Effects of cold dry air nasal stimulation on airway mucosal blood flow in humans.

Several studies have demonstrated that nasal challenges can induce reflex responses in the respiratory system. Some authors have described bronchoconstriction and modification of the pattern of breathing following nasal challenges by irritants and cold air. We propose to determine the effect of nasal stimulation with cold dry air on airway mucosal blood flow (Qaw) in the proximal tracheal bronchial tree of healthy humans. Nine healthy subjects participated in the study. Baseline measurement Qaw, nasal airway resistance (NAR) and airway caliber by specific airways conductance (SGaw) were followed by nasal challenge with cold dry air. Qaw, NAR and Sgaw were determined after the challenge. In those subjects in which a significant decline in Qaw was recorded the protocol was repeated after pretreatment with nasal anesthesia using topical lidocaine. Cold dry air challenge produced a significant decrease in mean Qaw for the nine subjects and this response was abolished by pretreatment with nasal anesthesia using topical lidocaine. There was no significant change in Sgaw and NAR after the challenge and topical lidocaine anesthesia. Our data indicates that nasal stimulation with cold dry air leads to a reduction in Qaw and that this effect may be mediated by a nasal reflex.

Effect of hyperventilation on airway mucosal blood flow in normal subjects.

The purpose of this study was to determine the effect of hyperventilation (40 L/min) with room air (25 degrees C; 70% relative humidity) and frigid air (-10 degrees C; 0% relative humidity) on airway mucosal blood flow (Qaw) in normal subjects (n = 7; 26 to 54 yr of age). Qaw was measured with the dimethyl ether uptake technique, which reflects blood flow in the mucosa of large airways corresponding to a 50-ml anatomic dead space segment extending distally from the trachea. Mean (+/- SE) baseline Qaw during quiet (room air) breathing was 6.6 +/- 0.6 ml/min (range, 3.9 to 10.9). Qaw failed to change significantly during and after eucapnic hyperventilation with room air (thermal stress, 224 cal/min). In contrast, eucapnic hyperventilation with frigid air (thermal stress, 720 cal/min) increased Qaw in every subject, with the peak value occurring either during or over a 30-min period after hyperventilation; by 60 min, Qaw had returned toward baseline. The mean maximal Qaw was 310 +/- 49% of baseline (p < 0.05). Neither type of hyperventilation had an effect on airway resistance. We conclude that in normal subjects, Qaw increases during and/or after eucapnic hyperventilation with frigid air, and that this response is related to the magnitude of the thermal stress rather than to the level of ventilation.

Nightly variability in the indices of sleep-disordered breathing in men being evaluated for impotence with consecutive night polysomnograms.

We retrospectively analyzed night-to-night variability in the indices of sleep apnea in a group of men who underwent consecutive polysomnograms (PSGs) in the evaluation of impotence. The study group consisted of 37 subjects. Fifty-seven percent of the subjects had an apnea/hypopnea index (AHI) of 5 or more on the first PSG, whereas 70% met this criterion on the second study. On both PSGs, 49% of the subjects exhibited an AHI of 10 or more. The AHI varied by 10 or more between the two PSGs in 32% of the cases. Using a threshold AHI of 5 or more to establish a diagnosis of sleep apnea, 22% of the subjects would not have been diagnosed by the first PSG, and the negative rate for the first PSG was 50%. The variability observed in the AHI could not be explained by differences in total sleep time; sleep stages [1 through 4 and rapid eye movement (REM) sleep]; the amount of time sleeping supine, or a combination of sleep stage and position. The mean AHI, the apnea/hypopnea-related nadir, and the mean oxyhemoglobin saturation did not differ among the two PSGs. Our observations support the notion that for groups of subjects the mean AHI is relatively constant across 2 nights of study in the sleep laboratory. However, when an AHI of 5 or 10 or more is the sole criterion used to establish the diagnosis of sleep apnea, a single PSG may not be sufficient to rule out the presence of a sleep apnea syndrome.

Airway blood flow responses to temperature and humidity of inhaled air.

We determined the effect of breathing cold dry air (-39 degrees C, 0.1% relative humidity, RH) and warm humid air (43 degrees C, 100% RH) on airway mucosal blood flow (Qaw) in normal human subjects (n = 8, age 25-53 years) at rest. Qaw was measured with a dimethylether uptake technique which reflects blood flow in the mucosa of large airways corresponding to a 50 ml anatomical dead-space segment extending distally from the trachea. Mean Qaw was 10.1 +/- 1.9 ml min-1 (mean +/- S.D.) during room air breathing (25 degrees C, 70% RH) and decreased to 4.7 +/- 2.1 ml min-1 during cold dry air breathing (p < 0.05). Within 20 min of resuming room air breathing, mean Qaw had returned to baseline. Breathing warm humid air had no significant effect on mean Qaw (8.2 +/- 1.4 ml min-1). These results indicate that quiet breathing of frigid air causes vasoconstriction in central airways.

Effect of inhaled and intravenous acetylcholine on bronchial blood flow in anesthetized sheep.

The reported effects of cholinergic agonists on bronchial blood flow (Qbr) have been inconsistent. The aim of the present study was to determine whether the inconsistency could be due to the mode of agonist administration (systemic vs. aerosol) or the anatomic site of blood flow in the bronchus (mucosal vs. deep wall). In 10 anesthetized mechanically ventilated adult sheep, we measured Qbr in main bronchi by color-coded microspheres, systemic and pulmonary arterial pressures, cardiac output, and lung resistance (RL) before and after acetylcholine (ACh) administered either as an aerosol (nebulized dose 100 micrograms) or as an intravenous bolus (2 micrograms/kg). Before drug administration, 72% of mean Qbr was distributed to the bronchial mucosa and the remainder was distributed to the deep bronchial wall. For a comparable increase in mean RL (150% for intravenous ACh and 205% for aerosol ACh), mean total Qbr normalized for systemic arterial pressure increased by 291% after intravenous ACh (P < 0.05) and decreased by 9% after aerosol ACh (not significant). Mucosal and deep wall Qbr increased proportionally. Atropine (0.2 microgram/kg) prevented the changes in Qbr and RL after intravenous ACh. Thus intravenous but not aerosol ACh increased blood flow in the mucosa and deep wall of extrapulmonary bronchi. This suggests that the muscarinic receptors mediating vasodilation are more accessible to intravascular than intrabronchial ACh.

Measurement of airway mucosal blood flow with dimethylether: validation with microspheres.

We have recently developed a noninvasive dimethylether (DME) uptake technique to estimate airway mucosal blood flow (Qaw) in humans (12). Because it was not feasible to validate the technique directly, we undertook the present study to compare Qaw as measured by DME (QDME) and by color-coded microspheres (QM) as a standard in seven anesthetized sheep prepared with a carotid and a left atrial catheter. QDME was determined by measuring DME uptake with multiple breath holds after passive inflation with a DME-helium gas mixture, simulating the technique used in humans. After the microspheres were injected into the left atrium, the sheep were killed and the tracheal segment corresponding to the dead space from which DME uptake was determined was removed, and its mucosa was stripped and processed for microsphere counts. Mean QDME was 35.6 ml.min-1.100 g-1 wet tissue (range 9.6-98.0 ml.min-1.100 g-1) and mean QM was 29.1 ml.min-1.100 g-1 (range 7.7-91.5 ml.min-1.100 g-1). There was a strong correlation between QDME and QM (r = 0.89; P = 0.01). Intravenous nitroglycerin and vasopressin caused comparable increases and/or decreases in QDME and QM (r = 0.87; P = 0.02). This suggests that the noninvasive DME uptake method measures Qaw accurately and supports its validity in human studies.

Effect of lung volume and intrathoracic pressure on airway mucosal blood flow in man.

We have recently described an inert soluble gas uptake technique (using dimethyl-ether, DME) for the non-invasive measurement of airway mucosal blood flow (Qaw) in humans. In the present study, we assessed the effects of lung volume and intrathoracic pressure on Qaw, in healthy non-smokers (age range 19-52 years). Qaw was calculated from the steady-state uptake of DME from a 50 ml segment of the anatomic dead space. The mean (+/- SD) Qaw of three consecutive measurements at a lung volume of FRC + 300 ml was 8.3 +/- 2.3, 8.6 +/- 2.6 and 8.3 +/- 2.7 ml.min-1 (n = 13; coefficient of variation 14 +/- 7%). At zero airway pressure, there was an inverse relationship between apparent Qaw on the one hand and lung volume and anatomic dead space (DS) on the other: mean Qaw was 12.2 +/- 5.3, 8.2 +/- 2.5 and 5.3 +/- 2.2 ml.min-1 at RV + 300 ml (DS = 131 +/- 11 ml), FRC + 300 ml (DS = 153 +/- 12 ml) and TLC (DS = 206 +/- 22 ml) positions, respectively (n = 11; P < 0.05 among all three). At a lung volume of FRC + 300 ml, an increase in intrathoracic pressure to +25 cmH2O (modified Valsalva maneuver) decreased mean Qaw to 3.3 +/- 2.8 ml.min-1 while a decrease in intrathoracic pressure to -35 cmH2O (modified Müller maneuver) increased mean Qaw to 17.1 +/- 7.4 ml.min-1 from a control value of 7.2 +/- 2.2 ml.min-1 (n = 7; P < 0.05 among all three). These results indicate that lung volume has an effect on apparent Qaw, presumably by influencing the depth to which the analyzed anatomical dead space segment extends into the bronchial tree. The results also show that changes in intrathoracic pressure alter Qaw, possibly reflecting concomitant changes in left ventricular output and its distribution to intrathoracic and extrathoracic vascular beds.

Airway mucosal blood flow in humans. Response to adrenergic agonists.

We measured the uptake of the soluble inert gas dimethyl ether (DME) from a segment of the conducting airways to estimate mucosal blood flow (Qaw) noninvasively. The subjects inhaled, from the functional residual capacity position, a 300-ml gas mixture containing 35% DME, 8% helium, 35% oxygen, and the balance nitrogen; they held their breath for 5 s and then exhaled into a spirometer. During exhalation, the instantaneous concentrations of DME and helium were recorded together with expired gas volume. The maneuver was repeated with breathhold times of 5, 10, 15, and 20 s. We calculated Qaw using the time-dependent decrease in DME concentration in relation to the helium concentration in an expired volume fraction between 80 and 130 ml (representing an anatomic dead-space segment distal to the glottis) and the mean DME concentration. In 10 healthy nonsmokers, mean (+/- SE) Qaw was 8.0 +/- 1.3 ml/min, or 8 +/- 2 microliters/min/cm2 mucosal surface. We obtained a value of 12 +/- 3 microliters/min/cm2 in a validation experiment in sheep. Inhaled methoxamine (nebulized dose 10 mg) caused a 65 +/- 19% decrease (p < 0.05), and albuterol (nebulized dose 2.5 mg) a 92 +/- 17% increase (p < 0.05), in mean Qaw in seven subjects, with the maximum changes occurring immediately or 15 min postinhalation. We conclude that the DME uptake method is an acceptable noninvasive means of estimating airway mucosal blood flow in humans and its modification by vasoactive substances.

Hyperekplexia: report of a nonfamilial adult onset case associated with obstructive sleep apnea and abnormal brain nuclear tomography.

We report the unique occurrence of hyperekplexia and obstructive sleep apnea (OSA) in a 48-year-old male. Polysomnography and multiple sleep latency testing excluded cataplexy, which can be confused with startle attacks. A new imaging finding was a nuclear tomography abnormality in the left frontal lobe. We postulate that this finding may represent a functional cortical lesion of a descending pathway that normally inhibits the startle reflex. Serious complications of pharmacotherapy with clonazepam, the drug of choice for hyperekplexia, can be avoided by first evaluating for OSA.

Obstructive sleep apnea. Treatment improves quality of life--and may prevent death.

Obstructive sleep apnea syndrome may be just an annoyance to an affected person's bed partner, or it can be a more serious and even dangerous condition for the person involved. One clue to the condition is daytime somnolence, although not all sleepy patients have the syndrome. If obstructive sleep apnea syndrome is confirmed by a polysomnogram, a trial of nasal continuous positive airway pressure (NCPAP) is warranted. If daytime somnolence is unaffected, then it is unlikely that the syndrome is the sole cause of the patient's sleepiness. Alternative diagnoses (eg, narcolepsy, atypical depression) should then be considered. Surgery, orthodontic devices, and pharmacotherapy are generally less effective than NCPAP and are usually reserved for patients who cannot tolerate NCPAP. Surgical techniques may be best suited for patients who have clearly defined craniofacial abnormalities and those who cannot tolerate NCPAP. Weight reduction to near ideal body weight and avoidance of benzodiazepines, opiates, and alcohol should be emphasized in all patients with suspected or confirmed sleep apnea.

The second generation of nasal continuous positive airway pressure devices. Are they created equal?

Nasal continuous positive airway pressure (NCPAP) is considered the preferred medical treatment of obstructive sleep apnea. Because NCPAP exerts its beneficial effects by maintaining positive airway pressure, we proposed to test the ability of the newer "second generation" NCPAP machines to maintain a constant airway pressure during simulated breathing on a lung model. Each of the seven new NCPAP devices tested were examined under conditions of changing inspiratory flow, end expiratory pressure (EEP) and resistance added to the patient end of the NCPAP hose. During inspiration airway pressure fell and in expiration it increased relative to the EEP in all machines. Using the standard NCPAP hose and a breathing pattern consistent with normal breathing during sleep, the maximum decline in pressure during simulated inspiration and excess pressure during simulated expiration was -0.5 cm H2O and 0.6 cm H2O, respectively. Adding resistance, increasing inspiratory flow but not EEP exaggerated this effect. All of the machines behaved similarly in this regard. Further, the performance of the NCPAP devices did not deteriorate after 6 hours of uninterrupted operation. We conclude that the second generation NCPAP machines may be interchanged without another laboratory trial to readjust the EEP.

Restrictive chest bellows disease and frontometaphyseal dysplasia.

We describe a patient with frontometaphyseal dysplasia (FMD), restrictive chest bellows disease, hypercapnic respiratory failure, and cor pulmonale. Treatment with intermittent supplemental oxygen, nocturnal nasal volume ventilation, and posture modification was successful in partial resolution of chronic hypoventilation and excessive daytime somnolence.

Sleep disturbances in men with asymptomatic human immunodeficiency (HIV) infection.

During the clinical latency phase of human immunodeficiency virus (HIV) disease the central nervous system may be infected and begin to manifest subtle dysfunction. Our early investigations demonstrated persistent alterations in the sleep architecture of HIV-infected asymptomatic men. The major aims of this study were to delineate alterations of sleep architecture in asymptomatic HIV-infected men, to identify and describe sleep behavior complaints and to seek a correlation between objective sleep parameters and subjective complaints of sleep behavior. The study sample consisted of 24 men, 14 HIV-infected and 10 HIV-negative, age-matched controls. The protocol included a comprehensive history and physical, two polysomnograms, urine toxicity, detailed written sleep questionnaire, the Pittsburgh Sleep Quality Index, the Spielberger State-Trait Anxiety Test and the Beck Depression Inventory. Our results indicated that sleep architecture differed from controls in that wakefulness, slow-wave sleep [SWS-stage 3 and 4 nonrapid eye movement (NREM) sleep] and stage rapid eye movement (REM) sleep were more evenly dispersed throughout the night. In particular, SWS was prevalent during the second half of recorded sleep. The observed changes in the NREM/REM cycle could not be explained on the basis of underlying psychopathology. Just as the course of individuals with HIV infection varies, it is expected that sleep abnormalities will vary. Considering the known relationships between NREM stage 3 and 4 and immune system function, it is possible that the observed alterations in the NREM/REM cycle are related to coincident changes in immunologic function. Quantitative measures of NREM sleep, especially SWS and REM sleep, are perhaps of greater significance than relative measures of sleep stages.(ABSTRACT TRUNCATED AT 250 WORDS)

Airway blood flow modifies allergic airway smooth muscle contraction.

We tested the hypothesis that airway perfusion modifies the contractile response of airway smooth muscle to allergen challenge by influencing the clearance of locally released spasmogens. In six intact, lightly sedated, sheep allergic to Ascaris suum, we measured tracheal mucosal blood flow (Qtr) with a soluble gas uptake method and tracheal dead space (Vtr), an index of airway smooth muscle tone, by helium dilution before and serially after local aerosol challenge with A. suum extract or ragweed extract (control). The former challenge was repeated during continuous intravenous infusion of either vasopressin or nitroglycerin, which by themselves had no effect on Vtr and decreased and increased Qtr, respectively. Ragweed had no effect on Qtr and Vtr, whereas A. suum increased mean (+/- SE) Qtr by 111 +/- 31% (p less than 0.05) and decreased mean Vtr by 15 +/- 2% (p less than 0.05) immediately after challenge, with Qtr returning to baseline by 40 min and Vtr by 80 min. Vasopressin infusion prevented the A. suum-induced increase in Qtr and prolonged the decrease in mean Vtr (p less than 0.05). During nitroglycerin infusion, A. suum failed to alter Qtr or Vtr. Vasopressin and nitroglycerin had no effect on the contractile responses of tracheal smooth muscle to A. suum in vitro. These results indicate that the effects of vasopressin and nitroglycerin on antigen-induced airway smooth muscle contraction in vivo were due to alterations in airway blood flow rather than to alterations in the release of or airway smooth muscle responsiveness to chemical mediators.

Independent control of mucosal and total airway blood flow during hypoxemia.

In the larger airways, the blood circulation forms a subepithelial (mucosal) and outer (peribronchial) microvascular network. This raises the possibility that blood flow in these two networks is regulated independently. We used hypoxemia as a stimulus to induce changes in tracheal mucosal blood flow normalized for systemic arterial pressure (Qtr n) measured with an inert soluble gas technique and total bronchial blood flow (Qbr) and normalized Qbr (Qbrn) measured with an electromagnetic flow probe in anesthetized sheep. Fifteen minutes of hypoxemia [PO2 40 +/- 7 (SD) Torr] decreased mean Qtr n from 1.1 +/- 0.4 to 0.8 +/- 0.4 ml.min-1.mmHg-1.10(2) (-27%; P less than 0.05; n = 7) and increased mean Qbr n from 12.1 +/- 3.2 to 17.1 +/- 5.4 ml.min-1.mmHg-1.10(2) (+41%; P less than 0.05; n = 6). The rise in Qbr correlated with cardiac output (r = 0.68; P less than 0.05). Phentolamine pretreatment (0.1 mg/kg iv) blunted the hypoxemia-related decrease of mean Qtr n (-8%; P = NS). Tyramine (2.5 mg) applied locally to the trachea decreased mean Qtr n significantly after 30 and 45 min by 31 and 19%, respectively (P less than 0.05). 6-Hydroxydopamine (0.2 mg 4 times for 1 h locally applied) prevented the hypoxemia-induced as well as local tyramine-induced decrease in mean Qtr n (0 and 0%).(ABSTRACT TRUNCATED AT 250 WORDS)

A comparison of nine nasal continuous positive airway pressure machines in maintaining mask pressure during simulated inspiration.

Nasal continuous positive airway pressure (CPAP) "splints" the airway and prevents inspiratory collapse of the upper airway in patients with obstructive sleep apnea. Nine nasal CPAP machines were compared for their ability to maintain airway pressure at various simulated inspiratory flows. Each machine was connected to a vacuum system at 20, 40, and 60 L/min flow after it was initially set at test pressures of 5, 10, or 15 cm H2O and the system or "mask" pressures were measured. In all machines, mask pressure fell during simulated inspiration and the declines in mask pressure were as high as 5 cm H2O. Because machines varied in their ability to maintain a test pressure, it is recommended that the nasal CPAP machine used in the home be the same as that which was tested in the sleep laboratory. If a different machine is used, it may require adjustment to assure efficacy.

Effect of histamine on tracheal mucosal perfusion, water content and airway smooth muscle in sheep.

We examined the response of tracheal mucosal blood flow normalized for systemic arterial pressure (Qtrn), water content (VH20) and luminal dead space (Vtr) to nebulized histamine in intact, lightly anesthetized sheep. Nebulized histamine produced rapid increases in mean Qtrn (+84%) and VH2O (+85%), and a decrease in mean Vtr (-17%) (P less than 0.05) within 5 min post completion of challenge. Mean Vtr rapidly returned to baseline, while mean Qtrn and VH2O remained elevated for 60 and 90 min after challenge, respectively. Pretreatment with chlorpheniramine (H1-antagonist) blocked the changes in Vtr and VH2O, and attenuated the increase in Qtrn. Metiamide (H2-antagonist) pretreatment abolished the increase in Qtrn and blunted the increase in VH2O, but had no effect on the decrease in VTR. 2-methylhistamine (H1-agonist) decreased mean Qtrn and Vtr (P less than 0.05) and dimaprit (H2-agonist) increased mean Qtrn (P less than 0.05) without changing Vtr. Neither 2-methylhistamine nor dimaprit significantly altered VH2O. Atropine blocked histamine induced decreases in Vtr and slightly attenuated the increases in Qtrn and VH2O. Thus, histamine increased airway smooth muscle tone and mucosal water content principally via H1 receptors, and mucosal perfusion via H2 receptors. The airway smooth muscle contraction involved muscarinic pathways.

Airway mucosal blood flow: response to autonomic and inflammatory stimuli.

A major portion of airway blood flow is distributed to the subepithelial tissue space and is strategically located to influence both epithelial and airway smooth muscle functions. To assess the magnitude and responsiveness of blood flow through the subepithelial microvasculature, we measured tracheal mucosal blood flow with a soluble gas method in intact sheep. We found responses of tracheal mucosal blood flow to pharmacological stimuli alpha- and beta- (adrenoceptor agonists) and inflammatory stimuli (antigen and histamine), and demonstrated that alterations in mucosal blood flow influence the magnitude and duration of allergic airway smooth muscle contraction in the trachea. Mucosal blood flow, which under certain circumstances is regulated independently of total airway blood flow, could play a critical role in the manifestations of and recovery from airway disease.