Bilateral leg edema, obesity, pulmonary hypertension, and obstructive sleep apnea.

BACKGROUND: Pulmonary hypertension is usually due to an underlying cardiac or pulmonary condition. An association between unexplained pulmonary hypertension and bilateral leg edema in primary care patients was found previously. We undertook this study to identify the frequency of obstructive sleep apnea (OSA) in ambulatory, adult patients with pulmonary hypertension who initially presented with bilateral leg edema. METHODS: Twenty ambulatory adults with bilateral leg edema, echocardiocardiographic evidence of pulmonary hypertension (estimated pulmonary artery systolic pressure >30 mm Hg) without left ventricular dysfunction, and no clinically apparent pulmonary disease [corrected] were enrolled from a suburban family practice and an inner-city family practice during a 3-year period. Spirometric assessment, pulse oximetry, rheumatologic evaluation, polysomnography, and questionnaire information regarding risk factors for pulmonary hypertension were obtained for each subject. RESULTS: Fifteen patients (75%) completed the study. Almost all of the subjects were obese. Nine (60%) of the 15 had OSA. None of the subjects demonstrated an obstructive pattern on spirometric evaluation results, but 9 (60%) had a restrictive spirometry pattern, consistent with their obesity. None of the subjects had daytime hypoxemia. Systemic hypertension was present in two-thirds of the subjects with OSA, and was absent in all of the subjects who lacked OSA. CONCLUSIONS: Bilateral leg edema in obese primary care patients is associated with both OSA and modest pulmonary hypertension. If these findings are generalizable, then bilateral leg edema may be an important clinical marker for underlying OSA.

A long-term randomized, cross-over comparison of auto-titrating and standard nasal continuous airway pressure.

This study is a 12-week randomized, cross-over, single-blind comparison of the tolerance, compliance, and symptomatic improvement obtained with standard nasal continuous positive airway pressure (CPAP) vs. an auto-titrating, self-adjusting device (APAP). Sixty newly diagnosed patients, 53 with obstructive sleep apnea (OSA) and seven with upper airway resistance syndrome were studied. Thirty-nine patients (65%) completed the 24-week protocol. Data were complete in 33. In these 33 patients CPAP and APAP reduced the Epworth Sleepiness score from 15+/-1 (+/-SEM) to 8+/-1 and 9+/-1 respectively (both <0.0001 from baseline but NS between modes). The APAP average pressure was lower than the CPAP pressure, 6.4+/-0.4 and 10.6+/-0.4 cm H20, respectively. The average daily machine use was greater with APAP, 6.0+/-0.3 hrs. versus 5.5+/-0.3 hrs. with CPAP (P < 0.04). The number of days of machine use, and the pattern of use were not different between CPAP and APAP. A higher proportion of patients who did not complete the study was randomized to CPAP for their initial treatment period. This study showed that: 1) CPAP and APAP produced an equivalent improvement in daytime sleepiness, 2) APAP pressure was lower than CPAP pressure, 3) patients wore the APAP device longer during nights they used the pressure support system, and 4) patients who began the study with APAP were more prone to continue treatment. We conclude that APAP was better tolerated and used a greater number of hours than CPAP, but the extent of improvement in excessive daytime sleepiness was similar between the two modes of therapy.

Treatment of obstructive sleep apnea.

Options for the treatment of obstructive sleep apnea are varied and ever-expanding. This article reviews the currently available treatment modalities in an evidence-based format. Focus is placed on the efficacy and limitations of each particular therapy.

Effect of ipratropium bromide treatment on oxygen saturation and sleep quality in COPD.

STUDY OBJECTIVES: Patients with COPD are at risk of experiencing a deterioration in arterial oxygen saturation (SaO2) during sleep, which is generally most pronounced during rapid eye movement (REM) sleep. Increased cholinergic tone has been suggested as a contributing factor to this decrease in SaO2. Therefore, we investigated whether 4-week treatment with ipratropium bromide inhalation solution 0.02% (qid) could improve sleep characteristics in COPD. DESIGN: Randomized, placebo-controlled, double-blind, two-arm parallel study of 4 weeks of treatment with ipratropium bromide solution or placebo. SETTING: Multicenter investigation. PATIENTS: Thirty-six patients with moderate-to-severe COPD (FEV1 < 65% of predicted). MEASUREMENTS AND RESULTS: Evaluation included polysomnographic, pulmonary function, and subjective quality of sleep (visual analog scale [VAS]) assessments. It was found that 4 week of treatment with ipratropium bromide solution in patients with COPD led to the following: (1) a significant (p = 0.05) improvement in mean nocturnal SaO2 with the more severe the nocturnal desaturation, the greater the improvement in SaO2; (2) significant (p = 0.03) improvement in perceived sleep quality (VAS: 5.5 +/- 0.5 after placebo; 7.2 +/- 0.5 after ipratropium); (3) a significant (p = 0.05) increase in REM sleep time (48.6 +/- 6.3 min after placebo; 66.5 +/- 6.4 min after ipratropium) with no effect on other sleep stages or total sleep time; and (4) a significant (p = 0.01) increase in pre-sleep FVC and flow rate at 50% of the vital capacity. CONCLUSIONS: These findings demonstrate that ipratropium bromide therapy can improve sleep SaO2 as well as sleep quality in patients with moderate-to-severe COPD.

Instability of ventilatory control in patients with obstructive sleep apnea.

Because of the oscillatory pattern of upper airway resistance and breathing during sleep in patients with obstructive sleep apnea (OSA), we hypothesized that OSA patients have an underlying instability of ventilatory drive to inspiratory muscles. To assess the stability of ventilatory drive in OSA patients and controls, we used the pseudorandom binary stimulation (PRBS) test and examined the closed- and open-loop responses to hyperoxic hypercapnia. The closed-loop response is produced by interactions of dynamic gain in controller, plant, and ventilatory feedback. The open-loop response reflects controller dynamic gain or frequency-dependent chemosensitivity. As compared with 16 nonapneic, nonobese control subjects, a group of nine obese OSA patients had a higher peak response and a more rapid and irregular recovery phase of the closed-loop CO2 response in the PRBS test. The two groups had similar open-loop responses in the PRBS test, suggesting that central dynamic CO2 chemosensitivity was not abnormal in OSA. We conclude that the differences between OSA patients and controls in the closed-loop response in the PRBS test are not due to differences in dynamic controller gain, but are related to differences in dynamic plant gain and/or negative ventilatory feedback. In addition to OSA, obesity may affect these variables and may have been responsible for our findings.

Pharmacologic treatment of sleep-disordered breathing.

Available literature on the use of pharmacologic agents for the treatment of sleep-disordered breathing was reviewed by evidenced-based methodology. Evidence tables were created and studies were graded according to study design and the number of subjects included. Scores for each group of studies evaluating each pharmacologic agent were established so that the quality of research for different drugs could be compared. The use of various ventilatory stimulants, psychotropic drugs, and antihypertensive agents were reviewed. The most objective data are available on theophylline and opioid antagonist/nicotine groups. Although more controlled studies would be helpful, relatively clear-cut indications for the use of ventilatory stimulants exist for hypercapnic obesity-hypoventilation patients (medroxyprogesterone), myxedema (thyroid replacement), central apnea (acetazolamide), and periodic breathing in congestive heart failure (theophylline). Few randomized, well-controlled trials have been published that evaluate pharmacologic agents in the treatment of classic OSA. To date, no one agent stands out as being useful for OSA. Future research will need to characterize subjects so that various subsets of patients can be tried on one or on a combination of various pharmacologic agents.

Serotonin-induced cortisol release in CPAP-treated obstructive sleep apnea patients.

Previously, we demonstrated elevated cortisol production/release in response to the administration of the serotonin precursor, L-5-hydroxytryptophan (L-5-HTP) in untreated patients with obstructive sleep apnea (OSA). We hypothesized that if this elevated cortisol response to L-5-HTP was related to OSA, this finding would not be present in OSA patients treated with nasal continuous positive airway pressure (nCPAP). Eleven OSA patients treated for at least 1 month with nCPAP were studied. On two different days, we measured blood cortisol level every 15 min for 4 h following the ingestion of L-5-HTP, 0.4 mg/kg, or placebo, both given with carbidopa, a peripheral tryptophan decarboxylase inhibitor, used to prevent peripheral L-5-HTP metabolism before brain absorption. For a given subject, the cortisol response was calculated as the difference between the area under the curve of the L-5-HTP and placebo responses. In the nCPAP-treated OSA patients, this net cortisol response, 577 +/- 240 min.micrograms/dL, was less than the value found in the previously studied untreated OSA group, 1,198 +/- 227 min.micrograms/dL (p < 0.05) and not different from the previously studied nonapneic control group, 469 +/- 154 min.micrograms/dL. From these results, we speculate that nCPAP treatment reverses the elevated cortisol response to serotonergic stimulation seen in untreated OSA patients.

Hypoglossal and phrenic motoneuron responses to serotonergic active agents in rats.

5-Hydroxytryptamine (serotonin, 5-HT) affects upper airway and chest wall inspiratory muscle control. The purpose of this study was to investigate the relative interaction of serotonergic agents on these two muscle groups. We measured the responses of the hypoglossal and phrenic nerves to the systemic administration of serotonergic-active agents and determined the receptor types through which these agents act in anesthetized, vagotomized, paralyzed and artificially ventilated rats. The serotonin precursor, L-5-hydroxytryptophan (L-5-HTP) produced equivalent stimulation of phasic inspiratory activity of the hypoglossal and phrenic nerves. General serotonin antagonists produced significant and equivalent diminution of both motoneuron pools. Specific 5-HT1A stimulation and 5-HT1C/2 antagonism enhanced ventilatory activity. We conclude: (1) a baseline level of serotonergic input to hypoglossal and phrenic motoneuron pools was present, (2) different 5-HT receptors had different effects on ventilatory neural activity, and (3) hypoglossal and phrenic motoneuron pools responded similarly to the serotonergic agents given.

Treatment of obstructive sleep apnea. A review.

Treatment of obstructive sleep apnea (OSA) has developed over the last 25 years from tracheostomy to a variety of options, including weight loss, nasal continuous positive airway pressure (N-CPAP), pharyngeal surgery, and medications. None of these options is definitive or curative, except possibly weight loss. The most widely prescribed treatment is N-CPAP, but recently published studies using objective measurement of patient compliance show less than ideal compliance. Attempts have been made to design pharyngeal surgery according to the site of upper airway collapse or narrowing, as identified by various techniques in wakefulness. How representative these studies are of upper airway physiology in sleep is questionable. Recent studies have shown improved surgical success in correcting OSA. However, disturbing data are available in a limited number of patients that demonstrate worsening of the OSA months after a favorable response to surgery. More studies assessing the long-term outcome of pharyngeal surgery are needed. Several pharmacologic agents have been used to treat OSA. Results with any particular agent are not better than with N-CPAP or surgery. However, studies of subgroups of patients with OSA in which a particular pharmacologic agent may be specifically indicated, such as thyroxine in hypothyroidism, have not been conducted (to our knowledge). An algorithm for the approach to treatment recommendations is presented. Basic to this algorithm is an objective presentation of therapeutic options to the patient with OSA and a respect for the patient's preferences.

Results of a multicenter study of nebulized inhalant bronchodilator solutions.

The efficacy, persistence of bronchodilator action, and safety of the quaternary ammonium anticholinergic agent, ipratropium bromide (500 microgram), and placebo were compared when each was added in solution form to the beta-adrenergic agonist solution, metaproterenol sulfate (15 mg), and administered three times daily for 12 weeks to a total of 213 patients with chronic obstructive pulmonary disease (COPD). Subjects had a mean forced expiratory volume in 1 second (FEV1) of approximately 1 liter (37% of predicted) and were permitted to use nonanticholinergic therapy for COPD throughout the trial. The study was a randomized, double-blind, 85-day, parallel-group, eight-center study. On a 3 test days, 1, 43, and 85, mean peak responses for FEV1 and forced vital capacity and mean area under the curve were significantly higher for the iprathropium bromide-metaproterenol combination than for metaproterenol only. Duration of action was also significantly longer for the combination therapy than for the beta-agonist alone on test days 1 and 43. Neither treatment regimen produced an demonstrable effect on daily morning peak expiratory flow rates, reported respiratory symptoms, or quality of life. Both treatment regimens were similarly well tolerated with a comparable frequency of adverse events. These results suggest that the combination of iprathropium bromide and metaproterenol inhalation solutions offers a potential therapeutic advantage to patients with symptomatic COPD over nebulized metaproterenol alone without the risk of increased side effects.

Ventilatory stability to CO2 disturbances in wakefulness and quiet sleep.

Oscillatory ventilatory pattern occurs more frequently in sleep despite the stabilizing factor of sleep-induced reduction in CO2 chemosensitivity. In nine young normal humans, we have tested the hypothesis that, despite a sleep-induced reduction in chemosensitivity, the transient central chemoreceptor-mediated change inspiratory ventilation (VI) caused by a standardized disturbance to chemoreflex ventilatory control is similar in quiet sleep and wakefulness. The equivalent VI response to a single-breath hyperoxic hypercapnic stimulus (i.e., inhaling a single breath of 0.01 liter of CO2 in O2--a direct measure of "closed-loop" dynamic response) was determined using pseudorandom binary CO2 stimulation and the prediction-error method of transfer function estimation. From these data, the response of VI to a single-breath increase of 1 Torr in end-tidal PCO2 was also derived, from which "dynamic" central chemosensitivity was calculated. Despite a 43% reduction in dynamic central chemosensitivity, the peak and the area under the closed-loop VI response are similar in wakefulness and quiet sleep, whereas sleep increases the duration of the response by 48%. Thus hyperoxic ventilatory stability is not reduced in quiet sleep relative to wakefulness. We propose that changes in dynamics of pulmonary gas exchange in sleep substantially offset the decreased chemosensitivity, thereby maintaining the gains and time constants of the central chemoreceptor-mediated component of the closed-loop ventilatory control system similar to those during wakefulness.

Pharmacologic treatment of obstructive sleep apnea.

From this review it is obvious that no one pharmacologic agent is universally useful in the treatment of OSA. However, as mentioned in the introductory remarks above, the expectation of beneficial results in a heterogenous population of patients with OSA by specific-acting pharmacologic agents may be somewhat irrational. In addition to this problem, studies performed to date are often not controlled and are usually investigations in small numbers of subjects. However, from the data produced it is apparent that OSA precipitated by endocrinologic problems will improve with hormone replacement. Medroxyprogesterone has been shown to be especially useful in patients with an obesity-hypoventilation component to their disease. Protriptyline may also be useful, but its usefulness is impaired by significant adverse effects. Most likely, both medroxyprogesterone and protriptyline would be more tolerable in female OSA patients, but unfortunately, most of the OSA patient groups studied to date have been composed exclusively of male subjects. Therefore, we do not know if these agents would be more effective and better tolerated in female patients with OSA. The roles of ACE inhibitors and buspirone are not yet established. Serotonin-active agents may be useful in some patients with OSA, but the characteristics of responders are not defined for appropriate patient selection. Much work remains ahead to identify effective pharmacologic agents for OSA. Once identified, these agents must be tested in representative patient groups with a double-blind, placebo-controlled study design in multicenter trials to test the value of these agents.(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormal serotonergic stimulation of cortisol production in obstructive sleep apnea.

Because serotonin (5-HT) precursor or reuptake inhibitors improve obstructive sleep apnea (OSA), we hypothesized that brain serotonergic activity may be decreased in OSA. To test this hypothesis, we measured the cortisol response to the ingestion of L-5-hydroxytryptophan (L-5-HTP), a 5-HT precursor that is decarboxylated to 5-HT in the brain. Either L-5-HTP or an identical-looking placebo was administered at 0800, and blood was obtained over the following 4 h for serum cortisol determination. A placebo-controlled ACTH stimulation test was performed to evaluate adrenal function. We found that a group of 11 OSA patients had significantly higher cortisol production after L-5-HTP administration compared with a group of 11 control nonapneic subjects. The pretest cortisol levels and ACTH stimulation test results were not different between the two groups. We conclude that the cortisol response to L-5-HTP was elevated in the OSA patients studied, most likely as a result of increased hypophyseal 5-HT activity. We speculate that the 5-HT postsynaptic receptors that induce corticotropin releasing factor production and release are upregulated, or supersensitized, as a result of a brain 5-HT-deficient state that exists during sleep in OSA. We anticipate that medullary serotonergic neurons that affect ventilation would be altered similarly.

Continuous versus bilevel positive airway pressure for obstructive sleep apnea.

Recent objective studies demonstrate relatively low hours of nightly use during nasal continuous positive airway pressure (CPAP) therapy for obstructive sleep apnea (OSA). Patients frequently complain of dyspnea or discomfort during CPAP use, especially during expiration (against the continuous pressure), which may be a reason for the low hours of use. We hypothesized that with decreased expiratory pressure, hours of nightly use would increase. Therefore, we randomized 83 OSA patients to receive either continuous or bilevel positive airway pressure when expiratory pressure is lower. To document objectively the effective use of either therapy, we built and installed elapsed-time and mask pressure sensors in the patients' positive airway pressure units. A total of 62 patients were evaluable and followed for 1 yr. Of these, 26 received bilevel and 36 CPAP pressures. The machine timers measured accumulated "machine-on" time, and the mask pressure sensor recorded the total time in which the mask pressure was within 2 cm H2O of the effective pressure (pressure shown to eliminate 95% of the obstructive apneas during a full night of polysomnography). The mean machine timer hours of CPAP were 5.0 +/- 0.19 SEM and 4.9 +/- 0.23 SEM during bilevel therapy (p NS) over a 12-mo period. The pressures required during CPAP or bilevel therapy were not different between high and low hourly users. Effective use, the percentage of time that the machine was running and the prescribed pressure was being delivered, was 80% in CPAP and 82% in the bilevel users (p NS). Both groups had equal complaints with regard to mask discomfort, machine noise, and nasal stuffiness.(ABSTRACT TRUNCATED AT 250 WORDS)

Respiratory muscle activity during sleep-induced periodic breathing in the elderly.

During spontaneous sleep-induced periodic breathing in elderly subjects, we have found that tidal volume oscillations are related to reciprocal oscillations in upper airway resistance. The purpose of this study was to address the mechanism of the relationship between oscillations in tidal volume and upper airway resistance in elderly subjects with sleep-induced periodic breathing. We hypothesized that the spontaneous periodic breathing observed in non-rapid-eye-movement (NREM) sleep in elderly subjects would be closely related to fluctuations in upper airway resistance and not to changes in central motor drive to ventilatory pump muscles. Therefore, in eight healthy elderly subjects, we measured costal margin chest wall peak moving time average electrical inspiratory activity (CW EMG), ventilation variables, and upper airway resistance during sleep. Five of eight subjects had significant sine wave oscillations in upper airway resistance and tidal volume. For these five subjects, there was a reciprocal exponential relationship between peak upper airway inspiratory resistance and tidal volume or minute ventilation [r = -0.60 +/- 0.20 (SD) (P < 0.05) and -0.55 +/- 0.26 (P < 0.05), respectively], such that as resistance increased, ventilation decreased. The relationship between CW EMG and tidal volume or minute ventilation was quite low (r = 0.12 +/- 0.32 and -0.07 +/- 0.27, respectively). This study demonstrated that oscillations in ventilation during NREM sleep in elderly subjects were significantly related to fluctuations in upper airway resistance but were not related to changes in chest wall muscle electrical activity. Therefore, changes in upper airway caliber likely contribute to oscillations in ventilation seen during sleep-induced periodic breathing in the elderly.

Mechanism of sleep-induced periodic breathing in convalescing stroke patients and healthy elderly subjects.

Cerebral vascular ischemic strokes are known to precipitate Cheyne-Stokes periodic breathing. Interestingly, Cheyne-Stokes-like breathing during sleep may be associated with obstructive sleep apnea (OSA) in some individuals. Therefore, it was reasoned that stroke patients with periodic breathing in sleep would be susceptible to OSA. Because oscillations in upper airway resistance can occur as a component of sleep-induced periodic breathing, we hypothesized that stroke patients with sleep-induced periodic breathing would have oscillations in upper airway resistance. These oscillations in resistance would be expected to contribute to OSA. We studied stroke patients with sleep-induced periodic breathing and control subjects to evaluate the relationship between upper airway resistance and ventilation in periodic breathing in sleep. Ventilation and upper airway resistance were measured in presleep wakefulness and in stage 2 NREM sleep. Mean tidal volume, minute ventilation, respiratory cycle timing variables, and upper airway resistance were not different between stroke and control subjects, either awake or asleep. Upper airway resistance increased and ventilation volume decreased from wakefulness to sleep in both groups. In an equivalent number of subjects from each group, reciprocal patterned oscillations in tidal volume and upper airway resistance were present at a 5 to 12.5 breath frequency during sleep. As upper airway resistance increased, tidal volume decreased. Stroke patients had wider fluctuations in upper airway resistance than control subjects, likely contributing to the higher number of sleep-disordered breathing events observed in the stroke patients.

Adaptive buffering of breath-by-breath variations of end-tidal CO2 of humans.

We have designed and implemented a computer-controlled system that uses an adaptive control algorithm (generalized minimum variance) to buffer the breath-by-breath variations of the end-tidal CO2 fraction (FETCO2) that occur spontaneously or are exaggerated in certain experimental protocols (e.g., induced hypoxia, any type of induced variations in the ventilatory pattern). Near the end of each breath, FETCO2 of the following breath is predicted and the inspired CO2 fraction (FICO2) of the upcoming breath is adjusted to minimize the difference between the predicted and desired FETCO2 of the next breath. The one-breath-ahead prediction of FETCO2 is based on an adaptive autoregressive with exogenous inputs (ARX) model: FETCO2 of a given breath is related to FICO2, FETCO2 of the previous breath, and inspiratory ventilation. Adequacy of the prediction is demonstrated using data from experiments in which FICO2 was varied pseudorandomly in wakefulness and sleep. The algorithm for optimally buffering changes in FETCO2 is based on the coefficients of the ARX model. We have determined experimentally the frequency of FETCO2 variations that can be buffered adequately by our controller, testing both spontaneous variations in FETCO2 and variations induced by hypoxia in young awake human subjects. The controller is most effective in buffering variations of FETCO2 in the frequency range of <0.1 cycle/breath. Some potential applications are discussed.

The carotid body in the motorneuron response to protriptyline.

Protriptyline (PRT) has been shown to preferentially stimulate upper airway inspiratory motorneurons relative to phrenic activity in hyperoxic hypercapnia in the decerebrate cat via a carotid body-independent mechanism. Since previous studies indicated that carotid body stimulation results in preferential activation of upper airway respiratory muscles during both hypercapnia and hypoxemia, we hypothesized that if PRT preferentially stimulated upper airway motorneurons, the mechanism of action might involve the carotid body. We investigated the effect of PRT on carotid body function by comparing the electrical activity of the hypoglossal (HYP) with that of the phrenic (PHR) nerve in carotid sinus nerve intact (CSNI) and CSN-sectioned (CSNX) anesthetized rats, before and after PRT (0.5 mg/kg i.v.), during 100% O2, 15% O2 (N2 balance), and 4% CO2 (O2 balance) administration. The moving time average (MTA) peak inspiratory electroneurogram activities of both the HYP and PHR nerves increased an equivalent amount after PRT injection during hyperoxia, in both CSNI and CSNX rats. During hypoxia, the HYP activity increased significantly more than the PHR activity only in CSNI rats after PRT injection. During hyperoxic hypercapnia, HYP MTAs increased a similar amount in the CSNI and CSNX rats. We conclude that the HYP and PHR respiratory motorneuron pool responses to PRT depend on the blood gas status at the time of drug administration.