Clinical patterns in asthma based on proximal and distal airway nitric oxide categories.

BACKGROUND: The exhaled nitric oxide (eNO) signal is a marker of inflammation, and can be partitioned into proximal [J'awNO (nl/s), maximum airway flux] and distal contributions [CANO (ppb), distal airway/alveolar NO concentration]. We hypothesized that J'awNO and CANO are selectively elevated in asthmatics, permitting identification of four inflammatory categories with distinct clinical features. METHODS: In 200 consecutive children with asthma, and 21 non-asthmatic, non-atopic controls, we measured baseline spirometry, bronchodilator response, asthma control and morbidity, atopic status, use of inhaled corticosteroids, and eNO at multiple flows (50, 100, and 200 ml/s) in a cross-sectional study design. A trumpet-shaped axial diffusion model of NO exchange was used to characterize J'awNO and CANO. RESULTS: J'awNO was not correlated with CANO, and thus asthmatic subjects were grouped into four eNO categories based on upper limit thresholds of non-asthmatics for J'awNO (>or= 1.5 nl/s) and CANO (>or= 2.3 ppb): Type I (normal J'awNO and CANO), Type II (elevated J'awNO and normal CANO), Type III (elevated J'awNO and CANO) and Type IV (normal J'awNO and elevated CANO). The rate of inhaled corticosteroid use (lowest in Type III) and atopy (highest in Type II) varied significantly amongst the categories influencing J'awNO, but was not related to CANO, asthma control or morbidity. All categories demonstrated normal to near-normal baseline spirometry; however, only eNO categories with increased CANO (III and IV) had significantly worse asthma control and morbidity when compared to categories I and II. CONCLUSIONS: J'awNO and CANO reveal inflammatory categories in children with asthma that have distinct clinical features including sensitivity to inhaled corticosteroids and atopy. Only categories with increase CANO were related to poor asthma control and morbidity independent of baseline spirometry, bronchodilator response, atopic status, or use of inhaled corticosteroids.

Quantifying proximal and distal sources of NO in asthma using a multicompartment model.

Nitric oxide (NO) is detectable in exhaled breath and is thought to be a marker of lung inflammation. The multicompartment model of NO exchange in the lungs, which was previously introduced by our laboratory, considers parallel and serial heterogeneity in the proximal and distal regions and can simulate dynamic features of the NO exhalation profile, such as a sloping phase III region. Here, we present a detailed sensitivity analysis of the multicompartment model and then apply the model to a population of children with mild asthma. Latin hypercube sampling demonstrated that ventilation and structural parameters were not significant relative to NO production terms in determining the NO profile, thus reducing the number of free parameters from nine to five. Analysis of exhaled NO profiles at three flows (50, 100, and 200 ml/s) from 20 children (age 7-17 yr) with mild asthma representing a wide range of exhaled NO (4.9 ppb < fractional exhaled NO at 50 ml/s < 120 ppb) demonstrated that 90% of the children had a negative phase III slope. The multicompartment model could simulate the negative phase III slope by increasing the large airway NO flux and/or distal airway/alveolar concentration in the well-ventilated regions. In all subjects, the multicompartment model analysis improved the least-squares fit to the data relative to a single-path two-compartment model. We conclude that features of the NO exhalation profile that are commonly observed in mild asthma are more accurately simulated with the multicompartment model than with the two-compartment model. The negative phase III slope may be due to increased NO production in well-ventilated regions of the lungs.

An elevated bronchodilator response predicts large airway inflammation in mild asthma.

Exhaled nitric oxide (eNO) is elevated in asthmatics and is a purported marker of airway inflammation. The bronchodilator response (BDR) has also been shown to correlate with markers of airway inflammation, including eNO at 50 ml/sec (FE(NO,50)) which is comprised of NO from both the proximal and distal airways. Using eNO at multiple flows and a two-compartment model of NO exchange, the eNO signal can be partitioned into its proximal [J'aw(NO) (nl/sec)] and distal contributions [CA(NO) (ppb)]. We hypothesized that the BDR reflects the inflammatory status of the larger airways with smooth muscle, and thus would correlate with J'aw(NO). In 179 predominantly (95%) Hispanic children with mild asthma (69 steroid naïve), and 21 non-asthmatic non-atopic controls, spirometry and eNO at multiple flows were measured prior and 10 min following inhalation of albuterol. A trumpet-shaped axial diffusion model of NO exchange was used to characterize J'aw(NO) and CA(NO). The BDR correlated moderately (r = 0.44) with proximal airway NO (J'aw(NO)), but weakly (r = 0.26) with distal airway/alveolar NO (CA(NO)), and only in inhaled corticosteroid naïve asthmatics. A BDR cut point as low as >or=8% had a positive predictive value of 83% for predicting an elevated J'aw(NO) or FE(NO,50). We conclude that the BDR reflects inflammation in the large airways, and may be an effective clinical tool to predict elevated large airway inflammation.

Impact of analysis interval on the multiple exhalation flow technique to partition exhaled nitric oxide.

Exhaled nitric oxide (eNO) is elevated in asthmatics and is a purported marker of airway inflammation. By measuring eNO at multiple flows and applying models of eNO exchange dynamics, the signal can be partitioned into its proximal airway [J' aw NO (nl/sec)] and distal airway/alveolar contributions [CA(NO)(ppb)]. Several studies have demonstrated the potential significance of such an approach in children with asthma. However, techniques to partition eNO are variable, limiting comparisons among studies. The objective of this study is to examine the impact of the analysis interval (time or volume) on eNO plateau concentrations and the estimation of J' aw NO and CA(NO). In 30 children with mild to moderate asthma, spirometry and eNO at multiple flows (50, 100, and 200 ml/sec) were measured. The plateau concentration of eNO at each flow was determined using two different methods of analysis: (1) constant time interval and (2) constant volume interval. For both methods of analysis, a two-compartment model with axial diffusion was used to characterize J' aw NO and CA(NO). At a flow of 200 ml/sec, the time interval analysis predicts values for eNO that are smaller than the volume interval analysis. As a result, there are significant differences in CA(NO) between the methods of analysis (volume > time). When using the multiple flow technique to partition eNO, the method of analysis (constant time vs. constant volume interval) significantly affects the estimation of CA(NO), and thus potentially the assessment and interpretation of distal lung inflammation.

Partitioned exhaled nitric oxide to non-invasively assess asthma.

Asthma is a chronic inflammatory disease of the lungs, characterized by airway hyperresponsiveness. Chronic repetitive bouts of acute inflammation lead to airway wall remodeling and possibly the sequelae of fixed airflow obstruction. Nitric oxide (NO) is a reactive molecule synthesized by NO synthases (NOS). NOS are expressed by cells within the airway wall and functionally, two NOS isoforms exist: constitutive and inducible. In asthma, the inducible isoform is over expressed, leading to increased production of NO, which diffuses into the airway lumen, where it can be detected in the exhaled breath. The exhaled NO signal can be partitioned into airway and alveolar components by measuring exhaled NO at multiple flows and applying mathematical models of pulmonary NO dynamics. The airway NO flux and alveolar NO concentration can be elevated in adults and children with asthma and have been correlated with markers of airway inflammation and airflow obstruction in cross-sectional studies. Longitudinal studies which specifically address the clinical potential of partitioning exhaled NO for diagnosis, managing therapy, and predicting exacerbation are needed.

Prevalence of increased esophageal muscle thickness in patients with esophageal symptoms.

BACKGROUND: Patients with achalasia, diffuse esophageal spasm (DES), and nutcracker esophagus have a thicker muscularis propria than normal subjects. The goal of our study was to determine the prevalence of increased muscle thickness in a group of unselected patients referred to the esophageal function laboratory for evaluation of the symptoms. METHODS: We studied 40 normal subjects and 94 consecutive patients. Manometry and ultrasound images were recorded concurrently, using a special custom-built catheter. Esophageal muscle thickness and muscle cross-sectional area were measured at 2 and 10 cm above the lower esophageal sphincter (LES). Patients were assigned manometric diagnosis and determination was made if they had increased muscle thickness and muscle cross-sectional area. RESULTS: Nearly all patients with well-defined spastic motor disorders, i.e., achalasia, DES, and nutcracker esophagus, revealed (a) an increase in the muscle thickness/cross-sectional area, (b) increase in esophageal muscle thickness/cross-sectional area was also seen, albeit at a lower prevalence rate, in patients with less well-characterized manometric abnormalities, i.e., hypertensive LES, impaired LES relaxation, and ineffective esophageal motility, and (c) 24% of patients with esophageal symptoms but normal manometry were also found to have an increase in muscle thickness/cross-sectional area. Dysphagia was more likely, and heartburn less likely in patients with increased muscle thickness, but there were no differences in chest pain and regurgitation symptoms between the groups. CONCLUSION: We describe, for the first time, increased muscle thickness in patients with esophageal symptoms and normal manometry. We suggest that increased esophageal muscle thickness is likely to be an important marker of esophageal motor dysfunction.

Common cavity pressure during gastroesophageal reflux: reassessment using simultaneous pressure, impedance, and ultrasound imaging.

An increase in intraesophageal pressure during transient lower esophageal sphincter (LES) relaxation [referred to as common cavity (CC) pressure] is thought to be a marker of gastroesophageal reflux (GER). Multiluminal impedance (MII) measurement is a sensitive marker of reflux entry into the esophagus during GER. We recorded GER using esophageal pressure, pH, impedance, and intraluminal ultrasound (US) images to understand the genesis of the esophageal CC pressure. Nine normal subjects underwent simultaneous MII/pH/pressure and US image recording of the esophagus for 2 h following a standardized meal. MII and pressure transducers were located at 5 and 15 cm above the LES. The US transducer and pH sensors were also placed at 5 cm above the LES. Refluxate entry into the esophagus by MII criteria was determined relative to the onset of CC pressure wave. Esophageal lumen cross-sectional area (CSA) and muscle CSA during GER were determined from the US images. Eighty liquid GER episodes identified using MII criteria, of which 55 were clearly associated with CC pressure waves, were analyzed. The GER reached 15 cm above LES in 49 of 55 (89%) by MII criteria, but the CC pressure wave was observed at 5 and 15 cm during all episodes. The propagation of the CC pressure wave was simultaneous between 5 and 15 cm during 49 of 55 (89%) of the GER episodes, but reflux entry by MII criteria was retrograde during 53 of 55 (96%) of these episodes. During 5 air-reflux episodes, MII showed a simultaneous reflux entry between the 5- and 15-cm site, however, the CC pressure preceded reflux entry during all of these episodes. There was poor correlation between the luminal CSA and the magnitude of CC pressure (R(2) = 0.144). US images revealed a close temporal correlation between CC pressure and the increase in esophageal muscle thickness and muscle CSA (markers of longitudinal muscle contraction). Disassociation between CC pressure and MII-detected reflux suggests that the onset of CC pressure is not due to GER. We speculate that longitudinal muscle contraction plays an important role in the genesis of CC pressure.

Asynchrony between the circular and the longitudinal muscle contraction in patients with nutcracker esophagus.

BACKGROUND & AIMS: The increases in intraluminal pressure and muscle cross-sectional area (CSA) during esophageal contraction are markers of circular and longitudinal muscle contractions. The goal of our study was to determine temporal synchrony between circular and longitudinal muscle contraction in healthy subjects and patients with nutcracker esophagus. METHODS: Pressure and high-frequency intraluminal ultrasound (HFIUS) images were recorded simultaneously in healthy subjects and patients with nutcracker esophagus at 2 and 10 cm above the lower esophageal sphincter during wet swallow. HFIUS images were digitized and analyzed for the muscle CSA. The time interval (delta-t) between the peak muscle CSA and the peak pressure was determined. RESULTS: In healthy subjects, a close temporal correlation existed between the peak contraction pressure and the peak muscle CSA with a maximum delta-t of 0.5 seconds at the 2- and 10-cm levels (0-0.5 seconds). On the other hand, the patient group had a median delta-t of 1.25 seconds (0.75-3.5 seconds) at the 2-cm level and 0.75 seconds (0-2.0 seconds) at the 10-cm level. Ninety-eight of 103 contractions in patients showed a delta-t >0.5 seconds. There was a significant correlation between delta-t and the amplitude of pressure wave, the duration of pressure wave, and the peak muscle CSA. The duration of pressure wave but not the duration of CSA wave was longer in patients with nutcracker esophagus as compared with healthy subjects. CONCLUSIONS: Patients with nutcracker esophagus show temporal asynchrony between the contractions of circular and longitudinal muscle layers.

Sensory and motor function of the esophagus: lessons from ultrasound imaging.

Catheter-based high-frequency intraluminal ultrasound imaging is a powerful tool to study esophageal sensory and motor function and dysfunction in vivo in humans. It can be combined with manometry, pH, and impedance measurement techniques to determine the relationships between different physiologic parameters. High-frequency intraluminal ultrasound imaging has provided a number of important insights regarding the longitudinal muscle function of the esophagus. On the basis of the ultrasound images and intraluminal pressure recordings, it seems that there is synchrony in the timing and the amplitude of contraction between the circular and longitudinal muscle layers. A sustained contraction of the longitudinal muscle layer is temporally related to esophageal chest pain and heartburn. The biomechanics of the esophageal wall and its relationship to sensory and motor function can be studied in humans in vivo by using high-frequency intraluminal ultrasound much more precisely than has previously been possible. Achalasia, diffuse esophageal spasm, and nutcracker esophagus are associated with hypertrophy of circular and longitudinal muscle layers. Finally, high-frequency intraluminal ultrasound imaging is the only technique that can detect reflux-related distention of the esophagus and its role in esophageal symptoms. Future approaches to display and quantify ultrasound image data are discussed. The principles of high-frequency intraluminal ultrasound described here are also applicable to study of the motor and sensory function of the other regions of the gastrointestinal tract.

Ultrasound system to measure esophageal varix pressure: an in vitro validation study.

We report our experience with an ultrasound system to measure esophageal varix pressure in an in vitro model. The ultrasound system consists of a 12.5 MHz frequency intraluminal ultrasound probe, a water infusion catheter, and a manometry catheter, all contained within a nondistensible latex bag. Esophagi and external jugular veins were harvested from five pigs. The vein and ultrasound system were placed inside the esophagus. One end of the vein was connected to a water reservoir to modulate its pressure; the other end was connected in two different ways to simulate hydrodynamic and hydrostatic flow conditions. The bag was inflated with water until vein occlusion was discernible on the ultrasound images. The influences of vein pressure, vein cross-sectional area and esophageal elasticity on the ultrasound measurement of vein pressure were assessed. A total of 108 trials were performed at nine different vein pressures. Complete vein occlusion occurred when the bag pressure was slightly greater (1.4 +/- 0.7 mmHg) than the vein pressure. For a vein pressure of 25 mmHg, the average occlusion and opening pressures were 27 +/- 0.2 and 25.7 +/- 0.3 mmHg, respectively (P < .05) suggesting that the vein opening pressure on the ultrasound images is more accurate than the vein closing pressure. In conclusion, the ultrasound technique can accurately measure intravariceal pressure in vitro. The bag pressure at the point of vein reopening is the best determinant of the vein pressure.

Crural diaphragm inhibition during esophageal distension correlates with contraction of the esophageal longitudinal muscle in cats.

Esophageal distension causes simultaneous relaxation of the lower esophageal sphincter (LES) and crural diaphragm. The mechanism of crural diaphragm relaxation during esophageal distension is not well understood. We studied the motion of crural and costal diaphragm along with the motion of the distal esophagus during esophageal distension-induced relaxation of the LES and crural diaphragm. Wire electrodes were surgically implanted into the crural and costal diaphragm in five cats. In two additional cats, radiopaque markers were also sutured into the outer wall of the distal esophagus to monitor esophageal shortening. Under light anesthesia, animals were placed on an X-ray fluoroscope to monitor the motion of the diaphragm and the distal esophagus by tracking the radiopaque markers. Crural and costal diaphragm electromyograms (EMGs) were recorded along with the esophageal, LES, and gastric pressures. A 2-cm balloon placed 5 cm above the LES was used for esophageal distension. Effects of baclofen, a GABA(B) agonist, were also studied. Esophageal distension induced LES relaxation and selective inhibition of the crural diaphragm EMG. The crural diaphragm moved in a craniocaudal direction with expiration and inspiration, respectively. Esophageal distension-induced inhibition of the crural EMG was associated with sustained cranial motion of the crural diaphragm and esophagus. Baclofen blocked distension-induced LES relaxation and crural diaphragm EMG inhibition along with the cranial motion of the crural diaphragm and the distal esophagus. There is a close temporal correlation between esophageal distension-mediated LES relaxation and crural diaphragm inhibition with the sustained cranial motion of the crural diaphragm. Stretch caused by the longitudinal muscle contraction of the esophagus during distension of the esophagus may be important in causing LES relaxation and crural diaphragm inhibition.

Symptom hypersensitivity to acid infusion is associated with hypersensitivity of esophageal contractility.

Several investigators have observed that repeated acid infusions induce stronger symptoms (symptom hypersensitivity). The goal of our study was to determine whether symptom hypersensitivity is associated with esophageal contractile hypersensitivity. Subjects with chronic heartburn symptoms underwent simultaneous pressure and ultrasound imaging of esophagus. Normal saline and 0.1 N HCl were sequentially infused into the esophagus, and subjects scored heartburn symptoms on a 1-10 scale. Saline and HCl infusions were repeated in 10 subjects with a positive Bernstein test. Esophageal contraction amplitude and duration and muscularis propria thickness were measured using a computerized method during recording. Acid infusion induced heartburn. Esophageal contractions had higher amplitudes (pressure 114.2 +/- 7.0%) and longer duration (116.8 +/- 4.4%) during acid infusion compared with saline infusion. Average muscle thickness was greater during acid infusion than saline infusion (107.0 +/- 2.0%). Sustained esophageal contractions (SECs) were identified during acid infusion. A second acid infusion (acid-2) induced heartburn with shorter latency (93.0 +/- 15.0 vs. 317.0 +/- 43.0 s) and stronger severity (8.5 +/- 0.5 vs. 5.3 +/- 0.8) than the first acid infusion (acid-1). Contraction amplitudes (140.2 +/- 13.0%), average muscle thickness (118.0 +/- 3.3%), and contraction duration (148.5 +/- 5.6 vs. 116.8 +/- 4.4%) were higher during acid-2 than acid-1. Also, numbers of SECs were greater during acid-2 than acid-1 (31 in 8 subjects vs. 11 in 6 subjects). Our data show that acid infusion into esophagus induces esophageal hypersensitivity and that a close temporal correlation exists between symptom hypersensitivity and contractility hypersensitivity.

Hypertrophy of the muscularis propria of the lower esophageal sphincter and the body of the esophagus in patients with primary motility disorders of the esophagus.

OBJECTIVES: Patients with diffuse esophageal spasm (DES) and nutcracker esophagus/high amplitude esophageal contraction (HAEC) have a thicker esophageal muscularis propria than do healthy subjects. The goals of this study were to determine the esophageal muscle cross-sectional area (MCSA), a measure of muscle mass, in patients with achalasia of the esophagus; and to compare it with that in patients with DES, patients with HAEC, and normal subjects. METHODS: Using a high-frequency ultrasound probe catheter, concurrent manometry and ultrasound images of the esophagus were recorded in four subject groups: normal volunteers, patients with HAEC, patients with DES, and patients with achalasia of the esophagus. Recordings were obtained from the lower esophageal sphincter (LES) and multiple sites in the esophagus 2, 4, 6, 8, and 10 cm above the LES. RESULTS: The LES and esophageal muscle thickness as well as esophageal MCSA were greater in all three patient groups than in the normal subject group. Muscle thickness and MCSA were observed to be greatest in patients with achalasia, which were greater than in patients with DES, which were greater than in those with HAEC, which in turn were greater than in normal subjects. CONCLUSIONS: We propose that an increase in the MCSA is an important feature of patients with primary motility disorders of the esophagus. The degree of increase in muscle mass may be an important determinant of the type and the severity of esophageal motor dysfunction.

Measuring esophageal distension by high-frequency intraluminal ultrasound probe.

Distension of the esophagus can cause heartburn and chest pain; however, none of the available techniques to study the esophagus measure esophageal distension. We evaluated the technique of high-frequency intraluminal ultrasound probe (HFIUS) to measure the esophageal cross-sectional area (CSA) during gastroesophageal reflux (GER). The following methods were used: 1) the CSA of agarose gel tubes of known dimensions were measured using ultrasound probes; 2) seven normal subjects were studied to evaluate the esophageal CSA during different bolus volumes (1, 5, 10, 15, and 20 ml) of water swallows (WS); and 3) simultaneous pressures, pH, and ultrasound images of the esophagus were recorded in healthy subjects. In vitro studies showed that the HFIUS measured the CSA of the tubes accurately. The maximal CSA of the distal esophagus during WS with boluses of 1, 5, 10, 15, and 20 ml were 54, 101, 175, 235, and 246 mm(2), respectively. Esophageal contents during 62 episodes of transient lower esophageal sphincter relaxations, 29 pH positive, and 33 pH negative GER episodes revealed that reflux of air into the esophagus occurred more frequently than liquid. The median CSA and estimated diameter of the esophagus during liquid GER was 44.1 mm(2) and 7.5 mm, respectively. We conclude that HFIUS is a valid technique to measure the CSA of the esophagus in vivo during GER. Distension of the esophagus during physiological GER is relatively small.

A novel ultrasound technique to study the biomechanics of the human esophagus in vivo.

The objectives of this study were to validate a novel ultrasound technique and to use it to study the circumferential stress-strain properties of the human esophagus in vivo. A manometric catheter equipped with a high-compliance bag and a high-frequency intraluminal ultrasonography probe was used to record esophageal pressure and images. Validation studies were performed in vitro followed by in vivo studies in healthy human subjects. Esophageal distensions were performed with either an isovolumic (5-20 ml of water) or with an isobaric (10-60 mmHg) technique. Sustained distension was also performed for 3 min in each subject. The circumferential wall stress and strain were calculated. In vitro studies indicate that the ultrasound technique can make measurements of the esophageal wall with an accuracy of 0.01 mm. The in vivo studies provide the necessary data to compute the Kirchhoff's stress, Green's strain, and Young's elastic modulus during esophageal distensions. The stress-strain relationship revealed a linear shape, the slope of which corresponds to the Young's modulus. During sustained distensions, we found dynamic changes of stress and strain during the period of distension. We describe and validate a novel ultrasound technique that allows measurement of biomechanical properties of the esophagus in vivo in humans.