The American Journal of Medicine (2005) 118, 948-956
REVIEW
AJM Theme Issue: OBESITY AND DIABETES
The obesity hypoventilation syndrome
Amy L. Olson, MD, Clifford Zwillich, MD, MACP
University of Colorado Health Sciences Center, Division of Pulmonary Sciences and Critical Care Medicine, and Denver
Veterans Affairs Medical Center, Denver, Colo.
KEYWORDS:
Obesity
hypoventilation
syndrome;
Obstructive sleep
apnea syndrome;
Obstructive sleep
apnea-hypopnea
syndrome;
Hypercapnia;
Hypoventilation;
Pickwickian
syndrome;
Obesity
ABSTRACT: The obesity hypoventilation syndrome, which is defined as a combination of obesity and
chronic hypoventilation, utimately results in pulmonary hypertension, cor pulmonale, and probable
early mortality. Since the classical description of this syndrome nearly fifty years ago, research has led
to a better understanding of the pathophysiologic mechanisms involved in this disease process, and to
the development of effective treatment options. However, recent data indicate the obesity hypoventilation syndrome is under-recognized, and under-treated. Because obesity has become a national
epidemic, it is critical that physicians are able to recognize and treat obesity-associated diseases. This
article reviews current definitions of the obesity hypoventilation syndrome, clinical presentation and
diagnosis, present understanding of the pathophysiology, and treatment options.
© 2005 Elsevier Inc. All rights reserved.
Obesity hypoventilation syndrome is commonly defined as a
combination of obesity (body mass index of ⬎30 kg/m2) and
awake arterial hypercapnia (PaCO2 ⬎45 mm Hg) in the absence
of other known causes of hypoventilation.1-3 Clinically, patients may present with symptoms such as excessive daytime
sleepiness, fatigue, or morning headaches, which are similar to
symptoms seen in obstructive sleep apnea-hypopnea syndrome.4 However, patients with obesity hypoventilation syndrome have daytime hypercapnia and hypoxemia, which is
associated with pulmonary hypertension and right-sided congestive heart failure (cor pulmonale).1 If untreated, recent studies indicate this syndrome results in substantial morbidity and
probable early mortality.5,6 Although the precise pathophysiology remains unknown, physiologic consequences of obesity
seem important.7 In a society in which approximately one third
Requests for reprints should be addressed to Amy L. Olson, MD,
University of Colorado Health Sciences Center, Division of Pulmonary
Sciences and Critical Care Medicine, 4200 East Ninth Avenue, Denver, CO
80262.
E-mail address: amy.olson@uchsc.edu.
0002-9343/$ -see front matter © 2005 Elsevier Inc. All rights reserved.
doi:10.1016/j.amjmed.2005.03.042
of adults are obese and the prevalence is expected to increase,8
recognition of this syndrome is essential because effective
treatment options exist.9
History and definitions
Obesity hypoventilation syndrome was classically described
as “Pickwickian syndrome” in a 1956 case report by Burwell.10 This patient resembled a character depicted by Dickens in his story, The Posthumous Papers of the Pickwick
Club, because both were obese with excessive hypersomnolence. Further, Burwell’s patient had hypoventilation during wakefulness, with hypoxemia-induced erythrocytosis,
pulmonary hypertension, and cor pulmonale.
Subsequent investigation of patients with Pickwickian syndrome found nocturnal respiratory abnormalities, such as multiple “respiratory pauses” (apneas),11 which led to further study
of these sleep-induced events. Research in eucapnic patients
revealed that occasional apneas (as the result of sleep-induced
Olson and Zwillich
Obesity hypoventilation syndrome
949
Table 1 Definitions of simple obesity, obstructive sleep apnea-hypopnea syndrome, and obesity hypoventilation syndrome with
respect to the body mass index, awake arterial pressure of carbon dioxide (PaCO2), and possible sleep-related breathing disorder that
may be present on night-time polysomnography
Simple obesity
Body mass index (kg/m )
ⱖ30
Awake PaCO2(mm Hg)
Associated sleep-related
breathing disorder by
nocturnal
polysomnography
Normal
Nocturnal monitoring demonstrates
⬍5 apneas, hypopneas, or
respiratory-related arousals per
hour
2
Obstructive sleep
apnea-hypopnea
syndrome
Obesity hypoventilation
syndrome
(Pickwickian syndrome)
Variable, but risk
increases with
increasing
weight
Normal
Nocturnal
monitoring
demonstrates
⬎5 apneas,
hypopneas or
respiratoryrelated
arousals per
hour
ⱖ30
⬎45
A. Obstructive sleep apneahypopnea syndrome: Nocturnal
monitoring demonstrates ⬎5
apneas, hypopneas or
respiratory-related arousals per
hour
B. Sleep hypoventilation
syndrome: Nocturnal
monitoring demonstrates one
or both of the following
1. An increase in PaCO2 ⬎10
mm Hg from awake supine
values
2. Oxygen desaturation during
sleep that is not explained by
apneic or hypopneic events
(hypercapnia is assumed
although not measured)
C. A combination of obstructive
sleep apnea-hypopnea events
and sleep hypoventilation
upper airway obstruction) were common and often asymptomatic, whereas frequent complete or partial apneas could cause
sleep fragmentation resulting in a range of clinical symptoms
including hypersomnolence. This syndrome is termed “obstructive sleepapnea-hypopnea syndrome.”12-15
Additional investigations found daytime hypercapnia in approximately 10% to 15% of patients with obstructive sleep
apnea-hypopnea syndrome.16,17 Other studies reported that although the majority (⬃90%) of patients with obesity and
daytime hypercapnia had concurrent obstructive sleep apneahypopnea syndrome, a small minority of patients with obesity
hypoventilation syndrome had no evidence of significant
apnea-hypopnea events during sleep.1,18,19 Instead, these patients had sustained periods of hypoventilation, particularly
during rapid eye movement sleep, which has been termed
“sleep hypoventilation syndrome.”20
In 1999, the American Academy of Sleep Medicine published recommendations to standardize definitions, eliminate confusion, and facilitate comparability of studies for
research purposes.20 By these definitions, patients with obesity hypoventilation syndrome may have obstructive sleep
apnea-hypopnea syndrome with hypercapnia, sleep hypoventilation syndrome, or a combination of sleep-related
breathing disorders (Table 1).21
The scope of the problem
Epidemiology
Although the prevalence of obesity hypoventilation syndrome is unknown, a recent study of severely obese (body
mass index ⱖ35 kg/m2) hospitalized patients found that
31% had daytime hypercapnia unexplained by other disorders.6 Although weight alone did not predict the presence of
hypoventilation, almost half of the patients with a body
mass index 50 kg/m2 or greater had chronic daytime hypoventilation. Although data have shown men to be at
higher risk for obstructive sleep apnea-hypopnea syndrome,22 the same has not been demonstrated for obesity
hypoventilation syndrome.23,24
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Morbidity and mortality
Evidence suggests this syndrome is associated with significant mortality and morbidity. Two older case series, published before treatment options became available and before
the routine use of in-hospital heparin prophylaxis, reported
high in-hospital mortality rates principally related to progressive respiratory failure or acute pulmonary embolism.25,26 A recent study found hospitalized patients had a
higher 18-month mortality rate of 23% compared with 9%
among patients with simple obesity. Notably, although
health care providers were informed of the obesity-associated hypoventilation, only 13% of patients were discharged
with therapies known to be effective.6
Cost
Little is known about health care use and cost for patients
with obesity hypoventilation syndrome. A recent Canadian
study found that during the 5 years before the diagnosis of
this syndrome, patients had more physician visits, generated
higher fees, and were more likely to be hospitalized than
patients with simple obesity. Two years after the diagnosis
was made and treatment was initiated, patients had a significant reduction in physician fees and days hospitalized.5
Clinical presentation and diagnosis
Patients with obesity hypoventilation may present with unexplained hypoxemia or a broad spectrum of symptoms
ranging from hypersomnolence or dyspnea to signs of rightsided congestive heart failure. Because these patients have a
concurrent sleep-related breathing disorder with sleepinduced exaggeration of hypercapnia and hypoxemia and
frequent arousals from sleep, presenting symptoms may
include fatigue, hypersomnolence, mood disorders, and
nocturnal or morning headaches.27 In patients with apneic or
hypopneic events, symptoms may include loud snoring, choking, gagging, and resuscitative snorting. Untreated patients
may develop secondary erythrocytosis and will ultimately develop pulmonary hypertension and cor pulmonale.28
Data suggest that obesity hypoventilation syndrome is
under-recognized and under-treated.6 We believe the diagnosis
is frequently missed because pulse oximetry is used to detect
oxyhemoglobin desaturation without consideration for the
presence of hypercapnia. As a result, patients may be inappropriately treated with supplemental oxygen alone, which does
not reverse hypoventilation. In our opinion, arterial blood gas
analysis should be obtained in any patient with morbid obesity
and unexplained hypoxemia or signs of cor pulmonale.
Arterial blood gas testing is required to confirm the
presence of daytime hypercapnia, and usually reveals compensated respiratory acidosis and hypoxemia. An elevated
serum bicarbonate level may suggest that chronic hypercapnia is present, because hospitalized patients with this syndrome have higher serum bicarbonate levels when com-
pared with patients with simple obesity (30 ⫾ 4 mEq/L vs
24 ⫾ 5 mEq/L, P ⫽ .01).6
Other conditions that cause chronic hypoventilation
should be considered during the evaluation. The history and
physical examination may reveal mechanical limitations
(underlying lung disease, kyphoscoliosis, or myopathy),
neuropathic conditions (diaphragmatic paralysis or neuropathy), or central control abnormalities (severe hypothyroidism, cerebrovascular accident, or central nervous system
disease) suggesting a diagnosis other than obesity hypoventilation syndrome.27,29
Laboratory testing should include a complete blood
count (to determine the existence of erythrocytosis), serum
electrolytes, including phosphorus and creatinine phosphokinase (to determine additional factors that may be contributing to respiratory muscle weakness), and thyroid-stimulating hormone.27 Thyroid function testing should be
performed because severe hypothyroidism has been shown
to cause alveolar hypoventilation in the absence of severely
impaired lung function.29,30 If hypoxemia-induced erythrocytosis is identified, recommendations state phlebotomy
should only be performed if the hematocrit is greater than
65% with symptoms of hyperviscosity.31
Pulmonary function testing should include spirometry,
lung volumes, a bronchodilator response, maximal inspiratory and expiratory pressures, and supine vital capacity (if
diaphragmatic paralysis is suspected).27,29 These studies
may support a diagnosis of chronic obstructive pulmonary
disease (COPD). Like obesity hypoventilation syndrome,
COPD can cause chronic hypoventilation. However, hypoventilation and hypercapnia are not common in COPD
unless the forced expiratory volume in 1 second is less than
1 liter. Flenley described the concurrent conditions of
COPD and obstructive sleepapnea-hypopnea syndrome,
which he termed the “overlap syndrome.”32 In these patients
with COPD, forced expiratory volume in 1 second that
exceeded 1 liter, and chronic hypoventilation, apneas and
hypopneas were prominent features on night-time polysomnography. If these patients are treated with supplemental
oxygen alone, symptoms do not improve and nocturnal
hypercapnia may worsen.33
Conditions that aggravate chronic hypoventilation
should be identified and treated. The history may reveal the
use of excessive alcohol, sedative-hypnotics, or narcotics,
which have been shown to be respiratory depressants and
should be avoided if possible.30
Finally, patients should be referred for night-time polysomnography testing to identify the underlying sleep disorder and to individualize treatment with either continuous
positive airway pressure or noninvasive mechanical ventilation.24,28 In patients with evidence of impending respiratory failure (such as an uncompensated respiratory acidosis,
significant hypoxemia, or mental status changes), immediate hospitalization is indicated. These patients require immediate ventilatory support.25,26
Olson and Zwillich
Obesity hypoventilation syndrome
951
Figure 1 The possible interactions among impaired respiratory mechanics, abnormal ventilatory drive, sleep-disordered breathing, and
neurohormonal insensitivity to leptin that lead to sustained daytime hypercapnia in obese patients. OSAHS, obstructive sleep apneahypopnea syndrome; SHVS, sleep hypoventilation syndrome.
Pathophysiology
Respiratory system mechanics
Overview
Significant impairment in respiratory system mechanics is
present when individuals with obesity hypoventilation syndrome are compared with similarly obese patients without
daytime hypercapnia. Reductions in total lung capacity,
vital capacity, functional residual capacity, and increases in
residual volume have been shown.7 Patients with more
upper body fat distribution tend to have more severe derangements in lung volumes, suggesting that fat distribution
may contribute to the pathogenesis.28
Despite significant research, the exact pathophysiologic
mechanisms leading to obesity hypoventilation syndrome
have not been clearly defined. The syndrome may result
from complex interactions among impaired respiratory mechanics, abnormal central ventilatory control, possible
sleep-disordered breathing, and neurohormonal aberrancies
(Figure 1).7,28
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Because of decreased respiratory system compliance and
increased resistance,34-38 these patients must maintain an
increased work and oxygen cost of breathing.7,34 This may
result in respiratory muscle fatigue. Maximal voluntary ventilation, a measure of ventilatory endurance, is reduced in
simple obesity and further reduced in obesity hypoventilation syndrome.7
Ventilatory control
Data suggest that abnormalities in ventilatory control are
also involved in the pathogenesis of this syndrome. Patients
with obesity hypoventilation syndrome can achieve eucapnia (or even hypocapnia) during voluntarily hyperventilation,39 implying that impairments in respiratory system mechanics alone do not explain the hypoventilation. Moreover,
investigators have identified abnormalities in both hypercapnic and hypoxemic ventilatory responses, which are
measurements of ventilatory control.7,38,40-46
The ratio of change in the diaphragmatic electromyogram response to increasing concentrations of inhaled carbon dioxide (⌬EMG/⌬PCO2) is thought to be a direct measure of central ventilatory drive.28 Patients with simple
obesity have an augmented ventilatory response, whereas
patients with obesity hypoventilation syndrome have a response similar to that of nonobese patients.46 These findings
imply that eucapnic obese patients have an increased central
ventilatory drive that is needed to compensate for the mechanical restrictions of obesity, whereas patients with obesity hypoventilation seem to lack this compensatory increased drive.40,42,45
Obstructive sleep apnea-hypopnea syndrome
and decreased ventilatory response
There is a significant relationship between obstructive sleep
apnea-hypopnea syndrome and obesity hypoventilation syndrome. Although it is not clear why only 10% to 15% of
patients with obstructive sleep apnea-hypopnea develop hypoventilation, it has been postulated that obstructive sleep
apnea-hypopnea syndrome may lead to a depressed ventilatory response and hypoventilation.16,28
Chronic exposure to hypoxia and sleep fragmentation
attenuate central ventilatory drive. Patients with cyanotic
congenital heart disease have a reduced hypoxic ventilatory
response, which is reversed when the shunt hypoxemia is
corrected.47 Healthy subjects with chronic exposure to hypoxia of altitude have a reduction in both the hypoxic and
hypercapnic ventilatory response.48 In addition, sleep deprivation in healthy volunteers decreases the hypercapnic ventilatory response.49
In obstructive sleep apnea-hypopnea syndrome, apneic
events result in sleep hypoxemia, hypercapnia, and increased ventilatory effort. This causes arousals, which improve upper airway patency and normalize blood gas ten-
sions.50 However, frequent apneas with arousals lead to
sleep fragmentation.28 In patients with obstructive sleep
apnea-hypopnea syndrome, this chronic exposure to hypoxemia and sleep fragmentation may, in susceptible individuals, lead to a diminished ventilatory drive and resultant
hypoventilation.28,47-49
Patients with these concurrent syndromes may be caught
in a “vicious cycle” (Figure 2). Apnea-induced hypoxemia
and sleep fragmentation may diminish the ventilatory response. This decreased ventilatory response, combined with
deranged lung mechanics,28 may prevent restoration of
post-apnea eucapnia, which leads to more severe exposure
to hypoxemia and hypercapnia and further attenuation of the
ventilatory response.21,51
There is evidence supporting this theory. Patients with
obstructive sleep apnea-hypopnea syndrome (and daytime
eucapnia) demonstrated an augmented ventilatory drive
with large tidal volume breaths after an apnea, whereas
patients with obesity hypoventilation syndrome did not have
a compensatory ventilatory response after apneas.21,44 Furthermore, the severity of hypercapnia has been correlated
with the severity of sleep-induced respiratory abnormalities,
the mechanical impairment of the respiratory system, and
the degree of daytime hypoxemia.51
Leptin and the ventilatory response
Recent evidence suggests that the protein leptin may be
involved in the pathogenesis of obesity hypoventilation syndrome. Leptin is produced by adipose tissue and acts on
receptors in the hypothalamus to suppress appetite.52-54 A
mutation in the gene that encodes the leptin protein causes
obesity in mice and in humans.55-57 In addition, leptin acts
on the central respiratory centers to stimulate ventilation,
whereas leptin deficiency has been associated with hypoventilation.58
Leptin-deficient mice hypoventilate, and leptin replacement
results in increased ventilation. In wild-type mice with dietinduced obesity, leptin levels increase more than 10-fold and
are associated with an increase in ventilation. These findings
suggest leptin may be involved in maintaining an adequate
level of ventilation for a given degree of obesity.58
Human obesity is also associated with elevated serum levels
of leptin,59 which may explain a means by which eucapnia is
maintained in most obese individuals. It has been speculated
that in some individuals leptin resistance may lead to a reduction in ventilation, but further research is necessary to confirm
this theory.58,60-62
Treatment
Weight loss
The ideal treatment for obesity hypoventilation syndrome is
weight loss, which improves most of the physiologic abnor-
Olson and Zwillich
Obesity hypoventilation syndrome
953
Figure 2 The vicious cycle of obesity hypoventilation syndrome (see text for further explanation). OHS, obesity hypoventilation
syndrome; OSAHS, obstructive sleep apnea-hypopnea syndrome.
malities thought to be involved in the pathogenesis and
ultimately leads to the restoration of daytime eucapnia.7,18,38
Weight loss of at least 10 kg results in a significant
improvement in vital capacity and maximum voluntary ventilation, and a significant reduction in daytime PaCO2.38
Although data are limited, weight loss has also been shown
to significantly increase central ventilatory drive as measured by the diaphragmatic electromyogram response to
carbon dioxide inhalation.38 In patients with obesity hypoventilation syndrome and concurrent obstructive sleepapnea hypopnea syndrome, weight loss reduced the number
of sleep-disordered breathing events (apneas and hypopneas), decreased the severity of desaturation associated
with any residual apneas, and led to the resolution of the
daytime hypercapnia.63
The National Institutes of Health consensus statement
addresses the issue of surgical treatment for obesity and
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The American Journal of Medicine, Vol 118, No 9, September 2005
obesity with associated comorbid conditions. According to
these guidelines, patients with a body mass index greater
than 35 kg/m2 and an obesity-related comorbid condition
(including obesity hypoventilation syndrome) or patients
with a body mass index greater than 40 kg/m2 are recommended for surgical treatment.64 Support for these recommendations comes from studies on the effect of gastric
surgery in patients with obesity hypoventilation syndrome
and obstructive sleep apnea-hypopnea syndrome. As a
group these patients had a significantly higher operative
mortality (2.4% vs 0.2%). However, gastric surgery was
associated with significant weight loss and improvement in
sleep apnea, lung volumes, arterial blood gases, polycythemia, and pulmonary hypertension.3,23,65
Although weight loss seems to be the optimal treatment
for this syndrome, it is slow to occur and difficult to achieve
and maintain. As a result, weight loss cannot be used as the
sole initial treatment. Furthermore, the optimal amount of
weight loss has not been studied, and the long-term outcome
of sustained weight loss is not known.7,18
Continuous positive airway pressure
and noninvasive mechanical ventilation
As previously stated, there are a variety of sleep-associated
respiratory disturbances (apneas, hypoventilation, or both)
that are found in obesity hypoventilation syndrome. Treatment that corrects the specific sleep-related breathing disorder results in the reversal of chronic daytime hypercapnia.66
In patients with concurrent obstructive sleep apneahypopnea syndrome, nocturnal continuous positive airway
pressure therapy (applied by nasal mask) is usually effective. This therapy provides continuous positive pressure
during the respiratory cycle, which maintains upper airway
patency, eliminates apneas and hypopneas, and restores
daytime eucapnia.67
A subset of patients with obstructive sleep apneahypopnea syndrome, however, will not respond to continuous positive airway pressure therapy, and may require
noninvasive mechanical ventilation to alleviate daytime hypercapnia. Noninvasive mechanical ventilation may be
achieved with a nasal mask and either a bilevel positive
airway pressure device or a volume ventilator. Bilevel systems permit independent adjustment of inspiratory and expiratory positive airway pressure. Differences between
these pressures assist with lung inflation during each respiratory cycle thereby supporting ventilation. The inspiratory
and expiratory pressures, like continuous positive airway
pressure, also maintain upper airway patency. Volume ventilation better ensures adequate alveolar ventilation and provides the advantage of allowing higher peak inspiratory
pressures.16
Several factors have been identified that may explain
why some patients with obesity hypoventilation syndrome
and obstructive sleep apnea-hypopnea syndrome are not
adequately treated with continuous positive airway pressure
alone. In some patients, despite high continuous positive
airway pressures, airway patency is not established. These
patients may need higher peak inspiratory pressures, which
only volume ventilation can provide. Other patients may
have concurrent sleep hypoventilation syndrome, which necessitates noninvasive ventilatory support to augment ventilation.16 Finally, in some patients, intolerance to therapy
may be a significant issue. Among patients who cannot
tolerate any form of ventilatory support, a tracheostomy
may be required.18,66
In patients with obesity hypoventilation syndrome whose
underlying sleep disorder is hypoventilation alone, noninvasive mechanical ventilation is the mainstay of treatment.
Hypoxia and hypercapnia develop as a consequence of
hypoventilation. Treatment with supplemental oxygen alone
is inadequate, and ventilatory support is required to correct
the hypercapnia.24,66
In addition to evidence that treatment directed at the
underlying sleep-associated respiratory disturbance alleviates daytime hypercapnia, there is emerging evidence that
treatment also alleviates symptoms such as morning headaches, morning drowsiness, sleepiness, dyspnea, and leg
edema.24
Progesterone
Medroxyprogesterone has been shown to increase hypercapnic chemosensitivity and improve ventilation in patients
with obesity hypoventilation syndrome.68,69 However, it
does not improve apnea frequency or symptoms of sleepiness,70 and there are limited data regarding adverse effects
and outcomes of long-term use. As a result, experts do not
currently recommend progesterone therapy.28
Conclusion
Because obesity has become a national epidemic, it is imperative that physicians are able to recognize and treat
obesity-associated diseases. Evidence suggests that obesity
hypoventilation syndrome is under-recognized, undertreated, and associated with a significant increase in mortality. These findings are particularly disturbing because
effective treatment options exist. Further investigations are
needed to completely understand the prevalence, pathophysiology, morbidity, and long-term treatment outcomes
associated with this syndrome.
Acknowledgment
The authors thank Ms. Jacklyn Martinez for her assistance
with article preparation.
Olson and Zwillich
Obesity hypoventilation syndrome
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