Ventilator advisory system employing load and tolerance strategy recommends appropriate pressure support ventilation settings: multisite validation study.

BACKGROUND: Loads on the respiratory muscles, reflected by noninvasive measurement of the real-time power of breathing (POBn), and tolerance of these loads, reflected by spontaneous breathing frequency (f) and tidal volume (Vt), should be considered when evaluating patients with respiratory failure. Pressure support ventilation (PSV) should be applied so that muscle loads are not too high or too low. We propose a computerized, ventilator advisory system employing a load (POBn) and tolerance (f and Vt) strategy in a fuzzy logic algorithm to provide guidance for setting PSV. To validate these recommendations, we performed a multisite study comparing the advisory system recommendations to experienced physician decisions. METHODS: Data were obtained from adults who were receiving PSV (n = 87) at three university sites via a combined pressure/flow sensor, which was positioned between the endotracheal tube and the Y-piece of the ventilator breathing circuit and was directed to the advisory system. Recommendations from the advisory system for increasing, maintaining, or decreasing PSV were compared at specific time points to decisions made by physician intensivists at the bedside. RESULTS: There were no significant differences in the recommendations by the advisory system (n = 210) compared to those of the physician intensivists to increase, maintain, or decrease PSV (p > 0.05). Physician intensivists agreed with 90.5% of all recommendations. The advisory system was very good at predicting intensivist decisions (r(2) = 0.90; p < 0.05) in setting PSV. CONCLUSIONS: The novel load-and-tolerance strategy of the advisory system provided automatic and valid recommendations for setting PSV to appropriately unload the respiratory muscles that were as good as the clinical judgment of physician intensivists.

Addition of sildenafil in patients with pulmonary arterial hypertension with inadequate response to bosentan monotherapy.

BACKGROUND: Pulmonary arterial hypertension (PAH) remains a progressive disease despite improvement when using one of three medication classes: prostanoids, endothelin receptor antagonists or phosphodiesterase-5 inhibitors. Combination therapy has been proposed for patients with unsatisfactory response to monotherapy. OBJECTIVES: To examine the effect of adding sildenafil to bosentan on 6 min walk distance (6MWD) and New York Heart Association (NYHA) classification in patients with PAH who achieved inadequate improvement with bosentan monotherapy. METHODS: Patients with idiopathic PAH or connective tissue disease-associated PAH, and who had either self-reported inadequate improvement in exercise tolerance or a decline in 6MWD after initial improvement, were included in the study (n=10). Data on 6MWD and NYHA class at baseline (before initiation of bosentan), three and six months after baseline, second baseline (before initiation of combination therapy with sildenafil), and three and six months after second baseline were analyzed for any changes. RESULTS: Mean time from initiation of bosentan monotherapy to initiation of combination therapy was 558 days (range 150 to 900 days). Six months after initiation of bosentan, 6MWD increased by 57.2 m above the baseline of 314.4 m. Six months after combination therapy, 6MWD was 62.80 m higher than the baseline before initiation of combination therapy of 339 m (P<0.02). The overall increase in 6MWD six months after combination therapy was higher than the first baseline by 87.4 m (P not significant). NYHA functional class did not improve with combination therapy in all patients. DISCUSSION: Initiating combination therapy in patients who achieve an inadequate improvement in exercise tolerance with monotherapy may result in further improvement in exercise tolerance.

Effect of maintenance azithromycin on established bronchiolitis obliterans syndrome in lung transplant patients.

BACKGROUND: Bronchiolitis obliterans syndrome (BOS), the main cause of late mortality following lung transplantation, is defined as an irreversible decline in forced expiratory volume in 1 s (FEV1). Previous studies using azithromycin for BOS in lung transplant patients have demonstrated a potential reversibility of the decline in FEV1. OBJECTIVES: To examine whether initiating azithromycin reverses decline in FEV1 in lung transplant recipients with established BOS of at least three months. METHODS: Pulmonary function tests were performed every three months in seven lung transplant recipients with established BOS of at least three months. FEV1 was recorded at six and three months before initiation, at time of initiation, and three, six, nine and 12 months postazithromycin initiation. The primary end point was change in FEV1. During the study, no immunosuppressive medication changes or acute rejection episodes occurred. RESULTS: Mean time from transplant to azithromycin initiation was 64 months (range 17 to 117 months). Mean time from BOS diagnosis to azithromycin initiation was 22 months (range three to 67 months). Rate of FEV1 decline from six months before azithromycin initiation, and rates of FEV1 increase from initiation to three and 12 months post-treatment initiation, were not statistically significant (P=0.32, P=0.16 and P=0.18, respectively). Following a trend toward improvement in the first three months after treatment initiation, FEV1 tended to stabilize. DISCUSSION: Although several studies address the possible benefit of maintenance azithromycin in lung transplant patients with BOS, the role of the drug remains unproven in these patients, and would best be addressed by a large randomized controlled trial.

Pulmonary Arterial Hypertension Specific Therapy in Patients with Combined Post- and Precapillary Pulmonary Hypertension.

BACKGROUND: Specific therapy for patients with PAH is associated with good outcomes. Little is known about the effect of this treatment in patients with Cpc-PH (PAPm ≥ 25 mmHg, PAWP > 15 mmHg, DPG ≥ 7 mmHg, and/or PVR > 3 WU). This study evaluates the outcome of treating patients with Cpc-PH using PAH specific therapy. METHODS: The primary outcome was survival. Secondary outcomes were WHO functional class and 6-minute walk distance (6-MWD). RESULTS: Twenty-six patients with Cpc-PH (half with VHD and half with HF) received PAHST. Six patients did not tolerate treatment due to pulmonary edema. No predictors for treatment intolerance were identified. In twenty patients who tolerated the treatment, the mean WHO functional class improved from 2.70 ± 0.21 at initial assessment to 2.22 ± 0.21 (p < 0.04) and 2.06 ± 0.21 (p < 0.03) at 6 and 9 months, respectively. Mean 6-MWD improved from 276.0 ± 38.50 meters at initial assessment to 343.9 ± 22.99 meters (p < 0.04) and 364.6 ± 34.85 meters (p = 0.07) at 6 and 9 months, respectively. Twelve patients died during the follow-up period. Mean survival for all patients was 1279.7 ± 193.60 days. CONCLUSION: PAHST may be beneficial in the treatment of Cpc-PH (both short and long term). Prospective randomized controlled trials of PAHST in this population are needed to assess its potential efficacy.

Metabolic Signatures of Lung Cancer in Sputum and Exhaled Breath Condensate Detected by 1H Magnetic Resonance Spectroscopy: A Feasibility Study.

OBJECTIVES: Lung cancer is one of the most lethal cancers. Currently, there are no biomarkers for early detection, monitoring treatment response, and detecting recurrent lung cancer. We undertook this study to determine if 1H magnetic resonance spectroscopy (MRS) of sputum and exhaled breath condensate (EBC), as a noninvasive tool, can identify metabolic biomarkers of lung cancer. MATERIALS AND METHODS: Sputum and EBC samples were collected from 20 patients, comprising patients with pathologically confirmed non-small cell lung cancer (n = 10) and patients with benign respiratory conditions (n = 10). Both sputum and EBC samples were collected from 18 patients; 2 patients provided EBC samples only. 1H MR spectra were obtained on a Bruker Avance 400 MHz nuclear magnetic resonance (NMR) spectrometer. Sputum samples were further confirmed cytologically to distinguish between true sputum and saliva. RESULTS: In the EBC samples, median concentrations of propionate, ethanol, acetate, and acetone were higher in lung cancer patients compared to the patients with benign conditions. Median concentration of methanol was lower in lung cancer patients (0.028 mM) than in patients with benign conditions (0.067 mM; P = 0.028). In the combined sputum and saliva and the cytologically confirmed sputum samples, median concentrations of N-acetyl sugars, glycoprotein, propionate, lysine, acetate, and formate were lower in the lung cancer patients than in patients with benign conditions. Glucose was found to be consistently absent in the combined sputum and saliva samples (88%) as well as in the cytologically confirmed sputum samples (86%) of lung cancer patients. CONCLUSION: Absence of glucose in sputum and lower concentrations of methanol in EBC of lung cancer patients discerned by 1H MRS may serve as metabolic biomarkers of lung cancer for early detection, monitoring treatment response, and detecting recurrence.

Basic principles of control of breathing.

The metabolic demands of the body, including consumption of oxygen and removal of carbon dioxide, vary widely in health and disease. Ventilation must adjust to meet these demands and accommodate volitional and behavioral activities. Control of breathing depends on a complex and intricate feedback control system that integrates these automatic and volitional aspects of ventilation. Sensors, including chemoreceptors and lung volume receptors, relay information to a central controller located primarily in the medulla. The central controller integrates this information and determines the level of activation of the effectors (the respiratory motoneurons and muscles), which affects ventilation and gas exchange. Inputs from suprapontine structures, including the cerebral cortex, are also important in integrating volitional aspects of breathing into the control system.

Directing therapy in pulmonary arterial hypertension using a target 6 min walk distance.

BACKGROUND: The most effective approaches to escalating advanced therapies in pulmonary arterial hypertension (PAH) are controversial. OBJECTIVE: To compare outcomes before and after introducing a target 6 min walk distance (6MWD) treatment strategy in PAH using registry data. METHODS: From 2001 to 2005, WHO class II to IV patients were treated with bosentan or prostanoids. In July 2005, a target 6MWD strategy was adopted. Monotherapy continued if 6MWD remained >350 m. For patients in whom 6MWD was ≤350 m, sildenafil was added. If 6MWD remained <350 m, prostanoids were considered. Changes in 6MWD, WHO class and survival rate were compared between periods. RESULTS: Before using the 6MWD strategy, there was a statistically significant improvement in mean WHO class at six, nine and 12 months (2.5±0.8 [P<0.015]; 2.5±0.8 [P<0.005]; and 2.5±0.9 [P<0.03], respectively) compared with baseline (2.9±0.9). There was a statistically significant increase in mean 6MWD at three, six, nine and 12 months (383±113 m [P<0.005]; 401±102 m [P<0.006]; 400±109 m [P<0.001]; and 399±110 m [P<0.004], respectively) compared with baseline (321±119 m). The survival rate was 95% at one and two years. From 2005 to 2009, there was a statistically significant improvement in mean WHO class at three, six, nine and 12 months (2.6±0.8 [P<0.05]; 2.3±0.9 [P<0.0001]; 2.3±0.9 [P<0.0001]; and 2.3±1.0 [P<0.0005], respectively) compared with baseline (2.8±0.7). There was statistically significant improvement in 6MWD at six months (381±126 m [P<0.05]), followed by a decline toward baseline (354±117 m). One- and two-year survival rates in the 6MWD target era were 95% and 80%, respectively. CONCLUSION: Based on registry data, adoption of this strategy did not affect survival rates, nor cause a sustained improvement in 6MWD by 12 months. WHO class improved similarly in both treatment groups.

Vascular compromise and hemodynamics in pulmonary arterial hypertension: model predictions.

A previously validated computer model of the normal pulmonary circulation is adapted to simulate pulmonary arterial hypertension (PAH) in humans. Model predictions are used to explore the suitability of currently accepted criteria for diagnosing PAH by correlating hemodynamic data with the degree of vascular compromise (disease severity). Model predictions demonstrate a hyperbolic relationship between vascular compromise, mean pulmonary artery pressure (PAPm) and pulmonary vascular resistance (PVR). PAPm and PVR change very little from disease initiation until a vascular compromise of 65% to 70% (surface area of 0.35 to 0.3 of baseline, respectively) is reached. Following that, further compromise is associated with a steep rise in PAPm and PVR. The relationship between vascular compromise and hemodynamics may explain the relative stability of cardiac output early in this disease process and, therefore, the lack of symptoms. It also explains the rapid deterioration following diagnosis if the disease remains untreated. Model predictions demonstrate the inadequacy of the current hemodynamic criteria for diagnosing PAH over a wide range of left atrial pressure and cardiac output combinations and for early detection of disease. The model provides an alternative approach to diagnosing PAH by translating hemodynamic data to degree of vascular compromise.

Treatment of pulmonary hypertension in patients with connective tissue disease and interstitial lung disease.

BACKGROUND: Pulmonary hypertension (PH) in patients with connective tissue disease (CTD) can occur in isolation or concomitantly with interstitial lung disease (ILD). Targeted therapies for PH can mitigate clinical deterioration in CTD patients with isolated PH; however, the effect of these therapies in CTD patients with PH and ILD (CTD-PH-ILD) are poorly characterized. OBJECTIVE: To investigate outcomes following long-term treatment of PH in patients with CTD-PH-ILD.  METHODS:   A retrospective evaluation of 13 CTD-PH-ILD patients who were treated with bosentan, sildenafil or bosentan plus sildenafil, was conducted. Immunosuppressants were prescribed as indicated. Patients underwent pulmonary function testing and assessment of 6 min walk distance at the time of treatment initiation and during follow-up. Patients were followed until time of death, lung transplantation or the end of the study. Kaplan-Meier estimates of survival were calculated and log-rank testing was used to analyze survival differences according to CTD subtype. RESULTS: Thirteen patients (seven with systemic sclerosis [SSc], four with overlap syndrome, and two with rheumatoid arthritis) were followed for a mean (± SD) duration of 33.8±21.7 months. The survival estimate at a median duration of 34 months was 85%; two patients with SSc died. Mortality rates were greater among patients with SSc versus other CTD subtypes (P=0.04). No changes from baseline to follow-up in mean forced vital capacity or exercise capacity, and no treatment-related toxicity, were observed. CONCLUSION: Treatment using PH-specific therapies in patients with CTD, PH and ILD was well tolerated. Further studies to investigate the efficacy of PH-specific therapies in CTD-PH-ILD patients are warranted.

An atypical presentation of liver enzyme elevation resulting from bosentan use.

Hepatocellular enzyme elevation is a known side effect of both bosentan and atorvastatin. However, a rise in liver enzyme level not characteristic of either agent individually may represent a reaction to their combination or an atypical reaction to bosentan alone. The present case report describes a patient who had been taking atorvastatin for many years and was started on bosentan for chronic thromboembolic pulmonary hypertension. After 19 weeks of therapy, she developed severe liver enzyme elevation that necessitated the discontinuation of both bosentan and atorvastatin. Although the safety of reintroducing bosentan in such a case is unknown, it was reintroduced in this patient because of the severity of her disease, the demonstrated treatment benefit and the lack of alternative treatment options. On reintroduction of bosentan alone, she again demonstrated significant liver enzyme elevation - this time occurring after only two doses. The present case highlights that bosentan can cause more rapid and severe hepatocellular enzyme elevation than previously believed, thus necessitating more frequent monitoring.

Comparison of per cent predicted and percentile values for pulmonary function test interpretation.

BACKGROUND: Pulmonary function tests (PFTs) are commonly interpreted as a fraction of predicted normal values, with an abnormal test often defined as less than 80% or greater than 120% of the predicted value. However, recommendations of the American Thoracic Society/European Respiratory Society suggest using a percentile-based approach to define an abnormal test (less than the fifth or greater than the 95th percentiles). OBJECTIVE: To compare PFT values obtained by the per cent predicted method with the percentile-based method for lung function parameters. METHODS: Full PFTs performed between January 2000 and July 2004, at the Health Sciences Centre (Winnipeg, Manitoba) were analyzed. Using the Crapo and Gutierrez equations, per cent predicted and percentile values were calculated. An abnormal test was defined as less than 80% or greater than 120% of predicted (per cent predicted method) or as less than the fifth or greater than the 95th percentiles (percentile method). Using the percentile method as reference standard, the diagnostic test characteristics of the per cent predicted method were calculated. RESULTS: The full PFTs of 2176 men and 1658 women were analyzed using the Crapo and Gutierrez equations. The mean (+/- SD) age of all subjects was 52+/-15 years. Per cent agreement between the two tests was more than 94% for all parameters except for reduced residual volume (88%). Per cent predicted methods had suboptimal sensitivity for abnormal total lung capacity (88% to 89%), increased residual volume (83% to 89%) and reduced diffusion capacity (89% with Crapo equations). Suboptimal specificity (83% to 86%) was observed for decreased residual volume. CONCLUSION: The results of the per cent predicted and percentile-based approaches for PFT interpretation were similar for the majority of lung function parameters. These two methods can be used interchangeably for spirometry. However, caution may be warranted in relying solely on per cent predicted methods for assessing lung volume or diffusion capacity.