What every physician needs to know:

Sleep is a natural, periodic, and reversible behavioral state of perceptual disengagement from and unresponsiveness to the environment. Defining features of sleep include minimal movement, assumption of a stereotypic posture, reversibility, and reduced response to stimulation.

Sleep is essential to life; however, the precise function of sleep remain elusive. Although because of the appearance of a sleeping subject, sleep is often viewed as a passive process, it represents a period of challenge rather than rest for the ventilator system.

Several hypotheses have attempted to explain the specific vital sleep functions. One theory defines sleep as a process that provides restoration and recovery of vital functions that have been degraded by continued wakefulness. A second theory proposes that sleep provides an opportunity for energy conservation by reducing metabolic rate and body temperature. An ecological theory posits that reduced motor activity during sleep decreases the likelihood of attracting predators.

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Classification of sleep stages relies upon three measurable neurophysiologic variables: electroencephalograph [EEG], eye movements (electrooculography [EOG]) and muscle activity (electromyography [EMG]). Standardized criteria that uses all three variables were published in the first sleep-scoring manual by Rectschaffen and Kales in 1968. The American Academy of Sleep Medicine (AASM) published a modified scoring manual in 2007, which is the basis for this review.

There are three stages: wakefulness, non-rapid-eye movement (NREM) sleep, and rapid-eye-movement (REM) sleep. NREM sleep is divided into three stages: N1 sleep, N2 sleep, and N3 sleep. REM sleep is often described as “paradoxical sleep” because of active CNS and paralyzed periphery.

Several conditions may alter sleep state disruption and function, including sleep apnea and period leg movement.


The EEG pattern during wakefulness is characterized by mixed-frequency, low-amplitude activity, often in association with high chin muscle tone, eye blinks, and random rapid eye movements. Quiet, relaxed wakefulness is characterized by 8-13Hz sinusoidal activity called alpha waves, which are best captured over the occipital region. This activity is attenuated by eye opening.

Non-rapid-eye-movement (NREM) sleep

The NREM sleep stage comprises the majority of nocturnal sleep. NREM sleep is divided into three stages:

N1 sleep is a transitional state characterized by a slowing of EEG frequency without increasing EEG amplitude from wakefulness. The dominant EEG activity is low-amplitude activity with a frequency range of 4-7 Hz(theta activity) and the appearance of occasional slow, rolling eye movements. Some degree of environmental awareness is retained during N1 sleep.

N2 sleep is characterized by loss of environmental awareness and a corresponding change in EEG. The appearance of sleep spindles and K complexes, both of which are transient wave forms that are superimposed on a background of dominant theta activity, indicate the transition to N2 sleep. Sleep spindles are rhythmic sinusoidal waves of 12-14 Hz frequency, which are best captured on central EEG leads. In contrast, K complexes are diphasic waves with well-delineated sharp upstroke (negative) components followed by slow down stroke (positive) components. K complexes also appear during transient arousals and in association with transient alpha wave forms.

N3 sleep is characterized by the appearance of slow waves in the delta range. By definition, slow waves are of low frequency (generally 0.5 to 2 Hz) and large amplitude (>75 μV). N3 sleep is scored when delta activity comprises at least 20 percent of an epoch. Aging is associated with decreased time in the N3 stage in men, but not in women.

Rapid eye movement (REM) sleep

REM sleep is often described as “paradoxical” sleep: active CNS and paralyzed periphery. The EEG is fast, with low amplitude (resembling N1 sleep), and there is reduced chin EMG activity. This phase of REM sleep is referred to as tonic REM sleep. REM sleep occurs in cycles every 90-110 minutes. It is often reduced in the laboratory environment, especially if complex instrumentation is used. This stage is also characterized by dreaming, relative atonia of all muscle groups except the diaphragm, and erections in men.

Rapid eye movements are the defining characteristic of this sleep stage, as clusters of rapid eye movements occur (phasic REM sleep) and are interspersed with periods of no eye movements (tonic REM sleep). The distinction between tonic and phasic REM reflects significant physiological changes and relatively complex EEG morphology. For example, intercostal muscle activity is diminished significantly during phasic REM sleep, manifested by paradoxical breathing during this stage of sleep. Patients with COPD may experience the most pronounced hypoventilation and oxyhenoglobin desaturation during phasic REM sleep.

Sleep Architecture

The term “sleep architecture” denotes the orderly progression of sleep stages in cycles of 90-120 minutes. A normal sleep cycle begins with transitioning from wakefulness to N1 sleep, and then descending to N2 and N3, followed by a period of REM sleep. the first occurrence of REM sleep occurs after ninety minutes. the sleep cycle is repeated every 90-110 minutes through the night.

In general, N3 sleep tends to predominate in the first half of the night, while REM sleep predominates in the second half of the night as REM periods lengthen toward the morning. for an average individual in his or her second decade, stage N1 is 2-5 percent of the total sleep time, stage N2 is 45-55 percent, stage N3 is 12-23 percent, and REM is 20-25 percent.

The distinction between tonic and phasic REM reflects significant physiological changes and relatively complex EEG morphology. For example, intercostal muscle activity is diminished significantly during phasic REM sleep, manifested by paradoxical breathing during this stage of sleep. Patients with COPD may experience the most pronounced hypoventilation and oxyhenoglobin desaturation during phasic REM sleep.

Several sleep disorders blur the boundaries between different states of consciousness by intrusion of features of one state into another state. Examples include but are not limited to narcolepsy, REM behavior disorder (RBD), and sleep walking.

Narcolepsy a condition of excessive daytime sleepiness in which features of REM sleep, such as muscle paralysis, intrude into wakefulness. Narcolepsy is manifested by the sudden attacks of muscle weakness caused by loss of muscle tone and is triggered by strong emotions.

The occurrence of REM sleep without atonia is the hallmark of a clinical condition called REM behavior disorder (RBD). Afflicted patients act out their dreams and may cause injury to themselves or others.

Patients who sleep walk vocalize and ambulate, all features of wakefulness, while they are in NREM sleep.

Circadian Rhythm

Circadian rhythms are twenty-four-hour cycles of behavior and physiology that are generated by endogenous biological clocks. In mammals, the suprachiasmatic nucleus (SCN) of the anterior hypothalamus has been identified as the site of the circadian pacemaker. The circadian period in humans synchronizes to the twenty-four-hour day by external influences, mainly light.

Sleep deprivation

Sleep deprivation occurs when the individual sleeps less than required for optimal functioning, health, and performance. The two broad categories of sleep deprivation are reduced total sleep time and poor sleep quality. Poor-quality sleep may be caused by frequent awakenings or arousals, with subsequent impairment in daytime functioning, fatigue, and/or daytime sleepiness.

Sleep deprivation is associated with significant adverse consequences. Studies in animals have shown that total sleep deprivation in the rat is ultimately fatal. Sleep deprivation in humans is associated with significant safety risks, such as increased numbers of motor vehicle accidents and industrial accidents. In fact, several catastrophic industrial accidents, including the Chernobyl nuclear accident and the Exxon Valdiz oil spill, have been due, at least in part, to sleep-deprived operators.

Sleep deprivation may occur because of sleep fragmentation secondary to sleep apnea or periodic leg movements of sleep. Afflicted patients report non-refreshing sleep and excessive daytime sleepiness despite adequate total sleep time. Sleep fragmentation may account for some of the neuro-cognitive consequences of sleep apnea.

Large-scale studies have shown that chronic sleep deprivation exerts substantial dose-related effects on neurobehavioral performance measures, increased mood disturbance, decreased motivation, and decreased driving ability with increased risk of motor vehicle accidents. In addition, sleep curtailment may have orexigenic effects and may be conducive to weight gain. This is an intriguing new finding with significant implications that may link sleep loss with the burgeoning obesity epidemic in the US. However, this link is speculative until confirmed by large-scale population studies.

Sleep deprivation is also associated with impaired quality of life, adverse cardiovascular consequences and even increased mortality. Sleep deprivation may also impair ventilatory responses to hypercapnia and hypoxia in healthy subjects. Impaired response to chemical stimuli may contribute to worsening respiratory function in patients with COPD or sleep apnea and in obese patients.

Sleep fragmentation

Several conditions, including sleep apnea and periodic leg movement, may cause sleep fragmentation.

Sleep state distribution is altered with aging, manifested by increased numbers of arousals, increased N1 sleep, and decreased N3 sleep. Epidemiologic evidence suggests that decreased N3 sleep is seen in men and not in women. Whether sleep fragmentation in the elderly is due to aging or to concomitant chronic conditions is unclear.

Alcohol, stimulants, tobacco, and withdrawal from sedatives may also cause sleep fragmentation, as may depression or withdrawal from antidepressants.

Physiologic changes during sleep

Physiologic changes during sleep include respiratory changes, cardiological changes, endocrine changes, and gastrointestinal.

Respiratory Changes

Loss of wakefulness stimulus to breathe renders ventilation critically dependent on chemorecepter and mechanorecepter stimuli.

Breathing through high-resistance tubing is associated with increased ventilatory effort to maintain alveolar ventilation. However, this response is lost during sleep, as “loads” are not perceived; therefore, ventilation decreases and PaCO2 increases.

During sleep, ventilation becomes dependent on chemoreceptor influences, so if hypocapnia is induced, complete inhibition of ventilation may occur (i.e., central apnea). The level of hypocapnia that causes central apnea is referred to as “the apneic threshold.” Hypocapnia is the most important mechanism of central sleep apnea.

Elevated PaCO2 (Hypercapnia) is common during sleep. This is one of very few physiologic situations where hypercapnia is tolerated.

Most of the studies on sleep effect have been in the area of NREM sleep, as REM is difficult to achieve under instrumented conditions. REM sleep is associated with muscle atonia, affecting many upper airway dilators and intercostals, while the diaphragm is spared. Minute ventilation decreases even more in REM sleep than in NREM sleep, and the respiratory rate becomes more irregular, especially in phasic REM sleep.

Cardiovascular changes

NREM sleep is characterized by autonomic stability that occurs because of increased parasympathetic tone compared to wakefulness. Therefore, NREM sleep is associated with decreased heart rate, cardiac output, blood pressure, and cerebral blood flow. In contrast, REM sleep is associated with heart rate variability, with transient increases in blood pressure, heart rate, and coronary blood flow during bursts of rapid eye movements, probably because of increased sympathetic activity. In addition, cerebral blood flow is increased during REM sleep relative to NREM sleep.

Endocrine Changes

The levels of circulating hormones are generally influenced either by the sleep-wake cycle or by circadian rhythm. Secretion of growth hormone and prolactin is tightly linked to the sleep-wake cycle, with the GH peak occurring during slow-wave sleep and the prolactin peak occurring shortly after sleep onset. In contrast, cortisol and testosterone secretion follows a circadian pattern where both are maximally secreted in the morning. Finally, circulating levels of thyroid-stimulating hormone (TSH) are influenced by both circadian rhythms and the sleep-wake cycle. TSH levels increase in the evening under circadian influences but decrease after sleep onset, primarily during slow-wave sleep.

Gastrointestinal changes

Basal gastric acid secretion follows a circadian rhythm, with peak secretion between 10 p.m. and 2 a.m. and a relative absence of basal secretion in the absence of meal simulation. The frequency of swallowing and esophageal peristaltic waves decreases significantly during NREM sleep. One of the important effects of sleep is increased acid contact time because of the sleep-related decreases in salivation, swallowing, and peristalsis. Moreover, the sensation of “heartburn” is attenuated during sleep, so gastro-esophageal reflux during sleep may contribute to the development of esophagitis, chronic cough, and exacerbations of nocturnal bronchial asthma.

Upper airway narrowing and increased upper airway resistance are normal physiologic events during sleep. Snoring occurs when upper airway resistance increases significantly, leading to “fluttering” of the soft palate because of turbulent flow. In extreme cases of upper airway narrowing, complete closure may occur, leading to obstructive sleep apnea.

Assessment of daytime sleepiness

There are both subjective and objective tests of daytime sleepiness. The subjective tests include the Epworth Sleepiness Scale (ESS) and the Stanford Sleepiness Scale (SSS), while the objective tests include the Multiple sleep Latency Test (MSLT) and the Maintenance of Wakefulness Test (MWT).

Subjective tests of sleepiness

The Epworth Sleepiness Scale (ESS)

The ESS is a subjective, self-administered instrument that can be completed within a few minutes to measure sleepiness under normal, relaxed daily conditions. The questionnaire consists of eight specific situations:

  • Sitting and reading

  • Watching television

  • Sitting inactively in a public place

  • Riding as a passenger in a car for one hour without a break

  • Lying down to rest in the afternoon when circumstances permit

  • Sitting and talking with someone

  • Sitting quietly after lunch without alcohol

  • Sitting in a car, while stopped for a few minutes in traffic

Each situation receives a score of zero to three, which is related to the likelihood of sleep occurring under that condition. The total score ranges from 0-24; a cutoff of 10 points is considered the threshold for excessive daytime sleepiness. The correlation between ESS and objective indices of sleep or performance is weak, so ESS should not be used as a screening tool for sleep apnea or other conditions of excessive sleepiness. The ESS is routine part of the initial and follow-up assessment for patients with sleep disorders.

Stanford Sleepiness Scale (SSS)

The SSS is a validated subjective measure of sleepiness for short-term subjective sleepiness. The patient is asked to select one of seven items that describe his or her current level of sleepiness.

1 = feeling active, vital, alert, wide awake

2 = functioning at a high level, not at peak, able to concentrate

3 = relaxed, awake, not at full alertness, responsive

4 = a little foggy, not at peak, let down

5 = fogginess, losing interest in remaining awake, slowed

6 = sleepiness, prefer to be lying down, fighting sleep, woozy

7 = almost in reverie, sleep onset soon, losing struggle to remain awake

Items 4-7 during regular waking hours represents significant sleepiness. The SSS is rarely used clinically; it is used mostly as a research tool.

Objective tests of sleepiness

Multiple Sleep Latency test (MSLT)

The MSLT is an objective, valid and reliable test for assessment of daytime sleepiness, the standard for objective tests of an individual’s tendency to fall asleep. In brief, the MSLT consists of five nap opportunities performed during regular waking hours in the sleep laboratory. Sleep latency is calculated from the average of latencies of all five nap opportunities. If sleep is not reached, the nap is considered to have a sleep latency of twenty minutes.

Medications that may alter sleep or sleep state distribution should be discontinued at least two weeks prior to testing because they can impact the ability to fall asleep. MSLT should be preceded by polysomnography to ascertain possible causes of sleep fragmentation, which may influences daytime sleepiness.

The MSLT is indicated as part of the standard testing for the diagnosis of narcolepsy because it can detect both excessive hypersomnia and the early onset of REM (sleep-onset rapid eye movements, or SOREMs), which are key features of narcolepsy. Nevertheless, the MSLT cannot be used to confirm or exclude the diagnosis of narcolepsy. In addition, it does not indicate whether the etiology of sleepiness is apparent, as in patients with obstructive sleep apnea syndrome. The MSLT may also be helpful in the evaluation of patients with suspected idiopathic hypersomnia.

The MSLT alone is not sufficient to evaluate driving risk, and there is no specific threshold for safe driving.

Maintenance of Wakefulness Test (MWT)

The maintenance of wakefulness test is a “mirror image” of MSLT in that it measures the ability to remain awake for a defined period of time. The MWT measures aspects of alertness/sleepiness, so it is not a substitute for MSLT, although the primary variable is also mean sleep latency. A threshold of less than eight minutes is considered abnormal, a value of at least forty minutes during all four sessions indicates absence of daytime sleepiness, and a value between eight and forty minutes is of uncertain significance.

The MWT suffers from the same limitations as those of MSLT in that it is of long duration, has a high cost, and is resource-intensive. It is often requested by third parties to evaluate driving risk, despite the absence of robust supportive data.

What’s the evidence?

Silber, MH, Ncoli-Israel, S, Bonnet, MH, Chokroverty, S, Grigg-Damberger, MM, Hirshkowitz, M. “The visual scoring of sleep in adults”. J Clin Sleep Med.. vol. 3. 2007. pp. 121-131.

Iber, C, Ancoli-Israel, S, Chesson, AL, Quan, SF. The AASM manual for the scoring of sleep and associated events. 2007.

Ohayon, MM, Carskadon, MA, Guilleminault, C, Vitiello, MV. “Meta-analysis of quantitative sleep parameters from childhood to old age in healthy individuals: developing normative sleep values across the human lifespan”. Sleep. vol. 27. 2004. pp. 1255-1273.

Redline, S, Kirchner, HL, Quan, SF, Gottlieb, DJ, Kapur, V, Newman, A. “The effects of age, sex, ethnicity, and sleep-disordered breathing on sleep architecture”. Arch Intern Med.. vol. 164. 2004. pp. 406-418.

Collop, NA, Salas, RE, Delayo, M, Gamaldo, C. “Normal sleep and circadian processes”. Crit Care Clin.. vol. 24. 2008. pp. 449-60.

Orr, WC, Chen, CL. “Sleep and the gastrointestinal tract”. Neurol Clin.. vol. 23. 2005. pp. 1007-1024.