Roden, Richard T.

Background: Cystic fibrosis (CF) is a genetic disorder in which patients have dysfunctional cystic fibrosis transmembrane regulatory (CFTR) proteins in the lungs that disrupt ion regulation resulting in a thick, viscous mucus layer on the airway epithelium. Consequential poor mucociliary clearance leads to repeated infections and chronic inflammation contributing to bronchiectasis which is associated with increased airway luminal area. CFTR modulator therapy can improve and even restore the function and expression of a mutated CFTR gene which has been shown to improve sweat chloride levels and pulmonary symptoms rapidly. However, the effect of CFTR modulator therapy on large conducting airway luminal area is unclear. We compared large conducting airway luminal area in patients with CF before and after initiating CFTR modulator therapy. We hypothesized that airway luminal area would normalize (decrease) after initiating CFTR modulator therapy. Methods: Twenty-three patients with CF (32±15 years, 11 female) with computed tomography (CT) imaging of their lungs before and after initiating CFTR modulator therapy were included in analyses. In each patient we measured seven large conducting airways (trachea, left and right main bronchus, bronchus intermediate, left and right upper lobe, and left lower lobe) before and after CFTR modulator therapy initiation. To control the potential effect of height, airway luminal area (mm2) was divided by patient height (cm). Paired t-tests compared differences between luminal area before after initiating CFTR modulator therapy. Results: Patients were taking CFTR modulator therapy for a median of 1.1 years (range: 22–2111 days) at the time of their CT imaging after initiating CFTR modulator therapy. Large conducting airway luminal area was not different before and after initiating CFTR modulator therapy in all seven airways: trachea (1.50±0.35 vs. 1.56±0.34 mm2/cm, p=0.14), right main bronchus (1.05±0.21 vs. 1.09±0.19 mm2/cm, p=0.11), bronchus intermediate (0.68±0.16 vs. 0.68±0.16 mm2/cm, p=0.54), right upper lobe (0.42±0.10 vs. 0.45±0.09 mm2/cm, p=0.27), left main bronchus (0.81±0.19 vs. 0.83±0.18 mm2/cm, p=0.21), left upper lobe (0.51±0.13 vs. 0.52±0.13 mm2/cm, p=0.45), and left lower lobe (0.44±0.11 vs. 0.46±0.10 mm2/cm, p=0.42). Conclusion: There was no change in large conducting airway luminal area after initiating CFTR modulator therapy suggesting CFTR modulator therapy may not reverse CF-associated airway luminal area changes. However, longitudinal analysis and investigation into the small airways are necessary for a comprehensive understanding of the effect of CFTR modulator therapy on airway luminal area changes. Funding: NIH (HL139854 to MJJ, HL131151 to SEB) and NSERC (PDF-577750-2023 to AHR). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Background: The compensatory reserve metric (CRM) provides a novel marker of hemodynamic status in prediction of sudden cardiovascular decompensation during central hypovolemia. The CRM has previously been calculated using arterial waveforms obtained from a photoplethysmographic volume-clamp technique. However, the in-field use of pulse oximetry is becoming more prominent in research and medicine. To improve in-field applicability of the CRM, this project aimed to validate pulse-oximetry derived CRM values relative to physiologic data during simulated hemorrhage through application of lower body negative pressure (LBNP). Methods: Forty-nine healthy adults (25 females) underwent a graded LBNP protocol with the following 5-minute stages: -0, -15, -30, -45, -60, -70, -80, -90, and 100 mmHg, or until the onset of pre-syncopal symptoms (tolerance) was reached. Arterial waveforms were sampled using pulse oximetry (Massimo Radical 7). The CRM was calculated using a validated one-dimensional convolutional neural network. A brachial artery catheter was used to measure intraarterial pressure. A 3-lead ECG was used to measure heart rate. SpO2 was measured using pulse oximetry. Cardiac output and stroke volume were estimated using the photoplethysmographic volume-clamp. Data were binned for the last thirty seconds of each completed stage, and at tolerance. Fixed-effect linear mixed models with repeated measures were used to examine the association between CRM values and physiologic variables. A priori significance was set at P<0.05. Results: The median LBNP stage reached was 70 mmHg (Range: 45-100 mmHg). Relative to baseline, at tolerance there was a 50±12% ( P<0.001) mean reduction in stroke volume, 65±27% ( P<0.001) increase in heart rate, 18±8% ( P<0.001) reduction in mean arterial pressure, 21±7% ( P<0.001) systolic blood pressure, 8±9% ( P<0.001) diastolic blood pressure, and 39±12% ( P<0.001) pulse pressure. The CRM obtained using pulse oximetry was significantly associated with a reduction in stroke volume ( P<0.001), increase in heart rate ( P<0.001), and reductions in systolic ( P=0.033), diastolic ( P=0.036), and pulse pressure ( P=0.002). There was no statistically significant association between CRM and cardiac output ( P=0.421), SpO2 ( P=0.408), or mean arterial pressure ( P=0.214). Conclusion: The CRM obtained using pulse oximetry may be a valid, reliable marker of hemodynamic status with promising in-field applications. Future studies warrant investigation of feasibility and applicability within various contexts ranging from the operating room to the battlefield. The presented work was funded in part by the Congressionally Directed Medical Research Program (Award No. DM180240) and Offce of Naval Research (Awards No. N00014-18-D-7001 and N00014-19-C-2017). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.