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. Author manuscript; available in PMC: 2020 Mar 1.
Published in final edited form as: Curr Pulmonol Rep. 2019 Mar 13;8(1):14–21. doi: 10.1007/s13665-019-0221-z

Central Sleep Apnea: a Brief Review

M Safwan Badr 1,*, John D Dingell 2, Shahrokh Javaheri 3,4,5
PMCID: PMC6883649  NIHMSID: NIHMS1524736  PMID: 31788413

Abstract

Purpose

The purpose of this review is to discuss the pathogenesis, clinical manifestations, diagnosis and treatment, including areas of controversy and uncertainty.

Recent Findings

Central apnea may be due to hypoventilation or to hypocapnia following hyperventilation. The occurrence of central apnea initiates a cascade of events that perpetuates breathing instability, recurrent central apnea and upper airway narrowing. In fact, breathing instability and upper airway narrowing are key elements of central and obstructive apnea. Clinically, central apnea is noted in association with obstructive sleep apnea, heart failure, atrial fibrillation, cerebrovascular accidents tetraplegia, and chronic opioid use.

Management strategy for central apnea aim to eliminate abnormal respiratory events, stabilize sleep and alleviate the underlying clinical condition. Positive pressure therapy (PAP) remains a standard therapy for central as well as obstructive apnea. Other treatment options include adaptive-servo ventilation (ASV), supplemental oxygen, phrenic nerve stimulation, and pharmacologic therapy. However, ASV is contraindicated in patients with central sleep apnea who had heart failure with reduced ejection fraction, owing to increased mortality in this population.

Summary

There are several therapeutic options for central apnea. Randomized controlled studies are needed to ascertain the long-term effectiveness of individual, or combination, treatment modalities in different types of central apnea.

Keywords: Central apnea, sleep, opioid, heart failure, positive-pressure therapy, CPAP, BPAP, adaptive-Servo ventilation

Introduction

Central apnea during sleep is not due to a single etiology. Rather, it is a manifestation of central breathing instability in a variety of clinical conditions.1,2 Although our understanding of the specific mechanism(s) of central apnea has grown appreciably in the past decade, the underlying pathophysiology remains incompletely understood. Further, the pathophysiologic overlap between central and obstructive sleep apnea (OSA) defies the separation into two distinct “silos”. Not surprisingly, a number of current treatment options for treatment of central sleep apnea (CSA) are derived from approaches used for the treatment of obstructive sleep apnea. This review will address the pathogenesis, clinical manifestations, diagnosis and treatment of CSA, including areas of controversy and uncertainty.

I. DETERMINANTS OF CENTRAL APNEA DURING NREM SLEEP

I.1. Initiation of Central Apnea

Central apnea is the result of transient inhibition of ventilatory motor output. Sleep state, transient hypocapnia, unstable ventilatory control system, upper airway reflexes, and depression of brain stem rhythm generation may all contribute to “turning off” the ventilatory motor output and the development of central apnea.

The fundamental mechanisms of central apnea could be due to hypoventilation or post-hyperventilation. Withdrawal of the wakefulness drive to breathe leads to decreased ventilatory motor output, which may be inconsequential in healthy individuals but leads to hypoventilation and even apnea in patients with inadequate ventilatory reserve such as those with neuromuscular disease or thoracic cage disorders. Opioid analgesics and other CNS suppressants may also contribute to hypoventilation. It is of note that hypoventilation-related central events may occur before diurnal hypercapnia is noted.

Central apnea occurs most commonly during non-rapid eye movement (NREM) sleep. The removal of the wakefulness “drive to breathe” during NREM sleep renders respiration critically dependent on chemical influences, especially PCO2. Thus, NREM sleep unmasks the apneic threshold, a phenomenon that is sleep state-dependent.3 Accordingly, central sleep apnea occurs if arterial PCO2 drops below a highly sensitive “apneic threshold”.2–4

Transient hypocapnia (PCO2 dropping below the steady state NREM PCO2) is a powerful mechanism of reduced ventilatory motor output during NREM sleep. However, several factors modulate and may counter the inhibitory effects of hypocapnia on ventilatory motor output.

Duration of hyperpnea:

The occurrence of central apnea requires hypocapnia that is sufficient in magnitude and duration to affect medullary central ventilatory control centers. Accordingly, brief hyperventilation rarely produce central apnea in sleeping humans5or dogs6 Therefore, short periods of hyperventilation (less than a minute) are unlikely to cause central apnea possibly due to insufficient medullary hypocapnia.

Short-term potentiation:

Brief active hyperventilation (e.g. hypoxia) elicits an excitatory neural mechanism referred to as short-term potentiation (STP) [3–5], which mitigate the post hyperventilation reduction in ventilatory motor output.7,8

In summary, the duration and the magnitude of hyperventilation may determine the level of medullary hypocapnia and short-term potentiation determines the occurrence of post-hyperventilation apnea during stable sleep. A practical application of the aforementioned phenomena is the infrequent occurrence of central apnea following acoustically induced arousals from sleep in healthy individuals without hypoxia.

Depression of rhythm generation:

Medications such as opioids suppress rhythm generation in the neurons of Pre-Botzinger complex, the presumed site of rhythm generation in mammals, located in the brain stem. Opioids, like beta agonists, act on seven transmembrane G protein receptors, but in contrast to beta agonists suppress downstream signal transduction by decreasing cyclic AMP.9 Some neurodegenerative disorders may cause central sleep apnea by a similar mechanism. In this case, neurokinin 1–expressing (NK1R) neurons of the pre-Botzinger complex are potentially permanently damaged.10

I.2. Recurrent central apnea and perpetuation of breathing instability

The ventilatory control system includes multiple components that operate as a closed feedback with the goal maintaining arterial blood gas tensions within a narrow physiologic range. The overall gain of the system is referred to as “loop gain”,11,12 which represents the overall response of the multiple components of the ventilatory feedback loop including: 1) the plant (representing the lung and respiratory muscles), 2) the controller (representing the ventilatory control centers and the chemoreceptors), and 3) the circulatory delay, dilution and diffusion required to carry the signal between the plant and the controller. Increased loop gain is the underlying mechanism of ventilatory control instability and development of central sleep apnea in heart failure.13

Central apnea occurs in cycles of apnea/hypopnea alternating with hyperpnea and NOT as isolated events. The occurrence of central apnea initiates a cascade of events that perpetuate unstable breathing (Figure 1) including the inertia of the ventilatory control system, upper airway narrowing/occlusion, hypoxia, hypercapnia and transient EEG arousal. The ventilatory control system exhibits marked inertia upon cessation of the ventilatory motor output. Consequently, rhythmic breathing does not resume until arterial PaCO214 is 4 to 6 mmHg above eupneic PaCO2. In addition, central apnea results in narrowing or occlusion of the pharyngeal airway15, which additional force to overcome gravitational craniofacial forces or mucosal tissue adhesion.16,17.Finally, the combination n of gas exchange derangements and transient EEG arousals results in ventilatory overshoot, hypocapnia and recurrent central apnea. This sequence explains why apnea rarely occurs as a single event (i.e., “apnea begets apnea”) Furthermore; central apnea is often accompanied by obstructive and mixed apnea in the same patient.

Figure 1. Schematic representation of central apnea.

Figure 1.

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Mechanisms that perpetuates breathing instability and recurrent central apnea

II. CLASSIFICATION OF CENTRAL SLEEP APNEA

II.1. The International Classification of Sleep Disorders (ICSD-3).18

The ICSD-3 provides the following classification of central apnea.

  • Central sleep apnea with Cheyne-Stokes breathing (CSB)

  • Central sleep apnea due a medical disorder without CSB

  • Central sleep apnea due to high altitude periodic breathing

  • Central sleep apnea due to a medication or substance

  • Primary central sleep apnea

Treatment-emergent central sleep apnea

The aforementioned classification is useful clinically by identifying clinical syndromes associated with central apnea. However, it is not based on pathophysiologic mechanisms and hence may not inform therapeutic decisions.

II.2. Pathophysiologic Classification

Central sleep apnea secondary to alveolar hypoventilation:

Individuals with diurnal hypercapnia, and those with marginal respiratory status, may develop sleep-related hypoventilation due to the removal of the wakefulness drive to breathe. The spectrum of disorders causing daytime hypercapnia is wide (1) and includes conditions such as neuromuscular diseases (post-polio syndrome, ALS, brain stem stroke, central alveolar hypoventilation, or severe abnormalities in pulmonary mechanics such as kyphoscoliosis). In the face of hypercapnia, the alveolar ventilation equation dictates that small alterations in ventilation will result in large changes in PCO2 (increased plant gain). Therefore, under such circumstances, a transient arousal from sleep, with associated small rise in ventilation could lower the PaCO2 below the apneic threshold with subsequent central apnea.

The presenting clinical picture of such individuals often includes features of sleep-disordered breathing, ventilatory failure, and features of the underlying disease. The specific etiology responsible for hypercapnic central sleep apnea in a given patient influence(s) the management strategy aimed at restoration of effective alveolar ventilation during sleep, and while awake if applicable. Treatment of choice is assisted ventilation (such as bilevel devices with back up rate); nasal CPAP and supplemental oxygen are unlikely to alleviate the condition. The latter may aggravate the condition, based on the pathophysiology discussed above, such that with suppression of hypoxic drive, PaCO2 increases further, with further increase in plant gain which increases the probability of developing central apnea during sleep.

Central apnea secondary to hyperventilation-

Post-hyperventilation hypocapnia is the most common underlying mechanism of central apnea. This type of apnea is characterized by transient instability of the ventilatory control system AND normal or increased alveolar ventilation. This type of CSA is most common in patients with heart failure who may be hypocapnic during wakefulness. In addition, such patients have a long circulation time which converts a negative feedback system to a positive one contributing to overshoot and undershoot of ventilation and persistent hyo-and hyperventilation.

III. CENTRAL APNEA RISK FACTORS

Several physiologic or pathologic factories may influence the susceptibility to develop central apnea including sleep state, age, gender, and several medical conditions.

a. Sleep state

The transition from wakefulness to NREM sleep may be associated with recurrent central apnea. The underlying etiology is the oscillation of sleep state oscillates between wakefulness and light sleep [30–33] with a reciprocal oscillation of PaCO2 around the “apneic threshold”). Transient arousal leads to brief hyperventilation; the ensuing hypocapnia results in central apnea upon resumption of sleep. Typically, these events resolve with consolidation of sleep and stabilization of PaCO2 above the apneic threshold. Sleep onset, manifesting as a transition from alpha to theta, is also associated with prolongation of breath duration34 which may manifest as central apnea in some individuals. Therefore, transient central apnea at sleep onset may be a normal phenomenon.

Central sleep apnea is uncommon during REM sleep. Decreased propensity to central apnea during REM sleep may be attributed to decreased hypercapnic and hypoxic ventilatory responses, and hence reduced loop gain,19 possibly due to inhibition of accessory chest wall muscles. Other mechanisms include increased ventilatory motor output during REM sleep relative to NREM sleep.20 Conversely, decreased accessory muscle activity during REM sleep may exacerbate REM-related hypoventilation in patients with diaphragm dysfunction or paralysis. Consequently, nadir tidal volume may be negligible and appear as central apnea (Pseudo CSA). Thus, central apnea during REM sleep represents transient hypoventilation rather than post-hyperventilation hypocapnia.

b. Age and gender

Central sleep apnea is more prevalent in older adults relative to middle-aged individuals.21,22 In one large epidemiologic study, the prevalence of central apnea (defined as a central apnea index [CAI] of ≥2.5) was 1.7% in the middle-aged group vs. 12.1% in the older adults group.23Physiologically, sleep state oscillations may precipitate central apnea in older adults.24 Older adults are more susceptible to induced central apnea. Using nasal mechanical ventilation to induce central apnea, Chowdhuri et al demonstrated that the magnitude of hypocapnia required to induce central apnea was smaller in older adults compared to young adults. (−2.6 ± 0.4 vs. −4.1 ± 0.4 mmHg, P = 0.01).25 Increased prevalence of central apnea may also be due to increased prevalence of co-morbid conditions such as hypothyroidism26, congestive heart failure,13 and atrial fibrillation27, in older adults.47

Epidemiologic studies have shown that central apnea is rare in women, with an overall prevalence of central apnea (CI > 0) in women of 0.3%, compared with 7.8% in men.4,28 This observation has been corroborated by studies demonstrating that men are more susceptible to the development of experimentally induced central apnea during relative to women mechanical ventilation. The magnitude of hypocapnia that is required to induce central apnea was −3.5 mmHg vs. −4.7 mmHg below room air level in men and women respectively4. Interestingly, the phase of the menstrual cycle did not influence the propensity to central apnea in women, indicating that gender difference was not due to progesterone.

c. Medical Conditions

Sleep-disordered breathing is common in patients with heart failure; in one study 51% of male patients with heart failure had sleep disordered breathing. The majority of the patients had central apnea (40%) and the remainder (11%.) had obstructive apnea.29 Risk factors for central apnea in this group of patients include male gender30, atrial fibrillation, age > 60 year, very low left ventricular ejection fraction (less than 30%), and hypocapnia Risk factors for OSA differed by gender; the only independent determinant in men was body mass index (BMI), whereas age over 60 was the only independent determinant in women.

Patients with central apnea and congestive heart failure (CHF) demonstrate pulmonary vascular congestion leading to hyperventilation and hypocapnia. Increased ventilation and reduced steady state PaCO2 decreases plant gain, which should be stabilizing.31 In other words, steady-state hypocapnia is potentially stabilizing rather than destabilizing. However, in patients with heart failure the magnitude of hypocapnia required to induce central apnea (referred to as the CO2 reserve) is small owing to controller gain below eupnea31

Sleep apnea is common after a cerebrovascular accident (CVA).32 Forty percent of the patients demonstrate central apnea as the predominant type of sleep disorder after a CVA.33 Likewise, central apnea occurs in 30% of patients with stable methadone maintenance treatment34. Finally, central apnea is common in several medical conditions including hypothyroidism, and renal failure. Nocturnal hemodialysis is associated with improvement in sleep apnea indices.35 The reported association between acromegaly and central sleep apnea36 was not corroborated in a cross-sectional study of a clinical cohort.37

Individuals living with spinal cord injury are at increased risk of central apnea.38,39Specifically, tetraplegia is associated with a high prevalence of central apnea/hypopnea, resembling Hunter-Cheyne-Stokes breathing. Those who do not manifest spontaneous central apnea demonstrate increased propensity to experimentally induced central apnea using noninvasive mechanical ventilation.

Central apnea occurring with no apparent risk factor is described as “idiopathic central apnea”. Increased chemo responsiveness and sleep state instability are commonly noted in these patients.40 Nevertheless, it is possible that these patients have occult cardio-cerebrovascular or metabolic disease. For example, central sleep apnea is more prevalent in patients with, or asymptomatic carotid atherosclerosis41

IV. CLINICAL FEATURES AND DIAGNOSIS

The underlying disease process and the occurrence of apneas during sleep are the two factors that influence the clinical features of hypercapnic central apnea. These include features of the underlying disease such as weakness and dyspnea, as well as features of sleep apnea syndrome, including daytime sleepiness, snoring, and poor nocturnal sleep as well as morning headache.

Patients with non-hypercapnic central apnea may present with the usual symptoms of sleep apnea syndrome, although generally do not endorse subjective daytime sleepiness.42 Frequent oscillation between wakefulness and stage 1 NREM sleep may cause sleep fragmentation and poor nocturnal sleep and perception of insomnia as the presenting symptoms.

Central sleep apnea may also be a found as an associated finding in a patient with OSA, either on the initial polysomnography or after restoring upper airway patency with positive pressure therapy. This phenomenon is referred to as “Treatment-Emergent Central Apnea”. The name implies a specific or unique clinical entity. However, it is likely that this phenomenon represents unmasking of the underlying breathing instability in patients with OSA. Spontaneous resolution occurs in the majority of patients with continued use of CPAP.43

Nocturnal polysomnography is the standard diagnostic method for the measurement of sleep and breathing. The latter includes detection of flow, measurement of oxyhemoglobin saturation and detection of respiratory effort.44 Detection of respiratory effort is important to distinguish central from obstructive apnea. This requires measurement of esophageal pressure, as a reflection of pleural pressure changes. However, the complexity and invasiveness of the procedure, and its cost have precluded widespread use. Instead, most clinical sleep laboratories utilize surface recording of effort, to detect displacement of the abdominal and thoracic compartments and dysynchrony during episodes of upper airway obstruction. Invasive esophageal or supra-glottic pressure measurement is reserved for selected cases and for research purposes.

The presence of cardiogenic oscillations (pulse artifacts) on the flow signal has been used as an indirect index of central etiology based on the assumption that pulse artifacts represent transmission of a pulse waveform from the thorax through a patent upper airway. Using fiber optic nasopharyngoscopy, Morrell et al found that cardiogenic oscillations were present even when the airway is completely occluded.44 Therefore, cardiogenic oscillations is not a reliable regarding the patency of the upper airway or the etiology of an apnea.

V. MANAGEMENT

Management strategy for central apnea incorporates clinical features, co-morbid conditions, and the polysomnographic findings in an individualized manner. Available therapeutic options include positive pressure therapy, phrenic nerve stimulation, and pharmacologic therapy including low flow supplemental oxygen administration.46

a. Positive pressure therapy (PAP)

Optimal treatment of concomitant clinical conditions is a critical first step, which may result in amelioration of the severity of central apnea. Positive pressure therapy could be delivered as continuous positive airway pressure (CPAP), bi-level pressure (B-PAP) or Adaptive servo ventilation (ASV). CPAP is the recommended treatment first line therapy for central apnea with about 50% response rate. Reasons for response to CPAP include: 1) a direct effect of CPAP on central apnea by preventing pharyngeal narrowing during central apnea15 and dampening the ensuing ventilatory overshoot., 2) co-occurrence of central and obstructive apnea, and 3) the difficulty distinguishing central from obstructive SDB on routine polysomnography. Interestingly, nasal CPAP has been shown to ameliorate central sleep apnea, even in the absence of obstructive respiratory events,47 especially supine-dependent central sleep apnea. Most of the studies on the use of nasal CPAP in central apnea address patients with CHF. Nasal CPAP may have significant salutary effects in patients with congestive heart failure and central sleep apnea. Several lines of evidence, both theoretical and empiric, underpin the use of CPAP in this setting. Specifically, CPAP suppresses CSA in 50% of patients with heart failure, with ensuring decrease in nocturnal ventricular arrhythmias

The premise that nasal CPAP therapy was an effective therapy for central apnea and CHF was not supported by empiric evidence. The Canadian Continuous Positive Airway Pressure trial, or CANPAP (80), tested the hypothesis that CPAP would improve the survival rate without heart transplantation in patients with heart failure and central sleep apnea. The study enrolled 258 patients who had heart failure and central sleep apnea; participants were randomly assigned to the nasal CPAP treatment group (n=128) or no CPAP (130 patients). CPAP was associated with improvement in intermediate outcomes, including the apnea-hypopnea index, ejection fraction, mean nocturnal oxyhemoglobin saturation, plasma norepinephrine levels, and the distance walked in 6 min at 3 months. However, there was no difference in the overall event rates (death and heart transplantation) between the two groups. Therefore, current evidence does not support the use of CPAP to extend life in patients who have heart failure and central sleep apnea. Conversely, post hoc analysis of the findings demonstrated a significant improvement in survival of heart failure patients in whom CSA was suppressed.48

Non-invasive positive pressure ventilation (NIPPV) using pressure support mode (bi-level nasal positive pressure) is effective in restoring alveolar ventilation during sleep. Clinical indications include nocturnal ventilatory failure and central apnea secondary to hypoventilation. There is evidence that NIPPV exerts a salutary effect on somnolence, fatigue and survival in patients with ventilatory failure secondary to amyotrophic lateral sclerosis.49 The effect on NIPPV on other neuromuscular conditions associated with nocturnal ventilatory failure remains unclear.

The development of central apnea may be mitigated by altering the mode of delivering positive pressure therapy. Specifically, Adaptive Servo Ventilation (ASV) provides varying amount of ventilatory support, against a background of positive end expiratory pressure (EPAP). In the new generation of ASV devices, EPAP changes automatically similar to auto-PAP used to treat OSA. There are 2 such devices available in US with completely different algorithms,50 making it difficult to be familiar with both devices.

Contrary to bi-level, pressure support devices, changes in respiratory effort results in reciprocal anticyclical changes in the magnitude of ventilatory support. There is evidence that ASV is more efficacious than CPAP, bi-level pressure support ventilation, or increased dead space in alleviating central sleep apnea.51However, a recent clinical multi-center (SERVE-HF) randomized clinical trial in patients with predominantly-central sleep apnea and hear-failure with reduced ejection fraction (HF-rEF) demonstrated increased mortality in patients randomized to ASV.52 Therefore, ASV is contraindicated in patients with HF-rEF and central apnea.53 Nevertheless, a concern about the specific algorithm used in the aforementioned trial52 raised the possibility that fixed - not automatic end-expiratory pressure, and aggressive inspiratory pressure may have contributed to excess mortality.54 An ongoing study, ADVENT-HF [Effect of Adaptive Servo Ventilation (ASV) on Survival and Hospital Admissions in Heart Failure]; NCT01128816) trial, is examining the role of ASV using a refined algorithm.

2. Pharmacological Therapy

The role of pharmacological therapy for central apnea is very modest, and there are no long-term controlled clinical trials demarcating the boundaries of effectiveness. There is evidence derived from small studies, but no large clinical trials, to support the use of acetazolamide and theophylline in the treatment of central apnea 89. Acetazolamide, a weak diuretic that causes mild metabolic acidosis has been shown in several studies to decrease the severity of central apnea. when administered as a single dose of 250 mg before bedtime 90. Improvement in central apnea and Cheyne-Stokes respiration was also demonstrated with the use of theophylline in patients with CHF 91, without adverse effect on sleep architecture. Nevertheless, pharmacologic therapy remains as a potential future opportunity awaiting definitive clinical trials.

3. Supplemental Oxygen (O2) and CO2

Several studies have demonstrated a salutary effect of supplemental O2 in patients with central apnea associated with heart failure.55Physiologically, supplemental oxygen may alleviate central apnea by mitigating the magnitude of hypoxemia and hence dampening the magnitude of post-apneic ventilatory overshoot. In addition, isocapnic hyperoxia has been shown to stimulate ventilation in a dose-dependent manner.56 The most likely explanation is increased cerebral PCO2 by the displacement of carbon dioxide from hemoglobin by the increased oxygen level (Haldane effect). The American Academy of Sleep Medicine (AASM) recommends nocturnal oxygen as a standard treatment for central apnea related to heart failure.46

Supplemental CO2 abolishes central apnea in patients with central sleep apnea. The mechanism of action is by raising PCO2 above the apneic threshold. However, this therapy is not practical given the need for a closed circuit to deliver supplemental CO2.

4. Phrenic Nerve Stimulation

Stimulation of the phrenic nerve is a physiologically appealing intervention that may be an option for patients with central apnea. A new commercially available implantable phrenic nerve stimulator that provides unilateral stimulation of the phrenic nerve. (remedé system, Respicardia Inc, Minnetonka, MN, USA) has been recently approved by the FDA for the treatment of moderate to severe central sleep apnea (CSA) in adult patients. Approval was based on a randomized clinical trial demonstrating improvement in central apnea indices, oxygenation, sleep metrics and quality of life.57 Phrenic nerve stimulation appears to be a promising therapeutic approach for central sleep apnea. The precise role of this therapy awaits studies of long term outcome, safety as well as comparative effectiveness.

VI. APPROACH IN SELECTED CLINICAL SYNDROMES

The heterogeneity of central sleep apnea mandates an individualized treatment approach. Several factors have to be considered for proper management of each patient:

  1. It is imperative to optimize treatment of the underlying condition such as CHF; Follow up polysomnography is needed to confirm improvement in the severity of apnea.

  2. A trial of nasal CPAP is warranted as a starting point. There is good evidence that many patients may respond to positive pressure therapy. The optimal pressure settings have to be determined by a lab observed titration polysomnography.

  3. The use of Bi-level-PAP in a pressure support mode is likely to aggravate the severity of central apnea. Adding a backup rate may be beneficial but should not be used for the treatment of CSA in HFrEF, given the potential for potential for adverse cardiac consequences from the constant inspiratory pressure in patients in whom right ventricle is preload-dependent.58

  4. Supplemental O2 may be beneficial in patients with CSA, particularly in patients with CHF-CSB.

  5. The use of pharmacologic agents, remain very modest. Confirmation with efficacy with polysomnography is essential. Likewise, administration of this drug requires meticulous attention to serum levels.

In conclusion, the pathogenesis of central sleep apnea varies depending on the clinical condition. Sleep-related withdrawal of the ventilatory drive to breathe is the common denominator among all cases of central apnea, whereas hypocapnia is the common pathway leading to apnea in non-hypercapnic central apnea. Conversely, in certain conditions, breathing rhythm is suppressed with development of central apnea while asleep, as it occurs with opioids. The pathophysiologic and etiologic heterogeneity may explain the protean clinical manifestations and the necessity of individualized therapy.

Footnotes

Conflict of Interest

Shahrokh Javaheri reports fees from Respicardia as a constulant.

M. Safwan Badr declares no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Contributor Information

M. Safwan Badr, Department of Internal Medicine, Division of pulmonary, critical; care and sleep medicine..

John D. Dingell, Wayne State University School of Medicine.

Shahrokh Javaheri, Sleep Laboratory, Bethesda North Hospital, Cincinnati, OH; Division of pulmonary Sleep and Critical Medicine, University of Cincinnati College of Medicine Cincinnati, OH; Division of Cardiology, The Ohio State University, Columbus,OH.

References

Papers of particular interest, published recently, have been highlighted as:

• Of importance

••Of major importance

  • 1.Javaheri S, Dempsey JA. Central sleep apnea. Compr Physiol. 2013;3(1):141–163. [DOI] [PubMed] [Google Scholar]
  • 2.Chowdhuri S, Badr MS. Central sleep apnoea. Indian J Med Res. 2010;131:150–164. [PubMed] [Google Scholar]
  • 3.Skatrud JB, Dempsey JA. Interaction of sleep state and chemical stimuli in sustaining rhythmic ventilation. J Appl Physiol Respir Environ Exerc Physiol. 1983;55(3):813–822. [DOI] [PubMed] [Google Scholar]
  • 4.Zhou XS, Shahabuddin S, Zahn BR, Babcock MA, Badr MS. Effect of gender on the development of hypocapnic apnea/hypopnea during NREM sleep. J Appl Physiol (1985). 2000;89(1):192–199. [DOI] [PubMed] [Google Scholar]
  • 5.Badr MS, Kawak A. Post-hyperventilation hypopnea in humans during NREM sleep. Respir Physiol. 1996;103(2):137–145. [DOI] [PubMed] [Google Scholar]
  • 6.Chow CM, Xi L, Smith CA, Saupe KW, Dempsey JA. A volume-dependent apneic threshold during NREM sleep in the dog. J Appl Physiol (1985). 1994;76(6):2315–2325. [DOI] [PubMed] [Google Scholar]
  • 7.Badr MS, Skatrud JB, Dempsey JA. Determinants of poststimulus potentiation in humans during NREM sleep. J Appl Physiol (1985). 1992;73(5):1958–1971. [DOI] [PubMed] [Google Scholar]
  • 8.Badr MS, Morgan BJ, Finn L, et al. Ventilatory response to induced auditory arousals during NREM sleep. Sleep. 1997;20(9):707–714. [DOI] [PubMed] [Google Scholar]
  • 9.Cao M, Javaheri S. Effects of Chronic Opioid Use on Sleep and Wake. Sleep Med Clin. 2018;13(2):271–281. [DOI] [PubMed] [Google Scholar]
  • 10.McKay LC, Janczewski WA, Feldman JL. Sleep-disordered breathing after targeted ablation of preBotzinger complex neurons. Nat Neurosci. 2005;8(9):1142–1144. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Khoo MC, Kronauer RE, Strohl KP, Slutsky AS. Factors inducing periodic breathing in humans: a general model. J Appl Physiol Respir Environ Exerc Physiol. 1982;53(3):644–659. [DOI] [PubMed] [Google Scholar]
  • 12.Wellman A, Malhotra A, Fogel RB, Edwards JK, Schory K, White DP. Respiratory system loop gain in normal men and women measured with proportional-assist ventilation. J Appl Physiol (1985). 2003;94(1):205–212. [DOI] [PubMed] [Google Scholar]
  • 13.Javaheri S A mechanism of central sleep apnea in patients with heart failure. N Engl J Med. 1999;341(13):949–954. [DOI] [PubMed] [Google Scholar]
  • 14.Leevers AM, Simon PM, Dempsey JA. Apnea after normocapnic mechanical ventilation during NREM sleep. J Appl Physiol (1985). 1994;77(5):2079–2085. [DOI] [PubMed] [Google Scholar]
  • 15.Badr MS, Toiber F, Skatrud JB, Dempsey J. Pharyngeal narrowing/occlusion during central sleep apnea. J Appl Physiol (1985). 1995;78(5):1806–1815. [DOI] [PubMed] [Google Scholar]
  • 16.Olson LG, Strohl KP. Airway secretions influence upper airway patency in the rabbit. Am Rev Respir Dis. 1988;137(6):1379–1381. [DOI] [PubMed] [Google Scholar]
  • 17.Morrell MJ, Arabi Y, Zahn BR, Meyer KC, Skatrud JB, Badr MS. Effect of surfactant on pharyngeal mechanics in sleeping humans: implications for sleep apnoea. Eur Respir J. 2002;20(2):451–457. [DOI] [PubMed] [Google Scholar]
  • 18.American Academy of Sleep Medicine Task F. International Classification of Sleep Disorders. 3rd ed. Darien IL 2014 [Google Scholar]
  • 19.Douglas NJ, White DP, Weil JV, Pickett CK, Zwillich CW. Hypercapnic ventilatory response in sleeping adults. Am Rev Respir Dis. 1982;126(5):758–762. [DOI] [PubMed] [Google Scholar]
  • 20.Orem J Medullary respiratory neuron activity: relationship to tonic and phasic REM sleep. J Appl Physiol Respir Environ Exerc Physiol. 1980;48(1):54–65. [DOI] [PubMed] [Google Scholar]
  • 21.Ancoli-Israel S, Kripke DF, Klauber MR, Mason WJ, Fell R, Kaplan O. Sleep-disordered breathing in community-dwelling elderly. Sleep. 1991;14(6):486–495. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Phillips BA, Berry DT, Schmitt FA, Magan LK, Gerhardstein DC, Cook YR. Sleep-disordered breathing in the healthy elderly. Clinically significant? Chest. 1992;101(2):345–349. [DOI] [PubMed] [Google Scholar]
  • 23.Bixler EO, Vgontzas AN, Ten Have T, Tyson K, Kales A. Effects of age on sleep apnea in men: I. Prevalence and severity. Am J Respir Crit Care Med. 1998;157(1):144–148. [DOI] [PubMed] [Google Scholar]
  • 24.Pack AI, Cola MF, Goldszmidt A, Ogilvie MD, Gottschalk A. Correlation between oscillations in ventilation and frequency content of the electroencephalogram. J Appl Physiol (1985). 1992;72(3):985–992. [DOI] [PubMed] [Google Scholar]
  • 25.Chowdhuri S, Pranathiageswaran S, Loomis-King H, Salloum A, Badr MS. Aging is associated with increased propensity for central apnea during NREM sleep. J Appl Physiol (1985). 2018;124(1):83–90. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Kapur VK, Koepsell TD, deMaine J, Hert R, Sandblom RE, Psaty BM. Association of hypothyroidism and obstructive sleep apnea. Am J Respir Crit Care Med. 1998;158(5 Pt 1):1379–1383. [DOI] [PubMed] [Google Scholar]
  • 27.Leung RS, Huber MA, Rogge T, Maimon N, Chiu KL, Bradley TD. Association between atrial fibrillation and central sleep apnea. Sleep. 2005;28(12):1543–1546. [DOI] [PubMed] [Google Scholar]
  • 28.Bixler EO, Vgontzas AN, Lin HM, et al. Prevalence of sleep-disordered breathing in women: effects of gender. Am J Respir Crit Care Med. 2001;163(3 Pt 1):608–613. [DOI] [PubMed] [Google Scholar]
  • 29.Javaheri S, Parker TJ, Wexler L, et al. Occult sleep-disordered breathing in stable congestive heart failure. Ann Intern Med. 1995;122(7):487–492. [DOI] [PubMed] [Google Scholar]
  • 30.Sin DD, Fitzgerald F, Parker JD, Newton G, Floras JS, Bradley TD. Risk factors for central and obstructive sleep apnea in 450 men and women with congestive heart failure. Am J Respir Crit Care Med. 1999;160(4):1101–1106. [DOI] [PubMed] [Google Scholar]
  • 31.Dempsey JA, Smith CA, Przybylowski T, et al. The ventilatory responsiveness to CO(2) below eupnoea as a determinant of ventilatory stability in sleep. J Physiol. 2004;560(Pt 1):1–11. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Cereda CW, Petrini L, Azzola A, et al. Sleep-disordered breathing in acute ischemic stroke and transient ischemic attack: effects on short- and long-term outcome and efficacy of treatment with continuous positive airways pressure--rationale and design of the SAS CARE study. Int J Stroke. 2012;7(7):597–603. [DOI] [PubMed] [Google Scholar]
  • 33.Parra O, Arboix A, Bechich S, et al. Time course of sleep-related breathing disorders in first-ever stroke or transient ischemic attack. Am J Respir Crit Care Med. 2000;161(2 Pt 1):375–380. [DOI] [PubMed] [Google Scholar]
  • 34.Wang D, Teichtahl H, Drummer O, et al. Central sleep apnea in stable methadone maintenance treatment patients. Chest. 2005;128(3):1348–1356. [DOI] [PubMed] [Google Scholar]
  • 35.Hanly PJ, Pierratos A. Improvement of sleep apnea in patients with chronic renal failure who undergo nocturnal hemodialysis. N Engl J Med. 2001;344(2):102–107. [DOI] [PubMed] [Google Scholar]
  • 36.Grunstein RR, Ho KY, Sullivan CE. Sleep apnea in acromegaly. Ann Intern Med. 1991;115(7):527–532. [DOI] [PubMed] [Google Scholar]
  • 37.Hernandez-Gordillo D, Ortega-Gomez Mdel R, Galicia-Polo L, et al. Sleep apnea in patients with acromegaly. Frequency, characterization and positive pressure titration. Open Respir Med J. 2012;6:28–33. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Sankari A, Bascom AT, Chowdhuri S, Badr MS. Tetraplegia is a risk factor for central sleep apnea. J Appl Physiol (1985). 2014;116(3):345–353.• This study identified tetraplegia as a distinct risk factor for central apnea, independent of opioid use.
  • 39.Sankari A, Bascom A, Oomman S, Badr MS. Sleep disordered breathing in chronic spinal cord injury. J Clin Sleep Med. 2014;10(1):65–72. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Xie A, Wong B, Phillipson EA, Slutsky AS, Bradley TD. Interaction of hyperventilation and arousal in the pathogenesis of idiopathic central sleep apnea. Am J Respir Crit Care Med. 1994;150(2):489–495. [DOI] [PubMed] [Google Scholar]
  • 41.Rupprecht S, Hoyer D, Hagemann G, Witte OW, Schwab M. Central sleep apnea indicates autonomic dysfunction in asymptomatic carotid stenosis: a potential marker of cerebrovascular and cardiovascular risk. Sleep. 2010;33(3):327–333. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Javaheri S, Parker TJ, Liming JD, et al. Sleep apnea in 81 ambulatory male patients with stable heart failure. Types and their prevalences, consequences, and presentations. Circulation. 1998;97(21):2154–2159. [DOI] [PubMed] [Google Scholar]
  • 43.Javaheri S, Smith J, Chung E. The prevalence and natural history of complex sleep apnea. J Clin Sleep Med. 2009;5(3):205–211. [PMC free article] [PubMed] [Google Scholar]
  • 44.Farre R, Montserrat JM, Navajas D. Noninvasive monitoring of respiratory mechanics during sleep. European Respiratory Journal. 2004;24(6):1052–1060. [DOI] [PubMed] [Google Scholar]
  • 45.Morrell MJ, Badr MS, Harms CA, Dempsey JA. The assessment of upper airway patency during apnea using cardiogenic oscillations in the airflow signal. Sleep. 1995;18(8):651–658. [DOI] [PubMed] [Google Scholar]
  • 46.Aurora RN, Chowdhuri S, Ramar K, et al. The treatment of central sleep apnea syndromes in adults: practice parameters with an evidence-based literature review and meta-analyses. Sleep. 2012;35(1):17–40.• Practice Parameters by the American Academy of Sleep Medicine (AASM) providing evidence-based recommendations for the treatment of central apnea.
  • 47.Issa FG, Sullivan CE. Reversal of central sleep apnea using nasal CPAP. Chest. 1986;90(2):165–171. [DOI] [PubMed] [Google Scholar]
  • 48.Arzt M, Floras JS, Logan AG, et al. Suppression of central sleep apnea by continuous positive airway pressure and transplant-free survival in heart failure: a post hoc analysis of the Canadian Continuous Positive Airway Pressure for Patients with Central Sleep Apnea and Heart Failure Trial (CANPAP). Circulation. 2007;115(25):3173–3180. [DOI] [PubMed] [Google Scholar]
  • 49.Hannan LM, Dominelli GS, Chen YW, Darlene Reid W, Road J. Systematic review of noninvasive positive pressure ventilation for chronic respiratory failure. Respir Med. 2014;108(2):229–243. [DOI] [PubMed] [Google Scholar]
  • 50.Javaheri S, Brown LK, Randerath WJ. Positive airway pressure therapy with adaptive servoventilation: part 1: operational algorithms. Chest. 2014;146(2):514–523. [DOI] [PubMed] [Google Scholar]
  • 51.Teschler H, Dohring J, Wang YM, Berthon-Jones M. Adaptive pressure support servo-ventilation: a novel treatment for Cheyne-Stokes respiration in heart failure. Am J Respir Crit Care Med. 2001;164(4):614–619. [DOI] [PubMed] [Google Scholar]
  • 52.Cowie MR, Woehrle H, Wegscheider K, et al. Adaptive Servo-Ventilation for Central Sleep Apnea in Systolic Heart Failure. N Engl J Med. 2015;373(12):1095–1105.• This study demonstrated the failure of adaptive servo ventilation (ASV) as a treatment for central apnea in patients with heart failure and reduced ejection fraction. Instead, this therapy was associated with increased all-cause and cardiovascular mortality. Therefore, ASV is contraindicated in this setting.
  • 53.Aurora RN, Bista SR, Casey KR, et al. Updated Adaptive Servo-Ventilation Recommendations for the 2012 AASM Guideline: “The Treatment of Central Sleep Apnea Syndromes in Adults: Practice Parameters with an Evidence-Based Literature Review and Meta-Analyses”. J Clin Sleep Med. 2016;12(5):757–761.• Updated Practice Parameters by the American Academy of Sleep Medicine (AASM). Recent findings mandated a change in the recommendations indicating a Standard level recommendation against the use of ASV to treat CHF-associated CSAS in patients with an LVEF of ≤ 45% and moderate or severe CSAS, and an Option level recommendation for the use of ASV in the treatment CHF-associated CSAS in patients with an LVEF > 45% or mild CHF-related CSAS
  • 54.Javaheri S, Brown LK, Randerath W, Khayat R. SERVE-HF: More Questions Than Answers. Chest. 2016;149(4):900–904. [DOI] [PubMed] [Google Scholar]
  • 55.Javaheri S, Ahmed M, Parker TJ, Brown CR. Effects of nasal O2 on sleep-related disordered breathing in ambulatory patients with stable heart failure. Sleep. 1999;22(8):1101–1106. [DOI] [PubMed] [Google Scholar]
  • 56.Becker HF, Polo O, McNamara SG, Berthon-Jones M, Sullivan CE. Effect of different levels of hyperoxia on breathing in healthy subjects. J Appl Physiol (1985). 1996;81(4):1683–1690. [DOI] [PubMed] [Google Scholar]
  • 57.Costanzo MR, Ponikowski P, Javaheri S, et al. Transvenous neurostimulation for central sleep apnoea: a randomised controlled trial. Lancet. 2016;388(10048):974–982.This is a randomized clinical trial demonstrating the effectiveness of transvenous neurostimulation in reducing the severity of central sleep apnea, including improvements in sleep metrics, oxygenation and quality of life.
  • 58.Javaheri S, Brown LK, Randerath WJ. Clinical applications of adaptive servoventilation devices: part 2. Chest. 2014;146(3):858–868. [DOI] [PubMed] [Google Scholar]

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