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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_4566_Библиотеки_им_академика_М_И_Перельмана
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Asthma, COPD and ILDs
https://t.me/medicina_free
Recognition of sleep quality and disturbance is particularly important when we
consider the impact pharmacological therapy has on quality of life. Pharmacological
agents that improve the quality of sleep in COPD are likely to have a beneficial clinical
impact that goes beyond that associated with improvements in lung mechanics and
gas exchange, particularly in relation to the quality-of-life measures that reflect the
psychological domain.
The consequences of nocturnal hypoxaemia
Higher daytime pulmonary artery pressures have been reported in COPD patients
with nocturnal oxygen desaturation and mild daytime hypoxaemia, when compared
with patients with no night-time desaturation. REM-associated falls in oxygen
saturation (S
sleep that can be reversed with supplemental oxygen, although most COPD patients
) are linked with an increase in pulmonary artery pressure during
pO
2
with sustained pulmonary hypertension (PH) are also hypoxaemic when awake.
There is no convincing evidence that isolated nocturnal PH in COPD is a significant
independent predictor of survival. An increase in premature ventricular contractions
during sleep has also been noted in COPD patients, the frequency of which decreases
with supplemental oxygen therapy.
There is evidence that nocturnal oxygen desaturation contributes to mortality,
particularly during acute exacerbations. There appears to be a significant relationship
between nocturnal oxygen desaturation and long-term survival; whether this
relationship is independent of lung function abnormalities and blood gases during
wakefulness is unclear.
Oxygen supplementation during sleep has not been demonstrated to improve longterm survival. Patients who die in hospital with an exacerbation of COPD have been
reported to be more likely to die at night in contrast with patients who die as the
result of a stroke or neoplasm, with excess nocturnal mortality most frequently seen
in hypercapnic patients.
Adequate monitoring during sleep, particularly of gas exchange, is therefore important
in patients who are admitted with acute exacerbations of COPD.
Investigating nocturnal respiratory abnormalities
As hypoxaemia is the most pronounced abnormality during sleep in patients with
COPD, studies that primarily focus on gas exchange, such as pulse oximetry, may
be sucient in most cases. More detailed sleep studies, such as cardiorespiratory
polygraphy (PG), are indicated where overlap syndrome is suspected. Full PSG is rarely
indicated in the assessment of sleep disturbances in COPD and can be reserved for
patients suspected of having a more complex mixed sleep disorder.
Management of respiratory abnormalities during sleep
COPD patients with respiratory disturbances during sleep should have their general
management optimised, as there is evidence that this initial approach is beneficial
to respiration and gas exchange during sleep. Specific sleep-related management
options are particularly directed at reversing gas exchange disturbances.
Oxygen therapy
The most clinically relevant impact of hypoventilation, especially during sleep, is
hypoxaemia. Oxygen supplementation therefore represents a core management
option for patients with COPD who demonstrate significant hypoxaemia. The decision
to prescribe oxygen therapy in this context should consider the patient’s awake oxygen
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ERS Handbook: Respiratory Sleep Medicine
Asthma, COPD and ILDs
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level, because oxygen supplementation that is confined to the night is not associated
with improved survival. Oxygen supplementation is therefore most appropriate for
patients who demonstrate awake hypoxaemia at a level that is sucient to also
warrant daytime supplementation.
There is concern that oxygen supplementation may be complicated by elevated
arterial carbon dioxide levels because the respiratory drive of some of these patients,
especially those with awake hypercapnia, may partly depend on hypoxia stimulus.
Low-flow oxygen therapy in the region of 2–4 L·min−1 is typically preferred in such
patients. However, the risk of aggravating hypercapnia in this setting is limited, usually
non-progressive and should not inhibit the prescription of oxygen supplementation in
appropriate circumstances.
Pharmacological therapy
Cholinergic tone is elevated at night. This may play a role in worsening airflow
limitation during sleep in COPD patients, contributing to deteriorating gas
exchange. The short-acting anticholinergic agent, ipratropium, and the long-acting
agent, tiotropium, have demonstrated increased oxygen saturation levels during
sleep without deterioration in sleep quality. The beneficial eects are particularly
evident during REM sleep when oxygen desaturation is most pronounced. The
long-acting β-agonist agent salmeterol has also been shown to improve sleeping
oxygen saturation levels in a similar way to anticholinergic therapy.
Hypnotic agents such as benzodiazepines should not be prescribed to patients with
COPD, as these agents may have a negative eect on respiration during sleep, with
consequent negative eects on gas exchange. However, the hypnotic zolpidem does
not appear to be associated with such negative eects, and therefore may be considered
a potential therapy for COPD patients who report debilitating sleep disturbances.
NIV
Pressure support, generally delivered as NIV, may be considered in patients who
fail to respond adequately to oxygen supplementation and optimisation of other
therapies. The most common manifestation of this insucient response is persistent
severe hypercapnia. It has long been recognised that NIV in the acute setting during
hospitalisation for exacerbations of COPD is associated with improved outcomes. The
widespread use of NIV in this setting has resulted in reduced demand on traditional
intensive care units.
Long-term nocturnal NIV has more recently been introduced as a management option
for COPD patients who demonstrate persistent hypercapnia outside the acute setting.
In the past, NIV in the chronic setting had diering results. More recently, however,
long-term improvements have been noted with NIV use in hypercapnic patients with
COPD, both aer acute exacerbation and in stable COPD with chronic hypercapnia. NIV
in this setting appears to be well tolerated and has been reported to improve daytime
gas exchange and respiratory muscle function, as well as sleep quality. Potential
mechanisms that may contribute to these benefits include rest for the respiratory
muscles, improved V’/Q’ relationships, and improved lung compliance, resulting in
reduced work of breathing. A potential long-term benefit relates to the resetting of
chemoreceptors, resulting in an improved chemoreceptor drive to breathe.
Interstitial lung diseases
Interstitial lung diseases (ILDs) are a large and diverse group of diseases that aect
the pulmonary parenchyma and interfere with gas exchange. The most prevalent
idiopathic ILD, idiopathic pulmonary fibrosis (IPF), typically occurs in older adults
235ERS Handbook: Respiratory Sleep Medicine
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and is usually associated with a poor prognosis. Growing evidence highlights the
significant eect of various comorbid diseases, such as OSA, on IPF’s natural course
and prognosis. Moreover, the most recent ocial guidelines for the diagnosis and
treatment of IPF acknowledge OSA as one of the most common comorbidities seen in
these patients (Raghu et al., 2022).
Prevalence
Determining the exact prevalence of OSA in ILD patients is challenging. Previous
research primarily considered the occurrence of OSA in IPF patients, revealing a
widespread prevalence. Nevertheless, with prevalence rates ranging 50–90%, OSA
seems to be more common in IPF patients than in the general population. This
pronounced variability in prevalence is due to the dierent study designs, diagnostic
methods and criteria used for OSA, as well as the demographic structure of the
populations studied. The majority of patients have moderate-to-severe OSA (AHI
of >15 events·h−1); central events account for <5% of all scored respiratory events.
Despite the increasing prevalence of OSA in IPF patients, the condition remains
under-diagnosed.
In other ILDs – scleroderma, ankylosing spondylitis, chronic hypersensitivity
pneumonitis and sarcoidosis – prevalence rates are similar to those seen in IPF
(44–83%), suggesting that increased OSA prevalence is not unique to the IPF
population. However, it is unclear whether particular forms or patterns of ILD increase
the risk more than others.
Pathophysiology
There is evidence of a complex and possibly bidirectional pathophysiological link
between OSA and ILD. The proposed mechanism is based on the theory of ‘trachea
traction’, which depicts the link between lung volumes and the upper airway. Briefly,
the decreased lung volumes observed in restrictive pulmonary diseases can reduce
the stability of the upper airways and increase resistance by reducing traction on the
upper airway. These changes may promote upper airway collapse, especially during
REM sleep, as FRC is further reduced due to decreased intercostal muscle activity.
However, it is debatable whether lung function and AHI are related in these patients.
Recurrent mechanical stretch that causes tractional injury, and oxidative stress that
is related to the intermittent hypoxia which characterises OSA, promote systemic
inflammation and tissue damage, potentially leading to pulmonary fibrosis.
GOR disease (GORD) is a frequent comorbidity in IPF. Microaspiration as a result of
GORD could cause inflammation. GORD should therefore be considered as another
potential mechanism that promotes the development of pulmonary fibrosis.
Figure 3 summarises the proposed pathophysiological relationships between OSA
and IPF.
Clinical presentation
Patients with OSA and IPF oen do not present with typical OSA symptoms, such EDS,
witnessed apnoeas and snoring (table 1). EDS has a prevalence of 20% in OSA and IPF,
witnessed apnoeas are reported in 13–29%, and snoring is reported by 38–48% of
patients. Daytime fatigue (43–75%), sleep onset and maintenance insomnia (52–67%),
and nocturnal cough (48–56%) are the three most common clinically reported
symptoms in patients with OSA and IPF. Patients also experience the most severe
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IPF
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Decreased lung volume
Decreased traction of the upper
Reduced upper airway stability
and increased resistance
especially during REM sleep
OSA
Recurrent stretch injury
Intermittent hypoxia-
oxidative stress
GORD-microaspiration
PH
Figure 3. Proposed pathophysiological links between IPF and OSA. Reproduced and modified
from Schiza et al. (2020) with permission.
airway
Upper airway collapse,
functional impairment in terms of sleepiness, depression symptoms, fatigue and quality
of life. It is therefore crucial for treating physicians to identify the clinical profile of IPF
patients with OSA, in order to implement an appropriate diagnostic and treatment plan.
Risk factors
Obesity, a well-known risk factor for OSA in the general population, could be a
potential predictor in ILD patients. However, its eect on the presence and severity of
OSA among ILD patients is not clear.
Another potential predictor is pulmonary function test (PFT) impairment. However,
no association between OSA severity and PFT measurement has been found. This is
probably because PFTs are performed in the upright position and cannot accurately
reflect lung function in the supine position during sleep.
Clinical consequences
OSA in IPF patients is associated with deteriorating clinical status and increased
mortality. Untreated OSA in IPF patients may alter sleep architecture and cause a
deterioration in nocturnal desaturation, leading to worse survival. Compared with
patients with no OSA or mild-to-moderate OSA, IPF patients with severe OSA have
a significantly higher risk of developing ischaemic heart disease. There is also a
considerable correlation between severe OSA and the presence of moderate-to-severe
coronary artery calcifications on high-resolution computed tomography (HRCT).
237ERS Handbook: Respiratory Sleep Medicine
Asthma, COPD and ILDs
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Table 1. Clinical presentation and PSG characteristics of OSA patients with IPF
Clinical presentation PSG characteristics
Insomnia relating to: Sleep macro- and microarchitecture
IPF Increased stage 1 sleep
Nocturnal oxygenation Decreased REM and slow-wave sleep
Alterations in sleep macro- and
microarchitecture
Dyspnoea Increased arousal index
Cough
Mood disorders
Depression
Anxiety
GORD
SDB
Daytime fatigue Respiratory pattern
Nocturnal cough Nocturnal oxygenation parameters
Snoring Increased periodic leg movements during sleep
Witnessed apnoeas
EDS
WASO: wakefulness aer sleep onset. Reproduced and modified from Schiza et al. (2015) with
permission.
Decreased sleep eciency
Increased WASO
Increased respiratory frequency during sleep
Rapid and shallow breathing (especially
during REM sleep)
Episodic desaturation during REM sleep
Desaturation during NREM sleep
Desaturation due to respiratory events
(apnoeas and hypopnoeas)
OSA in these patients also appears to be linked to higher right ventricular systolic
pressure, which may reflect PH.
Interestingly, the coexistence of OSA and IPF has been found to result in mild cognitive
impairment, relating to visuospatial abilities, language and working memory. OSA
could therefore be an important predictor of cognition deficit in these patients.
OSA also has an eect on the quality of life of patients with IPF and sarcoidosis,
particularly in the domains of the health-related quality of life questionnaire that
relate to physical health and level of independence.
Screening and diagnostic considerations
Despite the high prevalence of OSA in the IPF population, there are no clear guidelines
on screening for OSA in these patients. Well-known questionnaires that are used for
OSA screening, such as the ESS and the Sleep Apnea Scale of the Sleep Disorders
Questionnaire (SA-SDQ), have failed to identify OSA in populations with IPF. Other, more
accurate OSA screening tools include the STOP-Bang questionnaire and the oxygen
desaturation index from the oximetry recording. The ideal tool for OSA screening in
patients with IPF is yet to be found and overnight PSG remains the gold standard.
The main respiratory events observed in previous reports or IPF patients were
hypopnoeas rather than apnoeas; limited-channel sleep studies are therefore less
appropriate for accurate OSA diagnosis in patients with ILDs. A clinical care pathway
for OSA diagnosis in these patients is illustrated in figure 4.
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Diagnosis
Screening
Management
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Asthma, COPD and ILDs
Clinical
presentation
STOP-Bang
questionnaire
Positive
Overnight PSG
Positive
CPAP
initiation
Negative
Type III/IV
studies
Look for other causes
of symptoms
Potential barriers
to CPAP acceptance and
adherence
• Claustrophobia
• Nocturnal cough
• Insomnia
• Depression
• Rapid and shallow breathing
pattern
Figure 4. A diagnostic and management algorithm for patients with OSA and IPF.
PSG characteristics
Significant changes in sleep architecture have been observed in patients with ILDs,
including lower sleep eciency and REM sleep, an increase in stage 1 sleep and
arousals, and fragmented sleep (table 1). These patients also typically exhibit a
considerable drop in S
values during sleep (especially REM sleep).
pO
2
Intense
follow-up
Strategies to augment CPAP
adherence
• Heated humidification
• Antitussive agents
• Supplemental oxygen
• Additional titrations
• Antidepressant medication
239ERS Handbook: Respiratory Sleep Medicine
Asthma, COPD and ILDs
https://t.me/medicina_free
Treatment
As with the general population, in IPF patients, moderate-to-severe OSA should
be treated with CPAP. PAP appears eective in improving quality of life and sleep
parameters in IPF patients. In spite of these benefits, there are diculties in this
population that can make CPAP adherence problematic. These diculties include
claustrophobia, an irritating cough during sleep, insomnia and depression.
Intense follow-up could prevent or appropriately manage CPAP non-acceptance
or poor compliance (figure 4). Strategies to augment CPAP adherence include: the
use of heated humidification in association with antitussive agents; the use of
supplemental oxygen where there are prolonged desaturation periods due to rapid
and shallow breathing; careful titration in order to assess eective CPAP pressures;
and antidepressant medication. It is also crucial to identify OSA in IPF patients in the
early stages of the disease rather than close to death, when the likelihood of CPAP
adherence sharply increases.
Eective PAP treatment in IPF patients significantly improves the activities of
daily living. More specifically, patients with good PAP adherence show significant
improvements both in their quality of life and in their use of sleep instruments aer 1
year of treatment. In contrast, in those with poor PAP adherence, changes in quality
of life are less significant and the use of sleep instruments only improves in a minority
of patients. It is worth noting that eective OSA treatment also appears to improve
sleepiness, fatigue, sleep quality and life expectancy at 7-year follow-up.
In general, formal in-laboratory PAP titration is necessary in OSA patients with
comorbidities, such as ILDs. Auto-PAP titration has also been used in ILD patients
but data are scarce. Moreover, there are no data for alternative treatment use, such
as positional therapy and oral appliances, in patients with PAP therapy denial or
suboptimal adherence. To date, the eects of supplemental oxygen on OSA parameters
in ILD populations have not been thoroughly investigated. In addition, there has been
no research into the eects of immunosuppressive or antifibrotic therapies on OSA in
ILD patients.
Further reading
• Bonsignore MR, et al. (2018). Clinical presentation of patients with suspected obstructive
sleep apnea and self-reported physician-diagnosed asthma in the ESADA cohort. J Sleep Res;
27: e12729.
• Bonsignore MR, et al. (2021). Sleep-disordered breathing and asthma. In: Bassetti C, et al.,
eds. Sleep Medicine Textbook. 2nd Edn. Regensburg, European Sleep Research Society;
pp. 735–744.
• Cheng Y, et al. (2021). The prevalence of obstructive sleep apnea in interstitial lung disease:
a systematic review and meta-analysis. Sleep Breath; 25: 1219–1228.
• Hagmeyer L, et al. (2022). Sleep-related breathing disorders in idiopathic pulmonary fibrosis
are frequent and may be associated with pulmonary vascular involvement. Sleep Breath; in
press [https://doi.org/10.1007/s11325-022-02686-z].
• Khor YH, et al. (2021). Interstitial lung disease and obstructive sleep apnea. Sleep Med Rev;
58: 101442.
• Li SQ, et al. (2021). Impact of insomnia and obstructive sleep apnea on the risk of acute
exacerbation of chronic obstructive pulmonary disease. Sleep Med Rev; 58: 101444.
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ERS Handbook: Respiratory Sleep Medicine
Asthma, COPD and ILDs
https://t.me/medicina_free
• McNicholas WT (2017). COPD-OSA overlap syndrome: evolving evidence regarding
epidemiology, clinical consequences, and management. Chest; 152: 1318–1326.
• McNicholas WT, et al. (2019). Sleep in chronic respiratory disease: COPD and hypoventilation
disorders. Eur Respir Rev; 28: 190064.
• Mermigkis C, et al. (2015). Obstructive sleep apnea should be treated in patients with
idiopathic pulmonary fibrosis. Sleep Breath; 19: 385–391.
• Mermigkis C, et al. (2017). Sleep as a new target for improving outcomes in idiopathic
pulmonary fibrosis. Chest; 152: 1327–1338.
• Prasad B, et al. (2020). Asthma and obstructive sleep apnea overlap: what has the evidence
taught us? Am J Respir Crit Care Med; 201: 1345–1357.
• Raghu G, et al. (2022). Idiopathic pulmonary fibrosis (an update) and progressive pulmonary
fibrosis in adults: an ocial ATS/ERS/JRS/ALAT clinical practice guideline. Am J Respir Crit Care
Med; 205: e18–e47.
• Schiza S, et al. (2015). Idiopathic pulmonary fibrosis and sleep disorders: no longer strangers
in the night. Eur Respir Rev; 24: 327–339.
• Schiza SE, et al. (2020). Obstructive sleep apnea in pulmonary fibrosis. Curr Opin Pulm Med;
26: 443–448.
• Wang R, et al. (2022). Asthma and obstructive sleep apnoea in adults and children – an up-to-
date review. Sleep Med Rev; 61: 101564.
241ERS Handbook: Respiratory Sleep Medicine
Diabetes and metabolic
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syndrome
Marie Bruyneel and Maria R. Bonsignore
Metabolic syndrome is an adverse health outcome that is typically associated with
obesity. It is a cluster of metabolic risk factors for type 2 diabetes mellitus (T2DM)
and CVD, including central obesity, hypertension, hyperglycaemia, insulin resistance
and dyslipidaemia (high triglycerides and reduced high-density lipoprotein (HDL)
cholesterol). Metabolic syndrome is highly prevalent in Europe (18–43%, according
to the definition used) and is associated with increased mortality. There is a strong
relationship between metabolic syndrome and OSA. This was confirmed in a metaanalysis that reported an odds ratio of 3.45 (95% CI 2.33–5.12) of suering from
metabolic syndrome in patients with moderate-to-severe OSA aer adjustment for
obesity, age and sex. Metabolic syndrome is present in 50–87% of OSA patients.
Although visceral obesity is a common trait of metabolic syndrome and OSA, studies in
nonobese patients have also reported the association, with up to 39.6% of nonobese
OSA patients demonstrating characteristics of metabolic syndrome.
T2DM is oen associated with OSA, and a bidirectional relationship may exist
between the two diseases, mediated by both weight-dependent and physiologydependent mechanisms (figure 1). A recent meta-analysis highlighted the fact that
OSA and poor sleep quality are associated with a risk of developing diabetes (OR
2.02, 95% CI 1.57–2.61) that is of the same order of magnitude as traditional risk
Key points
• OSA is a risk factor for metabolic syndrome, even in lean patients; type 2
diabetes is very prevalent in OSA and a bidirectional relationship exists
between these diseases.
• Intermittent hypoxia, respiratory eorts, sleep fragmentation and sympathetic
activity related to night-time obstructive respiratory events have been
implicated in the dysregulation of glucose and lipid metabolism.
• The impact of CPAP on metabolic syndrome and T2DM is dicult to isolate,
but it seems to improve glucose metabolism and BP.
• Weight loss is the cornerstone of metabolic syndrome and T2DM treatment,
but recently developed drugs (GLP-1 receptor agonists and gliflozins) open
the door for new perspectives, as they lead to significant cardiovascular risk
reduction and reduce the likelihood of T2DM patients developing OSA.
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OSA
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Oxidative stress/
production of ROS
Inflammatory
cytokines (TNF-, IL-6)
B-cell death and
proliferation
Insulin secrection
Pancreas
Liver
Diabetes and metabolic syndrome
T2DM
Insulin resistance
Glucose intolerance
Leptin resistance
Sleep fragmentation Intermittent hypoxia
Sympathetic activation
Lipid biosynthesis – peroxidation
HIF SREBP steatosis (NAFLD)
Gluconeogenesis
Inflammation
Oxidative stress
Lipolysis free fatty acid
Lipoprotein clearance
Insulin sensitivity
Adipose tissue
Glucose metabolism
Muscle
Hypothalamic–pituitary axis stimulation
Hypothalamic–pituitary axis
Figure 1. Pathophysiological mechanisms leading to metabolic dysregulation in OSA. TNF: tumour necrosis factor; IL: interleukin; ROS: reactive oxygen species; HIF:
hypoxia-inducible factor; SREBP: sterol regulatory element binding protein.
243ERS Handbook: Respiratory Sleep Medicine
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