Functional correlates of lung involvement in Wegener's granulomatosis. Use of pulmonary function tests in staging and follow-up.

To examine the usefulness of pulmonary function testing in the clinical management of patients with Wegener's granulomatosis, 22 subjects with biopsy proved disease were evaluated using routine functional parameters. Although reduced lung volumes and diffusing capacity occurred frequently, the most common abnormality was in obstruction to airflow. Comparison of these functional parameters with roentgenographic and clinical findings revealed that reduced lung volumes were useful in detecting focal infiltrates, mass or cavitary lesions and diffuse interstitial involvement whereas airflow measurements were useful in detecting focal large airway lesions. In people with evidence of limitation of airflow, respiratory complications frequently developed in the form of acute tracheal obstruction of lobar collapse. In addition, serial evaluation of lung function during treatment revealed that although in most patients lung volumes and airflow obstruction improved or stabilized, a reduction of diffusing capacity was common. These studies suggest that routine pulmonary function testing may be a useful tool in the staging of patients with Wegener's granulomatosis and in following responses to therapy.

Breathing route influences upper airway muscle activity in awake normal adults.

Both nasal obstruction and nasal anesthesia result in disordered breathing during sleep in humans, and bypassing the nasal route during tidal breathing in experimental animals produces decreased electromyographic activity of upper airway (UA) dilating muscles. To investigate UA responses to breathing route in normal awake humans, we studied eight healthy males (ages 21-38 yr) during successive trials of voluntary nose breathing (N), voluntary mouth breathing (M), and mouth breathing with nose occluded (MO). We measured genioglossus electromyographic activity (EMGgg) with perorally inserted bipolar electrodes, alae nasi (EMGan) and diaphragm EMG activity (EMGdi) with surface electrodes, and minute ventilation (VE) with a pneumotachograph. Mean phasic inspiratory EMG activity of both UA muscles was significantly greater during N than during M or MO, even when a 2.5-cmH2O.l-1.s inspiratory resistance was added to MO (P less than 0.01). In contrast, neither EMGdi nor VE was consistently affected by breathing route. EMGgg during N was significantly decreased after selective topical nasal anesthesia (P less than 0.002); a decrease in EMGan did not achieve statistical significance. These data suggest that peak UA dilating muscle activity may be modulated by superficial receptors in the nasal mucosa sensitive to airflow.

Effect of inspired air temperature on genioglossus activity during nose breathing in awake humans.

Experimental data suggest the presence of sensory receptors specific to the nasopharynx that may reflexly influence respiratory activity. To investigate the effects of inspired air temperature on upper airway dilator muscle activity during nose breathing, we compared phasic genioglossus electromyograms (EMGgg) in eight normal awake adults breathing cold dry or warm humidified air through the nose. EMGgg was measured with peroral bipolar electrodes during successive trials of cold air (less than or equal to 15 degrees C) and warm air (greater than or equal to 34 degrees C) nasal breathing and quantified for each condition as percent activity at baseline (room temperature). In four of the subjects, the protocol was repeated after topical nasal anesthesia. For all eight subjects, mean EMGgg was greater during cold air breathing than during baseline (P less than 0.005) or warm air breathing (P less than 0.01); mean EMGgg during warm air breathing was not significantly changed from baseline. Nasal anesthesia significantly decreased the mean EMGgg response to cold air breathing. Nasal airway inspiratory resistance, measured by posterior rhinomanometry in six subjects under similar conditions, was no different for cold or warm air nose breathing [cold 1.4 +/- 0.7 vs. warm 1.4 +/- 1.1 (SD) cmH2O.l-1.s at 0.4 l/s flow]. These data suggest the presence of superficially located nasal cold receptors that may reflexly influence upper airway dilating muscle activity independently of pressure changes in awake normal humans.

Hypoxemia alone does not explain blood pressure elevations after obstructive apneas.

In patients with obstructive sleep apnea (OSA), substantial elevations of systemic blood pressure (BP) and depressions of oxyhemoglobin saturation (SaO2) accompany apnea termination. The causes of the BP elevations, which contribute significantly to nocturnal hypertension in OSA, have not been defined precisely. To assess the relative contribution of arterial hypoxemia, we observed mean arterial pressure (MAP) changes following obstructive apneas in 11 OSA patients during non-rapid-eye-movement (NREM) sleep and then under three experimental conditions: 1) apnea with O2 supplementation; 2) hypoxemia (SaO2 80%) without apnea; and 3) arousal from sleep with neither hypoxemia nor apnea. We found that apneas recorded during O2 supplementation (SaO2 nadir 93.6% +/- 2.4; mean +/- SD) in six subjects were associated with equivalent postapneic MAP elevations compared with unsupplemented apneas (SaO2 nadir 79-82%): 18.8 +/- 7.1 vs. 21.3 +/- 9.2 mmHg (mean change MAP +/- SD); in the absence of respiratory and sleep disruption in eight subjects, hypoxemia was not associated with the BP elevations observed following apneas: -5.4 +/- 19 vs. 19.1 +/- 7.8 mmHg (P less than 0.01); and in five subjects, auditory arousal alone was associated with MAP elevation similar to that observed following apneas: 24.0 +/- 8.1 vs. 22.0 +/- 6.9 mmHg. We conclude that in NREM sleep postapneic BP elevations are not primarily attributable to arterial hypoxemia. Other factors associated with apnea termination, including arousal from sleep, reinflation of the lungs, and changes of intrathoracic pressure, may be responsible for these elevations.

Phenylephrine-induced hypertension acutely decreases genioglossus EMG activity in awake humans.

To investigate the relationship between systemic blood pressure (BP) and upper airway dilator muscle activity, we recorded genioglossus electromyograms (EMGgg) during pharmacologically induced acute increases in BP in five healthy humans (ages 27-40 yr). EMGgg was measured with perorally placed fine-wire electrodes; phasic EMGgg was expressed as percentage of baseline activity. Subjects were studied supine, awake, and breathing through a face mask with their mouths taped. End-tidal PCO2 was monitored with a mass spectrometer; minute ventilation was measured with a pneumotachograph. Digital BP was monitored continuously with the Penaz method (Finapres, Ohmeda). Mean arterial pressure (MAP) at baseline was 89 +/- 6 (SD) mmHg. Phenylephrine was infused until MAP reached 15-25 mmHg above baseline (107 +/- 7 mmHg). Recording was continued until MAP returned to baseline (90 +/- 7 mmHg). Elevated BP was associated with a significantly decreased phasic EMGgg (P less than 0.005). With return of MAP to baseline, phasic EMGgg returned toward normal (P less than 0.01). Minute ventilation and end-tidal PCO2 did not differ among conditions. Genioglossus activity appears to be influenced by acute changes in systemic BP. We speculate that BP elevations accompanying obstructive apneas during sleep may decrease upper airway tone and facilitate subsequent apneas.

Effect of chest wall vibration on breathlessness in normal subjects.

This study evaluated the effect of chest wall vibration (115 Hz) on breathlessness. Breathlessness was induced in normal subjects by a combination of hypercapnia and an inspiratory resistive load; both minute ventilation and end-tidal CO2 were kept constant. Cross-modality matching was used to rate breathlessness. Ratings during intercostal vibration were expressed as a percentage of ratings during the control condition (either deltoid vibration or no vibration). To evaluate their potential contribution to any changes in breathlessness, we assessed several aspects of ventilation, including chest wall configuration, functional residual capacity (FRC), and the ventilatory response to steady-state hypercapnia. Intercostal vibration reduced breathlessness ratings by 6.5 +/- 5.7% compared with deltoid vibration (P less than 0.05) and by 7.0 +/- 8.3% compared with no vibration (P less than 0.05). The reduction in breathlessness was accompanied by either no change or negligible change in minute ventilation, tidal volume, frequency, duty cycle, compartmental ventilation, FRC, and the steady-state hypercapnic response. We conclude that chest wall vibration reduces breathlessness and speculate that it may do so through stimulation of receptors in the chest wall.

Upper airway anesthesia delays arousal from airway occlusion induced during human NREM sleep.

Six healthy subjects (5 males and 1 female, 26-40 yr old) were studied during non-rapid-eye-movement (NREM) sleep to assess the role of upper airway (UA) afferents in the arousal response to induced airway occlusion. Subjects wore an airtight face mask attached to a low-resistance one-way valve. A valve in the inspiratory circuit allowed instantaneous inspiratory airway occlusion and release; the expiratory circuit remained unoccluded at all times. Each subject was studied during two nights. On one night, occlusions were created during stable stage 2 NREM sleep before and after application of 4% lidocaine to the oral and nasal mucosa. On the other night, the protocol was duplicated with saline ("sham anesthesia") rather than lidocaine. The order of nights was randomized. Occlusions were sustained until electroencephalographic arousal. Three to 12 occlusions were performed in each subject for each of the four parts of the protocol (pre- and post-lidocaine, pre- and post-saline). The auditory threshold for arousal (1,500-Hz tone beginning at 30 dB) was also tested before and after UA lidocaine. For the group, arousal time after UA anesthesia was prolonged compared with preanesthesia arousal time (P less than 0.001); arousal time after sham anesthesia did not significantly increase from before sham anesthesia (P = 0.9). The increase in arousal time with UA anesthesia was greater than the increase with sham anesthesia (P less than 0.001). The auditory arousal threshold did not increase after UA anesthesia. Inspiratory mask pressure, arterial O2 saturation of hemoglobin, and end-tidal PCO2 during occlusions were similar before and after UA anesthesia.(ABSTRACT TRUNCATED AT 250 WORDS)

Endogenous opioids and ventilatory responses to hypercapnia in normal humans.

Though administration of opioid peptides depresses ventilation and ventilatory responsiveness, the role of endogenous opioid peptides in modulating ventilatory responsiveness is not clear. We studied the interaction of endogenous opioids and ventilatory responses in 12 adult male volunteers by relating hypercapnic responsiveness to plasma levels of immunoactive beta-endorphin and by administering the opiate antagonist naloxone. Ventilatory responsiveness to hypercapnia was not altered by pretreatment with naloxone, and this by itself suggests that endogenous opioids have no role in modulating this response. However, there was an inverse relationship between basal levels of immunoactive beta-endorphin in plasma and ventilatory responsiveness to CO2. Furthermore, plasma beta-endorphin levels rose after short-term hypercapnia but only when subjects had been pretreated with naloxone. We conclude that measurement of plasma endorphin levels suggests relationships between endogenous opioid peptides and ventilatory responses to CO2 that are not apparent in studies limited to assessing the effect of naloxone.

Endogenous opioids and ventilatory adaptation to prolonged hypoxia in goats.

To investigate whether endogenous opioid peptides mediate time-dependent changes in ventilatory control during prolonged hypoxia, we studied four adult goats at rest during 14 days at simulated high altitude in a hypobaric chamber (PB approximately 450 Torr). Arterial PCO2 fell during the first several hours of hypoxia, remained stable over the next 7 days, and then rose slightly (but without statistical significance) by day 14. Ventilatory responsiveness to CO2 increased during the first week of hypoxia. By day 14, while still greater than control, the ventilatory response to CO2 was less than that observed on day 7. Immunoactive beta-endorphin levels in plasma and CSF did not change during the 14-day period. Administration of naloxone on day 14 did not restore the ventilatory response to CO2 to the level observed during the first week of acclimatization. We conclude that in adult goats, time-dependent changes in ventilatory response to CO2 during acclimatization to prolonged hypoxia are not primarily attributable to alterations in endogenous opioid peptide activity.

Naloxone does not affect ventilatory responses to hypoxia and hypercapnia in rats.

Ventilatory responses (tidal volume, respiratory frequency, and minute ventilation) to steady-state hypoxia and steady-state hypercapnia were measured plethysmographically in awake unrestrained adult rats, before and after subcutaneous injection of placebo (saline) naloxone in doses up to 5.0 mg/kg. Naloxone did not alter the ventilatory responses to hypoxia or hypercapnia.

Clinical insights and basic science correlates in sarcoidosis.

More than a century has elapsed since the initial description of sarcoidosis, but critical aspects of the disorder remain poorly understood. Information obtained from epidemiologic observations and basic laboratory research suggests that the disease may represent an immunologic response to an exogenous agent in a genetically susceptible individual. However, a definitive etiologic role for any specific exogenous agent has never been proved, and a "candidate gene" underlying a predisposition to sarcoidosis has not yet been identified. This review presents an historical framework for considering available evidence regarding a transmissible agent in sarcoidosis and host susceptibility to the disease.

Alpha-methyldopa selectively reduces alae nasi activity.

1. Sedatives such as the benzodiazepines and alcohol reduce upper airway muscle activity. We hypothesized that a sedating antihypertensive, alpha-methyldopa, might have similar effects. To investigate this hypothesis we studied the effect of alpha-methyldopa on alae nasi electromyographic (EMG) activity during hypercapnia. 2. We studied ten healthy subjects and three subjects with obstructive sleep apnoea during CO2-stimulated breathing. In a preliminary study four subjects demonstrated a fall in alae nasi EMG activity 4 h after the ingestion of 500 mg of alpha-methyldopa during CO2 rebreathing. 3. In six additional normal subjects and three subjects with obstructive sleep apnoea, we studied the alae nasi EMG activity during steady-state hypercapnia with PCO2 held constant 5 torr (0.7 kPa) above baseline. On 2 separate days we studied subjects before and 2 h after they had ingested 750 mg of alpha-methyldopa or placebo. 4. In the normal subjects the mean alae nasi EMG activity fell by 34% 2 h after ingestion of alpha-methyldopa (P less than 0.05) without a change in other ventilatory parameters. 5. In the sleep apnoea group the individual mean alae nasi EMG activity fell 16-49%, with ventilation and tidal volume falling in one patient. 6. We conclude that alpha-methyldopa selectively reduces upper airway motor activity.

Low dose aminophylline selectively increases upper airway motor activity in normals.

Because certain pharmacologic agents differentially influence upper airway and diaphragm motor activity, we postulated that the adenosine antagonist theophylline might preferentially increase alae nasi activity in human subjects. Using a double-blinded, randomized, placebo controlled design, we studied the effect of low dose aminophylline (1-2 mg/kg) on alae nasi and diaphragm surface electromyographic (EMG) activity. Seven healthy volunteers served as subjects for two trials on separate days. Subjects breathed from a close circuit while end tidal PCO2 was held constant in the eucapnic range. During each trial we recorded EMG signals from the alae nasi and diaphragm before and after intravenous infusion of either aminophylline or placebo. After the administration of aminophylline, the mean alae nasi EMG signal increased 87 +/- 31 (SD)% (P less than 0.005) while the mean diaphragmatic EMG signal did not change. There was no significant change in either the alae nasi or diaphragmatic EMG signal after placebo. There was no change in minute ventilation, tidal volume, or respiratory frequency after either aminophylline or placebo. We speculate that low dose aminophylline produces a selective increase in upper airway muscle activity through stimulation of the reticular activating system.

Dyspnea: a sensory experience.

Dyspnea--an unpleasant or uncomfortable awareness of breathing or need to breathe--is a common symptom of patients with cardiopulmonary disease. Although often thought of as a single symptom, dyspnea probably subsumes many sensations. Experimental conditions used to induce dyspnea are characterized by discrete groups or clusters of descriptive phrases. Similarly, as the language of dyspnea is refined further, different disease states may be distinguishable by the nuances of breathlessness described by patients. Evidence is gathering that the sensations of dyspnea are modified by information from a variety of receptors throughout the respiratory system. The sense of effort, although still important in the breathlessness associated with mechanical loads, is insufficient to explain the dyspnea arising from a number of experimental and clinical conditions. As our understanding of the interactions between effort and afferent information from the respiratory system grows, new therapeutic interventions to alleviate dyspnea are likely to follow.

Phasic electromyographic activity of the genioglossus increases in normals during slow-wave sleep.

Obstructive apneas occur infrequently during Stage 3-4 NREM sleep (SWS), even in patients with severe obstructive sleep apnea. To investigate whether upper airway (UA) dilator muscle activity preferentially increases during SWS as a partial explanation for this phenomenon, we measured phasic electromyogram activity of the genioglossus muscle (EMGgg) during continuous Stage 2 NREM sleep and SWS in 5 healthy males. Subjects were studied supine during a complete cycle of nocturnal NREM sleep after partial sleep deprivation. EMGgg was measured with perorally inserted bipolar electrodes, and quantified as peak phasic inspiratory activity during all continuous epochs of NREM sleep. We found EMGgg to be increased during SWS relative to stage 2 sleep by a mean of 58% among all subjects (P = 0.02); neither end-tidal PCO2 nor inspired minute ventilation varied between these sleep stages. Upper airway resistance, measured in 3 of the subjects on a separate study night, was not different between SWS and Stage 2 sleep. We speculate that the increase in phasic EMGgg during SWS in our normal subjects may reflect a mechanism whereby UA patency tends to be preserved during this stage.

Cold facial stimulation reduces breathlessness induced in normal subjects.

Patients with breathlessness commonly describe subjective relief when seated near an open window or in front of a fan. Previous studies suggest that a flow of air or application of cold solutions to the face, nasal mucosa, or pharynx may alter ventilation. We hypothesized that a flow of cold air directed against the cheek would reduce the sensation of breathlessness associated with loaded breathing. Sixteen subjects breathed on a device with an inspiratory resistive load (63 cm H2O/L/s) while PCO2 was maintained at 55 torr for 5 min. All studies were performed 4 times with each subject, twice with cold air directed against the cheek (4 degrees to 10 degrees C, 4 km/h) and twice with no flow on the subject. Subjects were asked to rate their breathlessness using a modified Borg scale. Cold air directed on the face reduced breathlessness induced by an inspiratory resistive load and hypercapnia (6.2 +/- 1.7 Borg scale units with no flow, 5.1 +/- 1.7 with cold air; p less than 0.002) without causing a significant reduction in ventilation. This effect was not observed when cold air was directed to the leg and does not appear to be associated with a reduction in the ventilatory response to hypercapnia or with initiation of the diving reflex. We conclude that cold air directed against the cheek significantly reduces dyspnea associated with the combination of hypercapnia and an inspiratory resistive load.

Airway effects of monosodium glutamate in subjects with chronic stable asthma.

We studied the effect of oral monosodium glutamate (MSG) on airways function in 12 subjects with a history of chronic stable asthma in a double-blind, randomized, crossover protocol. Subjects ingested either 25 mg/kg of MSG or sodium chloride (equimolar to MSG) following a 6-hour fast. Spirometry [forced expiratory volume in 1 second (FEV1) and forced vital capacity] was performed before administration of the test substances and for a minimum of 4 hours thereafter. At no time during the observation period was the mean change in FEV1 more negative following MGS than following placebo. MSG is unlikely to be a contributing factor in bouts of bronchospasm in subjects with asthma, and routine avoidance of MSG by individuals with asthma need not be advised.

Breathlessness induced by dissociation between ventilation and chemical drive.

Suppression of ventilation by tasks such as talking may produce breathlessness in normal individuals under conditions when a strong respiratory drive exists, e.g., during exercise, and in patients with severe lung disease. To investigate the nature of breathlessness produced by a dissociation between ventilation and chemical drive, we studied ten naive normal subjects who breathed at various levels of ventilation while end-tidal PCO2 (PETCO2) was held at 55 mm Hg. After a 10-min equilibration period of free breathing at PETCO2 = 55 mm Hg, subjects used a visual target to adjust ventilation to five different levels ranging from 50% below to 50% above the chemically driven ventilation (CDV). Ratings of breathlessness were made on a visual analogue scale relative to the intensity of breathlessness experience at CDV. As ventilation was targeted to levels below CDV, all subjects became increasingly breathless; the response was more variable when ventilation was targeted to levels above CDV. Overall, the relationship between ventilation and breathlessness was described by a hyperbolic function, for which the coefficient of determination (R2) was 0.92. Ventilation was suppressed below CDV without recruitment of antagonistic muscles during inspiration. The intensity of breathlessness was not correlated with measures of respiratory effort. We conclude that suppressed ventilation is a useful model for the study of breathlessness not fully explained by measures of respiratory effort and we speculate that the dissociation between chemical drive and afferent signals produced by motion of the lung and chest wall is important in modulating the sensation of breathlessness.