Concise Clinical Review
Obesity Hypoventilation Syndrome
Mechanisms and Management
Amanda J. Piper1 and Ronald R. Grunstein1
1
Department of Respiratory and Sleep Medicine, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia; and Sleep and Circadian
Group, Woolcock Institute of Medical Research, University of Sydney, Sydney, New South Wales, Australia
Obesity hypoventilation syndrome describes the association be-
tween obesity and the development of chronic daytime alveolar
hypoventilation. This syndrome arises from a complex interaction
between sleep-disordered breathing, diminished respiratory drive,
and obesity-related respiratory impairment, and is associated with
significant morbidity and mortality. Therapy directed toward re-
versing these abnormalities leads to improved daytime breathing,
with available treatment options including positive pressure ther-
apy, weight loss, and pharmacological management. However, a lack
of large-scale, well-designed studies evaluating these various ther-
apies has limited the development of evidence-based treatment
recommendations. Although treatment directed toward improving
sleep-disordered breathing is usually effective, not all patients
tolerate mask ventilation and awake hypercapnia may persist de-
spite effective use. In the longer term, weight loss is desirable, but
data on the success and sustainability of this approach in obesity
hypoventilation are lacking. The review outlines the major mecha-
nisms believed to underlie the development of hypoventilation in
this subgroup of obese patients, their clinical presentation, and
current therapy options.
Keywords: obesity hypoventilation; hypercapnic respiratory failure;
noninvasive ventilation; sleep
Obesity is a major public health issue, and despite the increasing
attention this disorder has received over the past decade, not
only are obesity rates continuing to increase but also we are
seeing the emergence of an increasing number of individuals who
can be categorized as super obese (body mass index [BMI] .
50 kg/m2) (1). As weight increases, so do the health conse-
quences, including those related to the respiratory system.
Obesity hypoventilation syndrome (OHS) refers to the appear-
ance of awake hypercapnia (PaCO2 . 45 mm Hg) in the obese
patient (BMI . 30 kg/m2) after other causes that could account
for awake hypoventilation, such as lung or neuromuscular
disease, have been excluded. Although sleep-disordered breath-
ing is not currently part of the basic definition of OHS, breath-
ing during sleep in these individuals typically encompasses
a number of polysomnographic defined phenotypes, including
(Received in original form August 15, 2010; accepted in final form October 28, 2010)
Supported by National Health and Medical Research grants, Health Professional
Research Fellowship grant 245523 (A.J.P.) and Practitioner Fellowship grant
202916 (R.R.G.), and Centre for Clinical Research Excellence grants 264598 and
571241 (R.R.G.).
Correspondence and requests for reprints should be addressed to Amanda Piper,
Ph.D., Sleep Unit, Level 11, Building 75, Royal Prince, Alfred Hospital, Missenden
Road, Camperdown, NSW 2050 Australia. E-mail: ajp@med.usyd.edu.au
This article has an online supplement, which is accessible from this issues table of
contents at www.atsjournals.org
Am J Respir Crit Care Med Vol 183. pp 292298, 2011
Originally Published in Press as DOI: 10.1164/rccm.201008-1280CI on October 29, 2010
Internet address: www.atsjournals.org
repetitive frank obstructive sleep apnea (OSAS) with hyper-
capnia, flow limitation causing obstructive hypoventilation,
through to hypoventilation in all sleep stages (2). Sleep hypo-
ventilation alone does not define OHS unless daytime hyper-
capnia is also present. However, it is possible that obese patients
with hypoventilation during sleep without awake hypercapnia
have a prodromal form of OHS and will later develop chronic
hypercapnia. This may be similar to the clinical scenario
observed in patients with sleep-disordered breathing and neu-
romuscular disease (3).
The incidence of OHS increases significantly as obesity
increases, with a reported prevalence of around 10 to 20% in
outpatients presenting to sleep clinics (46) to almost 50% of
hospitalized patients with a BMI greater than 50 kg/m2 (7).
Current estimates suggest that around 0.3 to 0.4% of the
population may have OHS (8, 9). However, the accuracy of
prevalence data has been limited by inclusion of multiple small
studies, failure to exclude some patients with chronic obstruc-
tive pulmonary disease, and variable definitions of obstructive
sleep apnea (8). There are no prospective observational cohort
studies investigating which patients with OSA will develop OHS
with weight gain. Nevertheless, it is reasonable to assume there
are several hundred thousand individuals in the United States
with OHS. In this review, we highlight the pathophysiology that
determines which patients with obesity develop awake hypo-
ventilation and the clinical impact of OHS. Recent data on
management approaches are also discussed. The review em-
phasizes the importance of early detection and intervention in
patients with OHS, considering the substantial morbidity and
mortality associated with this disorder.
WHICH PATIENTS ARE LIKELY TO DEVELOP OHS?
One of the more intriguing aspects of the interaction of re-
spiratory function and obesity is that only some morbidly obese
patients develop awake hypoventilation. There are clearly specific
differences between obese individuals who maintain normal
ventilation awake and asleep, those who develop sleep-disordered
breathing with normal daytime ventilation, and those who exhibit
awake hypercapnia in the absence of lung or neuromuscular
disease. These interindividual differences are complex, reflecting
the diverse impact of obesity on breathing (10).
Respiratory Mechanics
Obesity, particularly when it is severe, is associated with signif-
icant changes in pulmonary mechanics and respiratory muscle
performance. However, many of these effects are magnified in
those obese patients who develop OHS compared with equally
obese individuals either with or without sleep-disordered breath-
ing (Table 1) (11). Breathing at abnormally low lung volumes
reduces chest wall and respiratory system compliance (12, 13)
and increases airway resistance (14). When expiratory reserve
Concise Clinical Review 293

TABLE 1. COMMONLY REPORTED PHYSIOLOGICAL DIFFERENCES BETWEEN OBESITY HYPOVENTILATION SYDROME AND EUCAPNIC
SEVERELY OBESE SUBJECTS
Obesity Hypoventilation Eucapnic Morbid Obesity References

FEV1/FVC Normal Normal 4, 7, 8, 10, 11, 18, 22, 62

Total lung capacity Slightly reduced Normal 4, 8, 11, 30, 31, 59, 62
Functional residual capacity Reduced Reduced 10, 13, 15, 31
Vital capacity Markedly reduced Normal/reduced 4, 5, 8, 16, 17, 30
Expiratory reserve volume Markedly reduced Reduced 15, 30, 62
Respiratory system compliance Markedly reduced Reduced 12, 16
Work of breathing Significantly increased Increased 16, 17
Respiratory drive Normal Increased 16, 2931
Inspiratory muscle strength Reduced Normal 16, 30
Ventilatory response to CO2 Normal/reduced Normal/increased 18, 30, 32, 33, 35
PaCO2 Increased/markedly increased Normal 6, 7, 11, 16, 17, 3133, 52
Serum bicarbonate Increased Normal 6, 7, 16, 31, 33
Leptin Markedly increased Increased 38

Adapted from Reference 81.

volume is low, small airway closure and air trapping occur,
resulting in expiratory flow limitation and the development of
intrinsic positive end-expiratory pressure (15). These changes are
more marked in the supine position and contribute to the
increased work of breathing by imposing a threshold load on
the inspiratory muscles (15, 16). It is not known whether the
development of intrinsic positive end-expiratory pressure is
greater in patients with OHS compared with equally obese
eucapnic individuals. However, it has been shown that the work
of breathing in sitting and supine (awake or in stage II sleep)
positions is significantly higher in patients with OHS compared
with similarly obese eucapnic patients (17).
There are several mechanisms to potentially explain the
greater impairment of respiratory function in OHS. First, in
those with more severe OHS, respiratory muscle performance
may be affected by the biochemical disturbance associated with
hypoventilation (acidosis and hypoxemia). Whether a primary
myopathic process also exists is currently unknown, as detailed
muscle structural analysis has not been performed in individuals
with OHS. Second, patients with OHS have a higher degree of
central fat distribution, as demonstrated by larger neck circum-
ferences and higher waist:hip ratios compared with eucapnic
obese patients or patients with OSAS (11, 18). Central adiposity
results in cephalic displacement of the diaphragm. This pro-
duces inefficient mechanical performance (19), which worsens
when the individual is lying supine. In addition, centrally dis-
tributed weight reduces lung volumes to a much greater degree
than weight deposited peripherally (20). This would contribute to
greater reductions in lung volumes and more marked mechanical
ventilatory constraints, which would increase the work of breath-
ing while reducing respiratory muscle efficiency in patients with
OHS. The distribution of excess weight is also important in gas
exchange with centrally obese individuals, regardless of sex or
BMI, exhibiting poorer gas exchange (21).
airway pressure (CPAP). A significant proportion of patients
with OHS diagnosed initially with sleep hypoventilation alone
will later exhibit OSA if withdrawn from noninvasive ventila-
tion (23). However, there are no large longitudinal studies that
inform on the development of OHS over time, and therefore it
is difficult to exclude the possibility that some patients can de-
velop OHS in the absence of upper airway dysfunction at some
time in the evolution of the disorder. The apnea-hypopnea index
has been shown in some studies to be an independent risk factor
for the development of hypercapnia (6, 8). However, the issue is
likely to be more complex than the frequency of events occurring
during sleep. Other authors have highlighted the importance of
the duration of disordered breathing events relative to the
interapnea period in the development of hypercapnia in patients
with obesity and OSA. When periods of abnormal breathing are
long and the time to restore ventilation is short and/or respiratory
efforts are reduced during the recovery period, acute increases in
CO2 can occur (24).
Recently, a model has been proposed that links this transient
retention of CO2 during apneic events in sleep with the
development of chronic awake hypercapnia (25). A key feature
of this model includes the eventual increase in renal bicarbonate
concentration to buffer these acute overnight increases in CO2. In

The Upper Airway

Despite the clear differences between OHS and eucapnic obese
patients with respect to respiratory function, there are obviously
other factors that influence the emergence of awake hypoventi-
lation, including sleep-disordered breathing.
There is a strong consensus that most patients with OHS
have underlying upper airway obstruction (2, 4, 10, 22). Patients Figure 1. Outline of some of the interactions between factors believed
typically report a past history of snoring and witnessed apneas, to be contributing to the development of hypercapnia in patients with
and approximately 90% demonstrate upper airway obstruction severe obesity. The (1) sign denotes this factor, if normal or increased,
on polysomnogram (4). Daytime symptomatology in OHS, such has a positive influence on maintaining ventilation. The (2) sign
as daytime sleepiness and poor concentration, is similar to that denotes factors that, if reduced or blunted, would contribute to
reported in OSAS. In many instances, OHS will respond to lowered ventilation and eventual hypercapnia. HCVR 5 hypercapnic
relief of upper airway obstruction by nasal continuous positive ventilatory response. Reprinted by permission from Reference 10.
294 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
turn, this results in depression of ventilatory responsiveness to
CO2 during wakefulness, eventually promoting daytime hypo-
ventilation (Figure 1). The greater ventilatory limitations im-
posed by more extreme central obesity and/or the development
of decreased central respiratory drive may initiate the acute
failure to compensate for sleep-disordered breathing. However,
for awake CO2 to emerge, the renal compensatory mechanism
must also be compromised (25). Because the presence of these
risk factors can vary considerably between similarly obese pa-
tients with OSAS, this model helps to explain why only a sub-
group of these individuals develop awake hypercapnia.
Sustained hypoxemia in the absence of obvious upper airway
dysfunction will also occur, and the proportion of sleep time
spent less than 90% (% total sleep time oxygen saturation as
measured by pulse oximetry [SpO2] , 90%) has been shown to
be strongly associated with the development of awake hyper-
capnia (8). Although it is not clear from individual studies
whether hypoxia was the cause or consequence of hypercapnia,
it is possible that hypoxia could interfere with the synthesis of
a number of neurotransmitters involved in central respiratory
control (26, 27). Although not yet studied in OHS, sustained
hypoxia during sleep delays arousal in response to resistive
loading in healthy nonobese males (28) and could contribute to
worsening sleep hypoventilation and CO2 retention.
Ventilatory Drive
Alterations in central respiratory drive also underpin which
obese patient with or without OSAS will develop daytime
hypercapnia. Normally, severe obesity is associated with in-
creased respiratory drive, which assists in maintaining eucapnia
despite abnormal chest wall mechanics and high work of
breathing (16, 29, 30). Those with OHS do not display this
augmented drive (30, 31). In addition, ventilatory responsive-
ness to hypoxia and hypercapnia is diminished (3234) and does
not appear to have a familial basis (35, 36). Rather, this seems
to be an acquired phenomenon, with recent work highlighting
the potential role of hormones or adipokines in this process.
Leptin is a circulating protein produced mainly by adipose
tissue (adipokine) that interacts with hypothalamic receptors to
inhibit eating. The leptin-deficient ob/ob mouse model has
provided some insight into potential mechanisms of OHS.
Compared with wild-type mice and other obese mouse models,
ob/ob mice do not produce functioning leptin and exhibit
features of OHS with impaired respiratory mechanics, de-
pressed ventilatory responsiveness, and awake hypercapnia.
They also have marked reductions in lung volumes, pulmonary
compliance, and abnormal respiratory muscle function (37).
Leptin replacement in these mice reverses their OHS, and in
this way, leptin can be considered a respiratory stimulant.
In humans, leptin deficiency in obesity is extremely rare, and
instead, similar to obesity in wild-type mice, there is a variable
elevation in circulating leptin. Clearly, if these high leptin levels
were biologically active there would be reduced eating and
subsequently weight loss. This is obviously not the case in
human obesity, and the problem instead is leptin resistance.
This may play a role in human obesity-related breathing
disorders, such as OHS or OSA. Therefore, the development
of a resistance to leptin, or perhaps more correctly a central
leptin deficiency, could contribute to the development of
awake hypoventilation by altering respiratory drive output as
well, affecting the mechanical properties of the lungs and chest
wall, attenuating the normal compensatory mechanisms used by
individuals to cope with obesity-related respiratory loads.
Plasma leptin levels are higher in OSAS or OHS compared
with weight-matched control subjects without sleep-disordered
breathing (38, 39). Importantly, leptin levels are a better pre-
VOL 183 2011
dictor of hypercapnia than degree of adiposity (38). Higher
serum leptin concentrations are also associated with both a re-
duced respiratory drive and a reduced response to hypercapnia
in severely obese individuals (40). Until recently, the concept of
using leptin to treat human obesity (and possibly OHS) has
been limited by leptin resistance. New data on possible ways of
overcoming leptin resistance and emerging clinical trials suggest
that in the future using recombinant leptin to reverse OHS may
be possible (41).
Other hormonal mechanisms may also be operative in OHS.
Growth hormone increases ventilatory responsiveness (42).
Lower 24-hour growth hormone levels, as indicated by lower
insulin-like growth factor I (IGF-I) levels, have been observed
in OHS, with a strong negative correlation between IGF-I and
both PaCO2 and bicarbonate reported (33). However, the effect
of recombinant growth hormone on OHS is unknown.
CLINICAL CONSEQUENCES OF OHS
Patients with OHS exhibit lower daytime PaO2 and higher PaCO2
compared with those with morbid obesity or OSAS and thus
spend a greater proportion of sleep time with SpO2 , 90% (4,
11, 43). In turn, this will result in more frequent presentation
with peripheral edema, pulmonary hypertension, and cor pul-
monale (4, 44). Patients with OHS are also more likely to report
moderate to severe dyspnea compared with eucapnic patients
with OSAS (45). However, clinical presentation in OHS may be
identical to patients with OSAS. Consequently, the diagnosis
can be overlooked not only in a sleep clinic population of
patients with chronic stable disease but even during hospitali-
zation for an acute illness (7, 46). Hospitalization rates and
ongoing use of health care service requirements are significantly
higher among patients with OHS compared with morbidly
obese eucapnic patients (47). Despite this high contact with
health care providers, there appears to be a significant delay in
the diagnosis of this disorder and the institution of definitive
therapy unless referral to a respiratory or sleep physician is
made (7, 45, 46).
Although large-scale longitudinal observation data are not
available in untreated OHS, patients with this condition are
more likely than eucapnic obese patients to require admission
to intensive care if hospitalized and are more likely to need
invasive ventilation (7). Furthermore, 18 months after hospital
discharge, mortality was 23% in a group of patients with OHS
compared with 9% in those with uncomplicated obesity (7). In
another study evaluating long term noninvasive ventilation,
almost half those who refused therapy (7/15) had died within
the follow-up period of 50 6 25 months compared with 3 of 54
patients managed with positive pressure therapy (44).
In addition to morbidity and mortality related to respiratory
complications, patients with OHS also exhibit greater cardio-
metabolic morbidity compared with those with OSAS or simple
severe obesity. Rates of systemic hypertension, congestive heart
failure, cor pulmonale, and angina are higher among patients
with OHS compared with those with eucapnic obesity (47, 48).
Patients with OHS are also characterized by higher insulin
resistance and more frequently are treated by glucose-lowering
medications (18). Given the known interaction of OSA, obesity,
and cardiometabolic disease, these findings in OHS are not
surprising (49, 50). In a recent prospective controlled study, an
increase in the proatherogenic chemokine regulated on activa-
tion, normal T-cell expressed and secreted, lower levels of the
antiatherogenic adipokine adiponectin, and impaired endothe-
lial function were seen in patients with OHS compared with
age- and BMI-matched eucapnic control subjects (18). The
presence of high inflammatory markers before and after treat-
Concise Clinical Review
ment for sleep-disordered breathing in OHS has also been
shown to be a factor associated with poor prognosis in this
population (51).
Symptoms and lifestyle limitations caused by the respiratory
and obesity aspects of OHS have a significant effect on quality
of life (22, 52, 53). These patients experience significant dyspnea
(44, 45) and daytime sleepiness (52), which can impact on both
the physical and mental/social aspects of quality of life (53).
Despite improving gas exchange during sleep and wakefulness
with treatment, many individuals still report low quality-of-life
scores, which may reflect the ongoing impact of comorbidities
present in severe obesity (22). In contrast, in a group of less
obese Japanese patients with OHS (mean BMI 36 6 9 kg/m2),
improvements in all domains of the SF-36, apart from bodily
pain, occurred after 3 to 6 months of CPAP therapy, with post-
treatment scores similar to those reported by nonobese and
healthy subjects (52). Improving quality of life is an important
aspect of intervention in patients with chronic hypoventilation,
including OHS, as there appears to be an association between
health-related quality of life and mortality (54).
At present no classification system for severity of OHS has
been established and generally accepted. However, various
characteristics of the disorder have been suggested by which
severity could be graded, including the degree of awake re-
spiratory failure, BMI, complications related to OHS, or even
the response to initial CPAP therapy (55). The clinical hetero-
geneity of OHS highlights the need for specific characterization
of patient cohorts to better understand the mechanisms un-
derlying this disorder and how this may influence the response
to different therapies (56).
SCREENING AND IDENTIFYING THE PROBLEM
To diagnose OHS, an increased awake PaCO2 is required. How-
ever, because arterial blood gases are not routinely performed
in sleep clinics and laboratories, and chronic presentation may
be similar to uncomplicated OSAS, the disorder can be over-
looked unless clinicians have a high index of suspicion. Recently
published medical guidelines for patients undergoing bariatric
surgery have recognized this issue and recommend that formal
respiratory evaluation, including arterial blood gases, be per-
formed as part of the preoperative assessment in those indivi-
duals with disordered sleep as well as those with super (BMI .
50) obesity (57). Despite such guidelines, there are no data on the
most appropriate cost-effective clinical screening pathway for
detection of OHS in patient populations.
Simple measures, such as pulse oximetry and serum bi-
carbonate, can be readily performed in clinics and serve as
useful screening tools to identify potential candidates with
OHS. A serum bicarbonate 27 mEq/L or greater has been
shown to be highly sensitive (92%) although not specific (50%)
for the presence of an increased CO2, and therefore clinically
a helpful procedure for screening (6). Similarly, PaO2 is gener-
ally less than 70 mm Hg in OHS, particularly in those with more
severe disease (11, 43). Therefore, a pulse oximetry reading of
less than 94% would suggest the need for an arterial blood gas
measurement to clarify the diagnosis (6).
Given the cost and limited facilities for performing full
polysomnography in many countries, there is increasing use of
simplified respiratory monitoring and autotitrating pressure
devices for the diagnosis and treatment of OSAS. Although
current clinical guidelines advise against the unattended titra-
tion of CPAP in OHS (58), it is likely that a proportion of
individuals will be managed in this way simply because the
disorder is not recognized. Although CPAP may be effective in
some patients (2, 22, 43), sustained nocturnal desaturation and
295
hypoventilation may persist in others, resulting in an incomplete
or worsening response to therapy (43, 59). Consequently, it is
important to identify patients with OHS before a CPAP titration
study.
Although monitoring CO2 during sleep using transcutaneous
CO2 is not widely deployed in most clinical centers, the tech-
nique can be of value in documenting the degree to which CO2
is retained, especially during REM sleep. In this way it may be
a useful technique to detect prodromal OHS in obese patients.
It has also been used in severely obese patients during positive
airway pressure (PAP) therapy, demonstrating good agreement
with PaCO2 measured from arterial blood sampling (60), al-
though careful calibration is required to ensure accuracy of
measurements. Nevertheless, there is a lack of evidence from
randomized controlled trials to determine whether the diagnosis
and management of patients with OHS using continuous trans-
cutaneous monitoring of CO2 offers any clinical benefits over
oxygen saturation and awake arterial blood gases measure-
ments alone.
WHAT IS THE BEST THERAPY FOR OHS?
Current treatment approaches for OHS can be broadly classed
into two areas: medical therapies, including PAP therapy de-
signed to treat sleep-disordered breathing and improve nocturnal
gas exchange, and surgical intervention to promote and maintain
weight loss.
Positive Pressure Therapy
Reversal of daytime CO2 can be achieved with CPAP therapy
alone when chronic hypercapnia is largely a consequence of
upper airway obstruction (2, 22, 43). Flow limitation producing
sustained periods of hypoventilation can also occur and again
will respond to CPAP therapy if sufficient pressure levels are
applied (2). In the majority of cases, titration of CPAP will be
the first approach to treatment (22, 61), with the goal of
normalizing oxygen saturation and preventing increases in
nocturnal CO2 levels. Pressure is titrated upward to eliminate
apneas, hypopneas, and snoring and to stabilize oxygen satura-
tion, with a switch to bilevel therapy if sustained desaturation
and elevated CO2 levels persist. During bilevel therapy, the
level of airway pressure delivered during inspiration (IPAP)
and expiration (EPAP) can be adjusted separately, with EPAP
increased to eliminate obstructive events while IPAP is in-
creased above the EPAP level to improve alveolar ventilation.
A pressure difference between IPAP and EPAP of at least 6 to
7cm H2O is generally required (44, 48, 62). In many published
studies, the move to bilevel therapy is undertaken within the
first night of PAP titration if SpO2 of 90% or greater is not
achieved despite the elimination of obstructive events. Based on
this approach, previous reports have suggested that around 20
to 50% of patients with OHS will fail CPAP and require longer-
term management with bilevel therapy (2, 43, 61). However, in
a small study of patients with OHS randomized to either CPAP
or bilevel therapy for a 3-month period, no between-group
differences in awake CO2, compliance with therapy, or daytime
sleepiness were found. This lack of difference was observed
even though 11 of the 18 patients randomized to CPAP therapy
continued to exhibit sustained oxygen desaturation between 80
and 88% during the first night of titration (22). Furthermore,
after 3 months of therapy, only four of these patients continued
to desaturate during sleep despite control of the upper airway,
suggesting that a complete initial response to CPAP therapy
may not be necessary for longer-term resolution of sleep and
daytime hypoventilation. Other work has shown that better
adherence with PAP therapy plays an important role in the
296 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
improvement in CO2 achieved in hypercapnic patients with
OSAS, irrespective of whether CPAP or bilevel therapy is used
(61). After an initial period of bilevel support, some individ-
uals can be effectively managed with CPAP alone (22, 23, 44,
63). Longer-term data will be required to provide treatment
algorithms that explain which patients can be initially man-
aged with CPAP from the outset or switched to this therapy
after a period of bilevel ventilation. Longer-term outcomes
would need to include quality of life, compliance, relapse, or
even mortality.
Longer-term observational studies of bilevel therapy have
consistently reported improved awake blood gases, daytime
sleepiness, and ventilatory responsiveness to CO2, fewer hospi-
talizations, and better quality of life compared with baseline
measures (47, 53). However, there is only limited evidence from
randomized trials comparing clinical outcomes between differ-
ent treatment modalities (22, 59, 64). Limitations of these trials
include the small number of patients studied (1036 patients),
the short-term nature of follow-up (single night to 3 mo), and
comparisons only performed between different types of PAP
(CPAP and bilevel, or bilevel with and without average
volumeassured pressure support ventilation), in groups with
relatively mild OHS based on daytime CO2 levels. The extent to
which the findings of these small randomized trials can be
applied to the broader OHS population requires confirmation in
larger multicenter studies. Several studies have reported higher
discontinuation rates among females compared with males with
OHS (44, 48), although the reasons for this are unclear. Given
the significantly higher mortality rate reported for patients with
untreated OHS compared with those continuing on therapy (7,
44), identifying causes and ensuring alternate therapy options
are offered to noncompliant PAP patients is important.
A substantial number of patients may require oxygen
therapy in addition to PAP initially to maintain SpO2 greater
than 90% (22, 44, 61), but once effective nocturnal ventilation is
established, this need decreases significantly. However, sub-
optimal oxygenation (defined by percentage of recording time
with SpO2 , 90%) both during wakefulness and sleep can be
present in some individuals despite improved daytime blood
gases, and although this did not translate into greater dyspnea
or daytime sleepiness in one study (63), daytime hypoxemia
both before and persisting after the initiation of PAP therapy
has been shown to be an independent predictor of poor survival
in OHS (51). To date, outcomes research in OHS has been
limited by lack of agreement on endpoints of therapy. We do
not really know what constitutes a normal awake PCO2 level in
these patients or what represents an acceptable or safe level of
oxygen desaturation level during sleep. One important future
research agenda is to define and provide evidence supporting
treatment goals in patients with OHS.
Even when patients are adherent to PAP therapy, up to 25%
may remain hypercapnic with an awake CO2 greater than 45 mm Hg.
This needs to be qualified, because adherence is frequently
defined as more than 4 or 4.5 hours of PAP therapy during sleep
(61). Given that the average sleep length in most individuals is
at least 6 to 7 hours per night, some adherent patients will be
exposed to residual hypoventilation, and therefore incomplete
reversal of awake hypercapnia may occur. In cases in which
severe daytime gas exchange abnormalities persist, or the patient
is intolerant of mask PAP therapy, alternate treatment options
need to be considered.
Tracheostomy
A reduction in nocturnal obstructive events and normalization of
awake CO2 can be achieved in some patients with severe OHS
VOL 183 2011
after undergoing a tracheostomy (65, 66). However, daytime
hypoventilation may persist (65, 66), whereas in others external
blockage of the tracheostomy by excess adipose tissue around the
neck can also occur (67). Therefore, although a tracheostomy may
be needed in a small subset of patients with OHS who are
intolerant of mask PAP therapy and who exhibit life-threatening
complications, it may not be a viable long-term option for therapy.
Bariatric Surgery
Early case studies reported significant improvements in lung
function, central respiratory drive, and daytime CO2 with
weight loss achieved through dietary management (68, 69).
Although weight loss is an important long-term goal in the
management of OHS, it is often difficult to achieve and main-
tain by medical management, and although sleep-disordered
breathing is often improved it is rarely cured.
Bariatric surgery is the most effective approach to achieving
more substantial degrees of weight loss and maintaining this loss
over longer periods (70). Although a number of studies have
shown significant improvements in lung volumes, especially
expiratory reserve volume (71, 72), and gas exchange (73) can
be achieved with surgical weight loss, few of these studies have
specifically looked at outcomes in patients with OHS (71, 74).
Most commonly, bariatric surgery is performed in morbidly
obese women, in whom the prevalence of OHS is lower than in
men (45). In a study looking at the prevalence of sleep-
disordered breathing in consecutive premenopausal women
presenting for bariatric surgery, 8% of the study group were
found to have OHS (75). However, details regarding postoper-
ative complications and longer-term outcomes were not pro-
vided. Although significant improvements in sleep-disordered
breathing occur after surgical weight loss, a recent metaanalysis
found that the apnea-hypopnea index remained high in many
individuals (76). The presence of persisting sleep-disordered
breathing is often not recognized, and patients may be reluctant
to undergo a postsurgical sleep breathing evaluation if they
perceive their sleep symptoms have resolved (77). Consequently,
this could lead to a substantial number of patients ceasing PAP
therapy prematurely after surgery (78).
The surgical approach to weight loss is being increasingly
used in super obese (BMI . 50 kg/m2) and super-super obese
individuals (. 60 kg/m2) (79, 80). Although significant and
sustained weight loss in these groups was reported, only one in
three patients achieved a reduction in BMI below 40 kg/m2 (79).
The need for and compliance with PAP therapy in these super
obese patients postsurgery has not been addressed, nor have
longer-term cardiovascular outcomes been adequately moni-
tored. Given general data on the relatively low level of com-
plications of bariatric surgery in experienced centers (80),
consideration should be given to more detailed research in-
volving this approach in the long-term management of OHS.
CONCLUSIONS AND FUTURE RESEARCH AGENDA
Although we are developing a better understanding of the
complex interactions involved in the development of OHS,
there is still the need for earlier diagnosis and more effective
management and follow-up strategies. This will require better
understanding of the epidemiology of OHS and particularly
which patients with obesity and sleep-disordered breathing de-
velop this condition over time. The emergence of an increasing
number of super obese individuals will pose management
challenges in the near future. Although improved breathing
during sleep and wakefulness can generally be achieved with
PAP therapy, the lack of large-scale, well-designed studies
evaluating long-term outcomes with various therapies has
Concise Clinical Review
limited the development of evidence-based treatment recom-
mendations. Endpoints of therapy need to be defined by appro-
priate clinical trials. This will require a coordinated multicenter
approach. Given the significant morbidity and mortality associ-
ated with untreated or poorly managed disease, more informa-
tion is needed regarding barriers to using therapy and outcomes
for patients in whom response to therapy is incomplete. Finally,
the extent to which surgical and new nonsurgical weight-loss
approaches impact on longer-term outcomes in OHS compared
with PAP therapy warrants further evaluation.
Author Disclosure: A.J.P. received $1,001$5,000 from ResMed Asia Pacific for
conducting workshops/lectures in 2008 and 2009, up to $1,000 from Respironics
Australia for a 2007 lecture, and up to $1,000 from Weinmann Germany for
a 2007 lecture. R.R.G. received up to $1,000 from Diagnoseit in advisory board
fees; up to $1,000 from Sanofi-Aventis in lecture fees; $50,001$100,000 from
Actelion, $10,001$50,000 from Sanofi-Aventis, $50,001$100,000 forom
Somnomed, and $50,001$100,000 from Fisher-Paykel in institutional grants;
holds $10,001$50,000 in stock or options in Diagnoseit; and received more
than $100,001 from NHMRC Australia and more than $100,001 from the
Australian Research Council.
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