Effects of respiratory syncytial virus persistence on airway responsiveness and inflammation in guinea-pigs.

Recurrent wheezing and asthma often develop after acute respiratory syncytial virus (RSV) bronchiolitis, but the mechanisms of these sequelae are poorly understood. Using a guinea-pig model of human RSV lung infection, the effects of long-term viral persistence on three hallmarks of asthma: nonspecific airway responsiveness, airway inflammation and airway remodelling were examined. Guinea-pigs were studied 100 days after intranasal instillation of either human RSV or uninfected vehicle, using: 1) acetylcholine challenge to test for airway hyperresponsiveness (AHR); 2) lung histology to quantify the numbers of airway eosinophils and metachromatic cells (mast cells/basophils); 3) airway morphometry of the areas of the airway subepithelial connective tissue, smooth muscle and adventitia, to test for airway remodelling; and 4) immunohistochemistry to identify lung cells containing RSV antigens. The RSV-inoculated group had significantly elevated AHR and airway eosinophils compared to uninfected control animals (p<0.05). There were no significant differences between the two groups in terms of numbers of airway metachromatic cells, or the areas of subepithelial connective tissue, smooth muscle or adventitia. Viral proteins were identified by immunohistochemistry within several types of lung cells. In conclusion, long-term persistence of respiratory syncytial virus in the guinea-pig lung is associated with airway hyperresponsiveness and airway eosinophilia, and these changes may be pertinent to the pathogenesis of postbronchiolitis wheezing and asthma in children.

Discordance between physicians and coders in assignment of diagnoses.

OBJECTIVE: To measure concordance between physicians and medical record coders in their assignment of diagnoses. DESIGN: Prospective cohort series. SETTING: Five hundred and fifty-bed, tertiary-care, university teaching hospital. Study participants. In-patients who were discharged from either the Cardiac Sciences Program (n=125), the Renal Program (n=43), or the HIV-AIDS Program (n=25) during the period May 18-July 1, 1995. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Physicians and coders assigned diagnoses for individual in-patients based on their independent interpretations of the patient chart and discharge summary sheet. All assigned diagnoses were coded using the ICD-9-CM classification system. Concordance was measured for the most responsible diagnosis and for all assigned diagnoses. Difference in calculated resource intensity weights based on physicians' and coders' assignment of diagnoses was also calculated. RESULTS: Concordance rates for the most responsible diagnosis in each program were: Cardiac Sciences [27%; 95% confidence interval (CI)=20-36%], Renal Program (35%; 95% CI=21-53%), and HIV-AIDS Program (20%; 95% CI, 6-41%). Concordance rates for all diagnoses per chart were similar: Cardiac Sciences (20%; 95% CI, 14-25%), Renal Program (25%; 95% CI, 20-33%), and HIV-AIDS Program (29%; 95% CI, 25-44%). Resource intensity weights assigned by coders for the Cardiac Sciences and HIV-AIDS Program were significantly higher than those assigned by the physicians.

Leukocyte activation does not mediate myocardial leukocyte retention during endotoxemia in rabbits.

Our goal was to determine whether coronary leukocyte retention after endotoxin infusion was due primarily to leukocyte activation. Leukocytes were activated by infusion of endotoxin into 12 blood donor rabbits. Separately, 12 isolated rabbit hearts were perfused with blood from an endotoxemic support rabbit to expose coronary endothelium to an inflammatory stimulus. During an infusion of 20 ml of donor blood into the isolated heart, the coronary transit time of leukocytes was determined by deconvolution of multiple measurements of injectate and collected leukocyte concentrations. With no leukocyte activation or inflammatory stimulation of endothelium, leukocyte transit time was 9.2 +/- 3.5 s, and 11.6 +/- 4.1 x 10(6) leukocytes were retained in the coronary circulation. Leukocyte activation alone did not alter transit time (9.8 +/- 3.2 s) or retention (9.3 +/- 4.6 x 10(6) leukocytes). Inflammatory stimulation of endothelium with and without leukocyte activation increased transit time (18.0 +/- 3.6 and 18.9 +/- 3.8 s, respectively; P < 0. 05) and retention (24.8 +/- 8.4 and 25.3 +/- 6.8 x 10(6) leukocytes, respectively; P < 0.05) to the same extent. Differential counts showed that neutrophils (but not lymphocytes) were slowed and retained. Inflammatory stimulation of endothelium caused coronary capillary endothelial swelling and pseudopod formation. Thus increased coronary neutrophil transit time and retention are due to structural changes of coronary endothelial cells or other effects of the inflammatory response occurring within coronary capillaries, not only due to activation of leukocytes.

Inflammatory cell distribution within and along asthmatic airways.

Asthmatic airways are infiltrated with inflammatory cells that release mediators and cytokines into the microenvironment. In this study, we evaluated the distribution of CD45-positive leukocytes and eosinophils in lung tissue from five patients who died with severe asthma compared with five patients with cystic fibrosis. For morphometric analysis, the airway wall was partitioned into an "inner" area (between basement membrane and smooth muscle) and an "outer" area (between smooth muscle and alveolar attachments). Large airways (with a perimeter greater than 3.0 mm) from patients with asthma or cystic fibrosis had a greater density of CD45-positive cells (p < 0.05) and eosinophils (p < 0.001) in the inner airway region compared with the same airway region in small airways. Furthermore, in small airways, asthmatic lungs showed a greater density of CD45-positive cells (p < 0.01) and eosinophils (p < 0.01) in the outer compared with the inner airway wall region. These observations indicate that there are regional variations in inflammatory cell distribution within the airway wall in patients with asthma that are not observed in airways from patients with cystic fibrosis. We speculate that this inflammatory cell density in peripheral airways in severe asthma may relate to the peripheral airway obstruction characteristic of this condition.

Logistic regression model to predict outcome after in-hospital cardiac arrest: validation, accuracy, sensitivity and specificity.

OBJECTIVE: To develop and validate a logistic regression model to identify predictors of death before hospital discharge after in-hospital cardiac arrest. DESIGN: Retrospective derivation and validation cohorts over two 1 year periods. Data from all in-hospital cardiac arrests in 1986-87 were used to derive a logistic regression model in which the estimated probability of death before hospital discharge was a function of patient and arrest descriptors, major underlying diagnosis, initial cardiac rhythm, and time of year. This model was validated in a separate data set from 1989-90 in the same hospital. Calculated for each case was 95% confidence limits (C.L.) about the estimated probability of death. In addition, accuracy, sensitivity, and specificity of estimated probability of death and lower 95% C.L. of the estimated probability of death in the derivation and validation data sets were calculated. SETTING: 560-bed university teaching hospital. PATIENTS: The derivation data set described 270 cardiac arrests in 197 inpatients. The validation data set described 158 cardiac arrests in 120 inpatients. INTERVENTIONS: none. MEASUREMENTS AND RESULTS: Death before hospital discharge was the main outcome measure. Age, female gender, number of previous cardiac arrests, and electrical mechanical dissociation were significant variables associated with a higher probability of death. Underlying coronary artery disease or valvular heart disease, ventricular tachycardia, and cardiac arrest during the period July-September were significant variables associated with a lower probability of death. Optimal sensitivity and specificity in the validation set were achieved at a cut-off probability of 0.85. CONCLUSIONS: Performance of this logistic regression model depends on the cut-off probability chosen to discriminate between predicted survival and predicted death and on whether the estimated probability or the lower 95% C.L. of the estimated probability is used. This model may inform the development of clinical practice guidelines for patients who are at risk of or who experience in-hospital cardiac arrest.

Acute pulmonary embolism: ancillary findings at spiral CT.

PURPOSE: To determine the value of parenchymal findings at contrast material-enhanced spiral computed tomography (CT) in patients suspected to have pulmonary embolism (PE). MATERIALS AND METHODS: Eighty-eight patients suspected to have PE underwent contrast-enhanced spiral CT and ventilation-perfusion scintigraphy. Concordance between CT and scintigraphic results was used to diagnose or exclude PE. Pulmonary angiography was attempted in all patients with discordant CT and scintigraphic results or indeterminate scans. Parenchymal CT scans were assessed by two radiologists who were not aware of the diagnosis and who had access only to lung window images. RESULTS: Twenty-six patients had PE; 62 did not. Wedge-shaped pleural-based consolidation was seen in 16 patients with PE (62%) and 17 patients without PE (27%) (P < .05) (sensitivity, 62%; specificity, 73%). Linear bands were seen in 12 patients with PE (46%) and 13 patients without PE (21%) (P < .05) (sensitivity, 46%; specificity, 79%). There was no statistically significant difference in the frequency of non-wedge-shaped consolidation, areas of decreased attenuation, or atelectasis. Central and lower-lobe segmental pulmonary arteries that contained emboli were enlarged (P < .05). CONCLUSION: Parenchymal findings may suggest further investigations when results of spiral CT are inconclusive in diagnosis of PE.

Effect of mechanical deformation on structure and function of polymorphonuclear leukocytes.

The present studies were designed to test the hypothesis that mechanical deformation of polymorphonuclear leukocytes (PMN) leads to functional changes that might influence their transit in the pulmonary capillaries. Human leukocytes were passed through 5- or 3-micron-pore polycarbonate filters under controlled conditions. Morphometric analysis showed that the majority of PMN were deformed and that this deformation persisted longer after filtration through 3-micron filters than through 5-micron filters (P < 0.05) but did not result in the cytoskeletal polarization characteristic of migrating cells. Flow cytometric studies of the filtered PMN showed that there was a transient increase in the cytosolic free Ca2+ concentration after both 3- and 5-micron filtration (P < 0.01) with an increase in F-actin content after 3-micron filtration (P < 0.05). Although L-selectin expression on PMN was not changed by either 5- or 3-micron filtration, CD18 and CD11b were increased by 3-micron filtration (P < 0.05). Priming of the PMN with N-formyl-methionyl-leucyl-phenylalanine (0.5 nM) before filtration resulted in an increase of CD11b by both 5 (P < 0.05)- and 3-micron (P < 0.01) filtration. Neither 5- nor 3-micron filtration induced hydrogen peroxide production. We conclude that mechanical deformation of PMN, similar to what occurs in the pulmonary microvessels, induces both structural and functional changes in the cells, which might influence their passage through the pulmonary capillary bed.

On the mechanism of mucosal folding in normal and asthmatic airways.

Previous studies have demonstrated that the airway wall in asthma and chronic obstructive pulmonary disease is markedly thickened. It has also been observed that when the smooth muscle constricts the mucosa buckles, forming folds that penetrate into the airway lumen. This folding pattern may influence the amount of luminal obstruction associated with smooth muscle activation. A finite-element analysis of a two-layer composite model for an airway is used to investigate the factors that determine the mucosal folding pattern and how it is altered as a result of changes in the thickness or stiffness of the different layers that comprise the airway wall. Results demonstrate that the most critical physical characteristic is the thickness of the thin inner layer of the model. Thickening of this inner layer likely is represented by the enhanced subepithelial collagen deposition seen in asthma. Other findings show a high shear stress at or near the epithelial layer, which may explain the pronounced epithelial sloughing that occurs in asthma, and steep gradients in pressure that could cause significant shifts of liquid between wall compartments or between the wall and luminal or vascular spaces.

Shape and position of the complete dose-response curve for inhaled methacholine in normal subjects.

Plateaus on the inhalation concentration-response curve have been described in normal subjects and patients with mild asthma. To determine the prevalence of plateaus on inhalation concentration-response curves, and the position of the curves in normal subjects, we measured complete dose-response curves for methacholine (1 mg/ml to 256 mg/ml) in 73 nonatopic, nonsmoking, nonasthmatic normal subjects between the ages of 20 and 76 yr. Measurements included FEV1, maximal expiratory flow at 50% and 30% of vital capacity on partial and complete forced expiratory flow-volume curves (Vmax50p, Vmax50c, Vmax30p, Vmax30c) and pulmonary resistance (RL). Plateau responses, EC50 values and slopes were measured. Plateaus were present in 25, 27, 24, 34, 35, and 16 subjects for FEV1, Vmax50c, Vmax30c, Vmax50p, Vmax30p, and RL, respectively. In those who achieved a plateau, the mean maximal decrease in FEV1 (+/- SD) was 21 +/- 8%, in Vmax50c it was 46 +/- 16%, in Vmax50p it was 67 +/- 12%, in Vmax30c it was 58 +/- 21%, and in Vmax30p it was 75 +/- 15%, and the increase in RL was 213 +/- 89%. In summary, the results of this study showed that easily identifiable plateaus develop on the inhalation concentration-response curves of approximately 40% of normal subjects after only moderate decreases in maximum flow and increases in RL. Maximal response at the plateau was greater on partial flow-volume curves and at lower lung volumes (30% versus 50% of VC). Comparison of these data with data from patients at risk for airway hyperresponsiveness will allow definition of the mechanisms leading to airway hyperresponsiveness.

Pulmonary transit time and diffusion limitation during heavy exercise in athletes.

To investigate relationships between pulmonary transit times (PTT) and pulmonary diffusion limitation during exercise, 10 high aerobic capacity athletes (VO2max = 5.15 +/- 0.52 l.min-1) who had multiple inert gas elimination analysis evidence suggestive of diffusion disequilibrium were studied at rest and maximal exercise. Diffusing capacity for oxygen (DLO2) was calculated from the inert gas data. First pass radionuclide angiography was performed using 99mTechnecium labeled erythrocytes and whole lung PTT and pulmonary blood volume (PBV) were calculated. PTT decreased from 9.32 +/- 1.41 sec at rest, to 2.91 +/- 0.30 sec during exercise and was correlated with diffusion limitation suggested by the inert gases (r = -0.58, P < 0.05). PBV increased during exercise to over 25% of whole blood volume and correlated with DLO2 (r = 0.82, P < 0.01). These data suggest that diffusion limitation is related to shortened PTT in athletes and that maximal recruitment of PBV may defend against diffusion limitation.

Density dependence of pulmonary resistance: correlation with small airway pathology.

The density dependence of maximal expiratory flow is not an effective test of the site of airway narrowing in obstructive lung disease. We hypothesized that the density dependence of pulmonary resistance (DD,RL) would be more closely related to the degree of airway narrowing and peripheral airway pathology in smokers. We measured maximal expiratory flow at 50% vital capacity (V'max50) and lung resistance (RL) breathing air and 80% helium-20% oxygen, and calculated density dependence of V'max50 and RL in 40 patients who had moderate airflow obstruction and in 10 normal subjects. We compared the density dependence of RL and V'max50 with the degree of airway obstruction and bronchiolar pathology scores in 27 patients with resected lung specimens. There were no differences in DD of V'max50 or RL between normal subjects and patients, and no relationship between the degree of obstruction or the bronchiolar pathology score and the DD of these measurements. There were significant relationships between V'max50, RL and the bronchiolar pathology scores. In conclusion, lung resistance and maximal expiratory flow are related to the severity of peripheral airway pathology, but there is no relationship between the severity of obstruction or the severity of peripheral airway pathology and the density dependence of maximal expiratory flow or lung resistance.

Erythrocyte and polymorphonuclear cell transit time and concentration in human pulmonary capillaries.

Pulmonary capillary transit times were examined in patients who required lung resection by use of 99mTc-labeled macroaggregates (99Tc-MAA) and chromium-labeled erythrocytes (51Cr-RBC) to measure regional blood flow and volume in the resected lung. Cell flow (cells.ml-1.s-1) to each resected lung sample was determined by multiplying the number of polymorphonuclear leukocytes (PMN) per milliliter of circulating blood by the blood flow to that sample. Capillary blood volume was obtained by multiplying the morphometrically determined fraction of pulmonary blood in capillaries by the total 51Cr-RBC volume in each sample. Cell concentrations (cells/ml) in capillary blood were calculated morphometrically, and capillary transit times were obtained by dividing cell concentration by cell flow. The results show that PMN transit times were 60-100 times longer than the RBC transit times, with a 22% overlap between their distributions. We conclude that PMN are concentrated with respect to RBC in pulmonary capillary blood because of differences in their transit times and that these long transit times provide an opportunity for PMN-endothelial interactions.

Blood transfusion as a cause of leucocytosis in critically ill patients.

The diagnosis of infection in the intensive care unit is confounded by the presence of non-infectious causes of leucocytosis. Unless such causes are recognised, time and effort will be spent on unnecessary investigations and treatments. In a prospective study we have shown that the transfusion of blood frequently (45/50 patients) causes an acute leucocytosis in such patients. This effect was not seen in 8 patients who received plasma. Blood transfusion should be added to the list of non-infectious causes of leucocytosis in the critically ill.

Mathematical coupling explains dependence of oxygen consumption on oxygen delivery in ARDS.

Because of potential for mathematical coupling of measurement errors in shared variables used to calculate oxygen consumption (FickVO2) and oxygen delivery (DO2), we asked whether determination of the FickVO2-DO2 relationship in individual patients with ARDS was statistically valid. We studied 17 clinically resuscitated patients with severe ARDS, measuring FickVO2, CalorimetricVO2 (using analysis of respiratory gases), and DO2 at regular intervals while DO2 was increased using an infusion of dobutamine. Overall, we found that DO2 (pre 482 +/- 143, post 616 +/- 170 ml O2/min.m2, p < 0.01) and FickVO2 (pre 130 +/- 23, post 147 +/- 24 ml O2/min.m2, p < 0.02) increased significantly with dobutamine infusion, but CalorimetricVO2 measured simultaneously did not change (pre 128 +/- 22, post 128 +/- 22 ml O2/min x m2, p = NS). In addition, unpooled weighted slope for FickVO2 versus DO2 (0.06) was significantly different from zero, but unpooled weighted slope for CalorimetricVO2 versus DO2 (0.01) was not significantly different from zero. Slopes of the FickVO2-DO2 relationship were significant for only three individual patients. Using methods by Stratton and colleagues to analyze the effect of mathematical coupling in the FickVO2-DO2 relationship, we found that in all patients the slope of measurement errors was greater than observed slope and that observed slope was greater than estimated true slope. Estimated true slope of the FickVO2-DO2 relationship in all individual patients was not significant. Therefore, we suggest that determination of the FickVO2-DO2 relationship in individual patients who are resuscitated and hemodynamically stable is most often not statistically significant.(ABSTRACT TRUNCATED AT 250 WORDS)

Regional and fibre type glycogen utilization patterns in the hamster diaphragm following swimming.

The purpose of this study was to determine the regional and myofibrillar ATPase (M-ATPase) fibre type glycogen utilization patterns in response to increased ventilation induced by pre-exhaustive (Pre-Exh) and exhaustive (Exh) durations of swimming. Twenty-eight hamsters were studied: six controls (Con), 11 Pre-Exh (swam 82 min), 11 Exh (swam to exhaustion). We examined the optical density of PAS-stained fibres from the different regions of the diaphragm as a measure of glycogen remaining after the exercise or control period. The optical densities of PAS-stained fibres in most M-ATPase fibre types and diaphragmatic regions for the Pre-Exh and Exh groups was less than those in the Con hamsters except for the optical densities of all the M-ATPase fibre types in the sternal region. The optical densities of PAS-stained fibres in different regions and M-ATPase fibre types did not differ in the Exh and Pre-Exh groups. This data indicates that significant glycogen utilization occurred in all three M-ATPase fibre types in the costal, and both the thoracic and abdominal surface of the crural diaphragm in hamsters following pre-exhaustive and exhaustive durations of swimming. Glycogen utilization was greater in type 1 fibres of the thoracic surface of the crural region than in the type 1 fibres of the sternal region of the Pre-Exh group. Further, significant utilization of glycogen did not occur in any of the three M-ATPase fibre types of the sternal region of the diaphragm following prolonged durations of swimming. It would appear that glycogen is an important substrate in the hamster diaphragm during swimming.(ABSTRACT TRUNCATED AT 250 WORDS)

Contributions of capillary pathway size and neutrophil deformability to neutrophil transit through rabbit lungs.

Neutrophil margination within the pulmonary capillary is due to a delay in their transit compared with that of red blood cells (RBC). This delay has been attributed to the large fraction of capillary segments that are narrower than spherical neutrophils and differences between the time required for deformation of neutrophils and that required for deformation of RBC. This study investigated the characteristics of neutrophil deformation in vivo and the perfusion patterns of segments within capillary pathways. Studies comparing the extraction of neutrophils with that of nondeformable microspheres in one transit through the pulmonary circulation suggest that neutrophils can undergo a rapid deformation from 6.4 to 5.0-5.1 microns, whereas larger deformations require a delay. Effective diameters of the perfused capillary pathways were larger than expected for a random distribution of capillary segment diameters within these pathways. The longer transit times of neutrophils in the upper regions of the lung were associated with a greater fraction of pathways containing narrow segments. These studies suggest that neutrophil deformability and capillary pathway diameters are important in determining the size of the marginated pool of neutrophils within the pulmonary capillaries.

Lung structure and function in cigarette smokers.

BACKGROUND: Cigarette smoking produces an inflammatory response in the airways of everyone but only 15-20% of smokers develop airways obstruction. The present study concerns the relative importance of peripheral airways inflammation and the emphysematous destruction of the parenchymal support of the airways in the pathogenesis of this obstruction. METHODS: A total of 407 patients with a diagnosis of lung tumour performed pulmonary function tests a day or two before a lung or lobar resection. The specimens were fixed in inflation and analysed at the gross and microscopic level to determine the extent and severity of the emphysematous process, the number of alveoli supporting the outer walls of the airways, and the average distance between alveolar walls. The severity of the inflammatory process in the respiratory and nonrespiratory bronchioles was also assessed using a previously established grading system. RESULTS: The lung function test showed that a decline in FEV1 was associated with an increase in residual volume and a decrease in the diffusing capacity for carbon monoxide and a reduction in the lung maximum elastic recoil pressure. The prevalence of grossly visible emphysema increased as FEV1 declined, but the extent and severity of these lesions and the number of alveoli supporting the outer walls of the peripheral airways was similar at all levels of FEV1. The system used to grade inflammatory response in the peripheral airways failed to identify a specific defect responsible for the physiological abnormalities. CONCLUSION: The reduction in FEV1 associated with chronic cigarette smoking can be partially explained by loss of lung elastic recoil pressure which reduces the force driving air out of the lung. This loss of elastic recoil pressure is attributed to microscopic enlargement of the air spaces rather than to grossly visible emphysema. The exact nature of the lesions responsible for the peripheral airways obstruction remains to be identified.

Prediction of heart rate and oxygen uptake during incremental and maximal exercise in healthy adults.

Measurement of heart rate and oxygen uptake during incremental exercise and at maximal exercise is useful in evaluating mechanisms responsible for exercise limitation in patients with cardiopulmonary disease. Presently used prediction equations are based on relatively small groups of subjects in whom there was an uneven distribution of subjects with regard to age and sex or based on equations that were from extrapolated data. Our prediction equations are based on data from 231 men and women equally divided within decades between 20 and 80 years. Patients exercised to a symptom-limited maximum on a cycle ergometer while measurements of heart rate and oxygen uptake were recorded. The relationship between heart rate and oxygen uptake throughout exercise (HR:VO2) was determined using a statistical technique that included each data point from each subject. The HR:VO2 throughout incremental exercise was best described by separate equations for women younger than 50 years and older than 50 years and for men younger than 70 years and older than 70 years. Prediction equations for maximal heart rate (HRmax) and maximal oxygen uptake (VO2max) were developed by linear regression and were selected from all possible combinations of parameters. The HRmax was most accurately predicted by age alone for both sexes. Unlike the HR:VO2 relationship, the slope of the line relating heart rate to age was not different for the older women compared with the younger women so that a single equation was derived to predict HRmax. A single equation for the men was also sufficient since the slope of heart rate to age was the same for all ages. To most accurately predict VO2max, a separate equation was required for both the women and men that included age, height, and weight.

Appropriate interpretation of indirect calorimetry for determining energy expenditure of patients in intensive care units.

Energy expenditure varies with patient agitation. We asked whether energy expenditure determined from 5 minutes of measurement with less than 5% variation in minute-to-minute measurements (short mean) was similar to energy expenditure determined from a longer measurement period (long mean; average duration: 31 minutes). The difference between the short mean and the long mean was less than 5% for 42 of 47 patients in intensive care units; the difference was more than 10% for 2 patients. We also generated a statistical model simulating energy expenditure measurement variations of 5% to 20%, and calculated the necessary measurement durations required to achieve a 3% error in measurement. The statistical model showed that for energy expenditure variations of 5%, 10%, 15%, and 20%, the necessary durations of measurement to achieve a 3% error were 3, 9, 16, and 25 minutes, respectively. We conclude that energy expenditure may be determined using the mean of a 5-minute period of measurement if variation in that measurement is less than 5%. Larger variation requires longer periods of measurement.