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Pathophysiology of sleep disordered breathing (Obstructive apnoea, central apnoea) 

Prof. Dr. J. Verbraecken Pulmonologist and Medical Coordinator Multidisciplinary Sleep Disorders Centre Antwerp University Hospital (Belgium) 

Wilrijkstraat 10, B‐2650 Edegem 

Johan.verbraecken@uza.be  

Summary The prevalence of reported sleep disturbances in a general population is high. Many of the complaints are the result of sleep‐related breathing disorders, due mainly to the occurrence of obstructive and central apnoeas. Sleep‐related breathing disorders refer to pathologies that are induced by sleep and affect mainly the inspiratory phase of respiration.  This presentation will focus on pathophysiology in obstructive and central sleep apnoea, with and without Cheyne‐Stokes respiration. These disorders constitute the end points of a spectrum with distinct yet interrelated mechanisms that lead to substantial pathology, i.e. increased upper airway collapsibility, control of breathing instability, increased work of breathing, disturbed ventilatory system mechanics and neurohormonal changes. Although a unifying concept for the pathogenesis is lacking, it seems that these patients are in a vicious circle. Knowledge of common patterns of sleep‐disordered breathing may help to identify these patients and guide therapy.  Breathing instability, central apnoeas, obstructive apnoeas Instability of the breathing pattern can go along with an increase in upper airway resistance, increased collapsibility of the upper airway and discoordination of local reflex mechanisms, and can cause obstructive apnoeas. Unstable and irregular breathing in itself can lead to periodicity and central apnoeas. The overall ventilatory control contribution to sleep apnoea can be quantified by the loop gain (the level of instability in the respiratory feedback control loop). The type of respiratory event (central or obstructive) may be determined by upper airway characteristics and by the synchronism between upper airway muscles and respiratory muscles.   Several pathophysiological processes will be described which play an important role in the pathogenesis of obstructive sleep apnoea: 

1. Structural narrowing of the upper airway 2. Balance of forces  3. Collapsibility of the upper airway 

The concept of the critical closing pressure (Pcrit) will be explained, as well as the mechanisms leading to control system instability and finally to central apnoea.   Mechanisms promoting central sleep apnoea are: 

1. depressed central drive 2. increased hypoxic and hypercapnic ventilatory drive 3. unmasking of the CO2 threshold 4. stage effects 5. upper airway reflexes 

 

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Patients with chronic heart failure often develop pulmonary congestion that will lead to stimulation of intrapulmonary receptors that stimulate ventilation. This will steer CO2 below the CO2 threshold, and hence provokes central apnoea.   Obesity hypoventilation syndrome Ventilatory muscle dysfunction, abnormal load responsiveness, increased respiratory work and CO2 production, impaired central respiratory drive and repeated airway occlusion during sleep are all possible pathophysiological components in obesity hypoventilation syndrome, but the precise contribution of each remains to be fully clarified. This issue will be discussed much more detailed in another lecture.  

 

Learning objectives This course addresses to all who are interested in practical sleep medicine (students, physicians, nurses, technicians), without preexisting specific knowledge on sleep disordered breathing.  The participants will become aware of the complex mechanisms involved in the pathogenesis of obstructive apnoea, central sleep apnoea, and obesity hypoventilation, and of the relative contribution of several theoretical models.   

- To get more insight in the pathophysiology of obstructive sleep apnoea - To get more insight in the pathophysiology of central sleep apnoea (with and without 

Cheyne‐Stokes respiration) - Awareness of the interaction between obstructive and central sleep apnoea 

 

References  Malhotra A, White D. Obstructive sleep apnea. The Lancet 2002, 360:237‐245. 

Winakur S.J., Smith P.L., Schwartz A.R. Pathophysiology and risk factors for obstructive sleep apnea. Sem Respir Crit Care Med 1998, 19(2):99‐112. 

Verbraecken J., De Backer W. Upper airway mechanics. Respiration 2009;78:121‐133.  (free access) 

Randerath W*, Verbraecken J* (* equal first authors), Andreas S, Arzt M, Bloch KE, Brack T, Buyse B, De Backer W, Eckert DJ, Grote L, Hagmeyer L, Hedner J, Jennum P, La Rovere MT, Miltz  C,  McNicholas  WT,  Montserrat  J,  Naughton  M,  Pepin  J‐L,  Pevernagie  D,  Sanner  B, Testelmans D, Tonia T, Vrijsen B, Wijkstra P, Levy P. Definition, discrimination, diagnosis, and treatment of central breathing disturbances during sleep. Eur Respir J 2017; pii: ERJ‐00959‐2016. (free access) 

Verbraecken J, McNicholas WT. Respiratory mechanics and ventilatory control in overlap syndrome and obesity hypoventilation. Respir Res 2013; 14:132. (free access) 

Terrill PI, Edwards BA, Nemati S, Butler JP, Owens RL, Eckert DJ, White DP, 

Malhotra A, Wellman A, Sands SA. Quantifying the ventilatory control contribution to sleep apnoea using polysomnography. Eur Respir J. 2015 Feb;45(2):408‐18. (free access) 

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Pathophysiology of Sleep Disordered Breathing (OSA and CSA)

Prof. Dr. Johan VerbraeckenDept Pulmonary Medicine and Multidisciplinary Sleep Disorders Centre

Antwerp University Hospital Belgium

DEFINITION “Obstructive sleep apnea syndrome”

• ≥ 5 obstructive apneas-hypopneas /hour of sleep

Plus one or more of the following:- Complaints of sleepiness - Non-restorative sleep- Fatigue- Insomnia complaints- Awakening with dyspnea - Asphyxia- Frequently snoring- Apneas witnessed by partner

• Diagnosis of : hypertension, mood disturbance, cognitive dysfunction, coronary artery disease, stroke, chronic heart failure, atrial fibrillation, type 2 diabetes

OR≥ 15 obstructive apneas-hypopneas/

hour of sleep

ICSD-3

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Repetitive obstructive apnoeas

FLOW = 0

Chest & Abdomen = paradoxical

FLOW

CHEST

ABDOMEN

O2 SATURATION

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Pathophysiology OSA

Upper airway collapse may occur due to:1) UA Size 2) Balance of forces3) Increased collapsibility

Anatomic abnormality

Airway as a rigid tube with flexible segment

Imbalance between activation of diaphragm and UA musclesImpaired reflex activation of UA dilator muscle activity

Pathogenesis OSA UA size: structural abnormalities

Normal (post UPPP)OSA Patient

Schellenberg JB et al AJRCCM 2000; 162: 740-748

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Pathogenesis OSA UA size: structural abnormalities

Schellenberg JB et al AJRCCM 2000; 162: 740-748

Etnic differences in pathophysiology

Chinese Caucasian

Craniofacial Restriction

Obesity

Craniofacial Restriction

Obesity

UA Obstruction

Lee et al Sleep 2010

Influence of etnicity

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Pathogenesis OSA UA size: structural abnormalities: MRI findings

Normal MRI(elliptic shape)

Patient MRI (palatal area)

(circular shape, reduced lateral dimensions)

Schwab et al Am J Respir Crit Care Med 1995;152:1673

Pathogenesis of OSA UA size: structural abnormalities

Cephalometric variables and BMI only explain 33% of the variance of AHI

Zucconi et al Thorax 1992;47:157-161

Hypotonic pharynx of sleeping apnoeic patients commonly collapses at multiple sites

Morrison et al Am Rev Respir Dis 1993;148:606

These findings are arguments against an important rolefor structural changes in the pathogenesis of OSA

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Open

AIRWAY

Closed AirwaySuction Local

Reflex

DilatorMuscleTone

InspiratoryDrive

PeripheralChemoreceptors Central

BreathingControl

CentralChemoreceptors

Upper AirwayDrive

Pathogenesis of OSA Balance of forces theory

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Mezzanotte WS et al J Clin Invest 1992; 89: 1571-79Remmers JE et al J Appl Physiol 1978; 44: 931-8Katz ES et al AJRCCM 2004; 170: 553-60

• Increased muscle activity in OSA.• Compensatory mechanism during sleep and wake.• But: ineffective fasic activity during apnoeas.

“Balance of forces” M. genioglossus activity in OSA

Disturbed reflex response

“Balance of forces” theoryImpaired reflex response

can be explained by: Nerve lesions

Svanborg 1998, 2001 Impairment in sensitivity

Kimoff, 2001 Association between neurological diseases and OSA

Demattéis, 2001 Cellular Inflammation at the UA level Could be related to the vibrations and trauma of snoring Could alter the functioning of the pharyngeal reflex

Paulsen FP et al Am J Respir Crit Care Med 2002;166:501-9 Boyd JH et al Am J Respir Crit Care Med 2004;170:541-6 Puig F et al Sleep 2005; 28: 1312-6

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SHCVR IHCVRl/min/mmHg mmHg

Controls (n=14) 1.66±0.16 39±1Heavy snorers (n=14) 1.26±0.20 33±5Normocapnic OSA (n=14) 2.41±0.26 * 40±2Hypercapnic OSA (n=11) 0.93±0.23 * 34±6Overlap OSA (n=11) 2.93±0.38 * 41±2

*p < 0.05 compared to controls

Verbraecken J et al Respir Physiol 1995;279-87

“Balance of forces” theoryAltered chemo-sensitivity

Pes

Arousal-threshold

Respiratory ‘drive’slope

DURATION OF AN EVENT

Response on increased upper airway resistance:Increased drive and reaching arousal threshold

DPmaxDP/ T respiratory response

Courtesy to D. Pevernagie

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Arousal threshold

Eckert D et al AJRCCM 2013;188(8):996-1004

Pathogenesis OSA Collapsibility of upper airway

Vimax=(Pus-Pcrit)/Rus

Park S et al Lung 1993;171:311-33

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Pathogenesis of OSA Collapsibility of upper airway

• Mechanical analogue of the upper airway consists of a collapsible locus surrounded by tissue pressure (critical pressure or Pcrit) and relatively rigid segments upstream in the nose and downstream in the hypopharynx

• When flow limitation occurs in the collapsible segment then

Vimax=(Pus-Pcrit)/Rus

During CPAP application Protocol: Gradual decrease of

CPAP pressure Flow regression/ extrapolation

Schwartz AR et al AJRCCM 1998; 157:1051-7

Sforza E et al AJRCCM 1999; 159:149-57

Pathogenesis OSA Measurement Pcrit: CPAP drop

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Pathogenesis OSA Collapsibility of upper airway (3)

• Normal human upper airway is characterised by a negative Pcrit– Schwartz A et al J Appl Physiol 1988;64:535-42

• Pcrit correlates with clinical picture of SRBD – Pcrit Normals < snorers < OH < OA– Gleadhill et al Am Rev Respir Dis 1991;143:1300-3

Pcrit higher in men

Kirkness el al 2008 J Appl Physiol 2008; 104: 1618-24

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Morrell MJ et al Am J Resp Crit Care Med 1998;158:1974–81

• 8 OSAS patients.• Fiberoptic imaging.

• Pharyngeal caliber.• Airflow.• Esophageal pressure.• 4 consecutive breaths preceding occlusion.

Time courseUA collapse: inspiratory or expiratory ?

Morrell M et al AJRCCM 1998;158:1974-81

Flow

Cross sectional area

Pathogenesis OSA Decrease in central drive

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Mechanisms promoting periodic breathing and CSA

Depressed central drive

Increased O2 (HVR) and CO2 drive (HCVR)

Unmasking of CO2 threshold

Stage effects

Upper airway reflexes

Pathogenesis periodic breathingDepressed central drive (1)

Wakefulness drive

Chemical drive

Environmental/ behavioral stimuli: Phonation, emotion, CV, temperature, exercise

SleepController gain (VE/PCO2)

- increased HCVR - cardiocirculatory

delay in CHF

Plant gain (‘lungs’)

(PCO2/VE) Loop gain

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Pathogenesis of periodic breathingController gain: Increased Chemical drive (2)

Verbraecken J et al Respir Physiol 1998;114:185-94

Std. Dev.Std. Err.Mean

Slope of the hypercapnic ventilatory response in central sleep apnea, obstructive sleep apnea and

healthy controls. Kruskal-Wallis ANOVA p=0.13

SHC

VR (l

/min

/mm

Hg)

0,8

1,4

2,0

2,6

3,2

3,8

4,4

CONTROLS CSA OSA

Measurement loop gain

Wellman A et al JAP 2011;110:1627-37

4.2/-1.4=-3

Loop gain: the ratio of ventilatory overshoot to the preceding reduction in ventilation

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Distribution loop gain

Eckert D et al AJRCCM 2013;188(8):996-1004

Pathogenesis of periodic breathingUnmasking of CO2 threshold (3)

• CA occurs after hyperventilation during sleep when PaCO2 drops below a certain level (apnoeic threshold)

• PaCO2 increases due to the sleep-induced increase in Ruaw. This protects subjects against central apneas since PaCO2 remains (longer) above the apneic threshold

– Skatrud et al J Appl Physiol 1983;55:813-22– Dempsey et al Am Rev Respir Dis

1986;133:1163-70

apnoea

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Unmasking of CO2 threshold (3) Role of Hypocapnia

Skatrud et al J Appl Physiol 1983;55:813-22

Normal breathing Apnoeic breathing

CO2 threshold: 3-6 mmHg below NREM setpoint PaCO2 (normoxia)1-2 mmHg below NREM setpoint PaCO2 (hypoxia)

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Arousal in CSA

Catecholamine hypersecretion

HV

Cyclic crescendo anddecrescendo change in breathing amplitude

(“waxing and waning”)

Quaranta AJ et al Chest 1997;111:467-473

-CAHI≥5-Crescendo-decrescendo pattern -Cycle period 40 to 90s-Minimal registration time 2h

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Idiopathic CSA or Cheyne-Stokes ?

ICSA

CSR

Obesity hypoventilation and OSA

Mokhlesi B et al Proc Am Thorac Soc 2008

Neurohormonal abnormalities 123

4

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Upper airway obstruction and OHSImbalance between CO2 load during respiratory events and post event ventilation

Magnitude and duration of post event ventilation: inadequate duration of hyperventilation

Berger KI et al JAP 2002; 93: 917–24

Acute hypercapnia causes a small ↑ in serum bicarbonate level, which blunts the HCVR.

Integrated approach: PALM

• The interaction between Pcrit and non-anatomical factors determine the presence or absence of OSA + severity.

• PALM: new classification system with integration of the different pathophysiological elements: – Passive critical closing pressure of the upper

airway, – Arousal threshold, – Loop gain, – Muscle responsiveness.

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Integrated approach: OSA phenotypes

Pcrit

PALM 1 ≥+2 cm H2O

PALM 2 -2 to +2 cm H2O

PALM 2A No non-anatomicaldeterminants

PALM 2B ≥ 1 non-anatomicaldeterminants

PALM 3 < -2 cm H2O

Low arousal threshold: <-15 cm H2O. Weak M Genioglossus response: <0.1%max incr EMG/cmH2OPes

Eckert D et al AJRCCM 2013;188(8):996-1004

Targeting the “upstream” mechanisms of OSA

Eckert D et al ERS Monogr 2015;67:9-23

This classification allows to develop new treatments for OSA according to the pathophysiological traits

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CONCLUSIONS

OSA: the pathogenesis is complex but increased collapsibility of the upper airway and increased instability of the breathing pattern both are contributing factors.

CSA and CSA-CSR: can predominantly be explained by increased chemical drive and activation of the CO2 threshold

OHS: Increased mechanical load, but it does not appear that obesity is the only determinant of OHS as only a minority of morbidly obese patients develops chronic hypercapnia

Phenotyping in OSA: the weight of the different pathophysiological mechanisms may vary in individual patients: useful targets for phenotyping.