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The current single exhalation method of measuring exhaled nitric oxide is affected by airway calibre.

The authors have observed that some patients with acute exacerbations of asthma do not have substantially higher levels of exhaled nitric oxide (NO). The study examined whether this could be explained by the effect of airway calibre on exhaled NO. Exhaled NO, height and forced expiratory volume in one second (FEV1) were measured in 12 steroid-naive asthmatics and 17 normal subjects. For comparison, another group of patients with airways disease (34 cystic fibrosis patients) were also studied. In 20 asthmatics (on various doses of inhaled steroids, 0-3,200 microg x day-1), exhaled NO was measured before and after histamine challenge (immediately after reaching the provocative concentration causing a 20% fall in FEV1) and in 12 of these patients, also after nebulized salbutamol to restore FEV1 to baseline. Studies were also conducted to examine possible confounding effects of repeated spirometry (as would occur in histamine challenge) and nebulized salbutamol alone in exhaled NO levels. Exhaled NO was measured using a single exhalation method with a chemiluminescence analyser at a constant flow rate and mouth pressure. There was a significant correlation between FEV1 and exhaled NO in steroid naive asthmatics (r=0.9, p<0.001) and cystic fibrosis patients (r=-0.48, p<0.05) but not in normal subjects (r=-0.13, p=0.61). Exhaled NO decreased significantly after histamine challenge and returned to baseline after bronchodilation by nebulized salbutamol (mean+/-SEM: 23.6+/-3.6 parts per billion (ppb) (prehistamine), 18.2+/-2.7 ppb (posthistamine) and 23.6+/-3.8 ppb (postsalbutamol) p=0.001). Repeated spirometry and nebulized salbutamol did not affect exhaled NO measurements significantly. Exhaled nitric oxide levels appear to be lower in circumstances of smaller airway diameter. Hence, within a subject nitric oxide levels may be artefactually decreased during bronchoconstriction. This may be caused by increased airflow velocity in constricted airways when the exhalation rate is kept constant.

Adult↗

Exhalation flow and pressure-controlled reservoir collection of exhaled nitric oxide for remote and delayed analysis.

BACKGROUND: Expiratory flow rate, soft palate closure, and dead space air may influence exhaled levels of nitric oxide (NO). These factors have not been evaluated in the reservoir collection of NO. METHODS: Exhaled NO was collected into a reservoir during a single flow and pressure controlled exhalation. RESULTS: NO collected in a reservoir containing silica gel was stable for 24 hours. Nasally delivered 4.8% argon measured by mass spectrometry did not contaminate exhaled argon levels (0.1 (0.02)%) in five volunteers during exhalation against a resistance (10 (0.5) cmH2O), hence proving an effective soft palate closure. Exhaled NO in the reservoir was 11 (0.2) ppb, 8.6 (0.1) ppb, 7.1 (0.6) ppb, and 6.6 (0.4) ppb in five normal subjects and 48.3 (18) ppb, 20.3 (12) ppb, 16.9 (0.3) ppb and 10.1 (0.4) ppb in 10 asthmatic subjects at four studied expiratory flows (5-6, 7-8, 10-11, and 12-13 l/min, respectively), with NO levels equal to direct measurement (7.3 (0.5) ppb and 17.4 (0.5) ppb for normal and asthmatic subjects respectively, p < 0.05) at the flow rate 10-11 l/min. Elimination of dead space proved necessary to provide NO levels comparable to the direct measurement. Exhaled NO collected into the reservoir without dead space during flow controlled exhalation against mild resistance provided close agreement (mean (SD) difference -0.21 (0.68), coefficient of variation 4.58%) with direct measurement in 74 patients (NO range 1-69 ppb). CONCLUSIONS: Flow and pressure controlled collection of exhaled NO into a reservoir with silica gel provides values identical to the direct measurement and may be used to monitor asthma at home and where analysers are not on site.

Adult↗

Evaluation of exhaled nitric oxide in schoolchildren at different exhalation flow rates.

Nitric oxide (NO) in exhaled air is believed to reflect allergic inflammation in the airways. Measured levels of exhaled NO vary with the exhaled flow rate, which therefore must be standardized. The aim of this study was to estimate the optimal exhalation flow rate when measuring NO in exhaled air. We studied 15 asthmatic children (8-18 y) with elevated NO levels and 15 age-matched controls and focused on how the quality of the NO curve profile, the discriminatory power, and the reproducibility were influenced by the exhalation flow rate. We used an on-line system for NO measurements at six different exhalation flow rates in the interval of 11-382 mL/s. The fraction of exhaled nitric oxide (FENO) was highly flow-dependent as was expected. Intermediate flow rates yielded a flat and stable NO plateau and were considerably easier to interpret than those obtained at the highest and lowest flow rates. The ratio of FENO between asthmatics and controls was lower at higher flow rates and a considerable overlap in NO values was demonstrated at all flow rates except 50 mL/s. The reproducibility was much lower at more extreme flow rates and was best at 50 mL/s. We conclude that a target exhalation flow rate of approximately 50 mL/s is to be preferred using the single-breath method for on-line NO measurements in schoolchildren.

Adolescent↗

Nasal contribution to exhaled nitric oxide during exhalation against resistance or during breath holding.

BACKGROUND: The concentration of nitric oxide (NO) is increased in the exhaled air of patients with inflammation of the airways, suggesting that this may be a useful measurement to monitor inflammation in diseases such as asthma. However, there have been concerns that exhaled NO may be contaminated by the high concentrations of NO derived from the upper airways, and that this may account for differences in reported values of exhaled NO using different techniques. A study was performed, with argon as a tracer, to determine the extent of nasal contamination of exhaled NO using different expiratory manoeuvres. METHODS: Exhaled and nasal NO were measured by a chemiluminescence analyser. Argon (4.8%) was delivered continuously to the nose. Gas was sampled from the posterior oropharynx and argon and carbon dioxide were measured by mass spectrometry at the same time as NO. RESULTS: During a single expiration against a low resistance and during breath holding there was no evidence for nasal contamination, whereas during exhalation without resistance argon concentration in the oropharynx was increased from 0.91% (95% CI 0.84% to 0.98%) in ambient air to 1.28% (0.9% to 2.24%, p < 0.0001) during a single breath or 2.37% (2.29% to 2.51%, p < 0.0001) during tidal breathing. CONCLUSIONS: Collection of exhaled NO in a reservoir during tidal breathing is likely to be contaminated by NO derived from the nose and this may underestimate any increases in NO derived from the lower respiratory tract in inflammatory diseases. However, with slow expiration against a resistance and created back pressure to close the soft palate, there is no contamination of exhaled air which then reflects concentrations of NO in the lower airways.

Adult↗

Challenge from methacholine, natural rubber latex, or 4,4-diphenylmethane diisocyanate in workers with suspected sensitization affects exhaled nitric oxide [change in exhaled NO levels after allergen challenges].

OBJECTIVE: Nitric oxide (NO) levels in the exhaled air of asthmatic patients have been shown to be increased. This observation has also been reported in workers who are allergic to laboratory animals. To determine if a challenge test with natural rubber latex (NRL) or 4,4'-diphenylmethane diisocyanate (MDI) would also produce an increase of NO exhalation in sensitized patients, we carried out this study. METHODS: Nine subjects with suspected occupational asthma were exposed to MDI, and 18 took part in a challenge test with gloves powdered with NRL. Nineteen subjects underwent a challenge test with methacholine (MCh). Exhaled NO was measured by a modified chemiluminescence analyzer according to the European Respiratory Society guidelines. RESULTS: We found that there was a decrease in exhaled NO concentrations 16-18 h after MCh challenge testing and subsequent bronchodilation with salbutamol, in three subjects. Three of nine participants had a significant immediate bronchial obstruction after exposure to MDI, of those three, two had MDI-specific IgE antibodies. After 22 h, their levels of exhaled NO had increased > 10 parts per billion (ppb). Eight of the 18 subjects participating in the NRL challenge test displayed an NO concentration increase of at least 10 ppb after 22 h (seven had NRL-specific IgE antibodies). A significant decrease in the one-second forced expiratory volume (FEV1) was documented in four of those eight participants after NRL challenge. CONCLUSIONS: There was no clear relationship between bronchial response, substance-specific IgE antibodies and an increase in exhaled NO levels. However, there was a tendency for subjects with substance-specific IgE antibodies and bronchial reaction to develop an increase in exhaled NO concentration. Further studies are needed to determine if analysis of NO from the lower respiratory tract can become a useful non-invasive tool for detecting lower airway inflammatory response even before clinical symptoms occur.

Adolescent↗

Relationship between exhaled air temperature and exhaled nitric oxide in childhood asthma.

Airway inflammation is a characteristic of asthma. Exhaled nitric oxide (eNO) has been demonstrated to be related to actual levels of airway inflammation in asthmatic patients. The purpose of this study was to investigate whether the temperature of exhaled air is related to eNO levels. Temperature of exhaled air and eNO were measured in 52 asthmatic children with a cross-sectional design. A significant relationship was demonstrated between eNO and temperature of peak and plateau exhaled air temperature. The relationship between both the peak and the plateau values and eNO was more evident when it was corrected for environmental temperature. These results suggest a relationship between exhaled nitric oxide and the temperature of exhaled air in asthmatic patients not treated with systemic steroids.

Adolescent↗

Exhaled breath condensate nitrite/nitrate and pH in relation to pediatric asthma control and exhaled nitric oxide.

BACKGROUND: Combining exhaled breath condensate (EBC) and exhaled nitric oxide (eNO) may be a useful, non-invasive method to assess airway inflammation in pediatric asthma. This cross-sectional study evaluated the relationship of both EBC nitrite/nitrate (NOx) and EBC pH with asthma control and eNO in asthmatic, normal, and atopic children. METHODS: A total of 92 children were recruited, comprising 62 with asthma, 14 with atopy only, and 16 who were normal and non-atopic. All completed a questionnaire for asthma symptoms and control. Variables measured were spirometry, EBC NOx, pH, and eNO. RESULTS: EBC NOx in those with asthma (mean 8.4 microM, CI 7.5-9.4) was significantly elevated when compared with normal (4.8 microM, CI 3.4-6.2, P = 0.0007) and atopic children (6.5 microM, CI 4.0-9.1, P = 0.02). The mean level of eNO was significantly higher in those with asthma (43.7 ppb, CI 34.7-51.1, P < 0.001) and atopy (24 ppb, CI 16.7-31.2, P < 0.05) when compared with normal children (11.5 ppb, CI 6.7-16.2). There was a significantly lower pH in those with asthma and a FEV(1) < 80% predicted (P = 0.03), but no significant overall differences in EBC pH between the three groups of children. There was a significant correlation between eNO and EBC NOx in the group as a whole, but not between eNO and EBC pH. CONCLUSIONS: Mean EBC NOx levels differ between children with asthma, atopy, and those who are normal, but it is not interchangeable with eNO. EBC pH may be an additional marker of asthma control.

Asthma↗

Exhaled breath condensate pH and exhaled nitric oxide in allergic asthma and in cystic fibrosis.

BACKGROUND: It has been proposed that the pH of airway lining fluid may regulate the fractional exhaled concentration of nitric oxide (Fe(NO)) in respiratory disease. METHODS: Fe(NO), exhaled breath condensate (EBC) pH, and EBC concentrations of nitrite plus nitrate (NO2/NO3) were compared in 12 subjects with stable asthma, 18 with stable cystic fibrosis (CF), and 15 healthy control subjects. Eight of the CF patients were studied on a separate occasion at the start of a pulmonary exacerbation. RESULTS: Fe(NO) was significantly greater in asthmatic subjects than in control subjects (mean 35 v 9 ppb, p<0.001). EBC pH, however, was similar in the asthmatic and control groups (median 5.82 v 6.08, p=0.23). Levels of NO2/NO3 were on average higher in EBC samples from asthmatic subjects, but the difference was not significant. In patients with stable CF both the Fe(NO) (mean 4 ppb, p<0.001) and EBC pH (median 5.77, p=0.003) were lower than in the control group. Levels of EBC NO2/NO3 (median 29.9 microM; p=0.002) in patients with stable CF, in contrast, were significantly higher than in control subjects. During CF exacerbations, EBC pH was further reduced (median 5.30, p=0.017) but Fe(NO) and NO2/NO3 were unchanged. CONCLUSIONS: These findings demonstrate a dissociation between EBC pH and Fe(NO) in inflammatory airways disease.

Adult↗

Exhaled monoxides as a pulmonary function test: use of exhaled nitric oxide and carbon monoxide.

Although there has been tremendous improvement in the technologic ability to measure exhaled gases and monitor biologic processes in the lung, it has not yet found a clinical role outside the research laboratory. Common themes seem to be significant overlap in the amount of exhaled gases in clinically distinct populations, confounding variables such as infection, smoking, and environmental exposure, and lack of consistent change with disease management. If these tests are ever to be used by the general pulmonologist, consistent links between the measurements and the response to disease modification will need to be demonstrated at the very least and, ideally, the clinician would like to see improved outcomes when these noninvasive tests are employed regularly.

Breath Tests↗

Collection of exhaled breath and exhaled breath condensate in veterinary medicine. A review.

Collection of exhaled breath (EB) and exhaled breath condensate (EBC) is a noninvasive method for obtaining samples from the lower airways. While this technique has been well established for the diagnosis of lower respiratory tract diseases in human medicine, only a few studies have been performed in veterinary medicine. This article critically reviews the collection methods and parameter values measured in various animal species published to date and points out directions for further research.

Animal Diseases↗

Comparison of exhaled and nasal nitric oxide and exhaled carbon monoxide levels in bronchiectatic patients with and without primary ciliary dyskinesia.

BACKGROUND: Primary ciliary dyskinesia (PCD) is associated with chronic airway inflammation resulting in bronchiectasis. METHODS: The levels of exhaled nitric oxide (eNO), carbon monoxide (eCO) and nasal NO (nNO) from bronchiectatic patients with PCD (n=14) were compared with those from patients with non-PCD bronchiectasis without (n=31) and with cystic fibrosis (CF) (n=20) and from normal subjects (n=37) to assess the clinical usefulness of these measurements in discriminating between PCD and other causes of bronchiectasis. RESULTS: Exhaled NO levels were lower in patients with PCD than in patients with non-PCD non-CF bronchiectasis or healthy subjects (median (range) 2.1 (1.3-3.5) ppb v 8.7 (4.5-26.0) ppb, p<0.001; 6.7 (2.6-11.9) ppb, p<0.001, respectively) but not lower than bronchiectatic patients with CF (3.0 (1.5-7.5) ppb, p>0.05). Nasal levels of nNO were significantly lower in PCD patients than in any other subjects (PCD: 54.5 (5.0-269) ppb, non-PCD bronchiectasis without CF: 680 (310-1000) ppb, non-PCD bronchiectasis with CF: 343 (30-997) ppb, control: 663 (322-1343) ppb). In contrast, eCO levels were higher in all patient groups than in control subjects (PCD: 4.5 (3.0-24.0) ppm, p<0.01, other bronchiectasis without CF: 5.0 (3.0-15.0) ppm, p<0.001; CF: 5.3 (2.0-23.0) ppm, p<0.001 v 3.0 (0.5-5.0) ppm). Low values in both eNO and nNO readings (<2.4 ppb and <187 ppb, respectively) identified PCD patients from other bronchiectatic patients with a specificity of 98% and a positive predictive value of 92%. CONCLUSION: The simultaneous measurement of eNO and nNO is a useful screening tool for PCD.

Adult↗

Effects of expiratory pressure on nitric oxide in exhaled breath. Is exhaled nitric oxide really unaffected by pressure?

The measurements of exhaled nitric oxide (ENO) concentrations in several previous reports have been quite disparate but the cause of this variability is unclear. In the present study, we have attempted to elucidate the effects of expiratory pressure upon ENO values by taking measurements at pressures ranging from 2 to 10 cmH2O in control subjects and in both smokers and asthmatics. Differences in ENO concentrations (delta pNO) were then estimated and the concentration levels were found to increase with elevated expiratory pressure levels in both the control volunteers and in the asthmatics (under 2 and 3 L/min flow rates). These results indicate that changes in expiratory pressure indeed affect ENO concentrations. The measurement of ENO concentrations in human patients must therefore be undertaken using standard procedures that must incorporate expiratory pressure levels in order to properly interpret ENO values.

Adolescent↗

Exhaled nitric oxide and hydrogen peroxide concentrations in asthmatic smokers.

BACKGROUND: Cigarette smoking is associated with decreased nitric oxide (NO) production and increased oxidative stress in the airways. Exhaled NO levels are not higher in asthmatic smokers than in healthy non-smokers, and the value of exhaled NO for diagnosing asthma in smokers has been questioned. OBJECTIVES: To compare exhaled NO concentrations between healthy and steroid-naive and steroid-treated asthmatic smokers and non-smokers. To also assess the acute effect of cigarette smoking on exhaled NO and hydrogen peroxide (H(2)O(2)) levels in asthmatic smokers. METHODS: Exhaled NO was measured by chemiluminescence and exhaled H(2)O(2) spectrophotometrically. In 7 steroid-naive asthmatic smokers exhaled NO and H(2)O(2) was measured both before and 15 min after smoking one cigarette. Data are given as median (range). RESULTS: Exhaled NO level was significantly higher in steroid-naive asthmatic smokers than in healthy smokers [7.7 (3.4-32.5) ppb vs. 3.2 (2.0-7.2) ppb, p < 0.001]. Exhaled NO values were lower in smokers than in non-smokers both in healthy subjects and in steroid-naive asthmatic patients. Steroid-treated asthmatic smokers had a tendency for lower exhaled NO values [5.4 (1.7-12.0) ppb] compared to steroid-naive asthmatic smokers. Cigarette smoking caused an acute increase in exhaled H(2)O(2) concentrations together with a decrease in exhaled NO concentration. CONCLUSIONS: Our data suggest that an elevation in exhaled NO concentration is associated with asthma in smokers. This difference may be useful for diagnosing the disease in smokers, but its clinical value needs further evaluation. Acute increase in exhaled H(2)O(2) concentrations suggests that smoking increases the oxidative stress in the asthmatic airways.

Adult↗

Effects of a leukotriene receptor antagonist on exhaled leukotriene E4 and prostanoids in children with asthma.

BACKGROUND: Leukotriene (LT) E(4) and 8-isoprostane concentrations are elevated in exhaled breath condensate in children with asthma. The effects of leukotriene receptor antagonists (LTRAs) on exhaled leukotriene and prostanoids in children with asthma are unknown. OBJECTIVE: (1) To study the effect of montelukast, a LTRA, on exhaled LTE(4), 8-isoprostane, and prostaglandin E(2) in children with asthma and atopic children; (2) to measure exhaled nitric oxide. METHODS: An open-label study with oral montelukast (5 mg once daily for 4 weeks) was undertaken in 17 atopic children with asthma and 16 atopic children without asthma. RESULTS: Pretreatment exhaled LTE(4) (P < .0001) and 8-isoprostane (P < .0001) values were higher in atopic children with asthma than in atopic children without asthma. In atopic children with asthma, montelukast reduced exhaled LTE(4) by 33% (P < .001), and this reduction was correlated with pretreatment LTE(4) values (r = -0.90; P = .0001). Posttreatment exhaled LTE(4) levels in children with asthma were higher than pretreatment LTE(4) values in atopic children without asthma (P < .004). Montelukast had no effect on exhaled LTE(4) in atopic children without asthma (P = .74), or on exhaled 8-isoprostane (atopic children with asthma, P = .94; atopic children without asthma, P = .55) and PGE(2) (atopic children with asthma, P = .56; atopic children without asthma, P = .93) in both groups. In atopic children with asthma, exhaled nitric oxide concentrations were reduced by 27% (P < .05) after montelukast. CONCLUSION: Leukotriene receptor antagonists decrease exhaled LTE(4) in atopic children with asthma. This reduction is dependent on baseline exhaled LTE(4) values. CLINICAL IMPLICATIONS: Measurement of exhaled LTE(4) might help identify children with asthma most likely to benefit from LTRAs.

Acetates↗