relationship during exercise; this was also true for DmCO-Q̇ and Vc-Q̇. V̇o2max was positively correlated with 1) DLCO, DmCO, and Vc at rest; and 2) the rest to end exercise change in DLCO, DmCO, and Vc. In conclusion, these data suggest that despite the age-associated deterioration in the structure and function of the pulmonary circulation, expansion of the pulmonary capillary network does not become limited during exercise in healthy individuals regardless of age or cardiorespiratory fitness level.NEW & NOTEWORTHY Healthy aging is a crucial area of research. This article details how differences in age and cardiorespiratory fitness level affect lung diffusing capacity, particularly during high-intensity exercise. We conclude that highly fit older adults do not experience a limit in lung diffusing capacity during high-intensity exercise. Interestingly, however, we found that highly fit older individuals demonstrate greater values of lung diffusing capacity during high-intensity exercise than their less fit age-matched counterparts.

The influence of pulmonary vascular pressures on lung diffusing capacity during incremental exercise in healthy aging

Alveolar‐capillary surface area for pulmonary gas exchange falls with aging, causing a reduction in lung diffusing capacity for carbon monoxide (DLCO). However, during exercise additional factors may influence DLCO, including pulmonary blood flow and pulmonary vascular pressures. First, we sought to determine the age‐dependent effect of incremental exercise on pulmonary vascular pressures and DLCO. We also aimed to investigate the dependence of DLCO on pulmonary vascular pressures during exercise via sildenafil administration to reduce pulmonary smooth muscle tone. Nine younger (27 ± 4 years) and nine older (70 ± 3 years) healthy subjects performed seven 5‐min exercise stages at rest, 0 (unloaded), 10, 15, 30, 50, and 70% of peak workload before and after sildenafil. DLCO, cardiac output (Q), and pulmonary artery and wedge pressure (mPAP and mPCWP; subset of participants) were collected at each stage. mPAP was higher (P = 0.029) and DLCO was lower (P = 0.009) throughout exercise in older adults; however, the rate of rise in mPAP and DLCO with increasing Q was not different. A reduction in pulmonary smooth muscle tone via sildenafil administration reduced mPAP, mPCWP, and the transpulmonary gradient (TPG = mPAP–mPCWP) in younger and older subjects (P < 0.001). DLCO was reduced following the reduction in mPAP and TPG, regardless of age (P < 0.001). In conclusion, older adults successfully adapt to age‐dependent alterations in mPAP and DLCO. Furthermore, DLCO is dependent on pulmonary vascular pressures, likely to maintain adequate pulmonary capillary recruitment. The rise in pulmonary artery pressure with aging may be required to combat pulmonary vascular remodeling and maintain lung diffusing capacity, particularly during exercise.

The influence of thoracic gas compression and airflow density dependence on the assessment of pulmonary function at high altitude

The purpose of this report was to illustrate how thoracic gas compression (TGC) artifact, and differences in air density, may together conflate the interpretation of changes in the forced expiratory flows (FEFs) at high altitude (>2400 m). Twenty‐four adults (10 women; 44 ± 15 year) with normal baseline pulmonary function (>90% predicted) completed a 12‐day sojourn at Mt. Kilimanjaro. Participants were assessed at Moshi (Day 0, 853 m) and at Barafu Camp (Day 9, 4837 m). Typical maximal expiratory flow‐volume (MEFV) curves were obtained in accordance with ATS/ERS guidelines, and were either: (1) left unadjusted; (2) adjusted for TGC by constructing a “maximal perimeter” MEFV curve; or (3) adjusted for both TGC and differences in air density between altitudes. Forced vital capacity (FVC) was lower at Barafu compared with Moshi camp (5.19 ± 1.29 L vs. 5.40 ± 1.45 L, P < 0.05). Unadjusted data indicated no difference in the mid‐expiratory flows (FEF25–75%) between altitudes (∆ + 0.03 ± 0.53 L sec−1; ∆ + 1.2 ± 11.9%). Conversely, TGC‐adjusted data revealed that FEF25–75% was significantly improved by sojourning at high altitude (∆ + 0.58 ± 0.78 L sec−1; ∆ + 12.9 ± 16.5%, P < 0.05). Finally, when data were adjusted for TGC and air density, FEFs were “less than expected” due to the lower air density at Barafu compared with Moshi camp (∆–0.54 ± 0.68 L sec−1; ∆–10.9 ± 13.0%, P < 0.05), indicating a mild obstructive defect had developed on ascent to high altitude. These findings clearly demonstrate the influence that TGC artifact, and differences in air density, bear on flow‐volume data; consequently, it is imperative that future investigators adjust for, or at least acknowledge, these confounding factors when comparing FEFs between altitudes.

Age‐dependent effects of thoracic and capillary blood volume distribution on pulmonary artery pressure and lung diffusing capacity

Aging is associated with pulmonary vascular remodeling and reduced distensibility. We investigated the influence of aging on changes in cardiac output (Q), mean pulmonary artery pressure (mPAP), and lung diffusing capacity in response to alterations in thoracic blood volume. The role of pulmonary smooth muscle tone was also interrogated via pulmonary vasodilation. Nine younger (27 ± 4 years) and nine older (71 ± 4 years) healthy adults reached steady‐state in a Supine (0°), Upright (+20°), or Head‐down (−20°) position in order to alter thoracic blood volume. In each position, echocardiography was performed to calculate mPAP and Q, and lung diffusing capacity for carbon monoxide (DLCO) and nitric oxide (DLNO) was assessed. Next, 100 mg sildenafil was administered to reduce pulmonary smooth muscle tone, after which the protocol was repeated. mPAP (P ≤ 0.029) and Q (P ≤ 0.032) were lower in the Upright versus Supine and Head‐down positions, and mPAP was reduced following sildenafil administration (P = 0.019), in older adults only. SV was lower in the Upright versus Supine and Head‐down positions in both younger (P ≤ 0.008) and older (P ≤ 0.003) adults. DLCO and DLNO were not greatly altered by position changes or sildenafil administration. However, the DLNO/DLCO ratio was lower in the Supine and/or Head‐down positions (P ≤ 0.05), but higher following sildenafil administration (P ≤ 0.007), in both younger and older adults. In conclusion, older adults experience greater cardiopulmonary alterations following thoracic blood volume changes, and pulmonary smooth muscle tone plays a role in resting mPAP in older adults only. Furthermore, mPAP is an important determinant of pulmonary capillary blood volume distribution (DLNO/DLCO), regardless of age.

Influence of Inhaled Amiloride on Lung Fluid Clearance in Response to Normobaric Hypoxia in Healthy Individuals

Wheatley, Courtney M., Sarah E. Baker, Bryan J. Taylor, Manda L. Keller-Ross, Steven C. Chase, Alex R. Carlson, Robert J. Wentz, Eric M. Snyder, and Bruce D. Johnson. Influence of inhaled amiloride on lung fluid clearance in response to normobaric hypoxia in healthy individuals. High Alt Med Biol 18:343-354, 2017. AIM To investigate the role of epithelial sodium channels (ENaC) on lung fluid clearance in response to normobaric hypoxia, 20 healthy subjects were exposed to 15 hours of hypoxia (fraction of inspired oxygen [FiO2] = 12.5%) on two randomized occasions: (1) inhaled amiloride (A) (1.5 mg/5 mL saline); and (2) inhaled saline placebo (P). Changes in lung fluid were assessed through chest computed tomography (CT) for lung tissue volume (TV), and the diffusion capacity of the lungs for carbon monoxide (DLCO) and nitric oxide (DLNO) for pulmonary capillary blood volume (VC). Extravascular lung water (EVLW) was derived as TV-VC and changes in the CT attenuation distribution histograms were reviewed. RESULTS Normobaric hypoxia caused (1) a reduction in EVLW (change from baseline for A vs. P, -8.5% ± 3.8% vs. -7.9% ± 5.2%, p < 0.05), (2) an increase in VC (53.6% ± 28.9% vs. 53.9% ± 52.3%, p < 0.05), (3) a small increase in DLCO (9.6% ± 29.3% vs. 9.9% ± 23.9%, p > 0.05), and (4) CT attenuation distribution became more negative, leftward skewed, and kurtotic (p < 0.05). CONCLUSION Acute normobaric hypoxia caused a reduction in lung fluid that was unaffected by ENaC inhibition through inhaled amiloride. Although possible amiloride-sensitive ENaC may not be necessary to maintain lung fluid balance in response to hypoxia, it is more probable that normobaric hypoxia promotes lung fluid clearance rather than accumulation for the majority of healthy individuals. The observed reduction in interstitial lung fluid means alveolar fluid clearance may not have been challenged.

Noninvasive assessment of cardiac output by brachial occlusion-cuff technique: comparison with the open-circuit acetylene washin method

Cardiac output (CO) assessment as a basic hemodynamic parameter has been of interest in exercise physiology, cardiology, and anesthesiology. Noninvasive techniques available are technically challenging, and thus difficult to use outside of a clinical or laboratory setting. We propose a novel method of noninvasive CO assessment using a single, upper-arm cuff. The method uses the arterial pressure pulse wave signal acquired from the brachial artery during 20-s intervals of suprasystolic occlusion. This method was evaluated in a cohort of 12 healthy individuals (age, 27.7 ± 5.4 yr, 50% men) and compared with an established method for noninvasive CO assessment, the open-circuit acetylene method (OpCirc) at rest, and during low- to moderate-intensity exercise. CO increased from rest to exercise (rest, 7.4 ± 0.8 vs. 7.2 ± 0.8; low, 9.8 ± 1.8 vs. 9.9 ± 2.0; moderate, 14.1 ± 2.8 vs. 14.8 ± 3.2 l/min) as assessed by the cuff-occlusion and OpCirc techniques, respectively. The average error of experimental technique compared with OpCirc was -0.25 ± 1.02 l/min, Pearsons correlation coefficient of 0.96 (rest + exercise), and 0.21 ± 0.42 l/min with Pearsons correlation coefficient of 0.87 (rest only). Bland-Altman analysis demonstrated good agreement between methods (within 95% boundaries); the reproducibility coefficient (RPC) = 0.84 l/min with R2 = 0.75 at rest and RPC = 2 l/min with R2 = 0.92 at rest and during exercise, respectively. In comparison with an established method to quantify CO, the cuff-occlusion method provides similar measures at rest and with light to moderate exercise. Thus, we believe this method has the potential to be used as a new, noninvasive method for assessing CO during exercise.