End-expiratory lung volume decreases during REM sleep despite continuous positive airway pressure.

PURPOSE: Patients with obstructive sleep apnea (OSA) may experience apneas and hypopneas primarily during stage R (REM) sleep when end-expiratory lung volume (EELV) reaches its nadir. The purpose of this study was to determine if REM-related reductions in EELV persist in the presence of continuous positive airway pressure (CPAP) prescribed during non-stage REM (NREM) sleep. METHODS: We prospectively recruited 17 subjects referred to the sleep laboratory for CPAP titration. CPAP was titrated per AASM protocol to control respiratory events. The change in EELV was measured using magnetometry. RESULTS: Of the 17 subjects, 12 (71%) had moderate to severe OSA. Despite the application of CPAP, there was a significant reduction in EELV between NREM and REM sleep (- 105.9 ± 92.2 to - 325.0 ± 113.1 mL, respectively, p < 0.01). The change in EELV between non-stage R (NREM) and REM significantly correlated with overall apnea-hypopnea index (AHI) (r = 0.5, p = 0.04), the number of respiratory arousals during REM (r = 0.5, p = 0.04), and prescribed level of CPAP (r = 0.7, p < 0.01). CONCLUSION: REM-related reductions in EELV are associated with worsening sleep disordered breathing and occur despite the presence of CPAP.

The Maximal Expiratory-to-Inspiratory Pressure Ratio and Supine Vital Capacity as Screening Tests for Diaphragm Dysfunction.

PURPOSE: The change in vital capacity from the seated to supine position (∆VC-supine) is used to screen for diaphragm dysfunction (DD), but some individuals are unable to tolerate the supine position. Since expiratory muscle function is often preserved in patients with isolated DD and inspiratory strength is reduced, the purpose of this study was to examine if the ratio of maximal expiratory pressure to maximal inspiratory pressure (MEP/MIP) may provide an alternative to ∆VC-supine when screening patients for DD. METHODS: We performed a cross-sectional analysis on 76 patients referred for evaluation of unexplained dyspnea and possible DD. MEP and MIP were measured in the seated position as well as the percent change in VC from the seated to supine position (∆VC-supine %). The presence of unilateral diaphragm paralysis (UDP), bilateral diaphragm paralysis (BDP), or normal diaphragm function (N) was confirmed by ultrasound. RESULTS: Of the 76 patients, 23 had N, 40 had UDP, and 13 had BDP. MEP/MIP was significantly greater for UDP compared to N (2.1(1.2-5.7) and 1.5(0.7-2.2), respectively) (median and interquartile range) and for BDP compared to UDP (4.3(2.3-7.5) and 2.1(1.2-5.7), respectively) (p < 0.001). The area (AUC) under the receiver-operating characteristic curve for MEP/MIP between N and UDP was 0.84 (95% confidence interval (CI) 0.74-0.94) and between UDP and BDP was 0.90 (95% CI 0.80-0.99). MEP/MIP had a strong monotonic relationship with ∆VC-supine % (Spearman's ρ = 0.68, p < 0.001). CONCLUSIONS: The MEP/MIP ratio provides a method with comparable sensitivity and specificity to ∆VC-supine % that can be used to screen patients with suspected isolated phrenic neuropathy and alleviates the need for measuring supine pulmonary function.

Diaphragm ultrasound as a predictor of successful extubation from mechanical ventilation.

INTRODUCTION: The purpose of this study was to evaluate if ultrasound derived measures of diaphragm thickening, rather than diaphragm motion, can be used to predict extubation success or failure. METHODS: Sixty-three mechanically ventilated patients were prospectively recruited. Diaphragm thickness (tdi) was measured in the zone of apposition of the diaphragm to the rib cage using a 7-10 MHz ultrasound transducer. The percent change in tdi between end-expiration and end-inspiration (Δtdi%) was calculated during either spontaneous breathing (SB) or pressure support (PS) weaning trials. A successful extubation was defined as SB for >48 h following endotracheal tube removal. RESULTS: Of the 63 subjects studied, 27 patients were weaned with SB and 36 were weaned with PS. The combined sensitivity and specificity of Δtdi%≥30% for extubation success was 88% and 71%, respectively. The positive predictive value and negative predictive value were 91% and 63%, respectively. The area under the receiver operating characteristic curve was 0.79 for Δtdi%. CONCLUSIONS: Ultrasound measures of diaphragm thickening in the zone of apposition may be useful to predict extubation success or failure during SB or PS trials.

A method for determining optimal mean airway pressure in high-frequency oscillatory ventilation.

BACKGROUND: "Optimal" mean airway pressure (MAP) during high-frequency oscillatory ventilation (HFOV) can be defined as the pressure that allows for maximal alveolar recruitment while minimizing alveolar overdistension. Choosing a MAP near or just below the point of maximal curvature (PMC) of the volume-pressure characteristics of the lung can serve as a guide to avoid overdistention during HFOV, while simultaneously preventing derecruitment. The purpose of this study was to assess whether optimal MAP at the PMC can be determined by using measures of PaO(2) in patients with acute respiratory distress syndrome (ARDS) undergoing HFOV. METHODS: We prospectively studied seven patients with ARDS who underwent HFOV after failed conventional ventilation. In addition, 11 healthy subjects were studied to validate measurements of changes in end-expiratory lung volume (∆EELV) using magnetometers. Using this validated method, plots of ∆EELV and MAP were constructed during decremental changes in MAP following a recruitment maneuver in seven ventilated patients with ARDS. The PMC was defined as the point where the slope of the ∆EELV versus MAP curve acutely changed. The MAP at the PMC was compared to that determined from plots of PaO(2) versus MAP. RESULTS: In the healthy cohort, measurements of ∆EELV obtained by magnetometry approximated the line of identity when compared to those obtained by spirometry. The MAP determined using either the ∆EELV or PaO(2) techniques were identical in all seven HFOV ventilated patients. Additionally, there was a significant correlation between the MAP associated changes in PaO2 and the MAP associated changes in ∆EELV (p < 0.001). CONCLUSIONS: The finding that MAP at the PMC is the same whether determined by measures of ∆EELV or PaO(2) suggest that bedside measures PaO(2) may provide an acceptable surrogate for measures of EELV when determining "optimal" MAP during HFOV.

Nocturia in Women With Obstructive Sleep Apnea.

Obstructive sleep apnea (OSA) is underdiagnosed in women compared with men. Women have a tendency to underreport or present with atypical symptoms such as behavior changes, insomnia, fatigue, and depression. Nocturia, waking up from sleep 2 times or more to void, has been shown to be associated with OSA, but it is not an included symptom in commonly used screening questionnaires in primary provider offices. About 50% of patients with OSA have nocturia, and treatment of OSA improves it. Recognition of nocturia as a relevant symptom of OSA is important for primary providers to provide timely referral for the diagnosis of OSA.

Discovery of the gene signature for acute lung injury in patients with sepsis.

The acute respiratory distress syndrome (ARDS)/acute lung injury (ALI) was described 30 yr ago, yet making a definitive diagnosis remains difficult. The identification of biomarkers obtained from peripheral blood could provide additional noninvasive means for diagnosis. To identify gene expression profiles that may be used to classify patients with ALI, 13 patients with ALI + sepsis and 20 patients with sepsis alone were recruited from the Medical Intensive Care Unit of the University of Pittsburgh Medical Center, and microarrays were performed on peripheral blood samples. Several classification algorithms were used to develop a gene signature for ALI from gene expression profiles. This signature was validated in an independently obtained set of patients with ALI + sepsis (n = 8) and sepsis alone (n = 1). An eight-gene expression profile was found to be associated with ALI. Internal validation found that the gene signature was able to distinguish patients with ALI + sepsis from patients with sepsis alone with 100% accuracy, corresponding to a sensitivity of 100%, a specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 100%. In the independently obtained external validation set, the gene signature was able to distinguish patients with ALI + sepsis from patients with sepsis alone with 88.9% accuracy. The use of classification models to develop a gene signature from gene expression profiles provides a novel and accurate approach for classifying patients with ALI.

Non-invasive measurements of exhaled NO and CO associated with methacholine responses in mice.

BACKGROUND: Nitric oxide (NO) and carbon monoxide (CO) in exhaled breath are considered obtainable biomarkers of physiologic mechanisms. Therefore, obtaining their measures simply, non-invasively, and repeatedly, is of interest, and was the purpose of the current study. METHODS: Expired NO (ENO) and CO (ECO) were measured non-invasively using a gas micro-analyzer on several strains of mice (C57Bl6, IL-10-/-, A/J, MKK3-/-, JNK1-/-, NOS-2-/- and NOS-3-/-) with and without allergic airway inflammation (AI) induced by ovalbumin systemic sensitization and aerosol challenge, compared using independent-sample t-tests between groups, and repeated measures analysis of variance (ANOVA) within groups over time of inflammation induction. ENO and ECO were also measured in C57Bl6 and IL-10-/- mice, ages 8-58 weeks old, the relationship of which was determined by regression analysis. S-methionyl-L-thiocitrulline (SMTC), and tin protoporphyrin (SnPP) were used to inhibit neuronal/constitutive NOS-1 and heme-oxygenase, respectively, and alter NO and CO production, respectively, as assessed by paired t-tests. Methacholine-associated airway responses (AR) were measured by the enhanced pause method, with comparisons by repeated measures ANOVA and post-hoc testing. RESULTS: ENO was significantly elevated in naïve IL-10-/- (9-14 ppb) and NOS-2-/- (16 ppb) mice as compared to others (average: 5-8 ppb), whereas ECO was significantly higher in naïve A/J, NOS-3-/- (3-4 ppm), and MKK3-/- (4-5 ppm) mice, as compared to others (average: 2.5 ppm). As compared to C57Bl6 mice, AR of IL-10-/-, JNK1-/-, NOS-2-/-, and NOS-3-/- mice were decreased, whereas they were greater for A/J and MKK3-/- mice. SMTC significantly decreased ENO by ~30%, but did not change AR in NOS-2-/- mice. SnPP reduced ECO in C57Bl6 and IL-10-/- mice, and increased AR in NOS-2-/- mice. ENO decreased as a function of age in IL-10-/- mice, remaining unchanged in C57Bl6 mice. CONCLUSION: These results are consistent with the ideas that: 1) ENO is associated with mouse strain and knockout differences in NO production and AR, 2) alterations of ENO and ECO can be measured non-invasively with induction of allergic AI or inhibition of key gas-producing enzymes, and 3) alterations in AR may be dependent on the relative balance of NO and CO in the airway.

Metabolic Myopathies and the Respiratory System.

Metabolic myopathies are a heterogeneous group of disorders characterized by inherited defects of enzymatic pathways involved in muscle cellular energetics and adenosine triphosphate synthesis. Skeletal and respiratory muscles are most affected. There are multiple mechanisms of disease. The age of onset and prognosis vary. Metabolic myopathies cause exercise intolerance, myalgia, and increase in muscle breakdown products during exercise. Some affect smooth muscle like the diaphragm and cause respiratory failure. The pathophysiology is complex and the evidence in literature to guide diagnosis and management is sparse. Treatment is limited. This review discusses the pathophysiology and diagnostic evaluation of these disorders.

Change in End-Expiratory Lung Volume During Sleep in Patients at Risk for Obstructive Sleep Apnea.

STUDY OBJECTIVES: As lung volume decreases radial traction on the upper airway is reduced, making it more collapsible. The purpose of this study was to measure change in end-expiratory lung volume (EELV) following sleep onset and to evaluate the relationship between change in EELV and sleep-disordered breathing. METHODS: Twenty subjects underwent overnight polysomnography, of whom 14 (70%) had obstructive sleep apnea (OSA). Change in EELV was measured throughout the night using magnetometry. Sleep was staged and respiratory events scored using American Academy of Sleep Medicine criteria. An additional 10 subjects had change in EELV measured simultaneously by magnetometer and spirometer while awake. RESULTS: In the subjects studied while awake, change in EELV calculated from magnetometer data correlated very strongly (r = 0.89, P < .001) with that obtained by spirometry. In the 20 subjects who underwent polysomnography, there was a decline in EELV for sleep stages N1, N2, N3, and R (REM sleep); 17.9 ± 121.0 mL (mean ± standard deviation), 228.5 ± 151.8 mL, 198.1 ± 122.1 mL, and 316.7 ± 131.9 mL, respectively. Mean EELV reduction during stage R sleep doubled that noted during non-stage R sleep (316.7 ± 131.9 mL versus 150.9 ± 89.7 mL, respectively) (P < .001). The difference in EELV between non-stage R and stage R sleep inversely correlated with mean oxygen saturation (r = -0.56, P = .06). EELV reduction in individuals with moderate and severe OSA was greater than in those with mild SDB but did not reach statistical significance. CONCLUSIONS: Magnetometry provides a precise, unobtrusive, and continuous means to study lung volume changes during sleep. EELV declines from sleep onset, reaching its nadir during stage R sleep. The reduction in EELV in stage R sleep was associated with lower mean oxygen saturation but was not associated with greater sleep-disordered breathing.

Markers of lung disease in exhaled breath: nitric oxide.

Management of airway inflammation requires proper monitoring and treatment to improve long-term outcomes. However, achieving this goal is difficult, as current methods have limitations. Although nitric oxide (NO) was first identified 200 years ago, its physiological importance was not recognized until the early 1980s. Many studies have established the role of NO as an essential messenger molecule in body systems. In addition, studies have demonstrated a significant relationship between changes in exhaled NO levels and other markers of airway inflammation. The technique used to measure NO in exhaled breath is noninvasive, reproducible, sensitive, and easy to perform. Consequently, there is growing interest in the use of exhaled NO in the management of asthma and other pulmonary conditions. The purpose of this review is to promote a basic understanding of the physiologic actions of NO, measurement techniques, and ways that research findings might translate to future application in clinical practice. Specifically, the article will review the role of exhaled NO in regard to its historical background, mechanisms of action, measurement techniques, and implications for clinical practice and research.

Physiology in Medicine: physiological basis of diaphragmatic dysfunction with abdominal hernias-implications for therapy.

An incisional hernia is a common complication after abdominal surgery. Complaints of dyspnea in this population may be attributed to cardiopulmonary dysfunction or deconditioning. Large abdominal incisional hernias, however, may cause diaphragm dysfunction and result in dyspnea, which is more pronounced when standing (platypnea). The use of an abdominal binder may alleviate platypnea in this population. We discuss the link between diaphragm dysfunction and the lack of abdominal wall integrity and how abdominal wall support partially restores diaphragm function.

Differential modulation by exogenous carbon monoxide of TNF-alpha stimulated mitogen-activated protein kinases in rat pulmonary artery endothelial cells.

Heme oxygenase-1 (HO-1) is an enzyme that is highly inducible by various cellular stressors, especially oxidant injury. Our laboratory and others have demonstrated that induction of HO-1 exerts an antiinflammatory effect both in vitro and in vivo. We hypothesized that carbon monoxide (CO), a major catalytic byproduct of heme catalysis by HO-1, may mediate this antiinflammatory effect by modulating signal transduction pathways, in particular the mitogen-activated protein (MAP) kinase pathway. Confluent primary cultures of rat pulmonary artery endothelial cells (RPAEC) were treated with tumor necrosis factor-alpha (TNF-alpha; 50 ng/ml), and whole-cell extracts were assayed for phosphorylated ERK1/2, JNK1/2, and p38 MAP kinases. These three major MAP kinase pathways were activated by TNF-alpha in a time-dependent manner. RPAEC treated with TNF-alpha in the presence of a low concentration of CO (1%) exhibited marked attenuation of the phosphorylation of ERK1/2 MAP kinase when compared with cells treated with TNF-alpha alone. A similar effect was seen on the upstream MEK 1/2 kinase. Interestingly, CO (1%) accentuated TNF-alpha-induced phosphorylated p38 MAP kinase. These effects of exogenous CO on the ERK1/2 and p38 systems could be replicated by overexpression of HO-1 in RPAEC, using an adenoviral vector. As these MAP kinases are implicated in the regulation of various inflammatory molecules and adhesion molecules, our data provide a potential mechanism by which HO-1, acting via CO, may modulate the inflammatory response by differential activation of the MAP kinase pathway.

Bronchoprovocation testing in asthma: effect on exhaled monoxides.

Exhaled carbon monoxide and nitric oxide reflect allergic inflammation in asthma and have clinical utility for monitoring disease severity. The effects of allergen challenge and of inflammatory versus non-inflammatory bronchoconstrictive stimuli on the exhalation kinetics of these gases are unclear. The aim of this study is to compare and contrast the effects of methacholine and allergen challenges on the exhaled levels of carbon monoxide and nitric oxide in a cohort of adult subjects with atopic asthma. Eight subjects underwent inhaled allergen testing, nine underwent methacholine testing, and five subjects underwent both tests. Additionally, seven healthy controls underwent a mock challenge. Mixed-expired and end-expiratory carbon monoxide and end-expiratory nitric oxide levels were measured together with spirometry before, during (i.e. after each step of the inhalations), and after the challenges. Decreases in both end-expiratory (-14.4% in 9/11 subjects, p = 0.04) and mixed-expired (-7.5%, 9/11 subjects, p = 0.007) levels of carbon monoxide were noted during the immediate phase of the allergen challenge, with similar reductions after methacholine challenge, but levels were unaffected by repeated forced vital capacity exhalations alone. End-expiratory nitric oxide increased during the immediate phase of allergen challenge in 10/13 subjects (+10.8%, p = 0.05), but decreased after methacholine challenge in 14/14 subjects (-32.2%, p = 0.00009). Bronchospasm negatively modulates exhaled carbon monoxide and nitric oxide, but the inflammatory stimulus of allergen exposure increases exhaled nitric oxide. Measurements of exhaled monoxides may need to be referenced to the FEV(1).

Exhaled carbon monoxide as a biomarker of inflammatory lung disease.

Carbon monoxide (CO) can be detected on the exhaled breath of humans. Exhaled CO (E-CO) originates from the inspiration of ambient CO and from endogenous metabolic sources that include heme metabolism catalyzed by heme oxygenase (HO) enzymes. HO occurs in both constitutive (HO-2) and inducible (HO-1) forms; the latter responds to pro-inflammatory or pro-oxidative stimuli. E-CO may arise in the airways from inducible HO-1 activity in the bronchial epithelium, alveolar macrophages and other lung cell types, as a consequence of local inflammation, and from the alveolae in equilibrium with carboxyhemoglobin (Hb-CO) in the pulmonary circulation. Elevations in Hb-CO in turn may reflect increases in ambient CO, as well as increased HO activity in systemic tissues. E-CO increases dramatically in active smokers and can be used to monitor the smoking habit. Elevations in E-CO have been observed in critically ill or post-surgical patients and those with various pulmonary diseases associated with inflammation, including chronic obstructive pulmonary disease (COPD), asthma, cystic fibrosis and infections. Despite improvements in the standardization and sensitivity of methods to detect E-CO, the predictive value of this measurement as a diagnostic tool remains unclear.

Hemodynamic and molecular response to intermittent hypoxia (IH) versus continuous hypoxia (CH) in normal humans.

The hemodynamic response to hypoxia may be influenced by exposure pattern and inducible biological signals, such as nitric oxide synthase (iNOS) expression. The systemic blood pressure (BP) and heart rate (HR) response to intermittent and continuous hypoxia (IH and CH) were examined as was the relationship between these responses and iNOS expression in 10 normal subjects. BP and HR were recorded during exposure to IH or CH (total hypoxic time=60 min/dayx3 days for each exposure profile), whereas arterial oxygen saturation (SpO2) was maintained at 80-90%. Total RNA was isolated from peripheral blood lymphocytes before exposure on Day 1 and 2 hours after the last exposure on Day 3, and it was assayed for iNOS messenger RNA (mRNA) expression using quantitative polymerase chain reaction (PCR). HR, systolic BP (SBP), and diastolic BP (DBP) increased during both experimental conditions (P<0.05), with no difference by exposure pattern or evidence of facilitation over 3 days. No significant change occurred in iNOS mRNA during IH or CH when pre- and post-exposure values were compared. However, iNOS expression at the end of Day 3 was negatively correlated with the average end-exposure DBP (r=-0.79) and mean BP (MBP; r=-0.76) on Days 1-3 of the IH (P<0.05), but not CH exposure. It is concluded that both IH and CH are associated with significant but comparable hemodynamic changes. The negative correlation between BP and iNOS mRNA with IH, but not CH, may suggest differential modulation of the hemodynamic response to the 2 exposure patterns.

Enhanced nitric oxide production associated with airway hyporesponsiveness in the absence of IL-10.

Interleukin (IL)-10 is an anti-inflammatory cytokine implicated in the regulation of airway inflammation in asthma. Among other activities, IL-10 suppresses production of nitric oxide (NO); consequently, its absence may permit increased NO production, which can affect airway smooth muscle contractility. Therefore, we investigated airway reactivity (AR) in response to methacholine (MCh) in IL-10 knockout (-/-) mice compared with wild-type C57BL/6 (C57) mice, in which airway NO production was measured as exhaled NO (E(NO)), and NO production was altered with administration of either NO synthase (NOS)-specific inhibitors or recombinant murine (rm)IL-10. AR, measured as enhanced pause in vivo, and tracheal ring tension in vitro were lower in IL-10(-/-) mice by 25-50%, which was associated with elevated E(NO) levels (13 vs. 7 ppb). Administration of NOS inhibitors N(G)-nitro-L-arginine methyl ester (8 mg/kg ip) or L-N(6)-(1-iminoethyl)-lysine (3 mg/kg ip) to IL-10(-/-) mice decreased E(NO) by an average of 50%, which was associated with increased AR, to levels similar to C57 mice. E(NO) in IL-10(-/-) mice decreased in a dose-dependent fashion in response to administered rmIL-10, to levels similar to C57 mice (7 ppb), which was associated with a 30% increment in AR. Thus increased NO production in the absence of IL-10, decreased AR, which was reversed with inhibition of NO, either by inhibition of NOS, or with reconstitution of IL-10. These findings suggest that airway NO production can modulate airway smooth muscle contractility, resulting in airway hyporesponsiveness when IL-10 is absent.

Alterations in nitric oxide and cytokine production with airway inflammation in the absence of IL-10.

IL-10 is an anti-inflammatory cytokine that suppresses NO synthase (NOS) and production of NO; its lack may promote NO production and alterations in cytokines modulated by NO with allergic airway inflammation (AI), such as IL-18 and IL-4. Therefore, we induced AI in IL-10 knockout ((-/-)) and IL-10-sufficient C57BL/6 (C57) mice with inhaled OVA and measured airway NO production, as exhaled NO (E(NO)) and bronchoalveolar lavage fluid nitrite levels. E(NO) and nitrite levels were elevated significantly in naive IL-10(-/-) mice as compared with C57 mice. With AI, E(NO) and nitrite levels increased in C57 mice and decreased in IL-10(-/-) mice. IL-18 production fell with both AI and addition of S-nitroso-N-acetyl-d,l-penicillamine (a NO donor) but was not significantly increased by chemical NOS inhibition by l-N(5)-(1-iminoethyl)-ornithine. IL-4 AI was increased significantly (up to 10-fold greater) in the absence of IL-10 but was reduced significantly with chemical inhibition of NOS. Airway responsiveness was lower in IL-10(-/-) mice and was associated with alteration in production of NO and IL-4. Thus, IL-4 production was increased, and likely decreased NO production, in a way not predicted by the absence of IL-10. Inhibition of IL-4 production, with inhibition of NOS in the absence of IL-10, demonstrated the importance of a NO and IL-4 feedback mechanism regulating this interaction.