Richard W. Hyde

Pulmonary Function, Diffusing Capacity, and Inflammation in Healthy and Asthmatic Subjects Exposed to Ultrafine Particles

Particulate air pollution is associated with asthma exacerbations and increased morbidity and mortality from respiratory causes. Ultrafine particles (particles less than 0.1 μ m in diameter) may contribute to these adverse effects because they have a higher predicted pulmonary deposition, greater potential to induce pulmonary inflammation, larger surface area, and enhanced oxidant capacity when compared with larger particles on a mass basis. We hypothesized that ultrafine particle exposure would induce airway inflammation in susceptible humans. This hypothesis was tested in a series of randomized, double-blind studies by exposing healthy subjects and mild asthmatic subjects to carbon ultrafine particles versus filtered air. Both exposures were delivered via a mouthpiece system during rest and moderate exercise. Healthy subjects were exposed to particle concentrations of 10, 25, and 50 μ g/m3, while asthmatics were exposed to 10 μ g/m3. Lung function and airway inflammation were assessed by symptom scores, pulmonary function tests, and airway nitric oxide parameters. Airway inflammatory cells were measured via induced sputum analysis in several of the protocols. There were no differences in any of these measurements in normal or asthmatic subjects when exposed to ultrafine particles at concentrations of 10 or 25 μ g/m3. However, exposing 16 normal subjects to the higher concentration of 50 μ g/m3 caused a reduction in maximal midexpiratory flow rate (−4.34 ± 1.78% [ultrafine particles] vs. +1.08 ± 1.86% [air], p =. 042) and carbon monoxide diffusing capacity (−1.76 ± 0.66 ml/min/mm Hg [ultrafine particles] vs. −0.18 ± 0.41 ml/min/mm Hg [air], p =. 040) at 21 h after exposure. There were no consistent differences in symptoms, induced sputum, or exhaled nitric oxide parameters in any of these studies. These results suggest that exposure to carbon ultrafine particles results in mild small-airways dysfunction together with impaired alveolar gas exchange in normal subjects. These effects do not appear related to airway inflammation. Additional studies are required to confirm these findings in normal subjects, compare them with additional susceptible patient populations, and determine their pathophysiologic mechanisms.

Evaluation of the forced oscillation technique for the determination of resistance to breathing

Total respiratory resistance (R(T)) was measured by the application of a sine wave of airflow to the mouth at the resonant frequency of the respiratory system. The mean respiratory resistance of 42 normal subjects, measured at a mean functional residual capacity of 3.3 liters, was 2.3, SD +/- 0.5, cm H(2)O/liter per sec, and the resonant frequency was between 5 and 8 cycle/sec. The airway resistance measured in these same subjects with the body plethysmograph at a mean panting thoracic gas volume of 3.5 liters was 1.3, SD +/- 0.3, cm H(2)O/liter per sec. Total respiratory resistance was found to vary inversely with lung volume (V) measured plethysmographically; prediction formulae for normal subjects based on this relationship are: R(T) (mean) = 7.1/V, R(T) (range) = 4.0/V to 11.6/V where V is in liters and R(T) is in cm H(2)O/liter per sec. When these criteria were applied to subjects with thoracic disease the following results were obtained: 17 subjects with obstructive lung disease all had elevated total respiratory resistance; 9 subjects with diffuse lung disease without airway obstruction all had normal respiratory resistance; all but 1 of 5 obese subjects and all but 2 of a heterogeneous group of 9 subjects without airway obstruction had normal respiratory resistance. Failure to take lung volume into account resulted in a considerable decrease in the ability to discriminate between obstructive and nonobstructive lung disease on the basis of the forced oscillation test. The resonant frequency of the respiratory system of patients with obesity or nonobstructive lung disease was similar to that obtained in the normal group; accurate evaluation of resonant frequency in subjects with obstructive lung disease was frequently not possible. The combined resistances of lung, thoracic wall and abdominal tissues were found to account for less than 43% of the total respiratory resistance in normal subjects and were only slightly increased by the presence of obesity, restrictive diseases of the thoracic wall, and hyperinflation of the thorax. The forced oscillation method is potentially of value in the study of resistance to breathing of patients who cannot undergo body plethysmography, such as acutely ill, anesthetized, or unconscious subjects. Accurate evaluation of R(T) requires an independent measure of lung volume as well as careful attention during measurements to the airflow rate, phase of respiration, and the adequacy of cheek compression and laryngeal relaxation.

Raynaud's phenomenon of the lung☆

To determine if pulmonary vessels develop vasospasm during Raynauds phenomenon, digital vasospasm was induced by hand immersion in 15 degrees C water (cold pressor test) in 17 subjects, and pulmonary function was measured during the subsequent 120 minutes. Five healthy persons were control subjects, seven subjects had well documented systemic disorders associated with Raynauds phenomenon (secondary Raynauds), and five subjects had a history of Raynauds phenomenon but no evidence of an associated disorder (primary Raynauds). The only measure of pulmonary function that changed significantly following cold pressor testing was carbon monoxide diffusing capacity. Subjects with primary Raynauds phenomenon had normal baseline carbon monoxide diffusing capacity (23.7 +/- 4.6 ml/minute/mm Hg) but demonstrated significant decreases (p less than 0.05) at 15 minutes (21.2 +/- 3.5 ml/minute/mm Hg), 45 minutes (19.5 +/- 3.7 ml/minute/mm Hg), and 120 minutes (17.1 +/- 2.1 ml/minute/mm Hg) after cold pressor testing. Subjects with secondary Raynauds phenomenon had low baseline carbon monoxide diffusing capacity (71 percent predicted) and showed no significant change following cold pressor testing. These findings indicate that digital vasospasm in patients with primary Raynauds phenomenon is part of a systemic vascular response that includes a decrease in the size of the pulmonary capillary bed.

Acute Respiratory Distress Syndrome in Pancreatitis

Abstract Analysis of the records of 50 consecutive patients with acute pancreatitis admitted to a general hospital showed that 9 (18%) had diffuse pulmonary infiltrates. Dyspnea and shock were comm...

Amantadine effect on peripheral airways abnormalities in influenza: a study in 15 students with natural influenza A infection

Amantadine HCl administration has resulted in accelerated resolution of influenza A illness. Prolonged abnormalities in pulmonary function have been described in uncomplicated influenza A. To study the effect of amantadine on these changes, we evaluated young adults with documented natural influenza A with clear chest examinations and X rays. Subjects received placebo or amantadine in random, double-blind fashion. Physiologic studies included maximal expiratory flow volume curves with air and helium-oxygen mixtures. Air flow rates were unchanged in all subjects throughout. Initially, both groups showed comparable decreases in mean helium-oxygen maximal expiratory flow rates. The amantadine group showed accelerated physiologic improvement: significant increase in helium-oxygen flow rates occurred within 7 days (P less than 0.05). The rate of improvement in the helium-oxygen flow rates in the placebo group was not statistically significant. These studies confirm peripheral airways dysfunction after uncomplicated influenza A and suggest that amantadine is associated with accelerated resolution of this dysfunction.

Peripheral neuropathy presenting with respiratory insufficiency as the primary complaint: Problem of recognizing alveolar hypoventilation due to neuromuscular disorders

Abstract A 57 year old farmer, initially believed to have hypoventilation secondary to medullary respiratory insensitivity, died with a peripheral neuropathy and marked involvement of the phrenic nerves. Peripheral neuropathy has not previously been reported to present in this manner. Routine pulmonary function tests that would help to distinguish patients with hypoventilation due to neuromuscular disorders from patients with hypoventilation due to diseases of the lung parenchyma and depression of the medullary respiratory centers were investigated. Five subjects with severe neuromuscular disease were studied (arterial carbon dioxide tension [pCO2]48 to 69 mm Hg, vital capacity [VC] 13 to 79 per cent of predicted and 1 second forced expiratory volume [FEV1] 76 to 96 per cent of VC). The mean ratio of maximum mid-inspiratory flow (MMIF) to maximum mid-expiratory flow (MMEF) was 0.79. In age-matched control subjects this ratio was 1.41. In addition to observing the ratio of MMIF to MMEF other effective clinical screening procedures to distinguish patients with hypoventilation secondary to neuromuscular disorders from patients with medullary respiratory insensitivity include (1) identification of weakness of the muscles used for ventilation by measuring the static maximum inspiratory and expiratory airway pressures, (2) determination of ability to lower the arterial pCO2 with voluntary hyperventilation, and (3) comparison of the maximum breathing capacity to the minute ventilation while breathing 7.5 per cent carbon dioxide for 3 minutes. The latter two measurements permit assessment of central hypoventilation in the presence of intrinsic lung disease.

Measurement of Lung Gas Volume and Regional Density by Computed Tomography in Dogs

To determine if computed tomography (CT) can accurately measure lung volume, we compared lung gas volume measured by helium dilution with the equivalent volume calculated from CT total lung volume and density in 13 supine dogs. CT lung gas volume underestimated helium volume by 34% (range: -63 to 0%). Studies of wooden lung phantoms varying in density from 0.082g/cc to 0.776g/cc showed that only 15% of this error could be mimicked by the phantoms. The rest of the discrepancy is attributed to the lungs irregular borders, and the sharp density gradients surrounding and within the lung that result in x-ray beam hardening, sampling limitations, and partial volume measurement errors. Serial biweekly measurements in three dogs for 14 weeks showed CT gas volume to be highly reproducible with less scatter than seen in the helium measurements. Density in the lungs of all dogs showed a uniform gradual decrease from approximately 0.60g/cc at the dependent surface to 0.20g/cc at the superior surface with relatively constant density at any horizontal level. These studies show that whereas CT underestimates gas volume in the lungs, serial measurements are highly reproducible in experimental studies and are a promising technique to monitor diseases or response to therapy. Density gradients in the lungs were sufficiently uniform so that disruption of the normal gradient may be an indicator of early lung disease.

Determination of Distribution of Diffusing Capacity in Relation to Blood Flow in the Human Lung

A method for appraising the distribution of diffusing capacity of the lungs (D(L)) in relationship to pulmonary capillary blood flow ([unk]Q(C)) in normal human subjects was derived from measurements of oxygen diffusing capacity (D(LO2)) and carbon monoxide diffusing capacity (D(LCO)) performed during breath holding. This method utilizes the fact that the observed D(LO2) is considerably reduced in value if uneven distribution of D(L) with respect to [unk]Q(C) (uneven D(L)/[unk]Q(C)) is present. In contrast, D(LCO) is barely affected by uneven D(L)/[unk]Q(C), and from its measured value one can calculate the value D(LO2) would have if no uneven D(L)/[unk]Q(C) were present (true D(LO2)). Once observed D(LO2) and true D(LO2) are known, the degree of uneven D(L)/[unk]Q(C) in the lung can be calculated. In five normal, resting, sitting subjects average values for true D(LO2) were 57 ml per (minute x mm Hg), and the directly measured D(LO2) was 33 ml per (minute x mm Hg). These values could be explained if one-half of total [unk]Q(C) were distributed to approximately 15% of total D(L). These measurements did not permit the determination of the alveolar to end capillary O(2) gradient, but calculations demonstrate that an important factor in determining its size may be the pattern of uneven D(L)/[unk]Q(C) present in the lungs. Estimations of the alveolar-end capillary O(2) gradient from measurements of D(LCO) or D(LO2) that do not take into account uneven D(L)/[unk]Q(C) may underestimate its size.

Rate of disappearance of labeled carbon dioxide from the lungs of humans during breath holding: a method for studying the dynamics of pulmonary CO2 exchange

The dynamics of CO(2) exchange in the lungs of man was studied by observing the rate of disappearance of a stable isotope of CO(2) ((13)CO(2)) from the alveolar gas during breath holding. Over 50% of the inspired isotope disappeared within the first 3 sec followed by a moderately rapid logarithmic decline in which one-half of the remaining (13)CO(2) disappeared every 10 sec. The large initial disappearance of (13)CO(2) indicated that alveolar (13)CO(2) equilibrated in less than 3 sec with the CO(2) stored in the pulmonary tissues and capillary blood. The volume of CO(2) in the pulmonary tissues calculated from this initial disappearance was 200 ml or 0.33 ml of CO(2) per milliliter of pulmonary tissue volume. The alveolar to end-capillary gradient for (13)CO(2) was calculated by comparing the simultaneous disappearance rates of (13)CO(2) and acetylene. At rest and during exercise this gradient for (13)CO(2) was either very small or not discernible, and diffusing capacity for CO(2) (D(LCO2)) exceeded 200 ml/(min x mm Hg). After the administration of a carbonic anhydrase inhibitor the rate of disappearance of (13)CO(2) decreased markedly. D(LCO2) fell to 42 ml/(min x mm Hg) and at least 70% of the exchange of (13)CO(2) with the CO(2) stores in the pulmonary tissues and blood was blocked by the inhibitor. These changes were attributed to impairment of exchange of (13)CO(2) with the bicarbonate in the pulmonary tissues and blood. The pH of the pulmonary tissues (V(tis)) was determined by a method based on the premise that the CO(2) space in the pulmonary tissues blocked by the inhibitor represented total bicarbonate content. At an alveolar P(CO2) of 40 mm Hg pH of V(tis) equalled 6.97 +/- 0.09.

Unintentional Iatrogenic Oxygen Pneumonitis—Response to Therapy

Abstract Five patients with respiratory insufficiency secondary to muscular weakness developed oxygen pneumonitis. During treatment with pressure-cycled ventilators attached to endotracheal tubes (...