Hypercapnic ventilatory response in patients with and without obstructive sleep apnea: do age, gender, obesity, and daytime PaCO(2) matter?

STUDY OBJECTIVE: To evaluate the relationship between obstructive sleep apnea (OSA) and ventilatory responsiveness to carbon dioxide in both men and women. DESIGN: An analysis of 219 patients referred to an university-based sleep center between 1989 to 1994 was conducted (104 with OSA and 115 without OSA; 43 women and 176 men). These patients had spirometry and a daytime hypercapnic ventilatory response (HCVR) test that was corrected to the patient's ability to attain maximal ventilation. Comparisons between OSA and no-OSA groups, as well as between men and women, were made using multivariate modeling techniques. RESULTS: There was no significant difference in the slope of correlated HCVR (cHCVR) between those with and without OSA (1.57 +/- 0.57 vs 1.63 +/- 0.66; p = 0.48). In men, an inverse correlation between daytime PCO(2) and cHCVR was observed in both crude and multivariate analyses (crude beta-coefficient = - 0.04 +/- 0.02, p = 0.02; adjusted beta-coefficient = 0.07 +/- 0.02, p < 0.01). Although age and cHCVR did not share a significant relationship in the crude analysis (crude beta-coefficient = - 0.01 +/- 0.01, p = 0.10), with adjustments for confounding variables, a significant inverse relationship between age and cHCVR was observed (beta-coefficient = - 0.02 +/- 0.01, p = 0.04). On the other hand, in women, only body mass index (BMI) was positively correlated with cHCVR (crude beta-coefficient = 0.03 +/- 0.01, p = 0.01; adjusted beta-coefficient = 0.04 +/- 0.01, p < 0.01). CONCLUSION: OSA disorder is not associated with a blunted ventilatory chemoresponsiveness to carbon dioxide. Elevated PaCO(2) and older age are significant correlates for a low cHCVR in men. For women only, BMI was associated with cHCVR. These findings suggest that men and women may have different ventilatory control mechanisms.

Effects of positive end-expiratory pressure on oscillated flow rate during high-frequency chest compression.

OBJECTIVE: To investigate the effects of positive end-expiratory pressure (PEEP) on end-expiratory lung volume (EELV) and mean oscillated flow rate (VOSC) during high-frequency chest compression (HFCC) in normal subjects and patients with severe COPD. DESIGN: Comparative study. SETTING: Pulmonary function and lung mechanics laboratory, University of Alberta Hospitals. PARTICIPANTS: Six normal subjects (five male; one female) and six patients with clinically stable COPD (five male; one female) with hypercapnia. INTERVENTIONS: A pneumatic vest system was operated at 10 Hz with a mean chest wall pressure of 16 cm H2O to provide the HFCC. A closed-circuit spirometer system permitted measurement of HFCC- and PEEP-induced changes in EELV that were expressed as per cent baseline functional residual capacity (FRC). An isothermic chamber connected near the mouthpiece permitted measurement of VOSC. RESULTS: For the normal subjects, HFCC caused a significant decrease in EELV to 82.0% of FRC (p < or = 0.01) and the addition of 4.8+/-0.5 cm H2O of PEEP during HFCC increased EELV to 97.5% FRC. In the COPD patients, HFCC decreased EELV to 92.3% of FRC (p < or = 0.01), and the addition of 3.7+/-1.0 cm H2O of PEEP increased EELV to 98.4% FRC. For the normal subjects, increasing EELV to near FRC caused VOSC during expiration to increase 14.6% (p < or = 0.01), but there was no significant effect on VOSC during inspiration (5.1% increase). In the COPD patients, PEEP increased VOSC during both inspiration (30.5%) and expiration (57.0%) (both, p < or = 0.01). CONCLUSIONS: Addition of a modest amount of PEEP during HFCC prevents the decrease in EELV and increases VOSC during both phases of spontaneous breathing in COPD patients. This higher VOSC during HFCC+PEEP may improve the effectiveness of HFCC in clearing mucus from the lungs of patients with airway disease.

Sleep quality and nocturnal respiratory function with once-daily theophylline (Uniphyl) and inhaled salbutamol in patients with COPD.

We compared the effects of evening administration of sustained-release theophylline (Uniphyl) and qid inhaled beta 2-agonist (salbutamol, two 100-micrograms puffs) on sleep quality and nocturnal oxygen saturation in 20 patients with COPD. Patients with FEV1 less than 70% predicted and FEV1/FVC ratio less than 70% were eligible to participate in this double-blind, crossover study, with 2-week treatment arms. Patients recorded morning and evening peak flow and symptoms in a daily diary. On the last day of each treatment period, overnight polysomnography was done. Spirometric indexes were measured before retiring and on awakening. Patients spent less time at less than 90% oxygen saturation (51 +/- 92 min vs 72 +/- 105 min; p = 0.03) during theophylline treatments than during salbutamol treatment. There was a smaller overnight decrease in FEV1 (0.04 L vs 0.13 L; p = 0.04) after theophylline than after sallbutamol treatment. FEV1/FVC ratio and maximum expiratory flow at 50% of vital capacity (V50) increased overnight with theophylline and decreased with salbutamol (p = 0.014, 0.025). Morning peak expiratory flow rate was higher with theophylline (4.0 +/- 1.7 L/s) than with salbutamol (3.6 +/- 1.8 L/s; p = 0.004). The duration of patient-reported nocturnal wheezing was lower with theophylline than with salbutamol (p = 0.006). There were no differences between treatments in sleep quantity, efficiency, staging, or subjective quality. We conclude that, compared with salbutamol, evening administration of once-daily theophylline results in better nocturnal oxygen saturation and an improvement in the overnight change in pulmonary function, without affecting sleep architecture, in patients with COPD.

Obstructive sleep apnea. Diagnosis and treatment.

The studies cited in this article highlight the remarkable effectiveness of nasal CPAP therapy in reversing the clinical consequences of obstructive sleep apnea and underscore the importance of long-term compliance with therapy. This information should be shared with patients to impress on them to continue with their treatment. The economic cost of sleepiness and sleep-related accidents to society has been estimated to be in the billions of dollars. This estimate would be even higher if the costs of treating the secondary medical conditions were also included. Considerable cost savings could be realized if more people are convinced to seek medical help and receive appropriate therapy as early as possible.

Validation of a portable sleep apnea monitoring device.

OBJECTIVE: To assess the sensitivity and specificity of a portable sleep apnea monitoring device (PolyG; CNS Inc; Chantassen, Minn) using standard polysomnography (PSG) as a gold standard. SETTING: The University of Alberta Hospitals Sleep Disorders Laboratory. PARTICIPANTS: One hundred and four consecutive patients referred for assessment of sleep complaints. MEASUREMENTS: Patients underwent simultaneous PSG and PolyG overnight recordings. The PSG included recordings of EEG, Chin electromyogram, electroculogram, ECG, oronasal airflow, thorax and abdomen respiratory movements, bilateral tibialis anterior electromyogram, and ear oximetry. The PolyG monitoring included oronasal airflow (thermistors), chest and abdomen pneumobelts, oximetry, ECG, and body position sensor. The raw data were screened and analyzed separately by two technicians without knowledge of results of the other system. RESULTS: The coefficient of correlation for apnea index (AI) was 0.94. The r value for apnea-hypopnea index (AHI) was 0.97. Using the criteria of AI more than 5 as diagnostic for sleep apnea syndrome, 23 out of the 104 patients had the disease based on PSG results. Twenty-six patients had AI more than 5 based on PolyG results. The sensitivity was 82.6% and the specificity was 91.4%. The positive predictive value was 73.1% and the negative predictive value was 94.9%. The overall accuracy was 89.4%. Using the criteria of AHI more than 15 as diagnostic for sleep apnea syndrome, 28 of the 104 patients had the disease based on the PSG results. Twenty-four patients had AHI more than 15 based on PolyG results. The sensitivity was 85.7% and the specificity was 94.7%. The positive predictive value was 85.7% and the negative predictive value was 94.7%. The overall accuracy was 92.3%. CONCLUSION: The PolyG monitoring device is useful in identifying patients without significant sleep apnea.

Hypercapnic ventilation response in patients with lung disease: improved accuracy by correcting for ventilation ability.

The hypercapnic ventilation response (HCVR) is positively correlated with forced expired volume in 1 s (FEV1). Therefore, subjects of small stature or patients with lung disease have low values for HCVR. However, indexing the HCVR for the subject's predicted maximal voluntary ventilation (MVV) results in a corrected HCVR (CHCVR) which is not dependent on FEV1 in normal subjects [Respiration 1993;60:197-202]. We hypothesized that the CHCVR would also be useful in assessing chemosensitivity in patients with poor lung function. To obtain the predicted MVV, we used the linear regression for FEV1 vs. measured MVV obtained from 411 patients with a wide range of FEV1 values (MVV = 31.2 x FEV1 + 11.8, r = 0.90, p < 0.001). We compared HCVR and CHCVR to the occlusion pressure response to hypercapnia (OPRH) in 34 patients with chronic obstructive pulmonary disease (COPD) and in 19 patients with low FEV1 due to small stature. All patients had been referred for assessment of possible sleep apnea. The results for the two groups of patients were similar. For the COPD patients, the HCVR had high values for sensitivity (86%) and negative predictive value (94%), but specificity, positive predictive value and accuracy were low (59, 35 and 65%, respectively). In contrast, CHCVR had high values for all the foregoing (86, 96, 100, 100 and 97%, respectively). Our results suggest that the CHCVR is useful in assessing chemosensitivity in patients who are ventilation-limited.

Sequential changes in canine pulmonary epithelial and endothelial cell functions after nitrogen dioxide.

Through its ability to cause lipid peroxidation, nitrogen dioxide (NO2) may affect the functional properties of both the pulmonary epithelium and endothelium. We evaluated this possibility in 13 mongrel dogs by exposing these animals to 200 or 400 ppm NO2 for 1 h. The changes in pulmonary epithelial permeability (using a radioaerosol technique), FRC, and endothelial function (the removal of radiolabeled serotonin, [14C]5-HT, and prostaglandin E1, [3H]PGE1, from the pulmonary circulation) were measured at 1 h and at 2, 7, or 14 days after NO2 exposure. In another six dogs, we evaluated changes in cell population and albumin in bronchoalveolar lavage (BAL) fluid caused by NO2. In the first two days after NO2 exposure, focal pulmonary edema was documented on microscopy, radioaerosol clearance was delayed, and FRC decreased slightly. BAL showed a marked increase in albumin, but the removal of trace amounts of 5-HT and PGE1 by the endothelium was not altered. All physiologic abnormalities returned to normal with time.

Tracheal mucus rheology in patients undergoing diagnostic bronchoscopy. Interrelations with smoking and cancer.

We examined the differences in tracheal mucus rheology between nonsmokers and smokers, and between smokers with and without lung cancer. Mucus was collected from patients undergoing diagnostic bronchoscopy without atropine by holding a cytology brush in contact with the tracheal mucosa for 10 to 15 s. Samples were obtained from 43 patients 24 to 79 yr of age: nine nonsmokers, 18 current smokers, and 16 exsmokers (greater than 6 months); 12 patients (nine smokers, three exsmokers) had lung cancer. Pulmonary function testing showed that the nonsmoker patients had significant restrictive lung disease, and the patients with cancer had significant irreversible airway obstruction. The viscoelastic properties of the mucus samples were determined by magnetic microrheometry. Two parameters are reported: G* (modulus of rigidity) and tan delta (loss tangent), each measured at 1 and 100 rad/s. G* is an index of overall deformability (elastic and viscous), and tan delta is the ratio of viscous to elastic deformability. For nonsmoker patients, the viscoelastic parameters were virtually identical to those found previously for normal volunteers. For smokers without cancer, the mucus had a lower value of tan delta 1 rad/s and therefore was predicted to be more easily transportable by ciliary action; for exsmokers without cancer, ciliary transportability as calculated from viscoelasticity was even higher because of both low tan delta and low G*. Mucus from patients with cancer was not significantly different from that of nonsmokers; however, the mucus was predicted to be less easily clearable by ciliary action than was that from smokers and exsmokers without cancer, mainly because of a higher tan delta at 1 rad/s.(ABSTRACT TRUNCATED AT 250 WORDS)

Computerized tomography versus perfusion lung scanning in canine radiation lung injury.

Computerized tomographic (CT) measurements of lung density were obtained before and serially after thoracic irradiation in dogs to detect the alterations caused by radiation therapy. Fourteen mongrel dogs were given either 2000 cGy (Group A, 10 dogs, right lower zone irradiation), 1000 cGy (Group B, 2 dogs, right lower zone irradiation), or 500 cGy (Group C, 2 dogs, right lung irradiation) in one fraction. Once before and bi-weekly after irradiation, the anesthetized dogs had thoracic CT scans. CT numbers for the irradiated area were compared to their preirradiation control values. Macro-aggregated albumin (MAA) perfusion lung scans were also obtained before and at weekly intervals after irradiation and were evaluated visually and quantitatively for abnormalities. When both these tests were abnormal, or at the end of the scheduled study, the dogs were sacrificed to confirm radiation lung injury histologically. Our results showed that CT numbers (as a measure of tissue density) were higher with higher doses of radiation. Among all the techniques used, only the quantitative assessment of macro-aggregated albumin perfusion scan detected abnormalities in all the dogs given 2000 cGy. Their abnormalities correlated well with the presence of radiation lung damage histologically, however, the applicability of these methods in the detection of early injury has to be further evaluated.

Reflex changes in tracheal smooth muscle tone during high-frequency oscillation.

We examined the effect of high-frequency oscillatory ventilation (HFOV) on tracheal smooth muscle tension and upper airway resistance in anesthetized dogs. The animals were ventilated via a low tracheostomy by HFOV or conventional intermittent positive pressure ventilation (IPPV) with and without added positive end-expiratory pressure (PEEP). The transverse muscle tension of the trachea above the tracheostomy was measured and found to be lower during HFOV when compared with IPPV or IPPV with PEEP. When both vagi were cooled to 8 degrees C to interrupt afferent traffic from the lungs, there was no longer any difference between the modes of ventilation. In a second series of experiments, the airflow resistance of the upper airway above the tracheostomy was measured (Ruaw). During HFOV, Ruaw was significantly lower than during either IPPV or IPPV with PEEP. We conclude that HFOV induces a relaxation of tracheal smooth muscle and a reduction of upper airway resistance through a vagally mediated mechanism.

Oxygen consumption during sleep: influence of sleep stage and time of night.

We measured oxygen consumption (VO2) in eight normal male volunteers during sleep, using the ventilated-hood method. Data were collected over 28 subject-nights. There was an overnight trend of gradually decreasing VO2 in the first 4 h, followed by a rise toward the morning. The minimum VO2 was 7.9% lower than that in the first hour. To examine the influence of sleep stages on the VO2, we compared the VO2 of a sleep stage (an overnight average of all epochs in that stage) with that of other stages. The results show that VO2 values in stages awake and 1 are significantly higher than all other stages. Stage rapid eye movement (REM) is significantly lower than stage 2, but stages 3 and 4 are not different from each other or from stages REM and 2. We also compared VO2 of sleep stages that occurred close to each other (within the same hour). VO2 in awake stage is again significantly higher than in all other stages, and stage 2 is higher than stages 3 and 4. However, no difference is found between stage 1 and stages 2, 3 and REM, nor is there any difference between REM and stages 2 and 3. The discrepancy between close-stage comparison and overnight-average comparison can be accounted for by the variation in VO2 of an individual stage with the time of night. Although there is a variation in time distribution of the stages overnight, this factor influences the overnight trend of VO2 in a minor fashion only.

Reflex tracheal contraction during pulmonary venous congestion in the dog.

1. The effect of pulmonary venous congestion on tracheal tone was studied in dogs anaesthetized with alpha-chloralose. Pulmonary venous congestion was produced by partial obstruction of the mitral valve to increase left atrial pressure by 10 mmHg. Tracheal tone was measured in vivo by an isometric force displacement method. 2. Tracheal tone increased by 6.3 +/- 0.3 g from a control level of 91.6 +/- 2.8 g when left atrial pressure was increased by 10.5 +/- 0.3 mmHg. This response was abolished by cooling the cervical vagi to 8 degrees C at a point caudal to the origin of the superior laryngeal nerves. Also, sectioning the superior laryngeal nerves abolished this increase in tracheal tone. 3. Afferent activity recorded from rapidly adapting receptors of the airways increased significantly during pulmonary venous congestion. This increase in activity was abolished by cooling the vagi caudal to the recording site to 8-9 degrees C. 4. Administration of propranolol (0.5 mg/kg) failed to abolish this increase in tracheal tone while atropine (3 mg/kg) did so. 5. Stimulation of left atrial receptors without an increase in left atrial pressure and stimulation of right atrial receptors with and without increases in right atrial pressure did not cause any change in tracheal tone. 6. It is suggested that pulmonary venous congestion is associated with a reflex increase in tracheal tone, the afferent limb of which is formed by pulmonary receptors discharging into myelinated fibres in the cervical vagi and the efferent limb by parasympathetic cholinergic fibres in the superior laryngeal nerves. The afferent receptors are likely to be the rapidly adapting receptors. This reflex may be of importance in the development of the respiratory symptoms associated with left ventricular failure.

Behaviour of canine pulmonary vagal afferent receptors during sustained acute pulmonary venous pressure elevation.

1. The effects of an acute sustained increase in pulmonary venous pressure induced by partial obstruction of the mitral valve on the activity of the four types of pulmonary receptors, namely, slowly adapting, rapidly adapting, pulmonary C-fibre and bronchial C-fibre receptors, were studied in the dog. 2. Fifteen slowly adapting receptors, eleven rapidly adapting receptors and nine bronchial C-fibre receptors showed significant sustained increases in activity when stimulated by the elevated left atrial pressure by 9.4 +/- 0.2 mmHg for 15 min. Nine pulmonary C-fibre receptors did not show a significant increase (six of these nine receptors increased their activity in response to the stimulus). 3. When the left atrial pressure was increased in graded steps of 5 mmHg for 5 min each up to 15 mmHg, a significant graded response was found in all of seven slowly adapting receptors, five rapidly adapting receptors and five bronchial C-fibre receptors. The five pulmonary C-fibre receptors examined also showed increases, but the changes were not statistically significant. 4. In response to stimulation by the elevated left atrial pressure, increases in activity occurred within 1 min of application of the stimulus in all the receptors and returned to control levels within 1 min of removal of this stimulus. 5. It is concluded that in the dog, pulmonary vagal receptors are influenced by small increases in pulmonary venous pressure induced by partial obstruction of the mitral valve. The changes appeared to be greatest in the case of rapidly adapting receptors. The physiological significance of these responses remains to be investigated.

High-frequency oscillatory ventilation increases canine pulmonary epithelial permeability.

To investigate the effect of high-frequency oscillatory ventilation (HFOV) on the pulmonary epithelial permeability, we measured the clearance rate of nebulized sodium pertechnetate (99mTcO4-) and diethylenetriaminepentaacetate (99mTc-DTPA) before and after a 4-h period of mechanical ventilation in anesthetized mongrel dogs. The animals also underwent experiments with 4 h of spontaneous breathing (SB) and intermittent positive-pressure ventilation (IPPV) with and without addition of positive end-expiratory pressure (PEEP) for comparison. After IPPV and SB there was no change in the clearance rate of either 99mTcO4- or 99mTc-DTPA. After IPPV + PEEP and HPOV (8 and 16 Hz), there was an increase in the clearance rate of 99mTc-DTPA, but an increase in clearance rate of 99mTcO4- was seen after IPPV + PEEP only. In a separate group of dogs an increase in end-tidal lung volume was demonstrated after 4 h of ventilation with IPPV + PEEP (but not after HFOV), and this may account for the measured increase in 99mTcO4- clearance. We conclude that an increase in 99mTc-DTPA clearance rate after HFOV signifies an increase in pulmonary epithelial permeability, possibly through the mechanism of damage to the intercellular junctions during HFOV.

Effects of irradiation on canine tracheal epithelium: a physiological and morphological correlate.

We delivered 20 Gy irradiation in one fraction to a 6 cm segment of trachea in 11 dogs. Tracheal mucous transport was studied before and whenever possible at weekly intervals after irradiation using a gamma camera system and 99m technetium labeled sulfur colloid. Ten of the eleven animals were sacrificed at three different time intervals (1-2, 15-16 and 30-34 weeks) post-irradiation, and the tracheal epithelium removed for studies using Ussing chambers followed by preparation for microscopic analysis. Mucous transport along the length of the trachea was normal before irradiation, but following irradiation it became abnormal in the irradiated zone. Compared to the epithelium from the cranial and caudal segments, the irradiated epithelium had similar bioelectric measurements (potential difference, short-circuit current and resistance) and mannitol permeability. Also, the changes in the bioelectric measurements following indomethacin (10(-6) M) and epinephrine (10(-6) M) used sequentially, were similar in both the control and irradiated tissues. Scanning electron microscopic analysis of the irradiated zone revealed patches of nonciliated epithelial cells among the ciliates. We conclude that irradiation caused a persistent replacement of ciliated cells with nonciliates throughout the entire study period and that this alteration impaired mucous transport but did not affect epithelial ion secretion or barrier function.

Effect of alprazolam on exercise and dyspnea in patients with chronic obstructive pulmonary disease.

To evaluate the efficacy of a mild anxiolytic, alprazolam, in relieving dyspnea, we conducted a randomized, placebo-controlled double-blind study on patients with chronic obstructive lung disease. Twenty-four patients had alprazolam (0.5 mg bid) or placebo administered for one week, followed by placebo for one week, then either placebo or alprazolam for the third week. Assessment tests were performed at the outset, end of the first and second weeks, and finally end of the third week. The parameters measured were: pulmonary function, exercise testing on a bicycle ergometer, and the distance covered in a 12 minute walk. Subjective sensations of dyspnea at rest and during guarded exercise, as well as subjective feelings of calmness or anxiety were also recorded. There was no difference in mechanical lung function, but the PO2 tended to decrease and PCO2 to increase after alprazolam administration. The maximum exercise level attained and the distance covered in the 12 minute walk was unchanged. The subjective perception of dyspnea was the same before and after alprazolam, at rest and during exercise. We conclude that alprazolam is not effective in relieving exercise dyspnea in patients with obstructive lung disease.

Altered pulmonary epithelial permeability in canine radiation lung injury.

A radioaerosol scanning technique measuring regional clearance of sodium pertechnetate (99mTcO-4) and 99mTc-labeled diethylenetriaminepentaacetate (99mTc-DTPA) was used to assess changes in canine pulmonary epithelial permeability following lung irradiation. Doses of 2,000 cGy (11 dogs), 1,000 cGy (2 dogs), and 500 cGy (2 dogs) were given in one fraction to either the entire right hemithorax (500 cGy) or the right lower lung (1,000 and 2,000 cGy). Radioaerosol scans, chest roentgenograms, and computerized tomograms (CT) were obtained before and serially after irradiation. A dose of 2,000 cGy resulted in a decrease in regional pulmonary epithelial permeability to both 99mTcO4- and 99mTc-DTPA; both showed significant decreases from the 2nd wk postirradiation onward. In comparison, CT and chest roentgenogram did not become abnormal until 7.1 +/- 2.8 (SD) and 8.2 +/- 2.6 wk, respectively. Doses of 1,000 and 500 cGy produced reversible decreases in 99mTcO4- clearance. Lung morphology showed definite changes of radiation pneumonitis after 2,000 and 1,000 cGy but not after 500 cGy at approximately 9, 17, and 12 wk postirradiation, respectively. These results suggest that dose-dependent changes in pulmonary physiology may precede obvious structural alterations in radiation lung injury.