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Pathophysiology of central sleep apnoea
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• Orr JE, et al. (2021). Research priorities for patients with heart failure and central sleep apnea.
An ocial American Thoracic Society research statement. Am J Respir Crit Care Med; 203:
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• Randerath W (2022). Positive airway pressure therapies in central sleep apnea. In: Janes SM,
ed. Encyclopedia of Respiratory Medicine. Vol. 5. Academic Press, pp. 181–196.
• Randerath W, et al. (2019). Central sleep apnoea and periodic breathing in heart failure:
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• Schmickl CN, et al. (2020). Acetazolamide for OSA and central sleep apnea: a comprehensive
systematic review and meta-analysis. Chest; 158: 2632–2645.
• Solin P, et al. (1999). Influence of pulmonary capillary wedge pressure on central apnea in
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• Solin P, et al. (2000). Peripheral and central ventilatory responses in central sleep apnea with
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• Wellman A, et al. (2003). Respiratory system loop gain in normal men and women measured
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• Xie A, et al. (2005). Cerebrovascular response to carbon dioxide in patients with congestive
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• Yu J, et al. (1998). Stimulation of breathing by activation of pulmonary peripheral aerents in
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64
ERS Handbook: Respiratory Sleep Medicine
Pathophysiology of
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hypoventilation
Annabel H. Nickol
Definition of hypoventilation and types of respiratory failure
Hypoventilation with a rise in P
respiratory failure (less descriptively known as ‘type II’ respiratory failure), is defined
as a P
mismatching, there will only be a reduction in P
>6 kPa (45 mmHg). As long as there is no ventilation/perfusion (V′/Q′)
aCO
2
Hypoxic respiratory failure (‘type I’ respiratory failure) is defined as a P
(<60 mmHg), and is caused by V′/Q′ mismatching; for example, due to pulmonary
emboli, lung fibrosis or pneumonia. While a P
hypoxic respiratory failure, clinicians should be vigilant and consider potential causes
of hypoxia before this low level is reached.
In clinical practice, hypoventilation and V′/Q′ mismatching commonly coexist, and
in this instance the reduction in P
rise in P
, with a widening of the alveolar–arterial oxygen tension gradient (P
aCO
2
is caused by reduced alveolar ventilation. Hypercapnic
aCO
2
that is proportionate to the rise in P
aO
2
aO
2
of <8 kPa is the arbitrary definition of
aO
2
is disproportionately large in comparison to the
aO
2
aCO
<8 kPa
A–aO
2
2
).
.
Key points
• Hypoventilation occurs when there is imbalance between respiratory muscle
strength, the load placed upon respiratory muscles, and ventilatory drive.
• Understanding the components of this triad enables clinicians to determine
the mechanisms and causes of ventilatory failure, and implement a targeted
strategy to aid recovery.
• Hypercapnia that is accompanied by disproportionate hypoxia, with widened
(alveolar–arterial) oxygen gradient, indicates concomitant V′/Q′ mismatching.
• Oxygen supplementation must be controlled in the context of hypercapnic
respiratory failure, or hypoventilation may be worsened by loss of hypoxic
ventilatory drive.
• Neuromechanical dissociation may lead to eventual blunting of neural drive
and reduced V′E.
• Patients with an acute exacerbation of COPD may have a low alveolar
ventilation despite an increased ventilatory drive, due to the higher load on
the ventilatory system.
65ERS Handbook: Respiratory Sleep Medicine
Pathophysiology of hypoventilation
22
(
)
()
(
)
−−
P
()
()
()
()
−−
.. .
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Alveolar oxygen tension (P
equation:
where PB is the atmospheric pressure (101 kPa at sea level), P
pressure at body temperature (6.3 kPa), F
respiratory quotient (0.8). For example:
If the P
predicted from the alveolar gas equation (usually no more than 2 kPa (15 mmHg) in
is greater than expected, i.e. the P
A–aO
2
) can be determined using the (simplified) alveolar gas
AO
2
P PP F P
=
AO B H O IO aCO
101 6 3 0 21 5 0 8
=×
AO
2
20 5 0 8 13 6
==
×
22
the inspiratory oxygen fraction and R the
IO
2
−
..
/ kPa
aO
/R
is water vapour
H2O
/
is significantly lower than the P
2
AO
young adults, but increasing with age), then there is also V′/Q′ mismatching.
When to suspect hypoventilation
Ventilatory failure can be screened for simply and easily with a focused history, and
checking for peripheral oedema (which may indicate cor pulmonale) and low oxygen
saturations. Oxygen saturations ≤94% should prompt an arterial or capillary blood gas
test. If these are not readily available, then screening can be done with a venous blood
gas; bicarbonate >27 mmol·L−1 indicates that there may be chronic hypercapnia.
Saturations and blood gases should always be carried out aer the patient has been
sat comfortably resting in a stable state (ideally for 20 min), and if any inspired oxygen
is in use, the method of delivery and flow rate/supplementary oxygen fraction should
be documented. If it is possible to come o oxygen for 20 min, then blood gases
measured on air are easier to interpret.
Another clue to incipient respiratory failure is the breathing pattern. The average tidal
volume for an adult is 500 mL and respiratory rate 12 breaths·min−1. In respiratory
failure, tidal volume is typically reduced; a strategy that allows the body to breathe over
the steeper, more ecient part of the pressure–volume curve, thereby reducing the
work of breathing. To compensate for this and attempt to maintain alveolar volume,
respiratory rate increases, so the respiratory rate to tidal volume ratio increases.
2
The respiratory pump in health
Ecient gas exchange requires adequate alveolar ventilation, flow of blood with
good oxygen-carrying capacity through the pulmonary vasculature and optimal
matching of ventilation to perfusion. In health, the respiratory pump has a capacity
that greatly exceeds the demands placed upon it, the ‘load’. The diaphragm usually
provides 70–80% of the inspiratory eort, and has both a high power output and high
endurance for sustained work. The respiratory control centres rapidly integrate aerent
stimuli from central and peripheral chemoreceptors, muscle, joint and lung aerents
and cortical inputs so that ventilatory drive is adjusted swily second by second to
match demand. Thus, P
with little ‘error signal’ in health. This perfectly balanced triad is illustrated in figure 1.
is kept remarkably constant both during rest and exercise,
aCO
2
The respiratory pump and hypoventilation
Hypoventilation is caused by loss of balance within the triad, with a reduction in
respiratory muscle strength, increase in ventilatory load or a reduction in ventilatory
drive, as illustrated in figure 2. When responding to a patient with hypercapnia, it is
useful to keep this schema in mind so that all potential causes are considered, and a
66
ERS Handbook: Respiratory Sleep Medicine
Pathophysiology of hypoventilation
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Adequate ventilation
Ventilatory
drive
Capacity
Hypoventilation
Load
Figure 1. The perfectly balanced triad of the respiratory pump in health. Respiratory muscle
capacity (strength and endurance) are sucient to overcome the modest respiratory load.
Ventilatory drive is perfectly controlled to adjust alveolar ventilation such that blood gases are
maintained within a narrow window without an error signal.
Adequate ventilation
Hypoventilation
Load
• Increased airway resistance
(e.g. COPD, bronchiectasis and
cystic fibrosis)
• Decreased compliance
(e.g. obesity and kyphoscoliosis)
• Upper airway resistance
(e.g. OSA)
Ventilatory
drive
• Removal of hypoxic ventilatory drive
(delivery of uncontrolled oxygen to a
patient with compensated
hypercapnia)
• Drugs (e.g. alcohol, sedatives and
anaesthesia)
• Brainstem lesions
• Intrinsic (Ondine's curse)
Capacity
• Decreased respiratory
muscle strength and
endurance (e.g. Duchenne
muscular dystrophy, motor
neurone disease, high spinal lesion)
Figure 2. Mechanisms of hypoventilation. Reduced respiratory muscle strength, an increase in
respiratory load or reduced ventilatory drive may lead to hypoventilation.
logical approach to reversing hypercapnia can be implemented, through treating the
underlying cause and – if indicated – consideration of ventilatory support, such as NIV.
Pathophysiology of hypoventilation in COPD
In COPD, respiratory load and work of breathing are increased through the following
mechanisms.
• Increased airways resistance due to loss of elastic recoil and thus support of the
airways, mucous and epithelial oedema, and through active expiration to try and
aid lung emptying, which increases intrathoracic pressure and hence further
narrows airways.
67ERS Handbook: Respiratory Sleep Medicine
Pathophysiology of hypoventilation
4
Resistance,
Lung volume, L
Lung volume
sistrictive lung
Pressure across respiratory system
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• Increased positive end expiratory pressure (PEEP) and gas trapping, brought about
by slow lung emptying, which is not complete before the next breath is required,
and floppy airways that close earlier than normal before end-expiration. The PAP at
end-expiration means that additional inspiratory eort is needed to reduce airway
pressure to below zero, so that inspiratory airflow can begin for the next breath.
• Breathing taking place at higher lung volumes. Here airways resistance is less (figure 3);
however, the disadvantage of breathing here at the top end of the lung’s pressure–
volume curve is that compliance of the lungs and chest wall are reduced (i.e. the
respiratory system is stier), thus also increasing the work of breathing (figure 4).
3
–1
O·s·L
2
2
cmH
1
Breathing at higher lung volumes
reduces work of breathing
0
024
68
Figure 3. Resistance–volume curve, showing reducing airways resistance as lung volumes increase.
Normal
Re
disease, e.g.
kyphoscoliosis
Figure 4. Pressure–volume curve for determination of respiratory system compliance (change in
volume/change in pressure) in health and restrictive disease. In health, breathing takes place
over the steep part of the pressure–volume curve where compliance is lowest. In COPD, breathing
takes place at the top of the curve, which is flattened, representing reduced compliance. In
restrictive disease, the whole curve is flattened.
68
ERS Handbook: Respiratory Sleep Medicine
Pathophysiology of hypoventilation
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Diaphragmatic muscle strength is preserved in COPD in vitro; however, flattening of
the diaphragm means that it is not working over the optimal part of its length–tension
curve, and so there is functional respiratory muscle weakness.
Tips for NIV strategy in hypoventilation due to COPD:
• Use generous pressure support to overcome airways resistance and achieve target
tidal volumes.
• Allow a prolonged expiratory time for lung emptying.
• Use sucient expiratory pressures to match and oset the patient’s PEEP.
Pathophysiology of hypoventilation in obesity and OSA
Work of breathing is increased due to the following.
• A reduction in chest wall compliance, which predominantly occurs in the diaphrag-
matic component of the chest wall due to abdominal obesity pushing caudally, in
contrast to the reduction in ribcage compliance that occurs in kyphoscoliosis.
• Abdominal obesity reduces lung volumes, forcing breathing to take place at the
bottom end of the pressure–volume curve, reducing compliance further.
• Increased expiratory flow limitation and PEEP due to decreased airway calibre at
lower lung volumes (figure 3).
• Increased upper airway resistance. The prevalence of severe OSA in obesity
hypoventilation is 72%, and ∼95% in milder OSA.
In addition, there may be hormonal blunting of ventilatory drive, for example due to
centrally occurring leptin resistance. Furthermore, sleep fragmentation – as occurs in
OSA – also leads to blunting of ventilatory drive.
Tips for ventilatory strategy in hypoventilation due to obesity and OSA:
• Use generous NIV pressure support to overcome low chest wall compliance and
airways resistance to achieve target tidal volumes.
• Use sucient expiratory pressure to match and oset the patient’s PEEP.
• Consider CPAP first-line for patients with obesity hypoventilation who are stable
and have been demonstrated to have severe OSA, as this may reduce the work of
breathing suciently to reverse hypoventilation.
Pathophysiology of hypoventilation in kyphoscoliosis
In kyphoscoliosis, the scoliotic component (lateral flexion deformity) is much
more detrimental to pulmonary mechanics than the kyphotic component (anterior
flexion deformity). Associated deformities of the spine and attached ribs lead to a
decrease in the volume of one hemithorax with narrowing of the intercostal spaces,
and a relative increase in the volume of the opposite hemithorax with widening of
the intercostal spaces. The concave side cannot reach a normal end-inspiratory
position, and the convex side cannot reach a normal end-expiratory volume. There
are marked reductions in lung volumes and chest wall compliance (figure 4), leading
to hypoventilation. In kyphoscoliosis there is loss of height, therefore predicted
lung volumes should be based upon arm-span rather than height. In the presence
of weakness of the thoracic respiratory muscles, uneven tension on the vertebral
column during growth eventually leads to curvature of the spine.
Tips for NIV strategy with hypoventilation due to kyphoscoliosis:
• Use generous pressure support to overcome low chest wall compliance and achieve
target tidal volumes.
69ERS Handbook: Respiratory Sleep Medicine
Pathophysiology of hypoventilation
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Pathophysiology of hypoventilation in neuromuscular weakness
In the presence of weakness of a single muscle, there is a remarkable ability for
compensation. For example, even in severe bilateral diaphragmatic paralysis, a
reasonable exercise load may still be sustained, albeit reduced compared to healthy
controls, due to recruitment, adaptation and training of extradiaphragmatic muscles.
During REM sleep, when the diaphragm is essentially the only ventilatory muscle le
working, bilateral diaphragm paralysis oen leads to dramatic falls in ventilation and
oxygen saturations.
However, global inspiratory or expiratory muscle weakness has a more profound eect
on pulmonary mechanics. Inspiratory muscle weakness leads to a reduction in total
lung capacity, albeit less marked than in kyphoscoliosis. Expiratory muscle weakness
leads to an increase in residual volumes and reduction in peak cough flow, so limiting
eective clearance of pulmonary secretions.
Tips for NIV strategy in hypoventilation due to neuromuscular weakness:
• Only modest pressures are needed to generate reasonable tidal volumes, since the
respiratory system remains compliant in the absence of kyphoscoliosis.
• Patients may lose the ability to trigger the ventilator in profound respiratory muscle
weakness, in which case pressure-control mode should be used.
• If patients become ventilator dependent (use ≥14 h·day−1), safety strategies for NIV
support should be put in place, e.g. provision of a second ventilator, with battery
back-up power for both machines.
• NIV can be helpful in alleviating orthopnoea, and some neuromuscular conditions
such as motor neurone disease can progress quickly. In this circumstance, NIV may
be started at a lower P
• Cough assistance may be required if there is insucient muscle strength for airway
threshold than in other conditions.
aCO
2
clearance when well (peak cough flow (PCF) ≤170 L·min−1), or at the time of a chest
infection (PCF ≤240 L·min−1).
Across all these causes of hypoventilation, there may be an increase in respiratory
rate to tidal volume ratio, which increases dead-space ventilation and worsens
hypoventilation.
Ventilatory drive, principles of controlled oxygen and hypoventilation
Ventilatory drive may be reduced by sedating drugs; for example, in a planned way
during anaesthesia when invasive ventilation maintains alveolar ventilation. It may
occur inadvertently; for example, due to accumulation of opiates in the face of renal
impairment, or in the face of extreme alcohol intoxication. Less commonly, a severe
brainstem event may supress ventilation, or very rarely a genetic condition in which
there is mutation of the PHOX2B gene (Ondine’s curse) leads to loss of ventilatory
drive during sleep.
The commonest cause of precipitating ventilatory failure in the healthcare setting is
inadvertent excess oxygen supplementation.
• In chronic hypercapnic ventilatory failure, compensatory renal retention of
bicarbonate leads to acid–base buering.
• Therefore, a raised P
• Chemoreceptors are not stimulated to increase ventilation in the usual way.
• However, even a modest degree of hypoxia (oxygen saturations of 88–92%) sitting
on the ‘shoulder’ of the oxygen–haemoglobin dissociation curve will stimulate
breathing so it is maintained (figure 5).
70
is not accompanied by the normal fall in pH seen acutely.
aCO
2
ERS Handbook: Respiratory Sleep Medicine
Pathophysiology of hypoventilation
S
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Target controlled
2
aO
P
aO
2
oxygen here
Figure 5. The oxygen–haemoglobin dissociation curve. In patients with proven or possible
hypercapnic respiratory failure, if supplementary oxygen is required it should be controlled
to target oxygen saturations of 88–92%. Higher oxygen saturations may remove hypoxic
ventilatory drive and precipitate worsening respiratory failure, because acid–base buering by
bicarbonate blunts the hypercapnic ventilatory response.
• Excess oxygen supplementation leading to saturations in the mid-to-high 90s
removes this hypoxic ventilatory drive, and can lead to worsening hypercapnic
respiratory failure and acidosis; instead, controlled oxygen should be given, for
example via a Venturi device.
• It can be tricky to maintain oxygen saturations in this narrow range of 88–92%
when oxygen supplementation is required; in this instance it is safer to broaden
the range to go low rather than high (85–92%).
Tips for treatment in view of hypoventilation with reduced ventilatory drive:
• Take a history of prescribed and recreational drugs that may contribute to blunted
ventilatory drive.
• Be mindful that opiates can accumulate in renal impairment.
• Supplemental oxygen should be controlled with target oxygen saturations of
88–92% (or 85–92% if it’s hard to stay within this target) in the presence of
compensated hypercapnia.
• Using NIV to reduce P
ventilatory drive when breathing spontaneously.
will gradually reduce bicarbonate and help restore
aCO
2
• It is sometimes reasonable to use a low dose of benzodiazepine or opiate to help a
patient with hypercapnia to tolerate NIV, because in this instance NIV will be taking
over the work of breathing.
• The greater the ‘dose’ of NIV (through increased alveolar ventilation or time using
the machine), the greater will be the fall in bicarbonate, allowing reversal of the
acid–base buering and some restoration of hypercapnic ventilatory drive. Thus,
ventilation will be increased when better and breathing spontaneously. This is
useful to bear in mind when helping a patient wean from ventilatory support.
Neural transmission
In an ideal situation, neural output would pass from the ventilatory control centres
via the spinal cord to the respiratory muscles, which would contract in a coordinated
71ERS Handbook: Respiratory Sleep Medicine
Pathophysiology of hypoventilation
The ideal
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indicator of drive
would be close
to the brain and
not aected by
disease state
Brain
Spinal motor
Peripheral nerves
Neuromuscular
junction
Diaphragm and other
respiratory muscles
Ventilation
Respiratory muscle EMG
P
and P
0.1
V'
E
Figure 6. The neural transmission pathway from brain to ventilation. Potential markers
of ventilatory drive are shown on the right, with the ideal indicator being as close to the brain
as possible.
fashion to produce airflow in and out of the lungs with minimal attenuation of the
signal at each step (figure 6). If this was the case, then V′E would be a very good indicator
of ventilatory drive. However, at each step along the pathway, there is the potential for
poor neural transmission to lead to attenuation of the ventilation; for example, due to
a spinal cord lesion, neuromuscular condition or altered pulmonary mechanics such
as COPD, kyphoscoliosis or OSA: so-called neuromechanical dissociation.
The ideal indicator of ventilatory drive would be as close to the brain as possible.
Animal studies have demonstrated that phrenic nerve activity is related to tracheal
pressure developed in the occluded airway 100 ms aer the onset of inspiration.
It was therefore suggested in humans that a simple, noninvasive measure, mouth
pressure 100 ms aer the onset of inspiration against a closed shutter, termed P
could serve as a good measure of central drive. This method has been widely used in
clinical studies and has been found to be of practical value. P
is one step ‘nearer the
0.1
brain’ than ventilation, and so may be a better indicator of drive. It has been observed
that the ventilatory response to rebreathing carbon dioxide in COPD is blunted in
patients who are hypercapnic compared to those who are normocapnic. It would be
a mistake to assume that this was because of blunted ventilatory drive; in fact P
was the same in both groups, showing that they had equivalent ventilatory drive,
but the ones who were hypercapnic had poor neural transmission due to greater
mechanical constraints. It was suggested that hypercapnia in COPD is due to poor
neuroventilatory coupling rather than decreased ventilatory drive.
There are some challenges using P
in COPD: mouth and pleural P
0.1
have been shown
0.1
to correlate poorly; onset of inspiration may be dicult to define in the presence of
PEEP; and airway occlusion during inspiration may be uncomfortable. An alternative
measure is the maximum rate of change of oesophageal pressure occurring over a
100-ms period during inspiration (ΔP
/Δt). This has been shown to correlate well
oesmax)
with end-tidal carbon dioxide tension during rebreathing in healthy volunteers and
with walk time in patients with severe COPD.
A further measure that is even closer to the brain is measurement of the respiratory
muscle EMG, with recordings being made transcutaneously over the chest wall to
oesMax
/t
0.1
0.1
,
72
ERS Handbook: Respiratory Sleep Medicine
Pathophysiology of hypoventilation
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measure costal diaphragmatic EMG, or via an oesophageal electrode to measure
crural diaphragmatic EMG.
Using these alternative measures, it has been demonstrated that patients with an
acute hypercapnia due to an infective exacerbation of COPD oen have increased
ventilatory drive, even though mechanical constraints lead to neuromechanical
uncoupling, and alveolar ventilation is thus reduced.
Further reading
• Simonds AK, ed. (2015). ERS Practical Handbook of Noninvasive Ventilation. Sheeld,
European Respiratory Society.
73ERS Handbook: Respiratory Sleep Medicine
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