Steven C. Chase

The blood transfer conductance for nitric oxide: Infinite vs. finite θNO

Whether the specific blood transfer conductance for nitric oxide (NO) with hemoglobin (θNO) is finite or infinite is controversial but important in the calculation of alveolar capillary membrane conductance (DmCO) and pulmonary capillary blood volume (VC) from values of lung diffusing capacity for carbon monoxide (DLCO) and nitric oxide (DLNO). In this review, we discuss the background associated with θNO, explore the resulting values of DmCO and VC when applying either assumption, and investigate the mathematical underpinnings of DmCO and VC calculations. In general, both assumptions yield reasonable rest and exercise DmCO and VC values. However, the finite θNO assumption demonstrates increasing VC, but not DmCO, with submaximal exercise. At relatively high, but physiologic, DLNO/DLCO ratios both assumptions can result in asymptotic behavior for VC values, and under the finite θNO assumption, DmCO values. In conclusion, we feel that the assumptions associated with a finite θNO require further in vivo validation against an established method before widespread research and clinical use.

Effect of β2-adrenergic receptor stimulation on lung fluid in stable heart failure patients

BACKGROUND The purpose of this study was to determine: (1) whether stable heart failure patients with reduced ejection fraction (HFrEF) have elevated extravascular lung water (EVLW) when compared with healthy control subjects; and (2) the effect of acute β2-adrenergic receptor (β2AR) agonist inhalation on lung fluid balance. METHODS Twenty-two stable HFrEF patients and 18 age- and gender-matched healthy subjects were studied. Lung diffusing capacity for carbon monoxide (DLCO), alveolar-capillary membrane conductance (DmCO), pulmonary capillary blood volume (Vc) (via re-breathe) and lung tissue volume (Vtis) (via computed tomography) were assessed before and within 30 minutes after administration of nebulized albuterol. EVLW was derived as Vtis - Vc. RESULTS Before administration of albuterol, Vtis and EVLW were higher in HFrEF vs control (998 ± 200 vs 884 ± 123 ml, p = 0.041; and 943 ± 202 vs 802 ± 133 ml, p = 0.015, respectively). Albuterol decreased Vtis and EVLW in HFrEF patients (-4.6 ± 7.8%, p = 0.010; -4.6 ± 8.8%, p = 0.018) and control subjects (-2.8 ± 4.9%, p = 0.029; -3.0 ± 5.7%, p = 0.045). There was an inverse relationship between pre-albuterol values and pre- to post-albuterol change for EVLW (r2 = -0.264, p = 0.015) and DmCO (r2 = -0.343, p = 0.004) in HFrEF only. CONCLUSION Lung fluid is elevated in stable HFrEF patients relative to healthy subjects. Stimulation of β2ARs may cause fluid removal in HFrEF, especially in patients with greater evidence of increased lung water at baseline.

Influence of Thoracic Fluid Compartments on Pulmonary Congestion in Chronic Heart Failure

INTRODUCTION Pulmonary congestion is a common finding of heart failure (HF), but it remains unclear how pulmonary and heart blood volumes (Vp and Vh, respectively) and extravascular lung water (EVLW) change in stable HF and affect lung function. METHODS Fourteen patients with HF (age 68 ± 11 y, LVEF 33 ± 8%) and 12 control subjects (age 65 ± 9 y) were recruited. A pulmonary function test, thoracic computerized tomographic (CT) scan, and contrast perfusion scan were performed. From the thoracic scan, a histogram of CT attenuation of lung tissue was generated and skew, kurtosis, and full-width half-max (FWHM) calculated as surrogates of EVLW. Blood volumes were calculated from the transit time of the contrast through the great vessels of the heart. RESULTS Patients with HF had greater Vp and Vh (Vp 0.55 ± 0.21 L vs 0.41 ± 0.13 L; Vh 0.53 ± 0.33 L vs 0.40 ± 0.15 L) and EVLW (skew 3.2 ± 0.5 vs 3.7 ± 0.7; kurtosis 19.4 ± 6.6 vs 25.9 ± 9.4; FWHM 73 ± 13 HU vs 59 ± 9 HU). Spirometric measures were decreased in HF (percentage of predicted: forced vital capacity 86 ± 17% vs 104 ± 9%; forced expiratory volume in 1 second 83 ± 20% vs 105 ± 11%; maximal mid-expiratory flow 82 ± 42% vs 115 ± 43%). Vp was associated with decreased expiratory flows, and EVLW was associated with decreased lung volumes. CONCLUSIONS Congestion in stable patients with HF includes expanded Vp and Vh and increased EVLW associated with reductions in lung volumes and expiratory flows.

Impact of chronic systolic heart failure on lung structure–function relationships in large airways

Heart failure (HF) is often associated with pulmonary congestion, reduced lung function, abnormal gas exchange, and dyspnea. We tested whether pulmonary congestion is associated with expanded vascular beds or an actual increase in extravascular lung water (EVLW) and how airway caliber is affected in stable HF. Subsequently we assessed the influence of an inhaled short acting beta agonist (SABA). Thirty‐one HF (7F; age, 62 ± 11 years; ht. 175 ± 9 cm; wt. 91 ± 17 kg; LVEF, 28 ± 15%) and 29 controls (11F; age; 56 ± 11 years; ht. 174 ± 8 cm; wt. 77 ± 14 kg) completed the study. Subjects performed PFTs and a chest computed tomography (CT) scan before and after SABA. CT measures of attenuation, skew, and kurtosis were obtained from areas of lung tissue to assess EVLW. Airway luminal areas and wall thicknesses were also measured. CT tissue density suggested increased EVLW in HF without differences in the ratio of airway wall thickness to luminal area or luminal area to TLC (skew: 2.85 ± 1.08 vs. 2.11 ± 0.79, P < 0.01; Kurtosis: 15.5 ± 9.5 vs. 9.3 ± 5.5 P < 0.01; control vs. HF). PFTs were decreased in HF at baseline (% predicted FVC:101 ± 15% vs. 83 ± 18%, P < 0.01;FEV1:103 ± 15% vs. 82 ± 19%, P < 0.01;FEF25–75: 118 ± 36% vs. 86 ± 36%, P < 0.01; control vs. HF). Airway luminal areas, but not CT measures, were correlated with PFTs at baseline. The SABA cleared EVLW and decreased airway wall thickness but did not change luminal area. Patients with HF had evidence of increased EVLW, but not an expanded bronchial circulation. Airway caliber was maintained relative to controls, despite reductions in lung volume and flow rates. SABA improved lung function, primarily by reducing EVLW.

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 effect of diuresis on extravascular lung water and pulmonary function in acute decompensated heart failure: Diuresis effect on EVLW and pulmonary function in ADHF

The effect of extravascular lung water (EVLW) and relationship to functional status as a result of acute decompensated heart failure (ADHF) are not well understood. We sought to quantify changes in clinical variables, EVLW, airway anatomy, spirometry, and diffusing capacity for carbon monoxide before and after treatment for ADHF.

Assessment of Thoracic Blood Volume by Computerized Tomography in Patients With Heart Failure and Periodic Breathing

BACKGROUND Periodic breathing (PB) is often observed in patients with HF at rest, with sleep and during exercise. However, mechanisms underlying abnormal ventilatory control are not entirely established. METHODS Eleven subjects with HF (10 males, age = 69 ± 12 y) and 12 age-matched control subjects (8 males, age = 65 ± 9 y) participated in the study. PB was defined as a peak in the 0.003-0.04 Hz frequency range of the flow signal during 6 minutes of awake resting breathing. Thoracic blood volumes (Vt, thorax; Vh, heart; Vp, pulmonary), mean transit times (MTTs), and extravascular lung water (EVLW) were quantified using computerized tomography. RESULTS PB was observed in 7 subjects with HF and was associated with worse functional status. The HF PB-present group had thoracic blood volumes nearly double those of control and HF PB-absent subjects (volumes reported as mL/m2 body surface area, P values vs control: control = 813 ± 246, HF PB-absent = 822 ± 161 P = .981, HF PB-present = 1579 ± 548 P = .002). PB was associated with longer pulmonary MTT (control = 6.7 ± 1.2 s, HF PB-absent = 6.0 ± 0.8 s, HF PB-present = 8.4 ± 1.6 s; P = .033, HF PB-present vs HF PB-absent). EVLW was not elevated in the PB group. CONCLUSIONS Subjects with HF and PB at rest have greater centralization of blood volume.

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.