Modulation of sulfur mustard toxicity by arginine analogues and related nitric oxide synthase inhibitors in vitro

Obstructive sleep apnea is a common medical disorder with significant adverse health consequences. The pathogenesis of pharyngeal obstruction during sleep, however, remains elusive. This article addresses the key mechanisms of upper airway (UA) obstruction including the role of transmural pressure, pharyngeal compliance, pharyngeal dilating muscle activity and non-neuromuscular factors. A proposed scheme of the pathophysiology of UA obstruction is outlined.     

Expandable metallic stent placement in patients with benign esophageal strictures: results of long-term follow-up

Prosthetic mandibular advancement (PMA) was applied to nine patients with obstructive sleep apnea syndrome (OSAS) and its therapeutic usefulness, mechanism of action, and clinical indication were discussed based on polysomnographic findings and serial examination of upper airway before and during PMA treatment. Apnea hypopnea index significantly decreased during PMA treatment compared with the value before treatment (P < 0.01) and the rate of the treatment responder counted 78.1%. Cephalometric variables indicated forward and inferior advancement of mandible in our subjects. Magnetic resonance imaging of the upper airway during sleep revealed a marked improvement of velophanryngeal obstruction in most subjects. In addition, intraesophageal negative pressure during sleep decreased significantly. Our results confirmed the high therapeutic efficacy of PMA for OSAS and indicated forward advancement of the mandible and decrease of negative pressure loading on upper airway with PMA might suppress velopharyngeal collapse. Thus, PMA was regarded as one of the treatments of choice for OSAS occurring based on with velopharyngeal narrowing.     

Airway remodeling: potential contributions of subepithelial fibrosis and airway smooth muscle hypertrophy/hyperplasia to airway narrowing in asthma

Recently, much attention has been focused on the airway structural changes accompanying chronic, severe asthma, and the potential ramifications of these changes for airway function and medical management. Airway remodeling may exaggerate airway narrowing by: (i) thickening of the airway wall internal to the smooth muscle, thereby increasing the luminal obstruction generated by a given degree of smooth muscle shortening; (ii) increasing the amount of smooth muscle, thereby increasing shortening; and/or (iii) reducing the load on the smooth muscle, either by increasing the compliance of the airway wall or by reducing airway-parenchymal interdependence. The possibility also exists that airway remodeling represents a protective mechanism against excessive airway narrowing. The major airway structural changes occurring in asthma are subepithelial protein deposition and increased airway smooth muscle mass (hypertrophy, hyperplasia, or both). Several investigators have found correlations between the magnitudes of subepithelial thickening and smooth muscle hypertrophy/hyperplasia and the severity of airways disease, though interpretation has been made difficult by study differences in patient population, treatment, indices of disease severity, and morphometric technique. Taken together, these data suggest that increases in airway remodeling may contribute significantly to the airflow obstruction observed in patients with asthma. However, data proving a causal relationship between airway remodeling and asthma severity remain elusive.     

Obstructive sleep apnea and related disorders

OSAS, a common cause of disrupted sleep and EDS, result from repetitive closure of the upper airway during sleep. It probably represents the most severe syndrome related to obstruction of the upper airway; less severe forms include UARS, a syndrome characterized by the need for increased effort to breath but no prominent apneas or hypopneas, and primary snoring. Initial clues to the presence of OSAS and related disorders are derived from the history and include loud snoring, EDS or insomnia, and witnessed apneas. Some patients, especially women, may complain mostly of tiredness or fatigue, and children may present with behavioral abnormalities. Obesity, a large neck circumference, and a crowded oropharynx are common on physical examination. Nonobese patients, in particular, often have retrognathia, a high-arched narrow palate, macroglossia, enlarged tonsils, temporomandibular joint abnormalities, or chronic nasal obstruction. The clinical suspicion of obstructed nocturnal breathing is confirmed by overnight polysomnography, and an MSLT may be used to assess sleepiness. Esophageal manometry during polysomnography facilitates diagnosis of UARS. Treatment most commonly consists of nasal CPAP or BPAP, although problems with compliance make surgical treatment preferable in some cases. Although UPPP eliminates sleep apnea only in a minority of patients, combining UPPP with maxillofacial procedures appears to improve outcomes. Other treatments such as the use of dental appliances or medications, weight loss, and positional therapy may be useful as adjunctive therapy for moderate to severe OSAS or as primary treatments for UARS or mild OSAS.     

Effects of bronchial vascular engorgement on airway dimensions

Airway vascular engorgement has been suggested to cause luminal narrowing and airflow obstruction. To determine the extent to which changes in bronchial vascular volume could influence airway dimensions, we studied the effects of left atrial pressure elevation on airway morphometry in sheep (n = 17). The bronchial branch of the bronchoesophageal artery was cannulated and perfused with autologous blood (0.6 ml.min-1.kg-1). A balloon-tipped catheter was inserted into the left atrial appendage to elevate left atrial pressure by 10 mmHg, and papaverine was infused into the bronchial artery to eliminate airway smooth muscle tone. Morphological measurements were made from rapidly frozen lungs excised in vivo. Left atrial pressure elevation caused a 79% increase in total vascular area (P = 0.0002). Average airway luminal area was significantly decreased from 86 to 71% of the airway maximal area (P < 0.0001). Noteworthy were the prominent bronchial vessels located within mucosal folds. However, when papaverine was infused during left atrial pressure elevation, despite a comparable total vascular area, luminal narrowing did not occur and remained at 87% of the maximal area (P = 0.6267). In conclusion, we found that engorgement of the bronchial vasculature leads to an increase in the vascular area in regions inside and outside the smooth muscle layer. The associated decrease in luminal area only occurs in the presence of airway smooth muscle tone. This suggests a reflex effect on the airway caused by the vascular engorgement. We conclude that vascular engorgement of the airway wall per se has a negligible effect on airway obstruction.     

Effect of pharmacokinetic sampling methods on aminoglycoside dosing in critically ill surgery patients

BACKGROUND: Airway obstruction after anesthesia may be caused or exaggerated by residual neuromuscular block, with loss of muscle support for collapsible upper airway structures. METHODS: Six male volunteers were studied before treatment, during stable partial neuromuscular block with vecuronium at a mean train-of-four (TOF) ratio of 50% (95% CI, 36-61%), and after reversal by neostigmine. Catheter-mounted transducers were placed in the pharynx and esophagus to estimate, respectively, the upper airway resistance, and the work of breathing (calculated as the time integral of the inspiratory pressure developed by the respiratory muscles, esophageal pressure time product) during quiet breathing, during breathing 5% carbon dioxide, and while breathing with an inspiratory resistor. Breathing with pressure at the airway opening held at pressures from -5 to 40 cm H2O were also tested to assess airway collapsibility. RESULTS: Although breathing through a resistor increased upper airway resistance from 1.2 (0.67, 1.72) cm H2O x l(-1) x s to 2.5 (1.32, 3.38) cm H2O x l(-1) x s, and carbon dioxide stimulation reduced resistance to 0.8 (0.46, 1.33) cm H2O x l(-1) x s, no effect of partial neuromuscular block (mean TOF ratio, 52%) on upper airway properties could be shown. CONCLUSIONS: Neuromuscular block with a TOF ratio of 50% can be present yet clinically difficult to detect in patients recovering from anesthesia. This degree of block has no effect on airway patency in volunteers, even during challenge. Airway obstruction during recovery from anesthesia thus is more likely to be caused by residual effects of general anesthetic agents or centrally acting analgesics, either alone or perhaps in concert with residual neuromuscular block.     

Effect of probucol on serum lipoprotein and apoprotein profiles in renal transplant patients

Compliance, distensibility, incremental elastic modulus (E(inc)), and pulse wave velocity are all terms used to describe the mechanical properties of arteries. Previous studies assessing the effects of smooth muscle relaxation on each of these parameters have produced conflicting results. Our laboratory has previously demonstrated that intrabrachial infusion of nitroglycerin in normal human subjects results in a large increase in brachial artery compliance without changing arterial wall stiffness as measured by E(inc). In the present study, the relationships among compliance, distensibility, E(inc), and pulse wave velocity under different levels of vascular tone are shown using data acquired by intravascular ultrasound as well as theoretical curves. We demonstrate that the effects of smooth muscle relaxation can be depicted as 2 separate steps: (1) a rightward shift to a new theoretical curve describing the relationship between 2 of the above elastic parameters that is solely due to changes in vessel geometry and (2) a shift along the new curve that is dependent on changes in wall stiffness.     

Forced oscillation technique for the evaluation of severe sleep apnoea/hypopnoea syndrome: a pilot study

The forced oscillation technique (FOT) is a noninvasive method of potential clinical interest for quantitatively assessing airway mechanics during sleep. We investigated the applicability of FOT as a diagnostic tool for noninvasive assessment of airflow obstruction in patients with sleep apnoea/hypopnoea syndrome (SAHS) during sleep. In seven patients previously diagnosed with severe SAHS (mean+/-SD apnoea/ hypopnoea index (AHI) 67+/-14) we performed a full polysomnography (PSG) together with on-line measurement of respiratory impedance (IZI) using FOT. For each patient we determined: 1) number of respiratory events conventionally detected by full PSG, those obtained by FOT and their degree of concordance; and 2) the characteristics and values of IZI during the respiratory events. FOT was well tolerated and easily applied in conjunction with a conventional sleep setup. The mean number of respiratory events x h(-1) detected by PSG and FOT were 55+/-16 and 58+/-17, respectively, with a strong concordance. IZI increased from a baseline of 11+/-4 to 50+/-20 cmH2O x L(-1) x s during apnoea (mean+/-SD). In all but one patient intermittent increases of IZI occurred immediately before each obstructive apnoea. In four patients, the increases of IZI developed at end-expiration whereas in two others occurred during inspiration. During hypopnoea most of the patients showed decreases of IZI during expiration. In conclusion, forced oscillation technique can be used as a noninvasive and complementary tool for the diagnosis of respiratory events and provides an on-line quantitative approach for continuous monitoring of airflow obstruction during sleep in patients with sleep apnoea/hypopnoea syndrome.     

Upper airway muscles and physiopathology of obstructive sleep apnea syndrome

Upper airway dilator muscle generate inspiratory pressure that balances subatmospheric pharyngeal pressure gene-rated by diaphragmatic contraction leading to reduce upper airway patency. Neural control of upper airway dilator muscles involve several categories of receptors such as vagal pulmonary receptors, upper airway mecanoreceptors, baroreceptors, chemoreceptors. Upper airway resistances increase during sleep and upper airway inspiratory muscle activity decrease especially during bursts of rapid eye movements in REM sleep. Sleep-related upper airway obstruction occurs when upper airway dilator pressure does not balance subatmospheric pharyngeal pressure. Several variables are involved in the pathophysiology of obstructive apneas such as upper airway anatomical factors, structural muscular dysfunction, changes in neural drive.     

Aspects of chronic airflow obstruction

This report questions several commonly used definitions and commonly accepted concepts. It suggest that the term, "chronic airflow obstructions," should replace the terms, "chronic obstructive pulmonary disease," "chronic obstructive lung disease," or "chronic airway obstruction," because it is flow that is obstructed. It is suggested the term, "chronic mucous hypersecretion," be used, rather than "chronic bronchitis," and that the latter be avoided. Chronic bronchitis should not be equated with narrowing of the airway and emphysema with loss of elastic recoil. Chronic bronchitis, emphysema, and lesions of the small airways probably occur together more frequently than chance will allow because of a common etiologic agent, tobacco smoke. Chronic mucous hypersecretion without other airway or parenchymal lesions seldom produces airflow obstruction and does not impair prognosis significantly. Central airways are important in chronic airflow obstruction. It is time that someone found out what is happening in subjects with abnormal results on tests of the function of small airways. The definition of "destruction" as it occurs in emphysema is deceptive, and loss of recoil and emphysema may be separate conditions. The dysfunction that occurs in emphysematous lungs is due mainly to associated airway lesions and may perhaps be due in part to the site and nature of emphysematous lesions (as opposed to loss of elastic recoil).     

Evaluation of diaphragmatic fatigue in obstructive sleep apnoeas during non-REM sleep

BACKGROUND: Resistive load applied to the airways may induce diaphragmatic fatigue, and hypoxaemia has been shown to predispose to the development of fatigue. Inspiratory muscle fatigue may occur in patients with obstructive sleep apnoea syndrome (OSAS), as these patients repetitively develop both inspiratory loading and hypoxaemia. The results of previous studies on this topic are inconclusive, probably because of the methodological approaches used. METHODS: Six obese patients with OSAS underwent a polysomnographic study. The diaphragmatic pressure time index (PTI) was evaluated as an indicator of diaphragmatic contraction, and the mean frequency of the diaphragmatic electromyogram power spectrum (Fm) and the maximum relaxation rate of transdiaphragmatic pressure (MRR) as indices of a fatiguing diaphragm. A total of 119 randomly selected apnoeas (each including 5-13 occluded efforts) were analysed throughout the night in non-REM sleep to assess possible muscle fatigue due to the high pressure generation in each apnoea. A breath-by-breath within-apnoea analysis was performed on the first three pre-apnoeic breaths, on all the occluded efforts, and on the first three unoccluded breaths following the apnoea interruption. Possible fatigue development due to the cumulative effect of apnoeas over the night was also evaluated. RESULTS: A progressive increase of Fm and MRR was found during the obstructive phase in all the subjects in the within-apnoea analysis. The overnight analysis did not show a reduction in either PTI, Fm, or MRR secondary to recurrent upper airway obstruction during the night. CONCLUSIONS: No evidence of diaphragmatic fatigue or impaired diaphragmatic contraction was found either within each apnoea or throughout the whole night, despite the generation of high PTI values during the apnoeic occluded phases. It is concluded that diaphragmatic fatigue does not occur in OSAS during non-REM sleep.     

Airway structure and function in Eisenmenger's syndrome

The responsiveness of airways from patients with Eisenmenger's syndrome (n = 5) was compared with that in airways from organ donors (n = 10). Enhanced contractile responses to cholinergic stimulation were found in airways from patients with Eisenmenger's syndrome. The maximal responses to acetylcholine, carbachol, and parasympathetic nerve stimulation in airway tissue from these patients were 221%, 139%, and 152%, respectively, of the maximal responses obtained in donor tissue. Further, relaxation responses to isoproterenol and levocromakalim were absent (n = 2) or markedly impaired (n = 3) in airways from patients with Eisenmenger's syndrome. This attenuated relaxation response was nonspecific in that it was also absent after vasoactive intestinal peptide, sodium nitroprusside, papaverine, and electrical field application. These observations can most likely be explained by a decrease in intrinsic smooth muscle tone, as precontraction of airways revealed relaxation responses that were equivalent to those obtained in donor tissues. Morphometric analysis of tissues used for the functional studies revealed no differences in the airway dimensions (internal perimeter) or airway wall components (e.g., smooth muscle, cartilage) or total area to explain these observations. Although the mechanism for this observed decrease in intrinsic airway smooth muscle tone is not certain, it may be due to alteration in the substructure of the airway wall or, alternatively, may result from the continued release of depressant factors in the vicinity of the smooth muscle which permanently alters smooth muscle responsiveness.     

Anamnestic and polygraphic parameters in obstructive sleep apnea syndrome patients with reduced nasal respiration during the day in comparison with obstructive sleep apnea patients with normal nasal respiration

Nasal obstruction is a predictive factor for snoring and may contribute to the development of an obstructive sleep apnea syndrome (OSAS). The aim of this study was to further evaluate the impact of nasal obstruction in OSAS. Therefore, we investigated 2 groups of OSAS-patients, matched pairs concerning gender, age, and BMI: OSAS-patients with nasal obstruction (N, n = 28), total nasal airflow < 500 ccm/s (referred to 150 pa pressure of difference or unilateral nasal resistance > 1 pa/ccm/s), and 28 OSAS-patients without nasal obstruction (control-group K, total nasal airflow > 700 ccm/s [referred to 150 pa pressure of difference or unilateral nasal resistance > 1 pa/ccm/s]). We performed anterior rhinomanometry, lung-function testing, cardio-respiratory polygraphy, and patients answered a standardized questionnaire. We found the following significant differences: 1) N complained more often (n = 17) about dyspnea at night than K (n = 7, p < 0.05, Chi2-test). 2) N had a higher apnea index (20.4 +/- 19.0/h) than K (9.6 +/- 10.0/h, p < 0.05, Student's t-test). There were, however, no significant differences concerning lung function, number of nocturnal hypopneas, nocturnal SaO2 and heart rate. Our results underline the importance of nasal ventilation in the pathogenesis of OSAS. At least in moderate cases of OSAS a therapy of nasal obstruction might be of success in order to abolish nCPAP-therapy or might reduce nasal problems during nCPAP-therapy and thus ameliorate patient's therapy compliance.     

Starling resister and stability of sleep ventilation

The upper airway can be described as a collapsible segment (the pharynx) interposed between two rigid bony (the cavum) or cartilaginous (the trachea) segments. Due to this structure, the pharynx behaves as a collapsible tube, in which airflow does not depend on the downstream pressure, but is limited to a maximum value which depends only on the upstream pressure and on the pressure surrounding the collapsible segment; this behavior, known as a Starling resistor can be modeled by the waterfall effect. Thus, the upper airways can be in three different conditions: an occluded condition, in which no flow is possible, a patent condition, in which flow depends on the difference between upstream and downstream pressures (according to Poiseuille's law), and a situation in which flow is limited. The behavior of the upper airway is largely dependent on its anatomic structure, but functional factors play a critical role. Among these sleep state is both a determinant of the collapsibility of the pharynx, and determined by the simulation of upper airway mechanoreceptors whose activity depends on the activity of respiratory muscles. Thus the interplay of three factors: ventilatory drive, upper airway collapsibility, and arousal threshold can predict most of the situations of stable and unstable ventilatory behavior during sleep. The level of the arousal threshold governs the stability of the ventilatory pattern, as it determines whether a combination of slow, respiratory effort, and blood gases can be maintained or is interrupted by an arousal.     

The critical transmural pressure of the abirway

The critical transmural pressure (Ptm) is defined as the transmural pressure of the airway at the site where and when flow is limited during a forced expiration. According to the presented theory, the maximal expiratory flow (Vmax) can be calculated from the relation between Ptm and the corresponding cross-sectional area of the airway (A). By means of a pitot-static tube, Ptm-A curves were constructed for several locations in the elastic airway of a mechanical model. From these curves local Vmax was calculated at different values of Ptm and compared with actual flow, i.e. measured Vmax for the entire airway. In the downstream part of the airway, the actual flow equalled calculated Vmax at most Ptm values. The site of flow limitation, being the most upstream point where actual flow equals calculated local Vmax could therefore be located. Theory and experiments showed positive as well as negative Ptm not influenced by change in upstream or downstream resistance. Flow limitation could therefore be initiated at distending as well as compressing pressures across the wall of the airway. V was regarded as a function of Ptm and the elastic recoil pressure of the lung (Pel). Measured and calculated iso-Pel, Ptm-V curves agreed well with one major exception: when Ptm less than Ptm measured curves were distorted due to a concomitant downstrean compression of the collapsible airway.     

Functional upper airway obstruction and chronic irritation of the larynx

Wheezing and dyspnoea are typical symptoms of asthma but can also be found in diseases of the extrathoracic airways. Functional upper airway obstruction may imitate, as well as complicate asthma. Functional upper airway obstruction was first described as a conversion disorder in young females with inspiratory stridor. Subsequently, it was found that functional upper airway obstruction was more often a secondary phenomenon in chronic asthma also involving the expiratory laryngeal airflow. During a period of 15 months, we diagnosed six cases of functional upper airway obstruction. Five patients were female and one male, and four were also asthmatics. Three cases showed chronic sinusitis with postnasal drip (PND) and/or gastro-oesophageal reflux. Both disorders may irritate the larynx. Treatment of sinusitis and gastro-oesophageal reflux led to a significant improvement of dyspnoea in all three of these patients. In asthma refractory to treatment and in the case of an asthmatic exacerbation without obvious cause, functional upper airway obstruction should be excluded to avoid unnecessary treatment with systemic steroids. Some of the possible causative factors of functional upper airway obstruction, such as postnasal drip and gastro-oesophageal reflux, are easily treatable.     

The rat suspension model is also a good tool for inducing muscle hyperactivity

The aim of the present study was to investigate changes in the mechanical characteristics of the rat epitrochlearis muscle as a result of a period of hyperactivity. A tail suspension model was used to impose postural activity in the forelimb musculature with the intention of inducing a relative slowness in the fast epitrochlearis muscle. A method of dual-controlled releases was used to obtain force-velocity and tension-extension relationships characterizing muscle mechanics. Results showed that: (1) mechanical characteristics are that of a fast-twitch muscle and (2) suspension induces a decrease in the maximal shortening velocity and a decrease in the compliance of series elastic elements. Changes in fibre type proportions are consistent with these mechanical adaptations. This demonstrates that an usual model of muscle hypoactivity can also be used for imposing hyperactivity of a postural nature, inducing muscle transformations towards a slower twitch muscle.     

Inflammatory cell distribution within and along asthmatic airways

Asthmatic airways are infiltrated with inflammatory cells that release mediators and cytokines into the microenvironment. In this study, we evaluated the distribution of CD45-positive leukocytes and eosinophils in lung tissue from five patients who died with severe asthma compared with five patients with cystic fibrosis. For morphometric analysis, the airway wall was partitioned into an "inner" area (between basement membrane and smooth muscle) and an "outer" area (between smooth muscle and alveolar attachments). Large airways (with a perimeter greater than 3.0 mm) from patients with asthma or cystic fibrosis had a greater density of CD45-positive cells (p < 0.05) and eosinophils (p < 0.001) in the inner airway region compared with the same airway region in small airways. Furthermore, in small airways, asthmatic lungs showed a greater density of CD45-positive cells (p < 0.01) and eosinophils (p < 0.01) in the outer compared with the inner airway wall region. These observations indicate that there are regional variations in inflammatory cell distribution within the airway wall in patients with asthma that are not observed in airways from patients with cystic fibrosis. We speculate that this inflammatory cell density in peripheral airways in severe asthma may relate to the peripheral airway obstruction characteristic of this condition.     

Pharyngeal pressure measurements in topodiagnosis of obstructive sleep apnea]

In order to improve the outcome of surgical treatment for obstructive sleep apnea syndrome certain reports have claimed to identify the site of obstruction in the upper airway. One of the various methods available for topodiagnosis is manometry using intraesophageal and intrapharyngeal pressure probes. In the present literature the surgical success rate for patients undergoing Uvulopalatoplasty (UPP) as treatment for retropalatal obstructions is approximately 50%. For patients with other sites of obstruction the success rate is below 10%. The aim of this study was to evaluate the different theories explaining the still low outcome of UPPP in patients with only retropalatal collapse. Findings showed that measurements within different sleep stages and at different pharyngeal activities during sleep can lead to different results concerning sites of obstruction. Additionally, any surgery to one part of the pharynx seems to influence the other parts of the pharynx in caudal and cranial directions. A literature theory dominates that the pharynx between the nasopharynx and lower hypopharynx acts like several Starling mechanism in series, in which are influences the other. Whether more complicated pressure measurements emphasizing the role of sleep stages and pharyngeal muscle activities could improve the surgical outcome of UPPP is the subject of present investigations. In any case the technical equipment and time consumption of the measurements required will probably disqualify the method for routine use.     

Air-liquid interfacial movement in models simulating airway reopening

In this model study, we simulated the initial airway reopening event in a rigid tube model. The air-liquid interface during airway reopening was assumed to be a simple axisymmetric meniscus similar to that of a two-phase flow in a rigid tube (radius R), where the applied pressures and the meniscus velocities were measured experimentally for fluids of different viscosities and surface tensions (gamma). Bulk flow contribution was deducted from the applied pressure to obtain the pressure accounting for interfacial movement (P*(int)). A semi-empirical formula for the interface was generated by dimensional analysis. The dimensionless interfacial pressure (P(int) = P*(int),R/gamma) was found to approach 2 for sufficiently small velocities, consistent with Bretherton's theoretical prediction. This formula also resembles that previously obtained in collapsible tubes simulating airways. The result suggests that the critical pressures required to reopen a collapsible airway and a non-collapsible one with the same radius are similar in magnitude (approximately 2 - 3gamma/R). However, in a collapsible airway, no significant bulk flow of lining fluids would develop while the interface proceeds, leading to a much smaller overall pressure for further reopening. Airway wall collapsibility thus could play a crucial role in maintaining proper ventilation through rapid reopening of the airway.