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Obesity hypoventilation
https://t.me/medicina_free
syndrome
Victor R. Ramírez Molina, Jean-Louis Pépin and Juan F. Masa Jiménez
Obesity is associated with multiple medical complications. As such, it is crucial
that a multidisciplinary care pathway is implemented that addresses metabolic,
cardiovascular and respiratory complications.
OHS is one of the major respiratory complications of obesity. Interest in OHS is
growing worldwide due to the high prevalence of class 3 morbid obesity. OHS is a
specific phenotype of obesity, which carries an increased risk of morbimortality and
is a major impediment to quality of life. OHS is characterised by hypercapnic chronic
respiratory failure that is not secondary to other causes, and amplified hypoventilation
during sleep, with or without associated severe sleep apnoea.
Definition
OHS is characterised by a combination of obesity (a BMI of ≥30 kg·m−2), SDB and daytime
hypercapnia (P
alternative neuromuscular, mechanical or metabolic explanation for hypoventilation.
Approximately 90% of patients with OHS also suer from OSA. All OHS patients
experience hypoventilation during sleep, defined as an increase in P
≥6.0 kPa (≥45 mmHg) at sea level), occurring in the absence of an
aCO
2
of >1.3 kPa
aCO
2
Key points
• OHS is characterised by a combination of daytime hypoventilation
(P
≥6.0 kPa (>45 mmHg)), SDB and obesity (a BMI of >30 kg·m−2),
aCO
2
occurring in the absence of other causes of hypoventilation.
• Three mechanisms are essential to the development of daytime hypercapnia
in OHS: the impact of obesity on the mechanical properties of the respiratory
system; a reduction in the drive to ventilation from the respiratory centre; and
various phenotypes of sleep breathing disorders.
• CPAP should be the primary modality when OHS is associated with severe OSA
– it is easy to implement and is more cost-eective than NIV.
• Cardiovascular and metabolic comorbidities are key prognostic factors and
significant predictors of mortality.
• Implementation of weight-loss management strategies in combination with
PAP therapies is essential.
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(>10 mmHg) above wakefulness baseline values, not explained by upper airway collapse
(i.e. apnoeas or hypopnoeas). 70% of patients have severe OSA. The other phenotype
exhibits solely non-obstructive sleep hypoventilation with no or mild OSA.
Epidemiology
The exact prevalence of OHS in the general population is unknown; current estimates
suggest that ∼0.15–0.4% of the ambulatory population of obese patients may have
OHS. The ratio of men to women varies and is close to 1:1 aer the menopause.
The incidence of OHS increases significantly in parallel with obesity, with a reported
prevalence of ∼10–20% in outpatients presenting to sleep clinics and of ≤50%
amongst hospitalised patients with a BMI >50 kg·m−2.
Pathogenesis
Three mechanisms are essential to the development of daytime hypercapnia in OHS:
1) the impact of obesity on the mechanical properties of the respiratory system;
2) a reduction in the drive to ventilation from the respiratory centre; and 3) various
phenotypes of sleep breathing disorders. Identification of one predominant underlying
mechanism or a combination of these mechanisms is key to risk stratification and to
predicting the response to PAP therapy.
The impact of obesity on the mechanical properties of the respiratory system
Fat deposits in the abdomen and the surrounding chest wall negatively impact
respiratory mechanics as they hamper diaphragm motion, alter lung compliance and
increase lower airway resistance owing to early small airway closure and gas trapping.
Respiratory muscle weakness has been reported but is not thought to be significant
and plays a marginal role in the initiation of hypercapnia.
Reduction in drive to ventilation from the respiratory centre
In OHS, there is an overall increased work of breathing that needs to be
counterbalanced by an increase in drive from the respiratory centre to the
respiratory muscles. If this increased respiratory drive is not achieved and sustained,
hypoventilation, initially confined to REM sleep, will develop during the daytime.
The respiratory centre’s inability to compensate for the high demands for work of
breathing can probably be explained by the dysfunction of the leptin axis. Leptin
is known to be a potent stimulant of ventilation. In morbidly obese OHS, central
resistance to leptin is associated with a deterioration in the ventilatory response to
carbon dioxide (CO2).
The two major sleep breathing disorder phenotypes in OHS
Phenotype without severe sleep apnoea (AHI <30 events·h–1) and prominent REM
hypoventilation
REM sleep is characterised by postural muscle atonia, and ventilation is primarily
dependent on diaphragm activity. During REM sleep in OHS, a deleterious combination
of events occurs: the aggravation of obesity-related mechanical constraints, which
deteriorates diaphragmatic function; and a reduction in central respiratory drive.
Hypoventilation (initially limited to REM sleep) follows, and this, in turn, induces a
secondary depression of the respiratory centre, leading to daytime hypercapnia.
This OHS phenotype, which essentially relates to REM hypoventilation, is primarily
responsive to NIV.
255ERS Handbook: Respiratory Sleep Medicine
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Phenotype with severe sleep apnoea (AHI ≥30 events·h–1) and limited REM
hypoventilation
The prevalence of OSA in OHS is ≤80–90%. Excessive adiposity surrounding the
upper airway and reduced lung volume are the main mechanisms by which obesity
synergistically reduces upper airway patency and increases collapsibility. Patients with
OHS essentially exhibit a specific pattern of long-lasting apnoeas and hypopnoeas with
limited post-event ventilatory compensation relating to the restricted activity of the
respiratory centre. The CO2 overload that occurs during obstructive respiratory events
is not eliminated by the resumption of ventilation, and progressively accumulates
throughout the night, contributing to diurnal hypoventilation at the end of the night.
This OHS phenotype is primarily connected to severe OSA and is more likely to be
eectively treated with CPAP.
Clinical presentation
OHS is generally diagnosed when patients are 50–70 years of age. The two most
common presentations are: exacerbation on acute respiratory acidosis, leading to
hospital admission (oen to intensive care or intermediate care); or during routine
patient evaluation for suspected OSA or dyspnoea.
Unfortunately, there is generally a delay before OHS is diagnosed. During this delay,
OHS patients aggregate cardiovascular and metabolic complications, and use more
healthcare resources than eucapnic obese patients matched for confounders. In
patients initially presenting with acute-on-chronic hypercapnic respiratory failure,
nearly 75% are misdiagnosed and treated for obstructive lung diseases (most
commonly COPD), in spite of demonstrating no reduction in FEV1/vital capacity (VC)
ratio during pulmonary function testing.
OHS patients are, by definition, obese (defined as a BMI of >30 kg·m−2). They generally
have daytime hypercapnia and frequently report the classic symptoms of OSA, which
include snoring, witnessed apnoeas, daytime sleepiness, morning headaches and,
more frequently than in classical OSA, dyspnoea with cor pulmonale at examination.
Obesity is obvious at physical examination, along with a large neck circumference,
reduced upper airway size, a prominent pulmonary component of the second heart
sound during cardiac auscultation and oedema of the lower extremities.
Diagnosis
Criteria for the diagnosis of OHS are: hypoventilation during wakefulness (P
>6.0 kPa (>45 mmHg)); and obesity (BMI of >30 kg·m−2 in adults, BMI of >95th
percentile for their age and sex in children). Hypoventilation is not primarily due to
a pulmonary parenchymal disease, an airway disease, pulmonary vascular pathology,
Table 1. The diagnostic criteria of OHS
Clinical criteria
P
≥6.0 kPa (≥45 mmHg) measured by blood gases
aCO
2
BMI ≥30 kg·m
−2
Other causes of hypoventilation discarded
Complementary findings
Serum bicarbonate level ≥27 mEq·L
Daytime hypoxaemia
#
: not essential to the diagnosis of OHS.
256
aCO
2
#
−1
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a chest wall disorder, medication, a neurological disease, muscle weakness, or an
idiopathic or congenital central hypoventilation syndrome. Table 1 presents the
diagnostic criteria for OHS.
Measurement of room air arterial blood gases is the reference test for alveolar
hypoventilation diagnosis. Screening methods that reflect the consequences of
hypoventilation – namely, elevated serum bicarbonate levels and hypoxaemia – have
been evaluated to determine whether their use facilitates the early identification of OHS.
An increase in serum bicarbonates is common in OHS and reflects the metabolic
compensation that is secondary to respiratory acidosis in the context of the chronic
nature of hypercapnia. Measuring serum venous blood bicarbonates is a sensitive way
of detecting chronic hypercapnia; it is also an accessible and noninvasive test. The
suggested serum bicarbonate cut-o point is 27 mEq·L−1; a serum bicarbonate level of
<27 mEq·L−1 has a 97% negative predictive value for excluding a diagnosis of OHS, and a
serum bicarbonate level of ≥27 mEq·L−1 should lead the clinician to perform confirmatory
arterial blood gas analysis. This threshold lacks specificity as many cardiometabolic
comorbidities and medications are associated with elevated bicarbonate levels.
Using pulse oximetry to assess hypoxaemia is simple, making it an attractive tool
for identifying obese patients who are likely to be hypercapnic. Hypoxaemia during
wakefulness is not always present in patients with OSA. Therefore, abnormal S
detected using pulse oximetry during wakefulness should encourage clinicians
to exclude OHS in patients with OSA. However, an abnormal S
discriminative eect than serum bicarbonate.
has a lower
aO
2
aO
2
A rise in CO2 levels (≥6.0 kPa (≥45 mmHg)) during wakefulness is required to define
permanent daytime hypoventilation. A variety of techniques are used to measure
CO2, such as daytime arterial blood gases, arterialised capillary blood gases, venous
blood gases, end-tidal CO2 and transcutaneous CO2 monitoring. Diurnal hypercapnia
is preceded by hypoventilation during sleep, meaning diurnal hypercapnia already
represents an advanced stage of OHS. In 2017, the European Respiratory Society (ERS)
proposed a classification system for the severity grades of hypoventilation in obesity,
which incorporated progressive changes in the degree of hypercapnia (table 2). The
highest grade of severity was defined as daytime hypercapnia plus cardiovascular and
metabolic comorbidities.
Table 2. Staging of hypoventilation in obesity
0 At risk No hypercapnia
I Obesity-associated
Intermittent hypercapnia when asleep, full recovery when
sleep ventilation
Serum bicarbonate level of ≥27 mEq·L−1 when awake
II Obesity-associated
Intermittent hypercapnia when asleep (P
sleep ventilation
Serum bicarbonate level of ≥27 mEq·L−1 when awake
Bicarbonate level is increased during day
III Obesity
Sustained hypercapnia (P
hypoventilation
IV OHS Sustained hypercapnia when awake, cardiometabolic
In OHS, progression to hypercapnia during the day is preceded by hypoventilation during sleep
that the patient does not recover from in the morning, with cardiometabolic consequences and an
increase in serum bicarbonate during the day as a result of sustained hypercapnia. #: defined as a
BMI of >30 kg·m−2. Reproduced and modified from Randerath et al. (2017) with permission.
#
asleep (P
aCO
or P
2
tcCO
morning > evening)
awake
comorbidities
in the morning as in the evening)
2
or P
aCO
2
≥6.0 kPa (≥45 mmHg)) when
aCO
2
tcCO
2
257ERS Handbook: Respiratory Sleep Medicine
Obesity hypoventilation syndrome
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The consequences of OHS
It is widely acknowledged that OHS patients exhibit a higher burden of comorbidities
than eucapnic obese subjects. A higher prevalence of right and le ventricular
dysfunction, le ventricular hypertrophy and pulmonary hypertension (PH) has been
noted. These comorbidities are usually present before OHS diagnosis.
HF, coronary heart disease and PH are frequently diagnosed during an acute
exacerbation of chronic hypercapnic respiratory failure, perhaps suggesting a more
severe phenotype of OHS. Ambulatory patients who receive an OHS diagnosis
tend to demonstrate a lower cardiovascular burden than those diagnosed during
hospitalisation for an acute condition.
Untreated OHS is associated with increased mortality, which is partially related to
cardiovascular morbidity. OHS patients are at a higher risk of developing HF (OR 9,
95% CI 2.3–35), ischaemic heart disease (OR 9, 95% CI 1.4–57.1) and cor pulmonale
(OR 9, 95% CI 1.4–57.1). It is therefore unsurprising that the high burden of CVD in
patients with OHS leads to a prevalence of PH ranging 30–88%.
In a prospective study of obese patients hospitalised on medical wards, Nowbar et al.
(2004) found that 47 patients with OHS had higher rates of admission to the intensive
care unit (40% versus 6%) and an increased need for invasive mechanical ventilation
(6% versus 0%) compared with 103 patients with a similar degree of obesity but
without hypoventilation. They also noted that patients who were discharged from
the hospital without treatment had a high mortality rate at 18 months (23% in OHS
versus 9% in eucapnic obese patients). Even with nocturnal NIV, it has been noted that
yearly mortality of patients with OHS remains high at 30%.
The main cause of death in OHS is CVD, which includes PH and right-sided HF. It has
been reported that most hospitalisations and deaths in untreated patients with OHS
are caused by respiratory complications, such as acute-on-chronic respiratory failure
and pulmonary embolism (PE). However, it has also been noted that in OHS patients
treated with long-term NIV, 48–90% of deaths are the result of cardiovascular
events. Elsewhere, it was found that aer a median of 5 years of follow-up, the most
common cause of death was of cardiovascular origin (56% CPAP patients and 54%
NIV subjects). This suggests that PAP may reduce morbidity and mortality caused by
respiratory problems but has less impact on cardiovascular outcome.
Indications for CPAP and NIV
PAP therapies – NIV and CPAP – are used worldwide as the primary treatment
modality in patients with OHS. Clinical series have reported an improvement in
symptoms, arterial blood gases and associated sleep disorders with their use. NIV
is the application of positive-pressure ventilation, usually with bilevel pressure
settings. CPAP is a continuous pre-set pressure during the respiratory cycle to prevent
obstructive apnoeas and hypopnoeas; unlike NIV, it does not provide additional
ventilatory support.
The benefits of CPAP and NIV
CPAP is a highly eective in the treatment of OSA. As most patients with OHS have
concomitant severe OSA, it is reasonable to expect that CPAP will help improve gas
exchange in a substantial group of patients by stabilising their upper airway. The shortterm benefits of CPAP include improvements in gas exchange and respiratory sleep
disorders, with good ecacy seen in 50–80% of cases. A time-course improvement of
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30–90 days is seen gas exchange. This is directly proportional to the hours of CPAP use,
with each additional hour decreasing P
by 0.40 kPa (3 mmHg).
by 0.24 kPa (1.8 mmHg) and increasing P
aCO
2
aO
2
NIV also produces an improvement in gas exchange, which translates into a
significant reduction in daytime P
a dose-dependent relationship between the hours of NIV use and the improvement
when awake and an increase in P
aCO
2
. There is
aO
2
in gas exchange. Symptoms such as sleepiness and dyspnoea improve significantly
with NIV, as do measures of health-related quality of life (HRQoL). NIV also achieves a
significant improvement in respiratory functional parameters, such as FVC and FEV1.
Similar long-term improvements have been observed with CPAP.
NIV and CPAP are equally eective in improving PH and le ventricular diastolic
dysfunction in OHS patients with coexistent severe OSA.
CPAP versus NIV: comparison in randomised controlled trials
A number of randomised controlled trials (RCTs) have compared the dierent
treatments options in OHS. Direct comparisons of CPAP and NIV, and NIV and
conservative measures have been performed. The three most widespread treatment
modalities have been evaluated: lifestyle interventions, CPAP and NIV.
Piper et al. (2008) performed a randomised trial that compared the short-term ecacy
of NIV and CPAP in 36 patients with OHS. Patients who demonstrated a favourable
response to their first night of CPAP treatment were selected for the trial. Of the 45
eligible patients, nine (20%) did not achieve an acceptable improvement with CPAP
based on the following criteria: an oxygen saturation level that remained <80%
continuously (>10 min) in the absence of apnoea; a rapid increase in transcutaneous
P
during REM sleep (>1.3 kPa (>10 mmHg)) or an increase in P
aCO
2
(>10 mmHg) overnight in patients with a daytime P
Aer 3 months, improvements in daytime sleepiness and blood gases were similar
of >7.3 kPa (>55 mmHg).
aCO
2
of >1.3 kPa
aCO
2
for the two treatments.
Borel et al. (2012) conducted a small, randomised study of 38 patients with mild
hypercapnia treated with NIV, and compared them with a control group treated with
conservative measures. Arterial blood gases, polysomnographic variables, carbohydrate
and lipid metabolism, and the inflammatory profile were analysed. The NIV group
demonstrated a significant reduction in daytime P
increased pH level. As expected, NIV treatment was associated with an improvement in
and bicarbonates, and an
aCO
2
all sleep variables, sleep architecture, average oxygen saturation, an oxygen saturation
time of <90% and AHI, and a positive significant correlation was seen between average
oxygen saturation during sleep and diurnal arterial blood gases. In contrast, no change
was observed in any of the metabolic and inflammatory parameters studied, although
follow-up was only 1 month. Patients in this study had a lower BMI and were less
hypercapnic than subjects included in other trials with mild OHS.
In another RCT, Howard et al. (2017) randomised the use of NIV and CPAP for
3 months in 60 participants. Their primary objective was to determine the frequency
of treatment failure, which they defined as hospital admission, persistent ventilatory
insuciency or lack of adherence. Secondary objectives included quality of life
relating to health and drowsiness. A total of 57 patients completed follow-up and
no dierences in treatment failure were noted between the groups (NIV 14.8%
when awake were
aCO
similar aer 3 months: NIV 5.3 h·night−1, CPAP 5.0 h·night−1 (p=0.62); P
6.12 kPa (44.2 and 45.9 mmHg), respectively (p=0.60). No significant dierences
2
5.89 and
aCO
2
259ERS Handbook: Respiratory Sleep Medicine
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were seen between the groups in terms of improvements in sleepiness and quality of
life. The baseline severity of ventilatory insuciency (baseline P
significant predictor of ventilatory insuciency at 3 months (OR 2.3; p=0.03). Cost-
level) was the only
aCO
2
eectiveness and the impact on mortality were not evaluated in this study.
The Pickwick study (Masa et al., 2015) is by far the largest clinical trial conducted
in patients with OHS, with a sample size of >300. In comparison with CPAP, NIV
treatment led to a greater degree of improvement in some of the respiratory functional
outcomes that were not assessed in the previous RCTs performed by Piper et al. (2008)
and Howard et al. (2017) (e.g. FEV1 and 6-min walk distance). In a separate study by
Corral et al. (2018), only NIV was shown to have a positive eect on cardiac structure
and function, assessed using echocardiography. Howard et al. (2017) observed a delay
before CPAP treatment made an improvement on daytime hypercapnia compared
with NIV treatment. This delay may explain the slightly lower medium-term ecacy
of CPAP, emphasising the importance of long-term outcome comparisons.
In order to assess the long-term ecacy of both PAP modalities, patients with
OHS and concomitant severe OSA enrolled in the Pickwick study were followed for
a minimum of 3 years. Some of the results of this second phase of the RCT have
been presented in abstract format (Sánchez-Quiroga et al., 2018). No significant
dierence was noted between CPAP and NIV in the primary long-term outcome of
hospitalisation days. Other hospital-resource use (hospital and intensive care unit
admissions and emergency department visits), incident cardiovascular events and
survival rates were similar for both treatments, with no significant dierences in PAP
compliance, dropouts and secondary side-eects.
The median (interquartile range (IQR)) follow-up in the Pickwick study was 5.44 years
(4.45–6.37 years) in all patients, 5.37 years (4.36–6.32 years) in the CPAP group and
5.55 years (4.53–6.50 years) in the NIV group. The mean± hospitalisation days per
patient-year were 1.63±3·74 in the CPAP group and 1.44±3.07 in the NIV group (adjusted
rate ratio 0.78, 95% CI 0.34–1.77; p=0.561). Adverse events were similar in both groups.
Given that CPAP has a lower complexity and cost, CPAP might be the preferred firstline PAP treatment modality.
Clinical implications
In clinical practice, patient characteristics should be taken into consideration when
selecting the most appropriate mode of PAP therapy. CPAP should be the initial
treatment modality if there is severe OSA, due to its relative simplicity, low cost and
ecacy. In OHS patients with nonsignificant OSA, NIV is the preference because the
nocturnal hypoventilation of these patients may depend on other mechanisms (see
section on Pathogenesis). NIV is also the preferred option: when previous CPAP has as
failed; in patients with a predominance of hypoventilation episodes over obstructive
episodes during sleep; in patients with greater obesity; and in patients with a higher
daytime P
and a lower P
aCO
2
If CPAP prevents obstructive episodes, and maintains adequate oxygenation and
ventilation, it may be a good option for long-term treatment. If not, NIV should be
used, aer close monitoring of the first 2–3 months of PAP (figure 1).
In obese patients with acute hypercapnic respiratory failure or hospitalised patients,
NIV should be the initial treatment modality, as it is likely to have a greater eect on
hypoventilation and on the severity of respiratory failure, and because OSA may not be
the only cause of acute respiratory failure in these patients.
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.
aO
2
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Obesity hypoventilation syndrome
Responders
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OHS
AHI ≥30 events·h
AHI <30 events·h
–1
–1
CPAP
Nonresponders
Switch to
NIV
Maintain
CPAP
Figure 1. OHS clinical applications. CPAP should be first-line treatment for OHS patients with
concomitant severe OSA. NIV should be first-line therapy for OHS patients with no OSA or milder
forms of OSA. If patients initially treated with CPAP do not show a favourable response to therapy
without adequate oxygenation and ventilation, they should switch to NIV therapy 2–3 months
aer initiating PAP therapy.
Non-PAP treatment
The original process behind the pathophysiology of OHS is obesity. Therefore, it is crucial
that weight-management strategies are incorporated into the care of patients with OHS,
in combination with PAP therapies. The overarching goal is to establish comprehensive
and multidisciplinary nutrition, exercise and rehabilitation programmes.
Only one randomised trial of multimodal, hybrid inpatient–outpatient motivation,
exercise and nutrition rehabilitation programmes, in addition to NIV, has been
performed (Mandal et al., 2018). This 3-month intervention resulted in improvements
in weight loss, exercise capacity and quality of life. However, these eects were not
sustained at 12 months due to the limited retention of patients at that stage.
OHS is characterised by reduced exercise tolerance and a high burden of cardiovascular
comorbidities. Innovative training modalities that go beyond the usual cycle exercise
training need to be developed to improve functional capacity and cardiovascular
health. The combination of NIV and exercise training has been shown to increase
exercise capacity and improve cardiometabolic risk factors in morbidly obese CPAPtreated patients with OSA. This certainly also applies to OHS.
Bariatric surgery is a cost-eective strategy for managing severe obesity in patients
with comorbidities such as OSA, and has been shown to have long-term ecacy. The
risk of surgery in patients with untreated OHS is high but once successfully established
on PAP therapy, these risks appear to be mitigated. No randomised controlled data
exist supporting the use of bariatric surgery specifically to treat OHS but extrapolation
of data from general obesity would suggest a significant improvement in SDB and
thus respiratory failure, secondary to the likely weight loss achieved.
Further reading
• Borel JC, et al. (2012). Noninvasive ventilation in mild obesity hypoventilation syndrome. A
randomized controlled trial. Chest; 141: 692–702.
• Borel JC, et al. (2017). Prevalence of obesity hypoventilation syndrome in ambulatory obese
patients attending pathology laboratories. Respirology; 22: 1190–1198.
• Corral J, et al. (2018). Echocardiographic changes with non-invasive ventilation and CPAP in
obesity hypoventilation syndrome. Thorax; 73: 361–368.
• Howard ME, et al. (2017). A randomised controlled trial of CPAP versus non-invasive ventilation
for initial treatment of obesity hypoventilation syndrome. Thorax; 72: 437–444.
261ERS Handbook: Respiratory Sleep Medicine
Obesity hypoventilation syndrome
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• Mandal S, et al. (2018). Nutrition and exercise rehabilitation in obesity hypoventilation
syndrome (NERO): a pilot randomised controlled trial. Thorax; 73: 62–69.
• Masa JF, et al. (2015). Ecacy of dierent treatment alternatives for obesity hypoventilation
syndrome. Pickwick Study. Am J Respir Crit Care Med; 192: 86–95.
• Masa JF, et al. (2016). Noninvasive ventilation in obesity hypoventilation syndrome without
severe sleep apnea. Thorax; 71: 899–906.
• Masa JF, et al. (2019). Long-term clinical eectiveness of continuous positive airway pressure
therapy versus non-invasive ventilation therapy in patients with obesity hypoventilation
syndrome: a multicentre, open-label, randomised controlled trial. Lancet; 393: 1721–1732.
• Masa JF, et al. (2019b). Obesity hypoventilation syndrome. Eur Respir Rev; 28: 180097.
• Mokhlesi B (2010). Obesity hypoventilation syndrome: a state-of-the-art review. Respir Care;
55: 1347–1362.
• Mokhlesi B, et al. (2008). Assessment and management of patients with obesity hypoventilation
syndrome. Proc Am Thorac Soc; 5: 218–225.
• Mokhlesi B, et al. (2019). Evaluation and management of obesity hypoventilation syndrome,
an ocial American Thoracic Society clinical practice guideline. Am J Respir Crit Care Med;
200: e6–e24.
• Nowbar S, et al. (2004). Obesity-associated hypoventilation in hospitalized patients:
prevalence, eects, and outcome. Am J Med; 116: 1–7.
• Pépin JL, et al. (2016). Prevention and care of respiratory failure in obese patients. Lancet Respir
Med; 4: 407–418.
• Piper AJ, et al. (2008). Randomised trial of CPAP vs bilevel support in the treatment of obesity
hypoventilation syndrome without severe nocturnal desaturation. Thorax; 63: 395–401.
• Ramírez Molina VR, et al. (2020). The heart in obesity hypoventilation syndrome. In:
Martínez-García MÁ, et al. (eds). Cardiovascular Complications of Respiratory Disorders (ERS
Monograph). Sheeld, European Respiratory Society; pp. 143–153.
• Randerath W, et al. (2017). Definition, discrimination, diagnosis and treatment of central
breathing disturbances during sleep. Eur Respir J; 49: 1600959.
• Sánchez-Quiroga MÁ, et al. (2018). CPAP vs NIV for long term treatment of obesity
hypoventilation syndrome: the results of the Pickwick randomized controlled trial. Am J Respir
Crit Care Med; 197: A1042.
• Tulaimat A, et al. (2014). Defining obesity hypoventilation syndrome. Thorax; 69: 491.
• Vivodtzev I, et al. (2018). Ventilatory support or respiratory muscle training as adjuncts to
exercise in obese CPAP-treated patients with obstructive sleep apnoea: a randomised
controlled trial. Thorax; 73: 634–643.
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Disorders that cause
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respiratory failure
Imran J. Meurling and Joerg Steier
Neuromuscular diseases (NMDs) and chest wall disorders (CWDs) combine a
heterogeneous group of diseases that can aect the respiratory muscle pump and
cause hypercapnic (type 2) respiratory failure. They cause hypoventilation through
dierent anatomical pathophysiology, involving the central nervous system (CNS),
the brainstem, the spinal cord, the lower motor neurones, the nerve roots and the
peripheral nerves, the neuromuscular junction, the respiratory muscles or the chest
wall. The result is an imbalance of the load/capacity ratio of the respiratory muscle
pump, leading to symptoms such as breathlessness and respiratory failure while
awake or nocturnal hypoventilation while asleep, as sleep state-related changes lead
to a further reduction in V′E (figure 1). In this chapter, the most common NMDs and
CWDs that cause respiratory failure are discussed.
Load/capacity ratio of the respiratory muscles
Progression of NMDs and CMDs is variable. Weak respiratory muscles can only
cope with the respiration load (or work of breathing) if the neural respiratory drive
increases to recruit more capacity. Normal healthy subjects breathe with ∼8% of their
maximal neural respiratory drive to activate their diaphragm to match the required
load. In disease, this may increase to 20–30% at rest, a situation that is frequently
associated with the perception of shortness of breath. However, if load increases
Key points
• Neuromuscular and chest wall disorders are a heterogeneous group of
conditions that can cause acute or chronic hypoventilation with hypercapnic
respiratory failure.
• Neuromuscular disorders can involve the CNS/brainstem and spinal cord, the
lower motor neurones, the neuromuscular junction, the peripheral nerves or
respiratory and chest wall muscles.
• Hypercapnic respiratory failure is caused by a reduced capacity of the
respiratory muscles, a (relatively) increased load on the respiratory muscles,
reduced neural eerent output (drive) or a combination of these factors.
• The severity and rate of progression varies significantly among neuromuscular
disorders and disease subtypes and needs to be considered in the context of
quality of life and long-term therapeutic options.
263ERS Handbook: Respiratory Sleep Medicine
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