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The pathophysiological concept of upper airway obstruction

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near future to become useful tools for clinicians to assess OSA patients and inform therapeutic decisions.

Conclusion

OSA pathogenesis can be explained by numerous mechanisms, including compromised upper airway anatomy, poor pharyngeal muscle responsiveness, respiratory control instability (high loop gain) and low respiratory arousal threshold. Endotypes provide therapeutic targets that may explain dierent clinical phenotypes and facilitate the development of novel therapies, allowing precision medicine for OSA in the future.

Further reading

• Eckert DJ, et al. (2013). Deﬁning phenotypic causes of obstructive sleep apnea. Identiﬁcation

of novel therapeutic targets. Am J Respir Crit Care Med; 188: 996–1004.

• Malhotra A, et al. (2020). Endotypes and phenotypes in obstructive sleep apnea. Curr Opin

Pulm Med; 26: 609–614.

• Patil SP, et al. (2004). A simpliﬁed method for measuring critical pressures during sleep in the

clinical setting. Am J Respir Crit Care Med; 170: 86–93.

• Perger E, et al. (2018). Targeting volume overload and overnight rostral ﬂuid shi: a new

perspective to treat sleep apnea. Sleep Med Rev; 42: 160–170.

• Perger E, et al. (2021). Upper airway muscles: inﬂuence on obstructive sleep apnoea

pathophysiology and pharmacological and technical treatment options. Curr Opin Pulm Med; 27: 505–513.

• Perger E, et al. (2022). Reboxetine plus oxybutynin for OSA treatment: a 1-week, randomized,

placebo-controlled, double-blind crossover trial. Chest; 161: 237–247.

• Sands SA, et al. (2018). Phenotyping pharyngeal pathophysiology using polysomnography in

patients with obstructive sleep apnea. Am J Respir Crit Care Med; 197: 1187–1197.

• Sands SA, et al. (2018). Quantifying the arousal threshold using polysomnography in

obstructive sleep apnea. Sleep; 41: zsx183.

• Tantucci C, et al. (1998). Application of negative expiratory pressure during expiration and

activity of genioglossus in humans. J Appl Physiol; 84: 1076–1082.

• Taranto-Montemurro L, et al. (2019a). The combination of atomoxetine and oxybutynin

greatly reduces obstructive sleep apnea severity. A randomized, placebo-controlled, doubleblind crossover trial. Am J Respir Crit Care Med; 199: 1267–1276.

• Taranto-Montemurro L, et al. (2019b). Targeting endotypic traits with medications for the

pharmacological treatment of obstructive sleep apnea. A review of the current literature. J Clin Med; 8: 1846.

• Taranto-Montemurro L, et al. (2020). Eects of the combination of atomoxetine and

oxybutynin on OSA endotypic traits. Chest; 157: 1626–1636.

• Terrill PI, et al. (2015). Quantifying the ventilatory control contribution to sleep apnoea using

polysomnography. Eur Respir J; 45: 408–418.

• Wellman A, et al. (2011). A method for measuring and modeling the physiological traits

causing obstructive sleep apnea. J Appl Physiol; 110: 1627–1637.

• Wellman A, et al. (2013). A simpliﬁed method for determining phenotypic traits in patients

with obstructive sleep apnea. J Appl Physiol; 114: 911–922.

ERS Handbook: Respiratory Sleep Medicine

Pathophysiology of central

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sleep apnoea

Winfried Randerath

Central breathing disturbances during sleep are characterised by simultaneous reductions or cessations of airﬂow and respiratory eort. The apnoeas or hypopnoeas alternate with periods of re-established or even increased ventilation, together constituting the respiratory cycle.

‘Periodic breathing’ represents a subtype of central breathing disturbances, characterised by a crescendo/decrescendo pattern of the ﬂow and eort. The ventilation increases up to a hyperventilatory maximum and decreases to hypopnoea or apnoea. The term ‘CSR’ should be preserved for the pattern of periodic breathing in patients with underlying cardiac or cerebrovascular diseases, especially HF or stroke.

Central breathing disturbances can be classiﬁed according to the ICSD into six subgroups (table 1). This classiﬁcation is based on underlying disorders (cardiac and

Key points

• CSA can be dierentiated based on clinical phenotypes and underlying pathophysiology.

• The dierentiation into hypercapnic and non-hypercapnic CSA focuses on the decrease or increase in V′E and respiratory drive.

• The loop gain of ventilation includes the plant gain and the controller gain. The plant gain describes the changes of the P ventilation. The controller gain determines the change of V′E in response to changes of the P of the blood gases and the circulation time.

• Non-hypercapnic CSA is characterised by an overshooting of the ventilation, changes of the apnoea threshold and increased chemosensitivity.

• Periodic breathing is a subgroup of CSA. It demonstrates a switch between the extremes of over- and undershoot of ventilation. Periodic breathing in HF patients is called CSR.

• Central disturbances are closely related to HF, atrial ﬁbrillation (AF) and brain infarction. Other subgroups, including CSA in medical or neurological disorders, CSA due to substance intake or high altitude, TECSA and primary CSA, dier in some pathophysiological aspects.

. The loop gain is inﬂuenced by the reception of changes

aCO

following changes of

aCO

55ERS Handbook: Respiratory Sleep Medicine

Pathophysiology of central sleep apnoea

Abdomen eort

Cycle length

₂

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Table 1. Classiﬁcation of central breathing disturbances by the ICSD (3rd edition)

CSA with CSR CSA due a medical disorder without CSR CSA due to high-altitude periodic breathing CSA due to a medication or substance Primary CSA TECSA

non-cardiac diseases), therapeutic inﬂuences (medication or substance intake, and mechanical treatment of upper airway obstruction) and environmental inﬂuences (high altitude). The cycle length diers substantially between the various forms of CSA. It is usually 45–90 s in patients with HF and CSA/CSR, while it is >40 s in primary CSA. The dierence comes from the ventilatory part of the cycle, while the apnoea duration does not dier between idiopathic CSA and CSA in HF (ﬁgure 1).

Besides this clinical approach, central breathing disturbances can also be dierentiated based on the underlying pathophysiology into hypercapnic and nonhypercapnic CSA (table 2). This emphasises the crucial relevance of respiratory drive in the pathophysiology of central breathing disturbances during sleep.

Hypercapnic CSA

Hypoventilation syndromes include diseases with reduced central respiratory drive or the inability to translate breathing impulses into thoracic movements. These include disorders of the central nervous system such as inﬂammatory or ischaemic diseases of the brain stem, neuromuscular diseases (e.g. amyotrophic lateral sclerosis) and thoraco-skeletal disorders (e.g. kyphoscoliosis). Central apnoeas appear during sleep in these patients as the ventilatory drive and muscle function are more severely reduced during sleep compared with the wake state, leading to hypoventilation and hypercapnia. However, hypercapnic CSA is much less prevalent compared to non-hypercapnic CSA.

Non-hypercapnic CSA

The pathophysiology of non-hypercapnic CSA is not yet fully understood. In contrast to CSA due to hypoventilation, these breathing disturbances are characterised by an increase of ventilation between the apnoeic/hypopnoeic periods. Ventilation switches

Flow

Thorax eort

Figure 1. The respiratory cycle in a patient with periodic breathing. The cycle is composed of the apnoeic period and the hyperventilation period. The total cycle length diers according to the underlying disease. Moreover, the relation between apnoea length and hyperventilation length is a marker of the loop gain. A short apnoea period and long hyperventilation represents low loop gain, while a long apnoea and short hyperventilation describes a high loop gain.

Hyperventilation

Apnoea

length

ERS Handbook: Respiratory Sleep Medicine

Pathophysiology of central sleep apnoea

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Table 2. Conditions leading to hypercapnic and non-hypercapnic CSA

Hypercapnic CSA: CSA associated with hypoventilation

Central congenital hypoventilation Type 2 Chiari malformation (Arnold–Chiari malformation) Muscular dystrophy Amyotrophic lateral sclerosis Scoliosis, post-polio syndrome Opioid-induced sleep apnoea

Non-hypercapnic CSA: CSA due to hyperventilation

High altitude HF Acromegaly Renal failure Idiopathic CSA Opioid-induced sleep apnoea

Reproduced and modiﬁed from Randerath (2022) with permission.

between the extremes of over- and undershoot. As a result, the carbon dioxide (CO2) level is in the lower range of normal or even reduced (hypocapnic CSA). This group of disturbances includes the subgroups of CSA in patients with underlying CVD, other medical or neurological diseases, high-altitude CSA, treatment-emergent CSA (TECSA) and primary CSA.

Findings in experimental models and patients with HF have predominantly formed our understanding of the pathophysiology, which will be described here. Additional aspects of the other types of CSA will be presented thereaer.

In healthy individuals, ventilation is primarily regulated by behavioural factors during wakefulness, but is mainly inﬂuenced by metabolism (the balance between production and elimination of CO2) during sleep. While an increase in P stimulates ventilation, breathing is diminished during hypocapnia. NREM sleep

(hypercapnia)

aCO

physiologically reduces ventilatory drive and V′E. The inﬂuence of the CO2 level is alleviated during REM sleep as muscle activity and arousability are reduced. Thus, CSA appears predominantly during NREM sleep. The inﬂuence of the oxygen (O2) level on ventilation is limited, unless hypoxaemia is severe. Therefore, it is speciﬁcally relevant in high-altitude CSA, as discussed later.

Although this is only a preliminary list, several pathophysiological aspects can be described as contributing to the phenomenon of CSA due to hyperventilation:

• The loop gain of the ventilatory system

• The apnoea threshold

• Hypoxic ventilatory response (HVR) and hypercapnic ventilatory response (HCVR)

• Arousals

• Lung mechanics

Loop gain

The ventilatory control system can be compared to a ‘loop gain’, known from engineering. Its main components include the plant gain and the controller gain. The actual P ventilation by noise, pain or cortical impulses (ﬁgure 2).

is inﬂuenced by any disturbance of respiration, e.g. stimulation of

aCO

The term ‘plant gain’ describes how strongly V′E inﬂuences the actual P individual person (ΔCO2/ΔV′E). These changes are measured by the ‘feedback gain’,

aCO

in an

57ERS Handbook: Respiratory Sleep Medicine

Pathophysiology of central sleep apnoea

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Dampening: hypoventilation Stimulation: hyperventilation

Brainstem

Control of

ventilation

Chemoreceptors

HVR and HCVR

Hypocapnia: dampening Hypoxia: stimulation

Figure 2. The components of the ventilatory control system and their relevance to the loop gain.

V′E is generated by lung and thoracic mechanics (plant gain). The plant gain varies inter- and

intra-individually and determines how the CO2 level changes in relation to changes of V′E. The central and peripheral chemoreceptors represent the feedback gain of the ventilatory system, which can be measured by the HVR and HCVR. The control of ventilation is deﬁned by the chemosensitivity of the system, which can be deﬁned by the change of the V′E in reaction to changes of the CO2 level. In unstable situations, these components inﬂuence each other in over- and undershooting: increase of the ventilation leads to hypocapnia, which is measured at the chemoreceptors and dampens ventilation, leading to reduction of V′E, whereas a decrease of ventilation leads to hypoxia, which stimulates ventilation and induces hyperventilation. Reproduced and modiﬁed from Randerath et al. (2019) with permission.

Increase of ventilation: hypocapnia Decrease of ventilation: hypoxia

Lung

V'E

represented by the chemoreceptors in the ventilatory system. The ‘controller gain’ represents the chemosensitivity of the system, which means the change of the ventilation due to changes of the CO2 (ΔV′E/ΔCO2). The perception of these variations can be inﬂuenced by a circulatory delay in CVD but its relevance is unclear. The translation of these data from animal trials to humans is questionable.

A strong response to breathing disturbances characterises a high loop gain. A high loop gain derives from either a high plant gain or a high controller gain. In other words, if small changes of CO2 induce distinct increases of the ventilation or if small changes of the ventilation induce distinct changes of CO2, the loop gain is high. A high loop gain results in instability of the system: overshooting of the ventilation, a continuous switch between hyperventilation and hypocapnia on the one hand and apnoeas and hypercapnia/hypoxia on the other. As muscle activity and the arousability (a tendency to arousal from sleep) are reduced during REM sleep, ventilatory overshoot is more oen present during NREM sleep.

ERS Handbook: Respiratory Sleep Medicine

Pathophysiology of central sleep apnoea

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Which factors contribute to the instability of the system? Chemical irritation of the pulmonary tissue receptors increases the central ventilatory drive in animals. The injection of hypertonic saline into the lungs of rabbits stimulates the pulmonary tissue receptors. This increases the activity of ventilatory muscles via central ventilatory drive. This activation could be abolished by vagotomy, indicating that the irritation in the lung periphery is transmitted by vagal aerent nerves.

Similarly, interstitial inﬂammatory processes can stimulate irritant receptors in humans. However, this irritation is much more common in HF patients, induced by pulmonary congestion. It has been shown that pulmonary congestion increases the AHI and the ventilatory drive. Consequently, improvement of cardiac function reduces hyperventilation and the AHI. This has been proved in trials based on invasive measurement of pulmonary artery wedge pressure, as a marker of le ventricular function. The higher the wedge pressure (impaired le ventricular function), the lower was the P

, i.e. pulmonary congestion is associated with hyperventilation.

aCO

In accordance with these physiological experiments, recent studies conﬁrmed the inﬂuence of pulmonary ﬂuid overload in HF patients. When the ﬂuid shi from the legs to the upper body compartments was measured, an association between ﬂuid shi and the neck circumference was found. Moreover, the overnight change in leg ﬂuid volume was associated with an increase in OSA and more extensive CSA.

Another group studied the development of CSA over the night course and found an increase of the central apnoea index between the ﬁrst and the last part of the night without any change of circulation time. Possible mechanisms for the increase of central apnoeas were discussed, including worsening of heart function with increase of ﬂuid shi, increasing hypoxic burden, leading to breathing plasticity and induction of apnoeas based on arousals following previous disturbances (vicious circle).

Apnoea threshold

The extent of V′E is determined by the prevailing P (the apnoeic threshold), breathing ceases. The dierence between the eupnoeic CO2 and the apnoeic threshold is called CO2 reserve (ﬁgure 3).

During normal breathing, the prevailing P the CO2 reserve is narrowed, the probability of an apnoea increases. On the one hand, the apnoea threshold has been shown to be elevated in CSA, without relevant change in P threshold, which is a typical ﬁnding in patients with unstable breathing. In this case,

. On the other hand, hyperventilation brings P

aCO

small variations in ventilation lead to oscillations in P threshold, resulting in a pattern of periodic breathing. The CO2 reserve is reduced in CSA patients and may be a target for therapeutic interventions.

Therapeutic interventions support these concepts of the pathophysiology. The application of acetazolamide in patients with spinal cord injury (a known risk factor for CSA) decreases the susceptibility to CSA due to decreased plant gain, widens the CO2 reserve, and decreases the apnoea threshold. In addition, buspirone, a serotonin receptor agonist, widens the CO2 reserve compared to trazodone and placebo. The drug also decreases the controller gain.

HVR and HCVR

The sensitivity of the peripheral and central chemoreceptors also inﬂuences the stability of the respiratory control system. The HCVR is a clinical parameter to estimate

. If it falls below a deﬁnite level

aCO

exceeds the apnoea threshold. Whenever

aCO

closer to the apnoea

aCO

above and below the apnoea

aCO

59ERS Handbook: Respiratory Sleep Medicine

Pathophysiology of central sleep apnoea

a) Normal b) Unstable c) Periodic

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Actual P

aCO

₂

CO2 reserve

₂

aCO

Apnoea

threshold

Figure 3. A schematic showing the importance of the apnoea threshold. The purple dots represent the actual P

is above the apnoea threshold, the person breathes regularly. The CO2 reserve between

aCO

the actual P gap between the actual P

and the apnoea threshold is high. b) In patients with unstable breathing, the

aCO

In this situation, minor increases of the ventilation reduce the actual P threshold, leading to a central apnoea. c) Periodic breathing presents as a small CO2 reserve and changes of the V′E, leading to oscillation of the actual P threshold. This is clinically known as periodic breathing.

, the blue lines represent the apnoea threshold. a) As long as the actual

aCO

and the apnoea threshold narrows, so the CO2 reserve is reduced.

aCO

above and below the apnoea

aCO

below the apnoea

aCO

the chemosensitivity. It describes the increase of V′E to increases of P by rebreathing exhaled air. HF patients without breathing disturbances and those with

, oen studied

aCO

OSA do not dier from normal in terms of HCVR. In contrast, the ventilatory response is signiﬁcantly increased in HF patients with CSA, similar to those with idiopathic CSA. These ﬁndings indicate an increased chemoresponsiveness of HF patients with CSA. Therefore, hyperreactivity of the chemoreceptors is a typical marker, not of HF in general, but only of patients with associated central breathing disturbances. From a clinical point of view, hyperreactivity of the chemoreceptors leads to a higher increase of V′E in response to a given P central apnoea and hypoxia during sleep and to the vicious circle of overshooting and

, resulting in chronic hypocapnia. This predisposes to

aCO

undershooting of ventilation. The chemosensitivity measured by the HVR and HCVR can be used to dierentiate

subgroups of HF patients with or without CSA and may guide treatment decisions. Those patients with low ﬁgures for both HVR and HCVR have the best survival while those with increased HVR or increased HCVR have signiﬁcantly poorer outcome, which is worse in those with both HVR and HCVR increased.

Data suggest that peripheral chemoreceptors play a dominant role in the pathophysiology of CSA in HF. The response to changes of the CO2 was compared with the circulation time. A high correlation between CO2 circulation time and lung-to-ear circulation time was found, indicating an overwhelming relevance of the peripheral chemoreceptors.

Other factors seem to play a minor role in the pathophysiology of CSA, including central chemoreception. The cerebral blood ﬂow diers between healthy subjects and CSA patients. Hypercapnia increases the cerebral blood ﬂow, but the vasoreactivity is diminished in CSA patients. The variations of the cerebral blood ﬂow physiologically counterbalance changes of the hydrogen ion (H+) concentration in the cerebral ﬂuid.

ERS Handbook: Respiratory Sleep Medicine

Pathophysiology of central sleep apnoea

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If these reﬂexes are dampened, cerebral alkalosis might be intensiﬁed, leading to a reduction of the ventilatory drive and central apnoea. Conversely, cerebral acidosis induces ventilatory overshoot and hyperventilation and thus destabilises respiration. The reaction of the cerebral vessels is signiﬁcantly reduced in patients with CSA, independent of the baseline ventilatory state. It can be inﬂuenced pharmaceutically. In the model of high-altitude CSA, acetazolamide plus dobutamine increased cerebral blood ﬂow (vasodilators), which was reduced under indomethacin. The vasodilators reduced the HCVR and the CSA index. In contrast, indomethacin increased the HCVR, while CSA was unchanged. Therefore, the increase of cerebral blood ﬂow stabilised ventilation.

Arousals

Arousals restore the waking state of non-chemical control of breathing. The set-point for CO2 is lower and the ventilatory response to variations of CO2 is increased during wakefulness as compared to sleep. During sleep/wake transitions, the prevailing CO2 level is higher than the new (wake) set-point, leading to a rapid increase of ventilation. This lowers the prevailing CO2 below the apnoeic threshold and induces a central apnoea. Due to the higher sensitivity of the chemoreceptors in CSA patients, increases of the ventilation aggravate the overshoot and therefore increase breathing disturbances. Thus, arousals and the associated sleep/wake transition promote the vicious circle of hyperventilation and central apnoea. Therefore, arousals may propagate the instability of respiration.

The relevance of arousals in the pathophysiology of central apnoeas was underlined by the eect of the non-benzodiazepine hypnotic zolpidem. The drug reduced the total AHI, the central AHI, and the index of respiratory and total arousals, without change of the arousal threshold or the CO2 reserve.

Lung mechanics in periodic breathing

The hyperventilation period in CSA and periodic breathing is associated with mechanical changes in lungs and thorax. Two patterns of the end-expiratory lung volume (EELV) during the ventilatory period can be dierentiated: the pattern is called ‘positive’ when the EELV exceeds the FRC, while it is ‘negative’ when the EELV is below the FRC (ﬁgure 4). The EELV represents the inﬂation of the lungs, which inﬂuences cardiac pre- and aerload, le ventricular transmural pressure, diameter of small airways, and ventilation/ perfusion matching. Clinical studies demonstrated that the negative pattern is associated with longer hyperpnoea and cycle time, higher N-terminal pro-brain natriuretic peptide and worse HF classes (according to the New York Heart Association classiﬁcation).

Additional pathophysiological aspects in speciﬁc subgroups of CSA

TECSA

The phenomenon of new appearance of central apnoea in patients treated for OSA has been shown most oen under PAP treatment, but can also appear under other eective therapies of upper airway obstruction (mandibular advancement devices and maxillo-mandibular osteotomy). Three subgroups have been described: treatmentemergent, treatment-resistant and treatment-persistent CSA.

CPAP-resistant CSA is pre-existing central apnoea that may become prominent when the obstructive component has been resolved. These events do not dier from other forms of CSA from a pathophysiological point of view.

61ERS Handbook: Respiratory Sleep Medicine

Pathophysiology of central sleep apnoea

Negative pattern

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Flow

Thorax eort

Abdomen eort

Flow

Thorax eort

Abdomen eort

₂

Positive pattern

₂

FRC

EELV

FRC

Figure 4. Two dierent patterns of periodic breathing. The negative pattern is characterised by a reduction of the EELV below the FRC. In contrast, it is elevated above the FRC in the positive pattern.

The huge majority of CSA that emerges under OSA treatment disappears aer 6–12 weeks of continuous unchanged therapy. The development of these events can be explained by transient changes of chemosensitivity and the ventilatory response:

• Untreated OSA is associated with an elevated respiratory drive during the upper

airway occlusion, well known by the overshoot of the ventilation when the airways are reopened. Thus, the respiratory drive adapts to a chronic increased level.

• This leads to a net reduction of the end-tidal CO2 during NREM sleep and a

reduction of the CO2 reserve.

• This destabilises ventilation as indicated by the clusters of breathing disturbances.

• Sucient treatment of the upper airway obstruction increases V′E. However, in

the early phase of eective OSA therapy, the ventilatory response is still on an elevated level.

• This increases the CO2 excretion, decreases end-tidal CO2 and induces central

apnoeas.

• Aer a few days or weeks of therapy, the ventilatory response adapts to the new

situation, normalises to a lower level, reduces CO2 excretion, normalises end-tidal CO2 and stabilises ventilation.

Only a minority of the events persist over the long term. The pathophysiology of this group of CPAP-persistent CSA is not clear. From our point of view, only this small group of patients should be described as TECSA.

CSA due to another medical cause, not HF

A huge variety of internal and neurological diseases can be associated with CSA. This includes stroke or brain stem and spinal cord lesions, and also muscular dystrophy, renal failure or acromegaly. Their pathophysiology is heterogeneous according to the underlying disease. It can include disruption of central ventilatory control, muscle weakness and metabolic alterations.

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Pathophysiology of central sleep apnoea

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CSA due to high altitude

The ventilatory response to changes in P additional role to the CO2 response in patients with severe hypoxaemia. This becomes

(Δ alveolar ventilation/ΔP

) plays an

clinically relevant in high-altitude CSA. In addition to the ventilatory response to changes in P increases the controller gain as compared to the normoxic situation. Staying in high

, hypoxia increases the ventilatory response to CO2. This interaction

altitude above 2500 m causes exposure to reduced atmospheric pressure and alveolar O2 tension. This eect will be pronounced during sleep. The hypoxaemia stimulates ventilation, resulting in hypocapnic alkalosis. The low CO2 level predisposes to central apnoea or hypopnoea. The ventilatory instability, the level of ventilatory overshoot and undershoot, depends on the individual HVR and HCVR.

CSA due to medication or substance

Opioids represent the most important group of drugs that induce respiratory disturbances during sleep. They depress respiration by interfering with µ-receptors in the pre-Bötzinger complex. Most data show a reduction of the HCVR, which dampens ventilation. It might normalise over several months of treatment. Some studies indicate an increased hypoxic ventilatory drive. In addition, opioids may reduce the activity of the upper airway muscles, leading to obstructive hypopnoeas. Patients with opioid-induced sleep apnoea oen present with atactic breathing, characterised by a chaotic pattern of dierent amplitudes and frequency of respiration. The underlying pathophysiology is unclear.

Ticagrelor, a reversible P2Y12 inhibitor antiplatelet drug, increases the chemosensitivity and therefore the ventilatory overshoot.

Primary CSA

The pathophysiology of primary CSA is characterised by increased HCVR, i.e. a higher sensitivity to changes of CO2. The CO2 reserve is reduced, causing predisposition to the development of central breathing disturbances.