Salmeterol vs theophylline: sleep and efficacy outcomes in patients with nocturnal asthma.

STUDY OBJECTIVES: To compare the efficacy, safety, and effects on sleep quality of salmeterol and extended-release theophylline in patients with nocturnal asthma. DESIGN: Randomized, double-blind, double-dummy, three-period crossover. SETTING: Outpatients at a single center. Patients spent 1 night during screening and 2 nights during each study period in a sleep laboratory for completion of sleep studies. PATIENTS: Male and female patients who were at least 18 years old with nocturnal asthma (baseline FEV1, 50 to 90% of predicted) and who required regular bronchodilator therapy. Patients on inhaled corticosteroids, cromolyn, and nedocromil were allowed into the study if their dosing remained constant throughout the study. INTERVENTIONS: Inhaled salmeterol (42 microg per actuation), extended-release oral theophylline (titrated to serum levels of 10 to 20 microg/mL), and placebo taken twice daily. MEASUREMENTS AND RESULTS: Efficacy measurements included nocturnal spirometry, nocturnal polysomnography, sleep questionnaires, and daily measurements of lung function and symptoms. Salmeterol was superior to theophylline (p < or = 0.05) in maintaining nocturnal FEV1 levels and was superior to placebo (p < or = 0.05) in improving morning and evening peak expiratory flow (PEF) and in decreasing nighttime albuterol use. The use of salmeterol significantly increased the percentage of days and nights with no albuterol use and decreased daytime albuterol use compared with theophylline and placebo (p < or = 0.05). Sleep quality global scores significantly improved with salmeterol and placebo (p < 0.001) but not with theophylline. The effects on sleep architecture were similar across treatment groups. CONCLUSIONS: Salmeterol (but not theophylline) was associated with sustained improvements in morning PEF, protection from nighttime lung function deterioration, reductions in albuterol use, and improvements in patient perceptions of sleep. No differences were seen in polysomnographic measures of sleep quality.

Acute renal failure following immunoglobulin therapy.

Intravenous IgG infusion has infrequently been reported to cause acute renal failure. In almost all these reports, a sucrose containing IgG product was believed to be the cause of renal injury. Sucrose-induced osmotic nephrosis has been well described in the literature. In this report, we describe a case of acute anuric renal failure following a large infusion of intravenous IgG containing sucrose. Urine cytology demonstrated typical osmotic injury to the renal tubular epithelial cells. Early recovery of renal function was achieved by dialytic removal of sucrose from the circulation.

Oral appliances for the treatment of snoring and obstructive sleep apnea: a review.

This paper, which has been reviewed and approved by the Board of Directors of the American Sleep Disorders Association, provides the background for the Standards of Practice Committee's parameters for the practice of sleep medicine in North America. The 21 publications selected for this review describe 320 patients treated with oral appliances for snoring and obstructive sleep apnea. The appliances modify the upper airway by changing the posture of the mandible and tongue. Despite considerable variation in the design of these appliances, the clinical effects are remarkably consistent. Snoring is improved and often eliminated in almost all patients who use oral appliances. Obstructive sleep apnea improves in the majority of patients; the mean apnea-hypopnea index (AHI) in this group of patients was reduced from 47 to 19. Approximately half of treated patients achieved an AHI of < 10; however, as many as 40% of those treated were left with significantly elevated AHIs. Improvement in sleep quality and sleepiness reflects the effect on breathing. Limited follow-up data indicate that oral discomfort is a common but tolerable side effect, that dental and mandibular complications appear to be uncommon and that long-term compliance varies from 50% to 100% of patients. Comparison of the risk and benefit of oral appliance therapy with the other available treatments suggests that oral appliances present a useful alternative to continuous positive airway pressure (CPAP), especially for patients with simple snoring and patients with obstructive sleep apnea who cannot tolerate CPAP therapy.

Development of the bi-directional ultrasound system for base of tongue imaging.

The use of conventional ultrasound systems to image the upper airway has been limited because ultrasound energy is attenuated by the air column. In an attempt to study upper airway geometry, we developed a computer controlled bi-directional ultrasound system which combines two conventional ultrasound devices with computer image processing to yield images of upper airway structures. Human studies and cadaver studies were performed to evaluate the system. Images acquired by the bi-directional ultrasound system were comparable to images from 3D volume rendered CT scans. This system may provide valuable data in the study of upper airway physiology and pathology.

Obstructive sleep apnea.

The high prevalence of obstructive sleep apnea (OSA) has only recently been appreciated, in part because the symptoms and signs of chronic sleep disruption are often overlooked in spite of their debilitating consequences. They typically develop insidiously during a period of years. We now know that the lives of millions of people each year are significantly impaired by the sequelae of OSA. Many of these patients go unrecognized, with tremendous medical and economic consequences for individual patients and for society. Evidence indicates that chronic, heavy snoring may be associated with increased long-term cardiovascular and neurophysiologic morbidity. Therefore considerable interest lies in the study of the epidemiology and the natural history of these related disorders. The fundamental problem in OSA is the periodic collapse of the pharyngeal airway during sleep. The pathophysiology of this phenomenon is reviewed in some detail. During apneas caused by obstruction, airflow is impeded by the collapsed pharynx in spite of continued effort to breathe. This causes progressive asphyxia, which increasingly stimulates breathing efforts against the collapsed airway, typically until the person is awakened. Hypopneas predominate in some patients and are caused by partial pharyngeal collapse. The clinical sequelae of OSA relate to the cumulative effects of exposure to periodic asphyxia and to sleep fragmentation caused by apneas and hypopneas. Some patients with frequent, brief apneas and hypopneas and normal underlying cardiopulmonary function may have considerable sleep disruption without much exposure to nocturnal hypoxia. Patients with sleep apnea often have excessive daytime sleepiness. As the disorder progresses, sleepiness becomes increasingly irresistible and dangerous, and patients develop cognitive dysfunction, inability to concentrate, memory and judgment impairment, irritability, and depression. These problems may lead to family and social problems and job loss. Cardiac and vascular morbidity in OSA may include systemic hypertension, cardiac arrhythmias, pulmonary hypertension, cor pulmonale, left ventricular dysfunction, stroke, and sudden death. The challenge for the clinician is to routinely consider the diagnosis and to incorporate several basic questions in the historical review of systems regarding daytime or inappropriate sleepiness. The diagnosis of OSA is made with polysomnography, and the decision to treat is based on an overall assessment of the severity of sleep-disordered breathing, sleep fragmentation, and associated clinical sequelae. The therapeutic options for the management of OSA are reviewed. Recognition and appropriate treatment of OSA and related disorders will often significantly enhance the patient's quality of life, overall health, productivity, and safety on the highways.

The post-cardiac injury syndrome following blunt chest trauma: case report.

The case of a 53-year-old man is reported in which the patient developed post-cardiac injury syndrome 2 weeks after blunt trauma to the thorax. The patient failed to respond adequately to ibuprofen but improved on corticosteroids. He suffered relapses 8 and 15 months after the original injury following reductions in the corticosteroid dosage. The patient at last follow-up had been asymptomatic for over 4 years.

Changes in upper airway muscle activation and ventilation during phasic REM sleep in normal men.

Several investigators have observed that irregular breathing occurs during rapid-eye-movement (REM) sleep in healthy subjects, with ventilatory suppression being prominent during active eye movements [phasic REM (PREM) sleep] as opposed to tonic REM (TREM) sleep, when ocular activity is absent and ventilation more regular. Inasmuch as considerable data suggest that rapid eye movements are a manifestation of sleep-induced neural events that may importantly influence respiratory neurons, we hypothesized that upper airway dilator muscle activation may also be suppressed during periods of active eye movements in REM sleep. We studied six normal men during single nocturnal sleep studies. Standard sleep-staging parameters, ventilation, and genioglossus and alae nasi electromyograms (EMG) were continuously recorded during the study. There were no significant differences in minute ventilation, tidal volume, or any index of genioglossus or alae nasi EMG amplitude between non-REM (NREM) and REM sleep, when REM was analyzed as a single sleep stage. Each breath during REM sleep was scored as "phasic" or "tonic," depending on its proximity to REM deflections on the electrooculogram. Comparison of all three sleep states (NREM, PREM, and TREM) revealed that peak inspiratory genioglossus and alae nasi EMG activities were significantly decreased during PREM sleep compared with TREM sleep [genioglossus (arbitrary units): NREM 49 +/- 12 (mean +/- SE), TREM 49 +/- 5, PREM 20 +/- 5 (P less than 0.05, PREM different from TREM and NREM); alae nasi: NREM 16 +/- 4, TREM 38 +/- 7, PREM 10 +/- 4 (P less than 0.05, PREM different from TREM)]. We also observed, as have others, that ventilation, tidal volume, and mean inspiratory airflow were significantly decreased and respiratory frequency was increased during PREM sleep compared with both TREM and NREM sleep. We conclude that hypoventilation occurs in concert with reduced upper airway dilator muscle activation during PREM sleep by mechanisms that remain to be established.

Upper airway resistance and geniohyoid muscle activity in normal men during wakefulness and sleep.

Sleep-related reduction in geniohyoid muscular support may lead to increased airway resistance in normal subjects. To test this hypothesis, we studied seven normal men throughout a single night of sleep. We recorded inspiratory supraglottic airway resistance, geniohyoid muscle electromyographic (EMGgh) activity, sleep staging, and ventilatory parameters in these subjects during supine nasal breathing. Mean inspiratory upper airway resistance was significantly (P less than 0.01) increased in these subjects during all stages of sleep compared with wakefulness, reaching highest levels during non-rapid-eye-movement (NREM) sleep [awake 2.5 +/- 0.6 (SE) cmH2O.l-1.s, stage 2 NREM sleep 24.1 +/- 11.1, stage 3/4 NREM sleep 30.2 +/- 12.3, rapid-eye-movement (REM) sleep 13.0 +/- 6.7]. Breath-by-breath linear correlation analyses of upper airway resistance and time-averaged EMGgh amplitude demonstrated a significant (P less than 0.05) negative correlation (r = -0.44 to -0.55) between these parameters in five of seven subjects when data from all states (wakefulness and sleep) were combined. However, we found no clear relationship between normalized upper airway resistance and EMGgh activity during individual states (wakefulness, stage 2 NREM sleep, stage 3/4 NREM sleep, and REM sleep) when data from all subjects were combined. The timing of EMGgh onset relative to the onset of inspiratory airflow did not change significantly during wakefulness, NREM sleep, and REM sleep. Inspiratory augmentation of geniohyoid activity generally preceded the start of inspiratory airflow. The time from onset of inspiratory airflow to peak inspiratory EMGgh activity was significantly increased during sleep compared with wakefulness (awake 0.81 +/- 0.04 s, NREM sleep 1.01 +/- 0.04, REM sleep 1.04 +/- 0.05; P less than 0.05). These data indicate that sleep-related changes in geniohyoid muscle activity may influence upper airway resistance in some subjects. However, the relationship between geniohyoid muscle activity and upper airway resistance was complex and varied among subjects, suggesting that other factors must also be considered to explain sleep influences on upper airway patency.

Geniohyoid muscle activity in normal men during wakefulness and sleep.

Reduction in the activity of upper airway "dilator" muscles during sleep may allow the pharyngeal airway to collapse in some individuals. However, quantitative studies concerning the effect of sleep on specific upper airway muscles that may influence pharyngeal patency are sparse and inconclusive. We studied seven normal men (mean age 27, range 22-37 yr) during a single nocturnal sleep study and recorded sleep staging parameters, ventilation, and geniohyoid muscle electromyogram (EMGgh) during nasal breathing throughout the night. Anatomic landmarks for placement of intramuscular geniohyoid recording electrodes were determined from a cadaver study. These landmarks were used in percutaneous placement of wire electrodes, and raw and moving-time-averaged EMGgh activities were recorded. Sleep stage was determined using standard criteria. Stable periods of wakefulness and non-rapid-eye-movement (NREM) and rapid-eye-movement (REM) sleep were selected for analysis. The EMGgh exhibited phasic inspiratory activity during wakefulness and sleep in all subjects. In six of seven subjects, mean and peak inspiratory EMGgh activities were significant (P less than 0.05) reduced during stages 2 and 3/4 NREM sleep and REM sleep compared with wakefulness. This reduction of EMGgh activity was shown to result from a sleep-related decline in the level of tonic muscle activity. Phasic inspiratory EMGgh activity during all stages of sleep was not significantly different from that during wakefulness. Of interest, tonic, phasic, and peak EMGgh activities were not significantly reduced during REM sleep compared with any other sleep stage in any subject. In addition, the slope of onset of phasic EMGgh activity was not different during stage 2 NREM and REM sleep compared with wakefulness in these subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Collapsibility of the human upper airway during normal sleep.

Upper airway resistance (UAR) increases in normal subjects during the transition from wakefulness to sleep. To examine the influence of sleep on upper airway collapsibility, inspiratory UAR (epiglottis to nares) and genioglossus electromyogram (EMG) were measured in six healthy men before and during inspiratory resistive loading. UAR increased significantly (P less than 0.05) from wakefulness to non-rapid-eye-movement (NREM) sleep [3.1 +/- 0.4 to 11.7 +/- 3.5 (SE) cmH2O.1-1.s]. Resistive load application during wakefulness produced small increments in UAR. However, during NREM sleep, UAR increased dramatically with loading in four subjects although two subjects demonstrated little change. This increment in UAR from wakefulness to sleep correlated closely with the rise in UAR during loading while asleep (e.g., load 12: r = 0.90, P less than 0.05), indicating consistent upper airway behavior during sleep. On the other hand, no measurement of upper airway behavior during wakefulness was predictive of events during sleep. Although the influence of sleep on the EMG was difficult to assess, peak inspiratory genioglossus EMG clearly increased (P less than 0.05) after load application during NREM sleep. Finally, minute ventilation fell significantly from wakefulness values during NREM sleep, with the largest decrement in sleeping minute ventilation occurring in those subjects having the greatest awake-to-sleep increment in UAR (r = -0.88, P less than 0.05). We conclude that there is marked variability among normal men in upper airway collapsibility during sleep.

Sleep and the ventilatory response to resistive loading in normal men.

Since upper airway resistance is known to increase during sleep, inadequate resistive load compensation may contribute to the normal decline in sleeping ventilation. We determined the acute and sustained (4 min) ventilatory response to a range of external inspiratory resistive loads (4, 8, 12, and 25 cmH2O.l-1.s) during wakefulness and non-rapid-eye-movement (NREM) and rapid-eye-movement (REM) sleep in seven normal men. We found that minute ventilation (VI) was well maintained with acute and sustained resistive loading during wakefulness. Immediate adjustments in ventilatory timing (prolongation of inspiratory duration) provided full compensation for airflow reduction. In marked contrast, resistive load application during NREM sleep invariably produced a significant (P less than 0.05) reduction in VI with progressively larger resistive loads producing progressively greater ventilatory decrements. This decline in ventilation was a product of a falling inspiratory flow rate with inadequate prolongation of inspiratory duration (TI). The largest decrements in ventilation occurred immediately after load application followed by partial ventilatory recovery, which occurred over time in concert with rising PCO2 and augmented ventilatory effort (as reflected by P0.1 or mouth occlusion pressure). Similar observations were made during REM sleep, although the responses were less consistent and fewer data were obtained. These observations support the hypothesis that poor load compensation for increased upper airway resistance contributes to the hypoventilation characteristic of normal sleep.

Effects of inhibitors of S-adenosylmethionine decarboxylase and ornithine decarboxylase on DNA synthesis in rat liver after partial hepatectomy.

The effects of inhibitors of polyamine synthesis on DNA synthesis in rat liver regenerating after partial hepatectomy were studied. Neither 1,1'-[(methylethanediylidene)-dinitrilo]-bis-(3-aminoguanidine), a potent irreversible inhibitor of S-adenosylmethionine decarboxylase, nor 1,3-diaminopropane, an indirect inhibitor of ornithine decarboxylase, strongly inhibited [3H]thymidine incorporation into DNA when given as a single injection 1 h after operation and 23 h before DNA synthesis was measured. However, when the two inhibitors were given together, DNA synthesis was completely prevented. The incorporation of [14C]leucine into protein was not affected by this treatment. Combined administration of the inhibitors partially prevented the rise in hepatic spermidine levels normally seen during liver regeneration, but neither drug was effective alone. Hepatic putrescine content measured 12 h after treatment was increased by the combined inhibitors whereas, spermine levels were not significantly changed. By 24 h after operation the effects of the combined inhibitors on spermidine levels had almost worn off but DNA synthesis was greatly inhibited. However, by 40 h after operation the inhibitor treatment had no effect on [3H]thymidine incorporation into DNA. Also treatment with the combined inhibitors abolished DNA synthesis at 24 h after partial hepatectomy only when given more than 6 h before measurement suggesting that the effect was indirect and required time to become apparent. These results are consistent with other recent studies in which prior accumulation of spermidine appeared to be required for normal DNA replication and cell division.