Excessive Sleepiness in Sleep-Related Breathing Disorders and Beyond

At an industry-sponsored symposium held in conjunction with CHEST 2003, the annual meeting of the American College of Chest Physicians in Orlando, Florida, three leading sleep researchers discussed the cardio-respiratory consequences associated with sleep apnea and sleep deprivation, and some of the treatment options available.

This program was supported by an educational grant from Cephalon, Inc.

The Physiology of Sleep and Sleep- Related Cardiorespiratory Functions

Meir Kryger, MD, FCCP, Professor of Medicine and Director of the Sleep Disorder Center at the University of Manitoba in Winnipeg, Manitoba, Canada, began the symposium by acknowledging that after a century and hundreds of articles studying sleep, several theories as to the purpose of sleep have been proposed, including the regeneration of tissues, conserving energy, hardwiring memories, and hiding from predators. To date, however, we still do not fully understand the function of sleep but we do know that it is essential for life.

Physiology of Sleep
Sleep is a fairly organized behavior that has been well studied. During normal sleep, a person goes from wakefulness to stages 1, 2, 3 and 4, and finally, after approximately 1.5 hours, the first episode of REM sleep occurs, which recurs about every 90 minutes with the episodes becoming longer as the night progresses. “During rapid eye movement sleep a lot of bad things happen that can make the cardiorespiratory systems much more vulnerable,” stated Dr. Kryger. For example, during REM sleep there can be irregular breathing patterns and variable blood pressure. During REM sleep, people are also paralyzed so that they cannot react to dream content. “The problem with this paralysis is that muscles are used to maintain the patency of the upper airway during sleep and so this can be a real big potential problem,” said Dr. Kryger, adding that ventilatory response to hypoxia and hypercapnia are both virtually absent in REM sleep, making persons at risk for adverse cardiorespiratory events. In addition, people with irregular sleeping patterns or sleep deprivation have been shown to have an increased risk of adverse cardiovascular events.

Sleep Apnea
Obstructive sleep apnea syndrome (OSAS) is a common disorder affecting approximately 4% of males and 2% of females (N Engl J Med. 1993;328:1230-1235). Sleep apnea interferes with sleep continuity, sleep architecture, and cardiorespiratory physiology. The major concern for patients with sleep apnea is that these people cannot sleep and breathe at the same time. When they stop breathing, they become apneic and are aroused in order to breath. This cycle repeats itself throughout the night. “We have repetitive hypoxemia, and hypercapnia. Cardiac arrhythmias can occur which can be either very fast or very slow and there can be constriction of the pulmonary and systemic circulations,” stated Dr. Kryger, adding, “as a result of the arousals, we have abnormal sleep structure which results in sleep disruption, reduction of slow wave sleep and rapid eye movement sleep.” In addition to these acute effects, there are also long-term complications, including hypertension in the systemic and pulmonary circulation and in the more severe cases, heart failure related to respiratory failure.

Disruption of the sleep cycle also affects the central nervous system and it is these cognitive problems that often lead patients to seek help.

The Typical Sleep Apnea Patient
The stereotypical sleep apnea patient is a middle-aged overweight male. According to Dr. Kryger, 70-80% of patients with sleep apnea are obese. The metabolic changes associated with obesity are similar to that seen in sleep apnea (Figure 1). Dr. Kryger stated that most patients with sleep apnea come for assessment because they are sleepy and it affects their quality of life at work and at home. More often than not, however, these patients are overweight with mild cardiorespiratory complications.

Death Due to Sleep Apnea
While sleep apnea can cause chronic changes in cardiorespiratory mechan-isms, the major concern with sleep apnea patients is that their sleepiness will result in them falling asleep while driving. This appears to be a well founded concern. “Studies done in the U.S., Canada, France, Australia, and Germany, have all shown basically the same thing; that patients with significant sleep apnea have about a two or more greater risk of having an automobile accident than any control group that you want to pick,” said Dr Kryger (Sleep. 1999;22: 790-795).

Concluding Remarks
Sleep apnea patients have many co-morbidities. Many of these co-morbidities may be caused by abnormal sleep physiology and any treatment that can improve the patient’s sleep pattern may help alleviate many of these co-morbidities.

Current Management of Obstructive Sleep Apnea

Nancy A. Collop, MD, FCCP, Associate Professor of Medicine in the Division of Pulmonary and Critical Care Medicine at the Johns Hopkins University in Baltimore, MD provided an overview of some of the treatment options available for sleep apnea. Currently, there are no pharmacological agents that are very effective in primary treatment of obstructive sleep apnea. Treatment consists of nonpharmacologic methods such as mechanical devices, surgery, or oral appliances.

Nonpharmacologic
One of the most common co-morbidities of sleep apnea is obesity (Table 1). Dr. Collop stated that weight loss has clearly been shown to improve sleep apnea and even small amounts of weight loss can result in dramatic improvements in the apnea-hypopnea index and should always be suggested in sleep apnea patients that are obese.

Mechanical
There are 3 types of positive airway pressure devices: the standard nasal CPAP, the auto-titrating CPAP, and the bi-level positive airway pressure. “The effects of CPAP on the upper airway are mostly as a pneumatic splint which expands the upper airway when the pressure is applied,” said Dr. Collop. This opens the airway to prevent obstruction, increase functional residual capacity, and decrease upper airway muscle activity. “It is a very successful form of therapy and in most patients we can find an adequate CPAP pressure that will eliminate their apnea and hypopneas,” stated Dr. Collop. Studies have shown that when used correctly, CPAP decreases sleepiness and sleep apnea, while improving quality of life, cognitive functions, nocturnal blood pressure control, vasodilator response, and pulmonary hemodynamics (Lancet.1994;343:572; Chest. 1996;109: 1269; Sleep. 1999;22: 849; Am J Respir Crit Care Med. 2002; 165:950; Am J Respir Crit Care Med. 2002; 165:152). CPAP can also decrease hospitalizations (Sleep. 1997;20:645) and decrease the number of at-fault car accidents (Am J Respir Crit Care Med. 2000;161:857).

The high efficacy of CPAP, however, is dependent on proper administration and compliance. Unfortunately, the greatest problem in treating patients with sleep apnea is compliance. Improving compliance requires intensive patient education. Compliance may also be improved with the use of auto-titrating CPAP devices. Dr. Collop warned the audience, however, that most compliance is improved by patient education and having a comfortable device. Simply switching to a bi-level machine will not improve compliance. With that being said, bi-level CPAP may be more appropriate for patients that have concomitant hypoventilatory syndromes such as obesity, hypoventilation or neuromuscular diseases.

Surgery
“There are a number of surgeries for obstructive sleep apnea which tells me right off the bat there is no one great surgery for obstructive sleep apnea and clearly no single surgery is routinely curative perhaps with the exception of tracheostomy, but we obviously like to avoid that type of surgery if possible,” said Dr. Collop. The current approach to surgery for sleep apnea is to evaluate the upper airway and determine which part of the upper airway is collapsing during sleep. The types of surgery that are done for obstructive sleep apnea include:

1. Nasal
• Septoplasty
• Turbinate reduction

2. Oropharyngeal
• Uvulopapatopharyngoplasty (UPPP)
• Tonsillectomy

3. Bone
• Maxillomandibular advancement
• Hyoid suspension

Oral Appliances
“The premise of oral appliances is to advance the mandible forward without doing surgery and displace the tongue anteriorly,” said Dr. Collop, adding, “it is typically fitted by a dentist or an oral surgeon and in the U.S. it is intermittently covered by insurance.” Most of these devices are mandibular repositioning appliances but there are also tongue-retaining appliances as well as combination oral appliances with CPAP. Success rates with these devices are dependent on the severity of the obstruction. In mild and moderate patients, efficacy is fairly high (47-100%) but drops in severe sleep apnea patients (0-47%).

The combination oral appliance and CPAP has the advantage of reducing the CPAP pressure required to be effective and it does not require head straps. This would be a good treatment option for patients who are claustrophobic with normal CPAP, uncomfortable with head straps, and/or intolerant of CPAP at higher pressures.

Concluding Remarks
Of all the treatment options available, nasal CPAP is the most effective. Unfor-tunately, these devices are only effective if the patient uses them and, prior to any treatment, patient education is very important. In some patients surgery is appropriate such as in a young non-obese patient that you don’t want to commit to life-long nasal CPAP. Finally, Dr. Collop said that oral appliances are good therapy for mild or positional sleep disorder breathing or for patients who may just have primary snoring.

Excessive Sleepiness: Causes, Consequences and Treatment Considerations

Thomas Roth, PhD, Division Head of the Henry Ford Sleep Disorders Center at the Henry Ford Hospital in Detroit, MI concluded the symposium with an overview of the excessively sleepiness and possible treatment options. “One of the reasons I am so interested in sleepiness is of all human behavior, it is actually a reasonably easy behavior to understand,” confessed Dr. Roth, adding, “there are only four things in the world which make us sleepy.” They are: 1) sleep at night (reduced length or continuity), 2) circadian phase, 3) CNS- acting drugs, and 4) CNS diseases.

While most Americans do not have sleep apnea, many do suffer from sleep deprivation. Approximately 29% of the general population have moderate sleepiness and 16% have excessive sleepiness (Clinical Companion to Sleep Disorders, 2nd Ed. Woburn, MA, Butterworth Heinemann, 1999) and the consequences of excessive daytime sleepiness are numerous (Table 1).

Prior to any pharmacological management to treat sleepiness, Dr. Roth said that treatment of the underlying cause of the poor sleeping pattern is essential, whether it is stress, sleep apnea, obesity, medications, and so forth. Of the pharmacologic agents available, most are CNS stimulants that may cause further cardiovascular problems. One medication that is neither a CNS stimulant nor affects the cardiovascular system is modafinil.

Modafinil
Modafinil is a wake-promoting agent with highly selective CNS activity in the sleep-wake centers of the brain. In most conditions studied, it appears to produce wakefulness independent of the underlying pathology. In preclinical models, it promotes wakefulness without increasing motor activity. At the cellular level, it is unclear how modafinil works. At high doses in vitro, it weakly binds to the dopaminergic reuptake site but at the doses used clinically, modafinil’s wake promoting effects do not appear to be mediated by a dopaminergic pathway. Unlike the amphetamines, modafinil does not have any cardiovascular adverse effects and has a very low abuse potential.

In a randomized, double-blind, placebo-controlled study of the efficacy and safety of modafinil for the treatment of daytime sleepiness, Dr. Alan Pack and colleagues gave patients with obstructive sleep apnea who were regular CPAP users, modafinil (200 mg/d, Week 1; 400 mg/d, Weeks 2 to 4; n = 77) or placebo (n = 80) for 4 weeks. They found that the modafinil-treated group had significantly higher Epworth Sleepiness Scale scores and significantly higher multiple sleep latency times (MSLT) (Am J Respir Crit Care Med. 2001;164:1675). Dr. Roth stated that since many people with sleep problems also have cardiovascular co-morbidities, it is imperative that any medication used to help the patients stay awake will not cause further cardiovascular problems. Studies on the safety of modafinil have shown it has no significant effect on blood pressure.

In a larger study involving 43 sites, 327 patients with obstructive sleep apnea were randomized to receive placebo, modafinil (200 mg/d) or modafinil (400 mg/d) for 12 weeks. In this study, patients’ inclusion criteria included residual daytime sleepiness and the use of a CPAP. The data was presented at the Associated Professional Sleep Society in Seattle, Washington in 2002 (Black et al. 2002; Schmidt-Nowara et al. 2002) and showed both doses of modafinil to improve wakefulness in patients without affecting CPAP use. “The biggest concern in this protocol was that if people become more alert, they would cease to use their CPAP,” said Dr. Roth. Fortunately, this was not the case.

Concluding Remarks
Excessive daytime sleepiness is a very important symptom both in the general population and in medicine. Once the primary therapy has been undertaken first, adjunctive therapy with compounds such as modafinil may have a significant clinical benefit.