Airway insufflation. Increasing flow rates progressively reduce dead space in respiratory failure.

We have previously shown that airway insufflation (AI) reduces dead space (VD) and minute ventilation (VL) in patients with respiratory failure, and when used chronically leads to lowered and more stable arterial PCO2. The present study was designed to measure the effect of increasing AI flow rate on VD and other aspects of gas exchange in respiratory failure in order to examine the hypothesis that AI exerts its main physiologic effect by progressive reductions of VD. Five patients with varying degrees of respiratory failure caused by either restrictive or obstructive lung disease were studied by means of the specialized techniques we developed to analyze gas exchange during AI. At 1 L/min (as in transtracheal oxygenation), at 5 L/min, and 8 L/min, AI produced progressive reductions in VD, tidal volume, and VL. Contrary to our previous study, some of these patients accompanied the decrease in VD with not only decreases in VL but with slight rises in alveolar ventilation (VA) and decrements in arterial PCO2. The greatest percentile decreases in VD and VL occurred in those with the smallest initial control values for each of these parameters. In summary, AI exerts its main effects on gas exchange through the reductions in VD that it produces, and the accompanying decreases in VL and/or slight increases in VA seem to stem from the latter.

The lung mucosa: a critical environmental battleground.

The entirety of the lung mucous membrane and epithelial surface are exposed to the environment; react to noxious environmental gases, vapors, and particles; and are under physiologic and humoral mediator control. In recent years much information has been gained regarding the mucous membrane of the tracheobronchial tree, its physiology, and its reaction to environmental hazards. The pharmacologic control of secretion, ciliary beat rate, and net mucus flow governs both the clearance of mucus and the clearance of particles. The physiologic factors that govern this clearance mechanism can be influenced by pharmacologic agents in patients with lung disease and presumably also in patients with purely environmental injury. The effects of ozone on lung function, lung compliance, and airway resistance have been well documented in adults and children. Environmental ozone also alters mucous membrane function, increasing mucociliary secretion rate and peripheral lung clearance. The speed-up in clearance implies an increase in mucous gland secretion, which may act unfavorably when ciliary beat is damaged, glandular hypertrophy is present, or flow-limiting segments exist, as is usually the case in bronchial asthma and chronic obstructive pulmonary disease. Thus, whereas the consequences of ozone may be modest for a normal, healthy individual, they presumably increase hazards for the individual with lung disease or damage. For this reason, efforts should be made to control or limit damage by ozone or other environmental inhalants in such individuals. This goal may be facilitated by a wider knowledge of the pharmacologic control of the mucous membrane.

Survival in patients with primary pulmonary hypertension. Results from a national prospective registry.

OBJECTIVE: To characterize mortality in persons diagnosed with primary pulmonary hypertension and to investigate factors associated with survival. DESIGN: Registry with prospective follow-up. SETTING: Thirty-two clinical centers in the United States participating in the Patient Registry for the Characterization of Primary Pulmonary Hypertension supported by the National Heart, Lung, and Blood Institute. PATIENTS: Patients (194) diagnosed at clinical centers between 1 July 1981 and 31 December 1985 and followed through 8 August 1988. MEASUREMENTS: At diagnosis, measurements of hemodynamic variables, pulmonary function, and gas exchange variables were taken in addition to information on demographic variables, medical history, and life-style. Patients were followed for survival at 6-month intervals. MAIN RESULTS: The estimated median survival of these patients was 2.8 years (95% Cl, 1.9 to 3.7 years). Estimated single-year survival rates were as follows: at 1 year, 68% (Cl, 61% to 75%); at 3 years, 48% (Cl, 41% to 55%); and at 5 years, 34% (Cl, 24% to 44%). Variables associated with poor survival included a New York Heart Association (NYHA) functional class of III or IV, presence of Raynaud phenomenon, elevated mean right atrial pressure, elevated mean pulmonary artery pressure, decreased cardiac index, and decreased diffusing capacity for carbon monoxide (DLCO). Drug therapy at entry or discharge was not associated with survival duration. CONCLUSIONS: Mortality was most closely associated with right ventricular hemodynamic function and can be characterized by means of an equation using three variables: mean pulmonary artery pressure, mean right atrial pressure, and cardiac index. Such an equation, once validated prospectively, could be used as an adjunct in planning treatment strategies and allocating medical resources.

Supramicron-sized particle clearance from alveoli: route and kinetics.

Particles inhaled and deposited in the alveoli of the lung, i.e., distal to the tracheobronchial mucociliary escalator, may theoretically be cleared by several routes, including solubilization, lymphatic drainage, and the mucociliary pathway. We studied the clearance routes and kinetics of an inert insoluble carbonized polystyrene particle of supramicron size (2.85 micron count median diameter) tagged with 57Co (half-life 270 days) in the adult unanesthetized sheep. The rate of particle clearance, assessed by gamma scintillation camera of the whole lung, showed a three-exponential function, comprising a rapid initial phase in the first 44 h of clearance for tracheobronchial deposition followed by a slower phase of mostly alveolar clearance in the next 30 days and a final phase of very slow relatively pure alveolar clearance. A balance study of particle route during clearance and autopsy of regional thoracic lymph nodes, blood, liver, and spleen demonstrated that this supramicron-sized particle cleared from alveoli predominantly via the mucociliary escalator of the tracheobronchial tree. Whole-lung lavage studies showed particle and macrophage recovery rates suggesting a sequestered state for alveolar-deposited particles, which may partly account for their slow clearance rates. The failure to find interstitial penetration by alveolar-deposited particles indicates that the macrophages engulfing these particles, at low particle burdens, travel normally in only one direction, i.e., from interstitium to alveolus and then to the mucociliary escalator.

Clinical role of bronchoalveolar lavage in adults with pulmonary disease.

BAL remains a powerful investigative tool. In a short span of 20 yr, it has helped tremendously in understanding some of the aspects of the pathogenesis of diseases involving the lower respiratory tract. To realize its full potential in the diagnosis and management of diseases involving the lower respiratory tract, there is a great need for standardization of the technical aspects of BAL as well as processing and analysis of the BAL cellular- and fluid-phase components. Despite these hurdles, BAL has been found to be diagnostic in several infectious and noninfectious diseases involving the lower respiratory tract, and it provides valuable information that may be helpful in characterizing the prognosis and response to therapy in certain interstitial diseases of the lung. It is expected that with future research, in particular long-term prospective epidemiologic and clinical studies in pneumoconioses and in other interstitial lung disease, BAL will prove more valuable in the diagnosis and management of such disease.

Determining deposition sites of inhaled lung particles and their effect on clearance.

An essential component of lung defense is clearance of particulates and infectious vectors from the mucus membrane of the tracheobronchial tree and the alveolar regions of the lung. To partition clearance between these areas we determined the bronchial branching pattern, the anatomical sites of particle deposition, and subsequent clearance in the same animal. Using a 2.85-microns particle tagged with 57Co for inhalation and deposition in the sheep lung, we followed clearance via a series of computer-stored gamma-scintillation lung images. The same sheep was reinhaled, and the particle distributions for both inhalations were compared. After the animals were killed, the bronchial branching pattern and length of the bronchial tree were documented. The number of particles depositing in all bronchi down to 1 mm diam was determined by scintillation counting, and the number in respiratory bronchioles and alveoli was microscopically counted. We conclude that particles deposited in bronchi greater than or equal to 1 mm diam clear in 2-4 h postdeposition. Bronchi distal to 1-mm-diam bronchi and alveoli clear evenly over 72 h, and the number of particles equal to the tracheobronchial deposition cleared after 45 h.

Large and small airway responses to bronchoconstrictors in the guinea pig and ferret.

In the isolated, perfused lung lobe of the ferret we evaluated the bronchoconstrictor response of its airways to methacholine and histamine, pharmacologic agents associated with the asthmatic state. The bronchus of excised lobes was cannulated and needle scarifications were made on the pleural surface to allow perfusate to exit. Lung airways were perfused at constant flow with equilibrated 95% O2/5% CO2, warmed Krebs-Ringers solution. Perfusion pressure was measured as a gauge of airway resistance. A concentration-dependent smooth muscle contraction of the ferret lung lobes was observed to methacholine and histamine. The ED50's of methacholine and histamine were 6.41 x 10(-6) M +/- 1.38 x 10(-6) (SEM) and 6.41 x 10(-6) M +/- 1.38 x 10(-6) (SEM) and 2.39 x 10(-6) M +/- 0.53 x 10(-6) (SEM), respectively. The maximum level of bronchoconstriction developed in the ferret (2.42 mmHg/ml/min +/- 0.28 SEM (resistance units] in response to methacholine, was six times greater than that found for histamine (0.42 mmHg/ml/min +/- 0.05 SEM). Responses to both agonists were less pronounced in the ferret lung preparation than those in a similar lung preparation of guinea pig. Compliance changes in both animals were also evaluated. The ferret did not demonstrate a compliance change in response to histamine as was seen for methacholine, suggesting that resistance changes precede compliance changes, or that the ferret airways are particularly resistant to histamine. Despite a lesser contractile response, the ferret has the advantage of a relatively large lung and long trachea that allow study in several preparations obtained from a single animal. It should prove a useful animal model for study of pulmonary pharmacology.

The acute administration of vasodilators in primary pulmonary hypertension. Experience from the National Institutes of Health Registry on Primary Pulmonary Hypertension.

The hemodynamic responses to acute vasodilator administration were evaluated in 163 patients who were entered into the National Institutes of Health Registry on Primary Pulmonary Hypertension (PPH) between 1981 and 1985. Of a total of 491 drug administrations in these patients, 135 administrations in 104 patients were performed in a manner acceptable to the Registry. A single vasodilator was tried in 79 patients and more than one vasodilator in 25 patients. Two-thirds of the patients were in New York Heart Association Functional Classes III or IV. When the effects of all vasodilators were grouped together, there were significant decreases from baseline in mean pulmonary artery pressure (60 +/- 2 to 57 +/- 2 mm Hg, p less than 0.05) and total pulmonary resistance index (32.5 +/- 1.7 to 25.1 +/- 1.4 mm Hg/L/min/m2, p less than 0.0001), and increases in cardiac index (2.1 +/- 0.1 to 2.7 +/- 0.1 L/min/m2, p less than 0.0001). Mean systemic blood pressure fell (88 +/- 1 to 79 +/- 1 mm Hg, p less than 0.0001), whereas PaO2 was unchanged (70 +/- 3 to 71 +/- 3 mm Hg, p = NS). A fall in total pulmonary resistance greater than 20% was observed in 55% of the adequate drug trials. Adverse effects occurred in 32 of the total 491 patient-drug trials and were generally minor. Hypotension requiring treatment developed in six patients. There were two deaths attributable to vasodilator administration. Patients who died or had hypotension requiring treatment had higher right atrial pressures than did other treated patients (15 +/- 2 versus 9 +/- 1 mm Hg, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Histopathology of primary pulmonary hypertension. A qualitative and quantitative study of pulmonary blood vessels from 58 patients in the National Heart, Lung, and Blood Institute, Primary Pulmonary Hypertension Registry.

Qualitative and quantitative studies were performed on pulmonary blood vessels in lung tissue obtained by biopsy, pneumonectomy, or autopsy from 58 patients in the Registry of Primary Pulmonary Hypertension sponsored by the Heart, Lung, and Blood Institute of the National Institutes of Health. In 49 patients (84%), the hypertensive vascular disease involved predominantly or exclusively muscular pulmonary arteries and arterioles. In each of these 49 patients, pulmonary artery medial hypertrophy was observed, and in 48 patients, it was also associated with intimal or luminal lesions. On the basis of the predominant histopathologic features, 25 of the 48 patients were classified as having pulmonary arteriopathy with plexiform lesions characterized by a combination of concentric laminar intimal fibrosis, eccentric intimal fibrosis, and plexiform lesions; in nine of these 25, recanalized thrombi were also present. Pulmonary arteriopathy with thrombotic lesions, defined by the presence of both eccentric intimal fibrosis and recanalized thrombi but without plexiform lesions, was observed in 19 patients. Intimal fibrosis, either concentric or eccentric, without plexiform or thrombotic lesions was found in four patients. Among the remaining nine patients in the Registry, pulmonary veno-occlusive disease was present in seven and chronic pulmonary venous hypertension in one. Pulmonary blood vessels were microscopically normal in a lung biopsy specimen from another patient. In general, patients with plexiform lesions and those with veno-occlusive disease had a much poorer prognosis than patients with thrombotic lesions. The present study shows the existence of several distinct histopathologic patterns of pulmonary vascular disease in individuals with primary pulmonary hypertension diagnosed by standardized clinical and laboratory criteria.

Airway insufflation: physiologic effects on acute and chronic gas exchange in humans.

Reduction in dead space through conventional tracheostomy has been used to treat patients with chronic CO2 retention. The insufflation of air directly into the trachea by transtracheal catheter (airway insufflation, AI) provides reductions in dead space as great or greater than those of tracheostomy. The physiologic effects of AI on gas exchange have not been adequately studied because instillation of gases into the trachea contaminates minute ventilation (VL), dead space volume (VD), tidal volume (VT), and other indices of gas exchange, as measured by usual technics. We overcame this problem by devising special methods of measuring inspired and expired ventilation, alveolar and dead space ventilation, and VT and VD by using pneumotachographic timing of inspiration and expiration so that true inspired and expired ventilation were calculated. We studied 5 patients with chronic CO2 retention from either COPD, scoliosis, or muscular dystrophy (annual average PaCO2 = 45 to 75 mm Hg) during 75 min of AI with serial gas exchange and arterial blood gas measurements. AI at about 5 L/min of room air through the trachea in 5 patients reduced VL by 18% (from 7.91 to 6.48 L/min), VT by 25% (from 450 to 338 ml), and VD by 37% (from 223 to 141 ml), while not affecting PaCO2 (from 51.8 to 48.2 mm Hg) or PaO2 (from 65.1 to 63.4 mm Hg). In 2 patients, AI administered continuously for 4 to 12 months (as 30 to 50% O2) maintained PaCO2 as well as or better than breathing enriched O2 from a tracheal collar via an open tracheostomy.(ABSTRACT TRUNCATED AT 250 WORDS)

Calculating concentration of inhaled radiolabeled particles from external gamma counting: external counting efficiency and attenuation coefficient of thorax.

We determined the overall external counting efficiency of radiolabeled particles deposited in the sheep lung. This efficiency permits the noninvasive calculation of the number of particles and microcuries (microCi) from gamma-scintillation lung images of the live sheep. Additionally, we have calculated the attenuation of gamma radiation (120 keV) by the posterior chest wall and the gamma-scintillation camera collection efficiency of radiation emitted from the lung. Four methods were employed in our experiments: (1) by light microscopic counting of discrete carbonized polystyrene particles with a count median diameter (CMD) of 2.85 microns and tagged with cobalt-57 (57Co), we delineated a linear relationship between the number of particles and the emitted counts per minute (cpm) detected by well scintillation counting; (2) from this conversion relationship we determined the number of particles inhaled and deposited in the lungs by scintillation counting fragments of dissected lung at autopsy; (3) we defined a linear association between the number of particles or microcuries contained in the lung and the emitted radiation as cpm detected by a gamma scintillation camera in the live sheep prior to autopsy (external counting efficiency); and (4) we compared the emitted radiation from the lungs of the live sheep to that of whole excised lungs in order to calculate the attenuation coefficient (ac) of the chest wall. The mean external counting efficiency was 4.00 X 10(4) particles/cpm (5.1 X 10(-3) microCi/cpm), the camera collection efficiency was 1 cpm/10(4) disintegrations per minute (dpm), and the ac had a mean of 0.178/cm. The external counting efficiency remained relatively constant over a range of particles and microcuries, permitting a more general use of this ratio to estimate number of particles or microcuries depositing after inhalation in a large mammalian lung if a similarly collimated gamma camera system is used.

Primary pulmonary hypertension. A national prospective study.

A national registry was begun in 1981 to collect data from 32 centers on patients diagnosed by uniform criteria as having primary pulmonary hypertension. Entered into the registry were 187 patients with a mean age (+/- SD) of 36 +/- 15 years (range, 1 to 81), and a female-to-male ratio of 1.7:1 overall. The mean interval from onset of symptoms to diagnosis was 2 years. The most frequent presenting symptoms included dyspnea (60%), fatigue (19%), and syncope (or near syncope) (13%). Raynaud phenomenon was present in 10% (95% of whom were female) and a positive antinuclear antibody test, in 29% (69% female). Pulmonary function studies showed mild restriction (forced vital capacity [FVC], 82% of predicted) with a reduced diffusing capacity for carbon monoxide (DLCO), and hypoxemia with hypocapnia. The mean (+/- SD) right atrial pressure was 9.7 +/- 6 mm Hg; mean pulmonary artery pressure, 60 +/- 18 mm Hg; cardiac index, 2.3 +/- 0.9 L/min X m2; and pulmonary vascular resistance index, 26 +/- 14 mm Hg/L/min X m2 for the group. Although no deaths or sustained morbid events occurred during the diagnostic evaluation of the patients, the typically long interval from initial symptoms to diagnosis emphasizes the need to develop strategies to make the diagnosis earlier.

Airway mucus membrane: effects of beta-adrenergic and anticholinergic stimulation.

Mucus hypersecretion and non-continuous clearance of tracheobronchial mucus contribute to airflow obstruction in several pulmonary disease entities. Bronchospasm, which is frequently associated with bronchial asthma, can present simultaneously with mucus transport abnormalities. Therapy designed to dilate airways may produce secondary effects, which are deleterious to effective transport of lung mucus. Sympathomimetic agents, such as beta-adrenergic agonists, reduce the tone of bronchial smooth muscle and enhance the flow of mucus within lung airways. Parasympatholytic agents also improve airflow in the lungs, but their effects at the mucus membrane of the airways may not be beneficial. Atropine, an anticholinergic agent, apparently has dose-dependent effects on human mucociliary function and, administered orally, can reduce large airway mucus transport. However, newer anticholinergic agents, such as ipratropium bromide, are effective bronchodilators and do not exhibit unfavorable effects on lung mucus transport in either subjects with normal mucus secretion or those with hypersecretory disease entities, such as bronchitis. In mildly symptomatic asthmatic patients, aerosolized ipratropium decreased airway obstruction without consistent positive or negative influence on lung mucociliary function.

Cardiovascular and respiratory consequences of tension pneumothorax.

The physiologic responses to acute pneumothorax were investigated in awake, standing sheep. Pleural pressure (Ppl) was raised in graded increments by injecting air from a 500 ml syringe into the pleural cavity of eight sheep to produce pneumothorax volumes of 0, 17, 35 and 45 ml.kg-1. At the maximum value of 45 ml.kg-1 (approximately equal to 1,400 ml), Ppl at end-expiration was raised to 10 +/- 2 mmHg (mean +/- SD) whereas end-inspiratory Ppl remained negative in half the sheep as the result of increased thoracic pressure swings. The most striking haemodynamic impairment was a 22% fall in stroke volume. Cardiac output, however, remained fixed at baseline values as a result of a 28% rise in heart rate. Although hypotension has been commonly held as a consequence of severe pneumothorax, mean systemic arterial pressure increased, rising by 19% in the entire group at the maximal pneumothorax tolerated. Pulmonary gas exchange was significantly disrupted by pneumothorax, as indicated by both a 40% fall in Pao2 and a 19% reduction in arterial oxygen content. Despite a reduction in tidal volume, the sheep initially remained eucapnic by generating an increased respiratory rate and slightly increasing minute-ventilation. However, at pneumothorax volumes of 45 ml X kg-1, the sheep were no longer able to sustain minute-ventilation and a small rise in PaCO2 followed. The reduced arterial oxygen content and the fixed cardiac output led to a progressive reduction in systemic oxygen transport.(ABSTRACT TRUNCATED AT 250 WORDS)

The adrenergic innervation of pulmonary vasculature in the normal and pulmonary hypertensive rat.

It would appear that susceptibility to chronic proliferative pulmonary hypertension in response to chronic alveolar hypoxia is most severe in species in which adrenergic innervation of pulmonary arteries is reduced or lacking. Intrapulmonary arteries of the rat have been reported to lack adrenergic innervation by some workers but not others. Since the rat develops severe proliferative pulmonary hypertension in response to prolonged alveolar hypoxia, the different divisions of the lung vasculature of Sprague-Dawley rats were thoroughly examined to determine the presence or absence of an adrenergic innervation. The degree of innervation in normal rats was compared with that of rats developing pulmonary hypertension. Both in normal and experimental pulmonary hypertensive rats the pulmonary arteries, all their branches and the small pulmonary veins with a smooth muscle media were found to be devoid of adrenergic innervation. In contrast, the cardiac-like muscle in the media of large pulmonary veins, the bronchial arteries and the vasa vasorum of larger vessels were richly innervated by adrenergic nerves. Thus the increase in medial smooth muscle which occurs in pulmonary arteries during chronic alveolar hypoxia is independent of a pre-existing adrenergic innervation or of such an innervation newly derived from that of adjacent vessels or structures. This is in contrast to systemic vessels where it has been suggested that increased adrenergic activity and density of innervation may augment hypertrophy of the media in hypertensive animals. Adrenergic nerves are suggested to have a protective action on pulmonary vessels.

Disassociation in the mucociliary function of central and peripheral airways of asymptomatic smokers.

Mucociliary function of peripheral airways in asymptomatic smokers may be impaired and contribute to the abnormal airway changes described in these subjects. Techniques using the inhalation and deposition of radioactive particles followed by gamma camera imaging were applied to healthy subjects discordant for smoking habit to determine if mucus transport of peripheral and central airways was altered by smoking. Smokers (n = 8) averaged 26 +/- 2 yr (mean +/- SEM) and less than 7.5 pack-years of smoking, with pulmonary function within normal limits; when compared with the nonsmokers (n = 8) of similar age, their expiratory volumes were similar, i.e., FEV1 as a percent of predicted averaged 94.5 +/- 4% (mean +/- SEM) in the smokers and 98.8 +/- 4% in the nonsmokers. Using 24-h particle retention and planar distribution of particles in the chest as indexes of peripheral and central deposition, the 2 groups had similar deposition patterns. Mucus clearance of particles deposited onto tracheobronchial airways was quantitated as the interval between initial deposition and the time required to attain 75, 50, and 25% retention levels. Six of the 8 smokers had 75% retention times comparable to those of the nonsmokers, but the 50 and 25% retention times differed significantly between the 2 groups (p less than 0.025). Smokers cleared lung mucus at slower rates, i.e., the intervals to attain 25 and 50% retention levels were 60 to 90% greater than the mean values observed for nonsmokers. Velocity of mucus streaming within stem bronchi was comparable for the 2 groups; beta 2-adrenergic stimulation increased mucus transport in the smokers to the baseline control rates of the nonsmokers.(ABSTRACT TRUNCATED AT 250 WORDS)

How alterations in pleural pressure influence esophageal pressure.

Although esophageal pressures have been substituted for direct pleural pressure measurement in humans, we have investigated the validity of this approach under circumstances when left and right pleural pressures are not equal. Esophageal and bilateral pleural pressures in awake sheep were compared by using matched balloon catheters in close proximity. In standing sheep, both end-expiratory pressures and inspiratory pressure swings were similar in all three catheter systems. However, when pleural pressures were made unequal, as during lateral recumbency or unilateral pneumothorax, the esophageal pressure reflected predominantly the right pleural pressure. These results suggest that esophageal pressures are useful estimates of pleural pressure under normal conditions when pleural pressures are equal bilaterally. However, the usefulness of esophageal pressures is limited in the presence of unilateral pneumothorax or other conditions where left and right pleural pressures are unequal. In the lateral decubitus position, positive end-expiratory pleural pressures were consistently observed. This was believed to be due to a combination of contraction of expiratory muscles, rapid respiratory rate resulting in insufficient expiratory time to reach an equilibrium pressure, and increased airways resistance resulting from compression of the dependent lung by the abdominal viscera. A single study in a paralyzed ventilated sheep showed less positive expiratory pressures, which were further reduced to zero or less when the respiratory rate was slowed to 10 breaths/min.