R. S. Harris

Use of recruitment maneuvers and high-positive end-expiratory pressure in a patient with acute respiratory distress syndrome.

Objective: To present the use of a novel high‐pressure recruitment maneuver followed by high levels of positive end‐expiratory pressure in a patient with the acute respiratory distress syndrome (ARDS). Design: Observations in one patient. Setting: The medical intensive care unit at a tertiary care university teaching hospital. Patient: A 32‐yr‐old woman with severe ARDS secondary to streptococcal sepsis. Interventions: The patient had severe gas exchange abnormalities because of acute lung injury and marked lung collapse. Attempts to optimize recruitment based on the inflation pressure‐volume (PV) curve were not sufficient to avoid dependent lung collapse. We used a recruitment maneuver using 40 cm H2O of positive end‐expiratory pressure (PEEP) and 20 cm H2O of pressure controlled ventilation above PEEP for 2 mins to successfully recruit the lung. The recruitment was maintained with 25 cm H2O of PEEP, which was much higher than the PEEP predicted by the lower inflection point (PFlex) of the PV curve. Measurements and Main Results: Recruitment was assessed by improvements in oxygenation and by computed tomography of the chest. With the recruitment maneuvers, the patient had a dramatic improvement in gas exchange and we were able to demonstrate nearly complete recruitment of the lung by computed tomography. A PV curve was measured that demonstrated a PFlex of 16‐18 cm H2O. Conclusion: Accumulating data suggest that the maximization and maintenance of lung recruitment may reduce lung parenchymal injury from positive pressure ventilation in ARDS. We demonstrate that in this case PEEP alone was not adequate to recruit the injured lung and that a high‐pressure recruitment maneuver was required. After recruitment, high‐level PEEP was needed to prevent derecruitment and this level of PEEP was not adequately predicted by the PFlex of the PV curve.

Relationship between airway narrowing, patchy ventilation and lung mechanics in asthmatics

Bronchoconstriction in asthma results in patchy ventilation forming ventilation defects (VDefs). Patchy ventilation is clinically important because it affects obstructive symptoms and impairs both gas exchange and the distribution of inhaled medications. The current study combined functional imaging, oscillatory mechanics and theoretical modelling to test whether the degrees of constriction of airways feeding those units outside VDefs were related to the extent of VDefs in bronchoconstricted asthmatic subjects. Positron emission tomography was used to quantify the regional distribution of ventilation and oscillatory mechanics were measured in asthmatic subjects before and after bronchoconstriction. For each subject, ventilation data was mapped into an anatomically based lung model that was used to evaluate whether airway constriction patterns, consistent with the imaging data, were capable of matching the measured changes in airflow obstruction. The degree and heterogeneity of constriction of the airways feeding alveolar units outside VDefs was similar among the subjects studied despite large inter-subject variability in airflow obstruction and the extent of the ventilation defects. Analysis of the data amongst the subjects showed an inverse relationship between the reduction in mean airway conductance, measured in the breathing frequency range during bronchoconstriction, and the fraction of lung involved in ventilation defects. The current data supports the concept that patchy ventilation is an expression of the integrated system and not just the sum of independent responses of individual airways.

Peripheral resistance: a link between global airflow obstruction and regional ventilation distribution

Airflow obstruction and heterogeneities in airway constriction and ventilation distribution are well-described prominent features of asthma. However, the mechanistic link between these global and regional features has not been well defined. We speculate that peripheral airway resistance (R(p)) may provide such a link. Structural and functional parameters are estimated from PET and HRCT images of asthmatic (AS) and nonasthmatic (NA) subjects measured at baseline (BASE) and post-methacholine challenge (POST). Conductances of 35 anatomically defined proximal airways are estimated from airway geometry obtained from high-resolution computed tomography (HRCT) images. Compliances of sublobar regions subtended by 19 most distal airways are estimated from changes in regional gas volume between two lung volumes. Specific ventilations (sV) of these sublobar regions are evaluated from 13NN-washout PET scans. For each pathway connecting the trachea to sublobar region, values of R(p) required to explain the sV distribution and global airflow obstruction are computed. Results show that R(p) is highly heterogeneous within each subject, but has average values consistent with global values in the literature. The contribution of R(p) to total pathway resistance (R(T)) increased substantially for POST (P < 0.0001). The fraction R(p)/R(T) was higher in AS than NA at POST (P < 0.0001) but similar at BASE (range: 0.960-0.997, median: 0.990). For POST, R(p)/R(T) range was 0.979-0.999 (NA) and 0.981-0.995 (AS). This approach allows for estimations of peripheral airway resistance within anatomically defined sublobar regions in vivo human lungs and may be used to evaluate peripheral effects of therapy in a subject specific manner.

Respiratory system reactance is an independent determinant of asthma control

The mechanisms underlying not well-controlled (NWC) asthma remain poorly understood, but accumulating evidence points to peripheral airway dysfunction as a key contributor. The present study tests whether our recently described respiratory system reactance (Xrs) assessment of peripheral airway dysfunction reveals insight into poor asthma control. The aim of this study was to investigate the contribution of Xrs to asthma control. In 22 subjects with asthma, we measured Xrs (forced oscillation technique), spirometry, lung volumes, and ventilation heterogeneity (inert-gas washout), before and after bronchodilator administration. The relationship between Xrs and lung volume during a deflation maneuver yielded two parameters: the volume at which Xrs abruptly decreased (closing volume) and Xrs at this volume (Xrscrit). Lowered (more negative) Xrscrit reflects reduced apparent lung compliance at high lung volumes due, for example, to heterogeneous airway narrowing and unresolved airway closure or near closure above the critical lung volume. Asthma control was assessed via the 6-point Asthma Control Questionnaire (ACQ6). NWC asthma was defined as ACQ6 > 1.0. In 10 NWC and 12 well-controlled subjects, ACQ6 was strongly associated with postbronchodilator (post-BD) Xrscrit (R(2) = 0.43, P < 0.001), independent of all measured variables, and was a strong predictor of NWC asthma (receiver operator characteristic area = 0.94, P < 0.001). By contrast, Xrs measures at lower lung volumes were not associated with ACQ6. Xrscrit itself was significantly associated with measures of gas trapping and ventilation heterogeneity, thus confirming the link between Xrs and airway closure and heterogeneity. Residual airway dysfunction at high lung volumes assessed via Xrscrit is an independent contributor to asthma control.

The effect of pregnancy and puerperium on the thiamine status of women.

Abstract The oral or intramuscular administration of thiamine to normal subjects causes the percentage excretion of thiamine and pyrimidine in the urine to increase as the dosage is increased on successive days until a peak is reached. Subsequent increases in dosage result in progressively less efficient excretion of thiamine or pyrimidine. This excretion peak has been observed in all sujects studied, whether normal, thiamine deficient or pregnant. The quantity of thiamine required to titrate this peak appears to be proportional to the thiamine status, is high for thiamine deficient persons and for women in advanced pregnancy and puerperium, and is low for those who are not deficient. Thiamine was administered orally and intramuscularly to measure the excretion peaks of sixteen pregnant women. Since approximately three times as much thiamine was needed in titrating the excretion peaks of these subjects during late pregnancy and early puerperium, it is suggested that the requirements for thiamine during pregnancy and lactation are three times those of nonpregnancy.

Allergic asthma is distinguished by sensitivity of allergen-specific CD4+ T cells and airway structural cells to type 2 inflammation

The development of allergic asthma requires type 2 airway inflammation as well as increased sensitivity of airway epithelial cells and smooth muscle to inflammation. Advanced analysis of asthma Not all individuals who have respiratory reactions to allergens progress to asthma. In this issue, Cho et al. found that although allergic asthmatics and allergic nonasthmatics both experienced inflammation after allergen challenge, asthmatics had more mucin and type 2 cytokines, and allergen-specific T cells sampled from the airspace had increased innate type 2 receptors. Using orientation-resolved optical coherence tomography, described by Adams et al., they demonstrated that allergic asthmatics also had increased airway smooth muscle mass. This technique allows for in vivo imaging of airway smooth muscle structure and function, which could shed light on the pathogenesis of many respiratory diseases. Despite systemic sensitization, not all allergic individuals develop asthma symptoms upon airborne allergen exposure. Determination of the factors that lead to the asthma phenotype in allergic individuals could guide treatment and identify novel therapeutic targets. We used segmental allergen challenge of allergic asthmatics (AA) and allergic nonasthmatic controls (AC) to determine whether there are differences in the airway immune response or airway structural cells that could drive the development of asthma. Both groups developed prominent allergic airway inflammation in response to allergen. However, asthmatic subjects had markedly higher levels of innate type 2 receptors on allergen-specific CD4+ T cells recruited into the airway. There were also increased levels of type 2 cytokines, increased total mucin, and increased mucin MUC5AC in response to allergen in the airways of AA subjects. Furthermore, type 2 cytokine levels correlated with the mucin response in AA but not AC subjects, suggesting differences in the airway epithelial response to inflammation. Finally, AA subjects had increased airway smooth muscle mass at baseline measured in vivo using novel orientation-resolved optical coherence tomography. Our data demonstrate that the development of allergic asthma is dependent on the responsiveness of allergen-specific CD4+ T cells to innate type 2 mediators as well as increased sensitivity of airway epithelial cells and smooth muscle to type 2 inflammation.

Functional effect of longitudinal heterogeneity in constricted airways before and after lung expansion

Heterogeneity in narrowing among individual airways is an important contributor to airway hyperresponsiveness. This paper investigates the contribution of longitudinal heterogeneity (the variability along the airway in cross-sectional area and shape) to airway resistance (R(aw)). We analyzed chest high-resolution computed tomography scans of 8 asthmatic (AS) and 9 nonasthmatic (NA) subjects before and after methacholine (MCh) challenge, and after lung expansion to total lung capacity. In each subject, R(aw) was calculated for 35 defined central airways with >2 mm diameter. Ignoring the area variability and noncircular shape results in an underestimation of R(aw) (%U(total)) that was substantial in some airways (∼50%) but generally small (median <6%). The average contribution of the underestimation of R(aw) caused by longitudinal heterogeneity in the area (%U(area)) to %U(total) was 36%, while the rest was due to the noncircularity of the shape (%U(shape)). After MCh challenge, %U(area) increased in AS and NA (P < 0.05). A lung volume increase to TLC reduced %U(total) and %U(area) in both AS and NA (P < 0.0001, except for %U(total) in AS with P < 0.01). Only in NA, %U(shape) had a significant reduction after increasing lung volume to TLC (P < 0.005). %U(area) was highly correlated, but not identical to the mean-normalized longitudinal heterogeneity in the cross-sectional area [CV(2)(A)] and %U(shape) to the average eccentricity of the elliptical shape. This study demonstrates that R(aw) calculated assuming a cylindrical shape and derived from an average area along its length may, in some airways, substantially underestimate R(aw). The observed changes in underestimations of R(aw) with the increase in lung volume to total lung capacity may be consistent with, and contribute in part to, the differences in effects of deep inhalations in airway function between AS and NA subjects.

Effects of inhaled CO administration on acute lung injury in baboons with pneumococcal pneumonia.

Inhaled carbon monoxide (CO) gas has therapeutic potential for patients with acute respiratory distress syndrome if a safe, evidence-based dosing strategy and a ventilator-compatible CO delivery system can be developed. In this study, we used a clinically relevant baboon model of Streptococcus pneumoniae pneumonia to 1) test a novel, ventilator-compatible CO delivery system; 2) establish a safe and effective CO dosing regimen; and 3) investigate the local and systemic effects of CO therapy on inflammation and acute lung injury (ALI). Animals were inoculated with S. pneumoniae (10(8)-10(9) CFU) (n = 14) or saline vehicle (n = 5); in a subset with pneumonia (n = 5), we administered low-dose, inhaled CO gas (100-300 ppm × 60-90 min) at 0, 6, 24, and/or 48 h postinoculation and serially measured blood carboxyhemoglobin (COHb) levels. We found that CO inhalation at 200 ppm for 60 min is well tolerated and achieves a COHb of 6-8% with ambient CO levels ≤ 1 ppm. The COHb level measured at 20 min predicted the 60-min COHb level by the Coburn-Forster-Kane equation with high accuracy. Animals given inhaled CO + antibiotics displayed significantly less ALI at 8 days postinoculation compared with antibiotics alone. Inhaled CO was associated with activation of mitochondrial biogenesis in the lung and with augmentation of renal antioxidative programs. These data support the feasibility of safely delivering inhaled CO gas during mechanical ventilation and provide preliminary evidence that CO may accelerate the resolution of ALI in a clinically relevant nonhuman primate pneumonia model.

Functional capacity, health status, and inflammatory biomarker profile in a cohort of patients with chronic obstructive pulmonary disease.

PURPOSE: Prior research has shown a significant relationship between 6-minute walking distance (6MWD) and health-related quality of life (HRQOL) in patients with chronic obstructive pulmonary disease (COPD). However, few studies have examined this relationship above and below the 350-m threshold that prognosticates survival and whether serum biomarkers could provide insight into the causes of quality-of-life differences above and below this threshold. METHODS: Measures of lung function, 6MWD, and HRQOL were compared in patients with COPD. Differences in HRQOL domains and serum biomarkers were compared in patients whose 6MWD were > or < 350 m. RESULTS: In patients walking < 350 m, scores in the physical domains of the SF-36 and the St. Georges Respiratory Questionnaire (SGRQ) were significantly different from scores of their counterparts with greater 6MWD. However, there was no association between any biomarkers and the physical domains of the SF-36 and the SGRQ. In patients walking < 350 m, only the IL-8 levels were associated with lower scores in SF-36 domains of emotional role, pain, vitality, and mental health (average r = −0.702; P = .01). In contrast, in patients walking > 350 m, surfactant protein D levels were associated with higher SF-36 scores in general pain, vitality, and social functioning (average r = 0.42; P = .04). CONCLUSIONS: In COPD, there is an association between 6MWD and the physical domains of the SF-36 and SGRQ in those patients walking < 350 m. The physical differences between patients walking < or > 350 m are not related to systemic inflammation. The association between interleukin 8 with nonphysical domains in patients with 6MWD < 350 m suggests that inflammation may play a larger role in the perceptive domain than previously recognized.

Deterioration of Regional Lung Strain and Inflammation during Early Lung Injury

Rationale: The contribution of aeration heterogeneity to lung injury during early mechanical ventilation of uninjured lungs is unknown. Objectives: To test the hypotheses that a strategy consistent with clinical practice does not protect from worsening in lung strains during the first 24 hours of ventilation of initially normal lungs exposed to mild systemic endotoxemia in supine versus prone position, and that local neutrophilic inflammation is associated with local strain and blood volume at global strains below a proposed injurious threshold. Methods: Voxel‐level aeration and tidal strain were assessed by computed tomography in sheep ventilated with low Vt and positive end‐expiratory pressure while receiving intravenous endotoxin. Regional inflammation and blood volume were estimated from 2‐deoxy‐2‐[(18)F]fluoro‐d‐glucose (18F‐FDG) positron emission tomography. Measurements and Main Results: Spatial heterogeneity of aeration and strain increased only in supine lungs (P < 0.001), with higher strains and atelectasis than prone at 24 hours. Absolute strains were lower than those considered globally injurious. Strains redistributed to higher aeration areas as lung injury progressed in supine lungs. At 24 hours, tissue‐normalized 18F‐FDG uptake increased more in atelectatic and moderately high‐aeration regions (>70%) than in normally aerated regions (P < 0.01), with differential mechanistically relevant regional gene expression. 18F‐FDG phosphorylation rate was associated with strain and blood volume. Imaging findings were confirmed in ventilated patients with sepsis. Conclusions: Mechanical ventilation consistent with clinical practice did not generate excessive regional strain in heterogeneously aerated supine lungs. However, it allowed worsening of spatial strain distribution in these lungs, associated with increased inflammation. Our results support the implementation of early aeration homogenization in normal lungs.