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PubMed2005

Exhaled nitric oxide is reduced in infants with rhinorrhea.

In infants, the effect of colds and other respiratory tract infections (RTI) on exhaled nitric oxide (FE(NO)) is not clear. In this study, we measured FE(NO) in 24 infants (14 boys) who presented with rhinorrhea, with or without cough but not wheeze. Twelve of these infants had a history of recurrent wheeze. Levels were compared with a group of 23 healthy infants (13 boys). Further, 8 infants (5 with a history of recurrent wheeze) with rhinorrhea were tested after symptoms had resolved. Infants with rhinorrhea had significantly lower FE(NO) than the healthy infants (11.9 vs. 23.8 ppb, respectively, P < 0.0007). Levels increased from 7.5 ppb to 34.1 ppb in the 8 infants tested with and without symptoms (P = 0.0002). Infants with rhinorrhea have reduced FE(NO), irrespective of their respiratory history.

Airway Resistance↗
PubMed2006

Reduced exhaled nitric oxide in children after testing of maximal expiratory pressures.

Spirometry in adult subjects can induce a fall in concentration of exhaled nitric oxide (FE(NO)). Scarce information is available on the FE(NO) decrease after spirometry or after other forced lung-function maneuvers in children. We compared changes in FE(NO) induced by repeated spirometry and testing of maximal expiratory pressures (P(Emax)). Twenty-four sex- and age-matched children aged 9-18 years (mean age +/- SD, 13.3 +/- 2.8 years; 12 healthy, 12 asthmatic) were allocated to 1-week-apart sessions of repeated maneuvers of either forced vital capacity (FVC) or P(Emax). Baseline FE(NO) measurements were followed by FVC or P(Emax) maneuvers every 15 min for 45 min, whereas FE(NO) was measured at each step for 60 min. After repeated P(Emax) but not after FVC maneuvers, FE(NO) values decreased significantly from baseline in both groups. In healthy children, geometric mean FE(NO) (95% confidence intervals) decreased from 9.1 (7.0-11.8) ppb at baseline to 8.2 (6.3-10.6) ppb at 15 min and 7.7 (5.6-10.6) ppb at 30 min (P < 0.05 and P < 0.01, respectively), and remained unchanged at 45 and 60 min. In asthmatic children, FE(NO) levels fell from 21.6 (13.3-34.9) ppb at baseline to 15.1 (9.1-25.1) ppb at 15 min and remained low at 30, 45, and 60 min: 17.8 (10.7-29.5) ppb, 17.5 (10.2-30.1) ppb, and 17.6 (10.6-29.2) ppb, P < 0.01, for all differences from baseline. Repeated P(Emax) and FVC maneuvers increased FE(NO) variability, as compared with repeated FE(NO) measurements alone. Previous forced lung-function maneuvers may affect FE(NO) measurements in children. Although P(Emax) testing has a greater influence than spirometry on FE(NO) levels in children, both procedures should be avoided before measuring FE(NO).

Adolescent↗
PubMed2006

Bubble CPAP elicits decreases in exhaled nitric oxide in rabbits.

Endogenous nitric oxide (NO) has a key role in pulmonary function, and the application of positive end-expiratory pressure (PEEP) can increase exhaled NO (FE(NO)) in anesthetized animals and isolated lungs. The influence of continuous positive airway pressure (CPAP), which is similar to PEEP, on the FE(NO) level has not been investigated in humans or in animals. The present study was undertaken to determine whether and how the application of CPAP in spontaneously breathing rabbits influences levels of FE(NO). We performed a randomized crossover study to measure FE(NO) levels in 12 ketamine-anesthetized rabbits that were intubated via tracheostomy for bubble CPAP (B-CPAP) or ventilator-derived CPAP (V-CPAP), which are two of the most popular CPAP modes and which have different pressure sources. The baseline FE(NO) level was 23.8 +/- 2.6 ppb, which increased to 27.1 +/- 2.9 ppb (P < 0.001) during V-CPAP and decreased to 18.6 +/- 2.2 ppb (P < 0.001) during B-CPAP. We used one high-frequency oscillatory ventilator to repeat the experiment, in which the conventional ventilation function of the ventilator was used in the baseline and V-CPAP periods, and the high-frequency function was used to replace B-CPAP. Changes in FE(NO) were similar to our previous findings. This study demonstrated that the application of CPAP did influence levels of FE(NO). We speculate that the decrease in FE(NO) during B-CPAP may have been related to the bubble-associated high-frequency oscillation.

Animals↗
PubMed2006

Determination of N epsilon-(carboxymethyl)lysine in exhaled breath condensate using isotope dilution liquid chromatography/electrospray ionization tandem mass spectrometry.

In order to identify new biomarkers for pulmonary diseases in exhaled breath condensate (EBC) it was the aim of this study to develop an analytical method for the identification and quantification of N epsilon-(carboxymethyl)lysine (CML) in EBC. As detection by liquid chromatography with positive electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS) offers the advantage of structurally related detection with the necessary specificity required for the identification of a substance, it was the method chosen for the determination of the non-volatile compound. Specific mass transitions and comparison of retention times with standards under given conditions were used for the unequivocal identification of CML in EBC of healthy subjects. Synthesis of isotopically labelled CML was performed and used as an internal standard for an accurate determination. It was possible to identify the advanced glycation end-product CML in 8 out of 10 healthy subjects. The concentration range determined in the quantifiable examined samples ranged between 35 and 110 pg/mL. EBC samples from 11 patients with different diseases such as diabetes and chronic obstructive pulmonary disease were also measured. In one patient with pneumonia a concentration of 1509 pg CML/mL EBC could be detected. This is the first time that CML has been identified and determined in EBC. The developed LC/ESI-MS/MS method could be used to address the utility of CML as a biomarker in pulmonary diseases.

Aged↗
PubMed2003

Determination of patterns of biologically relevant aldehydes in exhaled breath condensate of healthy subjects by liquid chromatography/atmospheric chemical ionization tandem mass spectrometry.

A method for the simultaneous determination of several classes of aldehydes in exhaled breath condensate (EBC) was developed using liquid chromatography/atmospheric pressure chemical ionization tandem mass spectrometry (LC/APCI-MS/MS). EBC is a biological matrix obtained by a relatively new, simple and noninvasive technique and provides an indirect assessment of pulmonary status. The measurement of aldehydes in EBC represents a biomarker of the effect of oxidative stress caused by smoke, disease, or strong oxidants like ozone. Malondialdehyde (MDA), acrolein, alpha,beta-unsaturated hydroxylated aldehydes [namely 4-hydroxyhexenal (4-HHE) and 4-hydroxynonenal (4-HNE)], and saturated aldehydes (n-hexanal, n-heptanal and n-nonanal) were measured in EBC after derivatization with 2,4-dinitrophenylhydrazine (DNPH). Atmospheric pressure chemical ionization of the analytes was obtained in positive-ion mode for MDA, and in negative-ion mode for acrolein, 4-HHE, 4-HNE, and saturated aldehydes. DNPH derivatives were separated on a C18 column using variable proportions of 20 mM aqueous acetic acid and methanol. Linearity was established over 4-5 orders of magnitude and limits of detection were in the 0.3-1.0 nM range. Intra-day and inter-day precision were in the 1.3-9.9% range for all the compounds. MDA, acrolein and n-alkanals were detectable in all EBC samples, whereas the highly reactive 4-HHE and 4-HNE were found in only a few samples. Statistically significant higher concentrations of MDA, acrolein and n-hexanal were found in EBC from smokers.

Air Pressure↗
PubMed1994

Nitric oxide is present in exhaled breath in humans: direct GC-MS confirmation.

The physiological role of nitric oxide (NO) is being investigated in many experimental and clinical settings. There is considerable evidence that NO is involved in the regulation of lung vascular function. In addition there are many studies reporting the beneficial effect of NO inhalation. NO formed from L-Arginine has been detected in exhaled breath using indirect mass spectrometry and chemiluminescence. Both methods provided good evidence for the presence of NO in breath samples but were not unequivocal. We therefore developed a method using gas-chromatography-mass spectrometry which allowed us to measure trace levels of NO in air and breath. Eight healthy volunteers supplied numerous breath samples for analysis. A clear peak for nitric oxide was observed in seven volunteers. The mean level was 13ppb (n = 7, range < 2 to 19ppb). This data is in good agreement with our previous data and unequivocally confirms the presence of nitric oxide in human breath.

Female↗
PubMed1997

Increased nitric oxide in exhaled gas is an early marker of hypovolemic states.

Acute hemorrhage is associated with a variety of physiologic and metabolic alterations, including vascular hyporeactivity and endothelial cell dysfunction. The lung is a major target organ during hemorrhagic shock. The effect of acute hemorrhage on NO production in the lung is not well described. In the present study we examined the effect of acute hemorrhage on exhaled NO (NOe), and studied how changes in blood volume and flow affect NOe. Anesthetized and mechanically ventilated rabbits were used. The effect of acute hemorrhage by slow exsanguination on NOe was examined using chemiluminescence. Because hemorrhagic shock is associated with decreased pulmonary blood flow, we established an isolated lung preparation perfused with autologous blood (Hct = 17.4%) and studied the effect of pulmonary flow rate on NOe independent of metabolic changes. In order to separate the effect of flow from the effect of changes in blood volume, we examined the effect of flow in isolated lungs perfused with a blood-free albumin solution (PAS). In the isolated lung, ventilation was similar to that used in the intact animal, and temperature, pH, pCO2, and PO2 were kept normal. Prior to exsanguination, baseline NOe in the intact animal was 24 +/- 3 ppb. At 5, 10, 15, and 20 min after initiating the hemorrhage, NOe rose to 31 +/- 3, 51 +/- 7, 94 +/- 10, and 154 +/- 16 ppb, respectively (P < 0.05). During baseline conditions in the blood-perfused isolated lungs (200 ml/min), NOe was 35 +/- 3 ppb. When flow was decreased to 70 and 0 ml/min, NOe increased to 37 +/- 3 and 56 +/- 6 ppb, respectively (P < 0.001). During baseline conditions in the PAS-perfused lungs (70 ml/min), NOe was 94 +/- 13 ppb and was unaffected by changes in flow. The perfusion pressure in the isolated lungs was in the normal range. Reduction in blood flow rate in the isolated lung was associated with less than twofold increase in NOe. This was attributed to reduction in red blood cell volume and not due to changes in blood flow rate. Reduction in flow in the intact animal during hemorrhage generated more than threefold increase in NOe, suggesting that neurohumoral mediators, in addition to changes in flow, play an important role in determining. NOe in the intact condition. NOe began to rise immediately after exsanguination began, and therefore may be a useful early marker of acute hemorrhagic shock and hypovolemia. This information may be useful in the intensive care setting.

Acute Disease↗
PubMed1987

Tetrachloromethane metabolism in vivo under normoxia and hypoxia. Biochemical and histopathological effects relative to alkane exhalation.

About 250 mumol/kg tetrachloromethane is metabolized by male Sprague-Dawley rats receiving a dose of 500 mumol/kg by inhalation. Determination of enzyme activities and histopathological assessment show that various parameters reflecting cellular injury do not differ for the same amount of tetrachloromethane metabolized under different oxygen partial pressures. On the other hand, the amounts of ethane and pentane exhaled under hypoxic conditions are greater than under normoxia. The previously reported differences in the toxicity of tetrachloromethane upon exposure under normoxia or hypoxia seem to be mainly due to the different amounts of tetrachloromethane metabolized under both conditions.

Alkanes↗
PubMed1976

Metabolism of nitrosamines in vivo. V Investigation on 14CO2 exhalation, liver RNA labelling and isolation of two metabolites from urine after administration of [2, 5-14C-]dinitrosopiperazine to rats.

The synthesis of N, N'-dinitrosopiperazine and N-nitrosopiperazine, both 14C-labelled in the 2-and 5-position is described. After i.p. application of 10 mg/69.5 muCi/kg[2, 5-14C]-N, N'-dinitrosopiperazine to rats no labelled 7-methylguanine was detected in the liver RNA; 1% of the radioactivity was exhaled as 14CO2, 1% excreted via the bile and about 40% excreted in the urine. Two of the urine metabolites were identified as 3-hydroxynitrosopyrrolidine and 1-nitrosopiperazinone-(3).

Animals↗
PubMed1984

Inhalation pharmacokinetics based on gas uptake studies. VI. Comparative evaluation of ethylene oxide and butadiene monoxide as exhaled reactive metabolites of ethylene and 1,3-butadiene in rats.

When ethylene oxide or butadiene monoxide is added to the atmosphere of a closed inhalation chamber occupied by Sprague-Dawley rats, a first-order elimination pattern is observed. When either of these compounds is IP injected into rats which are subsequently placed in the closed chamber, the course of epoxide in the atmosphere follows Bateman exponential functions. From the experimental data, the kinetic parameters for distribution and metabolic elimination of ethylene oxide and butadiene monoxide can be derived. When ethylene or 1,3-butadiene was added to the closed exposure systems and kept at atmospheric concentrations which assured maximal metabolic turnover of the olefin (i.e., concentrations above 1,000 ppm ethylene or 1,500 ppm 1,3-butadiene), exhalation of the appropriate epoxide occurred and led finally to a constant (plateau) concentration of the reactive metabolite in the system's atmosphere. Although the initial time-course was different between butadiene monoxide and ethylene oxide (with a high initial increase of ethylene oxide and a subsequent decrease) an analysis at steady-state (plateau concentrations) revealed that only 29% of the amounts of both epoxides which in theory are formed as primary metabolites from the parent olefins are systematically available (i.e., distributed in the entire organism). The discrepancy is probably related to first pass elimination of the epoxide.

Animals↗
PubMedDate not supplied

Bymixer provides on-line calibration of measurement of CO2 volume exhaled per breath.

The measurement of CO2 volume exhaled per breath (VCO2.br) can be determined during anesthesia by the multiplication and integration of tidal flow (V) and PCO2. During side-stream capnometry, PCO2 must be advanced in time by transport delay (TD), the time to suction gas through the sampling tube. During ventilation, TD can vary due to sample line connection internal volume or flow rate changes. To determine correct TD and measure accurate VCO2.br during actual ventilation. TD can be iteratively adjusted (TDADJ) until VCO2-br/tidal volume equals PCO2 measured in a mixed expired gas collection (PECO2) (J Appl. Physiol. 72:2029-2035, 1992). However. PECO2 is difficult to measure during anesthesia because CO2 is absorbed in the circle circuit. Accordingly, we implemented a bypass flow-mixing chamber device (bymixer) that was interposed in the expiration limb of the circle circuit and accurately measured PECO2 over a wide range of conditions of ventilation of a test lung-metabolic chamber (regression slope = 1.01: R2 = 0.99). The bymixer response (time constant) varied from 18.1 +/- 0.03 sec (12.5 l/min ventilation) to 66.7 +/- 0.9 sec (2.5 l/min). Bymixer PECO2 was used to correctly determine TDADJ (without interrupting respiration) to enable accurate measurement of VCO2.br over widely changing expiratory flow patterns.

Breath Tests↗
PubMed2001

Effect of ecNOS polymorphisms and coronary artery disease upon exhaled nitric oxide.

Exhaled nitric oxide (eNO) is thought to arise principally from the airway epithelium. NO regulates smooth muscle tone, and abnormal activity of NO synthase has been implicated in coronary artery disease (CAD). Polymorphisms of endothelial constitutive NO synthase (ecNOS) may affect NO generation and be associated with CAD. It was hypothesised that a polymorphism, such as the ecNOS intron 4 polymorphism (ecNOS4a), affects the levels of eNO via airway epithelial NOS. eNO levels were measured in 53 patients with ischaemic chest pain who had previously been genotyped for ecNOS polymorphisms, with sample enrichment for the ecNOS4a allele. Subjects were also assessed for two other ecNOS polymorphisms (T-786C substitution in the promoter region, and G5557T in exon 7), variably associated with vascular disease. Those homozygous for the 'a' allele (ecNOS4a/a) had a lower mean eNO (9.0 ppb) than those who were heterozygous (ecNOS4a/b, 13.6 ppb), who in turn had a lower level than those homozygous for the wild-type ecNOS4b/b (16.1 ppb). No association of eNO levels was found with the other polymorphisms. Levels of eNO remained significantly lower in the ecNOSa/a subjects than in the ecNOSa/b and ecNOSb/b subjects, even when controlled for angiographic CAD, and smoking habit. In addition, all subjects with CAD had a significantly lower mean eNO (12.1 ppb) than subjects without angiographic CAD (19.9 ppb). In this selected population low levels of eNO were thus associated with presence of the ecNOS4a allele and also with CAD.

Administration, Oral↗
PubMed2002

Direct measurement of the mercury content of exhaled air: a new approach for determination of the mercury dose received.

A new rapid technique is presented for determination of the dose of mercury inhaled; it is based on direct measurement of the concentration of mercury in exhaled air by use of a Zeeman mercury spectrometer RA-915+. It has been demonstrated experimentally that the dose received during short-term exposure to mercury vapor is determined more reliably by this method rather than by conventional techniques based on measurement of the mercury content in blood or urine.

Administration, Inhalation↗
PubMed2002

Inhaled ultrasonically nebulized distilled water decreases exhaled nitric oxide in asthma.

Exhaled nitric oxide (eNO) is increasingly used as a marker of disease activity in asthma. Inhaled hypertonic saline has been shown to induce bronchoconstriction and to decrease eNO in asthmatic subjects, whereas the effects of hypotonic solutions on eNO in these patients have not been studied. To evaluate the effect of ultrasonically nebulized distilled water (UNDW), an indirect hypotonic stimulus, on eNO, 17 asthmatic patients were enrolled and eNO from lower airways was measured by chemiluminescence. UNDW significantly reduced FEV(1) >or= 20% in 9 subjects (UNDW+), but had no effect in eight patients (UNDW-). Baseline eNO concentration were found to be 51.3 +/- 11.1 ppb in UNDW+ and 32.9 +/- 7.5 ppb in UNDW- patients, respectively ( p = 0.199, NS). UNDW inhalation significantly decreased eNO (from 51.3 +/- 11.1 ppb to 31.0 +/- 7.1 ppb in UNDW+ ( p < 0.020, n = 9) and from 32.9 +/- 7.5 ppb to 26.2 +/- 7.3 ppb in UNDW- subjects ( p < 0.024, n = 8), respectively). eNO percentage reduction in UNDW+ patients was significantly higher compared with UNDW- subjects (-37 +/- 4% vs -23 +/- 3%, p = 0.021). There was no correlation between FEV(1) changes and eNO percentage decreases in both UNDW+ and UNDW- subjects. In UNDW+ patients, acute bronchodilation induced by salbutamol caused a recovery in both FEV(1) and eNO, though eNO levels remained lower than baseline values. We concluded that UNDW inhalation can significantly decrease eNO in asthmatic patients, either responders or nonresponders to this indirect osmotic challenge; the reduction in eNO levels was only partly dependent on acute changes in airway caliber.

Administration, Inhalation↗
PubMedDate not supplied

The effects of age on exhaled breath nitric oxide levels.

A variety of factors influence exhaled breath nitric oxide (ENO) but few studies have examined ENO at the extremes of adult age. This investigation explores whether there is a difference in ENO between groups of older and younger individuals. A total of 48 normal subjects consisting of 23 younger (median age - 24 years) and 25 older (median age - 72 years) participants were studied. Carefully defined clinical and spirometric parameters, smoking history, and drug/medication documentation were determined to insure normalcy. Measurements of ENO were made using ATS/ERS recommended methodologies. The older group consistently showed higher ENO concentrations than-the younger subjects; median ENO values were 36.9 and 18.7 ppb, respectively (p < 0.001). The statistical significance held true when adjusting for multiple testing with the Holm method and accounting for outliers and medication usage. ENO levels are significantly higher in a normal older population. Comparing ENO between individuals at the extremes of age may depict differences more decidedly. Whether elevated ENO reflects underlying airway inflammation in older persons remains unanswered. It is possible that the difference in NO concentrations between older and younger groups represents only a marker of past oxidant exposures and holds no clinical significance. Additional investigations are necessary to elucidate the mechanisms and significances of elevated NO levels in the aged.

Adolescent↗
PubMed2002

Association between exhaled nitric oxide, ambient air pollution and respiratory health in school children.

OBJECTIVES: The aim of the study was to investigate whether the level of exhaled nitric oxide (eNO) provides a more sensitive measure to assess adverse pulmonary effects of air pollution than conventional lung function indices. METHOD: The non-selected cohort studied consisted of 68 children (aged 10-11 years) living in an urban environment. For 7 weeks respiratory complaints were reported daily by these children in a diary, and lung function measures and eNO levels were determined in the children once a week on days with various level of air pollution. RESULTS: During the study the increase in the levels of the various air pollutants was positively associated with eNO (6% to 31% increase; P<0.05) but not with lung function measures. In contrast to the lung function measures, the prevalence of respiratory symptoms such as "sore throat", "runny nose", "having a cold", and "sick at home" were positively associated with the level of eNO measured in the following week. CONCLUSIONS: Though clinically very meaningful, functional pulmonary measures appear to be too course to detect relatively mild clinical symptoms in response to exposure to air pollution. In an epidemiological setting the increase in eNO may represent a more suitable measure to assess such adverse effects.

Air Pollution↗
PubMed2005

Lung oxidative stress as related to exercise and altitude. Lipid peroxidation evidence in exhaled breath condensate: a possible predictor of acute mountain sickness.

Lung oxidative stress (OS) was explored in resting and in exercising subjects exposed to moderate and high altitude. Exhaled breath condensate (EBC) was collected under field conditions in male high-competition mountain bikers performing a maximal cycloergometric exercise at 670 m and at 2,160 m, as well as, in male soldiers climbing up to 6,125 m in Northern Chile. Malondialdehyde concentration [MDA] was measured by high-performance liquid chromatography in EBC and in serum samples. Hydrogen peroxide concentration [H(2)O(2)] was analysed in EBC according to the spectrophotometric FOX(2) assay. [MDA] in EBC of bikers did not change while exercising at 670 m, but increased from 30.0+/-8.0 to 50.0+/-11.0 nmol l(-1) (P<0.05) at 2,160 m. Concomitantly, [MDA] in serum and [H(2)O(2)] in EBC remained constant. On the other hand, in mountaineering soldiers, [H(2)O(2)] in EBC under resting conditions increased from 0.30+/-0.12 mumol l(-1) at 670 m to 1.14+/-0.29 mumol l(-1) immediately on return from the mountain. Three days later, [H(2)O(2)] in EBC (0.93 +/-0.23 mumol l(-1)) continued to be elevated (P<0.05). [MDA] in EBC increased from 71+/-16 nmol l(-1) at 670 m to 128+/-26 nmol l(-1) at 3,000 m (P<0.05). Changes of [H(2)O(2)] in EBC while ascending from 670 m up to 3,000 m inversely correlated with concomitant variations in HbO2 saturation (r=-0.48, P<0.05). AMS score evaluated at 5,000 m directly correlated with changes of [MDA] in EBC occurring while the subjects moved from 670 to 3,000 m (r=0.51, P<0.05). Lung OS may constitute a pathogenic factor in AMS.

Adolescent↗
PubMed2004

Exhaled nitric oxide in the clinical management of asthma.

Management of asthma has gradually evolved from the concept of controlling bronchial hyperresponsiveness to focusing on control of inflammation. The awareness of airway remodeling, and the emergence of data suggesting irreversibility of some of these changes, despite standard-of-care pharmacotherapies such as inhaled steroids, has highlighted the need for early detection; effective diagnosis and treatment; monitoring responses and adhering to treatment; and predicting exacerbations. Pre-clinical intervention strategies targeted toward picking up early suggestions of asthma before irreversible airway changes occur may open the door to primary prevention approaches. Although invasive methods, such as bronchial biopsy, remain the gold standard to understanding and treating asthma, there is a preference for noninvasive techniques for reasons of convenience, ease of use, and patient comfort. In this article, recent data that support the use of exhaled nitric oxide as a noninvasive biomarker of inflammation in clinical practice are reviewed.

Anti-Inflammatory Agents↗