Introduction
The neurophysiologic mechanisms governing sleep and wakefulness have been identified during recent years. These mechanisms have provided new insights into mechanisms of different arousal states and the impact of different anesthetic drugs on modulation of key components of the sleep-wake neuronal circuits. The similarities and differences between sleep and anesthesia states need to be understood in order to examine a patient’s vulnerability to anesthesia and different anesthetic drugs. These differences are also likely to determine the likelihood of complications in one state compared to the other, such as upper airway collapse, hypoventilation, and other respiratory problems.
Human Sleep
Sleep is defined as a state of decreased arousal that is actively generated by nuclei in the hypothalamus, brainstem, and basal forebrain and is crucial for the maintenance of health. Humans spend approximately one third of their lives sleeping. Sleep is described as being under the control of two processes: (1) a circadian clock (the circadian drive) that regulates the appropriate timing of sleep and wakefulness across the 24-hour day and (2) a homeostatic process (the homoeostatic drive) that regulates sleep need and intensity according to the time spent awake or asleep. The daily drive to sleep is modulated by the hypothalamic suprachiasmatic nuclei that coordinate circadian (24-hour) rhythm. The perceived sensation of sleepiness is likely the result of a circadian drive, process C (people tend to get sleepy according to their accustomed sleep times during a 24-hour cycle), along with a homeostatic drive, process S (sleep deprivation leads to increasing sleepiness). These two sleep drives are additive. Also, a temporal organization must be preserved to obtain a subjective experience of being refreshed and restful. For example, patients with chronic insomnia often have difficulties because the two sleep drives are not aligned with each other; in such patients, afternoon naps taken to compensate for sleep deprivation would likely delay sleep onset later in the night).
Normal sleep exhibits a dynamic architecture and is a nonhomogeneous state that can be divided into non–rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep. These two states cycle at an ultradian (less than 24 hour) rhythm of approximately 90- to 120-minute intervals, consolidated in bouts of 6 to 8 hours.
The American Academy of Sleep Medicine (AASM) has classified wakefulness and sleep into various stages based on characteristic electroencephalogram (EEG) patterns. Wakefulness , or stage W , is characterized by beta activity with eyes open (low amplitude, 12 to 40 Hz) and alpha activity with eyes closed (low amplitude, 8 to 13 Hz). NREM sleep has three distinct EEG stages, based on characteristic patterns on the EEG ( Fig. 50.1 ). Stage N1 sleep is characterized by attenuation of alpha activity during wakefulness, to a low amplitude, mixed frequency signal (4 to 7 Hz), and vertex sharp waves (prominent sharp waves lasting <0.5 second and maximal over the central EEG region). Stage N2 sleep is characterized by the presence of K-complexes (well-delineated, negative, sharp waves followed by a positive deflection, lasting 0.5 second) and sleep spindles (high-frequency bursts of 11 to 16 Hz, with tapering ends, distinct from the background rhythm and last ≥0.5 second). Stage N3 sleep is characterized by the presence of higher-amplitude (75 μV), lower-frequency (0.5 to 2 Hz) rhythms, also known as delta waves , accompanied by waxing and waning muscle tone, decreased body temperature, and decreased heart rate. Stage R , or REM sleep , is characterized by rapid eye movements, dreaming, irregular breathing and heart rate, and skeletal muscle hypotonia. In REM sleep, the EEG shows active high-frequency, low-amplitude rhythms (see Fig. 50.1 ). This activated EEG pattern has given rise to descriptions of REM sleep as “active” or “paradoxical” sleep and to the NREM phase of sleep as “quiet” sleep. Cognitive changes and vivid dreaming are well known to occur during REM sleep.
General Anesthesia
General anesthesia could be described as a reversible drug-induced coma. Nevertheless, anesthesia providers often refer to the unconsciousness induced by anesthetic drugs as sleep because of the negative connotation of the term coma . The EEG patterns of general anesthesia-induced consciousness are described in three periods (see Fig. 50.1 ).
Before induction of anesthesia , the patient has a normal, active EEG, with prominent alpha activity (10 Hz) when the eyes are closed. Small doses of hypnotic drugs acting on the γ-aminobutyric acid type A (GABA A ) receptors induce a state of sedation in which the patient is calm and easily arousable, with the eyes generally closed. This state is followed by a brief period of paradoxical excitation, characterized by an increase in beta activity on the EEG (13 to 25 Hz).
During the maintenance period, four distinct phases have been described. Phase 1, a light state of general anesthesia, is characterized by a decrease in EEG beta activity (13 to 30 Hz) and an increase in EEG alpha activity (8 to 12 Hz) and delta activity (0 to 4 Hz). During phase 2, the intermediate state, beta activity decreases and alpha and delta activity increases, with so-called anteriorization, that is, an increase in alpha and delta activity in the anterior EEG leads relative to the posterior leads. The EEG in phase 2 resembles that seen in stage 3, NREM (or slow-wave) sleep. Phase 3 is a deeper state, in which the EEG is characterized by flat periods interspersed with periods of alpha and beta activity (burst suppression). As this state of general anesthesia becomes more intense, the time between the periods of alpha activity lengthens, and the amplitudes of the alpha and beta activity decrease. Surgery is usually performed during phases 2 and 3. In phase 4, the most profound state of general anesthesia, the EEG is isoelectric (completely flat), indicated in conditions such as induced coma or neuroprotection during neurosurgery (also see Chapter 30 ).
During emergence from general anesthesia, the EEG patterns proceed in approximately reverse order from phase 2 or 3 of the maintenance period to an active EEG that is consistent with a fully awake state. Anesthetic drugs induce unconsciousness by altering neurotransmission at multiple sites in the cerebral cortex, brainstem, and thalamus. Recent advances in spectral EEG analysis have allowed spatiotemporal characterization of the effects of various intravenous and inhaled anesthetics.
Other Arousal States
Coma is characterized by a state of profound unresponsiveness, which could be drug-induced or a result of brain injury. EEG activity in comatose patients is variable and resembles the high-amplitude, low-frequency activity seen in patients under general anesthesia. The EEG patterns are also dependent on the severity and extent of brain suppression or injury (see Fig. 50.1 ).
Sleep and Anesthesia: How Different Are They?
The similarities and differences between sleep and anesthesia states should be understood. Sleep is a natural state of decreased arousal, controlled by circadian and homeostatic drives. Anesthesia, on the other hand, is a drug-induced state that is independent of these intrinsic rhythms. Sleep states are amenable to disruptive influences such as psychological and environmental factors. Anesthesia, on the other hand, is immune to such influences. Sleep is characteristically a nonhomogeneous state with distinct stages, periodic arousals, and variable body postures, occurring in a cyclic pattern. Anesthesia is a relatively homogeneous state, the depth and duration of which are directly dependent on drug pharmacokinetics and pharmacodynamics. In the presence of significant sensory stimulation, the sleep state gets disrupted and the subject arouses. Yet, a basic tenet of anesthesia is suppression of arousals, rendering the subject insensate to bodily injury during surgery. Sleep state reversal occurs spontaneously after putative restorative functions are completed. However, anesthesia state reversal requires voluntary stoppage of drug administration as well as effective drug elimination.
Functional Neuroanatomy of Sleep and Arousal Pathways
Common neurophysiologic mechanisms and neural pathways during sleep are also activated by anesthetic drugs. Sedative drug requirements decrease with both sleep deprivation and circadian rhythm disruption. Anesthesia on its own, in the absence of surgical stimulation, also has sleep-like restorative properties.
Anesthesia-induced loss of consciousness results from interactions of anesthetics with the neural circuits regulating sleep and wakefulness states. Ascending activation of the cerebral cortex by subcortical center activity is important in the maintenance of wakefulness. Deactivation of the thalamus occurs in imaging studies for both the sleep and anesthesia states, indicating that thalamic and extrathalamic pathways are involved in sleep state modulation.
Sleep state modulation is regulated by two groups of neural centers. The wakefulness promoting centers are the locus ceruleus (LC), dorsal raphe (DR), and tuberomammillary nucleus (TMN); and the sleep promoting center is primarily the hypothalamic ventrolateral preoptic nucleus (VLPO). One exception is the median preoptic area that contains both wake-active and sleep-active neurons. Discrete neurochemical mediators are involved in sleep stage transition during which the cholinergic (in brainstem and forebrain), noradrenergic (in the LC), and serotonergic (in the DR) activity are noted to be less active in NREM sleep; yet, the cholinergic activity increases in REM sleep. The GABAergic/galanin activity from the VLPO is increased in NREM sleep as it inhibits the histaminergic TMN. Orexinergic pathways from the perifornical nucleus are also inactive during NREM sleep and may be the cause of characteristic daytime hypersomnolence and disrupted nocturnal sleep, as noted in narcolepsy.
During wakefulness, the LC is active and exerts an inhibitory influence on the hypothalamic VLPO. When sleep starts, the LC activity decreases, disinhibiting the VLPO, which now exerts an inhibitory influence on key brainstem and thalamic centers and restrains the ascent of arousal promoting pathways to the cortex through them ( Fig. 50.2 ). VLPO projects back onto the LC causing feedback inhibition. Widespread inhibition of ascending arousal promoting pathways occurs, as well as reinforcement of LC output inhibition, resulting in sleep onset. The mutual inhibition between VLPO and LC acts to produce a switch-like, bistable states of wakefulness and sleep at a certain threshold. This effect is also caused by anesthetic drugs such as propofol and benzodiazepines, acting on the same target receptors and neural pathways that are integral to sleep and wakefulness.
Sleep-Disordered Breathing or Sleep-Related Breathing Disorders
Sleep-disordered breathing (SDB) is characterized by abnormalities of respiration patterns during sleep. The abnormal patterns of breathing are broadly grouped into obstructive sleep apnea (OSA) disorders, central sleep apnea (CSA) disorders, sleep-related hypoventilation disorders, and sleep-related hypoxemia disorders. OSA disorders are characterized by complete or incomplete upper airway closure during sleep. CSA disorders are characterized by reduction (hypopnea) or cessation (apnea) of airflow due to absent or reduced respiratory effort. Central apnea or hypopnea may occur in a cyclic, intermittent, or irregular (ataxic) fashion. We will primarily focus on OSA, as this is the most common entity encountered perioperatively.
Obstructive Sleep Apnea (OSA)
OSA is characterized by episodes of apnea or hypopnea during sleep, resulting in varying severity of hypoxemia and hypercapnia. The obstructive apnea or hypopnea is caused by repeated episodes of complete or partial closure of the pharynx, accompanied with hypoventilation and desaturation, and terminated by EEG arousal.
Pathophysiology of Upper Airway Collapse in OSA
Upper airway collapsibility and patency are dependent on a continuous balance between collapsing and expanding forces influenced by sleep-wake arousal. Polysomnographic data of important physiologic variables can be used to study characteristic features of an obstructive apnea ( Fig. 50.3 ). During wakefulness, the upper airway stability and patency are achieved by increased genioglossus muscle tone, which pulls the tongue forward. During sleep, upper airway collapse in OSA patients occurs owing to a complex interaction of multiple factors such as loss of upper airway dilating muscle tone, impaired response to mechanoreceptors sensing intrapharyngeal pressures, ventilator overshoot (high loop gain of the respiratory control system), and an increased arousal threshold. Moreover, patients with OSA have an upper airway that is predisposed to collapse, which occurs in the presence of smaller upper airway cross-sectional areas and increased critical closure pressures than those seen in patients without OSA. During NREM sleep and anesthesia, reduction of wakeful cortical influences, reflex gain, and ventilatory drive predispose to upper airway collapse and hypoventilation. These effects are more intense during general anesthesia as the decrease in tonic and phasic muscle activity is profound and abolition of protective arousal response predisposes to prolonged obstruction and more severe oxygen desaturation.
Clinical Diagnostic Criteria
Classically, the gold standard for the definitive diagnosis of OSA requires an overnight polysomnography (PSG) or sleep study. Based on the AASM recommendations, apneas and hypopneas are defined as a reduction in the rate of airflow from intranasal pressure of at least 90%, or between 50% and 90%, respectively, for at least 10 seconds accompanied by either a 3% to 4% decrease in oxygen saturation or an EEG arousal. Hypopneas are classified as obstructive if thoracoabdominal motion is out of phase or if airflow limitation is observed on the nasal pressure signal, whereas central hypopneas are classified when thoracoabdominal motion is in-phase and there is no evidence of airflow limitation on the nasal pressure signal. Mixed apneas are classified for events that begin as central for at least 10 seconds and end as obstructive, with a minimum of three obstructive efforts. Wherever applicable, ataxic breathing or Cheyne-Stokes type of respiration is also described.
The apnea-hypopnea index (AHI) is defined as the average number of abnormal breathing events per hour of sleep. OSA severity is determined by the AHI as follows: mild, 5 to 15 events per hour; moderate, more than 15 to 30 events per hour; and severe, more than 30 events per hour. The clinical diagnosis of OSA requires either an AHI of 15 or more, or an AHI more than or equal to 5 events, with symptoms such as excessive daytime sleepiness, unintentional sleep during wakefulness, unrefreshing sleep, loud snoring reported by a partner, or observed obstruction during sleep.
Polysomnography and Portable Devices
A laboratory-based sleep study is set up and analyzed by a registered sleep technologist using standard criteria. All studies are performed using a uniform montage of electrograms including central, occipital, and frontal EEGs; right and left electrooculogram (EOG); chin electromyogram (EMG); electrocardiogram (ECG); and anterior tibialis muscle EMG bilaterally. Thoracoabdominal motion is usually monitored by respiratory inductance plethysmography (RIP), and airflow is monitored using either a nasal pressure transducer or nasal thermistor. Arterial oxygen saturation (Sa o 2 ) is monitored by pulse oximetry. Body position and snoring are recorded manually.
Home sleep testing may be a viable alternative to standard PSG for the diagnosis of OSA in certain subsets of patients. The Portable Monitoring Task Force of the AASM has classified level 2 (full unattended PSG with seven or more recording channels), level 3 (devices limited to four to seven recording channels), and level 4 (monitors with one to two channels including nocturnal oximetry) devices. In particular, the level 2 portable PSG device has a diagnostic accuracy similar to that of standard PSG, whereas nocturnal oximetry is both sensitive and specific for detecting OSA in high-risk surgical patients. Preoperative overnight oximetry may be a useful screening test (when mean preoperative overnight saturation is less than 93%, oxygen desaturation index more than 29 events per hour, overnight duration of oxygen saturation less than 90% for more than 7% of total sleep time) and predicts postoperative adverse events. Portable devices may be considered when there is high pretest likelihood for moderate to severe OSA without other substantial comorbid conditions and proper standards for conducting the test and interpretation of results are met.
Prevalence of OSA in the General and Surgical Population
The prevalence of moderate to severe OSA (AHI ≥ 15 events per hour) is 13% among men and 6% among women, respectively, in the general population. The estimates were more frequent with increasing age and body mass index. The difference could be explained by the underdiagnosis of OSA, as 80% of patients with moderate to severe OSA remain undiagnosed. In the general population, OSA diagnosis is an independent risk factor for cardiovascular morbidity and mortality.
The prevalence of undiagnosed moderate to severe OSA (AHI > 15 events per hour) among surgical patients is difficult to assess but appears to be higher than that in the general population. Sixty percent of patients with moderate to severe OSA (AHI ≥15 events per hour) were not diagnosed by the anesthesia provider preoperatively (also see Chapter 13 ).
OSA and Comorbid Conditions
OSA is associated with long-term cardiovascular morbidity including myocardial ischemia, heart failure, hypertension, arrhythmias, cerebrovascular disease, metabolic syndrome, insulin resistance, gastroesophageal reflux, and obesity ( Box 50.1 ). Craniofacial deformities (e.g., macroglossia, retrognathia, midfacial hypoplasia), endocrine disorders (e.g., hypothyroidism, Cushing disease), and demographic (male, age older than 50 years) and lifestyle (e.g., smoking, alcohol consumption) are factors closely associated with OSA. Perioperative physicians (also see Chapter 13 ) should be aware of the possible coexistence of these medical conditions, which can possibly be improved preoperatively, and risk stratification may be instituted at the time of surgery.
Symptoms and Behaviors
Daytime sleepiness
Loud snoring
Nonrestorative sleep
Witnessed apneas by bed partner
Awakening with choking
Insomnia with frequent brief nocturnal awakenings
Lack of concentration
Cognitive deficits
Changes in mood
Morning headaches
Sleep walking, confusional arousals (arousals from NREM sleep)
Vivid, strange, or threatening dreams (arousals from REM sleep)
Gastroesophageal reflux
Nocturia
Drowsy driving, and motor vehicle accidents
Comorbid Conditions
Obesity
Large neck circumference
Craniofacial deformities (retrognathia, midfacial hypoplasia)
Crowded pharynx
Systemic hypertension
Hypercapnia or high serum bicarbonate
Cardiovascular disease
Cerebrovascular disease
Cardiac dysrhythmia
Metabolic syndrome
Pulmonary hypertension
Obesity hypoventilation syndrome
Cor pulmonale
Polycythemia
Floppy eyelid syndrome
NREM, Non–rapid eye movement; REM, rapid eye movement.
Surgery and OSA Severity
Factors contributing to the postoperative worsening of OSA have been defined. Compared to the preoperative baseline, the AHI significantly increased on the first night, with peak increase occurring on the third night. Preoperative AHI, age, and opioid dosage were significant predictors of postoperative AHI. These findings are clinically significant for surgical patients who may not be monitored as closely during the second and third postoperative nights.
Postoperative complications such as myocardial infarction, congestive heart failure, and pulmonary embolus can be more likely to occur during the second or third postoperative day. According to a 2015 analysis of the American Society of Anesthesiologists (ASA) Closed Claims Project database, 88% of opioid-induced respiratory depression incidents occurred within the first 24 hours of surgery, of which 97% were deemed as preventable. Multiple prescribers (33%), concurrent administration of nonopioid sedating medications (34%), and inadequate nursing assessments or response (31%) were identified as contributory factors. Life-threatening critical respiratory events with opioids occur mostly during the first 24 hours after surgery for all patients and within the first 72 hours for OSA patients. Factors such as OSA, intense levels of sedation, nighttime events, and postoperative acute renal failure are associated with fatality following these events. Increased postoperative complications on the second or third postoperative day may be associated with increased AHI and decreased oxygen saturation.
OSA and Postoperative Complications
A systematic review of 61 studies and a meta-analysis of 13 studies demonstrated that patients with OSA versus non-OSA were associated with a significantly higher risk of postoperative events, such as acute respiratory failure, desaturation, and intensive care transfer. Large population-based studies have shown that patients with a diagnosis of OSA have an increased risk of perioperative complications, such as the need for emergent endotracheal intubation, noninvasive or mechanical ventilation, aspiration of gastric contents–induced pneumonia, pulmonary embolism, and atrial fibrillation.
Recently, in 2015, a large perioperative database (26,000 patients in 50 U.S. hospitals) was analyzed to determine complications in patients with OSA. Compared with treated OSA, untreated OSA was independently associated with more cardiopulmonary complications, including unplanned reintubation of the trachea and myocardial infarction.
OSA patients who remain undiagnosed at the time of surgery are at increased risk of postoperative complications. Mutter and associates conducted a matched cohort analysis of polysomnography (PSG) data and health administrative data. Patients with undiagnosed OSA were found to have a threefold higher risk of cardiovascular complications, primarily cardiac arrest and shock, compared to diagnosed OSA patients with prescription of continuous positive airway pressure (CPAP) therapy. Severity of OSA may play an important factor. Patients with severe OSA (AHI >30) had a 2.7-fold increase in postoperative respiratory complications. If available, information on the diagnosis and severity of OSA in the anesthetic assessment may be helpful.
Clinical Pathways and Principles of Perioperative Management
The perioperative management of OSA patients is challenging, and a sound understanding of the condition is required of anesthesia providers involved in the care of such patients. The 2016 Society of Anesthesia and Sleep Medicine (SASM) guidelines for preoperative screening and assessment of adult patients with OSA recommend that screening for OSA may be useful to provide heightened awareness and potential risk reduction by implementing appropriate interventions ( Table 50.1 ). In addition, the American Society of Anesthesiologists (ASA) updated report on “Practice Guidelines for the Perioperative Management of Patients with Obstructive Sleep Apnea” offers guidance on perioperative management of OSA patients. The Society for Ambulatory Anesthesia (SAMBA) consensus statement has provided guidelines addressing the selection of suitable OSA patients for ambulatory surgery. Different clinical pathways and algorithms have been constructed to simplify the approach to OSA patients in the perioperative setting.
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