Inhaled furosemide attenuates hyperpnea-induced obstruction and intra-airway thermal gradients.

Inhaled furosemide attenuates exercise- and isocapnic hyperventilation-induced asthma; however, the mechanism for this phenomenon is unknown. Because the magnitude of the intra-airway thermal gradient that develops between the cooling of hyperpnea and the rewarming that occurs once hyperventilation ceases is directly related to the severity of thermally induced obstruction in humans, we wondered if furosemide blunted these temperature changes. To explore this issue, eight asthmatic subjects had tracheobronchial airstream temperature measures as they performed isocapnic hyperventilation with frigid air alone (HV) or with pretreatment with inhaled saline (S + HV) or 45 +/- 3 (SE) mg of furosemide (F + HV). HV and S + HV resulted in similar degrees of obstruction, whereas the mechanical decrements after F + HV were significantly less. In concert with this protective effect, F + HV resulted in less airstream cooling during hyperventilation and slower rewarming in the recovery period. Because the major source of heat to the airways is provided by its microcirculation, inhaled furosemide may be acting as a topical vasodilator serving to enhance heat availability and thus reducing the effective thermal burden of hyperpnea.

Acoustic rhinometry: effects of decongestants and posture on nasal patency.

To determine whether acoustic rhinometry can be used to detect changes in nasal patency caused by decongestants or posture, we studied 10 healthy volunteers. Maps of the effective cross-sectional area of the nasal cavity as a function of distance into the respiratory system were generated, and an index of nasal cavity volume was calculated in the right and left nostril of each subject. The volume index was reproducible in subjects. The mean of the intrasubject coefficients of variation was 7.9%. After administration of phenylephrine in the form of a nasal spray, the volume index increased in the right nostril from 29.8 +/- 3.6 to 40.9 +/- 4.4 cm3 (mean +/- SEM) (p less than 0.001) and in the left nostril from 26.3 +/- 2.1 to 38.0 +/- 3.0 cm3 (p less than 0.001). On another occasion in the same subjects, the volume index was determined before and 90 minutes after oral administration of 60 mg pseudoephedrine. The volume index for the sum of both nostrils increased from 56.7 +/- 4.7 to 65.1 +/- 5.2 cm3 (p less than 0.5). In another group of subjects, turning from the supine position to the right side caused right nasal volume to decrease from 29.3 +/- 4.4 to 19.5 +/- 3.6 cm3 (p less than 0.003) and the left nasal volume to increase from 20.9 +/- 2.8 to 25.5 +/- 3.2 cm3 (p less than 0.05). We conclude that acoustic rhinometry can provide a sensitive index of changes in nasal geometry.

Effects of ozone on lung mechanics and cyclooxygenase metabolites in dogs.

To determine if acute exposure to ozone can cause changes in the production of cyclooxygenase metabolites of arachidonic acid (AA) in the lung which are associated with changes in lung mechanics, we exposed mongrel dogs to 0.5 ppm ozone for two hours. We measured pulmonary resistance (RL) and dynamic compliance (Cdyn) and obtained methacholine dose response curves and bronchoalveolar lavagate (BAL) before and after the exposures. We calculated the provocative dose of methacholine necessary to increase RL 50% (PD50) and analyzed the BAL for four cyclooxygenase metabolites of AA: a stable hydrolysis product of prostacyclin, 6-keto-prostaglandin F1 alpha (6-keto-PgF1 alpha); prostaglandin E2 (PgE2); a stable hydrolysis product of thromboxane A2, thromboxane B2 (TxB2); and prostaglandin F2 alpha (PgF2 alpha). Following ozone exposure, RL increased from 4.75 +/- 1.06 to 6.08 +/- 1.3 cm H2O/L/sec (SEM) (p less than 0.05), Cdyn decreased from 0.0348 +/- 0.0109 TO .0217 +/- .0101 L/cm H2O (p less than 0.05), and PD50 decreased from 4.32 +/- 2.41 to 0.81 +/- 0.49 mg/cc (p less than 0.05). The baseline metabolite levels were as follows: 6-keto PgF1 alpha: 96.1 +/- 28.8 pg/ml; PgE2: 395.8 +/- 67.1 pg/ml; TxB2: 48.5 +/- 11.1 pg/ml; PgF2 alpha: 101.5 +/- 22.6 pg/ml. Ozone had no effect on any of these prostanoids. These studies quantify the magnitude of cyclooxygenase products of AA metabolism in BAL from dog lungs and demonstrate that changes in their levels are not prerequisites for ozone-induced changes in lung mechanics or airway reactivity.

Fast-responding automated airway temperature probe.

Rapid changes occur in the thermal profiles of asthmatic subjects following the cessation of hyperpnea, which include temperature increases of the order of 0.25 degrees C s-1 in the trachea. These thermal events could indicate abnormal blood flow in the airway wall of these patients, a factor which may be linked to the instability of their airway geometry. To monitor these events a series of fast-responding thermistors and associated electronics have been developed. The apparatus uses temperature sensors of very small mass and the interrupt processing capability of the IBM-AT compatible computer to achieve a system response time that is in an order of magnitude greater than previous devices. Stable, reproducible and easily calibrated, this device shows no hysteresis over a required operating range of 15-35 degrees C. It exceeds all standards for electrical safety of the American Hospital Association. This device can be used to monitor the thermal transients which are seen in the airways of asthmatic patients as their airways rewarm following hyperpnea.

Contribution of large airway to the input impedance of the respiratory system.

To evaluate the contribution of the large airway to total respiratory impedance, we develop a one-dimensional model of pressure and flow in these airways by coupling conservation of mass and momentum equations with the geometric information obtained by the acoustic reflection technique. We use this model to calculate the impedance of the respiratory system distal to the carina from impedance data estimated at the airway opening by the forced oscillation technique. Simulations show that the real part of the impedance distal to the carina is uniformly decreased from the impedance at the airway opening, indicating a resistive loss, while the imaginary part is increased as a function of frequency. We estimate parameter values for a six-parameter two-compartment lung model and for a three-parameter reduction of this model before and after the application of the upper airway data to the impedance spectrum. Although compliance terms seem to be minimally affected by the manipulation of the data, resistance and inertance terms are influenced in a fashion that suggests that the resistive contribution of the upper airway to total respiratory impedance is significant. Furthermore it appears that the elastic nature of the walls of the upper airway also impact on estimates of total respiratory impedance at the airway opening.

The effect of repetitive exercise on airway temperatures.

To determine if a relationship exists between intra-airway thermal events and the reduction in pulmonary mechanics that occur in asthmatics when they perform repetitive exercise, we recorded intrathoracic airstream temperatures in seven subjects during and after two identical bouts of cycle ergometry performed 30 min apart. From these data, global and regional thermal energy exchanges were calculated. Inspired air conditions, work loads, and minute ventilations were held constant for both trials. Pulmonary mechanics were measured prior to and serially after each challenge. As expected, the second provocation produced a smaller response than did the first. In association with these mechanical changes, the second challenge also produced less airway cooling and slower rewarming in the central airways. Hence, repetitive exercise trials performed over short intervals attenuate the essential thermal gradients necessary to produce obstruction. To the extent that these differences in intra-airway temperature reflect changes in perfusion, our data raise the possibility that the responsivity of the bronchial microcirculation of asthmatics may be altered by repetitive exercise.

Effect of facial cooling on mucosal blood flow in the mouth in humans.

1. To determine the effects of facial cooling on intraoral thermal events, we placed a thermal conductivity sensor on the buccal surface of the left cheek in six normal and six asthmatic subjects. Room temperature and cold stimuli were then applied to the integument surface of both sides of the face while mucosal surface temperature and thermal conductivity, as an index of blood flow, were recorded. 2. The room temperature challenge had no effect. Application of the cold stimulus to the exterior of the left cheek caused a monotonic decrease in temperature in the mouth in all subjects and was associated with a change in thermal conductivity in which blood flow increased and then fell to baseline despite a continued drop in temperature. These responses were purely local in that cooling of the right side of the face did not change the temperature or blood flow on the left side. No differences were noted between the asthmatic and normal subjects. 3. The data indicate that lowering the temperature of the skin of the face produces significant alterations in the thermal environment within the mouth. With facial cooling, buccal temperature falls and mucosal blood supply transiently rises. This effect appears to be a purely local thermally mediated event. Facial pressure and cutaneous reflexes do not play a role. The above changes may contribute to the conditioning of inspired air during oral breathing.

Proximal, tracheal, and alveolar pressures during high-frequency oscillatory ventilation in a normal rabbit model.

To study the effect of different high-frequency oscillatory ventilation parameters on airway pressure, we measured oscillatory pressure amplitude ([Paw[) and mean airway pressure (Paw) at three sites in open-chested normal rabbits: proximal, trachea, and alveolus. Five animals were studied to test a new pleural capsule design, which was then used in two groups of animals to measure right upper (n = 4) or middle (n = 5) lobe alveolar pressures. Animals were randomly sequenced through combinations of frequency (10, 15, and 20 Hz) and fractional inspiratory time (Ti) (0.3 and 0.5) while normoxic and eucapnic. During capsule testing, we noted that alveolar pressures increased (p less than 0.05) with increasing capsule mass, suggesting that compressive forces from the capsule may alter the capsule measurement. We thus used a low-mass (430 mg) transducer system in the rabbit high-frequency oscillatory ventilation experiments. Using multifactorial analysis of variance, we found significant main effects of Ti on Paw, and of measurement site on both [Paw[ and Paw (all p less than 0.009). Frequency did not influence variations in either [Paw[ or Paw. For both Ti settings, alveolar upper lobe Paw was lower compared with that of the middle lobe (p less than 0.0005). Lengthening Ti (0.3 to 0.5) increased tracheal Paw in each capsule group (p less than 0.0005). At Ti = 0.5, tracheal Paw exceeded Paw measured proximally (p less than 0.05). Our data support in vivo alveolar Paw inhomogeneity and demonstrate significant changes in pressures within the lung related to Ti during high-frequency oscillatory ventilation.

Radial heat and water transport across the airway wall.

The thermal profiles in the airways of healthy human volunteers and patients with asthma differ after cessation of hyperpnea. The asthmatic patients rewarm their airways more rapidly. To identify thermal properties and processes that could account for the difference between these populations, we developed a model describing the radial transport of heat and water across the trachea. A distinctive feature of the model is a variable parameter describing blood supply to the mucosal and submucosal layers. Simulations performed with the model are initiated by a breath-hold maneuver and are propagative in time. Blood perfusion rates in the airway wall, the thickness of the layer of airway surface liquid, and the mucosa-submucosa thickness, all thought to be more pronounced in asthmatic patients, were varied by changing model parameters and initial conditions. Increasing the thickness of the liquid layer by more than an order of magnitude had little effect on the temperature or water content in the airway lumen. Doubling the blood flow to the mucosa-submucosa resulted in a slight increase in airway temperature. When this effect was coupled, however, with an increase in the thickness of the mucosa-submucosa layer, the increase in temperature was more pronounced. Because the bronchial circulation is the major source of heat to the airway, these results indicate that differences in airway wall thickness coupled with differences in the magnitude or responsiveness of the bronchial microcirculation could account for the differences in intra-airway temperature between the two populations.

Effects of ozone on cyclooxygenase metabolites in the baboon tracheobronchial tree.

Short-term exposure to 0.5 parts per million (ppm) ozone has been shown to cause an increase in respiratory resistance in primates that can be diminished by 50% with pretreatment with cromolyn sodium. Because of the known membrane-stabilizing effects of cromolyn and the resultant inhibition of mediator production, we hypothesized a role for the products of arachidonic acid (AA) metabolism in these events. We exposed five adult male baboons to 0.5 ppm ozone on two occasions, once with cromolyn pretreatment and once without. Pulmonary resistance (RL) was monitored and bronchoalveolar lavage (BAL) was performed before and after each exposure. The BAL was analyzed for a stable hydrolysis product of prostacyclin, 6-keto-prostaglandin (PG) F1 alpha, PGE2, a stable hydrolysis product of thromboxane (Tx) A2, TxB2, and PGF2 alpha. RL increased after ozone exposure (1.62 +/- 0.23 to 3.77 +/- 0.51 cmH2O.l-1.s, difference 2.15; P less than 0.02), and this effect was partially blocked by cromolyn (1.93 +/- 0.09 to 3.18 +/- 0.40 cmH2O.l-1.s, difference 1.25; P less than 0.02). The base-line levels of the metabolites of AA in the BAL were as follows (in pg/ml): 6-keto-PGF1 alpha 72.78 +/- 12.6, PGE2 145.92 +/- 30.52, TxB2 52.52 +/- 9.56, and PGF2 alpha 22.28 +/- 5.42. Ozone exposure had no effect on the level of any of these prostanoids (P = NS). These studies quantify the magnitude of cyclooxygenase products of AA metabolism in BAL from baboon lungs and demonstrate that changes in the levels of these mediators in BAL are not prerequisites for ozone-induced increases in respiratory resistance.(ABSTRACT TRUNCATED AT 250 WORDS)

Responses to negative pressure surrounding the neck in anesthetized animals.

Continuous positive pressure applied at the nose has been shown to cause a decrease in upper airway resistance. The present study was designed to determine whether a similar positive transmural pressure gradient, generated by applying a negative pressure at the body surface around the neck, altered upper airway patency. Studies were performed in nine spontaneously breathing anesthetized supine dogs. Airflow was measured with a pneumotachograph mounted on an airtight muzzle placed over the nose and mouth of each animal. Upper airway pressure was measured as the differential pressure between the extrathoracic trachea and the inside of the muzzle. Upper airway resistance was monitored as an index of airway patency. Negative pressure (-2 to -20 cmH2O) was applied around the neck by using a cuirass extending from the jaw to the thorax. In each animal, increasingly negative pressures were transmitted to the airway wall in a progressive, although not linear, fashion. Decreasing the pressure produced a progressive fall in upper airway resistance, without causing a significant change in respiratory drive or respiratory timing. At -5 cmH2O pressure, there occurred a significant fall in upper airway resistance, comparable with the response of a single, intravenous injection of sodium cyanide (0.5-3.0 mg), a respiratory stimulant that produces substantial increases in respiratory drive. We conclude that upper airway resistance is influenced by the transmural pressure across the airway wall and that such a gradient can be accomplished by making the extraluminal pressure more negative.(ABSTRACT TRUNCATED AT 250 WORDS)

A model of muscular control of upper airway geometry.

Some disorders of the upper airway in humans are marked by decreased cross-sectional area and increased airway wall compliance. Based on our observations from studies performed in the isolated upper airway of dogs, we hypothesized that the size, and perhaps the geometry, of the airway was altered by changes in the relative activation levels of various muscle pairs. This could be accomplished either by altering the intensity of the neuromuscular input, or by activating muscle pairs which have different geometric orientation to the airway. We developed an analytic relationship to allow us to vary the stimulus level driving any one of six muscle pairs, each with a different anatomic orientation, to evaluate the relationship between those parameters and upper airway volume. With data generated from bilateral electrical stimulation of upper airway muscles, we described a shape factor which allowed us to predict the maximum force produced at optimal length. These findings were applied to a length/tension curve common to striated muscle to allow us to examine the muscle behavior at lengths other than optimal. The position of each muscle was described in spherical coordinates relative to an elastic cylinder, which represented the isolated, sealed upper airway. These coordinates defined the direction in which the force generated by each muscle pair would be applied. Three compliance constants determined the change in airway dimensions produced by the muscle force. This system and its variables were used to calculate the change in volume of the sealed upper airway chamber resulting from muscle contraction.(ABSTRACT TRUNCATED AT 250 WORDS)

Reproducibility of measurements of upper airway area by acoustic reflection.

To evaluate the extent and nature of the variability of measurements of upper airway area by acoustic reflection (AAAR), we made repeated measures of pharyngeal AAAR in 10 normal adult volunteers. We selected mean pharyngeal area as a better index of upper airway size than peak pharyngeal area or pharyngeal volume. Within-run variability of this measure was 8 +/- 4% (SD) (coeff of variation). This variability could not be explained by changes in lung volume or differences in phase of respiration. Five subjects had tracheal and pharyngeal area measured by using both the custom-made wax mouthpiece (W) and a commercial rubber pulmonary function mouthpiece (R). Reproducibility of pharyngeal AAAR was within 10% (coeff of variation) using R, but measurements of pharyngeal AAAR varied with the different types of mouthpiece, as W/R ranged from 0.72 to 1.70. In contrast, measurements of midtracheal area were similar for both mouthpiece types [mean W/R = 0.97 +/- 14 (SD)]. The acoustic reflection technique yields a reproducible index of pharyngeal size that does not vary with phase of respiration or modest changes in lung volume. Either W or R may be used to make clinical measurements, but the type of mouthpiece should be consistent and specified.

Instrumentation for estimating pulmonary function in patients on positive end-expiratory pressure.

For patients requiring PEEP during ventilation, e.g., patients with respiratory distress syndrome, performing traditional tests of lung function is a complicated problem. The pulmonary mechanics of these patients can change rapidly with potential for a negative impact on oxygenation. In an effort to address these problems, we designed a system with a three-way valve that permits the patient to be switched from the ventilator to a data collection system for the assessment of changes in the disease state. The short periods required for data collection (20 to 30 sec) do not interfere with patient care and are well within the limits of safety. A unique feature of the valved system is that it serves to maintain positive airway pressure during data collection. Tests show that, within the frequency range of interest, the mechanics of the measurement system are not altered by the DC pressures applied to the speaker and the valve itself does not contribute significantly to the serial impedance of the system.

Elastic characteristics of the airway wall.

To examine the elastic behavior of the upper airway, we obtained pressure-area plots from data gathered from acoustic images of the airway and measurements of mouth pressure during tidal breathing in 10 adult human volunteers (dA/dP). These plots revealed both tidal hysteresis and a change in slope as a function of distance along the airway. The slope of the regression line of the dA/dP plots decreased from the pharyngeal region to the trachea and became 0 at the thoracic inlet, the location of which was independently assessed. In most subjects the slope became negative distal to the thoracic inlet. Correlation coefficients between pressure and area approached 1 in the pharyngeal region and 0 at the thoracic inlet. When subjects breathed against a small resistive load (10 cmH2O.1(-1).s) pharyngeal, extrathoracic, and intrathoracic pressure-area plots were exaggerated but the slope at the thoracic inlet was unchanged. We conclude that this pressure-area characteristic defines regional differences in upper airway elasticity and delineates the transition point between the intra- and extrathoracic airways.

Intra-airway thermodynamics during exercise and hyperventilation in asthmatics.

To determine whether exercise and hyperventilation produce the same intrathoracic thermal events in asthmatics, we used a thermal probe to record airstream temperatures during both stimuli at multiple points within the tracheobronchial tree. From these data, the global and regionally distributed exchanges of water and heat that occurred throughout the respiratory tract were calculated. During each provocation, intra-airway temperatures fell equivalently, thereby producing similar intrathoracic water fluxes and heat transfers. Neither stimulus was associated with airway drying, and both resulted in similar distributed losses of thermal energy from the tracheobronchial tree despite small regional heat and water exchanges. The degree of airway obstruction was identical after both challenges; however, the onset of airway narrowing was earlier with hyperventilation and developed in association with more rapid rewarming. These data demonstrate that the hyperpnea of exercise and hyperventilation produce identical thermal consequences within the respiratory tract of asthmatics.

Relationship between lung volume and tracheal area as assessed by acoustic reflection.

To determine whether airway size correlates with measures of lung or body size, we used the acoustic reflection technique to calculate tracheal cross-sectional area in 103 healthy young adults. Men have significantly larger tracheas than women [2.48 +/- 0.08 vs. 1.91 +/- 0.05 (SE) cm2, P less than 0.001]. Within each sex, there is no correlation between tracheal size and body size or maximal expiratory flows. There is a significant positive correlation between tracheal area and vital capacity in males only (r = 0.36, P less than 0.01). These results support the concept of dysanapsis, relatively independent growth of the airways and lung parenchyma, as well as sex-related differences in airway size and growth. Inherent airway size may be a factor in the development and/or progression of lung disease.

Airway response to ultra short-term exposure to ozone.

To determine whether acute short-term exposure to oxidant pollutants can cause changes in respiratory mechanics, we gave 0.5 ppm ozone for 5 min to 7 baboons. We measured pulmonary resistance (RL) and obtained dose response curves to methacholine before and after the exposures. This brief insult increased resistance (control RL = 1.53 +/- 0.21 cm H2O.L-1 s; post-ozone RL = 3.53 +/- 0.54 cm H2O.L-1 s). On a second occasion, 6 of these animals were restudied before and after the administration of cromolyn sodium. Although this drug had no effect on the measurements of mechanics made in the control period, it significantly reduced the ozone-induced changes in mechanics. The increase in RL was 52% of that produced in the first study. The results demonstrated that the ozone injury with its acute and subacute airway sequelae occurs quite rapidly and after very brief exposure. The time course of the change in mechanics and the effects of cromolyn suggest the hypothesis that surface epithelial cells are disrupted, causing subsequent release of bronchoconstricting agents.

Heat and water flux in the intrathoracic airways and exercise-induced asthma.

To explore the relationship between the flux of heat and water within the respiratory tract during exercise and recovery to the development of exercise-induced asthma (EIA), we recorded airstream temperature at multiple points throughout the tracheobronchial tree in 10 normal and 10 asthmatic subjects before, during, and after cycle ergometry. In both groups, the intra-airway temperature fell progressively as ventilation increased, and there were no significant differences between the thermal profiles of the two populations at rest or during exercise. Calculation of water losses and the osmolality of the airway surface fluid failed to demonstrate significant airway drying in either group. With cessation of the work load, the airstream temperature increased abruptly, rising two times more rapidly in the asthmatics than the normals. Since the major source of heat in these experiments is the bronchial circulation, our findings suggest a reaction sequence consisting of vasoconstriction and airway cooling during exercise followed by a rapid resupply of heat when exercise ceases. The latter may cause the hyperplastic capillary bed in the airways of asthmatics to develop an exaggerated rebound hyperemia which may lead to airway edema and EIA.