26/8/22, 13:59 Clinical manifestations and diagnosis of obesity hypoventilation syndrome - UpToDate

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Clinical manifestations and diagnosis of obesity hypoventilation syndrome

Authors: Amanda Piper, PhD, Brendon Yee, MBChB, PhD
Section Editor: M Safwan Badr, MD
Deputy Editor: Geraldine Finlay, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Jul 2022. | This topic last updated: Jun 08, 2021.

INTRODUCTION

Obesity hypoventilation syndrome (OHS) is defined as the presence of awake alveolar hypoventilation in an obese individual which cannot be attributed to other
conditions associated with alveolar hypoventilation [1-3]. OHS is associated with increased cardiovascular morbidity and mortality. Consequently, early detection
and treatment are crucial to minimize these adverse effects.

The clinical manifestations, diagnosis, and complications of OHS are reviewed here, while the pathogenesis and treatment are discussed separately. (See
"Epidemiology and pathogenesis of obesity hypoventilation syndrome" and "Treatment and prognosis of the obesity hypoventilation syndrome" and
"Noninvasive positive airway pressure therapy for the obesity hypoventilation syndrome".)

DEFINITION

OHS is defined by raised awake arterial pressure of carbon dioxide (PaCO2) levels in patients with obesity in whom alternative causes hypercapnia and
hypoventilation have been excluded.

PROPOSED STAGING

However, it is now recognized that nocturnal hypoventilation precedes the development of awake hypercapnia, with earlier recognition and treatment of the
problem potentially reducing the development of significant comorbid conditions. Recognizing this, a European Respiratory Society taskforce has proposed a
staging schema for hypoventilation in patients with obesity (ie, body mass index [BMI] >30 kg/m2) [2]. Patients with obstructive sleep apnea (OSA) and no
hypercapnia were considered stage 0. Stages I and II represented patients with obesity-associated sleep hypoventilation but normal awake PaCO2 and either
serum bicarbonate <27 mmol/L (stage I) or >27mmol/L (stage II). Stages III and IV encompassed classically defined OHS patients with or without concurrent OSA.
Those in stage IV were distinguished from stage III by the presence of significant cardiometabolic comorbidities.

RISK FACTORS

The major risk factor for OHS is obesity (body mass index [BMI] >30 kg/m2), in particular, severe obesity (BMI >50 kg/m2), where prevalence may be as high as 50
percent. However, not all patients with obesity develop OHS.

Risk factors in obese patients are poorly defined but may include [4-6]:

● Significant increase in waist:hip ratio (ie, central obesity)

● Reduced lung function due to obesity
● Reduced inspiratory muscle strength
● Severe obstructive sleep apnea (OSA; eg, apnea hypopnea index >30 events per hour)  

Unlike OSA, male gender is not a risk factor for OHS [7-9]. However, women may present somewhat differently.

Patients with OHS usually present in the fifth and sixth decades of life.

CLINICAL MANIFESTATIONS

The clinical manifestations of OHS are nonspecific and reflect the manifestations of obesity, coexistent obstructive sleep apnea (OSA is present in 90 percent of
OHS) or of OHS-related complications (eg, pulmonary hypertension).

Symptoms and signs — Patients with OHS are obese (body mass index [BMI] >30 kg/m2), hypersomnolent individuals. Ninety percent have at least some
coexisting OSA (apnea-hypopnea index [AHI] >5 events per hour), with severe disease (eg, AHI >30 events per hour) seen in 70 percent of patients [10]. Symptoms
and physical findings of OSA include daytime hypersomnolence, loud snoring, choking during sleep, resuscitative snorting, fatigue, impaired concentration and
memory, a small oropharynx, and a thick neck [1,11]. The 10 percent of individuals with OHS who have coexistent sleep hypoventilation without significant OSA
present similarly to those with the OHS-OSA phenotype, except witnessed apneas during sleep are less common [11]. They are also more likely to be older
females [12,13]. However, standard history taking and questionnaires do not readily establish or exclude an OHS diagnosis [14]. The manifestations of OSA and

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nocturnal hypoventilation are provided in detail separately. (See "Clinical presentation and diagnosis of obstructive sleep apnea in adults" and "Central sleep
apnea: Risk factors, clinical presentation, and diagnosis", section on 'Clinical findings'.)

Many patients with OHS present late in the course of their disease and have manifestations of endstage disease including [1,6,15-17]:

● Severe hypoxemic hypercapnic respiratory failure - While many patients present with chronic stable symptoms or chronic hypercapnic respiratory failure,
about one-third of patients present with acute-on-chronic respiratory failure prompting hospital admission [15,17-21]. There is some evidence to suggest
that women may present later than men and are more likely to present with acute-on-chronic respiratory failure [19,22]. Such patients are often
misdiagnosed as having chronic obstructive pulmonary disease (COPD) or asthma, despite an absence of obstruction on pulmonary function testing [23].
Daytime hypoxemia and significant and sustained reductions in overnight oximetry (eg, peripheral saturation <80 percent) are features that are uncommon
in OSA or obesity alone [24]. (See "Pulse oximetry" and "Home sleep apnea testing for obstructive sleep apnea in adults", section on 'Pulse oximetry'.)

● Right heart failure from pulmonary hypertension (dyspnea on exertion, elevated jugular venous pressure, hepatomegaly, and pedal edema) and less
commonly, facial plethora from polycythemia.

Laboratory tests — OHS may be associated with the following findings:

● Elevated serum bicarbonate (>27 mEq/L) – Almost all patients with OHS have an elevated serum bicarbonate (venous and/or arterial), which is usually a
clue that the patient is chronically hypercapnic. However, it is nonspecific since other etiologies can raise the bicarbonate level (eg, dehydration,
medications) and it is not 100 percent sensitive since other conditions (eg, lactic acidosis, chronic hyperventilation) may lower the bicarbonate level.

This cut-off is based upon limited data. One observational study reported that a venous serum bicarbonate of >27 mEq/L had a 92 percent sensitivity for
identifying awake hypercapnia in obese individuals, although specificity was significantly lower (50 percent) [25]. A bicarbonate level <27 mEq/L had 97
percent negative predictive value for excluding the diagnosis in this study. Another study reported a sensitivity of 85 percent and specificity of 89 percent in
patients with levels >27 mEq/L when capillary blood gas samples were used [26].

● Hypercapnia (arterial pressure of carbon dioxide [PaCO2] >45 mmHg) – Consistent with the phenomenon of hypoventilation, all patients with OHS have
hypercapnia on arterial blood gas analysis when awake and on room air. Although most patients with OHS present with chronic elevations in the PaCO2,
about one-third have acute-on-chronic respiratory failure [17,20,21]. A raised bicarbonate (>27 mmol/L) or base excess (>3 mmol/L) in the absence of
another cause for a metabolic alkalosis in an obese individual with a PaCO2 <45 mmHg may be an early indicator of OHS, warranting closer investigation
[27,28]. (See "Arterial blood gases" and "Venous blood gases and other alternatives to arterial blood gases".)  

● Hypoxemia (PaO2 <70 mmHg) – Hypoxemia is usually present. The calculated alveolar-arterial (A-a) oxygen gradient is classically normal, although a mild
widening is not unusual related to ventilation-perfusion mismatching or coexistent parenchymal or vascular lung disease [29,30]. Severe nocturnal
desaturation is also common (eg, peripheral saturation <80 percent).

● Polycythemia — Polycythemia due to recurrent hypoventilation- or OSA-associated hypoxemia is uncommon but may be present as a late manifestation.

Pulmonary function tests — Although findings of restriction are more commonly seen in obese patients with OHS than in eucapnic obese patients, they are
nonspecific, and normal pulmonary function tests (PFTs) do not exclude the diagnosis. In general, PFTs are more useful for ruling out underlying causes of
hypoventilation. (See 'Exclude other causes of hypercapnia and alveolar hypoventilation' below.)

In OHS a restrictive pattern on PFTs due to obesity is common, particularly in those with a higher BMI (eg, BMI >50 kg/m2); both forced vital capacity (FVC) and
forced expiratory volume in one second (FEV1) are reduced, while the FEV1/FVC ratio is preserved [31,32]. More commonly, a reduction in functional residual
capacity and expiratory reserve volume is seen [32]. FVC values were found in one study to be lower in patients with OHS than OSA but the threshold was ill-
defined [4]. (See "Overview of pulmonary function testing in adults" and "Chest wall diseases and restrictive physiology".)

Severe restriction is uncommon with obesity and may indicate another restrictive lung disorder.

Imaging and cardiac studies — In OHS, typical findings on chest radiograph include elevation of both hemidiaphragms due to the obese abdomen and the
heart may be enlarged due to right ventricular hypertrophy or pericardial fat.

Evidence of right ventricle enlargement from pulmonary hypertension that complicates advanced OHS may be seen on electrocardiography (EKG) and
echocardiography [33,34].

DIAGNOSTIC APPROACH

The diagnostic approach focuses on establishing awake (often daytime) hypoventilation in an obese patient in the absence of other causes of alveolar
hypoventilation. Polysomnography with continuous nocturnal carbon dioxide monitoring is the gold standard for the evaluation of patients suspected of having
obesity hypoventilation syndrome (OHS). Testing should be performed to characterize the type of underlying sleep disordered breathing (ie, OHS with or without
coexisting obstructive sleep apnea [OSA]). (See 'Identify coexistent sleep disordered breathing' below.)

For patients who present with acute-on-chronic hypercapnic respiratory failure suspected to be due to OHS, immediate treatment with positive pressure therapy
is appropriate to stabilize their clinical condition [17,19,21]. Once the patient has improved and is stable, a diagnostic evaluation can be initiated. The treatment of
OHS is discussed separately. (See "Treatment and prognosis of the obesity hypoventilation syndrome" and "Noninvasive positive airway pressure therapy for the
obesity hypoventilation syndrome".)

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Suspecting obesity hypoventilation — A strong clinical suspicion for OHS is critical for the diagnosis. We typically initiate evaluation in obese patients (body
mass index [BMI] >30 kg/m2) with suspected or known OSA (or sleep disordered breathing), particularly those with severe OSA (eg, apnea hypopnea index >60
events per hour, since the prevalence is high in this population).

We also initiate evaluation in obese individuals with or without OSA who have the following clinical features:

● Unexplained awake room air peripheral saturation (SpO2) ≤94 percent or an overnight nadir saturation <80 percent
● Unexplained dyspnea on exertion  
● Symptoms and signs of pulmonary hypertension and/or right-sided heart failure (eg, elevated jugular venous pressure, hepatomegaly, and pedal edema)
● Facial plethora, which may indicate polycythemia
● A raised bicarbonate on venous blood sampling (see 'Laboratory tests' above)

Many of these features are more common in patients with OHS than in eucapnic obese individuals or in patients who have OSA alone [1,4,6,15-17,24,25,35].

Hypoventilation first becomes apparent during sleep in patients with obesity [2]. In one study, the prevalence of obesity-related sleep hypoventilation (ORSH) had
a prevalence of 19 percent amongst 94 obese patients (BMI >40kg.m-2). These individuals experienced a rise in carbon dioxide (CO2) during sleep with a normal or
raised bicarbonate during wakefulness while PaCO2 remained <45 mmHg [2]. Predictors of ORSH were awake oxygen saturation ≤93 percent, and a partial
arterial pressure of carbon dioxide of ≥45 mmHg in the supine position [36]. These findings have led some experts to suggest that ORSH is a precursor to OHS.
However, further studies are needed to confirm the evolution of ORSH to OHS.

Further details regarding the clinical manifestations of OHS are discussed above. (See 'Clinical manifestations' above.)

Indicators of chronic alveolar hypoventilation — In patients in whom OHS is suspected, the presence of chronic hypoventilation is usually inferred when a
chronic respiratory acidosis (hypercapnic respiratory acidosis) on arterial blood gas analysis (ABG) is demonstrated together with compensatory metabolic
alkalosis (ie, elevated bicarbonate).

● ABG – Whether an ABG should be obtained in all patients suspected of having OHS has been the subject of debate. We and others suggest that when the
suspicion for OHS is strong, an ABG should be measured. ABGs should be performed while the patient is awake, sitting upright, and breathing room air (so
that A-a oxygen gradient can be calculated). Where ABGs are difficult to obtain, venous blood sampling can be used as a surrogate for pH, PaCO2, and
bicarbonate [37,38]. (See "Arterial blood gases" and "Venous blood gases and other alternatives to arterial blood gases".)

● Serum bicarbonate – For those in whom the suspicion is low to moderate (eg, <20 percent), obtaining serum bicarbonate is typically sufficient. Based upon
the results we suggest the following:

• Bicarbonate level >27 mEq/L – An elevated bicarbonate level greater than 27 mEq/L, significantly increases the likelihood of OHS and an ABG should be
done to investigate for the presence of chronic hypercapnic acidosis (partial pressure of arterial carbon dioxide [PaCO2] >45 mmHg). ABGs can also
identify hypoxemia. Should chronic respiratory acidosis with compensatory metabolic alkalosis be identified, then OHS is likely, and if not identified then
OHS is unlikely. Interpretation of acid-base disturbances and distinguishing acute, acute-on-chronic, and chronic hypercapnia ( figure 1 and figure 2
and figure 3) are discussed separately (See "The evaluation, diagnosis, and treatment of the adult patient with acute hypercapnic respiratory failure",
section on 'Arterial blood gas analysis' and "Simple and mixed acid-base disorders", section on 'Respiratory acid-base disorders'.)

• Bicarbonate level is ≤27 mEq/L – If the bicarbonate level is ≤27 mEq/L, OHS is unlikely, particularly when the suspicion for OHS is low to moderate. An
ABG is not absolutely necessary in this population. However, the approach in this population should be individualized. An ABG may be considered in
obese patients with borderline elevations in bicarbonate, reduced oxygenation parameters, and suspected complex acid-base disturbance (eg, acute-on-
chronic hypercapnia, triple acid-base disturbance), as well as in those in whom an ABG would facilitate excluding an alternate diagnosis.

Exclude other causes of hypercapnia and alveolar hypoventilation — For those in whom a chronic respiratory acidosis with compensatory metabolic alkalosis
is found, additional testing is necessary to exclude other diseases that can cause or contribute to chronic alveolar hypoventilation or hypercapnia. Disorders that
commonly co-exist with obesity that may contribute to hypercapnia include chronic obstructive pulmonary disease (COPD), restrictive lung disease (eg,
neuromuscular weakness, severe interstitial lung disease, chest wall disease), hypothyroidism, electrolyte disturbances, and chronic sedative use [1,11]. Testing
should be individualized but generally includes:

● Serum chemistries and electrolytes – Electrolyte disturbances that may exacerbate hypercapnia include hypophosphatemia, hypomagnesemia, and
rarely, hypermagnesemia, hypokalemia, or hypercalcemia. If found, these should be corrected and the ABG repeated. (See "Hypomagnesemia: Clinical
manifestations of magnesium depletion" and "Hypophosphatemia: Clinical manifestations of phosphate depletion".)

● Complete blood count – Chronic hypoxemia from underlying lung disease may be associated with polycythemia, which may be a useful tool to monitor
response to therapy [31,39]. Although rare, an elevated eosinophil fraction on a complete blood count may be consistent with neuropathy from eosinophilic
myalgia. (See "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis", section on 'Neurologic disease' and "Diagnostic
approach to the patient with polycythemia", section on 'Causes of absolute polycythemia'.)

● Thyroid function tests – Hypothyroidism may contribute to the chronic ventilatory failure of OHS by decreasing chemo-responsiveness, causing OSA (due
to macroglossia and/or upper airway dilator muscle dysfunction), or causing either a myopathy or neuropathy that affects the respiratory muscles [40-43].
(See "Laboratory assessment of thyroid function" and "Hypomagnesemia: Clinical manifestations of magnesium depletion" and "Hypophosphatemia:
Clinical manifestations of phosphate depletion".)

● Pulmonary function tests – Pulmonary function tests (PFTs) including spirometry, lung volumes, diffusing capacity, and inspiratory and expiratory
pressures may facilitate the identification and severity of a potential underlying lung disease and should be performed in the chronic stable state. (See

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"Overview of pulmonary function testing in adults" and "Tests of respiratory muscle strength".)

● Imaging – A chest radiograph should be performed to exclude parenchymal lung disease, chest wall disease, asymmetrical elevation of a hemidiaphragm
(ie, diaphragm paralysis), and cardiomegaly.

● Other – Rarely, a toxicology screen (eg, concomitant benzodiazepine or narcotic use) or creatine phosphokinase (eg, contributing myositis) are obtained.

Further details regarding the evaluation of acute hypercapnia ( table 1) are discussed separately (see "The evaluation, diagnosis, and treatment of the adult
patient with acute hypercapnic respiratory failure")

IDENTIFY COEXISTENT SLEEP DISORDERED BREATHING

Ideally, in-laboratory polysomnography (PSG) is performed in all patients suspected as having OHS, in whom a diagnosis of obstructive sleep apnea (OSA) or
other sleep disordered breathing (SDB) does not already exist. However, many factors including third party payor issues, degree of obesity, and likelihood of OSA
or sleep-hypoventilation determine what sleep test is chosen.

● Factors favoring in-laboratory PSG include morbid obesity (body mass index [BMI] >40 kg/m2), high likelihood of sleep-related hypoventilation (as CO2
monitoring is available only with in-center testing), heart failure, and significant daytime or nocturnal hypoxemia.

● Home sleep apnea testing (HSAT) is not ideal for rule out OHS as HSAT is best suited for uncomplicated, high probability obstructive sleep apnea cases. It
should be noted that HSAT does not detect sleep-related hypoventilation, thus necessitating PSG with continuous nocturnal carbon dioxide monitoring.
HSAT may be suitable in those with non-morbid obesity (BMI 30 to 40 kg/m2) in whom the likelihood of OSA is high or those in whom the issue of cost
expressly prohibits PSG evaluation.

Although PSG or HSAT is not required to diagnose OHS, sleep testing distinguishes the 90 percent of patients with OHS who have coexistent OSA from the 10
percent of patients who have sleep-related hypoventilation alone [11,44]. Determining the type of SDB is important since it has implications for the type of
therapy administered. Further details regarding diagnostic testing are provided separately. (See "Clinical presentation and diagnosis of obstructive sleep apnea in
adults", section on 'Diagnostic tests' and "Home sleep apnea testing for obstructive sleep apnea in adults" and "Central sleep apnea: Risk factors, clinical
presentation, and diagnosis".)

Although, the apnea hypopnea index [AHI] is likely to be higher in OHS patients than those with eucapnic OSA, it doesn’t distinguish these groups [25,45].
However, patients with OHS tend to have severe OSA (eg, AHI >50/hour) [25,45,46] and usually have more profound oxygen desaturation during sleep than
patients with OSA alone, spending a significantly larger part of sleep time with saturations <90 percent [45,47,48]. (See "Polysomnography in the evaluation of
sleep-disordered breathing in adults".)

DIAGNOSIS

OHS is a diagnosis of exclusion that can be made when the following criteria are met:

● Obesity (body mass index [BMI] >30 kg/m2)

● Awake alveolar hypoventilation as indicated by a partial arterial pressure of carbon dioxide >45 mmHg
● Alternative causes hypercapnia and hypoventilation have been excluded (see 'Exclude other causes of hypercapnia and alveolar hypoventilation' above)

Although the majority also have sleep-disordered breathing (nocturnal obstructive and nonobstructive events), it is the awake (ie, typically daytime)
hypoventilation that is critical for diagnosis.

The absence of an alternative cause of hypercapnic hypoventilation is an important requirement for the diagnosis of OHS. In clinical practice, patients frequently
have additional diseases that cause acute and/or chronic hypercapnia. However, assessing the contributions of additional etiologies may be tricky and a matter of
clinical judgement. If a potential contributing etiology is mild or considered unlikely to cause hypercapnia, then it is appropriate to diagnose OHS. In contrast, if a
coexisting disease is severe and considered likely contributing to hypercapnia, OHS cannot be diagnosed with certainty. (See 'Exclude other causes of
hypercapnia and alveolar hypoventilation' above and 'Differential diagnosis' below.)

Because symptoms are nonspecific, the diagnosis of OHS is frequently delayed. It is commonly misdiagnosed as asthma or chronic obstructive pulmonary
disease [23] and some patients are not diagnosed until hospitalization for acute-on-chronic respiratory failure occurs. (See 'Symptoms and signs' above.)

DIFFERENTIAL DIAGNOSIS

The main competing diagnosis for the symptoms of OHS is obstructive sleep apnea (OSA). Apart from the presence of chronic respiratory acidosis with
compensatory metabolic alkalosis, both disorders are often clinically indistinguishable from one another. (See "Clinical presentation and diagnosis of obstructive
sleep apnea in adults", section on 'Clinical features'.)

Common etiologies for respiratory hypercapnia and alveolar hypoventilation are typically distinguished by history, examination, pulmonary function testing,
imaging, and laboratory findings:

● Chronic obstructive pulmonary disease (COPD) – COPD may be identified in those with a smoking history, obstruction on pulmonary function tests, and
imaging findings of emphysema. (See "Chronic obstructive pulmonary disease: Definition, clinical manifestations, diagnosis, and staging".)

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● Interstitial lung diseases (ILD) – ILD may be identified in those with imaging findings of parenchymal abnormalities and restriction on pulmonary function
tests. (See "Approach to the adult with interstitial lung disease: Clinical evaluation" and "Approach to the adult with interstitial lung disease: Diagnostic
testing".)

● Neuromuscular (NM) disorders – NM disorders may be identified by history (eg, weak cough), weakness on examination, and restrictive deficit and muscle
weakness on lung function testing. Chest imaging may reveal an elevated hemidiaphragm to suggest diaphragmatic paralysis. (See "Respiratory muscle
weakness due to neuromuscular disease: Clinical manifestations and evaluation".)

● Chest wall disorders – Such disorders (eg, kyphoscoliosis) may be obvious on clinical examination or on imaging. (See "Chest wall diseases and restrictive
physiology".)

● Hypothyroidism – Hypothyroidism is typically evident on laboratory testing. (See "Clinical manifestations of hypothyroidism" and "Diagnosis of and
screening for hypothyroidism in nonpregnant adults".)

● Chronic sedative use - Use of sedatives may be found on history or toxicology testing. (See "General approach to drug poisoning in adults".)

ASSESS COMPLICATIONS

All patients with obesity hypoventilation syndrome (OHS) should be assessed for common complications, many of which are shared with obesity alone ( table 2)
[49]. These are discussed in detail separately. (See "Overweight and obesity in adults: Health consequences" and "Treatment and prognosis of the obesity
hypoventilation syndrome", section on 'Treatment of comorbid conditions'.)

Specifically, patients with OHS should be assessed for the following common complications:

● Mild to moderate pulmonary hypertension (PH) – Up to two-thirds of patients with OHS have PH. Thus, at diagnosis we typically perform an
electrocardiogram and echocardiogram in this population to evaluate for PH, the details of which are discussed separately. (See "Pulmonary hypertension
due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Epidemiology, pathogenesis, and diagnostic evaluation in adults".)

● Cardiovascular and metabolic comorbidities – Conditions such as hypertension, congestive heart failure, and insulin resistance are all more common in
patients with OHS than in patients with eucapnic obesity, and may be present three or more years prior to the diagnosis of OHS [4,49-51]. Thus, at the time
of diagnosis we typically perform fasting bloods assessing plasma glucose, triglycerides, and cholesterol to ensure comorbid conditions have been
identified and are being appropriately managed. A cross sectional study of stable OHS patients found cardiovascular morbidity risk was significantly higher
in those with the predominantly sleep hypoventilation OHS phenotype despite these individuals exhibiting less severe nocturnal and awake gas exchange
compared with those who had OHS and significant OSA [52].

The natural history and prognosis of OHS is discussed separately. (See "Treatment and prognosis of the obesity hypoventilation syndrome".)

SUMMARY AND RECOMMENDATIONS

● Obesity hypoventilation syndrome (OHS) is defined as the presence of awake alveolar hypoventilation (partial arterial pressure of carbon dioxide [PaCO2]
>45 mmHg) in an obese individual (body mass index [BMI] >30 kg/m2), which cannot be attributed to other conditions associated with hypoventilation. (See
'Introduction' above and 'Diagnosis' above and 'Definition' above and 'Proposed staging' above.)

● The symptoms and clinical manifestations of OHS are nonspecific and are more reflective of the manifestations of obesity, coexistent obstructive sleep
apnea (OSA; eg, hypersomnolence, snoring, witnessed apneas), or OHS-related complications (eg, pulmonary hypertension). Sleep-related desaturation and
daytime hypoxemia are common. (See 'Clinical manifestations' above.)

● For those in whom OHS is strongly suspected (eg, morbidly obese patients with suspected or known OSA), we suggest that an arterial blood gas (ABG) be
obtained to look for evidence of alveolar hypoventilation (ie, PaCO2 >45 mmHg). For those in whom the suspicion is low to moderate (eg, <20 percent),
obtaining serum bicarbonate is typically sufficient; an elevated bicarbonate level >27 mEq/L, increases the likelihood of OHS and should prompt an ABG,
while a bicarbonate level ≤27 mEq/L suggests that OHS is unlikely, and unless an alternate etiology or complex acid-base disturbance is suspected, an ABG is
not usually indicated. For those in whom a chronic respiratory acidosis (PaCO2 >45 mmHg) with compensatory metabolic alkalosis is found, additional
testing is necessary to exclude other diseases that can cause or contribute to chronic alveolar hypoventilation or hypercapnia. (see 'Diagnostic approach'
above)

● For those with suspected OHS in whom a diagnosis of OSA does not already exist, in-laboratory polysomnography should ideally be performed based upon
the rationale that 90 percent of patients with OHS have coexistent OSA of at least mild to moderate severity while the remainder have sleep-related
hypoventilation only. Home sleep apnea testing may be a suitable alternative in those who do not have morbid obesity (ie, BMI 30 to 40 kg/m2) in whom the
likelihood of OSA is high or those in whom cost is an issue. (See 'Identify coexistent sleep disordered breathing' above.)

● OHS is a diagnosis of exclusion (obesity and awake alveolar hypoventilation which cannot be attributed to other conditions associated with hypoventilation).
Once diagnosed, all patients with OHS should be assessed for common complications, including pulmonary hypertension and cardiovascular disorders
( table 2). (See 'Diagnosis' above and 'Differential diagnosis' above and 'Assess complications' above.)

ACKNOWLEDGMENT

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The UpToDate editorial staff acknowledges Paul Suratt, MD, who contributed to an earlier version of this topic review.

Use of UpToDate is subject to the Terms of Use.

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GRAPHICS

Expected compensation ranges for simple acid-base disorders

Reproduced with permission from: Harrington JT, Cohen JJ, Kassirer JP. Mixed acid-base disturbances. In:
Acid/Base, Cohen JJ, Kassirer JP (Eds), Little, Brown, Boston: 1982. Copyright © 1982 Lippincott Williams &
Wilkins. www.lww.com.

Graphic 79833 Version 9.0

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Compensations to acute respiratory acidosis and

alkalosis

Combined significance bands for plasma pH and concentrations of

H+ and HCO3- in acute respiratory acidosis and alkalosis in humans.
In uncomplicated acute respiratory acid-base disorders, values for
the H+ and HCO3- concentrations will, with an estimated 95 percent
probability, fall within the band. Values lying outside the band
indicate the presence of a complicating metabolic acid-base
disturbance.

Arbus GS, Herbert LA, Levesque PR, et al. N Engl J Med 1969; 280:117. By permission
from the New England Journal of Medicine.

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Compensation to chronic respiratory acidosis

95% significance bands for plasma pH and H+ and HCO3–

concentrations in chronic hypercapnia. Because of the
compensatory rise in the plasma HCO3– concentration, there is
much less change in H+ concentration and pH than in acute
hypercapnia.

Schwartz WB, Brackett NC Jr, Cohen JJ. J Clin Invest 1965; 44:291. By copyright
permission of the American Society for Clinical Investigation.

Graphic 63315 Version 4.0

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Etiologies and mechanism of hypercapnia

Respiratory pathway affecting carbon dioxide elimination

Central nervous system

"Won't breathe"
↓

Peripheral nervous system

Respiratory muscles

↓
"Can't breathe"
Chest wall and pleura

Upper airway

Lungs Abnormal gas exchange: "Can't breathe enough"

Schematic figure representing the respiratory pathway, along which a variety of diseases can affect carbon dioxide elimination and result in hypercapnia. Note that gas exchange
abnormalities alone are relatively uncommon causes of hypercapnia, but gas exchange problems in the setting of reduced mechanical capability of the ventilatory pump are very
common explanations for acute and chronic hypercapnia.

Mechanism and etiologies of hypercapnia

Mechanism Etiologies

Decreased minute ventilation (global hypoventilation; extra pulmonary causes)

Decreased central respiratory drive Sedative overdose (eg, narcotic or benzodiazepine, some anesthetics, tricyclic antidepressants)
Encephalitis
Stroke
Central and obstructive sleep apnea
Obesity hypoventilation
Congenital central alveolar hypoventilation
Brainstem disease
Metabolic alkalosis
Hypothyroidism*
Hypothermia
Starvation

Decreased respiratory Primary spinal cord/lower motor Thoracic cage disorders Metabolic disordersΔ
neuromuscular or thoracic cage neuron/muscle disorders Kyphoscoliosis Hypophosphatemia
function Cervical spine injury or disease (eg, Thoracoplasty Hypomagnesemia
trauma syringomyelia)¶ Flail Chest Hypothyroidism
Amyotrophic lateral sclerosis Ankylosing spondylitis Hyperthyroidism
Poliomyelitis Pectus excavatum
Guillain-Barré syndrome Fibrothorax
Phrenic nerve injury
Critical illness polymyoneuropathy Toxins, poisoning, drugs
Myasthenia gravis Tetanus
Muscular dystrophy Dinoflagellate poisoning
Polymyositis Shellfish poisoning (red tide)
Tetanus Ciguatera poisoning
Transverse myelitis (eg, multiple Botulism
sclerosis) Organophosphates
Tick paralysis Succinylcholine and neuromuscular
Acute intermittent porphyria blockade
Eaton Lambert syndrome Procainamide
Neuralgic amyotrophy
Periodic paralysis
Glycogen storage and
mitochondrial diseases
Respiratory muscle fatigue

Increased dead space (gas exchange abnormalities; pulmonary parenchymal causes or airway disorders)

Anatomic Short shallow breathing

Physiologic Pulmonary embolism (usually severe)

Pulmonary vascular disease (usually severe)
Dynamic hyperinflation (eg, upper and lower airway disorders including chronic obstructive pulmonary disease, severe asthma)

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Endstage interstitial lung disease

Increased carbon dioxide production

  Fever
Thyrotoxicosis
Increased catabolism (sepsis, steroids)
Overfeeding
Metabolic acidosis
Exercise

Multifactorial

  Upper airway disorders◊

Severe laryngeal or tracheal disorders (stenosis/tumors/angioedema/tracheomalacia)
Vocal cord paralysis
Epiglottitis
Foreign body aspiration
Retropharyngeal disorders
Obstructive goiter

Decreased mechanical ventilation can also cause hypercapnic respiratory acidosis (eg, permissive hypercapnia). Importantly, any factor that limits the mechanical function of
the ventilatory pump (such as airway obstruction or weak muscles), when combined with a gas exchange abnormality (increased physiological dead space), may lead to
hypercapnia. For further details regarding the mechanisms that underlie these pathologies, please refer to the UpToDate topic on mechanisms, causes, and effects of
hypercapnia.

* Hyperthyroidism is also a rare cause of respiratory muscle weakness.

¶ Injury or disease process needs to be between cervical spine level 3 and 5 (C3 to 5) for clinically significant diaphragmatic paresis/paralysis to occur.

Δ Hypermagnesemia, hypokalemia, and hypercalcemia can also cause respiratory muscle weakness and contribute to hypercapnia.

◊ Upper airway disorders are rare causes of hypercapnia. They either diminish total ventilation or lead to dynamic hyperinflation and reduced tidal volume, while
simultaneously causing increased work of breathing and carbon dioxide production.

Graphic 103091 Version 3.0

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Medical impairments associated with obesity hypoventilation syndrome

Central nervous system

Cognitive deficit

Decrease neuronal drive

Upper airway

Obstructive sleep apnea

Increased intubation risk

Respiratory

Restrictive lung function

Pulmonary hypertension

Hypercapnia/hypoxemia

Metabolic

Central obesity

Metabolic syndrome

Chronic inflammation

IGF-1 deficit

Cardiovascular

Endothelial dysfunction

Coronary artery disease

Chronic heart failure

General

Peripheral edema

Increased morbi-mortality

Decreased physical activity

Graphic 94511 Version 1.0

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