Irregular breathing during sleep in patients with panic disorder.

OBJECTIVE: The authors examined the nocturnal breathing patterns of patients with panic disorder to determine whether these individuals had respiratory irregularities at a time when anxiety was not manifest. METHOD: Respiratory polysomnography was conducted on 14 medication-free patients with panic disorder and 14 healthy comparison subjects. Semiautomated indices of ventilatory variability were calculated for representative 3-minute, artifact-free sleep samples, and manually scored indices of irregular breathing were rated (blind to diagnosis) for the entire last 2 nights of sleep. RESULTS: Patients with panic disorder had evidence of abnormal sleep breathing as indicated by increased irregularity in tidal volume during REM and an increased rate of microapneas (i.e., brief [5-10-second] pauses in breathing). A subgroup of patients (including some with recent sleep panic attacks) had indices of subtle disorders in breathing during sleep that were above the 95th percentile for the comparison subjects. CONCLUSIONS: These findings extend the observations in the awake state that patients with panic disorder breathe more irregularly than healthy comparison subjects. The irregularities may be attributable to altered brainstem sensitivity to CO2 or to other as yet unexplained factors. A possible relationship between irregular nocturnal breathing and sleep panic attacks is discussed.

Short technical note: quantification of periodic breathing: preliminary studies.

Although the apnea/hypopnea index is the most widely used measure of breathing pattern abnormality during sleep, this index gives no information about the strength of the oscillation in the breathing pattern, its periodicity or its regularity. Such information may be required in research studies involving breathing patterns and how they are affected by interventions. We are exploring spectral analytic methods to determine two normalized indices, the periodicity index and the modified modulation index, to examine periodic breathing for all-night sleep studies. These methods are automatic and require no user interaction. Data were obtained from 11 heart failure patients who slept for a total of 21 nights in the sleep laboratory. Because individual patients had a marked regularity of their Cheyne-Stokes respiration during sleep, one would expect an extremely high correlation between the traditional measures of breathing pattern abnormality and these spectral analytic techniques. Indeed we found that there was an extremely high correlation between the periodicity index and the modulation index and the traditional measures of apnea/hypopnea index and the proportion of the night with periodic breathing (p less than 0.02 in all cases). When the breathing pattern was irregular but still with many apneas there was a discrepancy between the apnea index and the indices of periodicity. These techniques are still preliminary and future studies will determine their limitations in other patient populations and where the pattern is unstable.

Sleep apnea and body position during sleep.

In patients with obstructive sleep apnea, it is believed that body position influences apnea frequency. Sleeping in the lateral decubitus position often results in significantly fewer apneas, and some have recommended sleeping on the side as the major treatment intervention. Previous studies, although calculating apnea-hypopnea index (AHI) for supine and lateral decubitus positions, have not taken sleep stage into account. To examine the effect of both sleep stage and body position on apnea duration (AD) and frequency, we determined AHI and AD in all spontaneous body positions during rapid eye movement (REM) and non-REM (NREM) sleep by reviewing videotapes and polysomnograms from 11 overnight studies of 7 obese patients with severe sleep apnea. Consistent with previous work, AD was significantly longer in REM then in NREM (32.5 +/- 2.3 s versus 23.5 +/- 1.9 s; p less than 0.05). This difference persisted when adjusting for body position. AHI was greater on the back than on the sides (84.4 +/- 4.9/h versus 73.6 +/- 7.5/h, p less than 0.05), but after accounting for sleep stage, this difference remained only for NREM (103 +/- 4.8/h versus 80.3 +/- 9.2/h, p less than 0.05) and not for REM (83.6 +/- 5.3/h versus 71.1 +/- 4.2/h, p NS). Although reduced, AHI on the sides still remained clinically very high. Body position changed frequently throughout the night, but some patients spent little or no time on their back. We conclude that AD is longer in REM than NREM, regardless of position, and AHI is higher on the back only in NREM. As AHI remains very high on the sides, favoring the lateral decubitus position may not be as beneficial as previously thought in very obese patients. Less obese patients are more likely to benefit by position changes.

Benzodiazepines in congestive heart failure: effects of temazepam on arousability and Cheyne-Stokes respiration.

We studied seven male patients with moderate to severe congestive heart failure (CHF) [left ventricular ejection fraction (LVEF) = 22.4 +/- 6.7; mean +/- SD] in a double-blind crossover trial to determine the effects of temazepam 15 mg on arousability, sleep architecture, Cheyne-Stokes respiration (CSR) and nighttime oxygen saturation. Sleep architecture was not markedly improved with temazepam. There was no significant change in total sleep time (TST) (383.1 +/- 14.1 minutes to 396.6 +/- 15.4 minutes, p = ns) (mean +/- SE, placebo vs. temazepam) or total wake time (TWT) (96.9 +/- 14.0 vs. 81.4 +/- 14.0 minutes, p = ns). Sleep stage proportions did not change appreciably except for a reduction in stage 1 sleep (6.7 +/- 1.2% vs. 4.0 +/- 1.0%, p < 0.05). Microarousals per hour of sleep decreased with temazepam (21.1 +/- 2.7/hour vs. 13.9 +/- 2.1/hour placebo, p < 0.05), with the largest change occurring in stage 2 (24.9 +/- 5.4/hour vs. 15.0 +/- 3.1/hour, p < 0.05). Wake time during sleep (WDS) was reduced from 82.5 +/- 11.7 minutes to 54.5 +/- 9.4 minutes, p < 0.03. Daytime alertness was improved with temazepam as was indicated by an increase in mean latency to sleep [multiple sleep latency test (MSLT) = 7.1 +/- 2.4 vs. 5.7 +/- 2.0 minutes, p < 0.04) on days following treatment with temazepam. There was no significant change in CSR as a percentage of TST (38.7 +/- 13.6% vs. 32.5 +/- 11.8%, p = ns). However, the apnea/hypopnea index (AHI) (10% filter) was decreased in stage 1 (28.1 +/- 9.7/hour vs. 15.6 +/- 8.2/hour). Overnight oxygen saturation did not change with temazepam (95.1 +/- 0.6% both nights) and the percentage of TST spent below 90% oxygen saturation was minimal for both conditions (1.5 +/- 1.1% vs. 2.2 +/- 1.7%, p = ns). We conclude that CHF patients with CSR experience frequent arousals and that these arousals can be reduced with temazepam. There was an improvement in daytime somnolence. There was no worsening of nighttime oxygen saturation.

The effect of L-tryptophan on daytime sleep latency in normals: correlation with blood levels.

L-Tryptophan, an essential amino acid, is readily converted to serotonin, which is thought to be important for expression of slow wave sleep and possibly rapid eye movement (REM) sleep. A vast but often confusing literature exists on L-tryptophan effects on inducing, maintaining, or altering sleep. In this study we measured the effects of L-tryptophan on objective (multiple sleep latency) and subjective [Stanford Sleepiness Scale (SSS)] measures of sleepiness and examined their relationship to blood L-tryptophan levels. Ten healthy volunteers (eight men and two women; mean +/- SD age 34 +/- 10 years) received placebo or 1.2 or 2.4 g or L-tryptophan on separate days in random double-blind fashion. Sleep latency and SSS were measured initially and at 60 and 120 min after ingestion. Blood and urine were collected at regular intervals. Compared with placebo both L-tryptophan doses reduced sleep latency at 1 h, with the reduction persisting at 2 h for the 2.4-g dose only (p less than 0.05). There was a positive correlation between subjective and objective sleepiness measures but only with the 2.4-g dose (rs = 0.76, p less than 0.01). There was a highly significant correlation between blood L-tryptophan and sleep latency at 0, 60, and 120 min in all subjects for all drug conditions (r = 0.276, df = 79, p = 0.013). Very small amounts of free L-tryptophan or its metabolites were found in the urine, with the exception of kynurenic acid. We conclude that L-tryptophan consistently reduced sleep latency in normals and that this correlates with blood levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of zolpidem and triazolam on sleep and respiration in mild to moderate chronic obstructive pulmonary disease.

Sleep problems and nocturnal arterial oxygen desaturation are common in patients with chronic obstructive pulmonary disease (COPD). Hence, the safety and efficacy of new hypnotic agents must be ascertained in this group of patients. We performed a double-blind, randomized, single-dose, placebo and active drug controlled, crossover study in 24 patients with insomnia (subjective sleep latency > 30 minutes and sleep duration 4-6 hours) and mild to moderate COPD (mean FEV1 61 +/- 12(SD)% predicted) in order to establish the effects of zolpidem 5 mg and 10 mg on sleep and respiration and to compare these effects with triazolam 0.25 mg. Arterial oxygen saturation for the entire night, by hour and stage, and the apnea-hypopnea index for the entire night were not significantly different with placebo and the various drug conditions. Total sleep time and sleep efficiency were increased over placebo by all three drug conditions. Triazolam was more effective than zolpidem 5 mg but not zolpidem 10 mg, and there was no significant difference between zolpidem 5 mg and zolpidem 10 mg. Zolpidem 10 mg and triazolam both reduced the number of awakenings (> 15 seconds duration) per hour of sleep. Although there was a trend for triazolam to be more efficacious than zolpidem 10 mg, no statistically significant difference was found for any objective or subjective sleep variable. Likewise, zolpidem 10 mg tended to be more efficacious than zolpidem 5 mg, but the difference was only significant in terms of perceived sleep quality and ease of falling asleep.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of inhaled 3% CO2 on Cheyne-Stokes respiration in congestive heart failure.

Cheyne-Stokes respiration (CSR) in severe stable congestive heart failure (CHF) may be associated with significant nocturnal arterial oxygen desaturation and sleep disruption. Previous investigations of inhaled CO2 in CSR have been uncontrolled and of short duration, sleep has not been monitored electroencephalographically, and most patients studied have had neurological disease with or without cardiac disease. The purpose of our study was to document the effects of inhaled CO2 on CSR in patients with severe stable CHF (left ventricular ejection fraction < 35% and NYHA class 3 or 4 dyspnea) in controlled all-night polysomnographic studies. Six patients were studied for 3 nights and days: adaptation, control and inhalation of CO2. These patients received a constant F1CO2 = 0.03 in air (with a 4-5 mm Hg increase in PaCO2) on night 3. This caused virtual abolition of CSR as reflected by CSR duration/total sleep time (62-2.2%; p = 0.0012) and CSR duration/nonrapid eye movement (NREM) sleep time (73-2.4%; p = 0.00064), and NREM apnea index was reduced from 33.5 to zero (p = 0.026). The apparatus used to accurately control F1CO2, however, was intrusive and some features of sleep structure such as sleep latency were adversely affected. We conclude that inhalation of CO2 with a constant F1CO2 = 0.03 virtually eradicates CSR in all-night polysomnographically monitored studies in patients with severe stable CHF. The clinical significance of these findings remains to be determined.

Heart rate response to breath-hold, valsalva and Mueller maneuvers in obstructive sleep apnea.

We wished to assess the role of increased vagal tone and arterial oxygen saturation (SaO2) as determinants of HR response to voluntary respiratory maneuvers in OSAS. The changes in HR and SaO2 during breath-hold (B), Valsalva (V) and Mueller (M) maneuvers were determined in nine male subjects with OSAS while breathing RA or O2. Oxygen saturation was significantly lower breathing RA than O2 at the end of B (92.6 +/- 1.6 vs 97.2 +/- 0.8 percent), V (92.9 +/- 1.3 vs 95.2 +/- 1.7 percent), and M (92.7 +/- 1.2 vs 95.3 +/- 1.9 percent). Despite this, there was no significant difference between the HR change while breathing RA and O2 during B (12 +/- 18 vs 7 +/- 15 beats/minute), V (-2 +/- 12 vs -5 +/- 17 beats/minute), and M (5 +/- 16 vs 1 +/- 8 beats/minute). The change in HR was not related to the duration of B, V, or M or to the mouth pressure generated during V and M. In order to determine if awake HR response to the maneuvers reflected HR response to obstructive apnea, we examined the relationship between the HR response to B, V, and M during wakefulness and the response to obstructive apnea of similar duration while asleep. A significant correlation was found between the HR response to obstructive sleep apnea during sleep and the response to awake B (r = 0.67, p less than 0.001), V (r = 0.51, p less than 0.05), and M (r = 0.75, p less than 0.001). We conclude that in OSAS, increased vagal tone is a major determinant of HR response to voluntary respiratory maneuvers, that bradycardia can occur in the absence of hypoxemia, and that HR response to these maneuvers, especially to M, during wakefulness predicts HR response to obstructive apnea while asleep.

Sleep in postpolio syndrome.

Post-polio patients may develop additional neuromuscular and respiratory symptoms decades after the acute attack, the post-polio syndrome. We hypothesize some post-polio symptoms may be due to breathing disorders occurring during sleep. We performed polysomnography on 13 post-polio patients: group 1 (five patients) were those already on ventilatory assistance (rocking beds) and group 2 (eight patients), those without any assistance. Patients requiring new treatment were then evaluated on nasal CPAP or nasal mask ventilation. Group 1 patients, on rocking beds, demonstrated consistently poor sleep quality with decreased total sleep time, sleep efficiency, percentage stage 2, slow wave sleep, rapid eye movement sleep and an increase in the number of arousals and percentage stage 1 sleep. Respiratory abnormalities were also present and in all cases caused significant O2 desaturation. These patients did not respond to CPAP with the rocking bed. Repeat night-time polysomnography on nasal mask ventilation demonstrated an improvement in sleep structure and gas exchange. Three group 2 patients, (group 2a) had sleep within normal limits. The five remaining (group 2b) had poor sleep quality that was similar to but not as disrupted as group 1 patients. All but one patient demonstrated obstructive or mixed apnea and were treated effectively with nasal CPAP. One patient required nasal mask ventilation (due to mixed apnea and marked hypoventilation) to which there was a dramatic response. These patients demonstrated improved sleep quality and an improvement in daytime symptomatology. Sleep studies should be performed on post-polio patients with excessive daytime sleepiness and respiratory complaints. Those with obstructive and mixed apnea can often be treated with nasal CPAP. Those with hypoventilation syndrome and sleep apnea attributable to sleepiness and respiratory complaints. Those with obstructive and mixed apnea can often be treated with nasal CPAP. Those with hypoventilation syndrome and sleep apnea attributable to respiratory muscle weakness can be treated with nasal mask ventilation. Individuals already on respiratory assistance such as rocking beds who have features of respiratory failure can also be treated effectively with long-term nasal mechanical ventilation.

The entrainment of low frequency breathing periodicity.

It has been predicted by mathematical models of the respiratory control system that the delay between the lung and the respiratory controller may determine the cycle time found in periodic breathing. We examined cycle time of periodic breathing and circulation time in 11 patients known to have circulation delay due to heart failure. We did not find a significant relationship between the amount of periodic breathing and circulation delay, but found a very high correlation between circulation delay and the cycle time of periodic breathing (r2 = 0.825; p = 0.0001).

Respiration and abnormal sleep in patients with congestive heart failure.

We investigated the interaction between respiration and sleep in ten male outpatients with severe, stable, maximally treated congestive heart failure (CHF). Cheyne-Stokes respiration (CSR), defined as periodic breathing with apnea or hypopnea, was found in all patients with a mean duration of 120 +/- 87 minutes [50.2 +/- 34.4 percent total sleep time (TST)]. The CSR was found predominantly during stage 1 (20.6 +/- 6.7 percent TST) and stage 2 (25.8 +/- 6 percent TST) NREM sleep and occurred rarely during slow wave sleep (SWS) (1.6 +/- 1 percent TST) and REM sleep (1.6 +/- 0.5 percent TST). All apneas and hypopneas were central. Despite normal awake arterial oxygenation (SaO2) (96.1 +/- 1.6 percent), significant, severe hypoxemia was found during sleep in seven patients with SaO2 less than 90 percent for 9 to 59 percent TST (mean +/- SD, 23 +/- 23 percent TST), and this was significantly related to the duration of CSR (r = 0.66, p less than 0.05). The mean minimum SaO2 for sleep stage was lowest during stage 1 (82.1 percent +/- 2.6 percent) and stage 2 (78.9 percent +/- 2.8 percent) NREM sleep, intermediate during REM sleep (84.5 percent +/- 1.8 percent) and highest during SWS (87.6 percent +/- 2.7 percent). Sleep was disrupted to a variable extent in all patients with a short mean TST (287 +/- 106 minutes), a high proportion of stage 1 sleep (26 +/- 19 percent TST), virtual absence of SWS (5 +/- 7 percent TST) which was found in only four patients, and a high number of sleep stage changes (30 +/- 27/hour) and arousals (28 +/- 25/hour). Arousals occurred predominantly during stage 1 (17 +/- 20/hour) and stage 2 (10 +/- 7/hour) NREM sleep and the majority immediately followed the hyperpneic phase of CSR. The amount of CSR (percent TST) was inversely related to the length of TST (r = -0.73, p less than 0.05), and directly related to the number of sleep stage changes (r = 0.79, p less than 0.01) and the number of arousals (r = 0.66, p less than 0.05). We conclude that in severe, stable CHF, CSR occurs predominantly during light sleep, that despite normal awake arterial oxygen saturation, significant hypoxemia may develop during sleep due to CSR, and that sleep is unstable and disrupted due to frequent arousals caused by the hyperpneic phase of CSR. These sequelae of CSR may be important determinants of the clinical status and outcome of patients with severe CHF.

Identification and quantification of apneas by computer-based analysis of oxygen saturation.

Manual detection and quantitation of apneas from an all-night polysomnogram is very time-consuming. Because SaO2 changes with virtually every apnea event, we reasoned that by identifying cyclical SaO2 changes, we could calculate (1) an apnea-hypopnea index that would correlate very well with the manually derived apnea-hypopnea index, and (2) the duration of apnea-hypopnea events. We developed a computer algorithm to scan and detect dips in SaO2 data digitally stored as a time series by computer throughout overnight studies. Desaturations detected by computer were compared with the events detected manually in 9 all-night polysomnograms from 6 patients with typical obstructive sleep apnea. Events detected by one method but not the other were subsequently verified to determine the overall number of apnea-hypopnea events present and to determine false positive and false negative rates for the 2 methods of detection. The total number of apneas was 4,008. Both methods agreed on 3,639 of them. Of 77 manually recorded apneas not detected by computer, 24 were subsequently discounted (manual false positives, 24 of 4,007 = 0.6%) and 53 confirmed (computer false negatives, 1.32%). Of 358 events not detected manually, 316 were confirmed (manual false negatives, 7.9%) and 42 discounted (computer false positives, 1.1%). Using the final manual scoring as the reference, the computer program detected apneas with a sensitivity of 97.9%, and the predictive value of a computer-detected event was 90.8%. For event duration, a regression was performed on 3,623 matched apneas-hypopnea events, giving a coefficient of r = 0.9431, p less than 10(-6).(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of oxygen on respiration and sleep in patients with congestive heart failure.

STUDY OBJECTIVE: To determine the effect of supplemental oxygen on Cheyne-Stokes respiration, nocturnal oxygen saturation (SaO2), and sleep in male patients with severe, stable congestive heart failure. DESIGN: Randomized, single-blind, placebo-controlled crossover study. SETTING: Patients referred from outpatient cardiology clinics of two teaching hospitals. PATIENTS: Sequential sample of nine outpatients with severe, stable congestive heart failure. INTERVENTIONS: For each patient, sleep studies (after an adaptation night) from two consecutive randomized nights were compared; one study was done while the patient breathed compressed air and the other while the patient breathed oxygen (O2). Compressed air and oxygen were both administered through nasal cannulae at 2 to 3 L/min. MEASUREMENTS AND MAIN RESULTS: Cheyne-Stokes respiration, defined as periodic breathing with apnea or hypopnea, was found in all patients. Low-flow oxygen significantly reduced the duration of Cheyne-Stokes respiration (50.7% +/- 12.0% to 24.2% +/- 5.4% total sleep time), mainly during stage 1 NREM (non-rapid eye movement) sleep (21.3% +/- 7.1% to 6.7% +/- 2.3% total sleep time) with no significant change during stage 2 sleep, slow-wave sleep, or REM (rapid eye movement) sleep. Although patients had normal SaO2 (96.0% +/- 1.7%) while awake, severe sleep hypoxemia was common; breathing oxygen reduced the amount of time that SaO2 was less than 90% from 22.3% +/- 8.0% to 2.41% +/- 1.93% of total sleep time. Sleep, disrupted to a variable extent in all patients, improved with oxygen therapy: There was an increase in total sleep time from 275.3 min +/- 36.6 to 324.6 min +/- 23.3; a reduction in the proportion of stage 1 sleep (27.6% +/- 5.8% total sleep time to 15.2% +/- 2.6% total sleep time); and a reduction in the number of arousals (30.4/h +/- 8.0 to 13.8/h +/- 1.9). The apnea-hypopnea index was reduced from 30.0 +/- 4.7 to 18.9 +/- 2.4 with oxygen breathing. CONCLUSION: In severe, stable congestive heart failure, nocturnal oxygen therapy reduces Cheyne-Stokes respiration, corrects hypoxemia, and consolidates sleep by reducing arousals caused by the hyperpneic phase of Cheyne-Stokes respiration. Correction of nocturnal hypoxemia and sleep disruption may improve the clinical status of these patients.