Rates of sensor loss in unattended home polysomnography: the influence of age, gender, obesity, and sleep-disordered breathing.

OBJECTIVES: To evaluate study failure and sensor loss in unattended home polysomnography and their relationship to age, gender, obesity, and severity of sleep-disordered breathing (SDB). DESIGN: A cross-sectional analysis of data gathered prospectively for the Sleep Heart Health Study (SHHS). SETTING: Unattended polysomnography was performed in participants' homes by the staff of the sites that are involved in SHHS. PARTICIPANTS: 6,802 individuals who met the inclusion criteria (age >40 years, no history of treatment of sleep apnea, no tracheostomy, no current home oxygen therapy) for SHHS. RESULTS: A total of 6802 participants had 7151 studies performed. 6161 of 6802 initial studies (90.6%) were acceptable. Obesity was associated with a decreased likelihood of a successful initial study. After one or more attempts, 6440 participants (94.7%) had studies that were judged as acceptable. The mean duration of scorable signals for specific channels ranged from 5.7 to 6.8 hours. The magnitudes of the effects of age, gender, BMI, and RDI on specific signal durations were not clinically significant. CONCLUSION: Unattended home PSG as performed for SHHS was usually successful. Participant characteristics had very weak associations with duration of scorable signal. This study suggests that unattended home PSG, when performed with proper protocols and quality controls, has reasonable success rates and signal quality for the evaluation of SDB in clinical and research settings.

Effects of varying approaches for identifying respiratory disturbances on sleep apnea assessment.

Varying approaches to measuring the respiratory disturbance index (RDI) may lead to discrepant estimates of the severity of sleep-disordered breathing (SDB). In this study, we assessed the impact of varying the use of corroborative data (presence and degree of desaturation and/or arousal) to identify hypopneas and apneas. The relationships among 10 RDIs defined by various definitions of apneas and hypopneas were assessed in 5,046 participants in the Sleep Heart Health Study (SHHS) who underwent overnight unattended 12-channel polysomnography (PSG). The magnitude of the median RDI varied 10-fold (i.e., 29.3 when the RDI was based on events identified on the basis of flow or volume amplitude criteria alone to 2.0 for an RDI that required an associated 5% desaturation with events). The correlation between RDIs based on different definitions ranged from 0.99 to 0.68. The highest correlations were among RDIs that required apneas and hypopneas to be associated with some level of desaturation. Lower correlations were observed between RDIs that required desaturation as compared with RDIs defined on the basis of amplitude criteria alone or associated arousal. These data suggest that different approaches for measuring the RDI may contribute to substantial variability in identification and classification of the disorder.

Relation of sleepiness to respiratory disturbance index: the Sleep Heart Health Study.

Obstructive sleep apnea syndrome is a well recognized cause of excessive sleepiness; however, the relation of sleepiness to mild sleep-disordered breathing (SDB), which affects as much as half the adult population, is uncertain. In order to explore this relation, we conducted a cross-sectional cohort study of community-dwelling adults participating in the Sleep Heart Health Study, a longitudinal study of the cardiovascular consequences of SDB. The study sample comprises 886 men and 938 women, with a mean age of 65 (SD 11) yr. Sleepiness was quantified using the Epworth Sleepiness Scale (ESS). Sleep-disordered breathing was quantified by the respiratory disturbance index (RDI), defined as the number of apneas plus hypopneas per hour of sleep, measured during in-home polysomnography. When RDI was categorized into four groups (< 5, 5 to < 15, 15 to < 30, >/= 30), a significantly progressive increase in mean ESS score was seen across all four levels of SDB, from 7.2 (4.3) in subjects with RDI < 5 to 9.3 (4.9) in subjects with RDI >/= 30 (p < 0.001). There was no significant modification of this effect by age, sex, body mass index, or evidence of chronic restriction of sleep time or periodic limb movement disorder. The percentage of subjects with excessive sleepiness, defined as an ESS score >/= 11, increased from 21% in subjects with RDI < 5 to 35% in those with RDI >/= 30 (p < 0. 001). We conclude that SDB is associated with excess sleepiness in community-dwelling, middle-aged and older adults, not limited to those with clinically apparent sleep apnea.

Methods for obtaining and analyzing unattended polysomnography data for a multicenter study. Sleep Heart Health Research Group.

This paper reviews the data collection, processing, and analysis approaches developed to obtain comprehensive unattended polysomnographic data for the Sleep Heart Health Study, a multicenter study of the cardiovascular consequences of sleep-disordered breathing. Protocols were developed and implemented to standardize in-home data collection procedures and to perform centralized sleep scoring. Of 7027 studies performed on 6697 participants, 5534 studies were determined to be technically acceptable (failure rate 5.3%). Quality grades varied over time, reflecting the influences of variable technician experience, and equipment aging and modifications. Eighty-seven percent of studies were judged to be of "good" quality or better, and 75% were judged to be of sufficient quality to provide reliable sleep staging and arousal data. Poor submental EMG (electromyogram) accounted for the largest proportion of poor signal grades (9% of studies had <2 hours artifact free EMG signal). These data suggest that with rigorous training and clear protocols for data collection and processing, good-quality multichannel polysomnography data can be obtained for a majority of unattended studies performed in a research setting. Data most susceptible to poor signal quality are sleep staging and arousal data that require clear EEG (electroencephalograph) and EMG signals.

The Sleep Heart Health Study: design, rationale, and methods.

The Sleep Heart Health Study (SHHS) is a prospective cohort study designed to investigate obstructive sleep apnea (OSA) and other sleep-disordered breathing (SDB) as risk factors for the development of cardiovascular disease. The study is designed to enroll 6,600 adult participants aged 40 years and older who will undergo a home polysomnogram to assess the presence of OSA and other SDB. Participants in SHHS have been recruited from cohort studies in progress. Therefore, SHHS adds the assessment of OSA to the protocols of these studies and will use already collected data on the principal risk factors for cardiovascular disease as well as follow-up and outcome information pertaining to cardiovascular disease. Parent cohort studies and recruitment targets for these cohorts are the following: Atherosclerosis Risk in Communities Study (1,750 participants), Cardiovascular Health Study (1,350 participants), Framingham Heart Study (1,000 participants), Strong Heart Study (600 participants), New York Hypertension Cohorts (1,000 participants), and Tucson Epidemiologic Study of Airways Obstructive Diseases and the Health and Environment Study (900 participants). As part of the parent study follow-up procedures, participants will be surveyed at periodic intervals for the incidence and recurrence of cardiovascular disease events. The study provides sufficient statistical power for assessing OSA and other SDB as risk factors for major cardiovascular events, including myocardial infarction and stroke.

Muscle weakness in mechanically ventilated patients with severe asthma.

Patients who undergo mechanical ventilation for severe asthma are at risk of developing diffuse muscle weakness because of acute myopathy. The relative importance of corticosteroids and neuromuscular paralysis in causing the myopathy is controversial, and it is uncertain whether the chemical structure of the drug used to induce paralysis influences the risk of myopathy. Using a retrospective cohort study design, we evaluated 107 consecutive episodes of mechanical ventilation for severe asthma to assess (1) the incidence of clinically significant weakness in patients treated with corticosteroids alone versus corticosteroids with neuromuscular paralysis, (2) the influence of the duration of paralysis on the incidence of muscle weakness, and (3) the relative risk of weakness in patients paralyzed with the nonsteroidal drug atracurium versus an aminosteroid paralytic agent (pancuronium, vecuronium). The use of corticosteroids and a neuromuscular blocking agent was associated with a much higher incidence of muscle weakness as compared with the use of corticosteroids alone (20 of 69 versus O of 38, p < 0.001). The 20 weak patients were paralyzed significantly longer than the 49 patients who received a neuromuscular blocking agent without subsequent weakness (3.4 +/- 2.4 versus 0.6 +/- 0.7 d, p < 0.001). Eighteen of the 20 weak patients had been paralyzed for more than 24 h. The incidence of weakness was not reduced when paralysis was achieved with atracurium as opposed to an aminosteroid neuromuscular blocking agent. In conclusion, corticosteroid-treated patients with severe asthma who undergo prolonged neuromuscular paralysis are at significant risk for the development of muscle weakness, and the risk of weakness is not reduced by use of atracurium.

The Breuer-Hering reflex in humans. Effects of pulmonary denervation and hypocapnia.

Passive lung inflation in humans causes reflex expiratory prolongation that is abolished by vagal blockade. We have studied two aspects of this classic Breuer-Hering reflex in humans: the effect of pulmonary denervation from bilateral lung transplantation, and the effect of alveolar hypocapnia. Lung inflations were performed in six normal subjects and four lung transplant patients during triazolam-induced sleep using a negative pressure body box. Lung inflation with isocapnic gas in normal subjects resulted in expiratory prolongation lasting up to 60 s and occurring at a volume threshold of 40 to 60% of inspiratory capacity (1.1 to 1.7 L). Expiratory prolongation increased in a graded fashion as volume of lung inflation increased. Inhibition of inspiration at any given inflation volume was prolonged by inflations with air as compared with inflations with isocapnic gas. In lung transplant patients lung inflations of up to 2 L caused no prolongation of expiration. We conclude that bilateral lung transplantation abolished expression of the reflex in humans, and that in normal intact humans the duration of expiratory prolongation with lung inflation is prolonged by alveolar hypocapnia.

Role of vagal feedback from the lung in hypoxic-induced tachycardia in humans.

We assessed the cardiovascular responses to systemic normocapnic hypoxia in five normal subjects, five double lung transplant patients with lung denervation and intact hearts, and five patients with denervated hearts. Progressive normocapnic hypoxia was induced over 10-15 min and maintained for 2-3 min each at 90, 87, 84, and 80% arterial O2 saturation (SaO2). Normal subjects showed the most pronounced mean increase in heart rate (dHR/dSaO2 = 0.86 +/- 0.13 beat/min per 1% SaO2). Three lung-denervated subjects had normal tachycardiac responses (1.6, 0.9, and 0.69 beats/min per 1%), whereas the other two had distinctly lower responses (0.34 and 0.39 beat/min per 1%). Most of the lung-denervated subjects also showed a significant tachycardia with even mild hypoxia; none showed a bradycardiac response to any level of hypoxia. In the heart-denervated group, hypoxic tachycardia was significantly lower than normal (0.29 +/- 0.13 beat/min per 1%). We conclude that vagal feedback from the lungs is not required for the normal chronotropic response to hypoxia in humans; however, this mechanism may contribute significantly to the marked variability in hypoxic-induced tachycardia found among human subjects. These data in humans contrast with the progressive bradycardiac response to hypoxia reported in vagally denervated (or nonhyperpneic) dogs and cats.

Respiratory sinus arrhythmia in humans: an obligatory role for vagal feedback from the lungs.

Respiratory sinus arrhythmia (RSA) is used as a noninvasive measure of vagal cardiac input, but its causative mechanisms in humans remain undetermined. We compared the RSA of five lung-denervated double-lung transplant patients with intact hearts to six normal (N) control subjects, five heart-denervated patients, and two liver transplant patients at matched tidal volumes (VT's) and breathing frequencies. In N and liver transplant subjects, RSA was significant during eupnea and increased two- to threefold with increasing VT and inspiratory effort. In heart- and lung-denervated subjects, RSA at eupnea was significant but was only 53% of that in N subjects and was not respondent to changing VT, inspiratory effort, or breathing frequency. We also compared the RSA of N subjects during voluntary (active) and passive positive pressure ventilation at normocapnia. RSA was reduced from 11 +/- 2.2 beats/min during active ventilation to 5.4 +/- 0.8 beats/min during PPV. We conclude that vagal feedback from pulmonary stretch receptors is obligatory for the generation of a neurally mediated RSA in awake humans at normal and raised levels of VT and respiratory motor output. In intact humans, we also hypothesize an important effect for nonpulmonary central and/or peripheral modulation of RSA. It is likely that the key mechanisms for neurally mediated RSA in unanesthetized humans are mutually dependent.

Portable recording in the assessment of obstructive sleep apnea. ASDA standards of practice.

The objective assessment of patients with a presumptive diagnosis of obstructive sleep apnea (OSA) has primarily used attended polysomnographic study. Recent technologic advances and issues of availability, convenience and cost have led to a rapid increase in the use of portable recording devices. However, limited scientific information has been published regarding the evaluation of the efficacy, accuracy, validity, utility, cost effectiveness and limitations of this portable equipment. Attaining a clear assessment of the role of portable devices is complicated by the multiplicity of recording systems and the variability of clinical settings in which they have been analyzed. This paper reviews the current knowledge base regarding portable recording in the assessment of OSA, including technical considerations, validation studies, potential advantages and disadvantages, issues of safety, current clinical usage and areas most in need of further study.

Pulmonary embolism: confirmation with venous duplex US as adjunct to lung scanning.

PURPOSE: To assess the prevalence of deep venous thrombosis with venous duplex ultrasonography (US) in patients who underwent radionuclide lung scanning for evaluation of clinically suspected pulmonary embolism (PE) and to assess the clinical usefulness of this type of US in the selection of patients for anticoagulant therapy. MATERIALS AND METHODS: Two hundred eighty-five lung scan and duplex US examinations in 267 consecutive patients seen between January 1987 and June 1990 with clinical evidence of PE (151 men and 134 women, aged 17-98 years [mean, 57 years]) were retrospectively reviewed. Lung scans were divided into four groups: normal, depicting up to 30% probability of PE, indeterminate or intermediate probability of PE, and greater than 90% probability of PE. RESULTS: Thrombotic disease was confirmed with US in seven (21%) of 33 patients with normal lung scans and in 64 (25%) of 252 patients with abnormal lung scans. CONCLUSION: Venous duplex Doppler US is a useful adjunct to lung scanning in patients with signs and/or symptoms of PE.

Respiratory modulation of muscle sympathetic nerve activity in intact and lung denervated humans.

We determined the influences of breathing-induced changes in intrathoracic and intravascular pressures, central respiratory drive, and pulmonary vagal feedback on the within-breath variation in skeletal muscle sympathetic nerve activity (MSNA) in humans. MSNA (peroneal microneurography), arterial blood pressure (Finapres finger monitor), and tidal volume (VT) were recorded continuously in six normal subjects and four heart-lung transplant patients during: 1) spontaneous air breathing; 2) increased FICO2; 3) voluntary augmentation of VT with and without inspiratory resistance; and 4) positive pressure, passive mechanical ventilation. During conditions 3 and 4, which were performed under isocapnic conditions with a high MSNA background (either high resting activity or nonhypotensive lower body suction), subjects breathed at control or elevated VT with normal or prolonged inspiratory time (TI); breathing frequency was 12 breaths per minute. During control breathing in normal subjects there was a distinct within-breath pattern of MSNA, with approximately 70% of the activity occurring during low lung volumes (initial half of inspiration and latter half of expiration). This within-breath variation of MSNA was potentiated with increased VT breathing (> 85% of activity occurring during low lung volumes; p < 0.05 versus control breathing) and was similar during the voluntary and CO2-induced hyperpneas. MSNA decreased progressively and markedly from onset to late inspiration; fell slightly further, reaching its nadir at end-inspiration/onset-expiration; and rose sharply during mid-late expiration. Only the nadir of MSNA was associated with any change in arterial pressure. Resistive breathing, especially at elevated VT, caused a fall in arterial pressure and increased respiratory drive during inspiration, yet MSNA still declined as lung volume increased. Normal within-breath modulation of MSNA also was observed during control and elevated VT induced via positive pressure with passive ventilation, which reversed lung inflation/deflation-induced intrathoracic pressure changes and reduced or removed respiratory motor output. During control breathing in transplant patients the specific within-breath pattern of MSNA was somewhat different than that of the normal subjects, but on average, the overall low lung volume to high lung volume MSNA ratio was similar to normal subjects. In contrast to the normal subjects, however, there was no potentiation of the within-breath variation of MSNA with elevated tidal breathing. These findings indicate that during normal levels of tidal breathing most of the respiratory phase influence on muscle sympathetic outflow observed in normal conscious humans is independent of baroreceptor-sensed fluctuations in intrathoracic or intravascular pressures and of lung inflation-stimulated vagal afferent activity.(ABSTRACT TRUNCATED AT 400 WORDS)

Uvulopalatopharyngoplasty for obstructive sleep apnea: a community's experience.

Uvulopalatopharyngoplasty (UPPP) has become an accepted method for treating obstructive sleep apnea (OSA), with a reported success rate as high as 77%, depending upon inclusionary and outcome criteria. The authors reviewed the records of 90 patients with moderately severe OSA (apnea plus hypopnea index [AHI] greater than 20) who underwent UPPP at either a private community or an academic hospital. Forty percent of patients experienced more than a 50% reduction in their AHI with UPPP. Only 22 (24%) of the patients had a postoperative AHI less than 50% of the preoperative AHI and less than 20, i.e., met the authors' criteria for surgical success. The success rate for community otolaryngologists was no different than that achieved in the academic institution. When data from previously published reports were analyzed using these criteria for success, similar results were observed. This study suggests that the effectiveness of UPPP performed by the general otolaryngologic community is equivalent to that reported in the literature. However, more rigorous criteria must be applied to UPPP when evaluating its results and in counseling potential candidates for this procedure.

Pulmonary mycetomas in immunocompetent patients: diagnosis by fine-needle aspiration.

Mycetomas usually grow within preexisting cavities and frequently lead to pulmonary hemorrhage. We describe four males, aged 38 to 72 years, in whom myceotomas were diagnosed by FNA. Preexisting cavitary lesions resulted from tuberculosis, anaerobic abscess, and bullous lung disease (two cases). Fine needle aspiration yielded tangled mats of fungal hyphae (large and grossly visible in three cases) and acute inflammatory cells. The atypical cells often seen in the walls of such lesions were not identified. Cultures showed Aspergillus (3 cases) Pseudoallescheria boydii (1 case). The diagnosis was surgically confirmed in two cases. Two patients were too ill for surgery and the fourth refused. At 7 and 10 months, the two remaining individuals have pulmonary hemorrhage but no evidence of progression or malignancy. In poor surgical candidates, conservative management of mycetomas diagnosed by fine needle aspiration is appropriate. Excluding mycetoma secondary to cavitary lung carcinoma requires careful correlation of historical, clinical, radiographic, cytologic, and follow-up data.

Role of airway mechanoreceptors in the inhibition of inspiration during mechanical ventilation in humans.

The purpose of this study was to demonstrate a neuromechanical inhibitory effect on respiratory muscle activity during mechanical ventilation and to determine whether upper and lower airway receptors provide this inhibitory feedback. Several protocols were completed during mechanical ventilation: (1) positive and negative pressure changes in the upper airway, (2) airway anesthesia to examine the consequences of receptor blockade on respiratory muscle activity, (3) increasing FRC with positive end-expiratory pressure to study the effect of hyperinflation or stretch on respiratory muscle activity, and (4) use of heart-lung transplant patients to determine the effects of vagal denervation on respiratory muscle activity. All subjects were mechanically hyperventilated with positive pressure until inspiratory muscle activity was undetectable and the end-tidal PCO2 decreased to less than 30 mm Hg. End-tidal PCO2 (PETCO2) was increased by either adding CO2 to the inspired gas or decreasing tidal volume (50 ml/min). The PETCO2 where a change in inspiratory muscle activity occurred was taken as the recruitment threshold (PCO2RT). Neuromechanical feedback caused significant inspiratory muscle inhibition during mechanical ventilation, as evidenced by the difference between PCO2RT and PETCO2 during spontaneous eupnea (45 +/- 4 versus 39 +/- 4 mm Hg) and a lower PCO2RT when tidal volume was reduced with a constant frequency and fraction of inspired CO2. Recruitment threshold was unchanged during positive and negative pressure ventilation, during upper and lower airway anesthesia, and in vagally denervated lung transplant patients. These findings demonstrate that neuromechanical feedback causes highly significant inhibition of inspiratory muscle activity during mechanical ventilation; upper and lower airway receptors do not appear to mediate this effect.

Single night studies in obstructive sleep apnea.

The role of single night studies and the determinants of effective nasal continuous positive airway (CPAP) pressures were determined in 412 consecutive patients between 1984 and 1989. Patients chosen for analysis had an apnea index (AI) of greater than or equal to 20 hr-1 prior to CPAP. The AI was 67 +/- 30 hr-1, the body mass index (BMI) was 36 +/- 9 kg/m2, the age was 51 +/- 13 yr and the lowest oxygen saturation was 72 +/- 14%. Effective CPAP (9 +/- 3 cm H2O) was documented in 320 patients on single night studies and resulted in a 99% reduction in the frequency of obstructive events and improvement in the lowest O2 saturation to 94 +/- 5%. Only 18% of the variability in effective CPAP could be explained by AI and BMI. Single night studies are sufficient to establish effective CPAP in 78% of patients and offer considerable conservation of resources compared to routine multiple night studies. Effective CPAP pressures are variable and must be determined by incremental CPAP trials.

Components of excess ventilation in patients initiated on mechanical ventilation.

OBJECTIVE: To determine the causes of excess minute ventilation in patients initiated on mechanical ventilation. DESIGN: Prospective study of recently intubated, mechanically ventilated patients. SETTING: The medical ICU in a county hospital. PATIENTS: Fifty-two mechanically ventilated medical ICU patients were studied within 36 hrs of intubation. Patients were all supported with volume-cycled ventilation in the assist-control mode. INTERVENTIONS: Timed expired gas collection and an arterial blood gas. MEASUREMENTS AND MAIN RESULTS: Measurements of minute ventilation and CO2 production (VCO2) were made from a timed expired gas collection. PaCO2 was sampled during the gas collection and deadspace was determined. Minute ventilation, VCO2, deadspace, and PaCO2 values in the patients were compared with predicted normal values, and excess minute ventilation due specifically to each component was calculated. Patients were separated clinically into groups: adult respiratory distress syndrome (ARDS), sepsis, obstructive lung disease, pneumonia, and drug overdose. Comparisons were then made between groups. Excess minute ventilation for the entire study population was secondary to increased deadspace (39%), low PaCO2 (36%), increased VCO2 (15%), and the interactive effect of deadspace and VCO2 (10%). VCO2 contributed little to excess minute ventilation early in respiratory failure, even in the ARDS and sepsis groups. Deadspace contributed significantly to excess minute ventilation in all groups, especially in the ARDS group, where it accounted for 53% of the excess ventilation. Low PaCO2 set-point was the predominant cause of excess minute ventilation in the sepsis group, where it contributed to 57% of their total excess minute ventilation. CONCLUSIONS: Although all groups initiated on mechanical ventilation had an excess ventilatory requirement, the contribution of individual components varied considerably between clinical groups.

Tidal volume reduction in ARDS. Effect on cardiac output and arterial oxygenation.

During continuous positive pressure ventilation (CPPV), mean airway pressure and lung volume will be influenced both by the tidal volume (VT) employed and the amount of positive end-expiratory pressure (PEEP). The effect of varying levels of CPPV on PaO2 and cardiac output (Q) has been previously assessed by adjusting the level of PEEP at constant VT. This study examined the influence of a 200-ml reduction in VT, at a constant PEEP of 15 cm H2O, on the PaO2 and Q of 21 patients with adult respiratory distress syndrome (ARDS). The relationship between change in Q and change in total respiratory system compliance (Cst) after VT reduction was also examined. VT reduction from 14.1 +/- 0.8 ml/kg to 11.2 +/- 0.9 ml/kg yielded an increase in Q (+ 15 +/- 12 percent, p less than 0.01) without a significant change in PaO2 (-6.3 +/- 15.0 mm Hg, p = 0.08). Cst increased with VT reduction (+ 3.1 +/- 1.8 ml/cm H2O). There was only a modest correlation (r = +0.42, p = 0.06) between delta Q percent and delta Cst following VT reduction. VT reduction at high level PEEP may yield a significant improvement in Q and net O2 delivery, but the degree of hemodynamic improvement is variable and is not reliably predicted noninvasively by measurement of Cst.

Influence of acid-base status on plasma catecholamines during exercise in normal humans.

The influence of acid-base status on plasma catecholamines during exercise was investigated in six healthy volunteers. Incremental exercise to 175 W was performed on a bicycle ergometer under four conditions: 1) control, 2) during forced hyperventilation (HV), 3) after pretreatment with acetazolamide (AZE), and 4) while breathing 4% CO2. Resting plasma norepinephrine (PNE) and epinephrine (PE) were not different among the four protocols despite higher resting pH during HV and lower resting pH after AZE [control, 7.4 +/- 0.02; HV, 7.48 +/- 0.03 (P less than 0.005); AZE, 7.36 +/- 0.01 (P less than 0.005) (P values indicate significant differences from the control protocol)]. Resting pH was not different from control during the 4% CO2 study (7.4 +/- 0.01). At the 175-W exercise load, there were significant differences in both pH and PNE. During the control test, pH was 7.38 +/- 0.02, PNE was 951 +/- 164 pg/ml, and PE was 264 +/- 132 pg/ml. During HV, pH was 7.46 +/- 0.5 (P less than 0.001), PNE was 976 +/- 67 pg/ml, and PE was 210 +/- 27 pg/ml. After AZE, pH was 7.31 +/- 0.2 (P less than 0.001), PNE was 1,866 +/- 561 pg/ml (P less than 0.005), and PE was 382 +/- 264 pg/ml. While subjects breathed 4% CO2, pH was 7.29 +/- 0.02 (P less than 0.001), PNE was 1.842 +/- 617 pg/ml (P less than 0.01), and PE was 467 +/- 275 pg/ml.(ABSTRACT TRUNCATED AT 250 WORDS)