Protocol design and synopsis: Omalizumab as Monotherapy and as Adjunct Therapy to Multiallergen OIT in Children and Adults with Food Allergy (OUtMATCH).

Background: Food allergy is common and causes substantial morbidity and even mortality. Safe and effective treatments for food allergy would therefore be highly desirable, especially for individuals with multiple food allergies. Objectives: Our aim was to describe a phase 3 study on treatment of patients with multiple food allergies with omalizumab. Methods: The study was developed as a collaboration between the Consortium for Food Allergy Research, the National Institute of Allergy and Infectious Diseases, and 2 industry sponsors (Genentech and Novartis). Results: The study is currently under way, enrolling participants from age 1 year to age 55 years who are allergic to peanut and at least 2 other foods (including milk, egg, wheat, cashew, hazelnut, and walnut). The study is designed to address 3 major questions. First, stage 1 will study the potential value of omalizumab for the treatment of patients with peanut allergy and at least 2 other common food allergens. Second, stage 2 will directly compare treatment of patients with multifood allergies using omalizumab as monotherapy versus treatment with omalizumab-facilitated multiallergen oral immunotherapy in which omalizumab is used as an adjunctive treatment. Third, stage 3 will address the longer-term outcomes following these treatment approaches, including the introduction of dietary forms of the study foods to induce or maintain desensitization. Conclusions: This phase 3 study will provide important information on the potential of omalizumab to treat patients with multiple food allergies.

Pregnancy outcomes in the omalizumab pregnancy registry and a disease-matched comparator cohort.

BACKGROUND: The Observational Study of the Use and Safety of Xolair (omalizumab) during Pregnancy (EXPECT) pregnancy registry was a prospective observational study established in 2006 to evaluate perinatal outcomes in pregnant women exposed to omalizumab and their infants. OBJECTIVE: This analysis compares EXPECT outcomes with those from a disease-matched population of pregnant women not treated with omalizumab. Data from a substudy of platelet counts among newborns are also presented. METHODS: The EXPECT study enrolled 250 women with asthma exposed to omalizumab during pregnancy. The disease-matched external comparator cohort of women with moderate-to-severe asthma (n = 1153), termed the Quebec External Comparator Cohort (QECC), was created by using data from health care databases in Quebec, Canada. Outcome estimates were age adjusted based on the maternal age distribution of the EXPECT study. RESULTS: Among singleton infants in the EXPECT study, the prevalence of major congenital anomalies was 8.1%, which was similar to the 8.9% seen in the QECC. In the EXPECT study 99.1% of pregnancies resulted in live births, which was similar to 99.3% in the QECC. Premature birth was identified in 15.0% of EXPECT infants and 11.3% in the QECC. Small for gestational age was identified in 9.7% of EXPECT infants and 15.8% in the QECC. CONCLUSION: There was no evidence of an increased risk of major congenital anomalies among pregnant women exposed to omalizumab compared with a disease-matched unexposed cohort. Given the observational nature of this registry, however, an absence of increased risk with omalizumab cannot be definitively established.

Effect of montelukast or salmeterol added to inhaled fluticasone on exercise-induced bronchoconstriction in children.

OBJECTIVES: To evaluate the effect of montelukast, 5 mg, or inhaled salmeterol, 50 microg, added to inhaled fluticasone in reducing the maximum percentage decrease in forced expiratory volume in 1 second (FEV1) after a standardized exercise challenge and response to rescue bronchodilation with albuterol in children aged 6 to 14 years with persistent asthma and exercise-induced bronchoconstriction (EIB). METHODS: Randomized, double-blind, double-dummy, multicenter, 2-period, 4-week, crossover study conducted between December 22, 2005 and November 14, 2008 at 30 centers in Europe, Asia, Mexico, and South America. Patients with asthma receiving inhaled corticosteroids demonstrated an FEV1 of 70% or higher of the predicted value and EIB (defined as a decrease in FEV1 > or = 15% compared with preexercise baseline FEV1 on 2 occasions before randomization). Standardized exercise challenges were performed at baseline (prerandomization) and at the end of each active treatment period. RESULTS: Of 154 patients randomized, 145 completed the study. Montelukast, compared with salmeterol, significantly reduced the mean maximum percentage decrease in FEV1 (10.6% vs 13.8%; P = .009), mean area under the curve for the first 20 minutes after exercise (116.0% x min vs 168.8% x min; P = .006), and median time to recovery (6.0 vs 11.1 minutes; P = .04). Response to albuterol rescue after exercise challenge was significantly greater (P < .001) with montelukast. Montelukast and salmeterol were generally well tolerated. CONCLUSIONS: Attenuation and response of EIB to albuterol rescue after exercise challenge were significantly better with montelukast than with salmeterol after 4 weeks of treatment.

Genioglossal muscle response to CO2 stimulation during NREM sleep.

STUDY OBJECTIVES: The objective was to evaluate the responsiveness of upper airway muscles to hypercapnia with and without intrapharyngeal negative pressure during non-rapid eye movement (NREM) sleep and wakefulness. DESIGN: We assessed the genioglossal muscle response to CO2 off and on continuous positive airway pressure (CPAP) (to attenuate negative pressure) during stable NREM sleep and wakefulness in the supine position. SETTING: Laboratory of the Sleep Medicine Division, Brigham and Women's Hospital. PATIENTS OR PARTICIPANTS: Eleven normal healthy subjects. INTERVENTIONS: During wakefulness and NREM sleep, we measured genioglossal electromyography (EMG) on and off CPAP at the normal eupneic level and at levels 5 and 10 mm Hg above the awake eupneic level. MEASUREMENTS AND RESULTS: We observed that CO2 could increase upper-airway muscle activity during NREM sleep and wakefulness in the supine position with and without intrapharyngeal negative pressure. The application of nasal CPAP significantly decreased genioglossal EMG at all 3 levels of PETCO2 during NREM sleep (13.0 +/- 4.9% vs. 4.6 +/- 1.6% of maximal EMG, 14.6 +/- 5.6% vs. 7.1 +/- 2.3% of maximal EMG, and 17.3 +/- 6.3% vs. 10.2 +/- 3.1% of maximal EMG, respectively). However, the absence of negative pressure in the upper airway did not significantly affect the slope of the pharyngeal airway dilator muscle response to hypercapnia during NREM sleep (0.72 +/- 0.30% vs. 0.79 +/- 0.27% of maximal EMG per mm Hg PCO2, respectively, off and on CPAP). CONCLUSIONS: We conclude that both chemoreceptive and negative pressure reflex inputs to this upper airway dilator muscle are still active during stable NREM sleep.

Tonic and phasic respiratory drives to human genioglossus motoneurons during breathing.

A tongue muscle, the genioglossus (GG), is important in maintaining pharyngeal airway patency. Previous recordings of multiunit electromyogram (EMG) suggest it is activated during inspiration in humans with some tonic activity in expiration. We recorded from populations of single motor units in GG in seven subjects during quiet breathing when awake. Ultrasonography assisted electrode placement. The activity of single units was separated into six classes based on a step-wise analysis of the discharge pattern. Phasic and tonic activities were analyzed statistically with the coefficient of determination (r2) between discharge frequency and lung volume. Of the 110 motor units, 29% discharged tonically without phasic respiratory modulation (firing rate approximately 19 Hz). Further, 16% of units increased their discharge during expiration (expiratory phasic and expiratory tonic units). Only half the units increased their discharge during inspiration (inspiratory phasic and inspiratory tonic units). Units firing tonically with an inspiratory increase had significantly higher discharge rates than those units that only fired phasically (peak rates 25 vs. 16 Hz, respectively). Simultaneous recordings of two or three motor units showed neighboring units with differing respiratory and tonic drives. Our results provide a classification and the first quantitative measures of human GG motor-unit behavior and suggest this activity results from a complex interaction of inspiratory, expiratory, and tonic drives at the hypoglossal motor nucleus. The presence of different drives to GG implies that complex premotor networks can differentially engage human hypoglossal motoneurons during respiration. This is unlike the ordered recruitment of motor units in limb and axial muscles.

Respiratory control stability and upper airway collapsibility in men and women with obstructive sleep apnea.

Obstructive sleep apnea (OSA) is two to three times more common in men as in women. The mechanisms leading to this difference are currently unclear but could include gender differences in respiratory stability [loop gain (LG)] or upper airway collapsibility [pharyngeal critical closing pressure (Pcrit)]. The aim of this study was to compare LG and Pcrit between men and women with OSA to determine whether the factors contributing to apnea are similar between genders. The first group of 11 men and 11 women were matched for OSA severity (mean +/- SE apnea-hypopnea index = 43.8 +/- 6.1 and 44.1 +/- 6.6 events/h). The second group of 12 men and 12 women were matched for body mass index (BMI; 31.6 +/- 1.9 and 31.3 +/- 1.8 kg/m2, respectively). All measurements were made during stable supine non-rapid eye movement sleep. LG was determined using a proportional assist ventilator. Pcrit was measured by progressively dropping the continuous positive airway pressure level for three to five breaths until airway collapse. Apnea-hypopnea index-matched women had a higher BMI than men (38.0 +/- 2.4 vs. 30.0 +/- 1.9 kg/m2; P = 0.03), but LG and Pcrit were similar between men and women (LG: 0.37 +/- 0.02 and 0.37 +/- 0.02, respectively, P = 0.92; Pcrit: 0.35 +/- 0.62 and -0.18 +/- 0.87, respectively, P = 0.63). In the BMI-matched subgroup, women had less severe OSA during non-rapid eye movement sleep (30.9 +/- 7.4 vs. 52.5 +/- 8.1 events/h; P = 0.04) and lower Pcrit (-2.01 +/- 0.62 vs. 1.16 +/- 0.83 cmH2O; P = 0.005). However, LG was not significantly different between genders (0.38 +/- 0.02 vs. 0.33 +/- 0.03; P = 0.14). These results suggest that women may be protected from developing OSA by having a less collapsible upper airway for any given degree of obesity.

Lung volume and continuous positive airway pressure requirements in obstructive sleep apnea.

Previous studies have demonstrated that lung volume during wakefulness influences upper airway size and resistance, particularly in patients with sleep apnea. We sought to determine the influence of lung volume on the level of continuous positive airway pressure (CPAP) required to prevent flow limitation during non-REM sleep in subjects with sleep apnea. Seventeen subjects (apnea-hypopnea index, 42.6 +/- 6.2 [SEM]) were studied during stable non-REM sleep in a rigid head-out shell equipped with a positive/negative pressure attachment for manipulation of extrathoracic pressure. An epiglottic pressure catheter plus a mask/pneumotachometer were used to assess flow limitation. When lung volume was increased by 1,035 +/- 22 ml, the CPAP level could be decreased from 11.9 +/- 0.7 to 4.8 +/- 0.7 cm H(2)O (p < 0.001) without flow limitation. The decreased CPAP at the same negative extrathoracic pressure yielded a final lung volume increase of 421 +/- 36 ml above the initial value. Conversely, when lung volume was reduced by 732 +/- 74 ml (n = 8), the CPAP level had to be increased from 11.9 +/- 0.7 to 17.1 +/- 1.0 cm H(2)O (p < 0.001) to prevent flow limitation, with a final lung volume decrease of 567 +/- 78 ml. These results demonstrate that relatively small changes in lung volume have an important effect on the upper airway in subjects with sleep apnea during non-REM sleep.

The effect of sleep onset on upper airway muscle activity in patients with sleep apnoea versus controls.

Pharyngeal dilator muscles are important in the pathophysiology of obstructive sleep apnoea syndrome (OSA). We have previously shown that during wakefulness, the activity of both the genioglossus (GGEMG) and tensor palatini (TPEMG) is greater in patients with OSA compared with controls. Further, EMG activity decreases at sleep onset, and the decrement is greater in apnoea patients than in healthy controls. In addition, it is known that the prevalence of OSA is greater in middle-aged compared with younger men. Thus, we had two goals in this study. First we compared upper airway muscle activity between young and middle-aged healthy men compared with men with OSA. We also explored the mechanisms responsible for the decrement in muscle activity at sleep onset in these groups. We investigated muscle activity, ventilation , and upper airway resistance (UAR) during wakefulness and sleep onset (transition from alpha to EEG activity) in all three groups. Measurements were obtained during basal breathing (BB) and nasal continuous positive airway pressure (CPAP) was applied to reduce negative pressure-mediated muscle activation). We found that during wakefulness there was a gradation of GGEMG and UAR (younger < older < OSA) and that muscle activity was reduced by the application of nasal CPAP (to a greater degree in the OSA patients). Although CPAP eliminated differences in UAR during wakefulness and sleep, GGEMG remained greater in the OSA patients. During sleep onset, a greater initial fall in GGEMG was seen in the OSA patients followed by subsequent muscle recruitment in the third to fifth breaths following the alpha to transition. On the CPAP night, and GGEMG still fell further in the OSA patients compared with control subjects. CPAP prevented the rise in UAR at sleep onset along with the associated recruitment in GGEMG. Differences in TPEMG among the groups were not significant. These data suggest that the middle-aged men had upper airway function midway between that of young normal men and the abnormal airway of those with OSA. Furthermore it suggests that the initial sleep onset reduction in upper airway muscle activity is due to loss of a 'wakefulness' stimulus, rather than to loss of responsiveness to negative pressure, and that this wakefulness stimulus may be greater in the OSA patient than in healthy controls.

Assessment of automated scoring of polysomnographic recordings in a population with suspected sleep-disordered breathing.

STUDY OBJECTIVES: To assess the accuracy of an automated system (Morpheus I Sleep Scoring System) for analyzing and quantifying polysomnographic data from a population with sleep-disordered breathing. SETTING: Sleep laboratory affiliated with a tertiary care academic medical center. MEASUREMENTS AND RESULTS: 31 diagnostic polysomnograms were blindly analyzed prospectively with the investigational automated system and manually by 2 registered polysomnography technologists (M1 & M2) from the same laboratory. Sleep stages, arousals, periodic limb movements, and respiratory events (apneas and hypopneas) were scored by all 3. Agreement, Cohen kappa, and intraclass correlation coefficients were tabulated for each variable and compared between scoring pairs (A-M1, A-M2, M1-M2). The 26,876 epochs (224 hours of recording time) were analyzed. For sleep staging, agreement/kappa were A-M1: 78%/0.67, A-M2: 73%/0.61, and M1-M2: 82%/0.73. The mean respiratory disturbance indexes were M1: 20.6+/-23.0, M2: 22.5+/-24.5, and A: 23.7+/-23.4 events per hour of sleep. The respiratory disturbance index concordance between each scoring pair was excellent (intraclass correlation coefficients > or = 0.95 for all pairs), although there was disagreement in the classification of moderate sleep-disordered breathing (percentage of positive agreement: A-M1, 37.5% and A-M2, 44.4%) defined as a respiratory disturbance index between 15 and 30 events per hour of sleep. For respiratory-event detection, agreement/kappa were A-M1 and A-M2: 90%/0.66 and M1-M2: 95%/0.82. The agreement and kappa for limb movement detection were A-M1: 93%/0.68, A-M2: 92%/0.66, and M1-M2: 96%/0.77. The scoring of arousals was less reliable (agreement range: 76%-84%, kappa range: 0.28-0.57) for all pairs. CONCLUSIONS: Agreement between manual scorers in a population with moderate sleep-disordered breathing was close to the average pairwise agreement of 87% reported in the Sleep Heart Health Study. The automated classification of sleep stages was also close to this standard. The automated scoring system holds promise as a rapid method to score polysomnographic records, but expert verification of the automated scoring is required.

Using a wrist-worn device based on peripheral arterial tonometry to diagnose obstructive sleep apnea: in-laboratory and ambulatory validation.

STUDY OBJECTIVES: To assess the accuracy of a wrist-worn device (Watch_PAT 100) to diagnose obstructive sleep apnea in the home. DESIGN: Participants completed 2 overnight diagnostic studies with the test device: 1 night in the laboratory with concurrent polysomnography and 1 night in the home with only the Watch_PAT. The order of the laboratory and home study nights was random. The frequency of respiratory events on the PSG was quantified using indexes based on 2 definitions of hypopnea: the respiratory disturbance index (RDI) using American Academy of Sleep Medicine Task Force criteria for clinical research, also referred to as the Chicago criteria (RDI.C), and the Medicare guidelines (RDI.M). The Watch_PAT RDI (PAT RDI) and oxygen desaturation index (PAT ODI) were then evaluated against the polysomnography RDI.C and RDI.M, respectively, for both Watch_PAT diagnostic nights, yielding IN-LAB and HOME-LAB comparisons. SETTING: Sleep laboratory affiliated with a tertiary-care academic medical center. PATIENTS: 30 patients referred with suspected OSA. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: The polysomnography and PAT measures were compared using the mean [2 SD] of the differences and the intra-class correlation coefficient (ICC). The receiver-operator characteristic curve was used to assess optimum sensitivity and specificity and calculate likelihood ratios. For the IN-LAB comparison, there was high concordance between RDI.C and PAT RDI (ICC = 0.88, mean difference 2.5 [18.9] events per hour); RDI.M and PAT ODI (ICC = 0.95, mean difference 1.4 [12.9] events per hour; and sleep time (ICC = 0.70, mean difference 7.0 [93.1] minutes) between the test device and PSG. For the HOME-LAB comparison, there was good concordance between RDI.C and PAT RDI (ICC = 0.72, mean difference 1.4 [30.1] events per hour) and RDI.M and PAT ODI (ICC = 0.80, mean difference 1.6 [26.4] events per hour) for the test device and PSG. Home studies were performed with no technical failures. CONCLUSIONS: In a population of patients suspected of having obstructive sleep apnea, the Watch_PAT can quantify an ODI that compares very well with Medicare criteria for defining respiratory events and an RDI that compares favorably with Chicago criteria for defining respiratory events. The device can be used with a low failure rate for single use in the lab and home for self-administered testing.

Ventilatory control and airway anatomy in obstructive sleep apnea.

Ventilatory instability may play an important role in the pathogenesis of obstructive sleep apnea. We hypothesized that the influence of ventilatory instability in this disorder would vary depending on the underlying collapsibility of the upper airway. To test this hypothesis, we correlated loop gain with apnea-hypopnea index during supine, nonrapid eye movement sleep in three groups of patients with obstructive sleep apnea based on pharyngeal closing pressure: negative pressure group (pharyngeal closing pressure less than -1 cm H(2)O), atmospheric pressure group (between -1 and +1 cm H(2)O), and positive pressure group (greater than +1 cm H(2)O). Loop gain was measured by sequentially increasing proportional assist ventilation until periodic breathing developed, which occurred in 24 of 25 subjects. Mean loop gain for all three groups was 0.37 +/- 0.11. A significant correlation was found between loop gain and apnea-hypopnea index in the atmospheric group only (r = 0.88, p = 0.0016). We conclude that loop gain has a substantial impact on apnea severity in certain patients with sleep apnea, particularly those with a pharyngeal closing pressure near atmospheric.

The influence of gender and upper airway resistance on the ventilatory response to arousal in obstructive sleep apnoea in humans.

The termination of obstructive respiratory events is typically associated with arousal from sleep. The ventilatory response to arousal may be an important determinant of subsequent respiratory stability/instability and therefore may be involved in perpetuating obstructive respiratory events. In healthy subjects arousal is associated with brief hyperventilation followed by more prolonged hypoventilation on return to sleep. This study was designed to assess whether elevated sleeping upper airway resistance (R(UA)) alters the ventilatory response to arousal and subsequent breathing on return to sleep in patients with obstructive sleep apnoea (OSA). Inspired minute ventilation (V(I)), R(UA) and end-tidal CO(2) pressure (P(ET,CO(2))) were measured in 22 patients (11 men, 11 women) with OSA (mean +/-s.e.m., apnoea-hypopnoea index (AHI) 48.9 +/- 5.9 events h(-1)) during non-rapid eye movement (NREM) sleep with low R(UA) (2.8 +/- 0.3 cmH(2)O l(-1) s; optimal continuous positive airway pressure (CPAP) = 11.3 +/- 0.7 cmH(2)O) and with elevated R(UA) (17.6 +/- 2.8 cmH(2)O l(-1) s; sub-optimal CPAP = 8.4 +/- 0.8 cmH(2)O). A single observer, unaware of respiratory data, identified spontaneous and tone-induced arousals of 3-15 s duration preceded and followed by stable NREM sleep. V(I) was compared between CPAP levels before and after spontaneous arousal in 16 subjects with tone-induced arousals in both conditions. During stable NREM sleep at sub-optimal CPAP, P(ET,CO(2)) was mildly elevated (43.5 +/- 0.8 versus 42.5 +/- 0.8 Torr). However, baseline V(I) (7.8 +/- 0.3 versus 8.0 +/- 0.3 l min(-1)) was unchanged between CPAP conditions. For the first three breaths following arousal, V(I) was higher for sub-optimal than optimal CPAP (first breath: 11.2 +/- 0.9 versus 9.3 +/- 0.6 l min(-1)). The magnitude of hypoventilation on return to sleep was not affected by the level of CPAP and both obstructive and central respiratory events were rare following arousal. Similar results occurred after tone-induced arousals which led to larger responses than spontaneous arousals. V(I) for the first breath following arousal under optimal CPAP was greater in men than women (11.0 +/- 0.4 versus 7.6 +/- 0.6 l min(-1)). These results demonstrate that the ventilatory response to arousal is influenced by pre-arousal airway resistance and gender. Whether this contributes to the perpetuation of respiratory events and the pathogenesis of OSA is unclear.

The influence of lung volume on pharyngeal mechanics, collapsibility, and genioglossus muscle activation during sleep.

STUDY OBJECTIVES: Previous studies in both awake and sleeping humans have demonstrated that lung-volume changes substantially affect upper-airway size and pharyngeal resistance and, thus, may influence pharyngeal patency. We sought to systematically investigate the isolated effects of lung-volume changes on pharyngeal collapsibility and mechanics and genioglossus muscle activation during stable non-rapid eye movement sleep. We hypothesized that lower lung volumes would lead to increased pharyngeal collapsibility, airflow resistance, and, in compensation, augmented genioglossus muscle activation. DESIGN: Nineteen normal individuals (age, 30.4 +/- 0.5 years; body mass index: 24.5 +/- 0.4 kg/m2) were studied during stable non-rapid eye movement sleep in a rigid head-out shell equipped with a variable positive/negative pressure attachment for manipulations of extrathoracic pressure and, thus, lung volume. SETTING: Sleep physiology laboratory. PARTICIPANTS: Normal healthy volunteers. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: We measured change in end-expiratory lung volume (EELV) (magnetometers), genioglossus electromyogram (GGEMG) (intramuscular electrodes), pharyngeal pressure, and collapsibility of the pharynx in response to a brief pulse of negative pressure (-8 to -15 cm H2O) under the following conditions: (1) baseline, (2) increased EELV (+1 liter), and (3) decreased EELV (-0.6 liter). Reduced lung volumes led to increased inspiratory airflow resistance (7.54 +/- 2.80 cm H2O x L(-1) x s(-1) vs 4.53 +/- 1.05 cm H2O x L(-1) x s(-1), mean +/- SEM, P = 0.02) and increased genioglossus muscle activation (GGEMG peak 14.6% +/- 1.5% of maximum vs 8.6% +/- 1.5% of maximum, maximum P = 0.001) compared to baseline. The pharynx was also more collapsible at low lung volumes (4.3 +/- 0.5 cm H2O vs 5.4 +/- 0.6 cm H2O, P = 0.04). CONCLUSIONS: We conclude that upper-airway muscles respond to changes in lung volumes but not adequately to prevent increased collapsibility. These results suggest that lung volume has an important influence on pharyngeal patency during non-rapid eye movement sleep in normal individuals.

Recent advances in understanding the pathogenesis of obstructive sleep apnea.

PURPOSE OF REVIEW: The pathogenesis of obstructive sleep apnea (OSA) is incompletely understood. Historically it was believed that patients with OSA have a small upper airway (often due to obesity) that is kept patent during wakefulness by the activity of upper airway dilating muscles. With the reduction in muscle tone at sleep onset, the airway collapses and causes apnea. While this appears to be the case for many patients with OSA, other patients show no major airway anatomic defects or minimal obesity. RECENT FINDINGS: This has led to the concept that other factors such as unstable ventilatory control and changes in lung volume during sleep may be involved in the pathogenesis of OSA. Recently there have been several advances in our understanding of how these mechanisms are involved in OSA pathogenesis. SUMMARY: A more complete understanding of apnea pathogenesis may improve therapeutic techniques and reduce the consequences of OSA.

Control of upper airway muscle activity in younger versus older men during sleep onset.

Pharyngeal dilator muscles are clearly important in the pathophysiology of obstructive sleep apnoea syndrome (OSA). We have previously shown that the activity of both the genioglossus (GGEMG) and tensor palatini (TPEMG) are decreased at sleep onset, and that this decrement in muscle activity is greater in the apnoea patient than in healthy controls. We have also previously shown this decrement to be greater in older men when compared with younger ones. In order to explore the mechanisms responsible for this decrement in muscle activity nasal continuous positive airway pressure (CPAP) was applied to reduce negative pressure mediated muscle activation. We then investigated the effect of sleep onset (transition from predominantly alpha to predominantly theta EEG activity) on ventilation, upper airway muscle activation and upper airway resistance (UAR) in middle-aged and younger healthy men. We found that both GGEMG and TPEMG were reduced by the application of nasal CPAP during wakefulness, but that CPAP did not alter the decrement in activity in either muscle seen in the first two breaths following an alpha to theta transition. However, CPAP prevented both the rise in UAR at sleep onset that occurred on the control night, and the recruitment in GGEMG seen in the third to fifth breaths following the alpha to theta transition. Further, GGEMG was higher in the middle-aged men than in the younger men during wakefulness and was decreased more in the middle-aged men with the application of nasal CPAP. No differences were seen in TPEMG between the two age groups. These data suggest that the initial sleep onset reduction in upper airway muscle activity is due to loss of a 'wakefulness' stimulus, rather than to loss of responsiveness to negative pressure. In addition, it suggests that in older men, higher wakeful muscle activity is due to an anatomically more collapsible upper airway with more negative pressure driven muscle activation. Sleep onset per se does not appear to have a greater effect on upper airway muscle activity as one ages.

Pegylated interferon and ribavirin-induced interstitial pneumonitis with ARDS.

A 49-year-old man with cirrhosis due to hepatitis C virus developed interstitial pneumonitis documented by surgical lung biopsy specimen evaluation after two weekly doses of pegylated interferon-alpha(2)b in combination with ribavirin. He developed ARDS and died after 26 days of hospitalization from multisystem organ failure. This case suggests that interstitial pulmonary disease can occur with pegylated interferon-alpha(2)b therapy.

Within-breath control of genioglossal muscle activation in humans: effect of sleep-wake state.

Pharyngeal dilator muscles are clearly important in the pathogenesis of obstructive sleep apnoea syndrome. Substantial data support the role of a local negative pressure reflex in modifying genioglossal activation across inspiration during wakefulness. Using a model of passive negative pressure ventilation, we have previously reported a tight relationship between varying intrapharyngeal negative pressures and genioglossal muscle activation (GGEMG) during wakefulness. In this study, we used this model to examine the slope of the relationship between epiglottic pressure (Pepi) and GGEMG, during stable NREM sleep and the transition from wakefulness to sleep. We found that there was a constant relationship between negative epiglottic pressure and GGEMG during both basal breathing (BB) and negative pressure ventilation (NPV) during wakefulness (slope GGEMG/Pepi 1.86+/-0.3 vs. 1.79+/-0.3 arbitrary units (a.u.) cmH2O(-1)). However, while this relationship remained stable during NREM sleep during BB, it was markedly reduced during NPV during sleep (2.27+/-0.4 vs. 0.58+/-0.1 a.u. cmH2O(-1)). This was associated with a markedly higher pharyngeal airflow resistance during sleep during NPV. At the transition from wakefulness to sleep there was also a greater reduction in peak GGEMG seen during NPV than during BB. These data suggest that while the negative pressure reflex is able to maintain GGEMG during passive NPV during wakefulness, this reflex is unable to do so during sleep. The loss of this protective mechanism during sleep suggests that an airway dependent upon such mechanisms (as in the patient with sleep apnoea) will be prone to collapse during sleep.

Anatomic and physiologic predictors of apnea severity in morbidly obese subjects.

STUDY OBJECTIVES: While obesity is the most common risk factor for the development of obstructive sleep apnea, the correlation between measures of obesity and apnea severity is only moderate. We thus attempted to identify anatomic and physiologic predictors of apnea severity. DESIGN: We combined a careful assessment of upper airway anatomy, upper airway physiology, and ventilatory control in a group of obese individuals to identify predictors of apnea severity. SETTING: Tertiary care academic medical center. PATIENTS: 14 morbidly obese subjects being evaluated for weight-reduction surgery. INTERVENTIONS: N/A MEASUREMENT AND RESULTS: We found no relationship between obesity (weight or body mass index) and apnea severity (respiratory disturbance index, RDI). However, those with severe apnea (RDI > 30) were found to have higher peak genioglossus EMG (GGEMG) (23.5 +/- 1.9 vs. 14.1 +/- 3.7 %max, p = 0.05) and greater airway collapsibility during pulses of negative pressure (7.6 +/- 0.9 vs. 4.4 -/+/-0.7 cmH2O, p =0.02). Airway collapsibility was significantly associated with RDI (r = 0.62, p < 0.01) as was peak GGEMG (r = 0.55, p < 0.05). Of the anatomic variables airway shape (A-P/lateral ratio) and volume change of the pharyngeal airway between total lung capacity and residual volume were different between those with and without severe apnea. Both correlated with RDI (A-P/lateral ratio: r = 0.70, p < 0.01 and volume change: r = 0.77, p < 0.01). CONCLUSIONS: We believe these findings suggest that specific anatomic and physiologic properties of the airway interact with obesity to predispose to the development of airway collapse during sleep.