Pulmonary & Respiratory Medicine

Aim: To explore adequate parameters for EMD of ABP signal; to determine the intrinsic characteristics of ABP waveform through the analysis of IMFs’ averaged period and its energy density; to examine the effect of different respiration patterns on IMFs extracted from ABP waveform by CEEMD.

Arterial blood pressure (ABP) reflects cardiac function, vessel compliance, and cardiorespiratory interaction and ABP analysis provides the estimators of this physiological information. But it is inconvenient for quantitative ABP assessment due to several influences, such as respiration. Recently, a novel adaptive method, called empirical mode decomposition (EMD), was proposed, and it was useful for non-stationary intrinsic characteristics extraction. Though some literatures examined that EMD helps for physiological signal analysis study, the method applied for ABP signal still needs further investigation. This study proposed a standard procedure of specific EMD for ABP intrinsic characterization during spontaneous breathing, 6-cycle breathing, and hyperventilation. The extracted components, called intrinsic mode functions (IMFs), were determined with the examined parameters, including ensemble number, added noise, and the stop criterion. The IMFs of ABP signal were categorized into five major intrinsic components, including the noise and irregular fluctuation (IMF1), beat-to-beat cardiac intervals (IMF2), characteristics of pressure waveform morphology (IMF3), base beat (IMF4), and respiratory related fluctuation (IMF5 and IMF6).

The results showd that the characteristics of IMFs were quantified by averaged period and corresponding energy density with good reproducibility. The proposed algorithm produced meaningful IMFs representing the cardiac rhythm, intrinsic waveform mophology, and the intrinsic influence of respiration fluctuations. EMD helps for analyzing the underlying mechanisms of control processes, including cardiorespiratory coupling and interactions among organ systems at multiple time scales.

Objective: A blunt costophrenic (CP) angle in chest radiographs is known as a sign of pleural effusion, but is also observed in pulmonary emphysema. However, healthy young adult subjects with a blunt CP angle were often encountered in company annual medical examinations. The goal of the study was to evaluate radiographic measurements, spirometry, and cough symptoms in such subjects with a stable blunt CP angle obtained in a company medical check to clarify the underlining condition.

Methods: Radiographic measurements were made for the diameter of the main bronchus (MB), the tracheal width (TR), and the lung area (LA) estimated from the product of the height of the right lung and internal chest diameter in posteroanterior chest radiographs. The MB/LA and TR/LA ratios were calculated as markers of dysanapsis. An interview was performed to obtain information on cough symptoms.

Results: The MB/LA and TR/LA ratios were both significantly lower in subjects with a blunt CP angle than in controls without blunt CP angles. Spirometry in the subjects with blunt CP angles indicated that 57.2% of parameters, including FEF25-75%, FEF75%, FEF50%, PEF, and FEV1/FVC, were subnormal and 84.1% of the subjects had a concave maximal expiratory flow-volume curve. These spirometric findings suggest the presence of airflow limitation involving the small airways. In correlation analyses, the MB/LA ratio was significantly associated with FEF25-75%/FVC, PEF, and FEF50%; and the TR/LA ratio was positively correlated with FEF25-75%/FVC and FEF50%. In interviews, 62% of subjects with a blunt CP angles stated that they had experienced cough symptoms in recent years or in the past.

Conclusion: A stable blunt CP angle is associated with dysanapsis and airflow limitation. These changes may explain the high rate of cough among subjects with a stable blunt CP angle.

It is presumed that bronchial hyperreactivity (BHR) can occur with any inhaled agent and may be a reason for discontinuation of inhalation therapy in cystic fibrosis (CF) patients. On the other hand, inhalation of antibiotics is being increasingly used to eradicate or treat infections. This review focuses on identifying the mechanisms of BHR for a better understanding of its impact on inhalation treatment. BHR in CF is suggested to be secondary to underlying airway disease (associated to poor pulmonary function, chronic inflammation and aerosol distribution) or to be a separate condition occurring more in CF. Furthermore, certain characteristics of the aerosol solution itself, such as the active molecule, chemical additives and particle size, can cause BHR. Recombinant human DNase (rhDNase), hypertonic saline (HS) and the antibiotics tobramycin, colistin and aztreonam lysine for inhalation (AZLI) are frequently used inhalation drugs in the treatment of CF. Prevalence of BHR related to both short and long-term inhalation of these drugs as reported in the literature was investigated. Acute BHR is documented in up to two thirds of CF patients. Despite the widespread use of rhDNase, HS, tobramycin, colistin and AZLI, only one long-term trial looked for, but did not demonstrate, BHR at the end of the trial period.

Objective: The occurrence of non-hemolytic transfusion reactions is highest with platelet and plasma administration. Some of these reactions are characterized by endothelial leak, especially transfusion related acute lung injury (TRALI). Elevated concentrations of inflammatory mediators secreted by contaminating leukocytes during blood product storage may contribute to such reactions, but platelet-secreted mediators may also contribute. We hypothesized that platelet storage leads to accumulation of the endothelial permeability mediator vascular endothelial growth factor (VEGF), and that intravascular administration of exogenous VEGF leads to extensive binding to its lung receptors.

Methods: Single donor, leukocyte-reduced apheresis platelet units were sampled over 5 days of storage. VEGF protein content of the centrifuged supernatant was determined by ELISA, and the potential contribution of VEGF from contaminating leukocytes was quantified. Isolated-perfused rat lungs were used to study the uptake of radiolabeled VEGF administered intravascularly, and the effect of unlabeled VEGF on lung leak.

Results: There was a time-dependent release of VEGF into the plasma fraction of the platelet concentrates (62 ± 9 pg/ml on day one, 149 ± 23 pg/ml on day 5; mean ± SEM, p<0.01, n=8) and a contribution by contaminating leukocytes was excluded. Exogenous 125I-VEGF bound avidly and specifically to the lung vasculature, and unlabeled VEGF in the lung perfusate caused vascular leak.

Conclusion: Rising concentrations of VEGF occur during storage of single donor platelet concentrates due to platelet secretion or disintegration, but not due to leukocyte contamination. Exogenous VEGF at these concentrations rapidly binds to its receptors in the lung vessels. At higher VEGF concentrations, VEGF causes vascular leak in uninjured lungs. These data provide further evidence that VEGF may contribute to the increased lung permeability seen in TRALI associated with platelet products.

Goodpasture's disease is a fulminant rapidly progressive disease characterized by autoantibodies to the alpha-3 chain of type IV collagen (Goodpasture's antigen). It can present as a glomerulonephritis alone, or as a pulmonaryrenal syndrome with alveolar haemorrhage. We report here a classical case of Goodpasture's disease presenting as a pulmonary-renal syndrome with serum anti-glomerular basement membrane (GBM) antibody negativity and positive perinuclear anti-neutrophil cytoplasm antibodies (p-ANCA).

Objective: Severe sepsis is a leading cause of mortality and morbidity in the critically ill with no reliably effective treatments. The goal of this study was to determine whether intravenous ascorbic acid impacted novel biomarkers in sepsis.

Methods: This is a retrospective study of a phase I, randomized, double-blinded, placebo controlled safety trial of intravenous ascorbic acid in severe sepsis. In the safety trial, 24 patients were randomized to receive full ICU standard of care support plus intravenous ascorbic acid (50 or 200 mg/kg/24h) for 4 days or placebo. Novel biomarkers of sepsis such as circulating cell free DNA (cf-DNA), mitochondrial DNA (mtDNA), endogenous antimicrobial proteins (alpha-4-defensin [α4D] and bactericidal permeability interacting protein [BPI]) and the red cell distribution width (RDW) were measured.

Results: Cf-DNA values were higher in non-survivors at baseline and remained elevated for 96 hours. MtDNA levels increased in the placebo group, but declined in the treatment groups without reaching statistical significance. RDW increased significantly only in the placebo group, while expression of the antimicrobial proteins increased significantly only in the treatment groups.

Conclusion: Ascorbic acid infusion may improve sepsis outcomes by reducing cf- and mtDNA levels while augmenting endogenous antimicrobial proteins and preserving RDW.

Background: Spaceflight missions may require crewmembers to conduct extravehicular activities (EVA). Prebreathe protocols in preparation for an EVA entail 100% hyperoxia exposure that may last for a few hours and be repeated 2-3 times weekly. Each EVA is associated with additional challenges such as low levels of total body cosmic/ galactic radiation exposure that may present a threat to crewmember health. We have developed a mouse model of total body radiation and hyperoxia exposure and identified acute damage of lung tissues. In the current study we evaluated the usefulness of dietary flaxseed (FS) as a countermeasure agent for such double-hit exposures.

Methods: We evaluated lung tissue changes 2 weeks post-initiation of exposure challenges. Mouse cohorts (n=5/ group) were pre-fed diets containing either 0% FS or 10% FS for 3 weeks and exposed to: a) normoxia (Untreated); b) >95% O2 (O2); c) 0.25Gy single fraction gamma radiation (IR); or d) a combination of O2 and IR (O2+IR) 3 times per week for 2 consecutive weeks, where 8-hour hyperoxia treatments were spanned by normoxic intervals.

Results: At 2 weeks post challenge, while control-diet fed mice developed significant lung injury and inflammation across all challenges, FS protected lung tissues by decreasing bronchoalveolar lavage fluid (BALF) neutrophils (p<0.003) and protein levels, oxidative tissue damage, as determined by levels of malondialdehyde (MDA) (p<0.008) and nitrosative stress as determined by nitrite levels. Lung hydroxyproline levels, a measure of lung fibrosis, were significantly elevated in mice fed 0% FS (p<0.01) and exposed to hyperoxia/radiation or the combination treatment, but not in FS-fed mice. FS also decreased levels of a pro-inflammatory, pro-fibrogenic cytokine (TGF-ß1) gene expression levels in lung.

Conclusion: Flaxseed mitigated adverse effects in lung of repeat exposures to radiation/hyperoxia. This data will provide useful information in the design of countermeasures to early tissue oxidative damage associated with space exploration.

Objective: High flow nasal cannula therapy (HFT) has been shown to be similar to nasal continuous positive airway pressure (nCPAP) in neonates with respect to avoiding intubation. The objective of the current study is to determine if there are trends for adverse safety and long-term respiratory outcomes in very low birth weight infants (<1500 g) from centers using HFT as their primary mode of non-invasive respiratory support compared to data from the largest neonatal outcomes database (Vermont Oxford Network; VON).

Methods: A multicenter, retrospective analysis of pulmonary outcomes data was performed for the calendar years 2009, 2010 and 2011. Performance of five HFT centers was compared with population outcomes from the VON database. The five HFT centers routinely use flow rates between 4-8 L/min as described by the mechanistic literature. Weighted average percentages from the five HFT centers were calculated, along with the 95% confidence intervals (CI) to allow for comparison to the VON means.

Results: Patient characteristics between the HFT centers and the VON were not different in any meaningful way, despite the HFT having a greater percentage of smaller infants. The average VON center primarily used nCPAP (69% of all infants) whereas the HFT centers primarily used HFT (73%). A lesser percentage of VLBW infants in the HFT cohort experienced mortality and nosocomial infection. Compared to VON data, an appreciably lesser percent of the HFT cohort were receiving oxygen at 36 weeks and less went home on oxygen.

Conclusions: Considering there was no trend for adverse events, and there was a trend for better outcomes pertaining to long-term oxygen use, these data support claims of safety for HFT as a routine respiratory management strategy in the NICU.

Previous investigators reported that gas exchange consistently worsened when cardiac output (Qt) was increased under normal and pathological conditions. The aim of the present paper is to offer an alternative explanation, besides the one previously proposed that was based on some attenuation of hypoxic pulmonary vasoconstriction. The new concept emphases the inherent heterogeneity of regional blood flow (Q), as well as the skewed relationship between ventilation perfusion ratio (V/Q) and arterial oxygen tension (PaO2). Namely, PaO2 is exquisitely sensitive to any change of V/Q ratio from 0 to 1, which is many times more than that from 1 to 100. As Qt is increased, the additional pulmonary flow is by no means uniformly distributed. Thus, either ventilation (V) remains stable or even becomes more variable, V/Q heterogeneity increases at increased Qt. The higher Q in most regions reduces their corresponding V/Q ratios from the previously normal value of about 0.8 to 1, precipitously into the hypoxic range towards true shunt (V/Q = 0) and increases the V/Q mismatch. In contrary, the simultaneously created higher V/Q units cannot mitigate these adverse changes because of the sigmoid shape of hemoglobin oxygen dissociation curve. By this mechanism, diseased lungs are more susceptible to hypoxemia when Qt is increased due to their pre-existing V/Q abnormalities.

Background: The role of right atrial (RA) dilatation for predicting mortality in normotensive patients with pulmonary embolism (PE) has not been thoroughly studied.

Methods: We used the RIETE Registry data to evaluate the prognostic value of RA dilatation (visual estimate) on transthoracic echocardiography (ETT) in patients with acute PE presenting with systolic blood pressure levels ≥90 mm Hg.

Results: As of April 2013, 7,677 normotensive patients with acute PE underwent ETT within the first 48 hours. Of these, 2,268 (29.5%) had RA dilatation. At 30 days, 212 patients (2.76%) died, of whom 59 (0.77%) died of confirmed PE. Patients with RA dilatation had a 6-fold higher rate of fatal PE (1.85% vs. 0.31%; odds ratio [OR]: 5.98; 95% CI: 3.44-10.8) and a 2-fold higher all-cause mortality (4.32% vs. 2.11%; OR: 2.10; 95% CI: 1.59-2.76) compared with those without RA dilatation. On multivariable analysis, RA dilatation independently predicted fatal PE (relative risk [RR]: 3.71; 95% CI: 1.68-8.17), while right ventricle hypokinesis did not (RR: 1.36; 95% CI: 0.66-2.80).

Conclusions: Among normotensive patients with acute PE, RA dilatation on ETT independently predicted fatal PE at 30 days.

Increased nitric oxide (NO) production in the expired air has been associated with a number of disease conditions and may reflect the severity of inflammation in the lungs. Measurement of exhaled NO concentration has been proposed as a novel clinical tool for assessing airway inflammation and response to drug therapy. In spite of international guidelines aimed at standardizing the measurement of exhaled NO, clinicians remain skeptical due to the necessity of a significant degree of subject collaboration required by the procedure to obtain meaningful measurements. We hypothesized that exhaled NO concentration may be best measured by using end tidal NO concentration during a breath by breath monitoring. We tested laboratory staff and monitored their NO concentration online using a fast response chemiluminescence NO analyzer during normal breathing at rest for 5 minutes. First we confirmed that the NO analyzer was adequately fast to record fully the swings during normal breathing. We then compared the average end tidal NO value (NOet) from 6 to 10 breaths, to the NO value obtained from the plateau from a single slow vital capacity maneuver as recommended by the ATS guidelines (NOplat). End of exhalation was identified using end tidal carbon dioxide measurement. NOet while breathing room air was 24.3 ± 4.2 (SE) ppb and was not significantly different compared to 22.4 ± 2.8 (SE) ppb using NOplat. Additionally breathing high level of NO of up to 88 ppb did not affect either NOet or NOplat significantly suggesting that both measurements are independent of inhaled NO concentration. NO value at end of exhalation was very reproducible from breath to breath and did not require any special effort on the part of the subject. We recommend using NOet measurement instead of the NOplat value that is highly dependent on the exhalation rate and cooperation of the subject. NOet is much easier to record in children, elderly and patients with respiratory disease. The main requirement for measuring NOet is to have a fast response NO analyzer to record the full swings in NO concentration during normal breathing and to have a way of identifying end exhalation.

Rationale: Studies in Hispanic/Latino populations have shown ethnicity to be either a predictive or protective factor for COPD mortality and it is unclear whether this disagreement is attributable to ethnic differences in smoking rates, smoking behavior or differences in genetic susceptibility.

Objectives: This study will examine the role of smoking behavior as a means of explaining differences in risk for COPD mortality between Hispanics and non-Hispanic whites.

Methods: Participants were recruited into a cohort study from the San Luis Valley in Colorado beginning in the early 1980’s and followed for mortality until 2012. COPD and cardiovascular disease are often comorbid conditions and account for the competing risk of CVD in the analysis of COPD mortality. Mortality searches were conducted regularly and all ICD codes were collected for mortality event. Primary and secondary causes of each event were assessed using appropriate codes.

Results: Hispanic current smokers did not differ from NHW current smokers in years smoked (p=0.6) but Hispanic former smokers accumulated more years smoked compared to NHW former smokers (22 vs. 20, p=0.047). Hispanic ethnicity was significantly protective for COPD mortality adjusting for age, gender, pre-existing emphysema, hypertension and smoking status and accounting for the effect of CVD mortality (RR=0.58, 95% C.I. 0.34-0.99, p=0.035). Further adjustment for smoking behavior mitigated this effect.

Conclusions: The lower COPD mortality seen in Hispanic smokers may be due lower cumulative exposure to tobacco smoke. Thus, smoking behavior may play a key role in explaining differences in COPD mortality as they relate to Hispanic ethnicity.

Bronchial reactivity is a physiological property of healthy airways to develop a moderate airway obstruction in response to various non-specific stimuli, which is altered in several pulmonary diseases. The active effector of airway reactivity is airway smooth muscle (ASM). The contractile status of airway smooth muscle is under the control of many extracellular messengers acting on specific membrane receptors. Binding of the contractile messengers to their specific membrane receptors increases cytosolic Ca2+ concentration ([Ca2+]i). The shape of the resulting calcium signal is sensed by the contractile apparatus and hence determines the pattern of the contractile response. Agonists can also modify the sensitivity of the contractile apparatus to calcium, via phosphorylation and dephosphorylation of a network of regulatory proteins. These mechanisms can be altered in several respiratory diseases such and COPD, asthma, or exposure to air pollutants, leading to hyperreactivity, which can be pharmacologically controlled by drugs acting on the mechanisms of ASM contraction. The article describes the major intracellular mechanisms responsible for the excitation-contraction coupling in airway smooth muscle cell.

Our insight into cystic fibrosis (CF) disease and diseases associated with CF gene mutations has significantly increased in recent years, particularly after the discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene over two decades ago. This has resulted in a widened spectrum of phenotypic manifestations of CF ranging from the classic multisystem disease in infancy and early childhood to adults with single-organ manifestations of CF such as chronic sinopulmonary disease, pancreatitis and obstructive azoospermia. As a consequence, the diagnosis of CF can be difficult to establish or exclude. Extensive CFTR genotyping has been limited by the inability to interpret the functional and clinical significance of a large number of identified CFTR mutations. As identified CFTR mutations can either be “disease-causing”, “of varying clinical consequences”, “benign” or have unknown consequences, the identification of mutations on both alleles may be insufficient alone to confirm the diagnosis of CF. More recently though, the number of mutations recognized to be disease-causing was greatly expanded by the Clinical and Functional Translation of CFTR (CFTR2) project. This review article discusses the role and yield of CFTR mutation analysis in the diagnosis of CF.

Objective: A survey was developed and distributed to pharmacists who have earned the certified asthma educator credential (AE-C) to assess asthma education services provided and their perceived value of the AE-C. Design: A 28 item survey was developed, pretested and distributed electronically. Participants: 224 AE-C certified pharmacists practicing within the United States were invited to participate. Main Outcome Measures: Information pertaining to the level of education, professional affiliations, and practice setting was collected along with other demographic attributes.We also inquired about the types of asthma education services provided, related clinical activities, and whether AE-C pharmacists or their employers had received reimbursement for time spent providing such services. Results: A total of 57 (25.4%) pharmacists from 30 different states completed the survey. Respondents were primarily female (79.2%); had earned a Pharm.D. degree (81.1%); completed a post-graduate year 1 (PGY1) residency (37.7%); with most practicing in either an ambulatory care (49.1%) or academic (35.8%) setting. The majority of respondents (84.4%) indicated they would recommend the AE-C credential to a pharmacist colleague. Professional advancement, improved confidence in managing asthma, and increased credibility were among the reported benefits of the AE-C. Limited recognition of the credential among pharmacists and lack of reimbursement for services were perceived barriers to pursing an AE-C. Conclusion: AE-C pharmacists are playing an integral role in managing patients with asthma. The AE-C credential has been viewed favorably by most pharmacists who have earned this credential. However, efforts to increase awareness of the AE-C among pharmacists may be necessary.