Respiratory insufficiency in patients with neuromuscular weaknesses such as ALS is the subject of a new study at the Minnesota Regional Sleep Disorders Center.

Respiratory insufficiency is thought to be a major contributor to morbidity and mortality in disease states associated with neuromuscular weakness, such as amyotrophic lateral sclerosis (ALS). Respiratory insufficiency is the major cause of sleep-disordered breathing in patients with ALS and may be manifested by hypoxemia and hypercapnia during sleep. Many patients with ALS and sleep-disordered breathing, however, may have very little nocturnal hypoxemia or hypercapnia, but may display marked activation of the accessory respiratory muscles during sleep, preserving minute ventilation but causing significant sleep fragmentation. Despite the bulbar weakness seen in many patients, purely obstructive apnea is much less common than central or mixed apnea in ALS patients.1 The diagnosis and treatment methods that are best for sleep-disordered breathing in ALS patients remain unknown. Research is now being proposed to address the nocturnal respiratory insufficiency in the ALS population.

ALS affects the anterior horn cells of the spinal cord, causing progressive muscle weakness and eventual respiratory failure. Respiratory insufficiency is often more severe during sleep, since the diaphragm is affected. This means that breathing in the supine position can precipitate hypercapnia, hypoxia, and subsequent sleep disturbances. Rapid–eye-movement (REM) sleep exacerbates this problem, since the accessory muscles of respiration used during wakefulness and non-REM sleep undergo atonia during REM sleep. A significant number (33%) of newly diagnosed ALS patients have sleep-disordered breathing, and many of those without sleep-disordered breathing (80%) still have significant disruption of sleep architecture.2 Some ALS patients (26%) have complete absence of REM sleep.2 This lack of REM sleep may be indicative of general sleep deprivation, which may be associated with decreased central respiratory sensitivity to increased carbon dioxide levels. Screening for this type of neuromuscular nocturnal hypoventilation is difficult because traditional screening methods for respiratory insufficiency, such as pulmonary function testing3 and overnight oximetry, do not correlate well with the level of sleep-disordered breathing. Other testing methods, such as overnight polysomnography (PSG), are needed to identify hypoventilation in neuromuscular weakness during sleep.

Effects of Bilevel PAP on % REM

Improvement of % REM with bilevel mechanical ventilation in ALS.

Nighttime Bilevel PAP in ALS Patients
Sleep deprivation due to nocturnal hypoventilation may cause impairments in cognitive function in ALS patients. Noninvasive positive-pressure ventilation in ALS patients has been shown to improve cognitive deficits over time4 and to improve quality of life.5 Evidence suggests that bilevel positive airway pressure (PAP) used at night may improve survival,6,7 quality of life,5 and quality of sleep in ALS patients,1 but how and when to initiate bilevel PAP therapy remain unclear. Some patients with ALS undergo formal sleep-laboratory analysis to determine bilevel PAP settings, but most are given bilevel PAP units set at levels determined in a clinical setting. Our research at Hennepin County Medical Center, Minneapolis, will evaluate patients with ALS who have new signs and/or symptoms of respiratory insufficiency by performing a sleep study and initiating bilevel PAP using two different protocols.

The first bilevel PAP protocol will be clinical and uses the Borg8 scale as a measure of dyspnea. The goal of bilevel PAP adjustment in clinic will be to achieve the best relief of dyspnea possible in the supine position, as measured using the Borg scale. The second protocol will be sleep laboratory driven using PSG testing to determine the best bilevel PAP settings. The goals of bilevel PAP adjustment in the sleep laboratory will be to decrease upper-airway obstruction (eliminate snoring, round the inspiratory flow envelope, decrease phasic chin electromyogram [EMG] activity, and decrease the frequency of apneas/hypopneas), to improve hypercapnia, to decrease respiratory effort (decrease respiratory rate and/or quantitative respiratory muscle EMG activity), to eliminate nonobstructive apneas, to improve hypoxemia, and to improve sleep architecture.

Patients will receive bilevel PAP, with settings to be determined using both a sleep-laboratory protocol and a clinical protocol; we plan to compare patient outcomes for the two protocols. We anticipate that treating patients with ALS who have confirmed nocturnal respiratory insufficiency with bilevel PAP according to a sleep-laboratory protocol (which includes overnight polysomnography) will be superior to treating the same patient population using empiric bilevel PAP adjusted during wakefulness. To evaluate this hypothesis, we propose to treat symptomatic ALS with trials of bilevel PAP during sleep. Settings are to be determined either by comfort levels (as determined by best Borg dyspnea scale ratings) titrated during wakefulness in the clinic or by optimal sleep and respiration, as determined during PSG monitoring. Both groups will undergo further PSG testing to determine whether one mode is more effective than the other in treating the consequences of sleep-disordered breathing. Patients will receive both kinds of bilevel PAP treatment in a crossover fashion (both during the night of the sleep study and again 2 weeks after the sleep study). The effects of treatment will be measured using the Borg dyspnea scale, the Epworth sleepiness score, sleep-efficiency results, EMG findings, and other measures. Patients will receive 2 weeks’ treatment using each bilevel mode, followed by evaluation of each mode using an ALS functional rating scale, a short-form health survey, the Calgary Quality of Life Scale, and the Borg scale. Comparison of the effects of each mode of bilevel PAP should help us to establish whether overnight titration is superior to titration in the clinic.

Bilevel PAP appears to improve quality of life, cognitive function, and survival in ALS patients, but the mechanisms of these improvements are not entirely understood. It appears that unloading of the respiratory musculature (with subsequent reductions in the work of breathing) is a major factor in the positive effects of bilevel PAP in ALS. Another benefit of bilevel PAP closely related to unloading the respiratory musculature is improvement in sleep content (specifically, an increase in REM sleep).9 Since all voluntary muscles except the diaphragm are essentially paralyzed during REM sleep, it appears that the need for accessory muscle action to maintain ventilation inhibits REM sleep, especially in patients with diaphragm weakness. There is marked improvement in the amount of REM sleep obtained during the administration of bilevel PAP. It may be that restoration of REM sleep is due to the unloading of accessory muscles during REM.

Unpublished data from our laboratory suggest that this is the case. This means that bilevel titration protocols should probably have unloading of scalene and intercostal muscle groups as primary endpoints of therapy. This could be followed by scalene and intercostal EMG amplitudes (with adequate titration) showing marked attenuation of EMG tracings. Other benefits using this approach may include improvement in both nocturnal and diurnal gas exchange and correction of chronic respiratory muscle fatigue.

Nocturnal Hypoventilation Markers
There are several markers of nocturnal hypoventilation: new onset of fatigue, confusion, headaches, orthopnea, increasing daytime sleepiness, dyspnea on exertion, sleep-onset or sleep-maintenance insomnia, hypercapnia, and increasing peripheral edema. Declining forced vital capacity, maximum inspiratory pressure, and maximum expiratory pressure may suggest susceptibility to nocturnal hypoventilation, but are quite nonspecific. Patients enrolled in our study will have three of the listed markers, but as there are few data regarding initiation of bilevel PAP in ALS, this enrollment criterion is somewhat arbitrary. Improvement of these symptoms and findings should occur upon the initiation of bilevel PAP, and we should be able to quantify that improvement.10

While there are no prospective randomized trials quantifying the effect of bilevel PAP in ALS patients with nocturnal hypoventilation, what data exist suggest that bilevel PAP is very effective in improving sleep-disordered breathing and accompanying sleep fragmentation and in reversing the effects of chronic respiratory muscle fatigue. This should result in improved survival,6,7 quality of life5, and quality of sleep in ALS patients.1 We suggest that unloading of the respiratory musculature at night should be a primary endpoint in bilevel titration, and effective respiratory support at night should result in attenuation of the respiratory muscle EMG. We hope to evaluate the efficacy of clinical titration of bilevel PAP, in comparison with titration during overnight polysomnography. We anticipate that sleep-laboratory titration will be superior to titration in the clinic alone, but this is yet to be established. We hope that our study will help to answer this question.

Vance Bachelder, MD, is Pulmonary Critical Care Fellow at the University of Minnesota. He begins a sleep fellowship at Hennepin County Medical Center in July 2003.

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