A comparison of double-strength beclomethasone dipropionate (84 microg) MDI with beclomethasone dipropionate (42 microg) MDI in the treatment of asthma.

STUDY OBJECTIVE: To compare the efficacy and safety of a double-strength formulation of beclomethasone dipropionate (BDP 84) metered-dose inhaler (MDI) with that of beclomethasone dipropionate (BDP 42) MDI in the treatment of chronic asthma. DESIGN: A 28-day, randomized, double-blind, double-dummy, placebo-controlled, multicenter study. SETTING: Outpatient. PATIENTS: A total of 423 patients aged 12 to 65 years (mean range, 34 to 36 years) with moderate asthma (FEV1, 50 to 80% of predicted) who required long-term inhaled corticosteroids were enrolled. INTERVENTIONS: Patients were randomized to receive BDP 84, two oral inhalations bid (336 microg/d), BDP 42, four oral inhalations bid (336 microg/d), or placebo. A fourth treatment arm administering BDP 84, eight oral inhalations bid (HD BDP 84; 1,344 microg/d) was also included to determine whether a dose-response relationship could be demonstrated. MEASUREMENTS: Spirometry, clinical observations. RESULTS: The three active treatments were significantly more effective (p < or = 0.01) than placebo at all time points in improving FEV1, the primary efficacy parameter; BDP 42 and BDP 84 were comparable to each other at every time point. Secondary pulmonary function tests (FVC, forced expiratory flow at 25 to 75% of FVC, and peak expiratory flow rate) showed similar results. All three active treatments were well tolerated. A dose response between 336 microg/d and 1,344 microg/d was demonstrated. CONCLUSION: In this well-controlled 28-day study, BDP 42 and BDP 84 were shown to be comparable in efficacy and safety on a microgram-for-microgram basis.

MR imaging parameters in the study of lung water. A preliminary study.

The use of magnetic resonance (MR) to evaluate lung water is made difficult by several factors: paucity of proton signal from normal lung, respiratory and cardiac motion, and long relaxation times of lung fluids. To optimize scanning parameters for this use, and to test MR's ability to detect and quantitate regional and temporal variations in signal intensity in hydrostatic pulmonary edema, in vivo experiments were performed with a 0.5 tesla whole body MR imaging device. Human volunteers were studied in prone and supine positions using spin echo technique (TE = 30 msec) with varying TR, and with respiratory and cardiac gating. In addition, sedated, intubated, chronically prepared sheep were paralyzed to control extraneous motion and allow the use of a high frequency ventilator, thereby eliminating respiratory gating. Elevated pulmonary hydrostatic pressure was induced in these sheep by inflation of a left atrial balloon. Relative signal intensity from the lung rises with lengthening TR. Cardiac gating diminishes motion artifact, but masks extravascular water by enhancing signal from slowly flowing blood by an average of 44%. A gravity-dependent gradient of signal intensity predictably shifts in supine and prone positions. The use of longer TRs, respiratory gating, and cardiac gating all proportionally prolong data acquisition times to an objectionable degree. Without the use of gating, a gradual rise in relative signal intensity is seen in the sheep lung following the establishment of elevated hydrostatic pressure in the pulmonary circuit, and is most pronounced in the dependent portion of the lung.(ABSTRACT TRUNCATED AT 250 WORDS)

Epithelial and endothelial flux after bypass in dogs: effect of positive end-expiratory pressure.

Cardiopulmonary bypass (CPB) causes lung injury that occasionally progresses to the adult respiratory distress syndrome (ARDS). We measured the effect of 10 cmH2O of positive end-expiratory pressure (PEEP) on small solute and protein flux in dogs 1 wk before and 2 h after the completion of CPB. As an index of alveolar epithelial permeability, the clearance from lung to blood of inhaled technetium-99m-labeled diethylenetriaminepentaacetic acid (99mTc-DTPA) was measured. To assess microvascular endothelial integrity, the rate of accumulation in the lung interstitium of intravascular 113mIn-transferrin was measured. The clearance half time (t 1/2) for 99mTc-DTPA in the study dogs declined from 18.8 +/- 1.9 min (mean +/- SE) at base line to 9.4 +/- 2.0 min during PEEP (P less than 0.05). Two hours after CPB, the t 1/2 was 8.1 +/- 1.6 min at base line and unchanged during PEEP. The 113mIn-transferrin rate of accumulation was unchanged by PEEP before CPB. After CPB, the index was 3.25 +/- 0.95 slope/min X 10(-3) (P less than 0.05). Of the five dogs with a significant slope, four showed a decrease in microvascular flux during PEEP, although for the group the mean change in slope was not significant (P = 0.10). We conclude that the application of PEEP does not increase 99mTc-DTPA clearance in lungs already injured by CPB, and may actually decrease the apparent microvascular protein flux in some cases.

Effect of raised thoracic pressure and volume on 99mTc-DTPA clearance in humans.

Although positive airway pressure is often used to treat acute pulmonary edema, the effects on epithelial solute flux are not well known. We measured independently the effect of 1) positive pressure and 2) voluntary hyperinflation on the clearance of inhaled technetium-99m-labeled diethylenetriaminepentaacetic acid (99mTc-DTPA) in six nonsmokers and six smokers. Lung volumes were monitored by inductance plethysmography. Each subject was studied in four situations: 1) low end-expiratory volume (LO-), 2) low volume plus 9 cmH2O continuous positive airway pressure (LO+), 3) high end-expiratory volume (HI-), and 4) high volume plus continuous positive airway pressure (HI+). The clearance half time of 99mTc-DTPA for the nonsmokers decreased from 64.8 +/- 7.0 min (mean +/- SE) at LO- to 23.2 +/- 5.3 min at HI- (P less than 0.05). Positive pressure had no synergistic effect. The mean clearance half time for the smokers was faster than nonsmokers at base line but unaffected by similar changes in thoracic volume and pressure. We conclude that, in nonsmokers, positive airway pressure increases 99mTc-DTPA clearance primarily through an increase in lung volume and that smokers are immune to these effects.

Somatostatin inhibits the ventilatory response to hypoxia in humans.

The effects of a 90-min infusion of somatostatin (1 mg/h) on ventilation and the ventilatory responses to hypoxia and hypercapnia were studied in six normal adult males. Minute ventilation (VE) was measured with inductance plethysmography, arterial 02 saturation (SaO2) was measured with ear oximetry, and arterial PCO2 (Paco2) was estimated with a transcutaneous CO2 electrode. The steady-state ventilatory response to hypoxia (delta VE/delta SaO2) was measured in subjects breathing 10.5% O2 in an open circuit while isocapnia was maintained by the addition of CO2. The hypercapnic response (delta VE/delta PaCO2) was measured in subjects breathing first 5% and then 7.5% CO2 (in 52-55% O2). Somatostatin greatly attenuated the hypoxic response (control mean -790 ml x min-1.%SaO2 -1, somatostatin mean -120 ml x min-1.%SaO2 -1; P less than 0.01), caused a small fall in resting ventilation (mean % fall - 11%), but did not affect the hypercapnic response. In three of the subjects progressive ventilatory responses (using rebreathing techniques, dry gas meter, and end-tidal Pco2 analysis) and overall metabolism were measured. Somatostatin caused similar changes (mean fall in hypoxic response -73%; no change in hypercapnic response) and did not alter overall O2 consumption nor CO2 production. These results show an hitherto-unsuspected inhibitory potential of this neuropeptide on the control of breathing; the sparing of the hypercapnic response is suggestive of an action on the carotid body but does not exclude a central effect.

Effects of inspiratory resistance loading on lung fluid balance in awake sheep.

Because pulmonary edema has been associated clinically with airway obstruction, we sought to determine whether decreased intrathoracic pressure, created by selective inspiratory obstruction, would affect lung fluid balance. We reasoned that if decreased intrathoracic pressure caused an increase in the transvascular hydrostatic pressure gradient, then lung lymph flow would increase and the lymph-to-plasma protein concentration ratio (L/P) would decrease. We performed experiments in six awake sheep with chronic lung lymph cannulas. After a base-line period, we added an inspiratory load (20 cmH2O) and allowed normal expiration at atmospheric pressure. Inspiratory loading was associated with a 12-cmH2O decrease in mean central airway pressure. Mean left atrial pressure fell 11 cmH2O, and mean pulmonary arterial pressure was unchanged; calculated microvascular pressure decreased 8 cmH2O. The changes that occurred in lung lymph were characteristic of those seen after other causes of increased transvascular hydrostatic gradient, such as increased intravascular pressure. Lung lymph flow increased twice base line, and L/P decreased. We conclude that inspiratory loading is associated with an increase in the pulmonary transvascular hydrostatic gradient, possibly by causing a greater fall in interstitial perimicrovascular pressure than in microvascular pressure.

Effects of adenosine on ventilatory responses to hypoxia and hypercapnia in humans.

Adenosine infusion (100 micrograms X kg-1 X min-1) in humans stimulates ventilation but also causes abdominal and chest discomfort. To exclude the effects of symptoms and to differentiate between a central and peripheral site of action, we measured the effect of adenosine infused at a level (70-80 micrograms X kg-1 X min-1) below the threshold for symptoms. Resting ventilation (VE) and progressive ventilatory responses to isocapnic hypoxia and hyperoxic hypercapnia were measured in six normal men. Compared with a control saline infusion given single blind on the same day, adenosine stimulated VE [mean increase: 1.3 +/- 0.8 (SD) l/min; P less than 0.02], lowered resting end-tidal PCO2 (PETCO2) (mean fall: -3.9 +/- 0.9 Torr), and increased heart rate (mean increase: 16.1 +/- 8.1 beats/min) without changing systemic blood pressure. Adenosine increased the hypoxic ventilatory response (control: -0.68 +/- 0.4 l X min-1 X %SaO2-1, where %SaO2 is percent of arterial O2 saturation; adenosine: -2.40 +/- 1.2 l X min-1 X %SaO2-1; P less than 0.01) measured at a mean PETCO2 of 38.3 +/- 0.6 Torr but did not alter the hypercapnic response. This differential effect suggests that adenosine may stimulate ventilation by a peripheral rather than a central action and therefore may be involved in the mechanism of peripheral chemoreception.

Microvascular and macrovascular endothelial cells produce different constrictor substances.

The media from cultured microvascular and macrovascular endothelial cells (conditioned media, CM) were collected and tested for constrictor activity in sheep coronary artery rings and tracheal smooth muscle strips in vitro (isometric force), expressed as percentage of contraction produced by 80 mM KCl. Both microvascular (micro) and macrovascular (macro) CM caused a sustained slow-onset contraction (P less than 0.05) of the coronary artery rings by 71 +/- 10% (micro; n = 7) and 67 +/- 8% (macro; n = 6) and tracheal smooth muscle strips by 33 +/- 14% (micro; n = 6) and 34 +/- 6% (macro; n = 11); the calcium antagonist gallopamil (10(-7) M) attenuated these effects by 25-55%. Unconditioned medium and medium conditioned by cultured tracheal smooth muscle cells had no constrictor activity on coronary artery rings or tracheal smooth muscle strips. Synthetic endothelin (ET-1) also produced contraction of coronary artery rings and tracheal smooth muscle strips. The mean levels of ET-1 measured by radioimmunoassay were 1,200 pg/ml in the macro CM and 33 pg/ml in the micro CM. Depleting macro CM of ET-1 by affinity columns constructed with protein A agarose and anti-ET-1 antibody removed the contractile activity for coronary artery rings and tracheal smooth muscle strips. Thus ET-1 did not appear to be the contractile substance in the micro CM. Preliminary characterization of the contractile substance in micro CM revealed that it was heat stable, had a molecular weight of less than 10,000, was inactivated by trypsin, and retained its activity after two cycles of freeze-thawing.(ABSTRACT TRUNCATED AT 250 WORDS)

Dose-ranging study of a new steroid for asthma: mometasone furoate dry powder inhaler.

A new formulation of mometasone furoate (MF) for administration by dry powder inhaler (DPI) was evaluated for the treatment of asthma. A 12-week, double-blind, placebo-controlled dose-ranging study compared the efficacy and safety of three doses of MF DPI (100, 200 and 400 mcg b.i.d) with beclomethasone dipropionate (BDP) 168 mcg b.i.d. administered by metered dose inhaler in 365 adult or adolescent patients being treated with inhaled glucocorticoids. The mean change from baseline to endpoint (last treatment visit) for forced expiratory volume in 1 sec (FEV1) was the primary efficacy variable. Secondary efficacy variables included other objective measures of pulmonary function [forced vital capacity (FVC), forced expiratory flow 25-75% (FEV25-75%.) and peak expiratory flow rate (PEFR)] as well as subjective measures of therapeutic response (patients' daily evaluation of asthma symptoms and physicians' evaluation). At endpoint, all four active treatments were significantly more effective than placebo (P < 0.01) in improving FEV1 (MF DPI 5 to 7%, BDP 3%, placebo -6.6%) and all other measures of pulmonary function (FVC: MF DPI 4 to 5%, BDP 2%, placebo -4.7%; FEF25-75%: MF DPI 6 to 18%, BDP 7.5%, placebo -9.5%; PEFR (AM): MF DPI 5 to 10%, BDP 5.7%, placebo -7%). A consistent trend was observed for better improvement in patients treated with MF DPI 200 mcg b.i.d. than with MF DPI 100 mcg b.i.d., with no apparent additional benefit of MF DPI 400 mcg b.i.d. Results for the MF DPI 100 mcg b.i.d. and BDP 168 mcg b.i.d. treatment groups were similar. Patients' and physicians' subjective evaluations of symptoms found similar improvement in the MF DPI 200 and 400 mcg b.i.d. treatment groups, which were slightly better than that in the MF DPI 100 mcg b.i.d. group. Symptoms tended to worsen in the placebo group. MF DPI was well tolerated at all dose levels and the most frequently reported treatment-related adverse effects were headache, pharyngitis and oral candidiasis. No evidence of HPA-axis suppression was detected in any treatment group. In summary, all doses of MF DPI were well tolerated and significantly improved lung function and MF DPI 400 mcg (200 mcg b.i.d.) was the optimal dose in this study of patients with moderate persistent asthma.

Massive hydrothorax complicating occult cirrhosis.

This case emphasizes that absence of ascites does not rule out cirrhosis as the cause of a massive pleural effusion. Consideration of hemochromatosis as a cause of cirrhosis is worthwhile both for the patient and his family, as the course of the cirrhosis may be benefited by periodic phlebotomy to reduce the iron overload, and disease may be prevented in asymptomatic relatives.

Enhancement of tumor necrosis factor-induced endothelial cell injury by cycloheximide.

Tumor necrosis factor (TNF), a potent polypeptide mediator released by activated monocytes and macrophages, has a number of proinflammatory effects on endothelial cells. TNF is cytotoxic to tumor cells in vivo and in vitro, but TNF-induced toxicity to endothelial cells is less well established. We now report that cycloheximide (CHX), an inhibitor of protein synthesis, renders endothelial cells highly susceptible to TNF-induced lysis. TNF alone did not change the overall rate of protein synthesis by endothelial cells, whereas the addition of CHX completely abolished protein synthesis. Endothelial cells incubated in TNF alone in high concentrations (up to 1,000 U/ml) showed minimal rounding up and release of 51Cr. Likewise, CHX alone (5 micrograms/ml) had no significant effect on endothelial cell morphology and release of 51Cr. However, incubation of endothelial cells in both CHX and TNF caused injury in a dose-dependent manner. Morphological evidence of cell retraction, rounding, and detachment began within 2 h, but specific 51Cr release did not begin to rise until after 4 h. These changes were not observed when endothelial cells were incubated with TNF/CHX at 4 degrees C. The combination of TNF/CHX was lethal to all endothelial cells tested (bovine pulmonary artery, human umbilical vein, and human aorta), with human aortic cells showing the most pronounced changes. We conclude that healthy endothelial cells are resistant to TNF-induced lysis, but inhibition of their ability to make protein renders them highly susceptible.

Unprecedented sedative requirements during delirium tremens.

A 34-yr-old male in delirium tremens required a total of 2640 mg iv diazepam for adequate sedation. Doses of benzodiazepines clearly must be individualized, and doses higher than those currently recommended may be required.

Failure of aerosolised 99mTc DTPA clearance to predict outcome in patients with adult respiratory distress syndrome.

The rate of clearance of technetium-99m labelled diethylene triamine pentacetic acid (99mTc DTPA) was measured in 32 patients with adult respiratory distress syndrome to determine if a more rapid clearance rate, possibly reflecting a more severe abnormality of pulmonary function, was associated with a reduced likelihood of recovery from pulmonary failure. Although the mean rate of clearance from lung to blood (T1/2LB) of 99mTc DTPA was more rapid in the patients (T1/2LB = 29 (SEM 3.2) min than in 42 normal subjects (T1/2LB = 59 (1.8)min), there was no difference between the clearance rate in the 18 patients who recovered from respiratory failure (T1/2LB = 31 (5) min) and the 14 who died (T1/2LB = 27 (4) min). Additionally, not all patients studied had abnormally rapid clearance rates. In 12 of the 32 patients the T1/2 fell within the range for normal individuals; this was found more commonly in patients who were predisposed to develop adult respiratory distress syndrome by pancreatitis or massive blood transfusion. These data suggest that a single measurement of 99mTc DTPA clearance in patients with established respiratory failure and adult respiratory distress syndrome is of no value in assessing the likelihood of recovery from this condition.

Endothelin-1 from pulmonary artery and microvessels acts on vascular and airway smooth muscle.

The conditioned medium (CM) from microvascular and macrovascular endothelial cell (EC) cultures was tested for constrictor activity. Sheep coronary artery rings, under 1 g tension, and sheep tracheal smooth muscle strips, under 2 g tension, were hung in organ baths containing Krebs-Henseleit solution (39 degrees C) and were equilibrated with 95% O2 and 5% CO2. Isometric force was measured in response to 80 mM KCl and constrictor responses to 100% CM were expressed as a percentage of maximum KCl response. Serum-free CM from confluent microvascular endothelial cells caused a sustained, slow-onset contraction of the coronary rings similar to that obtained with CM from macrovascular ECs. Indomethacin (5 microM) added to either the microvascular or macrovascular CM enhanced the constrictor responses by 1.6- and 1.8-fold, respectively, and the constrictor effects of both media were reduced by the calcium antagonist gallopamil (10 nM). CM from macrovascular EC caused a sustained contraction of tracheal strips similar to microvascular CM. In both cases, constriction was preceded by a brief relaxation as noted in vascular smooth muscle. Unconditioned medium had no constrictor activity on either vascular or airway smooth muscle. Microvascular-derived constrictor activity was heat stable. There was a slight loss of activity in the heat-treated CM from the macrovascular cells compared with control CM. Constrictor effects on tracheal smooth muscle were partially reversed by 1 microM gallopamil.

Effects of somatostatin, naloxone and prochlorperazine on the control of ventilation in man.

In seven normal subjects the ventilatory responses to progressive isocapnic hypoxia and hyperoxic hypercapnia were measured during rebreathing. During an infusion of somatostatin (10 nmol/min) the mean hypoxic response decreased by 66% (control: -1.6 SD 1.2 litres min-1 %-1 SaO2; somatostatin: -0.6 SD 0.7) but the mean hypercapnic response was unchanged (control: 2.0 SD 0.8 litre min-1 mmHg-1; somatostatin: 2.3 SD 1.2). There was no change in resting VO2 or VCO2 during somatostatin infusion. The opiate antagonist, naloxone (0.1 mg/kg, intravenously), caused little change in either response (mean hypoxic response: -1.7 SD 1.0 litre min-1 %-1 SaO2; mean hypercapnic response: 2.4 SD 0.9 litre min-1 mmHg-1). In five of the subjects the dopamine antagonist, prochlorperazine (10 mg, intravenously), increased the mean hypoxic response by 134% (control: -1.9 SD 1.4 litres min-1 %-1 SaO2; after prochlorperazine: -3.8 SD 1.6; P less than 0.05). The mean hypercapnic response after this drug was also increased (control: 2.1 SD 1.0 litre min-1 mmHg-1; after prochlorperazine: 3.1 SD 1.0) but this change did not achieve significance. The selective effect of somatostatin on the hypoxic response, suggestive of an action on the carotid body, was not inhibited by prior injection of either naloxone or prochlorperazine, and its mode of action remains to be found.

Positive end-expiratory pressure increases pulmonary clearance of inhaled 99mTc-DTPA in nonsmokers but not in healthy smokers.

Positive end-expiratory pressure (PEEP) is widely used in the treatment of severe pulmonary oedema, although its effects on the clearance of water and small solutes from alveolus to blood are not well characterized. We studied the effect of the application of 10 cmH2O of PEEP on the flux of inhaled 99mTc-diethylene-triamine-penta-acetic acid (DTPA) from lung to blood in six healthy smoking and six nonsmoking subjects. The rate of flux was corrected for possible changes in pulmonary blood volume during PEEP by use of an intravenous injection of 99mTc-DTPA. The baseline clearance rate (K, % X min-1) for nonsmokers was 1.48 +/- 0.12 (mean +/- SE) and increased to 2.40 +/- 0.29 during PEEP (p less than 0.05). In contrast, the mean clearance rate for smokers was 3.26 +/- 0.82 at baseline and 3.03 +/- 0.82 during PEEP (p = NS). The application of positive end-expiratory pressure appears to increase alveolar solute flux in nonsmokers but not in smokers, suggesting that the pathway for solute clearance in smokers is governed by different rate-limiting steps to those of nonsmokers.

Comparison of lung vascular and epithelial permeability indices in the adult respiratory distress syndrome.

Measurements of pulmonary clearance of inhaled 99mTc-DTPA and transvascular 113mIntransferrin flux were made in 12 patients with established ARDS and 14 volunteer control subjects (7 smokers and 7 nonsmokers). Smokers had significantly increased 99mTc-DTPA clearance (clearance rate constant, 3.6 +/- 0.8; mean +/- SEM) compared with nonsmokers (1.2 +/- 0.1). All patients with ARDS had increased clearance of 99mTc-DTPA (5.2 +/- 0.9), but the finding was nonspecific in that increased clearance overlapped with the findings in normal smokers. Protein flux in smokers (protein flux units, 0.0 +/- 0.2) was similar to that in nonsmokers (0.3 +/- 0.2). In 9 of the 12 patients with ARDS, protein flux was increased, and as a group (3.2 +/- 1.0) they differed significantly (p less than 0.01) from the combined smoking and nonsmoking control subjects (0.2 +/- 0.1, n = 14). The parameters of DTPA clearance and transvascular protein flux correlated well in the patients with ARDS (Spearman's rank correlation = 0.71, p less than 0.01). Although 99mTc-DTPA clearance is a sensitive technique in ARDS, a single study in this context does not allow a diagnostic conclusion because of its non-specificity. Abnormal protein flux appears to be more specific for ARDS but was not a universal finding in the patients studied.

A comparison of 99mTc-DTPA and 113mIn-DTPA aerosol clearances in humans. Effects of smoking, hyperinflation, and in vitro oxidation.

As an index of permeability of the alveolar epithelium, the clearance of an inhaled aerosol of 99mTc-DTPA is increased in several disease states. However, the usefulness of the test to assess the severity of disease is limited because healthy smokers also have abnormally rapid rates of clearance. Because the stability of the 99mTc-DTPA bond might be a contributory factor, we tested the affinity of 99mTc for DTPA in vitro, and in groups of healthy smokers (n = 13) and nonsmokers (n = 7) we measured the clearances of 99mTc-DTPA and 113mIn-DTPA, which have a similar molecular shape and charge. In vitro, sodium hypochlorite or hydrogen peroxide released as much as 98% of free 99mTc from the 99mTc-DTPA complex. When incubated with human neutrophils stimulated with phorbol myristate acetate, between 4 and 7% of free 99mTc-DTPA was released after 30 min, and 12% was released after 60 min. In vivo, the clearances of both 99mTc-DTPA and 113mIn-DTPA in the smokers (n = 13) were faster than in the nonsmokers (n = 7) (p less than 0.05). Within the smokers, the mean 99mTc-DTPA clearance (T1/2 25 +/- 4 min) was faster than the mean 113mIn-DTPA clearance (34 +/- 6 min), (p less than 0.05). For nonsmokers, the difference was smaller (T1/2 99mTc-DTPA, 56 +/- 6; T1/2 113mIn-DTPA, 62 +/- 6) and not significant. During hyperinflation, smokers (n = 8) and nonsmokers (n = 8) both demonstrated an increase in 113mIn-DTPA clearance.(ABSTRACT TRUNCATED AT 250 WORDS)

Increased pulmonary transvascular protein flux after canine cardiopulmonary bypass. Association with lung neutrophil sequestration and tissue peroxidation.

We examined the hypothesis that increased pulmonary transvascular protein flux after cardiopulmonary bypass (CPB) is mediated in part by neutrophil-derived, oxygen-free radicals. Measurements of transvascular lung 113mIn-transferrin flux, transpulmonary neutrophil counts, and plasma concentrations of thiobarbituric acid (TBA) reactive substances were made in 8 dogs after CPB and in 6 dogs who underwent thoracotomy alone. The TBA reactivity is indicative of lipid peroxidation and was used as an index of oxygen-free radical release. All 14 dogs had a baseline measurement of lung protein flux 1 wk prior to thoracotomy. In the bypass dogs, lung protein flux was -0.2 +/- 0.3 protein flux units (mean +/- SEM) at baseline and increased significantly after bypass to 3.3 +/- 1.0 (p less than 0.01). The control thoracotomy group had baseline values similar to the baseline studies in the CPB dogs (0.2 +/- 0.3 units), but no significant difference was noted after thoracotomy. The CPB dogs showed initial significant parallel falls in left atrial (LA) and central venous (CV) neutrophil counts during bypass (baseline, 5.3 +/- 0.7 X 10(9) cells/L in both sample sites, falling to 3.0 +/- 0.5 and 2.9 +/- 0.5, respectively, p less than 0.001), but a significant CV-LA transpulmonary gradient existed only when pulmonary perfusion recommenced after a period of total asystole. Concentration of TBA reactive substances increased significantly during the course of bypass (baseline LA, 6.4 +/- 0.5 nmol/L, baseline CV, 6.4 +/- 0.5, increasing to 9.8 +/- 1.0 and 9.4 +/- 1.6 at the end of bypass, respectively, p less than 0.01), but likewise, there was a significant transpulmonary gradient only after reversal of asystole.(ABSTRACT TRUNCATED AT 250 WORDS)

The responsiveness of disease-specific and generic health measures to changes in the severity of asthma among adults.

The objective of the study was to compare the validity of asthma-specific and generic health outcome measures in relation to changes in the severity of asthma and to treatment. Adult patients (n = 142) participating in a randomized placebo-controlled trial at six clinics were assessed at baseline, prior to the withdrawal (placebo) or continuation of treatment with Vanceril and again after 8 weeks. The criterion measures of change in severity included pulmonary function expressed as the percent predicted FEV1, five physician-assessed asthma severity measures (cough, chest tightness, wheezing, shortness of breath and overall condition) and two patient-assessed severity measures (night-time symptoms and overall symptoms). The 8 week change scores were estimated for all generic and specific measures and the results were compared across groups of patients who did and did not change in terms of clinical criteria of disease severity and across treatment groups. The responsiveness of each generic and specific measure was estimated independently using the relative validity (RV) methodology, which compares F-ratios for the mean change scores across measures in analyses of the same comparison groups. RV coefficients estimate how much worse each measure discriminated between comparison groups, relative to the best measure (RV = 1.0). Four standardized asthma-specific measures and a total scale score (based on the Marks questionnaire), an individualized asthma-specific scale measuring limitations in activities most important to each patient (based on the Juniper method) and two newly-developed scales measuring physical and psychosocial symptoms were used as outcome measures, generic health outcome measures included eight functional health and well-being scales as well as the physical and mental health summary scales from the SF-36 health survey. A standardized asthma-specific scale was most valid in discriminating between groups of patients who did and did not change according to all of the clinical criterion variables studied and in discriminating between treated and untreated groups. Different scales performed best, depending on the clinical criterion. The asthma-specific Marks breathlessness scale was significant in all nine comparisons (RV = 0.62-1.0) and was most valid in discriminating between groups in six of nine tests. The overall scale also performed well in all comparisons (RV = 0.58-1.0). The newly-developed physical symptoms scale was significant in discriminating between groups in eight out of nine tests (RV = 0.52-1.0) and was most valid in three of the nine, including the treatment comparison. The psychosocial impact scale discriminated significantly in eight of the nine comparisons (RV = 0.16-0.38), but was less valid than other specific measures. The asthma-specific individualized activities scale discriminated significantly in seven of the nine tests, but performed less well than the other specific measures (RV = 0.21-0.35) and was not significant in the treatment comparison. One or more SF-36 scales discriminated significantly between groups in all nine comparisons. Two of those scales (physical functioning and role-physical) were consistently more valid than the others (RV = 0.17 and 0.58, respectively) and were the only two generic scales that discriminated between groups of patients defined in terms of changes in FEV1 (RV = 0.26-0.58). The SF-36 physical summary scale discriminated significantly between groups in all nine comparisons (RV = 0.19-0.61) and was the most valid generic measure in the treatment comparison (RV = 0.55). The SF-36 mental summary scale was significant only for the two patient-assessed changes in disease severity (RV = 0.31 and 0.32) and for physician-assessed overall severity (RV = 0.12). A comprehensive battery of generic and specific measures is likely to be most useful in understanding the impact of changes in disease severity on the functional health and well-being of adults with asthma, a