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Biomedical subjects

J M Drazen

Publications and source records attributed to J M Drazen.

At least 235 records · Page 13Linked to original sources

Enhancement of plasma levels of biologically active leukotriene B compounds during anaphylaxis in guinea pigs pretreated by indomethacin or by a fish oil-enriched diet.

The changes in arterial plasma concentrations of immunoreactive leukotriene B (LTB) were compared after antigen challenge of two groups of sensitized, mepyramine-treated, and mechanically ventilated guinea pigs, one fed a diet enriched with fish oil and the other a control diet enriched with beef tallow. The lung tissue of animals fed a fish oil-enriched diet (FFD) for 9 to 10 wk incorporated eicosapentaenoic acid (EPA) and docosahexaenoic acid to constitute 8 to 9% of total fatty acid content, whereas these alternative fatty acids constituted less than 1% of the total fatty acid content of the lung tissue of animals on a beef tallow-supplemented diet (BFD). The maximum increase after antigen challenge in immunoreactive LTB4 from 0.16 +/- 0.04 ng/ml to 0.84 +/- 0.25 ng/ml in BFD animals and from 0.47 +/- 0.11 to 5.1 +/- 1.4 ng/ml immunoreactive LTB (LTB4 and LTB5) in FFD animals was significant (p less than 0.02) for each. Furthermore, the increase in total immunoreactive LTB in mepyramine-treated FFD animals was significantly greater than the increase in LTB4 in mepyramine-treated BFD guinea pigs at 2 to 8 min after antigen challenge (p less than 0.05). Resolution of arterial plasma immunoreactive LTB from pooled samples by reverse-phase high-performance liquid chromatography demonstrated that the sum of LTB4 and LTB5 in FFD animals exceeded that of LTB4 in BFD animals and that the quantity of LTB4 in the FFD animals was at least as great as that in the BFD animals during anaphylaxis. The products eluting at the retention times of LTB4 and LTB5 exhibited the chemotactic activity of their respective synthetic standards. The combination of indomethacin and mepyramine markedly augmented the antigen-induced increase in arterial plasma immunoreactive LTB4 concentrations in BFD animals, but had no effect on immunoreactive LTB levels in FFD animals. Limited in vivo measurements showing a lesser increase of plasma immunoreactive thromboxane B2 in the FFD relative to the BFD animals during anaphylaxis and ex vivo measurements showing a decreased LTB4-stimulated (cyclooxygenase product-dependent) contractile response of pulmonary parenchymal strips from the FFD relative to the BFD animals provide evidence for blockade in the cyclooxygenase pathway in the FFD animals. The measurements of arterial plasma LTB indicate that indomethacin treatment alone, which inhibits cyclooxygenase activity, and FFD treatment each augment the metabolism of arachidonic acid by the 5-lipoxygenase pathway in animals pretreated with mepyramine.(ABSTRACT TRUNCATED AT 400 WORDS)

Anaphylaxis↗

Density dependence of maximal expiratory flow before and during tracheal constriction in dogs.

The effect of carbachol-induced central bronchoconstriction on density dependence of maximal expiratory flow (MEF) was assessed in five dogs. MEFs were measured on air and an 80% He-20% O2 mixture before and after local application of carbachol to the trachea. Airway pressures were measured using a pitot-static probe, from which central airway areas were estimated. At lower concentrations of carbachol the flow-limiting site remained in the trachea over most of the vital capacity (VC), and tracheal area and compliance decreased in all five dogs. In four dogs, decreases in choke point area predominated and produced decreases in flows. In one dog the increase in airway "stiffness" apparently offset the fall in area to account for an increase in MEF. Density dependence measured as the ratio of MEF on HeO2 to MEF on air at 50% of VC increased in all five dogs. Increases in density dependence appeared to be related to increases in airway stiffness at the choke point rather than decreases in gas-related airway pressure differences. Lower concentrations produced a localized decrease in tracheal area and extended the plateau of the flow-volume curve to lower lung volumes. Higher concentrations caused further reductions in tracheal area and greater longitudinal extension of bronchoconstriction, resulting in upstream movement of the site of flow limitation at higher lung volumes. Density dependence increased if the flow-limiting sites remained in the trachea at mid-VC but fell if the flow-limiting site had moved upstream by that volume.

Air↗

Effect of tidal volume and anesthetic agent on airway responsiveness to histamine.

Dose-response relationships for bronchoconstriction in response to aerosal histamine were assessed before and after vagotomy in 11 dogs anesthetized with barbiturates and in 9 dogs anesthetized with alpha-chloralose-urethan. The dose-response relationships following vagotomy were assessed during spontaneous ventilation and during muscular paralysis and mechanical ventilation with tidal volume (VT) similar to each animal's VT prior to vagotomy. After vagotomy the spontaneous VT of both groups increased but the VT of the alpha-chloralose-urethan group was significantly less than that of the barbiturate group. The histamine responsiveness of the animals anesthetized with barbiturates was significantly greater during mechanical ventilation when VT was reduced to prevagotomy levels compared with during spontaneous ventilation. In contrast, the histamine responsiveness of the alpha-chloralose-urethan group was not significantly changed by reducing VT to prevagotomy levels. In six other dogs anesthetized with pentobarbital sodium and studied after vagotomy, responsiveness to histamine aerosol during controlled ventilation with breaths of prevagotomy VT was greater than responsiveness during mechanical ventilation with large volume breaths given immediately afterward. Thus the magnitude of VT of dogs after vagotomy may influence airway responsiveness, and the influence of anesthetic agents on airway responsiveness after vagotomy may in part be due to their effects on VT. Furthermore, bronchodilation accompanying large volume ventilation persists after vagotomy, suggesting that it is not exclusively mediated by changes in parasympathetic activity.

Airway Resistance↗

Expiratory flow limitation and dynamic pulmonary hyperinflation during high-frequency ventilation.

Dynamic hyperinflation of the lungs occurs during high-frequency oscillatory ventilation (HFOV) and has been attributed to asymmetry of inspiratory and expiratory impedances. To identify the nature of this asymmetry, we compared changes in lung volume (VL) observed during HFOV in ventilator-dependent patients with predictions of VL changes from electrical analogs of three potential modes of impedance asymmetry. In the patients, when a fixed oscillatory tidal volume was applied at a low mean airway opening pressure (Pao), which resulted in little increase in functional residual capacity, progressively greater dynamic hyperinflation was observed as HFOV frequency, (f) was increased. When mean Pao was raised so that resting VL increased, VL remained at this level during HFOV as f was increased until a critical f was reached; above this value, VL increased further with f in a fashion nearly parallel to that observed when low mean Pao was used. Three modes of asymmetric inspiratory and expiratory impedance were modeled as electrical circuits: 1) fixed asymmetric resistance [Rexp greater than Rinsp]; 2) variable asymmetric resistance [Rexp(VL) greater than Rinsp, with Rexp(VL) decreasing as VL increased]; and 3) equal Rinsp and Rexp, but with superimposed expiratory flow limitation, the latter simulated using a bipolar transistor as a descriptive model of this phenomenon. The fixed and the variable asymmetric resistance models displayed a progressive increase of mean VL with f at either low or high mean Pao. Only the expiratory flow limitation model displayed a dependence of dynamic hyperinflation on mean Pao and f similar to that observed in our patients. We conclude that expiratory flow limitation can account for dynamic pulmonary hyperinflation during HFOV.

Adult↗

Effect of lung volume on pulmonary mechanics in guinea pigs.

The lung volume (VL) dependence of several dynamic pulmonary mechanical properties of the guinea pig lung were determined over the range of the vital capacity (10-100% VC) with the vagi intact and sectioned. We found dynamic compliance to be strongly VL dependent, decreasing as much as 85% between functional residual capacity (FRC) and total lung capacity (TLC). Below FRC, dynamic compliance either remained unchanged or decreased, depending upon the technique used in its measurement. Pulmonary resistance (RL) decreased monotonically with increasing VL, whereas pulmonary conductance was linearly related to VL. Conductance was much less sensitive to VL than compliance, increasing only 28% between FRC and TLC. The sensitivity of pulmonary conductance to VL was substantially increased by subtracting the resistance of the tracheal cannula from RL. Specific pulmonary conductance was not independent of VL but decreased approximately 45% over the range of the VC. Pulmonary inertance was found to be unaffected by VL. Extrapolation from these data indicate that small differences in FRC, which might be expected within and between studies relying on pulmonary mechanical measurements, would most strongly affect compliance estimates and only moderately alter resistance estimates. It also indicates that the use of specific pulmonary conductance does not remove VL as an independent variable.

Airway Resistance↗

Nonuniformity of canine lung washout by high-frequency ventilation.

Ethane washout during low tidal volume (25-100 ml) high-frequency (3-40 Hz) ventilation (HFV) was studied in seven excised dog lungs. The lungs were initially equilibrated with 1% ethane, and then the concentration of ethane was monitored by mass spectrometry from multiple anatomic sites along the tracheobronchial tree during washout. We observed that the lung changed from a uniform distribution of ethane concentrations to a nonuniform distribution by a three-phase process. The first phase was nearly complete within the first 15 s and probably corresponds to concentration gradients being established in the central airways. During the second phase of washout, which lasted for several minutes, the concentrations in the various alveolar regions diverged. In the final phase, the regional concentrations remained at fixed ratios, and washout from all sites in the lung was at a constant fractional rate. These data are consistent with a model in which the duration of the second phase and the magnitude of the regional concentration differences established in this phase are dependent on both the magnitude of differences between regional transport paths and the nature of regional coupling by a common transport path to the airway opening.

Animals↗

CO2 elimination by high-frequency oscillation: effects of vagosympathetic stimulation.

The effects of electrical stimulation of the vagi on gas transport mediated by high-frequency, low tidal volume ventilation (HFV) was examined in 10 anesthetized, paralyzed, propranolol-treated dogs. Gas transport efficiency was estimated by measuring the rate of CO2 removed from the lungs (Vco2) achieved during 45-s bursts of HFV applied before (control 1), during, and after (control 2) electrical stimulation of the transected vagi. During vagal stimulation the heart rate was maintained by electrical pacing. During the 15-s phase of vagal stimulation pulmonary impedance increased from 3.6 +/- 0.7 to 6.2 +/- 2.2 cmH2O X l-1 X s, and Vco2 increased. When the electrical stimulation of the vagi was stopped, impedance and Vco2 returned to prestimulation values. Vco2 was always higher during electrical stimulation of the vagi when HFV of a fixed volume was applied over a range of frequencies or when a fixed oscillation frequency was used over a range of tidal volumes. The effects of vagal stimulation on HFV-mediated gas transport were quite similar to the effects of moving the locations of the bias flow inlet and outlet into the lung such that tracheal volume was decreased by 20 ml, an amount equivalent to estimated change in control airway volume thought to occur during vagal stimulation. We simulated the effects of vagal stimulation and decreased tracheal volume on Vco2 by using a previously described model of HFV-mediated gas transport.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Finite difference analysis of respiratory heat transfer.

A numerical computer model of heat and water transfer within the tracheobronchial tree of humans was developed based on an integral formulation of the first law of thermodynamics. Simulation results were compared with directly measured intraluminal airway temperature profiles previously obtained in normal human subjects, and a good correlation was demonstrated. The model was used to study aspects of regional pulmonary heat transfer and to predict the outcomes of experiments not yet performed. The results of these simulations show that a decrease in inspired air temperature and water content at fixed minute ventilation produces a proportionately larger increase in heat loss from extrathoracic airways relative to intrathoracic, whereas an increase in minute ventilation at fixed inspired air conditions produces the opposite pattern, with cold dry air penetrating further into the lung, and that changes in breathing pattern (tidal volume and frequency) at fixed minute ventilation and fixed inspiratory-to-expiratory (I/E) ratio do not affect local air temperature profiles and heat loss, whereas changes in I/E ratio at fixed minute ventilation do cause a significant change.

Asthma↗

Circulatory heat sources for canine respiratory heat exchange.

We assessed the roles of the pulmonary and bronchial circulations as potential heat sources to the pulmonary airways during respiratory heat loss, by observing the changes in airstream temperature that accompanied temporary occlusion of the pulmonary or bronchial circulations. Baseline end-expiratory and end-inspiratory airstream temperatures were 35.4 +/- 0.2 degrees C (SEM) and 30.9 +/- 0.3 degrees C, respectively, among all trials. With occlusion of the lower lobe pulmonary arteries for 3 min ipsilateral end-expiratory and end-inspiratory airstream temperatures fell by 2.8 +/- 0.2 and 1.1 +/- 0.2 degrees C, respectively, during hyperpnea with room temperature air, and by 3.5 +/- 0.5 and 1.8 +/- 0.2 degrees C, respectively, during hyperpnea with frigid air. In marked contrast, interruption of the bronchial circulation for 3 min had no effect on airstream temperatures. These data indicate that under these conditions, the pulmonary circulation, but not the bronchial circulation, serves as an important local heat source for respiratory heat exchange within the pulmonary airways.

Animals↗

Inhalation challenge with sulfidopeptide leukotrienes in human subjects.

What is the meaning of these findings to the practicing chest physician? First, leukotrienes are potent airway constrictors; they are capable of reproducing the type of airway constriction observed in asthma. The role of leukotrienes in this regard has yet to be established, but experiments to test the importance of these agents in this setting are likely to be performed soon. Specifically, several leukotriene receptor antagonists or synthesis inhibitors have been identified and may provide the tools needed to test this crucial hypothesis. Second, the leukotrienes are unique bronchoactive agents in that the degree of hyperresponsiveness between normal and asthmatic subjects varies markedly with the bronchoconstrictor index used to assess response. When one compares normal subjects to asthmatic subjects, there is substantial overlap in leukotriene sensitivity among groups when V30-P is used as the bronchoconstrictor index. However, when the FEV1 is used as the bronchoconstrictor index, there is little overlap in sensitivity between normal and asthmatic subjects, and the separation between the two groups is even more clearly made than it is with histamine or methacholine challenge. Thus, LTD4 inhalation challenge may replace the histamine and methacholine challenges in the diagnosis of cryptic shortness of breath. Third, the differential sensitivity of various bronchoconstrictor indices in both normal and asthmatic subjects when leukotrienes are used may provide clues as to the locus of airway hyperresponsiveness in asthma. Thus, leukotrienes hold the promise of new ways to treat and diagnose asthma, as well as providing new insights into the pathobiology of the disease itself.

Administration, Intranasal↗

Effect of temperature on beta receptor responsiveness in guinea pig pulmonary tissues.

Cumulative concentration-effect relationships of isoproterenol (isoprenaline) on guinea pig tracheal spirals and lung parenchymal strips were determined in organ baths kept at 37 degrees C or at 18 degrees C. The IC50's for isoproterenol at 18 degrees C were significantly (p less than .01) higher than those for isoproterenol at 37 degrees C in both the tissues; although the parenchymal response was affected more than that of the trachea by cooling. pA2 values for propranolol were determined on both tracheal spirals and parenchymal strips at 37 degrees C and 18 degrees C. The pA2 values were decreased in both the tissues by cooling. The decrease was more prominent in the parenchyma than in the trachea, a finding consistent with the concentration-effect relationships studies mentioned above.

Airway Resistance↗

Effects of milrinone on contractile responses of guinea pig trachea, lung parenchyma and pulmonary artery.

The effects of milrinone, a bipyridine with known vasodilator activity, on guinea pig tracheal-spirals, lung parenchymal strips and pulmonary artery rings in vitro were compared with the effects of isoproterenol and aminophylline on these tissues. The concentration of milrinone that produced 50% relaxation (IC50) of tracheal spirals constricted by carbachol was 3.6 X 10(-5) M. Isoproterenol (IC50, 9.5 X 10(-8) M) was significantly (P less than .001) more potent and aminophylline (IC50, 1.2 X 10(-4) M) was significantly (P less than .001) less potent than milrinone in this effect. The IC50 for milrinone for lung parenchymal strips contracted by histamine was 3.2 X 10(-5) M, whereas the IC50 for isoproterenol was significantly (P less than .001) less, 1.4 X 10(-7) M; aminophylline produced only limited relaxation of lung parenchymal strips. Milrinone relaxed pulmonary artery rings constricted by norepinephrine with an IC50 of 3.8 X 10(-6) M, whereas neither isoproterenol nor aminophylline produced a 50% relaxation. Pretreatment of tracheal spirals, lung parenchymal strips and pulmonary artery rings with 1.6 X 10(-4) M milrinone inhibited subsequent contraction by carbachol, histamine and norepinephrine, respectively. The relaxant effects of milrinone were not influenced by treatment with atropine, cimetidine, mepyramine, phentolamine or propranolol. However, indomethacin blocked milrinone's relaxant effects on tracheal spirals effectively, but not on pulmonary artery rings or lung parenchymal strips, suggesting distinct modes of action on various tissue types.

Aminophylline↗

Effect of bias flow rate on gas transport during high-frequency oscillatory ventilation.

Ventilatory support with low tidal volume, high-frequency oscillatory ventilation (HFOV) usually uses a bias flow system to provide fresh gas. Although the bias flow rates (Vbf) used previously have varied widely among experimental configurations, the precise role of the bias flow in HFOV-mediated gas transport has not been defined. We assessed the effect of bias flow rate on gas transport during HFOV by measuring CO2 removal rate (MCO2) in anesthetized, paralyzed dogs, using a wide range of bias flow rates (0.7-28.9 L X min-1). When a fixed tidal volume of 40 ml was applied at HFOV frequencies of 2-12 Hz, MCO2 was proportional to the time-averaged alveolar-bias flow CO2 concentration difference. Thus, when Vbf was reduced below a value which resulted in a substantial increase in bias flow CO2 concentration, MCO2 was reduced. These findings are consistent with a simple framework in which the relative magnitudes of the resistances to gas transport of the airways and of the bias flow (1/Vbf) determine the contribution of the bias flow rate to overall gas transport during HFOV. This relationship may be employed to assess the intra-airway contribution to HFOV-mediated gas transport at any bias flow rate, and may therefore allow comparison of results from experiments utilizing various bias flow rates.

Animals↗

Radiographic visualization of airway wall movement during oscillatory flow in dogs.

It has been suggested that radial movement of the central airway walls during oscillatory flow might contribute to the increased frequency dependence of compliance seen in chronic obstructive pulmonary disease (COPD) (J. Appl. Physiol. 26: 670-677, 1969). Radial airway wall motion has also been invoked to explain the frequency-dependent decreases in the efficiency of gas exchange during low-volume high-frequency ventilation (HFV) in histamine-bronchoconstricted dogs and in patients with respiratory insufficiency. To test the possibility that airway wall motion increases with bronchoconstriction, we measured central airway diameters using cinebronchoradiography in anesthetized tracheostomized dogs during oscillatory HFV [50 and 100 ml tidal volume (VT) at frequencies (f) of 2, 6, and 12 Hz], under control conditions, during electrical stimulation of the vagi, and after exposure to histamine aerosol. Cineradiobronchograms from two dogs were evaluated quantitatively for tracheal diameter and for lengths and diameters of a number of major airways. Under control conditions, the diameter of the airways fluctuated 7-9% of the mean with VT of 50 ml and 9-18% with VT of 100 ml in the range of frequencies studied. Bronchoconstriction produced by aerosolized histamine increased radial airway wall movement to 10-47% with VT of 50 ml, and during vagal stimulation diameters changed 7-20% at VT of 50 ml. After histamine, the central airways displayed large diameter changes during HFV, whereas more peripheral airways were markedly constricted and did not change in diameter.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Nonhomogeneity of lung response to inhaled histamine assessed with alveolar capsules.

To assess the homogeneity of airway responses to inhaled histamine we examined regional alveolar pressure excursions (PA) arising from small-amplitude oscillations applied at the airway opening (Pao). In five anesthetized and vagotomized dogs the sternum was split and the anterior right lung field exposed. PA was sampled using four capsules affixed to the right apical and middle lobes while lung impedance (ZL) and airway impedances (Zaw) were measured during conventional tidal breathing and during forced oscillations (2-60 HZ at 10 cmH2O distending pressure). During tidal breathing after exposure to aerosol histamine regional PA's could be separated into three groups by plotting Lissajous figures of PA vs. Pao: PA in phase with Pao (no looping), PA lagging Pao (moderate looping), and PA decreasing while Pao was increasing and vice versa (paradoxical looping), suggesting unresponsive, responsive, and closed pathways, respectively, between the airway opening and specific alveolar zones. During high-frequency oscillation the corresponding PA spectra were markedly different from control spectra and revealed resonant amplification, overdamped resonance, and marked attenuation, respectively. With induced bronchospasm resonant amplification of PA was damped on average. However, the more obstructed and closed pathways were protected from resonant amplification, and the more open (nonlooping) pathways were subjected to resonant amplification greater than in the control state. In spite of this markedly nonhomogeneous behavior, frequency dependence of ZL was consistent with the model by Mead (J. Appl. Physiol. 26: 670-673, 1969), which ignores nonhomogeneity of peripheral compartments. These data demonstrate that the response of airways to inhaled histamine is nonhomogeneous but that frequency dependence of ZL above 2 Hz is not sufficient to characterize this nonhomogeneity.

Aerosols↗

Pressure-flow relationships of endotracheal tubes during high-frequency ventilation.

We studied the pressure-flow relationships of various endotracheal tubes (ETT) at frequencies (f) and tidal volumes (VT) in the range used for high-frequency ventilation (HFV) (f: 2-32 Hz, VT: 15-100 ml). Sinusoidal flows were applied to ETT inserted into a rigid bottle or into the tracheae of three anesthetized paralyzed dogs, while pressure fluctuations were measured both proximal and distal to the ETT. The pressure drops in the ETT were nonlinearly related to the peak flow rate and were VT dependent, suggesting that turbulent frictional head loss and convective acceleration were important. The pressure drops measured in vitro were found to be in good agreement with the predictions of a nonlinear oscillatory pressure-flow equation (derived herein), which incorporate the effects of turbulent frictional losses, convective acceleration, inertance, and compliance. The pressure drops measured in situ were 30-50% higher than with the corresponding f-VT combinations in vitro. Possible explanations of these differences are junctional losses at the tip of the ETT or the nonrigid character of the trachea.

Animals↗

Photographic measurement of pleural surface motion during lung oscillation.

The regional pleural surface expansion of an excised dog lung was measured during high-frequency ventilation (HFV) using synchronized stroboscopic photography to stop lung motion at 20 evenly spaced intervals over a respiratory cycle during ventilation at 1 Hz with a volume of 100 ml, 15 Hz with 100 ml, or 30 Hz with 50 ml. The lungs were also photographed during quasi-static deflation. The pleural surface was marked with ink dots to form 84 approximately square figures. The side lengths and areas of each of the 84 "squares" were measured for each frame of each photo sequence. At 1 Hz and during the quasi-static deflation the lung ventilated nearly synchronously, although minor nonuniformities were noted on both small and large length scales. At 15 and 30 Hz, the lung expanded asynchronously and nonuniformly, with a 78% increase in surface expansion per 100 ml of tracheal tidal volume, as frequency was increased from 1 to 30 Hz. These nonuniformities in expansion suggest marked interregional airflow and elastic wave propagation in the parenchyma during HFV.

Animals↗

Breathing pattern affects airway wall temperature during cold air hyperpnea in humans.

We studied the influence of flow rate on respiratory heat exchange in 9 healthy adult subjects using a new noninvasive technique, the single-breath temperature washout (SBTW) curve. The SBTW curve is a plot of exhaled gas temperature versus exhaled volume during a standard exhalation and consists of an initial rise (within the first 200 ml) to a plateau temperature that persists through the remainder of exhalation. We found that exhaled gas temperatures within the initial expirate were colder at every airway locus than corresponding intra-airway gas temperatures at end-inspiration, suggesting that heat exchange occurs between lumenal gas and the relatively cooler airway walls during exhalation. The SBTW plateau temperatures were: (1) lower after preconditioning the airways with rapid (80 L/min) isocapnic hyperpnea of frigid air than after less rapid (40 L/min) cold-air hyperpnea or after quiet breathing; (2) lower when, after identical airway preconditioning regimens, the SBTW exhalation was performed with a slower (0.5 versus 2.5 L/s) expiratory flow; and (3) lower when SBTW curves were obtained after airway preconditioning using respiratory patterns with larger inspiration-expiration duration (I:E) ratios (5:1 versus 1:5) at fixed minute ventilation and respiratory rate. Our results indicate that the global respiratory gas-wall heat transfer coefficient increases with velocity to the 0.9 power, a finding similar to that in previous studies of turbulent flow in rigid pipes.

Adult↗