Matthew N. Bartels

Sildenafil for chronic obstructive pulmonary disease: a randomized crossover trial.

Abstract Rationale: Pulmonary hypertension with exercise is common in chronic obstructive pulmonary disease (COPD) and may contribute to exercise limitation in this disease. We aimed to determine the effects of treatment with sildenafil on exercise capacity in patients with COPD and emphysema. Methods: We performed a randomized, double-blind, placebo-controlled 2-period crossover trial of sildenafil thrice daily in ten adults with COPD and emphysema on CT scan without pulmonary hypertension. We randomized study participants to 4 weeks of sildenafil (or placebo) followed by a 1-week washout and then 4 weeks of placebo (or sildenafil). The 2 primary outcomes were the 6-minute walk distance and oxygen consumption at peak exercise. Results: Sildenafil had no effect on 6-minute walk distance (placebo-corrected difference = -7.8 m, 95% confidence interval, -23.2 to 7.5 m, p = 0.35) or oxygen consumption at peak exercise (placebo-corrected difference = -0.1 ml/kg/min, 95% confidence interval -2.1 to 1.8 ml/kg/min, p = 0.89). Sildenafil increased the alveolar-arterial oxygen gradient (p = 0.02), worsened symptoms (p = 0.04), and decreased quality-of-life (p = 0.03). Adverse events were more frequent while receiving sildenafil (p = 0.005). Conclusions: Routine sildenafil administration did not have a beneficial effect on exercise capacity in patients with COPD and emphysema without pulmonary hypertension. Sildenafil significantly worsened gas exchange at rest and quality of life. (clinicaltrials.gov NCT00104637).

Racial and Ethnic Disparities in Survival in Lung Transplant Candidates with Idiopathic Pulmonary Fibrosis

Minority patients have worse outcomes than nonminority patients in a variety of pulmonary diseases. We aimed to compare the survival of Black and Hispanic patients to that of others with idiopathic pulmonary fibrosis (IPF). We performed a retrospective cohort study of patients with IPF who were evaluated for lung transplantation at our center. Kaplan‐Meier survival curves and Cox proportional hazards models were used to compare survival between groups. Black and Hispanic patients had spirometry, lung volumes and diffusion capacity that were similar to others, but had worse exercise capacity. Minority patients had a significantly increased risk of death compared to others independent of transplantation status (hazard ratio = 3.3, 95% CI 1.2–8.9, p = 0.02). Differences in exercise capacity, pulmonary hemodynamics and socioeconomic factors appeared to account for some of the differences in survival. Black and Hispanic patients with IPF had an increased risk of death following referral for lung transplantation. This finding may be due to differences in disease progression and/or differences in access to medical care among minority patients. Future studies should confirm our findings in a larger cohort. The elimination of racial and ethnic disparities in outcome should be a priority for clinicians and researchers in this field.

Aerobic fitness and body mass index in individuals with schizophrenia: Implications for neurocognition and daily functioning

Previous reports indicate that among healthy individuals low aerobic fitness (AF) and high body-mass index (BMI) predict poor neurocognition and daily-functioning. It is unknown whether these associations extend to disorders characterized by poor neurocognition, such as schizophrenia. Therefore, we compared AF and BMI in individuals with schizophrenia and non-clinical controls, and then within the schizophrenia group we examined the links between AF, BMI, neurocognition and daily-functioning. Thirty-two individuals with schizophrenia and 64 gender- and age-matched controls completed assessments of AF (indexed by VO2max) and BMI. The former also completed measures of neurocognition, daily-functioning and physical activity. The schizophrenia group displayed significantly lower AF and higher BMI. In the schizophrenia group, AF was significantly correlated with overall neurocognition (r=0.57), along with executive functioning, working memory, social cognition, and processing speed. A hierarchical regression analysis indicated that AF accounted for 22% of the neurocognition variance. Furthermore, AF was significantly correlated with overall daily-functioning (r=0.46). In contrast, BMI displayed significant inverse correlations with neurocognition, but no associations to daily-functioning. AF was significantly correlated physical activity. The authors discuss the potential use of AF-enhancing interventions to improve neurocognitive and daily-functioning in schizophrenia, along with putative neurobiological mechanisms underlying these links, including Brain-Derived Neurotrophic Factor.

The effect of ventilation on spectral analysis of heart rate and blood pressure variability during exercise.

Heart rate variability (HRV) and systolic blood pressure variability (BPV) during incremental exercise at 50, 75, and 100% of previously determined ventilatory threshold (VT) were compared to that of resting controlled breathing (CB) in 12 healthy subjects. CB was matched with exercise-associated respiratory rate, tidal volume, and end-tidal CO(2) for all stages of exercise. Power in the low frequency (LF, 0.04-0.15 Hz) and high frequency (HF, >0.15-0.4 Hz) for HRV and BPV were calculated, using time-frequency domain analysis, from beat-to-beat ECG and non-invasive radial artery blood pressure, respectively. During CB absolute and normalized power in the LF and HF of HRV and BPV were not significantly changed from baseline to maximal breathing. Conversely, during exercise HRV, LF and HF power significantly decreased from baseline to 100% VT while BPV, LF and HF power significantly increased for the same period. These findings suggest that the increases in ventilation associated with incremental exercise do not significantly affect spectral analysis of cardiovascular autonomic modulation in healthy subjects.

High attenuation areas on chest computed tomography in community-dwelling adults: the MESA study

Evidence suggests that lung injury, inflammation and extracellular matrix remodelling precede lung fibrosis in interstitial lung disease (ILD). We examined whether a quantitative measure of increased lung attenuation on computed tomography (CT) detects lung injury, inflammation and extracellular matrix remodelling in community-dwelling adults sampled without regard to respiratory symptoms or smoking. We measured high attenuation areas (HAA; percentage of lung voxels between −600 and −250 Hounsfield Units) on cardiac CT scans of adults enrolled in the Multi-Ethnic Study of Atherosclerosis. HAA was associated with higher serum matrix metalloproteinase-7 (mean adjusted difference 6.3% per HAA doubling, 95% CI 1.3–11.5), higher interleukin-6 (mean adjusted difference 8.8%, 95% CI 4.8–13.0), lower forced vital capacity (FVC) (mean adjusted difference −82 mL, 95% CI −119–−44), lower 6-min walk distance (mean adjusted difference −40 m, 95% CI −1–−80), higher odds of interstitial lung abnormalities at 9.5 years (adjusted OR 1.95, 95% CI 1.43–2.65), and higher all cause-mortality rate over 12.2 years (HR 1.58, 95% CI 1.39–1.79). High attenuation areas are associated with biomarkers of inflammation and extracellular matrix remodelling, reduced lung function, interstitial lung abnormalities, and a higher risk of death among community-dwelling adults. Increased lung attenuation on CT may identify subclinical lung injury and inflammation in community-dwelling adults http://ow.ly/97k3300tvKX

Evaluation of Pulmonary Function and Exercise Performance by Cardiopulmonary Exercise Testing Before and After Lung Transplantation

BACKGROUND Detailed description of functional exercise outcomes before and after lung transplantation is lacking. The objective of this study was to describe and compare posttransplant improvement in lung function and peak exercise parameters in patients with advanced lung disease. METHODS The study included 153 patients who underwent lung transplantation over 7 years who had complete cardiopulmonary exercise testing (CPET) and pulmonary function tests (PFTs) before and after lung transplantation. CPET and PFT within 30 months pretransplant and posttransplant were compared. RESULTS Pulmonary function markedly improved posttransplant as FVC increased 67%, maximum voluntary ventilation increased 91%, and FEV(1) increased 136%. However, peak oxygen consumption increased only 19%, peak CO(2) production increased 50%, and peak work increased 78%. Although transplant recipients had a 1.5- to 2.0-fold increase in exercise capacity posttransplant, peak exercise capacity remained at 50% of the predicted normal, suggesting a maximal limitation. Subgroup stratification into quartiles based on pretransplant exercise capacity revealed the greatest exercise benefit to be in the lowest functional pretransplant groups. CONCLUSIONS Lung transplant recipients have an increase in exercise capacity that does not match the improvement in lung function, indicating that poor strength, deconditioning, or other peripheral factors play a significant role in the limitation of exercise benefit posttransplantation. Further elucidation of the mechanisms of exercise limitation may allow for improved exercise outcomes posttransplant.

Titrated oxygen requirement and prognostication in idiopathic pulmonary fibrosis

The supplemental oxygen flow rate is a common bedside measure of gas exchange impairment. We aimed to determine whether a titrated oxygen requirement (TOR) predicted mortality in idiopathic pulmonary fibrosis (IPF). We examined 104 adults with IPF enrolled in a prospective cohort study and a validation cohort of 151 adults with a variety of interstitial lung diseases (ILDs). The TOR was defined as the lowest oxygen flow rate required to maintain an oxyhaemoglobin saturation of 96% while standing. Cox proportional hazards models and time-dependent receiver operating characteristic curves were used to examine survival time. A higher TOR was associated with a greater mortality rate independent of forced vital capacity and 6-min walk test results in IPF (adjusted hazard ratio (per 1 L·min−1) 1.16, 95% CI 1.06–1.27). The TOR was at least as accurate as pulmonary function and 6-min walk testing at predicting 1-yr mortality. Findings were similar in other ILDs. The TOR is a simple, inexpensive bedside measurement that aids prognostication in IPF.

Aerobic exercise for cognitive deficits in schizophrenia — The impact of frequency, duration, and fidelity with target training intensity

Individualswith schizophrenia display substantial deficits in cognitive functioning (Green et al., 2004) for which available treatments offer only limited benefits. Recent reports have indicated that aerobic exercise (AE) leads to improvements in both aerobic fitness (AF; Vancampfort et al., 2015; Armstrong et al., submitted for publication) and cognitive functioning among individual with schizophrenia (Kimhy et al., 2015; Kimhy et al., 2014). A recent review of trials examining exercise interventions in people with schizophrenia have suggested that clinical benefits from such trials are related to the dose of exercise, with interventions employing at least 90min of moderate-to-vigorous exercise per week result in clinical improvements (i.e., Firth et al., 2015). However, the specific AE training characteristics that contribute to cognitive improvements remain largely unknown. To address this issue, we examined the impact of frequency, duration, and fidelity with target training intensity on changes in cognition in 13 individuals with schizophrenia (average age = 36.31, SD = 11.16; 38% female) who completed an AE training program as part of a single-blind randomized clinical trial examining the impact of AE on cognition (Kimhy et al., 2015). Detailed descriptions of the trial and the AE procedures have been published elsewhere (Kimhy et al., 2015; Kimhy et al., in press). Briefly, the AE program was informed by the American College of Sports Medicine and federal guidelines for the frequency, intensity, time, and type of AE (US Department of Health and Human Services, 2008). The program involved three one-hour AE sessions/week over 12 weeks. The sessions opened with a 10-min warm-up period, after which participants exercised individually for 45 min, ending with a 5-min cool-down period. A trainer was present during the AE sessions for guidance and support, along with a research assistant who collected behavioral data. Changes in cognitive functioning from baseline to 12 weeks were indexed by changes in the composite scores of the MATRICS Consensus Cognitive Battery. Additionally, at baseline participants completed a cardiopulmonary exercise test (CPET) to determine their AF (VO2 peak; ml/kg/min) and maximal heart rate (HRmax). The latter was used to determine the in-session target AE training intensity for each participant. Targets were set to 60% of HRmax in week 1, 65% in week 2, 70% in week 3, and 75% in weeks 4–12. The AE intensity was indexed by the in-session heart rate recorded using Polar RS400 heart rate monitors (Polar Electro Inc., Lake Success, NY) worn by participants during sessions. The monitors were programmed to emit a soft beep if a participants heart rate fell below the individually-targeted AE intensity level for a particular week of training. On such occasions, the trainer encouraged the participant to achieve their target goal. Following the completion of the 12-week training program, all participants completed a second CPET to determine changes in AF.

Lung Volume Reduction Surgery Using the NETT Selection Criteria

BACKGROUND The National Emphysema Treatment Trial (NETT) proved that lung volume reduction surgery (LVRS) was safe and effective in patients with certain clinical characteristics and using defined inclusion-exclusion criteria. Based on the selection criteria developed in that trial, we performed bilateral LVRS on 49 patients during the period of February 2004 until May 2009. METHODS Forty-nine patients underwent lung volume reduction by either median sternotomy (10) or video-assisted thoracoscopic surgery (39) selected according to NETT described parameters. Preoperative characteristics were the following: mean (±SD) age 62.5±6.6 years, preoperative FEV1 (forced expiratory volume in the first second of expiration) 691 cc (±159), % of predicted FEV1 25.3 (±6.2), preoperative Dlco (diffusing capacity of lung for carbon monoxide) 7.6 (±2.7), and % of predicted DLCO 27% (±7.3). All patients had upper lobe predominant disease and either low exercise capacity (n=23) or high exercise capacity (n=26) as defined by the NETT. RESULTS There was no operative or 90-day mortality. Median length of stay was 8 days (interquartile range=6 to 10). Two patients required reintubation and tracheostomy but were decannulated prior to discharge. The BODE index (body mass index, airflow obstruction, dyspnea, and exercise capacity), a multidimensional predictor of survival in chronic obstructive pulmonary disease, improved -2.3 (±1.5, p<0.0001) (missing data: 5 of 42, 11.9%) and the FEV1 improved 286 cc (±221, p<0.0001), both 1 year after surgery. Probability of survival was 0.98 (95% CI [confidence interval]=0.94 to 1) at 1 year, and 0.95 (95% CI=0.88 to 1) at 3 years. CONCLUSIONS Surgical lung volume reduction for emphysema can be performed in patients using selection criteria developed by the NETT with very low surgical risk and excellent midterm results. Surgical LVRS is the standard against which other nonsurgical treatments for advanced emphysema should be judged.

Evaluation of blood pressure and baroreflex sensitivity by radial artery tonometry versus finger arteriolar photoplethysmography

BACKGROUND Published normative data of noninvasive blood pressures (BPs) and autonomic modulations have been primarily derived from the finger arteriole using the Finapres (Ohmeda Co., Englewood, CO), a device that is no longer manufactured. Currently, beat-to-beat BP are obtained from the radial artery using the Colin tonometer. METHODS We compared BP and autonomic parameters in a crossover design between the two devices in 29 subjects during seated rest and a 0.1-Hz breathing protocol. In addition, we tested whether finger arteriolar BP differences were due to pressure changes exerted by the radial tonometer. RESULTS Uniformly, BP measured at the radial artery were significantly higher than those from the finger arteriole. Radial BP (106 +/- 19.5 mm Hg) were higher than finger arteriolar BP (95.8 +/- 13.7 mm Hg) (P <.005). Tonometric baroreflex sensitivity (BRS) (24.0 +/- 18 msec/mm Hg) was higher compared to photoplethysmographic BRS (12.0 +/- 7.7 msec/mm Hg; P <.0003). Systolic BP (radial artery) (115 +/- 25 mm Hg) were higher compared to finger arteriolar BP (97.7 +/- 19 mm Hg; P <.0025) during breathing, as was BRS (25.9 +/- 11.6 msec/mm Hg v 21.5 +/- 11.6 msec/mm Hg; P <.05). Differences in the low frequency systolic BP (LF(SBP)), representative of sympathetic vasomotor modulation, between the two methods, whether absolute, normalized, or log-transformed were not observed. CONCLUSIONS There were no differences in arteriolar BP values in the presence or absence of radial artery tonometric pressure. These findings indicate that differences exist in systolic BP and BRS using the tonometer (radial artery) versus the Finapres (Ohmeda Co.) (finger arteriole). Furthermore, these differences are not due to pressure exerted by the radial artery tonometer that supplies blood to the finger arteriole.