Adhesion molecules, endothelin-1 and lung function in seven population-based cohorts.

CONTEXT: Endothelial function is abnormal in chronic obstructive pulmonary disease (COPD); whether endothelial dysfunction causes COPD is unknown. OBJECTIVE: Test associations of endothelial biomarkers with FEV1 using instrumental variables. METHODS: Among 26 907 participants with spirometry, ICAM-1, P-selectin, E-selectin and endothelin-1 were measured in subsets. RESULTS: ICAM-1 and P-selectin were inversely associated with FEV1 among European-Americans (-29 mL and -34 mL per standard deviation of log-transformed biomarker, p < 0.001), as was endothelin-1 among African-Americans (-22 mL, p = 0.008). Genetically-estimated ICAM-1 and P-selectin were not significantly associated with FEV1. The instrumental variable for endothelin-1 was non-informative. CONCLUSION: Although ICAM-1, P-selectin and endothelin-1 were inversely associated with FEV1, associations for ICAM-1 and P-selectin do not appear causal.

Clinical presentation, radiographic findings, and diagnostic methods of pulmonary blastomycosis: a review of 100 consecutive cases.

BACKGROUND: We sought to determine the relationship among radiographic findings, clinical presentation, and diagnostic testing of pulmonary blastomycosis. METHODS: We reviewed the medical records of 100 consecutive patients with pulmonary blastomycosis. RESULTS: Air-space infiltrates were the usual radiographic finding of pulmonary blastomycosis. Mass-like infiltrates were associated more with chronic than acute presentations. Air-space and mass-like infiltrate were predominately involved in the upper lobes. Sputum analysis made the initial diagnosis of blastomycosis most often. Acute and chronic presentations were not different between immunosuppressed patients and the remainder of the patients. In addition, infiltrates on chest radiographs in immunosuppressed patients were similar to the other patients. CONCLUSIONS: In an endemic area, pulmonary blastomycosis should be considered for any pulmonary infiltrate, especially in the upper lobes. Sputum analysis in most cases aids in the diagnosis, but bronchoscopy and/or tissue biopsy should be considered if the suspicion of blastomycosis is high and sputum analysis is inconclusive, negative, or not possible. Follow-up with chest radiographs after antifungal therapy is reasonable until complete resolution or fibrotic changes in patients with pulmonary blastomycosis.

Respiratory muscle performance, pulmonary mechanics, and gas exchange between the BiPAP S/T-D system and the Servo Ventilator 900C with bilevel positive airway pressure ventilation following gradual pressure support weaning.

STUDY OBJECTIVE: Our objective was to compare respiratory muscle performance, pulmonary mechanics, and gas exchange between the BiPAP S/T-D ventilation system (Respironics Inc; Murrysville, PA) and the Servo Ventilator 900C (Siemens-Elma AB; Sweden) with similar inspiratory and expiratory airway pressure in patients who are recovering from acute respiratory failure. STUDY DESIGN: A prospective, randomized, clinical trial. SETTING: Medical ICU. PATIENTS AND METHODS: We studied 27 medical patients on mechanical ventilators following gradual pressure support weaning. Each patient breathed while in the following equivalent modes: (a) an inspiratory pressure preset (pressure support mode) of 5 cm H2O with an external positive end-expiratory pressure (PEEP) of 5 cm H2O on the Servo Ventilator 900C and (b) an inspiratory pressure preset of 10 cm H2O with an expiratory pressure preset of 5 cm H2O on the BiPAP S/T-D. Using the CP-100 pulmonary monitor, we compared the total work of breathing (WOB), the pressure-time index (PTP), and other pulmonary mechanics and gas exchange parameters between the two modes. RESULTS: The WOB injoules per liter (mean +/- SE) (0.76+/-0.08 vs 0.73+/-0.08, p = 0.70), the WOB in joules per minute (8.62+/-1.06 vs 8.11+/-0.96, p = 0.60), and the PTP in cm H2O/s/min (187+/-18 vs 167+/-18, p = 0.21) between the BiPAP S/T-D and the Servo Ventilator 900C were not statistically different. There were statistically significant differences between the two ventilators in auto-PEEP (1.34+/-0.37 vs 0.88+/-0.30 cm H2O, p = 0.03), duty cycle (0.44+/-0.01 vs 0.37+/-0.01, p < 0.001), and expiratory airway resistance (11.81+/-1.53 vs 8.75+/-1.22 cm H2O/L/s, p < 0.001), but not in respiratory rate (27.48+/-1.54 vs 28.06+/-1.61 breaths/min, p = 0.40) or in minute ventilation (10.43+/-0.59 vs 10.27+/-0.37 L/min, p = 0.66). There was a statistically significant difference in the ratio of Pa(O2) to the fraction of inspired oxygen (F(IO2)) (333+/-21 vs 300+/-22, p < 0.03) but not in Pa(CO2) (48+/-2 vs 47+/-2 mm Hg, p = 0.59) between the BiPAP S/T-D and the Servo Ventilator 900C. CONCLUSIONS: Despite differences in initiating and maintaining the inspiratory and expiratory phases, in breathing circuits, and in ventilator circuits between the two ventilators, the performance of the BiPAP S/T-D is equally efficacious to that of a conventional mechanical ventilator in supporting respiratory muscles. Thus, the BiPAP S/T-D is safe and effective when used in mechanically ventilated patients recovering from acute respiratory failure who do not require total ventilatory support.

Variability, reproducibility, and data-collection time of pulmonary bedside monitoring.

Breath-by-breath pulmonary function testing at the bedside is now available both with special-purpose stand-alone equipment and with the new generation of ventilators. The authors studied the variability of, reproducibility of, and ideal length of data collection for nine indices of pulmonary function that may be useful for ventilatory management, weaning, and patient comfort. Work of breathing (as both J/L and J/min), pressure-time product, rapid shallow breathing index, respiratory time fraction, respiratory drive, change in esophageal pressure during inspiration, expiratory airway resistance, and dynamic compliance were measured in ten normal subjects and in eight patients being weaned from mechanical ventilation. All nine indices were reproducible when compared by paired t-test with two separate sets of data collected in normal subjects. Repeated measures in the normal subjects allowed calculation of 95% confidence intervals for the nine variables. There was no statistically significant difference between data collections of 5 minutes compared with those of 10 and 15 minutes. Breath-by-breath variability ranged from a coefficient of variation of 3% for the shallow breathing index in one patient to 131% for the work of breathing in J/min in another. Population variability ranged from values reported previously for other pulmonary parameters to nearly double for some parameters. The authors conclude that a 5-minute data collection time is sufficient to obtain reliable breath-by-breath data at the bedside. While taken together these indices may provide clinically useful information, their usefulness individually remains to be demonstrated because of their large variability.

Effects of Elevated Cytosolic Calcium on ACh-Induced Swine Tracheal Smooth Muscle Contraction.

Increased intracellular calcium concentration ([Ca(2+)](i)) is required for smooth muscle contraction. In tracheal and other tonic smooth muscles, contraction and elevated [Ca(2+)](i) are maintained as long as an agonist is present. To evaluate the physiological role of steady-state increases in Ca(2+) on tension maintenance, [Ca(2+)](i) was elevated using ionomycin, a Ca(2+) ionophore or charybdotoxin, a large-conductance calcium-activated potassium channel (K(Ca)) blocker prior to or during exposure of tracheal smooth muscle strips to ACh (10(-9) to 10(-4) M). Ionomycin (5 &mgr;M) in resting muscles induced increases in [Ca(2+)](i) to 500 +/- 230 nM and small increases in force of 2.6 +/- 2.3 N/cm(2). This tension is only 10% of the maximal tension induced by ACh. Charybdotoxin had no effect on [Ca(2+)](i) or tension in resting muscle. After pretreatment of muscle with ionomycin, the concentration-response relationship for ACh-induced changes in tension shifted to the left (EC(50) = 0.07 +/- 0.05 &mgr;M ionomycin; 0.17 +/- 0.07 &mgr;M, control, p < 0.05). When applied to the muscles during steady-state responses to submaximal concentrations of ACh, both ionomycin and charybdotoxin induced further increases in tension. The same magnitude increase in tension occurs after ionomycin and charybdotoxin treatment, even though the increase in [Ca(2+)](i) induced by charybdotoxin is much smaller than that induced by ionomycin. We conclude that the resting muscle is much less sensitive to elevation of [Ca(2+)](i) when compared to muscles stimulated with ACh. Steady-state [Ca(2+)](i) limits tension development induced by submaximal concentrations of ACh. The activity of K(Ca) moderates the response of the muscle to ACh at concentrations less than 1 &mgr;M. Copyright 1996 S. Karger AG, Basel

Calcium Mobilization and Muscle Contraction Induced by Acetylcholine in Swine Trachealis.

The roles of Ca(2+) mobilization in development of tension induced by acetylcholine (ACh, 0.1-100 &mgr;M) in swine tracheal smooth muscle strips were studied. Under control conditions, ACh induced a transient increase in free cytosolic calcium concentration ([Ca(2+)](i)) that declined to a steady-state level. The peak increase in [Ca(2+)](i) correlated with the magnitude of tension at each [ACh] after a single exposure to ACh, while the steady-state [Ca(2+)](i) did not. Removal of extracellular Ca(2+) had little effect on peak [Ca(2+)](i) but greatly reduced steady-state increases in [Ca(2+)](i) and tension. Verapamil inhibited steady-state [Ca(2+)](i) only at [ACh] <1 &mgr;M. After depletion of internal Ca(2+) stores by 10 min exposure to ACh in Ca(2+)-free solution and then washout of ACh for 5 min in Ca(2+)-free solution, simultaneous re-exposure to ACh in the presence of 2.5 mM Ca(2+) increased [Ca(2+)](i) to the control steady-state level without overshoot. The tension attained was the same as control for each [ACh] used. Continuous exposure to successively increasing [ACh] (0.1-100 &mgr;M) also reduced the overshoot of [Ca(2+)](i) at 10 and 100 &mgr;M ACh, yet tension reached control levels at each [ACh] used. We conclude that the steady-state increase in [Ca(2+)](i) is necessary for tension maintenance and is dependent on Ca(2+) influx through voltage-gated calcium channels at 0.1 &mgr;M ACh and through a verapamil-intensitive pathway at 10 and 100 &mgr;M. The initial transient increase in calcium arises from intracellular stores and is correlated with the magnitude of tension only in muscles that have completely recovered from previous exposure to agonists. Copyright 2001 S. Karger AG, Basel

Strategies for maximizing your chances for weaning success. Limitations--and advantages--of common predictive indices.

Using indices to predict weaning outcome can avoid premature extubation and unnecessary prolongation of ventilatory support. Unfortunately, none of the indices is consistently able to predict outcome. The key to successful weaning is to assess respiratory function repeatedly with several indices, not just one. The patient should be able to sustain spontaneous breathing for at least 24 hours on minimal partial ventilatory support (a pressure support or a continuous positive airway pressure of 5 cm H2O or a T piece, for example). Indices of maximal inspiratory pressure; work of breathing; and rapid, shallow breathing are useful in evaluating a patient's respiratory muscle performance; airway occlusion pressure is helpful as well when increased neuromuscular drive is a problem.

A Gaussian method to improve work-of-breathing calculations.

The work of breathing is a calculated index of pulmonary function in ventilated patients that may be useful in deciding when to wean and when to extubate. However, the accuracy of the calculated work of breathing of the patient (WOBp) can suffer from artifacts introduced by coughing, swallowing, and other non-breathing maneuvers. The WOBp in this case will include not only the usual work of inspiration, but also the work of performing these non-breathing maneuvers. The authors developed a method to objectively eliminate the calculated work of these movements from the work of breathing, based on fitting to a Gaussian curve the variable P, which is obtained from the difference between the esophageal pressure change and the airway pressure change during each breath. In spontaneously breathing adults the normal breaths fit the Gaussian curve, while breaths that contain non-breathing maneuvers do not. In this Gaussian breath-elimination method (GM), breaths that are two standard deviations from that mean obtained by the fit are eliminated. For normally breathing control adult subjects, GM had little effect on WOBp, reducing it from 0.49 to 0.47 J/L (n = 8), while there was a 40% reduction in the coefficient of variation. Non-breathing maneuvers were simulated by coughing, which increased WOBp to 0.88 (n = 6); with the GM correction, WOBp was 0.50 J/L, a value not significantly different from that of normal breathing. Occlusion also increased WOBp to 0.60 J/L, but GM-corrected WOBp was 0.51 J/L, a normal value. As predicted, doubling the respiratory rate did not change the WOBp before or after the GM correction.(ABSTRACT TRUNCATED AT 250 WORDS)

Cromakalim effects of acetylcholine-induced changes in cytosolic calcium and tension in swine trachealis.

The effects of cromakalim, an ATP-sensitive K+ channel activator, on changes in cytosolic calcium concentration [( Ca++]i) and tension induced by acetylcholine (ACh; 0.1-10 microM) were examined in swine tracheal smooth muscle. Cromakalim (10 microM) hyperpolarized muscle cells by approximately 18 mV from -58 mV (resting membrane potential) to -76 mV. Cromakalim relaxed muscle contractions evoked by ACh at a concentration of 0.1 microM, but not at higher concentrations. Measurement of [Ca++]i using Fura-2 demonstrated that except at 0.1 microM ACh, cromakalim did not alter peak increases in [Ca++]i. At 0.1 microM ACh, the peak transient was decreased, but not eliminated. Cromakalim reduced steady-state increases in [Ca++]i at ACh less than or equal to 1 microM, but not 10 microM ACh. Tension was similarly affected. These data suggest that ACh-induced increases in steady-state [Ca++]i and tension are inhibited by cromakalim-induced hyperpolarization. The initial ACh-induced transient increase in [Ca++]i is not greatly altered. Cromakalim did not alter the transient peak tension and [Ca++]i relationship. The relationship between steady-state [Ca++]i/tension (EC50 = 321 nM) obtained for control, cromakalim inhibition and after glibenclamide reversal of cromakalim inhibition falls to the left of the peak transient [Ca++]i/tension relationship (EC50 = 587 nM). Thus, the Ca++ sensitivity of the contractile proteins during steady-state stimulation by ACh was increased from that at rest. We conclude that electromechanical coupling is important in ACh-induced contraction at concentrations less than 1 microM. Pharmacomechanical coupling with little or no sensitivity to changes in potential is important at higher ACh concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Concentration-dependence of acetylcholine-induced changes in calcium and tension in swine trachealis.

Acetylcholine (ACh)-induced increases in intracellular calcium concentration ([Ca++]i) and tension were measured simultaneously in swine tracheal smooth muscle strips loaded with the calcium-sensitive fluorescent dye Fura-2. ACh at concentrations greater than or equal to 3 x 10(-8) M induced concentration-dependent increases in tension which reached a maximum at 10(-4) M. Increases in [Ca++]i occurred at all [ACh] tested (10(-8) to 10(-4) M). After addition of ACh at concentrations greater than 3 x 10(-7) M, [Ca++]i increased rapidly to a concentration dependent-peak then declined to a concentration-independent steady state approximately 250 nM above the resting [Ca++]i of 257 +/- 12 nM. There was a steep relationship (slope factor greater than 3) between the peak tension and the peak [Ca++]i reached at each [ACh]. The rate of decline of [Ca++]i to the steady state at [ACh] greater than 73 x 10(-7) M was well correlated with the peak [Ca++]i reached. We conclude that the peak increase in calcium induced by ACh sets the level of tension to be attained and the rate of decline of the transient increase in [Ca++]i. The steady-state [Ca++]i is sufficient for maintenance of tension.

Mechanical ventilation in patients with acute severe asthma.

PURPOSE: Acute respiratory failure necessitating intubation and mechanical ventilation in patients with acute severe asthma is relatively uncommon, and there are few data available regarding positive pressure ventilation in critically ill patients with asthma. We therefore decided to evaluate our experience with the use of mechanical ventilation for acute asthma and to critically review previous reports on this subject. PATIENTS AND METHODS: A retrospective analysis of all medical records of patients who required mechanical ventilation for acute severe asthma was performed for the period of 1980 to 1988. Various clinical parameters were reviewed and examined via Fisher's exact test for association with survival. RESULTS: Twenty-seven patients who underwent ventilation for a total of 32 episodes of mechanical ventilation comprised our study group. The overall mortality was 22%. A total of 76 complications were documented, including six episodes of barotrauma. The mean duration of artificial ventilation was 114 hours for nonsurvivors and 77 hours for survivors (p less than 0.05). CONCLUSION: Although there appears to be a trend toward increased survival after mechanical ventilation for acute asthma, ventilation of critically ill asthmatic patients continues to be a potentially perilous venture associated with significant morbidity and mortality.

Communication between the PC and laboratory instruments.

In this paper we describe communications between a personal computer and any instrument with a serial port for the purpose of collecting data or controlling equipment and a program for performing this task. From a user-defined file, the software reads the communication parameters: baud rate, data bits, stop bits and parity. The communication protocol is also read: echo, acknowledge and end-of-transmission characters. The software can be used to determine the protocol, to check the integrity of the communications, and can form the basis of a program for more specific applications.

Effects of drug-induced pulmonary phospholipidosis on lung mechanics in rats.

Chronic administration of amphiphilic drugs to rats induces pulmonary phospholipidosis (P), a disease characterized by accumulation of phospholipids and large foamy macrophages in alveolar spaces. We investigated whether P induced by chlorphentermine (CPH) causes changes in lung volumes and mechanics in this species. Groups of rats were fed CPH (50 mg.kg-1.day-1) for 1, 2, 3, 5, 9, and 14 wk. After each treatment period, lung volumes and mechanics were studied in the anesthetized, paralyzed, supine rat. Partial pressure-volume (PV) curves were developed at 3 and 6 ml above functional residual capacity (FRC; PV3, PV6), followed by maximal [up to total lung capacity (TLC)] PV curves. FRC was determined by saline displacement. Lungs were then fixed for histopathological examination. A subgroup of animals was allowed a recovery period of 6 wk, after the 9 wk of CPH administration. Pair-fed rats served as controls (CTR) at each time point. Lung weight increased in CPH-treated (CPH-T) rats from 1.5 +/- 0.2 (SD) g at week 1 to 5.8 +/- 1.4 g at week 14, reflecting the development of P. TLC, FRC, transpulmonary pressure at FRC, the shape of maximal PV curves, and static expiratory lung compliance computed from maximal PV data points did not change in CPH-T rats. However, partial PV curves of CPH-T lungs (particularly PV3) were shifted downward and to the right of those of CTR at 2, 3, 5, and 9 wk, indicating increased recoil pressure in phospholipidotic lungs at these time points.(ABSTRACT TRUNCATED AT 250 WORDS)

Pulmonary tissue volume and blood flow as functions of body surface area and age.

We measured pulmonary tissue volume (Vt) and capillary blood flow (Qc) by rebreathing acetylene as the soluble gas in 94 male and 82 female patients with normal healthy lungs. We found that the standard deviation of Vt was a function of Vt and that the standard deviation of Qc was a function of Qc; logarithm transforms were used to prevent this. A significant correlation exists between log Vt and body surface area (BSA) and log Vt and vital capacity (VC). For both sets of regressions older subjects (greater than or equal to 40 years of age) exhibited greater variability about the regression line than younger subjects; therefore the 2 age groups of subjects were analyzed separately for tissue volume. We describe regression equations of log Vt vs. BSA or VC for younger male, younger female, older male, and older female patients. The normal limits by sex and age groups are also included. A significant correlation was found between log Qc, BSA, and age. Thus 2 equations, for male and female patients, are used to predict log Qc based on these 2 covariates.

A regression analysis program to fit nonseparable equations.

A program to perform a nonlinear best fit for separable and nonseparable equations is described. This software is written in Turbo-Pascal so that it can be run both on CP/M systems or PC-DOS systems; in the latter, graphics can be performed using the Turbo Graphix Toolbox. From initial estimates the regression coefficients as well as the statistics are calculated. Two examples are shown: one of a separable equation describing receptor binding; the second of a nonseparable equation, describing the displacement of labeled agonist by an inhibitor. The only difference in the fit between a separable and a nonseparable equation is that the latter requires iterations for an estimate of the dependent variable every time that new regression coefficients are calculated.

Teaching medical decision analysis: the hepatitis B vaccine.

The process of formal decision analysis is illustrated by using the case of the hepatitis B vaccine in a computer program designed to teach both subjects to medical students. The software presents the medical facts, determines personal risks, allows input of personal values and calculates utilities for the various branches of the decision tree. There are three possible choices: vaccinate; screen first for antibodies against the hepatitis B virus and vaccinate only if negative; and wait (do not vaccinate). The decision with the utility of the highest numerical value is assumed to be the best under the given set of circumstances. Unlike commercial packages, this software contains the information internally and does not require that the user be familiar with either medical decision analysis or with the medical aspects of hepatitis. The program is available for PC's.

Distribution of ventilation and perfusion: a teaching model.

Models can be used as teaching tools to study complex phenomena. This model uses simplifications of blood gas subroutines to provide fast execution of the effect of the distribution of ventilation and blood flow in the lung on arterial blood gases. Assumptions are made that introduce only small errors but that avoid the use of iterations which would slow down execution. The use of Turbo-Pascal as the programming language allows for not only speed in development and execution but also portability to a variety of computers including CP/M systems and IBM-PCs.