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Vulnerability to Postoperative Complications in Obstructive Sleep Apnea: Importance of Phenotypes

Altree, Thomas J. MBBS, FRACP*; Chung, Frances MBBS, FRCPC; Chan, Matthew T. V. PhD; Eckert, Danny J. PhD*

Author Information
doi: 10.1213/ANE.0000000000005390
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Obstructive sleep apnea (OSA) is characterized by repetitive narrowing and partial or complete collapse of the pharyngeal airway, resulting in hypoxia, hypercapnia, and frequent arousals during sleep. The estimated global prevalence is nearly 1 billion.1 Accordingly, many patients undergoing surgical procedures also have OSA and most are undiagnosed.2 Prevalence varies depending on the procedure but can be as high as 91% for bariatric surgery3 and the OSA severity is often severe.2 Others without OSA may develop sleep-disordered breathing in the immediate postoperative setting.4 OSA increases the risk of postoperative complications. Indeed, patients with OSA have higher rates of postoperative cardiac complications, acute respiratory failure, and need for transfer to the intensive care unit.5–8 Postoperative deaths and brain damage are more likely in the setting of unwitnessed OSA-related events, no supplemental oxygen, lack of respiratory monitoring, and coadministration of opioids and sedatives.8 Therefore, early preoperative identification and optimal management of these patients is recommended.9

Table. - Summary of Novel Noninvasive Methods to Characterize OSA Phenotypes
Study Phenotypes measured Advantages Disadvantages
Signal processing of standard polysomnography records
 Terrill et al (2015)17
 Azarbarzin et al (2017)23
 Sands et al. (2018)18
Pcrit, MR, LG, AT
• No further testing required beyond a standard diagnostic sleep study • Requires a sleep study
• Requires computing/signal processing expertise
• Not currently available beyond research setting
Prediction models based on standard polysomnography outputs/clinical data
 Edwards et al (2014)16 AT
Pcrit, AT
• No further testing required beyond a standard diagnostic sleep study and routine clinical information • Requires a sleep study
• Further validation (especially for new machine learning approach) required
 Dutta et al (2020)15
CPAP titration
 Landry et al (2017)20
 Osman et al (2020)24
• Robust estimation of upper airway collapsibility • CPAP titration study in addition to a diagnostic sleep study required
• CPAP manipulations and accurate airflow signal beyond standard clinical care required to optimize prediction accuracy
Wakefulness tests
 Hirata et al (2016)21 Pcrit • Can be performed during the day in a clinical setting • Requires custom-built specialized equipment and software not currently available beyond the research setting
• Potentially uncomfortable
 Osman et al (2019)25 Pcrit
 Wang et al (2018)19 LG
 Messineo et al (2018)22 LG
Abbreviations: AT, respiratory arousal threshold; CPAP, continuous positive airway pressure; LG, loop gain; MR, muscle responsiveness; OSA, obstructive sleep apnea; Pcrit, upper airway collapsibility.

Figure 1.
Figure 1.:
Schematic of the 4 key phenotypes that contribute to obstructive sleep apnea pathogenesis. The key determinant is (A) impaired upper airway anatomy, which is quantified during sleep according to the critical closing pressure “Pcrit” technique, an adaption of the Starling resistor model. Nonanatomical phenotypes include (B) a low respiratory arousal threshold (waking up too easily to minor pharyngeal narrowing; (C) high loop gain (unstable control of breathing/too sensitive to small changes in CO2); and (D) poor upper airway muscle responsiveness. Approximately 70% of people with obstructive sleep apnea have impairment in one or more of the nonanatomical phenotypic traits. Adapted from Carberry et al11 and Aishah and Eckert.12 EEG indicates electroencephalogram; EMGMTA, 100 ms moving time average of the rectified, raw genioglossus electromyogram; EMGraw, raw genioglossus electromyogram; Pcrit, critical closing pressure of the upper airway.

OSA is a heterogeneous disease.10 While all patients have a degree of upper airway anatomical impairment due to a narrow, crowded, or collapsible pharyngeal airway, the extent to which anatomical features contribute to OSA varies markedly from patient to patient. Indeed, more than two-thirds of patients with OSA have additional “nonanatomical” traits or phenotypes that contribute to disease pathogenesis.10 These nonanatomical traits include poor upper airway dilator muscle function during sleep, instability of ventilatory control, and a low threshold for awakening (cortical arousal) to minor respiratory events during sleep (Figure 1). All 4 OSA phenotypes have specific vulnerabilities for the development of postoperative complications. Although gold-standard methodology to quantify OSA phenotypes is invasive and constrained to research settings,13,14 novel approaches such as automated signal-processing analysis of standard polysomnography data and simple wakefulness tests offer promise as noninvasive, clinically deployable tools to estimate OSA phenotypes15–26 (Table).


Impaired Upper Airway Anatomy

The most common predisposition to OSA is a narrow, crowded, or collapsible upper airway. Obesity is a major factor that contributes to reduced pharyngeal airspace. Adipose tissue deposition in the soft tissues of the neck and pharyngeal muscles crowds the upper airway. The specific location of adipose tissue likely plays an important role in OSA development. Obese patients with OSA have more fat in the tongue compared to obese people without OSA.27 Abdominal fat also plays an important role. Decreased resting lung volume caused by central adiposity reduces caudal traction on the upper airway structures, increasing pharyngeal collapsibility.28

Craniofacial shape and size also impact pharyngeal airway cross-sectional area. Decreased mandible length and depth increase OSA risk in men.29 Smaller upper airway bony dimensions may pose specific risk for upper airway collapse in Asians.30,31 An anatomically long upper airway (common in men) is more prone to collapse. Indeed, increased upper airway length and inferior position of the hyoid bone are both associated with a diagnosis of OSA.32,33

Body and head position can also influence upper airway collapsibility. Supine sleep position is associated with increased upper airway collapsibility compared to lateral.34 Collapsibility increases with head flexion and reduces with extension.35 This is an important mechanism for improvement in airway patency with the common “chin lift” maneuver. Supine position also leads to rostral fluid shifts, with redistribution of fluid into various tissues, including those surrounding the upper airway. This increases pharyngeal tissue pressure, reduces cross-sectional area, and increases upper airway collapsibility.36

A key physiological outcome of impaired upper airway anatomy is an increase in the luminal pressure at which upper airway collapse occurs. This measurement is known as the critical closing pressure of the upper airway (Pcrit). Severe anatomical compromise is designated where a Pcrit of >2 cm H2O is recorded during sleep. Conversely, circumstances where a negative pressure of less than −5 cm H2O is required to collapse the airway (ie, a Pcrit of <−5 cm H2O) indicate an airway that is not prone to collapse.10 Pcrit values close to atmospheric indicate intermediate anatomical compromise. Given that all patients with OSA have at least some degree of upper airway impairment, patients with OSA have, on average, a higher Pcrit than those without OSA.37 However, due to the varying degree to which upper airway impairment and the nonanatomical traits contribute to the pathogenesis of OSA between individuals, there is considerable variability in Pcrit levels in people who have OSA ranging from −5 to +5 cm H2O and beyond.10,37


In addition to impaired upper airway anatomy, 3 specific nonanatomical phenotypes play key roles in OSA pathogenesis. These nonanatomical traits have only recently been characterized.10 Postoperative factors may affect each of these traits in unique ways, increasing the risk of complications.

Upper Airway Muscle Responsiveness

The pharyngeal airway subserves multiple important functions. These include speech, swallowing, and breathing. There is a complex interplay between multiple muscles within this nonrigid structure to facilitate these important functions. Without a rigid bony structure, airway patency is at risk and reliant on unimpaired function of pharyngeal muscles. These muscles increase their activity levels and serve to dilate the upper airway in response to airway narrowing (or negative pharyngeal pressure). This process is termed “upper airway muscle responsiveness.”

Two key muscles involved in upper airway muscle responsiveness are genioglossus and tensor palatini. Genioglossus, the largest upper airway dilator, is located at the base of the tongue. Genioglossus has a phasic activation pattern with greater activity during inspiration versus expiration.38 This serves to counteract airway narrowing from suction pressures generated during inspiration. Genioglossus activation is partly dependent on sleep state and is also influenced by input from brainstem pattern generator neurons, pharyngeal airway pressure-sensitive mechanoreceptors, and chemical drive via hypoxia and hypercapnia.39–42

In contrast to the phasic contraction of genioglossus, tensor palatini tends to display a tonic (ie, constant) level of activation during quiet breathing. Like genioglossus, tensor palatini activity is mediated by several factors that influence neural drive but is strongly influenced by the sleep state.42 In experiments where upper airway resistance is minimized with continuous positive airway pressure (CPAP), tensor palatini activity markedly reduces at sleep onset but then remains relatively constant across sleep stages. Under the same conditions, genioglossus activity progressively diminishes from deeper slow-wave sleep, to lighter stage 2 sleep (N2), to rapid eye movement (REM) sleep.42,43

The ability of the pharyngeal muscles to effectively increase muscle tone in response to respiratory stimuli (such as hypercapnia) during sleep is important in OSA pathogenesis. Over one-third of OSA patients have impaired upper airway dilator muscle responsiveness.10 When exposed to airway narrowing during sleep, there is either no or very little muscle activation. A subset of patients with OSA have increased muscle activity in response to airway narrowing, yet the response is ineffective. Reasons for reduced “muscle effectiveness,” despite an appropriate increase in neural drive, include a dissociation between neural drive and dilator muscle response, impaired dilator muscle coordination, altered muscle mechanics (ie, due to fat deposition), and increased fatiguability secondary to changes in muscle fiber type.44–46

Given that patients with OSA do not experience airway obstruction awake, the interplay between the anatomical vulnerability and sleep-dependent reductions in upper airway muscle responsiveness is a key concept in understanding OSA pathogenesis. However, this interaction is not a dominant factor in every patient with OSA, where other nonanatomical processes play an important role.

Respiratory Arousal Threshold

Respiratory stimuli (ie, hypoxia, hypercapnia, or respiratory loading) induce brief awakenings from sleep. These awakenings are known as cortical arousals. The degree of stimulus or respiratory effort required to induce a cortical arousal, measured as the nadir epiglottic or esophageal pressure just before cortical arousal, is known as the respiratory arousal threshold. The arousal threshold varies markedly between individuals.47,48 Individuals who wake up very easily to minor levels of airway narrowing/respiratory effort (low arousal threshold) are susceptible to increased frequency of awakenings during sleep. At least one-third of people with OSA have a low arousal threshold.10

It was originally thought that an arousal was a protective response that was universally required for an obstructed airway to reopen through a state-related increase in upper airway dilator muscle activity.49 However, this notion has been challenged after the discovery that airflow can be restored in OSA in the absence of arousal via protective neuromuscular mechanisms. Indeed, in some cases, arousals can exacerbate detrimental cyclical breathing patterns in OSA, as the instability of sleep onset, with its associated reduction in ventilatory drive, is propagated by recurrent arousals in those with low arousal thresholds.48

Within an individual, arousal tends to occur at a relatively constant level of negative intrathoracic pressure. Approximately 30%–50% of patients with OSA exhibit arousals in response to very small changes (0 to −15 cm H2O) in negative intrathoracic pressure. A low arousal threshold phenotype is likely to be important in the pathogenesis of OSA in most nonobese people with OSA.50

There are 3 main pathways by which a low arousal threshold contributes to OSA. First, arousals prevent the progression of sleep into deeper stages where respiratory control is more stable.51 Respiratory events occur less frequently in deep sleep.52 Deep sleep is associated with a transient increase in the arousal threshold and increased genioglossus muscle activity.42,53 Frequent arousals, irrespective of cause, prevent the progression from lighter N1 (stage 1 sleep) and N2 into deeper more stable stage 3 sleep (N3; slow wave).54 Second, low arousal threshold reduces the opportunity for upper airway dilator muscle activation. As airway obstruction increases, there is a buildup of respiratory stimuli that increases drive to the pharyngeal dilator muscles. However, the arousal threshold is also sensitive to these inputs. People with a low arousal threshold typically experience arousal before the pharyngeal dilators receive sufficient drive to activate and reestablish adequate airway patency.55 Third, arousals can trigger events that lead to ventilatory instability. Cortical arousals cause sudden increases in minute ventilation. On return to sleep, the increased ventilation can drive arterial CO2 below the apnea threshold, resulting in central apnea and ventilatory control instability.48,56 Nonetheless, while continual cortical arousals to minor airway narrowing/blood gas disturbances can perpetuate OSA severity, arousal also serves a vital protective role to rapidly restore airflow during more severe breathing disruptions.54 Thus, in the anesthetized state, suppression of arousal mechanisms requires careful monitoring until consciousness and protective arousal responses are restored.

Loop Gain

Ventilatory drive during sleep is highly dependent on blood CO2 levels. The ventilatory response to fluctuations in CO2 varies between individuals. In individuals with unstable or overly sensitive responses, OSA may occur.57 In engineering, the sensitivity of a system controlled by feedback loops that modulate output is known as loop gain. Regarding ventilatory control, loop gain is defined as the ratio of the ventilatory response to a disturbance, for example, a rise in arterial CO2 tension. When the response is out of proportion to the stimulus, for example, excessive hyperventilation that overcompensates for a small change in CO2, loop gain is high. High loop gain systems are prone to oscillations and are inherently unstable, because they predispose to repetitive fluctuations of CO2 levels between hyperventilation and the apnea threshold. Indeed, high loop gain contributes to OSA in several ways. First, ventilatory overshoot may cause rapid, large negative inspiratory pressures that increase suction forces within the pharyngeal airway in excess of levels to which the upper airway dilators can adequately respond.14 Second, oscillations in ventilation can lower the drive to the upper airway dilators during periods of decreased ventilation. Thus, a mismatch between pharyngeal dilator muscle activity and upper airway resistance may occur, resulting in airway collapse.10 Over one-third of patients with OSA have high loop gain. In OSA patients with only mild-to-moderately impaired upper airway anatomy, high loop gain plays an important role in disease pathogenesis.10,58


Figure 2.
Figure 2.:
Schematic of interactions between opioids, OSA phenotypes, and OSA disease severity based on human studies that have formally measured the effects of opioids on phenotypes. The outside oval (lighter blue, black text) depicts the known effect of opioids on OSA phenotypes. The inner oval (darker blue, white text) depicts the combined effects of opioids and OSA phenotypes on OSA severity. ↑ = increase; ↔ = no change; ↓ = decrease. Larger symbols indicate greater magnitude of effect. Refer to the text for further detail. *Expected change based on the findings from Meurice et al.60 OSA indicates obstructive sleep apnea.

The immediate postoperative period is a time of heightened risk for patients with OSA. Specific postoperative risk factors have the potential to alter the 4 key OSA phenotypes in complex and potentially different ways between patients. Indeed, the interplay between common postoperative procedures such as opioid use and their effect on OSA phenotypes, and therefore OSA severity, varies considerably between individuals and is likely to be significantly influenced by baseline phenotypic characteristics and individual susceptibility (Figure 2).59


Impaired CPAP Delivery

CPAP is highly efficacious at reversing anatomical impairment of the upper airway.61 CPAP reduces breathing disturbances and hypoxemia postoperatively in patients with OSA.62 However, numerous postoperative factors may compromise effective CPAP administration to the surgical patient. Surgery that involves the upper airway may cause edema or hematomas that temporarily worsen anatomical impairment and reduce CPAP tolerance. Postoperative CPAP compliance is low at only 45%.63 Factors such as pain, nausea and vomiting, and inability to sleep may all play a role in decreased CPAP tolerance. The presence of any tubes at the mouth or nose, for example, nasogastric tubes, may render CPAP ineffective due to inadequate mask seal. Certain upper airway structures (eg, epiglottis) may be vulnerable to disfunction following opioids and other central nervous system (CNS) depressants64 which may make CPAP delivery more challenging, although this has not been investigated.

Rostral Fluid Shifts

Rostral fluid shift that occurs while the patient is supine may increase upper airway impairment in the postoperative period.65 This is most likely in those who already have fluid retention (eg, those with cardiac failure or renal impairment). Postoperative use of lower-limb compression devices to prevent deep vein thrombosis may exacerbate supine-related physiological rostral fluid shifts/risk of upper airway collapse in susceptible individuals.66


There is conflicting evidence regarding the effect of opioids on upper airway impairment in patients with OSA.67 Opioids have been linked to increased upper airway obstruction in the perioperative setting.68,69 However, whether a direct effect of opioids on upper airway collapsibility is an important contributor to these OSA-opioid relationships (Figure 2) is unclear because the methods used to study it have varied and have not included the gold-standard Pcrit measure. In a small pilot study of healthy individuals, Pcrit was lower (less collapsible airway) after naloxone infusion.60 This suggests a possible link between increased upper airway collapsibility and opioids. However, in a study of 21 men with OSA following a single dose of modified-release morphine 40 mg before sleep, Pcrit did not change versus placebo.70 There are no studies on the effects of other opioids on upper airway collapsibility. However, it is conceivable that higher doses of opioids, particularly when combined with other CNS depressants, may worsen upper airway stability in the postoperative setting. This requires further investigation.



Few studies have directly measured the effects of opioids on upper airway electromyographic activity. The available results are somewhat conflicting. In isoflurane-anesthetized rats, fentanyl delivered via microdialysis perfusion into the hypoglossal motor nucleus, which innervates genioglossus, suppresses genioglossus activity.71 This was reversed by naloxone. In anesthetized cats, fentanyl depressed laryngeal abductor motoneuron discharge.72 These studies suggest a negative effect of opioids on upper airway muscle responsiveness. However, modified-release morphine 40 mg did not change genioglossus muscle responsiveness during sleep in 21 men with OSA versus placebo.70 The effects of other opioids, different doses, and in combination with other anesthetic agents on pharyngeal muscle function in patients with OSA remains unknown.

Incomplete Reversal of Neuromuscular Blocking Agents

Postoperative residual neuromuscular blockade is associated with critical respiratory events related to upper airway obstruction.73 Partial neuromuscular blockade that is insufficient to evoke respiratory symptoms reduces genioglossus function.74 Incomplete reversal of neuromuscular blockage postoperatively is therefore a risk factor for reduced upper airway muscle responsiveness in patients with OSA. Reversal of neuromuscular blockade with sugammadex may be associated with less postoperative pulmonary complications than neostigmine in patients with OSA.75 However, there is currently insufficient evidence to recommend any specific reversal agents over others to reduce the risk of postoperative respiratory complications.76


Opioids and Other Sedatives

Knowledge of the effects of opioids and other sedatives on the respiratory arousal threshold in OSA is scarce. Acute doses of opioids can reduce slow-wave sleep,77 where the arousal threshold is typically higher (harder to wake up). Thus, opioids may induce a postoperative shift toward lighter stages of sleep that are associated with a lower threshold for arousal (easier to wake up). This would tend to increase OSA severity as measured by the number of apneic or hypopneic episodes per hour of sleep - the apnea-hypopnea index (AHI). Conversely, the CNS-depressant effects of opioids on chemical, behavioral, and respiratory motor control could raise the threshold for arousal during sleep.78 Thus, OSA severity in people with an underlying low arousal threshold phenotype could paradoxically reduce with modest doses of opioids postoperatively, assuming the other phenotypic traits are not adversely affected.

Several studies have quantified the effects of common sedative hypnotics such as trazodone, zolpidem, zopiclone, eszopiclone, triazolam, and temazepam on the respiratory arousal threshold in patients with OSA.54,79–83 On average, standard acute doses of these agents increase the respiratory arousal threshold by ~20%–30%.54,79–83 While responses to hypnotics differ between individuals, the AHI either does not systematically change or in some cases decreases. For example, eszopiclone 3 mg increases the arousal threshold and reduces the AHI by approximately 45% without worsening hypoxemia in patients with a low respiratory arousal threshold.79 Conversely, hypnotics can prolong respiratory events and worsen hypoxemia in patients with a high arousal threshold and severe OSA.81,82 In the only study to date to quantify the effect of an acute dose of morphine on the respiratory arousal threshold in people with OSA, there was no difference versus placebo.70 Interestingly, in chronic pain patients on long-term opioids, the combination of opioids and a hypnotic actually reduces the risk for OSA, presumably due to an increase in arousal threshold.84 Thus, postoperative patients with OSA and low arousal thresholds may be unaffected or possibly even improve in the presence of modest doses of opioids or other sedative medications. However, there is the risk of worsening hypoxemia in individuals with high arousal thresholds and severe OSA, or where substantial respiratory depressant doses of these drugs have been used. Hence arousal threshold estimation16 is potentially important in estimating postoperative risk in people with OSA (Table).



In patients with OSA who have an increased ventilatory response to hypercapnia (ie, high loop gain), opioids may paradoxically stabilize an overly sensitive ventilatory control system, provided baseline respiratory depression is modest. For example, acute administration of morphine reduces central respiratory response to elevated arterial CO2.85,86 In addition, controlled-release oral morphine 30–40 mg reduces sensitivity to hypercapnia awake, the magnitude of which is associated with individual reductions in OSA severity.87,88 Similarly, morphine 40 mg reduces loop gain and ventilatory responses to hypercapnia when the arterial CO2 tension increases 5 mm Hg above eupnea during sleep in men with OSA.70 Thus, those with mild-to-moderate OSA with high loop gain may paradoxically respond positively to modest opioid use, while those prone to more extreme changes in blood gases (such as morbidly obese individuals with severe OSA) are at increased risk of harm. As with the arousal threshold, strategies to estimate loop gain17 are likely to be helpful in managing perioperative risk in people with OSA (Table).

Supplemental Oxygen

Oxygen stabilizes breathing by reducing peripheral chemoreceptor responsiveness to hypoxia and hypercapnia in OSA.19,89 Thus, supplemental oxygen may help to reduce high loop gain and control breathing instability in certain patients with OSA19,89,90 (ie, those with high loop gain) in the postoperative setting. Although loop gain measures were not performed, postoperative supplemental oxygen improves oxygenation and decreases AHI without increasing the duration of apnea-hypopnea events. However, 11% had significant CO2 retention.91


OSA is a heterogeneous disease that increases the risk of postoperative complications. On exposure to postoperative risk factors, underlying OSA phenotypes play a key role in determining the magnitude of this risk. Each OSA phenotype is susceptible to specific postoperative risk factors. Some risk factors, such as opioids, have potentially different effects on OSA severity depending on the underlying phenotype of each patient. Characterization of OSA phenotypes, for which simplified clinical tools are beginning to emerge15–26 (Table), have the potential to provide important insight to help clinicians to deliver safer, more personalized postoperative management and care. However, given that most people with OSA remain undiagnosed, the challenge to develop clinically deployable tools to identify those most at risk remains a priority.


Name: Thomas J. Altree, MBBS, FRACP.

Contribution: This author helped with the design, manuscript drafting, manuscript revision, and final review of the submitted manuscript and agreed to be accountable for all aspects of the study.

Conflicts of Interest: None.

Name: Frances Chung, MBBS, FRCPC.

Contribution: This author helped with the design, manuscript revision, and final review of the submitted manuscript and agreed to be accountable for all aspects of the study.

Conflicts of Interest: F. Chung reports research support from the Ontario Ministry of Health and Long-Term Care, University Health Network Foundation, Up-to-date royalties, consultant to Takeda Pharma and Masimo, STOP-Bang proprietary to University Health Network.

Name: Matthew T. V. Chan, PhD.

Contribution: This author helped with the design, manuscript revision, and final review of the submitted manuscript and agreed to be accountable for all aspects of the study.

Conflicts of Interest: None.

Name: Danny J. Eckert, PhD.

Contribution: This author helped with the design, manuscript drafting, manuscript revision, and final review of the submitted manuscript and agreed to be accountable for all aspects of the study.

Conflicts of Interest: Outside the submitted work, D. J. Eckert receives Cooperative Research Centre Project Grant Funding, a research collaboration between the Australian Government, Academia and Industry (Industry partner: Oventus Medical). He also has research grants on sleep apnea pharmacotherapy and serves as a consultant for Apnimed and Bayer.

This manuscript was handled by: Toby N. Weingarten, MD.


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