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Evaluation of PAP ecacy
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In most portable monitoring devices, apnoea/hypopnoea underestimation is caused
by the following.
• Lack of EEG data:
• the denominator used (time in bed or time of registration or time corrected
through the use of surrogates of sleep/wake state) to obtain the index will
impact the results;
• associated respiratory arousals are not evaluated systematically, or surrogates
are used.
• Lack of desaturation in some patients, which is a criterion used in the definition of
hypopnoea.
Therefore, portable monitoring devices induce a loss of accuracy. Thus, it is important
to be aware of the methodological limitations of the monitoring device used when
assessing treatment ecacy.
AHI during PAP treatment
Despite the limitations mentioned previously, the term AHI is oen used
indiscriminately. The advantage of using AHI is that it alerts caregivers to the level of
severity and to the ecacy of the treatment.
AHI improvement can be expressed in dierent ways: reaching a specific threshold
(e.g. <5 events·h−1 is considered normal in adults) or a specific level of reduction
(e.g. reduction >50%) with an AHI below a chosen threshold. In the recent National
Institute for Health and Care Excellence (NICE) guideline, the expert committee
agreed that the aim of treatment is to achieve an AHI of <5 events·h−1, which is not
always reached in practice, despite a substantial improvement in symptoms or quality
of life. The AASM guideline mentions that when using portable monitoring, the PSG
titration study should reflect control of the patient’s obstructive respiration by a low
AHI (preferably <5 events·h−1) at the selected pressure at sea level and a minimum
S
>90% with a leak within acceptable parameters.
aO
2
Although classifications developed to depict OSA severity are oen based on AHI, OSA
is a complex and heterogeneous disease. Therefore, the concept of phenotyping for
personalised medicine for OSA patients is growing in the scientific literature, providing
a large panel of subtypes of OSA patients, and paving the way for tailored medicine.
Despite these considerations, there are no high-level studies (evidence) establishing
the degree of AHI improvement to be reached, and even fewer studies considering
specific OSA phenotypes. For example, in phenotypes associated with REM sleep
OSA or positional OSA, the total AHI is not an exact indication of the disease severity.
According to the AASM guideline, an optimal titration reduces RDI to <5 events·h−1
for a ≥15-min duration and should include supine REM sleep at the selected pressure
that is not continually interrupted by spontaneous arousals or awakenings.
Oxygen parameters under PAP treatment
Measures considered to be clinically significant are ODI (number of ≥3% or 4%
events·h−1), mean S
and interesting concept is hypoxic burden, but due to dierent methods in the
aO
2
computation of this new parameter, additional research and prospective validation
are still needed to fully understand the link between hypoxic burden and patient
outcomes. Limitations of portable monitoring devices in the calculation of the
index have been described earlier in this chapter. Using portable monitoring devices
194
, time below a certain S
threshold and lowest S
aO
2
ERS Handbook: Respiratory Sleep Medicine
. A new
aO
2
Evaluation of PAP ecacy
https://t.me/medicina_free
that assess S
intermittent hypoxia at diagnosis is more useful than using them in patients without
during the follow-up of PAP treatment in patients with identified
aO
2
oxygen desaturation. However, the exact amount of improvement regarding oxygen
parameters under PAP treatment that should be reached is still not completely clear.
Moreover, presence of comorbidities (e.g. COPD, OHS) will impact this assessment.
In those patients, portable monitoring assessing oximetry alone is not advised in the
follow-up of PAP treatment ecacy.
Evaluation of BP and other cardiovascular events under PAP treatment
PAP treatment and arterial hypertension
The relationship between OSA and arterial hypertension (AHT) has been studied for many
years. The prevalence of OSA in the AHT population increases where there is resistant
hypertension. OSA triggers direct and intermediate mechanisms associated with the
development and persistence of AHT (see chapter 4.1 of this Handbook). Therefore,
together with the fact that OSA is an important treatable cause of secondary AHT, it is
important to diagnose OSA and to evaluate the potential benefits of CPAP treatment.
Definition of AHT and methods used for monitoring AHT are described in table 1.
It is complex to identify the conditions required to reach a beneficial eect on AHT and
when it should be expected. A common relevant finding is that there is a positive and
linear dose–response relationship between increased CPAP daily use, severity of AHI
and AHT, and the reduction in BP levels. Aer starting antihypertensive drug therapy,
it is important to review the patient at least once within the first 2 months to assess
the eects on BP. Many studies have used 24-h BP measurement, which is considered
to be the most accurate diagnostic method. The frequency of the re-evaluation will
depend on the severity of AHT, the urgency to achieve BP control and the patient’s
comorbidities (at least yearly is advised). Clinicians should measure BP and weight in
routine follow-up. Obesity is a confounding factor in the association between AHT and
OSA and significant fluctuations in weight will impact both diseases.
Molecular phenotyping classifies individuals based on molecular features. In the
HIPARCO study, aer 3 months of adherent CPAP treatment in resistant hypertension
patients, reduced micro (mi)RNAs and decreases in aldosterone-to-renin ratios
(positively correlated to the change in mean BP values) were significantly greater
in the responder group. Currently, cardiovascular markers such as miRNAs are not
assessed in clinical practice and future studies are needed to establish the relevance
of the newly identified phenotype and potential applications.
Table 1. Definitions of hypertension according to oce, ambulatory and home BP levels
Oce BP
Ambulatory BP
Daytime (or awake) mean ≥135 and/or ≥85
Night-time (or asleep) mean ≥120 and/or ≥70
24 h mean ≥130 and/or ≥80
Home BP mean ≥135 and/or ≥85
To diagnose AHT, use repeated oce BP measures or out-of-oce 24-h ambulatory BP mean
or home BP mean. #: conventional oce BP, rather than unattended oce BP. Reproduced from
Williams et al. (2018) with permission.
#
SBP mmHg DBP mmHg
≥140 and/or ≥90
195ERS Handbook: Respiratory Sleep Medicine
Evaluation of PAP ecacy
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PAP and other cardiovascular events
Observational data showed that PAP treatment improves the ecacy of cardioversion
for atrial fibrillation (AF) (leading to the same risk of recurrence than in patients
without OSA) and improves catheter ablation success rates. ODI and magnitude of
desaturation (mean S
with higher risk of new-onset AF (in patients aged <65 years) and recurrence
during sleep and the lowest S
aO
2
during sleep) are associated
aO
2
aer cardioversion. 6 months of CPAP therapy reverses atrial remodelling in OSA.
Moreover, screening AF patients for OSA improves identification of ‘high-risk’
patients for thromboembolism, while OSA treatment improves thromboembolic risk
by attenuating impact of OSA itself.
A grey area exists regarding the use of the pulse transit time (PTT), an indirect
quantitative measure of inspiratory eort. This parameter is evaluated in dierent
studies, but has been less used in clinical practice. This is probably linked to the lack
of specificity of this parameter (e.g. also aected by nonrespiratory arousals), the
existence of clinical limitations (e.g. in patients with cardiovascular comorbidities
or taking specific medication) and the diculty in identifying an acceptable level of
therapeutic improvement under PAP therapy.
In summary, the evaluation of PAP therapy ecacy in OSA patients is mainly based
on improvement in disease severity (AHI/RDI), sleepiness and sleep-related quality of
life, combined with a well-used PAP therapy and absent or, at most mild PAP-related
side-eects, allowing for good tolerance and comfort. Technical methods used for PAP
initiation, titration and follow-up are described in other chapters of this Handbook. The
evolution of symptoms can be evaluated by a full sleep history. Use of questionnaires
can be a useful adjunct, but several questionnaires lack reliability or validation in
OSA patients. In patients with persistent symptoms or PAP-related problems, PSG
or portable monitoring during PAP treatment is recommended. It is important to be
aware of possible portable monitoring limitations with regard to assessment of AHI/
RDI and oxygen parameters. The exact level of adequate improvement in several
parameters (including dierent oxygen parameters and breathing eort) needs to be
further elucidated.
Further reading
• Abma IL, et al. (2016). Measurement properties of patient-reported outcome measures
(PROMs) in adults with obstructive sleep apnea (OSA): a systematic review. Sleep Med Rev;
28: 18–31.
• Craig S, et al. (2022). Investigation and management of residual sleepiness in CPAP-treated
patients with obstructive sleep apnoea: the European view. Eur Respir Rev; 31: 210230.
• Kuhn E, et al. (2017). Eects of CPAP and mandibular advancement devices on health-related
quality of life in OSA: a systematic review and meta-analysis. Chest; 151: 786–794.
• Kushida CA, et al. (2008). Clinical guidelines for the manual titration of positive airway pressure
in patients with obstructive sleep apnea. J Clin Sleep Med; 4: 157–171.
• Levy P, et al. (2015). Overall treatment strategies. In: Barbé F, et al., eds. Obstructive Sleep
Apnoea (ERS Monograph). Sheeld, European Respiratory Society; pp. 305–325.
• Linz D, et al. (2018). Association of obstructive sleep apnea with atrial fibrillation and
continuous positive airway pressure treatment: a review. JAMA Cardiol; 3: 523–540.
196
ERS Handbook: Respiratory Sleep Medicine
Evaluation of PAP ecacy
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• National Institute for Health and Care Excellence (NICE) (2021). Obstructive Sleep Apnoea/
Hypopnoea Syndrome and Obesity Hypoventilation Syndrome in over 16s. NICE Guideline
[NG202]. www.nice.org.uk/guidance/ng202 Date last updated: 20 August 2021.
• Patil S, et al. (2019). Treatment of adult obstructive sleep apnea with positive airway pressure:
an American Academy of Sleep Medicine systematic review, meta-analysis, and GRADE
assessment. J Clin Sleep Med; 15: 301–334.
• Sánchez-de-la-Torre M, et al. (2015). Precision medicine in patients with resistant hypertension
and obstructive sleep apnea. J Am Coll Cardiol; 66: 1023–1032.
• Williams B, et al. (2018). 2018 Practice Guidelines for the management of arterial hypertension
of the European Society of Hypertension and the European Society of Cardiology: ESH/ESC
Task Force for the Management of Arterial Hypertension J Hypertens; 36: 2284–2309.
197ERS Handbook: Respiratory Sleep Medicine
Prognostic impact of central
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sleep apnoea
Winfried Randerath
CSA diers from OSA, not only in terms of the underlying pathophysiology and
comorbidities, but also in clinical symptoms. While EDS is the most prominent
adverse eect of OSA, patients with CSA may not report daytime symptoms at all,
or may complain of nonrestorative sleep or symptoms of any underlying disease.
The lack of typical or limiting symptoms questions the indication to treat CSA.
Therefore, the question arises of whether the suppression of CSA improves outcome
of aected patients. The results of the SERVE-HF trial (ASV for CSA in systolic HF)
questioned the beneficial eect of treatment of CSA in periodic breathing for
prognostic purposes.
Proceedings in our understanding of OSA have focused on the determination and
definition of dierent phenotypes. This influences our approach to the patients,
regarding risk stratification and therapeutic decisions. Despite the huge heterogeneity
of underlying causes of CSA and the variety of PSG and clinical presentations,
consideration of phenotypes in CSA is still deficient. This may be due to the lower
prevalence of CSA impeding sucient cluster analyses.
Therefore, the aim of this chapter is to define, more precisely, the potential risk of
CSA. Are there subgroups of phenotypes in the CSA population and do they dier in
terms of outcome? Available literature focuses almost exclusively on patients with
HF. Therefore, we will discuss HF subgroups, clinical phenotypes, pathophysiological
characteristics and potential biomarkers that indicate prognostic impact in HF patients
with CSA. A summary of the clinical and pathophysiological markers of poor outcome
in CSA that are discussed in this chapter is given in table 1.
Key points
• CSA is associated with impaired outcome in HF patients.
• Patients with HF and CSA represent a heterogeneous population, requiring
characterisation based on clinical and physiological parameters.
• Detailed characterisation will allow for an individualised diagnosis and
selection of treatment.
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Prognostic impact of CSA
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Table 1. Clinical and pathophysiological markers of poor outcome in CSA
HF with reduced ejection fraction
Phenotype of male, elderly patients with predominant CSA
Parameters of unstable breathing
High loop gain
Exercise oscillatory ventilation
Increased HCVR
Increased HVR
Periodic breathing pattern/CSR
Negative pattern of end-expiratory lung volume
Hypoxic burden
Time with oxygen saturation <90%
Oxygen desaturation index
Time with oxygen desaturation by >4%
HF subgroups
Prospective cohort studies showed the impact of sleep-related breathing disturbances
(SRBD) in patients with HF. Patients with reduced le ventricular ejection fraction
(LVEF) associated with untreated CSA or OSA have a significantly higher mortality risk
compared to patients without SRBD and to those treated with PAP.
The severity of systolic HF is associated with the reduction of LVEF. This seems to
play a major role in the interpretation of the results of the SERVE-HF study, which is
extensively discussed in the next chapter in this Handbook, ‘Central sleep apnoea in
chronic heart failure’ (chapter 9.2). Predefined secondary analyses of the data showed
that the risk of impaired survival under ASV was only relevant in those patients with
a LVEF below 30%. These data suggest that the mortality risk of CSA patients with HF
depends substantially on the severity of HF.
These results are supported by data from the FACE trial, a prospective cohort of
unselected HF patients with dierent severity of le ventricular impairment. Based on
cluster analyses, six clinical phenotypes were described. The groups diered according
to LVEF, whether they had OSA or CSA, age, comorbidities and treatment acceptance
of ASV. The risk for the combined primary end-point of mortality, hospitalisation,
cardiac transplantation, and implantation of ventricular assist device was significantly
increased in the cluster of male patients with low LVEF and CSA. The eect was
independent of the treatment with ASV.
These findings indicate that a stratification of the CSA population regarding the
severity of le ventricular impairment is crucial and may be an important step in a
therapeutic algorithm.
Pathophysiological risk factors
The apnoea threshold, the chemoresponsiveness and the loop gain of the respiratory
system characterise the pathophysiology of CSA (see chapter 3.2 ‘Pathophysiology of
central sleep apnoea’). The loop gain describes the extent of the ventilatory response
to a given disturbance. A high loop gain is defined by a long apnoea period associated
with a high ventilatory overshoot (amplitude of ventilation). This constellation (long
apnoeic period, severe hyperventilation) indicates poor treatment response, while a
low loop gain (short apnoeic period, mild hyperventilation) is associated with a better
199ERS Handbook: Respiratory Sleep Medicine
Prognostic impact of CSA
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response to oxygen or PAP therapy. In addition, the exercise oscillatory ventilation can
help in identifying the instability of respiration. It is characterised by a high variability
of the V’E during exercise tests. The exercise oscillatory ventilation is a common
pattern of HF and an indicator of poor prognosis.
In addition, chemosensitivity to hypoxia and hypercapnia is associated with outcome
of HF patients with a reduced LVEF. Patients with increased hypoxic ventilatory
response (HVR) and hypercapnic ventilatory response (HCVR) show a significantly
worse outcome compared to those with either increased HVR or HCVR or to those
with normal HVR and HCVR. All these data indicate that instability of the respiratory
system is at least a marker of poor prognosis. These data on the relevance of instability
of respiration are in line with findings from SERVE-HF and FACE showing increased
mortality in those patients with higher amounts of CSR (which describes the PSG
finding of periodic breathing in patients with HF).
Lung mechanics in CSA
The ventilatory cycle of inspiration and expiration is accompanied by changes of
intrathoracic volume and pressure. Two patterns of the end-expiratory lung volume
have been discriminated in patients with periodic breathing and CSA. The positive
pattern is defined by an end-expiratory lung volume exceeding FRC, while the
negative pattern is characterised by a lower end-expiratory lung volume compared to
FRC (see chapter 3.2 ‘Pathophysiology of central sleep apnoea’). The negative pattern
is associated with longer hyperpnoea and cycling time, higher N-terminal pro-brain
natriuretic peptide as a marker of impaired le ventricular function and worse New
York Heart Association classes. It has been hypothesised that the positive expiratory
pressure might support stroke volume in patients with worse cardiac function.
Hypoxia as a biomarker
There is growing evidence in OSA that the number of breathing disturbances
during sleep is less relevant to the outcome of patients compared to associated
symptoms (such as sleepiness) or consequences (such as oxygen desaturation).
Several parameters are used to describe the behaviour of oxygen saturation during
sleep. These include the index of desaturations by 3% or 4% during total sleep
time, the amount of time with oxygen saturation <90%, and the time with oxygen
desaturation by >4%. These parameters are oen summarised under the term of
hypoxic burden. Although the optimal parameter describing the hypoxaemic burden
is as yet unclear, more and more data show the prognostic relevance of hypoxia
during sleep.
Summary
Emerging evidence shows a heterogeneity in clinical presentation and patient
characteristics, not only in OSA but also in CSA and periodic breathing. Patients
dier in terms of the severity of le ventricular impairment. Severely reduced LVEF
seems to be the most relevant risk factor for unfavourable outcome in CSA patients.
In addition, the instability of ventilation seems to have a major prognostic relevance.
Several biomarkers indicate the grade of instability, including the loop gain, the
chemoresponsiveness and the exercise oscillatory pattern. Mechanical influences like
the end-expiratory lung volume as well as hypoxic burden require further evaluation
and discussion.
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Prognostic impact of CSA
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Further reading
• Brack T, et al. (2005). Fluctuations in end-expiratory lung volume during Cheyne–Stokes
respiration. Am J Respir Crit Care Med; 171: 1408–1413.
• Eulenburg C, et al. (2016). Mechanisms underlying increased mortality risk in patients with
heart failure and reduced ejection fraction randomly assigned to adaptive servoventilation in
the SERVE-HF study: results of a secondary multistate modelling analysis. Lancet Respir Med;
4: 873–881.
• Giannoni A, et al. (2009). Combined increased chemosensitivity to hypoxia and hypercapnia as
a prognosticator in heart failure. J Am Coll Cardiol; 53: 1975–1980.
• Granitza P, et al. (2018). Is dynamic desaturation better than a static index to quantify the
mortality risk in heart failure patients with Cheyne–Stokes respiration? Chaos; 28: 106312.
• Javed F, et al. (2020). Association of serious adverse events with Cheyne–Stokes respiration
characteristics in patients with systolic heart failure and central sleep apnoea: a SERVE-Heart
Failure substudy analysis. Respirology; 25: 305–311.
• Kazimierczak A, et al. (2011). Resolution of exercise oscillatory ventilation with adaptive
servoventilation in patients with chronic heart failure and Cheyne–Stokes respiration:
preliminary study. Kardiol Pol; 69: 1266–1271.
• Khayat R, et al. (2015). Sleep disordered breathing and post-discharge mortality in patients
with acute heart failure. Eur Heart J; 36: 1463–1469.
• Naito R, et al. (2022). Association between frequency of central respiratory events and clinical
outcomes in heart failure patients with sleep apnea. J Clin Med; 11: 2403.
• Perger E, et al. (2017). Distinct patterns of hyperpnea during Cheyne–Stokes respiration:
implication for cardiac function in patients with heart failure. J Clin Sleep Med; 13: 1235–1241.
• Randerath W, et al. (2017). Definition, discrimination, diagnosis and treatment of central
breathing disturbances during sleep. Eur Respir J; 49: 1600959.
• Sands SA, et al. (2011). Loop gain as a means to predict a positive airway pressure suppression
of Cheyne–Stokes respiration in patients with heart failure. Am J Respir Crit Care Med; 184:
1067–1075.
• Tamisier R, et al. (2022). Adaptive servo ventilation for sleep apnoea in heart failure: the FACE
study 3-month data. Thorax; 77: 178–185.
• Wang J, et al. (2021). Therapeutic value of treating central sleep apnea by adaptive servo-
ventilation in patients with heart failure: a systematic review and meta-analysis. Heart Lung;
50: 344–351.
• Watanabe E, et al. (2017). Prognostic importance of novel oxygen desaturation metrics in
patients with heart failure and central sleep apnea. J Card Fail; 23: 131–137.
201ERS Handbook: Respiratory Sleep Medicine
Central sleep apnoea in
https://t.me/medicina_free
chronic heart failure
Winfried Randerath
Central breathing disturbances are a frequent symptom in patients with HF with
reduced and preserved le ventricular function. The decision to treat depends on
clinical symptoms on the one hand and prognostic relevance on the other. It has
been discussed that HF patients with CSA oen do not report typical sleep apnoea
symptoms, such as daytime sleepiness (see chapter 9.1, ‘Prognostic impact of central
sleep apnoea’). Other problems, such as reduced quality of life, disturbed sleep and
nocturia, may be more prominent. Moreover, for some patients the symptoms of
the underlying heart disease can be more limiting so that symptoms of breathing
disturbances may be ignored. Thus, clinicians should be urged towards a detailed
questioning of patients and relatives.
There is growing evidence, mainly from long-term observations of cohorts, suggesting
reduced survival in HF patients with central breathing disturbances compared to those
with regular breathing. A European Respiratory Society (ERS) task force recommended
an approach to patients with CSA and chronic HF. It is based on the optimisation of
the underlying disease, the dierentiation of OSA and CSA, the level of le ventricular
ejection fraction (LVEF) and the clinical symptomatology (figure 1).
Key points
• Optimisation of the underlying HF is a precondition to any additional specific
treatment.
• Symptomatic approaches include oxygen supply, PAP treatment and
pharmacological agents. They interact with dierent components of the
underlying pathophysiology.
• Oxygen and CPAP reduce central breathing disturbances in HF by a mean of 50%.
PAP stabilises peripheral airways, improves ventilation–perfusion mismatch and
gas exchange and influences fluid accumulation and cardiac function.
• ASV counterbalances ventilatory over- and undershoot of periodic breathing.
It most eectively normalises central breathing disturbances.
• Current limitations of the prescription of ASV have to be respected but are
under discussion.
• There is no evidence for the use of BPAP in spontaneous/timed or timed
mode or NIV.
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ERS Handbook: Respiratory Sleep Medicine
CSAOSA
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Stroke, renal
failure, other
comorbidities
apnoea
Opioid-
induced sleep
periodic
Idiopathic
respiration
AHI <15
disease
of underlying
Optimal therapy
Persistent
AHI <15
opioids?
Reduction/
withdrawal of
Persistent
AHI <15
CPAP
events per h
events per h
CSA AHI ≥15
events per h
events per h
CSA AHI ≥15
events per h
CSA in chronic heart failure
AHI <15
events per h
ASVASV
Persistent
events per h
CSA AHI ≥15
AHI <15
events per h
CPAP CPAP
Persistent
events per h
CSA AHI ≥15
ASV
in HF
CSA/CSR
cardiac
Optimal
Persistent
events per h
CSA AHI ≥15
ASV
CPAP
symptoms
symptoms
CPAP
Persistent
events per h
CSA AHI ≥15
HF
therapy
Continuing
CPAP
AHI <15
events per h
emergent
Persistent/
events per h
CSA AHI ≥15
ASV
Figure 1. Current practice on the treatment of CSA, including periodic breathing. This figure describes the current practice of how the members of the ERS task force
treat patients with CSA or coexisting OSA and CSA, and is not intended as a general recommendation. Reproduced and modified from Randerath et al. (2017a) with
permission.
Persistent
events per h
CSA AHI ≥15
Minor
treatment
Predominant
LVEF ≤45% LVEF >45%
Predominant
CSA/CSR
OSA
Severe
203ERS Handbook: Respiratory Sleep Medicine
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