"Closing volume" changes in alloxan-induced pulmonary edema in anesthetized dogs.

"Closing volume" (CV) was measured by the single-breath oxygen (SBO2) test in six dogs (alloxan group) before and after alloxan 100-200 mg/kg iv) was injected. CV increased significantly (P less than 0.05) from 32 +/- 3.2% (base line) to 45 +/- 3.5 % in period 1 (0-30 min after alloxan), but vital capacity (VC), respiratory system pressure volume (PV) curves, and alveolar plateau slopes did not change. No radiologic evidence of pulmonary edema was demonstrated in two dogs studied in period 1. CV decreased to 20 +/- 3.9% during period 2 (30-80 min after alloxan) and was associated with tracheal frothing, decreased VC, changes in the PV curve, and alveolar plateau slope, as well as histologic evidence of severe pulmonary edema. CV was 29 +/- 3.0%, and there were no changes in VC, PV curves, or alveolar plateau slopes in 6 other dogs studied for 2 h (control group). CV increased during period 1 before pulmonary edema could be demonstrated by changes in VC, PV curves, or radiography, but in period 2 lung function was so altered that CV by the SBO2 technique gave no useful information.     

Intravenous acid infusion without lowering arterial pH stimulates breathing

The aim of this study was to determine whether increases in ventilation would occur during intravenous acid infusion even if systemic arterial pH was held constant. In six awake ponies, HCl (500 ml, approximately 0.312 M) was infused into the right atrium at a total dose of 1.0 meq/kg over 18 min while an equivalent dose of NaOH was infused into the left heart to restore systemic arterial pH to normal. Total ventilation increased at the onset of the infusion and remained elevated although systemic arterial pH was normal to slightly alkaline. The increase in ventilation during the initial 2 min of the infusion coincided with an increase in pulmonary arterial PCO2 and decrease in pulmonary arterial pH. As the infusion progressed, however, pulmonary arterial pH and PCO2 returned to near control values due to the recirculation of systemic arterial blood with an acid-base status that had been altered consequent to the hyperventilation. Pulmonary arterial blood pressure was increased significantly during the entire infusion. Infusion of equivalent doses of hypertonic saline led to only minor alterations in the variables that were measured. These experiments demonstrate that this dose of intravenous HCl can increase ventilation independent of reductions in systemic arterial pH. Because increases in ventilation and pulmonary arterial H+ were not well correlated throughout the entire infusion, and pulmonary arterial blood pressure was increased, it is not clear if the mechanism for this ventilatory response is due to stimulation of pulmonary chemoreceptors, pulmonary vascular mechanoreceptors, or some other mechanism unrelated to increases in systemic arterial H+ concentration.     

Factors in the development of arterial hypoxemia in middle-aged and elderly people

Partial pressure of oxygen and carbon dioxide in alveolar air and arterial blood, lung diffusion capacity and its components, ventilation parameters, ventilation-perfusion ratio were determined in healthy people aged 60-89 (45 subjects) and aged 20-31 (19 subjects, controls). In elderly and old people PO2 in arterial blood was found to decrease with increasing alveolar-arterial PO2 gradient. In other words, arterial hypoxemia was determined by the disturbance in gas exchange between alveolar air and blood of lung capillaries. The diffusion capacity of lung decreased at the expense of membrane factor. Its age-related dynamics was mainly due to a decrease in the pulmonary diffusion surface occurring because of improper coordination of ventilation and perfusion in the lungs. The discrepancy of pulmonary ventilation and perfusion proved to be the leading factor of arterial hypoxemia in late ontogenesis.     

Effects of increased ventilation on lung lymph flow in unanesthetized sheep

To determine the effect of an increase in spontaneous minute ventilation on lung fluid balance, we added external dead space to the breathing circuit of six tracheostomized, unanesthetized, spontaneously breathing sheep in which lung lymph fistulas had been created surgically. The addition of 120-180 ml of dead space caused minute ventilation to increase by 50-100% (secondary to increases in both tidal volume and frequency), without changing pulmonary arterial pressure, pulmonary capillary wedge pressure, cardiac output, or arterial blood gas tensions. The increase in spontaneous ventilation was associated with an average increase of 27% in lung lymph flow (P less than 0.05) and an average reduction of 11% in the lymph-to-plasma concentration ratio (L/P) for total protein (P less than 0.05). Lymph flow and L/P for total protein approached stable values after 2-3 h of hyperpnea, and the increase in lymph flow persisted for at least 18 h of dead-space breathing. Removal of dead space was associated with a rapid return (within 45 min) of lymph flow to base-line levels. These results suggest that hyperpnea increases the pulmonary transvascular filtration rate. Since no changes in vascular pressures or cardiac output were observed, this increase in transvascular filtration is most likely due to a fall in interstitial fluid pressure.     

拉萨高原居民肺容量的测定

对年龄、身高和体重相同的拉萨男性世居藏族39人和男性移居汉族43人的肺容量进行了测定。结果显示:藏族组的肺活量(VC)、肺总容量、胸围均大于汉族组,残气量有大于汉族组之趋势(P=0.06)。胸围的大小与VC呈正相关。5岁前和18岁后移居高原者之肺容量无差别。结果提示,拉萨世居藏族具有较大的肺容量,这对提高肺弥散功能和维持运动时的血氧饱和度有重要意义。     

Exercise response after rapid intravenous infusion of saline in healthy humans.

Patients with chronic heart failure have an abnormal pattern of exercise ventilation (Ve), characterized by small tidal volumes (Vt), increased alveolar ventilation, and elevated physiological dead space (Vd/Vt). To investigate whether increased lung water in isolation could reproduce this pattern of exercise ventilation, 30 ml/kg of saline were rapidly infused into nine normal subjects, immediately before a symptom-limited incremental exercise test. Saline infusion significantly reduced forced vital capacity, 1-s forced expiratory volume, and alveolar volume (P < 0.01 for all). After saline, exercise ventilation assessed by the Ve/Vco(2) slope increased from 24.9 +/- 2.4 to 28.0 +/- 2.9 l/l, (P < 0.0002), associated with a small decrease in arterial Pco(2), but without changes in Vt, Vd/Vt, or alveolar-arterial O(2) difference. A reduction in maximal O(2) uptake of 175 +/- 184 ml/min (P < 0.02) was observed in the postsaline infusion exercise studies, associated with a consistent reduction in maximal exercise heart rate (8.1 +/- 5.9 beats/min, P < 0.01), but without a change in the O(2) pulse. Therefore, infusion of saline to normal subjects before exercise failed to reproduce either the increase in Vd/Vt or the smaller exercise Vt described in heart failure patients. The observed increase in Ve can be attributed to dilution acidosis from infusion of the bicarbonate-free fluid and/or to afferent signals from lung and exercising muscles. The reduction in maximal power output, maximal O(2) uptake, and heart rate after saline infusion may be linked to accumulation of edema fluid in exercising muscle, impairing the diffusion of O(2) to muscle mitochondria.     

Effect of volume history on distribution of inspired gas in asthmatics

Twelve stable adult asthmatics slowly inhaled boluses of He at 20, 40, or 60% vital capacity (VC); these volumes were achieved either by expiring from total lung capacity (TLC) or by inspiring from residual volume (RV). Inspirations were continued to TLC and then were followed by slow expirations to RV while expired He was measured as a function of expired volume. At 20% VC slopes of alveolar plateaus (phase III) were positive, at 40% VC they were flat, and at 60% VC they were negative; at 20 and 60% VC the slopes were steeper than those in normals. When boluses were administered at 40 and 60% VC, He washout curves were independent of lung volume history. However at 20% VC the slope of phase III was significantly less positive when boluses were given after inspiration from RV than after expiration from TLC. In eight subjects, who were given inhaled beta-agonists, slopes of all He washouts decreased and became independent of volume history at 20% VC. We conclude that in asthmatics at low lung volumes the airways that determine ventilation distribution behave as though they have less hysteresis than the lung parenchyma probably due to increased airway tone.     

Pattern of diaphragmatic activity during forced expiratory vital capacity

We measured transdiaphragmatic pressure (Pdi) during forced expiratory vital capacity (FVC) maneuvers in 13 normal subjects and electromyographic activity of the diaphragm (edi) in 8 of these subjects. In all subjects, Pdi increased at the initiation of the FVC. In most, this increase lasted 30--50 ms and reached levels well above the Pdi observed at total lung capacity (TLC). After the initial transient increase, approximately half of the subjects demonstrated a substantial fall in Pdi to values near the relaxation level in the mid-vital capacity (VC) volume range, while half showed a second large increase in Pdi in this volume range. Seven of eight subjects tested showed a rapid decrease in Edi at the onset of the FVC, reaching a minimum in 30--50 ms. After this initial transient decrease, Edi increased in six subjects in the mid-VC volume range, in association with secondary rises in Pdi. In two subjects, Edi remained low throughout the remainder of the FVC, and Pdi in the mid VC range was generally lower. These results are consistent with the conclusion that the diaphragm is neither electromyographically silent nor mechanically unimportant during the FVC. Changes in abdominothoracic configuration, superimposed upon "antagonistic" activity of the diaphragm, result in substantial reductions in pleural (esophageal) pressure that may influence regional lung emptying during the FVC.     

Effects of positive end-expiratory pressure on the right ventricle

Transmural cardiac pressures, stroke volume, right ventricular volume, and lung water content were measured in normal dogs and in dogs with oleic acid-induced pulmonary edema (PE) maintained on positive-pressure ventilation. Measurements were performed prior to and following application of 20 cmH2O positive end-expiratory pressure (PEEP). Colloid fluid was given during PEEP for ventricular volume expansion before and after the oleic acid administration. PEEP significantly increased pleural pressure and pulmonary vascular resistance but decreased right ventricular volume, stroke volume, and mean arterial pressure in both normal and PE dogs. Although the fluid infusion during PEEP raised right ventricular diastolic volumes to the pre-PEEP level, the stroke volumes did not significantly increase in either normal dogs or the PE dogs. The fluid infusion, however, significantly increased the lung water content in the PE dogs. Following discontinuation of PEEP, mean arterial pressure, cardiac output, and stroke volume significantly increased, and heart rate did not change. The failure of the stroke volume to increase despite significant right ventricular volume augmentation during PEEP indicates that positive-pressure ventilation with 20 cmH2O PEEP decreases right ventricular function.     

Short-term hypoxic exposure at rest and during exercise reduces lung water in healthy humans.

Hypoxia and hypoxic exercise increase pulmonary arterial pressure, cause pulmonary capillary recruitment, and may influence the ability of the lungs to regulate fluid. To examine the influence of hypoxia, alone and combined with exercise, on lung fluid balance, we studied 25 healthy subjects after 17-h exposure to 12.5% inspired oxygen (barometric pressure = 732 mmHg) and sequentially after exercise to exhaustion on a cycle ergometer with 12.5% inspired oxygen. We also studied subjects after a rapid saline infusion (30 ml/kg over 15 min) to demonstrate the sensitivity of our techniques to detect changes in lung water. Pulmonary capillary blood volume (Vc) and alveolar-capillary conductance (D(M)) were determined by measuring the diffusing capacity of the lungs for carbon monoxide and nitric oxide. Lung tissue volume and density were assessed using computed tomography. Lung water was estimated by subtracting measures of Vc from computed tomography lung tissue volume. Pulmonary function [forced vital capacity (FVC), forced expiratory volume after 1 s (FEV(1)), and forced expiratory flow at 50% of vital capacity (FEF(50))] was also assessed. Saline infusion caused an increase in Vc (42%), tissue volume (9%), and lung water (11%), and a decrease in D(M) (11%) and pulmonary function (FVC = -12 +/- 9%, FEV(1) = -17 +/- 10%, FEF(50) = -20 +/- 13%). Hypoxia and hypoxic exercise resulted in increases in Vc (43 +/- 19 and 51 +/- 16%), D(M) (7 +/- 4 and 19 +/- 6%), and pulmonary function (FVC = 9 +/- 6 and 4 +/- 3%, FEV(1) = 5 +/- 2 and 4 +/- 3%, FEF(50) = 4 +/- 2 and 12 +/- 5%) and decreases in lung density and lung water (-84 +/- 24 and -103 +/- 20 ml vs. baseline). These data suggest that 17 h of hypoxic exposure at rest or with exercise resulted in a decrease in lung water in healthy humans.     

Pharyngeal cross-sectional area in normal men and women

Pharyngeal size and the dynamic behavior of the upper airway may be important factors in modulating respiratory airflow. Patients with obstructive sleep apnea are known to have reduced pharyngeal cross-sectional area. However, no systematic measurements of pharyngeal area in healthy asymptomatic subjects are available, in part due to the lack of simple, rapid, and noninvasive measurement techniques. We utilized the acoustic reflection technique to measure pharyngeal cross-sectional area in 24 healthy volunteers (14 males, 10 females). Pharyngeal area was measured during a continuous slow expiration from total lung capacity (TLC) to residual volume (RV). We compared pharyngeal cross-sectional areas in males and females at three lung volumes: TLC, 50% of vital capacity (VC), and RV. In males, pharyngeal areas (means +/- SD) were 6.4 +/- 1.3 cm2 at TLC, 5.4 +/- 0.9 cm2 at 50% VC, and 4.1 +/- 0.8 cm2 at RV. In females, pharyngeal areas were 4.8 +/- 0.6 cm2 at TLC, 4.2 +/- 0.5 cm2 at 50% VC, and 3.7 +/- 0.6 cm2 at RV. The difference in area between males and females was statistically significant at TLC and 50% VC but not at RV. However, when the pharyngeal cross-sectional area was normalized for body surface area, this difference was not significant. In males there was a negative correlation of pharyngeal area with age. We conclude that sex differences in pharyngeal area are related to body size, pharyngeal area shows a similar variation with lung volumes in males and females, and in males pharyngeal area reduces with age.     

Relation between Pulmonary Gas Exchange and Closing Volume before and after Substantial Weight Loss in Obese Subjects

Relations between expiratory reserve volume (ERV), closing volume (CV) as a percentage of vital capacity (CV/VC%), and pulmonary gas exchange have been investigated in the sitting and supine postures in eight severely obese subjects before and after substantial weight loss. CV/VC% exceeded predicted values but did not change with posture or weight loss; the increase could have been owing to the smoking habits of the subjects. Arterial oxygen pressure (PaO₂) was significantly less in the supine than in the sitting posture and improved after weight loss in six subjects. The reduction in PaO₂ was correlated with the extent to which dependent airways were closed within the range of tidal breathing, shown by increasing negativity of ERV-CV as a percentage of VC. A good correlation was also found between PaO₂ and ERV, an easier measurement for routine use. Improvement of pulmonary gas exchange occurred only in those patients who lost weight to within 30% in excess of ideal.     

Effect of a regional increase in alveolar pressure on pulmonary blood flow.

We examined whether wedging a catheter (0.5 cm OD) into a subsegmental airway in dog (n = 6) or pig lungs (n = 5) and increasing pressure in the distal lung segment affected pulmonary blood flow. Dogs and pigs were anesthetized and studied in the prone position. Pulmonary blood flow was measured by injecting radiolabeled microspheres (15 microns diam) into the right atrium when airway pressure (Pao) was 0 cmH2O and pressure in the segment distal to the wedged catheter (Ps) was 0, 5, or 15 cmH2O and when Pao = Ps = 15 cmH2O. The lungs were excised, air-dried, and sectioned. Blood flow per gram dry weight normalized to cardiac output to the right or left lung, as appropriate, was calculated for the test segment, a control segment in the opposite lung corresponding anatomically to the test segment, the remainder of the lung containing the test segment (test lung), and the remainder of the lung containing the control segment (control lung). The presence of the catheter reduced blood flow in the test segment compared with that in the control segment and in the test lung. Blood flow was not affected by increasing pressure in the test segment. We conclude that, in studies designed to measure collateral ventilation in dog lungs, the presence of the wedged catheter is likely to have a greater effect on blood flow than the increase in pressure associated with measuring collateral airway resistance.     

Increased pulmonary vascular filtration pressure does not alter lung liquid secretion in fetal sheep.

The purpose of this study was to determine whether an increase in pulmonary vascular filtration pressure affects net production of liquid within the lumen of the fetal lung. We studied 14 chronically catheterized fetal lambs [130 +/- 3 (SD) days gestation] before, during, and after a 4-h rapid (500 ml/h) intravenous infusion of isotonic saline. In seven fetuses we measured pulmonary arterial and left atrial pressures, lung lymph flow, and protein osmotic pressures in plasma and lymph. In eight lambs with a chronically implanted tracheal loop cannula, we measured the change in luminal lung liquid volume over time by progressive dilution of tracheally instilled 125I-albumin, which stays within the lung lumen. Saline infusion increased pulmonary vascular pressures by 2-3 mmHg and decreased the plasma-lymph difference in protein osmotic pressure by 1 mmHg. Lung lymph flow increased from 1.9 +/- 0.6 to 3.9 +/- 1.2 (SD) ml/h; net production of luminal lung liquid did not change (12 +/- 5 to 12 +/- 6 ml/h). Thus an increase in net fluid filtration pressure in the pulmonary circulation, which was sufficient to double lung lymph flow, had no significant effect on luminal lung liquid secretion in fetal sheep.     

Expiratory muscle activity during pulmonary edema in the anesthetized dog.

The present study evaluated the reflex response of the expiratory muscles to pulmonary congestion and edema. The electromyograms of two thoracic and four abdominal expiratory muscles were recorded in 12 anesthetized dogs. Pulmonary edema was induced by rapid saline infusion in six dogs and injection of oleic acid into the pulmonary circulation in the remaining six dogs. Both forms of pulmonary edema reduced pulmonary compliance, interfered with gas exchange, and induced a rapid and shallow breathing pattern. The electrical activity of all abdominal muscles was suppressed during both forms of pulmonary edema. In contrast, the electromyogram activity of the thoracic expiratory muscles was not significantly affected by pulmonary edema. Acute pulmonary arterial hypertension produced in two dogs by inflating a balloon in the left atrium had no effect on ventilation or expiratory muscle electrical activity. In two vagotomized dogs, pulmonary edema did not inhibit the expiratory muscles. We conclude that pulmonary edema suppresses abdominal but not thoracic expiratory muscle activity by vagal reflex pathway(s). Extravasation of fluid into the lung appears to be more important than an increase in pulmonary vascular pressure in eliciting this response.     

A control system for arterial blood gases

A system was developed to control arterial O2 and CO2 partial pressure (Pao2, and Paco2) simultaneously and independently of each other. The system makes changes in inspired fractional concentration of O2 and CO2 based on values for end-tidal O2 and CO2 partial pressure. The system was applied in 23 normal subjects. In attempts to maintain a Pao2 of 90 Torr and a Paco2 of 40 Torr, arterial blood gases were 91.1 +/- 6.5 (SD) Torr for Pao2 and 41.2 +/- 3.2 Torr for Paco2. In attempts to maintain a Pao2 of 40 Torr and a Paco2 of 40 Torr, arterial blood gases were 40.4 +/- 3.9 Torr for Pao2 and 38.9 +/- 2.5 Torr for Paco2. In attempts to maintain a Pao2 of 90 Torr and a Paco2 of 55 Torr, arterial blood gases were 98.1 +/- 11.5 Torr for Pao2 and 52.8 +/- 3.4 Torr for Paco2. Coefficients of variations ranged from 7.1 to 11.7% for Pao2 and 6.4 to 7.8% for Paco2.     

Respiratory mechanics and breathing pattern during and following maximal exercise

We looked for evidence of changes in lung elastic recoil and of inspiratory muscle fatigue at maximal exercise in seven normal subjects. Esophageal pressure, flow, and volume were measured during spontaneous breathing at increasing levels of cycle exercise to maximum. Total lung capacity (TLC) was determined at rest and immediately before exercise termination using a N2-washout technique. Maximal inspiratory pressure and inspiratory capacity were measured at 1-min intervals. The time course of instantaneous dynamic pressure of respiratory muscles (Pmus) was calculated for the spontaneous breaths immediately preceding exercise termination. TLC volume and lung elastic recoil at TLC were the same at the end of exercise as at rest. Maximum static inspiratory pressures at exercise termination were not reduced. However, mean Pmus of spontaneous breaths at end exercise exceeded 15% of maximum inspiratory pressure in five of the subjects. We conclude that lung elastic recoil is unchanged even at maximal exercise and that, while inspiratory muscles operate within a potentially fatiguing range, the high levels of ventilation observed during maximal exercise are not maintained for a sufficient time to result in mechanical fatigue.     

Serial changes in nasal potential difference and lung electrical impedance tomography at high altitude.

Recent work suggests that treatment with inhaled beta(2)-agonists reduces the incidence of high-altitude pulmonary edema in susceptible subjects by increasing respiratory epithelial sodium transport. We estimated respiratory epithelial ion transport by transepithelial nasal potential difference (NPD) measurements in 20 normal male subjects before, during, and after a stay at 3,800 m. NPD hyperpolarized on ascent to 3,800 m (P < 0.05), but the change in potential difference with superperfusion of amiloride or isoprenaline was unaffected. Vital capacity (VC) fell on ascent to 3,800 m (P < 0.05), as did the normalized change in electrical impedance (NCI) measured over the right lung parenchyma (P < 0.05) suggestive of an increase in extravascular lung water. Echo-Doppler-estimated pulmonary artery pressure increases were insufficient to cause clinical pulmonary edema. There was a positive correlation between VC and NCI (R(2) = 0.633) and between NPD and both VC and NCI (R(2) = 0.267 and 0.418). These changes suggest that altered respiratory epithelial ion transport might play a role in the development of subclinical pulmonary edema at high altitude in normal subjects.     

Genetic variation of the beta2-adrenergic receptor is associated with differences in lung fluid accumulation in humans.

The beta2-adrenergic receptors (beta2AR) play an important role in lung fluid regulation. Previous research has suggested that subjects homozygous for arginine at amino acid 16 of the beta2AR (Arg16) may have attenuated receptor function relative to subjects homozygous for glycine at the same amino acid (Gly16). We sought to determine if the Arg16Gly polymorphism of the beta2AR influenced lung fluid balance in response to rapid saline infusion. We hypothesized that subjects homozygous for Arg at amino acid 16 (n=14) would have greater lung fluid accumulation compared with those homozygous for Gly (n=15) following a rapid intravenous infusion of isotonic saline (30 ml/kg over 17 min). Changes in lung fluid were determined using measures of lung density and tissue volume (computerized tomography imaging) and measures of pulmonary capillary blood volume (Vc) and alveolar-capillary conductance (DM, determined from the simultaneous assessment of the diffusing capacities of the lungs for carbon monoxide and nitric oxide). The saline infusion resulted in elevated catecholamines in both genotype groups (Arg16 283+/-117% vs. Gly16 252+/-118%, P>0.05). The Arg16 group had a larger decrease in DM and increase in lung tissue volume and lung water after saline infusion relative to the Gly16 group (DM -13+/-14 vs. 0+/-26%, P<0.05; lung tissue volume 13+/-11 vs. 3+/-11% and lung water +90+/-66 vs. +48+/-144 ml, P=0.10, P<0.05, for Arg vs. Gly16, respectively, means+/-SD). These data suggest that subjects homozygous for Arg at amino acid 16 of the beta2AR have a greater susceptibility for lung fluid accumulation relative to subjects homozygous for Gly at this position.