Central Sleep Apnea

Introduction

• CSA is characterized by cessation of breathing during sleep due to loss of ventilatory effort for at least 10 seconds, with the upper airway open.
• There are 6 different types of CSA.¹

1. Primary CSA
2. CSA due to Cheyne-Stokes breathing pattern
3. CSA due to a medical condition, not Cheyne-Stokes
4. CSA due to high altitude periodic breathing
5. CSA due to drugs or substances
6. Primary sleep apnea of infancy/apnea of prematurity

Etiology and Pathophysiology

• The pathophysiology of CSA is highly dependent on specific etiologies and is divided into six main categories; however, it is unified by the transient inhibition of the ventilatory motor output during sleep and by failure of the respiratory drive, leading to loss of respiratory muscle function and cessation of airflow into the lungs.²
• The two physiological mechanisms that develop CSA in non-rapid eye movement (REM) sleep³:

1. PaCO₂ regulation of ventilation
2. Hyper-sensitive hypocapnic apneic threshold

Type 1: Primary/Idiopathic CSA

• Occurs in the absence of another etiology.
• This is the rarest form of CSA, with a prevalence estimated to be around 4 to 7%.

Type 2: CSA with Cheyne- Stokes Breathing

• This is most commonly associated with heart failure, atrial fibrillation, and other cardiovascular diseases.⁴ 
• Cheyne-Stokes respirations are characterized by a crescendo-decrescendo pattern of breathing followed by episodes of apnea.
• Apneic episodes occur when the partial pressure of carbon dioxide (PaCO₂) falls below the apneic threshold due to ventilatory overshoot during the hyperventilation period of the Cheyne-Stokes respiratory cycle. These patients tend to be hypocapnic, placing their PaCO₂ values closer to the apneic threshold and increasing susceptibility to central apnea.

• The pathophysiology of this process is likely due to elevated left ventricular pressures and pulmonary congestion, which increases chemoreceptor sensitivity, and reduced cerebral blood flow, subsequently affecting the ventilatory control centers in the brain.

Type 3: CSA Due to Medical Conditions

• CSA secondary to medical conditions, excluding Cheyne-Stokes breathing patterns, encompasses a wide variety of etiologies, including but not limited to:
  • Neurological: ischemic stroke (especially brainstem), spinal cord injury
  • Nephrologic: renal failure
  • Neuromuscular: amyotrophic lateral sclerosis
  • Endocrine: acromegaly²
  • Complex sleep apnea/treatment-emergent CSA⁶
• The pathophysiology of these underlying conditions can vary, but ultimately results in hypocapnia below the apneic threshold, leading to reduced ventilatory drive. This is often accompanied by alterations in chemosensitivity to arterial carbon dioxide (PaCO₂).
• Treatment-emergent CSA develops in a patient with a primary diagnosis of OSA. It develops as a consequence of treatment with a positive airway pressure device.
• The pathophysiology is not fully understood but is thought to involve multiple factors, including upper airway obstruction, ventilatory system instability, the interaction between arousal threshold and activation of lung stretch receptors, and prolonged circulatory time.
• The use of bilevel positive airway pressure (BiPAP) for OSA has been associated with a higher risk of treatment-emergent CSA than continuous positive airway pressure (CPAP).

Type 4: CSA due to High-Altitude Periodic Breathing

• CSA related to high-altitude periodic breathing can occur at altitudes above 2,000-3,000 meters, but it is most commonly seen above 5,000 meters above sea level.
• Periodic breathing at high altitude is characterized by repeated clusters of breath followed by apneic events, which can occur at varying intervals.⁷
• CSA at high altitude occurs in much shorter intervals and lasts 30 seconds, compared with heart failure patients, because there is no delay in circulatory time.
• The pathophysiology results from hypoxia at high altitude, which stimulates ventilatory changes, increases ventilation, and causes hypocapnia. Over time, both hypoxic and hypercapnic ventilatory responses may increase, potentially creating a positive feedback loop that results in persistent sleep apnea.
• It is usually temporary and often resolves with acclimatization, although the time to resolution can range from days to months. Some individuals may be unable to fully acclimate, resulting in ongoing symptoms.

Type 5: CSA Due to Drugs or Substances

• This is most commonly seen with opioids but can also be seen with other medications that are known to affect respiratory drive or effort, such as baclofen, valproic acid, gabapentin, sodium oxybate, and ticagrelor.⁸
• Opioids affect the pontomedullary centers of the brain that are involved in breathing, resulting in ataxic breathing patterns.

• It is uncertain why other medications, such as ticagrelor, which binds to and inhibits the P2Y12 receptor on platelets to prevent platelet aggregation, can cause dyspnea, periodic breathing, and the development of CSA.
• Usually, discontinuing these medications resolves CSA.

Type 6: Primary Apnea of Infancy/Apnea of Prematurity

• Primary apnea of infancy, also known as apnea of prematurity, is most commonly seen in preterm infants. Nearly all infants born before 28 weeks of gestational age experience this condition. While approximately 50% of infants between 28 and 37 weeks are affected. However, apnea of prematurity can occur at any gestational age.
• Primary apnea of infancy is defined as a sudden cessation of breathing that lasts at least 20 seconds and is accompanied by bradycardia, oxygen desaturation (cyanosis), pallor, and/or marked hypotonia.
• Please see the OA summary on apnea of prematurity and postoperative apnea for more details. Link
• This condition should be differentiated from periodic breathing, which consists of a pattern of hyperventilation followed by a brief period of apnea lasting 5-10 seconds. Periodic breathing is common in the first 2-4 weeks of life and usually resolves by 6 weeks; it is considered physiologic rather than pathologic.
• The pathophysiology of apnea of prematurity is thought to result from immature respiratory centers in the brain and attenuated responses to hypoxia and hypercarbia. This may be further exacerbated in infants who have difficulty coordinating sucking and breathing during feeding, as well as exaggerated laryngeal reflexes that can suppress central respiratory drive.
• Apneic episodes can be triggered by multiple factors, including hypoxia, hypercarbia, hypoglycemia, hypothermia, and certain iatrogenic medications.

Evaluation

• The signs and symptoms of CSA include poor sleep quality and sleep fragmentation, nocturnal awakenings, excessive daytime sleepiness, fatigue, morning headaches, impaired concentration, mood changes and irritability, and nocturia. Many of these symptoms overlap with those of OSA; however, OSA often includes snoring, obesity, and other symptoms of upper airway obstruction, which is not necessarily seen in CSA. Cheyne-Stokes breathing is another sign of CSA, but it may not be present in all varieties of CSA.
• The gold standard for diagnosing sleep apnea is nocturnal polysomnography.
  • Primary CSA is diagnosed on polysomnography by the presence of ≥ 5 episodes of central apnea or hypopnea per hour of sleep with no evidence of Cheyne-Stokes breathing and at least one symptom of disrupted sleep.
  • CSA with Cheyne-Stokes breathing is diagnosed with the same apnea-hypopnea and symptom criteria needed for primary CSA, with the additional findings of three or more consecutive central apneas or hypopneas separated by a crescendo-decrescendo respiratory pattern with a cycle length of ≥ 40 seconds.
  • Treatment-emergent CSA requires an initial diagnosis of OSA with an apnea-hypopnea index ≥ 5, followed by resolution of obstructive events and the emergence of CSA during positive airway pressure therapy.
• To clarify, patients with OSA typically experience obstructed airflow despite continued inspiratory effort due to upper airway collapse. With PAP therapy, upper airway obstruction is relieved, and airflow resumes during normal respiratory cycles. However, some patients may develop CSA during ongoing PAP therapy, characterized by the loss of inspiratory effort in the absence of upper airway obstruction. This phenomenon is more commonly observed among patients receiving BiPAP than among those receiving CPAP.

Treatment

• Positive airway pressure devices, including CPAP or BiPAP with a backup rate, adaptive servo-ventilation, have been shown, under certain conditions, to reduce the number of apneic episodes in patients with CSA due to heart failure, polypharmacy medication/ substance use, or other medical conditions.¹ 
• According to the American Academy of Sleep Medicine, this recommendation is conditional because of low certainty of evidence and should be tailored on a case-by-case basis.
• Nocturnal oxygen therapy without the use of positive airway pressure has also been shown to decrease the number of apneic episodes in patients with heart failure and in those with sleep apnea related to high altitude. However, this recommendation is also conditional given the low certainty of the evidence.¹⁰
• Unilateral phrenic nerve stimulators are conditionally recommended for patients with heart failure and primary CSA based on evidence that suggests an improvement in quality of life and reduction of daytime sleepiness independently of heart failure status. Because this therapy is an invasive procedure, it is recommended that alternative treatment options be considered first.
• Pharmacologic sleep aids, such as triazolam and zolpidem, may improve sleep stability and reduce wakefulness. However, their use in this setting remains investigational.²
• Respiratory stimulants, such as acetazolamide, a carbonic anhydrase inhibitor, may reduce the frequency of central apnea episodes by inducing a mild metabolic acidosis that increases respiratory drive.²
• Buspirone and mirtazapine may reduce the incidence of CSA in spinal cord injury.²
• Theophylline, a nonselective adenosine receptor antagonist, may increase ventilatory drive by inhibiting adenosine receptors in the medulla.²

Anesthetic Considerations

Preoperative Considerations

• Consider that many patients are unaware of their sleep apnea before undergoing surgery, with some studies reporting rates as high as 80%.¹⁰
• For patients with risk factors and comorbidities, a thorough history, physical examination, and review of systems should be obtained, with particular attention to symptoms associated with sleep apnea, as outlined above. Additionally, these patients should undergo laboratory work and diagnostic testing specific to the etiology of their sleep apnea.²
  • Patients with heart failure and cardiovascular disease should have a recent echocardiography and electrocardiography, as well as a recent cardiology evaluation. It is important to determine the severity of the heart failure and identify associated comorbidities, such as pulmonary hypertension, which can be exacerbated by sleep apnea. These patients should also have recent laboratory studies, including a complete blood cell count and a comprehensive metabolic panel, and may require an arterial blood gas analysis.⁵
  • Patients with spinal cord or neurologic injuries and musculoskeletal pathologies should undergo a complete neurological examination, with a clear understanding of the level of injury, as well as appropriate imaging if indicated.
  • Patients on chronic opioid therapy should receive a thorough evaluation of their medication, dosages, and side effects.
  • Opioid-naive patients receiving opioids for acute pain management should undergo a thorough review of the pain medication administration during this period, with a close assessment of the patient’s response and any adverse reactions.
  • Infants presenting for surgery should undergo a comprehensive birth history, including gestational age, developmental milestones, and any complications during birth and during the neonatal period.⁹
• Determine whether the patient’s comorbidities have been optimized and whether additional workup or treatment is required prior to surgery.
• For same-day surgeries, determine whether the patient is an appropriate candidate for an ambulatory surgical unit or requires an inpatient hospital setting.
• Review the patient’s polysomnography results to determine the severity of sleep apnea.²
• Determine whether the patient is receiving or adhering to treatment for sleep apnea. Patients who require PAP therapy should bring their device with them in anticipation of a possible overnight admission.
• Formulate a postoperative disposition plan and determine the need for admission. Review your institution’s guidelines; many recommend admission with telemetry/continuous pulse oximetry monitoring, or intensive care unit admission, for severe sleep apnea.

Intraoperative Considerations

• Consider alternative anesthetic techniques, such as local, regional, and neuraxial anesthesia when appropriate.
• Anesthetic medications impair arousal and ventilatory response, increasing the frequency and duration of apneic episodes. They may also attenuate chemoreceptor response to CO₂ and oxygen.⁴
  • Patients with sleep apnea demonstrate increased sensitivity to opioids and often require less than 50% of the dose compared to patients of similar age and weight without sleep apnea. This applies to intravenous, oral, and neuraxial doses.
  • These patients may also exhibit increased sensitivity to other sedative medications, such as benzodiazepines. There is also an additive sedative effect with the administration of both opiates and benzodiazepines.
  • Patients with sleep apnea are more susceptible to neuromuscular blocking agents. Therefore, complete reversal should be confirmed using quantitative twitch monitoring.
  • Consider multimodal pain management strategies, including nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, local anesthetics, magnesium, dexamethasone, gabapentin, lidocaine infusion, gabapentin/pregabalin, and dexmedetomidine/clonidine.
• Avoid deep extubation in these patients and ensure that extubation criteria are met.¹

Postoperative Considerations

• Patients with sleep apnea are at risk for oxygen desaturation, respiratory failure, and cardiac events.² The American Society of Anesthesiology recommends delaying discharge until the risk of respiratory depression and oxygen desaturation has resolved without the need for supportive interventions.
• Non-REM and REM sleep patterns are disrupted in the postoperative period, potentially exacerbating symptoms of sleep apnea.
• Re-evaluate the need for supplemental oxygen requirement, positive airway pressure therapy, and confirm the patient’s postoperative disposition based on their status in the postoperative care unit.
• Review postoperative orders and consider an acute pain service consultation for patients who may require high-dose postoperative opiate therapy. If a patient-controlled analgesia is considered, initiate the therapy at a lower dose with appropriate lockout intervals and without a basal infusion.
• Consider postoperative regional anesthesia when appropriate to minimize opioid requirements.