Patricia A. McClean

Effect of low concentrations of ozone on inhaled allergen responses in asthmatic subjects

The relation between inhalation of ambient concentrations of ozone and airway reactivity to inhaled allergens may be important in asthma, since both agents can produce inflammatory changes in the airways. Seven asthmatic patients (mean age 40 [SD 13] years), with seasonal symptoms of asthma and positive skin tests for ragweed or grass, took part in a study to investigate whether exposure to low concentrations of ozone potentiates the airway allergic response. The patients were studied during 4 separate weeks in the winter. In each week there were 3 study days: on days 1 and 3 methacholine challenges were carried out; and on day 2 the subject received one of four combined challenges in a single-blind design--air breathing followed by inhalation of allergen diluent (placebo); ozone followed by inhalation of allergen diluent; air followed by allergen; or ozone followed by allergen. The ozone concentration was 0.12 ppm during 1 h of tidal breathing at rest, and allergens were inhaled until the forced expiratory volume in 1 s (FEV1) had fallen by 15% (PC15). There were no significant differences in baseline FEV1 after exposure to ozone but PC15 was significantly reduced when allergen was preceded by ozone inhalation: the mean PC15 after air was 0.013 (SD 0.017) mg/ml compared with 0.0056 (0.0062) mg/ml after ozone (p = 0.042). Thus, low ozone concentrations, similar to those commonly occurring in urban areas, can increase the bronchial responsiveness to allergen in atopic asthmatic subjects. This effect does not seem to be the result of changes in baseline airway function.

Exhaled nitric oxide and bronchial reactivity during and after inhaled beclomethasone in mild asthma.

The measurement of exhaled nitric oxide (ENO) is recognized as a marker of airway inflammation. ENO was measured in 10 nonsteroid-treated asthmatics at recruitment, during 3 weeks of inhaled beclomethasone (1000 microg/day) and for 3 weeks after withdrawal. Baseline ENO was increased in asthma compared with nonasthmatics (85.0+/-54.5 vs. 24.5+/-14.8 ppb, p < 0.0001). After inhaled steroid, there was no significant change in forced expiratory volume in 1 sec (FEV1) and forced vital capacity (FVC), but methacholine PC20 rose significantly (p = 0.0345). ENO (mean+/-SD; % baseline) fell after 1 week on steroid to 60.6+/-31.1 and rose to 95.3+/-46.1 at 1 week after withdrawal. ENO did not correlate with PC20 or FEV1. The changes in ENO and PC20 were inversely correlated (r2 = 0.325). ENO may be an index of airway inflammation and therapeutic response in bronchial asthma.

A significant proportion of exhaled nitric oxide arises in large airways in normal subjects

Nitric oxide (NO) of endogenous origin is present in exhaled breath. An increase in exhaled NO concentration (ENO) has been described in bronchial asthma and ENO falls after inhaled steroid therapy. The sources of ENO may include pulmonary blood, the gas exchange region, conducting airways and the nasal cavity. In four healthy volunteers, a catheter was placed in a main bronchus after topical anesthesia in order to sample airway NO (CNO). Exhaled nitric oxide of bronchopulmonary and oropharyngeal origin (ENO(b/o)) was measured while excluding nasal NO and was controlled for expiratory flow. During the same exhalation, ENO(b/o) was compared to CNO at multiple sites in the airway as the catheter was progressively withdrawn. Mean CNO concentration in a position corresponding to a main bronchus was 51.4 +/- 10.8% of ENO(b/o). As the catheter was withdrawn, mean CNO concentration progressively increased both in absolute values and as a proportion of ENO(b/o), until in the oropharynx, it was 96.1 +/- 5.2% ENO(b/o). We conclude that a significant proportion of ENO(b/o) arises in the large airways and trachea in normal subjects and contains a minor oropharyngeal component.

Nasal nitric oxide: a comparison of measurement techniques.

Nasal nitric oxide measurement may be a surrogate marker of upper airway inflammation. There is, however, no standardized measurement technique; and this led us to examine measurement techniques for acceptability and reproducibility. In five subjects we examined the flow dependence of nasal NO. In 13 healthy volunteers, nasal NO was measured on-line by five methods: 1) Tidal nasal and oral breathing: NO sampling during exclusive nasal followed by exclusive oral tidal breathing; 2) Fixed flow exhalation: NO sampling during exclusive nasal followed by exclusive oral exhalation at 100 mL/second from total lung capacity; 3) Nasal-oral aspiration: air aspirated from the mouth via both nares at 100 mL/second with glottis closure; 4) Aspiration from one nares: air aspirated from one nares at 3.3 mL/second using nitric oxide analyzer sample line with velum closure; 5) Nasal Insufflation: NO sampled at one nares as air insufflated into the other nares at a flow of 100 mL/second with velum closure. Acceptability of all methods was assessed by subjects and technicians. Nasal NO concentration showed a significant inverse correlation with transnasal flow rate. All methods showed excellent reproducibility as assessed by the intraclass correlation coefficient except tidal breathing, which showed highly variable breath-to-breath NO levels, although mean breath values were reproducible. Mean nasal NO concentrations with methods 1, 2, 3, 4, and 5 were 32.1, 50.2, 62.8, 1381, and 60.0 ppb, respectively. Velum closure was not always achieved in methods 4 and 5, whereas methods 1 and 2 required separate nasal and oral procedures. Method 5 had reduced acceptability. NO concentrations were similar with methods that used the same airflow (2, 3, and 5). Nasal NO can be sampled in different ways with excellent reproducibility. In view of the flow dependence of nasal NO, it is vital to use a constant flow rate, and lower airway NO contribution must be excluded or subtracted. The fixed flow exhalation appears to be the preferred method as it is highly reproducible and acceptable.

Aerodynamic Influences on Nasal Nitric Oxide Output Measurements

Nitric oxide (NO) concentration in aspirated nasal air is flow-dependent. Nasal NO outputs calculated from steady-state plateaux at flows < 1 l/min are substantially smaller than those at flows > 2 l/min. This study aimed to determine the differences in NO output as calculated from the NO concentration plateaux in aspirated nasal air, resulting from different aspiration flows. Nasal NO was determined by chemiluminescent analysis of air obtained from the nasal passages in series during velopharyngeal closure in 8 healthy adults (flows: 0.2-3.7 l/min) and 5 with symptomatic allergic rhinitis (flows: 0.2-3.7 l/min). Mean NO output in the healthy subjects was stable at approximately 315 nl/l/min at flows of 0.2-0.7 l/min, and increased to a second steady output level of approximately 400 nl/l/min (+28%, p < 0.0001) at more physiological flow rates of 2.7 l/min and higher. The symptomatic subjects had substantially higher NO output at all flows (p < 0.001) (709.3 nl/min at 3.7 l/min) than the non-allergic subjects. The flow dependency of the nasal NO output may be explained by failure at low flows for the air stream to penetrate the peripheral parts of the complex nasal passages, and by the presence of a laminar flow regime in which a marginal lamina would tend to insulate the main stream from the mucosa. Thus, previously reported NO outputs obtained at low flows may underestimate nasal NO output compared to output at higher and more physiological transnasal airflow rates, thus affecting interpretation of results.

Nasal nitric oxide is independent of nasal cavity volume.

This study was performed to evaluate the relationship between nasal nitric oxide (NO) and changes in nasal cavity volume resulting from the topical application of xylometazoline and saline and between upright and supine posture. Nasal NO was measured using a fixed high flow technique that avoids contamination with lower airways NO. In nine healthy subjects nasal NO concentration was measured by a rapid response chemiluminescent analyzer. A tapered tube was inserted in one nostril, into which room air was insufflated to produce a constant flow of 100 ml/second; another tube was inserted into the opposite nostril for NO sampling (air exit side). Subjects were instructed to keep the vellum closed while NO was sampled through a sideport connected to the analyzer. Nasal cavity volume was measured by acoustic rhinometry from a segment of the acoustic pathway, 2 to 5 cm from the nostril. Nasal cavity volume and NO measurements were made at baseline, 15 minutes, and 60 minutes after intervention (administration of saline 0.9%, xylometazoline or posture changes on 3 consecutive days). Xylometazoline produced a significant increase in nasal cavity volume, together with a significant reduction in NO level at 15 and 60 minutes after intervention. In addition, the change from seated to supine position decreased the total nasal volume significantly, but without changes in nasal NO. No correlation was found between the magnitudes of changes in nasal NO and the changes in nasal volume. Topical application of xylomethazoline resulted in increased nasal cavity volume and reduced NO output. In contrast to previous published reports, a technique using high flow rate insufflation demonstrated an abscence of correlation between the magnitudes of changes in nasal NO and nasal cavity volume brought about by decongestant, saline, or posture.

Nasal Nitric Oxide Does Not Control Basal Nasal Patency or Acute Congestion following Allergen Challenge in Allergic Rhinitis

Nasal nitric oxide (NO), a powerful vasodilator, could control the filling of nasal capacitance vessels, thus determining nasal patency and mediating the acute congestion accompanying allergen challenge. We examined the effect of topical N-nitro-l-argininemethyl-ester (l-NAME; 100 to 200 mg), an NO synthase inhibitor, on nasal NO and on nasal patency assessed by acoustic rhinometry in 7 subjects with nasal allergy, and in 4 subjects we examined the effects of nasal allergen challenge on nasal NO before and after a short course of nasal steroid. After l-NAME, nasal NO fell to 42.1% ± 15.7% of baseline (p < .0001) with no significant change in minimal cross-sectional area. After allergen challenge, acute congestion was associated with a significant fall in nasal NO, which returned to baseline by 4 hours, when the congestion resolved. Repeat challenge after 2 weeks of nasal corticosteroid yielded similar findings. A role for NO in modulating vascular tone was not supported by the present study.

Effect of Ketosis on Respiratory Sensitivity to Carbon Dioxide in Obesity

We investigated whether the respiratory defect in the obesity-hypoventilation syndrome might respond to dietary manipulation. The effects of hypocaloric ketogenic regimens on the ventilatory response to carbon dioxide were studied in a manner excluding changes in weight or thoracic mechanics as factors. Six obese subjects with hyporesponse (less than 1.1 1/min/mm Hg) and 12 with normal response were fasted or given a diet containing 400 kcal per day of protein. During ketosis carbon dioxide response more than doubled in those with hyporesponse (0.8 +/- 0.1 to 1.8 +/- 1/min/mm Hg, P less than 0.05) but was unchanged in those with normal response. This improvement could not be accounted for by changes in weight, pulmonary function, pH or degree of ketosis between the two groups. However, a significant positive (r = 0.70; P less than 0.001) correlation between ketone-body concentrations and carbon dioxide response was observed in subjects with hyporesponse. These results indicate that depressed sensitivity to carbon dioxide in obese patients can be increased by dietary manipulation.

Tiotropium and Simplified Detection of Dynamic Hyperinflation

STUDY OBJECTIVE To detect dynamic hyperinflation (DH) by evaluating reduction in inspiratory capacity (IC) during metronome-paced hyperventilation (MPH) in patients with moderate-to-severe COPD, studied before and after treatment with tiotropium. METHODS IC and FEV(1) were measured before and immediately after MPH at two times resting the respiratory rate for 20 s in 60 COPD patients (28 men; mean age, 66 +/- 10 years [+/- SD]) before and after 30 days of treatment with tiotropium bromide, 18 mug. Patients were encouraged to maintain a constant tidal volume during MPH. RESULTS At baseline, mean FEV(1) was 1.5 +/- 0.1 L (+/- SE) [57 +/- 1.6% of predicted], mean FVC was 2.6 +/- 0.1L (77 +/- 1.8% of predicted), and mean FEV(1)/FVC was 56 +/- 1%. After 180 mug of aerosolized albuterol sulfate, mean FEV(1) was 1.7 +/- 0.1 L (63 +/- 1.5% of predicted) [p < 0.001] and mean FEV(1)/FVC was 58 +/- 1%. Compared to baseline, after 30 days and 1.5 h after tiotropium there was an increase in IC of 0.18 +/- 0.04L (p < 0.0001); FEV(1) of 0.13 +/- 0.03 L (5.6 +/- 0.8% of predicted; p = 0.0002); FVC of 0.22 +/- 0.05 L (6.5 +/- 1.3% of predicted; p < 0.001); and decrease in end-expiratory lung volume (EELV)/total lung capacity (TLC) of - 3.1 +/- 0.6% (p = 0.0001); a decrease in end-inspiratory lung volume (EILV)/TLC of - 2.9 +/- 1.3% (p = 0.03); and no change in TLC (- 0.06 +/- 0.05 L). Results following MPH-induced DH at baseline and after 30 days of tiotropium were similar, with decreases in IC (- 0.35 +/- 0.03 L; p < 0.001); FEV(1) (- 0.05 +/- 0.04 L; p = 0.2); and FVC (- 0.22 +/- 0.03 L; p < 0.0001); no change in TLC; and increases in EELV/TLC (11.8 +/- 1.0% of predicted; p < 0.0001) and EILV/TLC (4.0 +/- 1.3% of predicted, p < 0.003). CONCLUSION In patients with moderate-to-severe COPD, tiotropium did not reduce MPH-induced DH and reduction in IC, compared to baseline. However, because tiotropium induced bronchodilation and increased baseline IC, lower operational lung volumes may blunt the effect of MPH-induced DH. The noninvasive simplicity of MPH-induced DH provides a clinically useful screening surrogate to monitor changes in IC following treatment with tiotropium.

Unilateral Nasal Nitric Oxide Measurement after Nasal Surgery

This study was designed to validate and standardize a method for unilateral nasal nitric oxide (NO) measurement. Fourteen healthy volunteers and 11 patients who had undergone unilateral medial maxillectomy were enrolled. Nasal NO was measured unilaterally by means of a dual pump system, and bilateral nasal NO was measured by aspirating air through the nasal airway in series. The median unilateral NO output was 195 nL/min on the surgical side and 291 nL/min on the contralateral, surgically untreated side (p = .006). The NO output was not significantly different between nostrils in the control group (p = .82). With the bilateral technique, there was no significant difference between the surgery group and the healthy-subjects group (p = .72). The unilateral nasal NO technique is sensitive in determining unilateral differences in nasal NO production. The NO outputs from the nostrils were similar in normal subjects regardless of the nasal cycle, but were significantly lower on the operated side in the unilateral nasal surgery group.