Inflammatory markers and BDNF in obstructive sleep apnea (OSA) in Parkinson's disease (PD).

OBJECTIVE: Obstructive sleep apnea (OSA) exacerbates Parkinson's disease (PD) manifestations including cognitive dysfunction. Both OSA and PD have been associated with inflammation. Brain-derived neurotrophic factor (BDNF) has been implicated in cognitive function. We aimed to investigate inflammatory cytokines and BDNF in relation to OSA and PD symptoms. METHODS: In a prospective observational study, patients with PD underwent overnight polysomnography. Morning serum levels of interleukin (IL)-1ß, IL-6, IL-8, TNFα, and BDNF were quantified at baseline (n = 64) and 6 months (n = 38). Outcomes included non-motor and motor standard scores; Montreal Cognitive Assessment (MoCA); and Epworth Sleepiness scale (ESS). Associations were assessed using linear regression, adjusting for age, sex and body mass index. RESULTS: At baseline, IL-6 was associated with the Apnea-Hypopnea Index (ß = 0.013, p = 0.03), and the Oxygen Desaturation Index (ß = 0.028, p = 0.002). No other associations between cytokines and sleep parameters were found. Motor dysfunction was associated with IL-6 (ß = 0.03, p = 0.001). ESS was associated non-significantly with IL-6 (ß = 0.04, p = 0.07) and BDNF (ß = 555, p = 0.06). At follow-up, change in IL-6 was associated with change in non-motor (ß = 0.08, p = 0.007), and motor (ß = 0.03, p = 0.001) symptoms. Change in BDNF was associated with change in ESS (ß = 1450, p = 0.02). INTERPRETATION: We found an association between IL-6 levels and both OSA severity and PD motor dysfunction. At follow-up, increasing IL-6 correlated with deterioration of motor and non-motor PD symptoms. Increasing BDNF correlated with increasing sleepiness. Further work with a larger sample size is needed, but our results support the hypothesis that OSA-related inflammation plays a role in PD manifestations and progression.

High false-positive rate of questionnaire-based restless legs syndrome diagnosis in multiple sclerosis.

BACKGROUND/OBJECTIVES: Restless legs syndrome (RLS) is diagnosed by self-reported symptoms. Multiple sclerosis (MS) patients have disease-related symptoms which could mimic RLS. This study assessed the: (1) false-positive rate for questionnaire-based RLS diagnosis in MS patients and (2) utility of periodic leg movements during wakefulness (PLMW) on overnight polysomnography (PSG) in identifying true-positive RLS patients. METHODS: Ambulatory MS patients without known sleep disorders were recruited. Subjects completed the International RLS Study Group (IRLSG) diagnostic questionnaire (IRLDQ) and underwent full overnight PSG. IRLDQ-positive patients underwent clinical evaluation to confirm the diagnosis and completed the RLS severity scale (IRLS). RESULTS: Seventy-one MS patients (mean age 46.8 ± 10.4 years) were evaluated. Thirty-eight had a positive IRLDQ. RLS diagnosis was confirmed in 22, yielding a false-positive rate of 42% [95% confidence interval (CI) 26-59%], predominantly attributable to paresthesiae (n = 7), and cramps and/or muscle spasms (n = 4). IRLS scores were not significantly different between subjects with confirmed and nonconfirmed RLS. The PLMW index was significantly higher in patients with confirmed RLS (55.4 ± 41.9 vs. 29.7 ± 18.8, p = 0.03). The sensitivity of a PLMW index >70/h for true-positive IRLDQ was 8/22 = 36%, 95% CI: 17.2-59.3, and the specificity was 16/16 = 100%, 95% CI: 79.4-100. CONCLUSIONS: MS patients have a high false-positive rate of RLS diagnosis using a standardized questionnaire largely attributable to MS-related sensorimotor symptoms. While detailed clinical evaluation is essential for confirming RLS diagnosis, the PLMW index may provide useful adjunctive information.

Impact of sleep disorder treatment on fatigue in multiple sclerosis.

BACKGROUND: We recently reported that sleep disorders are significantly associated with fatigue in multiple sclerosis (MS). OBJECTIVE: The objective of this paper is to assess the effects of sleep disorder treatment on fatigue and related clinical outcomes in MS. METHODS: This was a controlled, non-randomized clinical treatment study. Sixty-two MS patients completed standardized questionnaires including the Fatigue Severity Scale (FSS), Multidimensional Fatigue Inventory (MFI), Epworth Sleepiness scale (ESS) and Pittsburgh Sleep Quality Index (PSQI), and underwent polysomnography (PSG). Patients with sleep disorders were offered standard treatment. Fifty-six subjects repeated the questionnaires after ≥ three months, and were assigned to one of three groups: sleep disorders that were treated (SD-Tx, n=21), sleep disorders remaining untreated (SD-NonTx, n=18) and no sleep disorder (NoSD, n=17). RESULTS: FSS and MFI general and mental fatigue scores improved significantly from baseline to follow-up in SD-Tx (p <0.03), but not SD-NonTx or NoSD subjects. ESS and PSQI scores also improved significantly in SD-Tx subjects (p <0.001). Adjusted multivariate analyses confirmed significant effects of sleep disorder treatment on FSS (-0.87, p = 0.005), MFI general fatigue score (p = 0.034), ESS (p = 0.042) and PSQI (p = 0.023). CONCLUSION: Treatment of sleep disorders can improve fatigue and other clinical outcomes in MS.

Obstructive sleep apnea is associated with fatigue in multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) patients often suffer from fatigue. OBJECTIVE: We evaluated the relationship of obstructive sleep apnea (OSA) to fatigue and sleepiness in MS patients. METHODS: Ambulatory MS patients without known sleep disorders and healthy controls underwent diagnostic polysomnography and a multiple sleep latency test (objective sleepiness measure). Fatigue was measured with the Fatigue Severity Scale (FSS) and the Multidimensional Fatigue Inventory (MFI), and subjective sleepiness by Epworth Sleepiness Scale. Covariates included age, sex, body mass index, Expanded Disability Status Scale (EDSS), depression, pain, nocturia, restless legs syndrome, and medication. RESULTS: OSA (apnea-hypopnea index ≥ 15) was found in 36 of 62 MS subjects and 15 of 32 controls. After adjusting for confounders, severe fatigue (FSS ≥ 5) and MFI-mental fatigue (>group median) were associated with OSA and respiratory-related arousals in MS, but not control subjects. Subjective and objective sleepiness were not related to OSA in either group. In a multivariate model, variables independently associated with severe fatigue in MS were severe OSA [OR 17.33, 95% CI 2.53-199.84], EDSS [OR 1.88, 95% CI 1.21-3.25], and immunomodulating treatment [OR 0.14, 95% CI 0.023-0.65]. CONCLUSIONS: OSA was frequent in MS and was associated with fatigue but not sleepiness, independent of MS-related disability and other covariates.

Sleep disorders and fatigue in multiple sclerosis: evidence for association and interaction.

Fatigue is highly prevalent in multiple sclerosis (MS). It appears to be multifactorial, with "primary" or disease-related factors involved, as well as "secondary" factors, including comorbidities. Sleep disturbances are frequent in MS as well, and often result from disease-related factors. Subjective sleep disturbances in MS have been extensively studied and have been associated with fatigue. Sleep disorders in the general population have been associated with fatigue as well. However, data on objectively diagnosed sleep disorders in MS are less conclusive. Studies of sleep in MS have often suffered from low numbers of study subjects and suboptimal methodology. We review the current knowledge on sleep disturbances in MS and the relationship to fatigue. Data from neuroimaging studies and studies of molecular consequences of sleep disorders in the general population, with particular attention to sleep-disordered breathing (SDB), are briefly reviewed. Potential biologic interactions with MS are discussed in this context. We conclude that further studies of sleep disorders in MS are needed, to objectively establish their significance in this disease, and also to document any impact of treatment of sleep disorders on biologic and clinical outcomes such as fatigue.

Increased upper airway cytokines and oxidative stress in severe obstructive sleep apnoea.

Inflammation may contribute to upper airway pathophysiology in obstructive sleep apnoea (OSA). Our objective was to compare upper airway pro-inflammatory cytokine expression, oxidative stress and connective tissue deposition in severe (n = 25) versus mild (n = 17) OSA patients. Upper airway surgical specimens were separated by predominance of either mucosal or muscle tissue. Expression levels of interleukin (IL)-1α, IL-6, interferon-γ, RANTES (regulated on activation, normal T-cell expressed and secreted), transforming growth factor (TGF)-ß and l-selectin were measured by ribonuclease protection assay. Oxidative stress was assessed via protein carbonyl group detection by immunoblotting. Histochemistry was employed for immunolocalisation of selected cytokines and connective tissue morphometry. In the severe OSA group, expression of IL-1α, IL-6 and TGF-ß was significantly higher in mucosa-predominant tissues, whereas in muscle-predominant specimens, RANTES expression was greater in severe OSA. Increased protein carbonylation was observed in severe OSA within both mucosal and muscle compartments. Immunohistochemistry localised TGF-ß to submucosal and perimuscular inflammatory cells, while IL-6 was primarily localised to myocytes. Consistent with the pro-fibrotic cytokine profile observed in mucosa-predominant tissue, morphometric analysis revealed greater submucosal and perimuscular connective tissue in severe OSA subjects. There is increased pro-inflammatory and pro-fibrotic cytokine expression, oxidative stress, and connective tissue deposition in upper airway tissues from severe versus mild OSA patients.

Shift in sleep apnoea type in heart failure patients in the CANPAP trial.

In patients with heart failure (HF), the predominant type of sleep apnoea can change over time in association with alterations in circulation time. The aim of this study was to determine whether, in some patients with HF, a spontaneous shift from mainly central (>50% central events) to mainly obstructive (>50% obstructive events) sleep apnoea (CSA and OSA, respectively) over time coincides with improvement in left ventricular ejection fraction (LVEF). Therefore, sleep studies and LVEFs of HF patients with CSA from the control arm of the Canadian Continuous Positive Airway Pressure for Patients with Central Sleep Apnea and Heart Failure (CANPAP) trial were examined to determine whether some converted to mainly OSA and, if so, whether this was associated with an increase in LVEF. Of 98 patients with follow-up sleep studies and LVEFs, 18 converted spontaneously to predominantly OSA. Compared with those in the nonconversion group, those in the conversion group had a significantly greater increase in the LVEF (2.8% versus -0.07%) and a significantly greater fall in the lung-to-ear circulation time (-7.6 s versus 0.6 s). In patients with HF, spontaneous conversion from predominantly CSA to OSA is associated with an improvement in left ventricular systolic function. Future studies will be necessary to further examine this relationship.

Obstructive sleep apnoea and its association with gestational hypertension.

Hypertension develops in 10% of pregnancies. Snoring, a marker of obstructive sleep apnoea, is a newly identified risk factor for gestational hypertension. Moreover, obstructive sleep apnoea is an independent risk factor for incident hypertension in the non-pregnant population. The aim of the present study was to test the hypothesis that obstructive sleep apnoea is associated with new onset of hypertension among pregnant females. A case-control study was performed involving 17 pregnant females with gestational hypertension and 33 pregnant females without hypertension. Subjects were frequency-matched for gestational age and recruited in a tertiary obstetrical centre. Obstructive sleep apnoea was ascertained by polysomnography and defined by an apnoea/hypopnoea index (AHI) of >or=15 events x h(-1), without requirement for desaturation. The mean+/-sd AHI for normotensive pregnant females was 18.2+/-12.2 events x h(-1) compared with 38.6+/-36.7 events x h(-1) for females with hypertensive pregnancies. The crude odds ratio for the presence of obstructive sleep apnoea given the presence of gestational hypertension was 5.6. The odds ratio was 7.5 (95% confidence interval 3.5-16.2), based on a logistic regression model with adjustment for maternal age, gestational age, pre-pregnancy body mass index, prior pregnancies, and previous live births. In conclusion, gestational hypertension appears to be strongly associated with the presence of obstructive sleep apnoea.

Efficacy of daytime continuous positive airway pressure titration in severe obstructive sleep apnoea.

The aim of this study was to evaluate manual nasal continuous positive airway pressure (nCPAP) titration during daytime polysomnography compared with conventional overnight titration for patients with severe obstructive sleep apnoea. Thirty-two patients who underwent daytime titration were retrospectively matched (for age, sex, body mass index and apnoea/hypopnoea index (AHI)) to a group titrated overnight during the same period. Successful titration was defined as the identification of the nCPAP level (effective nCPAP (Peff)) required to eliminate respiratory events during all sleep stages. After 3 months of therapy on nCPAP at Peff, nCPAP utilization history was obtained and a group of patients underwent a repeat polysomnogram (PSG) and completed a follow-up Epworth Sleepiness Scale (ESS) score. Initial titration was successful in 91% of daytime patients and 91% of overnight patients. The success of daytime titration was not related to diagnostic AHI or ESS score. Subjective nCPAP utilization was statistically similar in both groups. On the follow-up PSG, there were no significant differences between daytime (n=11) and overnight (n=11) patients in measures of sleep quality or respiratory disturbance. Both groups demonstrated similar and significant improvements in ESS score. These findings suggest that the effective nasal continuous positive airway pressure can be accurately established during daytime titration in a substantial proportion of severe, symptomatic obstructive sleep apnoea patients.

Upper airway sensation in snoring and obstructive sleep apnea.

Previous studies indicate that upper airway (UA) sensory receptors play a role in the maintenance of UA patency and contribute to arousal in response to airway occlusion. An impairment of UA sensory function could therefore predispose to UA obstruction during sleep. We hypothesized that UA sensation is impaired in obstructive sleep apnea (OSA), and that sensation improves after treatment with nasal continuous positive airway pressure (CPAP). We measured two-point discrimination (2PD) and vibratory sensation thresholds (VT) in 37 patients with OSA (mean [+/- SE] apnea- hypopnea index [AHI] = 39 +/- 5 events/h), 12 nonapneic snorers (SN), and 15 control subjects (CL). Sensory thresholds were determined in the UA and on the lip and hand as control sites. Both 2PD and VT were similar among the three groups at the lip and hand sites but were significantly reduced in the UA of OSA and SN subjects versus CL (p < 0.05). Values for 2PD and VT in the UA of OSA versus SN were not significantly different. Sensory measures were repeated after 6 mo in 23 OSA patients treated with CPAP as well as in 18 untreated patients. Thresholds for 2PD and VT at control sites remained identical in both groups, as did 2PD for the UA. However, VT in the UA showed a significant improvement in treated (4.4 +/- 0.2 pre-CPAP versus 3.8 +/- 0.2 mm post-CPAP, p < 0.05) but not untreated patients. These findings indicate the presence of a selective impairment in the detection of mechanical stimuli in the UA of patients with OSA and SN, which is partially reversible after treatment with nasal CPAP in patients with OSA.

Accuracy of oximetry with thermistor (OxiFlow) for diagnosis of obstructive sleep apnea and hypopnea.

OBJECTIVES: To evaluate the diagnostic accuracy for obstructive sleep apnea and hypopnea (OSAH) of the OxiFlow (OF) device which combines oximetry with recording of thermistor airflow. DESIGN & SETTING: Patients scheduled for overnight diagnostic polysomnography (PSG) were studied with OF either simultaneously during laboratory PSG (L-OF, n=86), at home on a separate night (H-OF, n=66), or both (n=55). PATIENTS: 97 patients with suspected OSAH, of whom 40 had OSAH defined as an apnea-hypopnea index (AHI) of more than 15 events per hour of sleep on PSG. INTERVENTIONS: NA. MEASUREMENTS & RESULTS: The automated respiratory disturbance index (RDI) generated by the OF software considerably underestimated the AHI by PSG for both L-OF and H-OF. Altering the parameters for hypopnea identification by the software did not improve this. Visual inspection of the computerized OF tracings added considerable diagnostic information, but a manual count of RDI during visual review overestimated AHI. For the identification of cases vs. non-cases of OSAH, receiver operating characteristic area-under-the-curve statistics ranged from 0.77-0.90 for L-OF and from 0.71-0.77 for H-OF. Combining automated analysis with subsequent visual inspection of OF tracings yielded an overall sensitivity of 86% and specificity of 74% for the diagnosis of OSAH during H-OF recordings. Analysis of potential technician time saved indicated a benefit from the use of OF. CONCLUSIONS: OF has diagnostic utility for the identification of OSAH. However, because of hardware and software limitations, it is unclear whether this device is superior to oximetry alone.

Treatment of obstructive airway disease with a cysteine donor protein supplement: a case report.

Oxidant/antioxidant imbalance can occur in obstructive airways disease as a result of ongoing inflammation. Glutathione (GSH) plays a major role in pulmonary antioxidant protection. As an alternative or complement to anti-inflammatory therapy, augmenting antioxidant protection could diminish the effects of inflammation. We describe a case of a patient who had obstructive lung disease responsive to corticosteroids, and low whole blood GSH levels. After 1 month of supplementation with a whey-based oral supplement designed to provide GSH precursors, whole blood GSH levels and pulmonary function increased significantly and dramatically. The potential for such supplementation in pulmonary inflammatory conditions deserves further study.

Sleep architecture in a canine model of obstructive sleep apnea.

Obstructive sleep apnea (OSA) causes recurrent sleep disruption that is thought to contribute to excessive daytime sleepiness in patients with this disorder. The purpose of this study was to determine the specific effects of OSA on overall sleep architecture in a canine model of OSA. The advantage of this model is that sleep during long-term OSA can be compared to both normal sleep before OSA and recovery sleep after OSA. Studies were performed in four dogs in which sleep-wake state was monitored continuously by a computer that received telemetered EEG and EMG signals. Whenever sleep was detected, the computer sent a signal to close a valve through which the dog breathed; when the dog awoke the occlusion was released. In each dog, data were analyzed from 4 consecutive nights in three phases: a control phase before induction of OSA, a phase during long-term OSA (mean = 85 days, apnea index = 59/hour), and a recovery phase after cessation of OSA. During recovery there was a significant increase in the amount of rapid-eye-movement (REM) sleep compared to the OSA phase (p < 0.01), as well as significant increases in sleep efficiency and decreases in wakefulness (p < 0.01), similar to that reported in OSA patients. The REM rebound during recovery, however, could not be attributed to overall REM deprivation since the amount of REM sleep during the OSA phase was not different from the control phase (p = 0.708). This finding suggests that REM rebound during recovery from OSA is not the result of an overall REM sleep deficit per se. Rather, repeated sleep disruption due to the effects of repetitive apneas and hypoxia may lead to an increased REM sleep drive that manifests itself as a REM sleep rebound during recovery sleep after OSA.

Ventilatory and arousal responses to hypoxia and hypercapnia in a canine model of obstructive sleep apnea.

We have previously described a canine model of obstructive sleep apnea (OSA) in which sleep-wake state is monitored continuously by a computer that produces tracheal occlusion when sleep occurs. Our aim was to assess the effects of long-term application of this model on resting ventilation and on the ventilatory and arousal responses to hypercapnia and hypoxia. Five dogs were maintained on the model for 15.5 +/- 1.7 (mean +/- SE) wk, with a mean apnea index of 57.5 +/- 4.5 occlusions/h of sleep. Resting ventilation and the ventilatory and arousal responses to progressive hypoxic and hypercapnic rebreathing were assessed during wakefulness (W) and both slow-wave (SWS) and rapid-eye-movement (REM) sleep at baseline prior to intervention, at the end of the OSA phase, and following a 1 to 3-mo recovery period. During the period of OSA there were small changes in respiratory timing at rest, but no significant changes in PCO2 or SaO2. As compared with baseline, the ventilatory response to hypoxia during OSA was strikingly reduced during W, and significantly although less markedly reduced during SWS and REM. The reduction was due to a decreased breathing frequency response to hypoxia. In addition, during OSA there was a significant decrease from baseline in SaO2 at arousal during hypoxic rebreathing in both SWS and REM. All responses returned to normal during recovery. In contrast to hypoxia, hypercapnic ventilatory responses during OSA were slightly increased over their baseline values both in W and SWS, owing to a leftward shift of the ventilation-versus-PCO2 relationship. During recovery, these responses reverted partly to baseline for W and reverted completely to baseline for SWS. There were no significant changes in arousal PCO2 during hypercapnic rebreathing in either SWS or REM across the pre-OSA baseline, OSA, and post-OSA recovery periods. We conclude that long-term application of the OSA model is associated with a selective, reversible decrease in ventilatory and arousal responses to hypoxia.

Effect of obstructive sleep apnea versus sleep fragmentation on responses to airway occlusion.

Although the acute physiologic responses to apnea in patients with obstructive sleep apnea (OSA) have been well documented, the changes in these responses over the course of the disease have not been investigated. The purpose of this study was to use a canine model of OSA to examine the long-term effects of sleep apnea on the acute responses to airway occlusion during sleep. Four dogs were studied during a control period before induction of OSA, during a period of OSA (83-133 d), and following cessation of OSA. At least 6 mo after completion of the OSA protocol, the dogs were re-studied on a sleep fragmentation protocol (30-60 d) to determine the impact of a similar degree of sleep disruption, without OSA, on the acute responses to airway occlusion. OSA and sleep fragmentation both resulted in lengthening of the time to arousal in response to acute airway occlusion (p < 0.02) and in greater arterial oxygen desaturation (p < 0.05), peak inspiratory pressures (p < 0.003), and surges in maximum systolic and diastolic blood pressure during airway occlusion (p < 0.01). There were no differences between the changes observed during OSA and during sleep fragmentation. We conclude that the changes in the acute responses to airway occlusion resulting from OSA are primarily the result of the associated sleep fragmentation.

Lack of evidence for diaphragmatic fatigue over the course of the night in obstructive sleep apnoea.

The aim of this study was to determine whether diaphragmatic fatigue develops over the course of the night in patients with obstructive sleep apnoea (OSA). Patients with severe OSA underwent overnight polysomnography with the addition of gastric and oesophageal catheters for measurement of transdiaphragmatic pressure (Pdi) (n = 7) and a gastro-oesophageal electrode for determination of diaphragmatic electromyogram (EMGdi) (n = 5). Analyses of Pdi and EMGdi were performed to detect fatigue during the large inspiratory efforts at the end of apnoeas in Stage 2 sleep at the beginning and end of the night. Measurements included Pdi values, shape analysis of the Pdi waveform, the relaxation rate (tau R) of Pdi, EMGdi and its relationship to Pdi, and the centroid frequency (fc) of EMGdi. End of apnoeic Pdi and EMGdi increased from the beginning to end of the night (e.g. 19 +/- 14% increase in Pdi; p < 0.05). The rate of increase in Pdi and EMGdi during apnoeas did not change. The Pdi versus EMGdi relationship was linear, and remained unchanged over the course of the night. There was no significant change in the shape of the Pdi waveform, and there were no changes in tau R from the beginning to the end of the night (0.13 +/- 0.01 s for both periods). There was also no shift in the fc of the EMGdi power spectrum (94 +/- 5 vs 93 +/- 6 Hz; NS), and no change in the relationship of fc to Pdi or EMGdi from the beginning to the end of the night. These findings do not support the development of diaphragmatic fatigue over the course of the night in obstructive sleep apnoea.

Effect of topical upper airway anesthesia on apnea duration through the night in obstructive sleep apnea.

It has previously been reported that the duration of obstructive apneas increases from the beginning to the end of the night (M. Charbonneau, J. M. Marin, A. Olha, R. J. Kimoff, R. D. Levy, and M. Cosio. Chest 106: 1695-1701, 1994). The purpose of this study was to test the hypothesis that stimulation of upper airway (UA) sensory receptors during obstructed inspiratory efforts contributes to arousal and apnea termination and that a progressive attenuation of this mechanism through the night contributes to apnea lengthening. We studied seven patients (six men, one woman) with severe obstructive sleep apnea (apnea-hypopnea index = 93 +/- 26 events/h) during two consecutive nights of polysomnographic monitoring. On one night (random order), we performed topical UA anesthesia with 0.2% tetracaine and on the control night, sham anesthesia. We measured apnea duration, esophageal pressure (Pes) during apneas, and apneic O2 desaturation. Consistent with previous findings, apnea duration, number of efforts per apnea, and peak Pes at end apnea increased from the beginning to the end of the control nights. UA anesthesia produced a significant increase in apnea duration at the beginning of the night but no change in apnea length at the end of the night. Peak Pes and the rate of increase in Pes during the anesthesia nights were greater than during control nights, but the rate of increase in Pes was similar for the beginning and end of the control and anesthesia nights. These findings suggest that UA sensory receptors play a role in mediating apnea termination at the beginning of the night but that the contribution of these receptors diminishes as the night progresses such that greater inspiratory efforts are required to trigger arousal, leading to apnea prolongation.

Sleep fragmentation in obstructive sleep apnea.

Obstructive sleep apnea is associated with fragmentation of sleep due to the repeated occurrence of end-apneic arousal throughout the night. Arousals are provoked by stimuli generated during upper airway obstruction. Mechanoreceptor stimuli produced during obstructed inspiratory efforts appear to play a major role in mediating the end-apneic arousal response. The sleep disruption resulting from repeated arousals plays a major role in the pathogenesis of most of the consequences of OSA (i.e. neuropsychiatric, respiratory, and cardiovascular) and may contribute to the progression of OSA severity. However, the relative contribution of sleep fragmentation versus hypoxia in producing these complications and the precise mechanisms require further studies to be elucidated. A recently developed animal model of long-term repeated airway occlusion during sleep and a modification of the model to produce isolated sleep fragmentation should provide important new insights in this field. Treatment of the sleep disruption owing to OSA is achieved by minimizing the occurrence of arousal-promoting stimuli. This is obtained by maintaining upper airway patency during sleep.

Mechanism of apnea lengthening across the night in obstructive sleep apnea.

We have previously shown in patients with obstructive sleep apnea (OSA) that the length of apneas increases from the beginning to the end of the night (Chest 1994;106:1695-1701). To investigate this, in light of recent evidence that neural feedback related to inspiratory effort during apneas plays an important role in apnea termination (Am. J. Respir. Crit. Care Med. 1994;149:707-714), we measured transdiaphragmatic pressure (Pdi) and the diaphragm tension-time index (TTdi = Pdi/Pdi(max)) Ti/Ttot) during overnight polysomnography in seven male subjects with severe OSA (mean apnea-hypopnea index [AHI] = 64.1 +/- 8.8 [SD] events/h). We assessed apnea duration, SaO2, and inspiratory effort during apneas at the start and end of the night in Stage 2 sleep. Mean apnea duration increased from 26.6 +/- 2.0 s (SEM) to 32.6 =/- 2.5 s (p < 0.05). The rate of fall in SaO2 during apneas decreased, and end-apneic SaO2 remained unchanged across the night, suggesting a possible role for metabolic factors in mediating the increase in apnea duration. Both Pdi and TTdi at end-apnea just prior to arousal increased significantly from the beginning to the end of the night (e.g., Pdi from 41.0 +/- 4.9 to 49.9 +/- 7.9 cm H20; p < 0.05). These findings, together with those in previous studies, suggest that there is a blunting over the night of the arousal response to neural stimuli produced during obstructed inspiratory effort, which plays a major role in mediating apnea lengthening across the night in OSA.