Pulmonary, Sleep, and Critical Care Updates

Update in Sleep Medicine 2010

Babak Mokhlesi1 and David Gozal2
1
Section of Pulmonary and Critical Care Medicine, Department of Medicine, and 2Department of Pediatrics, University of Chicago Pritzker
School of Medicine, Chicago, Illinois

In the course of 2010, the Journal published several original

investigations that relate to sleep-disordered breathing (SDB)
as a multisystem disorder involvement. As in previous years (1,
2), the goal of this update is to highlight some of the seminal
discoveries in the field that will undoubtedly impact on our
understanding of disease mechanisms and consequences.

PATHOPHYSIOLOGY AND DIAGNOSIS OF

SLEEP-DISORDERED BREATHING
To better understand the mechanism by which obstructive apneic
events lead to accelerated desaturations, Sands and colleagues
developed a mathematically derived hypothesis, and tested it in
lambs by simulating recurrent apneas and continuously measuring arterial and mixed venous oxygen saturation and cardiac
output (3). Sands and colleagues demonstrated that in contrast
to isolated apneic events, the primary mechanism behind rapid
and severe recurrent oxyhemoglobin desaturation during recurrent obstructive apnea is that arterial oxyhemoglobin saturation and mixed venous oxyhemoglobin saturation undergo
asynchronous changes during the recurrent apnea and postapnea ventilatory phases leading to a surge in pulmonary oxygen
uptake, and ultimately to depletion of alveolar oxygen stores
starting as soon as the second apneic event. This model substantially helps to explain the important role of mixed venous oxygen
saturation in the pathophysiology and severity of intermittent
hypoxemia seen in patients with SDB (4). To further advance our
understanding of the consequences of chronic intermittent hypoxia, Rukhadze and colleagues investigated whether intermittent hypoxia for 34 to 40 days affected the aminergic innervation
of hypoglossal motor neurons that innervate tongue-protruding
muscles in adult rats (5). Chronic intermittent hypoxiaexposed
rats exhibited a higher density of norepinephrine and serotonin
terminals in the region of the hypoglossal motor nucleus, a finding
that is compatible with the higher level of upper airwaydilating
muscle activity during wakefulness in patients with obstructive
sleep apnea (OSA).
To further elucidate whether there is increased propensity
for central apnea due to ventilatory instability in patients with
OSA, Salloum and colleagues used positive pressure ventilation
during stable human sleep to compare the apneic threshold, CO2
reserve, and controller gain between subjects with and without
OSA (6). Compared with control subjects, subjects with OSA
exhibited increased CO2 chemoreflex sensitivity and lower CO2
reserve, and such findings were improved after 1 month of treat-

Correspondence and requests for reprints should be addressed to Babak

Mokhlesi, M.D., M.Sc., Associate Professor of Medicine, Section of Pulmonary
and Critical Care Medicine, Department of Medicine, University of Chicago
Pritzker School of Medicine, 5841 S. Maryland Avenue, MC 0999, Chicago, IL
60637. E-mail: bmokhles@medicine.bsd.uchicago.edu
Am J Respir Crit Care Med Vol 183. pp 14721476, 2011
DOI: 10.1164/rccm.201101-0140UP
Internet address: www.atsjournals.org

ment with continuous positive airway pressure (CPAP), thereby

resulting in improved ventilatory stability. This finding suggests
that in addition to overcoming upper airway obstruction, adherent
use of CPAP will ameliorate the underlying ventilatory instability,
and can ultimately lead to a decrease in CPAP-emergent central
apneas that occur in up to 15% of patients with OSA during the
initial nights of therapy (7). Similarly, ventilatory instability can
be exacerbated by exposure to a hypoxic environment, for example, high altitude. Bloch and colleagues undertook a field
study in 34 healthy mountaineers climbing to an altitude of 7,546
m over the course of 20 days, and examined whether periodic
breathing persists during prolonged sojourns at high altitudes (8).
The authors demonstrated that over the course of a climb to high
altitude there was progressive hypoxemia and increased minute
ventilation that were associated with an increasing prevalence
of central apneas and hypopneas, a shorter cycle time of periodic
breathing, and a reduced circulatory delay. Moreover, periodic
breathing prevailed during most of the night at high altitude, and
increased further with progressive ascent to higher elevation, in
spite of the improvements in oxygen saturation associated with
acclimatization. In an effort to explore novel therapeutic approaches to central hypoventilation, Kanbar and colleagues set out
to determine whether activation of Phox2b medullary neurons by
photostimulation can selectively stimulate breathing in unanesthesized rats (9). Using a lentiviral approach to transfect Phox2b-positive
neurons, the investigators induced expression of photoactivatable cationic channels, which on targeted photostimulation led
to robust increases in respiratory rate, tidal volume, and diaphragmatic electromyogram (EMG) amplitude with minimal
increases in blood pressure. Although these findings shed insights
into the role of Phox2b in homeostatic respiratory control, further
studies are needed to assess the changes associated with conditions such as obesityhypoventilation in this restricted population
of neurons.
Larkin and colleagues conducted the first candidate gene
study of OSA in European Americans and African Americans by
selecting 52 biologically plausible genes involved in pathways that
are linked to OSA, such as obesity, craniofacial development,
inflammation, and ventilatory control (10). After adjusting for
age, sex, and body mass index, variants of C-reactive protein and
glial cell linederived neurotrophic factor were associated with
the apneahypopnea index (AHI) and the dichotomous OSA
trait (AHI > 15) in European Americans. In African Americans,
only the rs9526240 polymorphism within the serotonin receptor2a (HTR2a) gene was associated with OSA, and the degree of
association was attenuated after adjusting for body mass index,
suggesting that HTR2a exerts its influence on OSA via body
weight. These findings are of interest because glial cell line
derived neurotrophic factor plays an important role in the development of pathways underlying ventilatory control, and the
potential association of SDB with variants in the C-reactive
protein gene further highlights the role of inflammatory pathways in OSA. Moreover, these initial population-based findings
provide a working framework for future genetic studies in sleep
disorders.

Pulmonary, Sleep, and Critical Care Updates

Waxman and colleagues compared the performance of a large

memory storage and retrieval artificial neural network with
simultaneous polysomnography to predict apneas and hypopneas
in patients with untreated OSA 30 to 120 seconds before the respiratory events occur (11). The neural network performed better
in predicting apneas compared with hypopneas, in predicting
respiratory events during non-REM sleep compared with REM
sleep, and in predicting the event with a 30-second lead time
compared with longer intervals. The submental EMG signal, as
a surrogate of upper airway dilator muscle activity, was the most
useful signal to predict apneas. In contrast, heart rate variability
(a measure of autonomic function) and submental EMG were
useful for predicting hypopneas.

CEREBROVASCULAR, NEUROCOGNITIVE, AND

CARDIOVASCULAR CONSEQUENCES OF
SLEEP-DISORDERED BREATHING
Sleep-Disordered Breathing, Stroke, Cerebrovascular
Function, and Cognition

Adding to the growing body of research implicating OSA in the

pathogenesis of risk factors associated with ischemic stroke,
Redline and colleagues quantified the incidence of ischemic
stroke with sleep apnea in a community-based sample of 5,442
participants without stroke and enrolled in the Sleep Heart Health
Study (SHHS), a longitudinal cohort study with a median followup of 8.7 years (12). Covariate-adjusted Cox proportional hazard
models demonstrated a significant positive association between
obstructive AHI and ischemic stroke in all categories of OSA
severity. In women the obstructive AHI was not significantly
associated with stroke. To further our understanding of the
relationship between SDB and cerebrovascular regulation,
Morgan and colleagues sought to examine the cerebrovascular
responses to hypercapnia in a subgroup of participants from the
community-based longitudinal Wisconsin Sleep Cohort Study
(13). Transcranial Doppler was used to measure cerebral flow
velocity during wakefulness while undergoing a rebreathing test
that raised end-tidal CO2 by 10 mm Hg. They found that mean
arterial oxygen saturation during sleep was an independent
predictor of cerebrovascular CO2 responsiveness. In other words,
individuals with SDB had blunted hypercapnic vasodilation of
the cerebral circulation, and such vascular impairments may be
reversible, in part, with CPAP treatment of OSA. Mehra and
colleagues performed a cross-sectional analysis of the Cleveland
Family Study to examine the association between SDB severity
as measured by the AHI and levels of prothrombotic markers
including plasminogen activator inhibitor-1 and fibrinogen (14).
They found that after adjustment for confounders, both fibrinogen and plasminogen activator inhibitor-1 increase with the
AHI, even at SDB levels considered to be mild (AHI , 15). This
finding adds to the growing body of literature establishing
a strong association between SDB and vascular disease (15, 16).
Obstructive Sleep Apnea, Neurocognition,
and Brain Morphology

To assess the impact of OSA and age on cognitive performance

and brain activation, Ayalon and colleagues studied 14 treatmentnaive patients with sleep apnea and compared them with agematched healthy control subjects (17). After an overnight
polysomnogram, subjects underwent a functional magnetic resonance imaging session that included a sustained attention and
verbal encoding task. Middle-aged patients with OSA (mean age,
53.2 6 3.6 yr) showed reduced performance for word recall,
slower reaction time, and decreased brain activation compared
with younger patients with OSA and control subjects. These

1473

findings suggest that OSA combined with increasing age can

overwhelm the brain capacity to compensate and maintain intellectual performance, supporting the notion of a double insult
for clear manifestations of reduced intellectual capacity to emerge
(18).This study suggests that OSA can augment or accelerate the
typical decline in performance and cognition seen with normal
aging. Although cognitive function has many domains, an important component is memory. Twigg and colleagues performed
a detailed examination of memory function in 60 participants with
OSA and 60 healthy volunteers (19). OSA, including milder
forms of disease, was associated with impairments in verbal but
not in visual memory, and the deficit was independent of a general
attention deficit. To better delineate the impact of OSA on brain
morphology, Morrell and colleagues used voxel-based morphometric analysis of T1-weighted three-dimensional structural magnetic resonance imaging in 60 patients with OSA and compared
them with control subjects (20). Patients with OSA had focal
areas of reduction in gray matter volume compared with nonapneic control subjects, suggesting that OSA can lead to gray
matter loss and contributes to cognitive decline. Taken together,
there is mounting evidence that OSA adversely affects cognitive
function and brain morphology. More studies are needed to
establish whether long-term CPAP therapy can effectively halt
and even reverse these abnormalities.
To examine whether moderate daily physical activity can
attenuate spatial learning deficits and central nervous system
oxidative stress induced by intermittent hypoxia during sleep,
Gozal and colleagues randomly assigned young adult rats to
either 3 months of normal activity or physical activity, and then
exposed them to either normoxia or intermittent hypoxia during
the last 14 days (21). The water maze technique was used to
quantify spatial learning. In contrast to normal activity combined
with intermittent hypoxia exposure, rats exposed to physical
activity and intermittent hypoxia did not develop learning and
memory deficits, and had reduced oxidative stress in the brain.
Further validation studies in humans are needed to confirm the
novel concept that regular physical activity can be used to
attenuate the neurocognitive and cardiometabolic consequences
of OSA.
Sleep-disordered Breathing and
Cardiovascular Consequences

Endothelial dysfunction is a preclinical vascular abnormality

that has been shown to precede the development of subsequent
vascular disease and atherosclerosis. Numerous studies have
demonstrated endothelial dysfunction in patients with OSA.
Patt and colleagues evaluated the microcirculation of seven
patients with OSA (AHI . 15) without any cardiovascular risk
factors and compared it with that of age- and weight-matched
control subjects (22). Endothelial function as determined by the
brachial artery flowmediated dilation technique, forearm subcutaneous biopsy, and isolation of microcirculatory endothelial
cells was performed at baseline and after 12 weeks of CPAP
therapy. Subjects with OSA had reductions in flow-mediated
dilation and CPAP therapy improved endothelial function.
The long-term effect of CPAP in hypertensive patients with
sleep apnea was examined in two large randomized-controlled
trials by the Spanish Sleep and Breathing Group. In the first
study CPAP treatment decreased systolic blood pressure by
1.89 mm Hg (P 5 0.06) and diastolic blood pressure by 2.19 (P 5
0.0008), with the most significant decrease in blood pressure
being achieved in patients who used CPAP for more than 5.6
hours per night (23). In the second study CPAP decreased mean
24-hour blood pressure by 1.5 mm Hg (P 5 0.01). Mean nocturnal
blood pressure dropped by 2.1 mm Hg (P 5 0.01) (24). In another
randomized controlled cross-over trial, Pepin and colleagues

1474

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE

compared the effect of CPAP treatment with the effect of the

antihypertensive valsartan in reducing mean 24-hour ambulatory blood pressure in untreated hypertensive patients diagnosed with OSA (25). Twenty-three patients were randomly
assigned to either CPAP or valsartan for 8 weeks and then, after
a 4-week washout period, were crossed over to the other arm of
the trial. The change in 24-hour mean blood pressure in the
CPAP arm was 22.1 6 4.9 mm Hg (P , 0.01) and 9.1 6 7.2 mm
Hg in the valsartan arm (P , 0.001), and these differences were
significant for both daytime and nighttime blood pressure. The
difference between the two groups was 27.0 mm Hg (95%
confidence interval, 10.9 to 23.1 mm Hg). Taken together, the
evidence from randomized controlled trials suggests that CPAP
has a small, albeit statistically significant, beneficial effect on
systemic blood pressure in hypertensive individuals with OSA.
The clinical relevance of this degree of reduction in blood
pressure remains uncertain.
Both SDB and air pollution have been linked to increased
risk of cardiovascular events. To test the biological plausibility
of whether elevated ambient pollution is associated with an
increased risk of SDB and nocturnal hypoxemia, Zanobetti and
colleagues used the available data from the SHHS cohort to
elucidate whether particulate air matter less than 10 mm in
diameter (PM10) is associated with sleep quality and indices of
SDB (26). During summertime, increases in PM10 were associated with increases in respiratory disturbance index, in percentage of sleep time below 90% oxygen saturation, and with reduced
sleep efficiency. Whether reduction in air pollution exposure
leads to decreases in the severity of SDB will require further
research.

CLINICAL CONSEQUENCES OF INSUFFICIENT SLEEP

AND OBSTRUCTIVE SLEEP APNEA
Metabolic Consequences of Insufficient Sleep and
Obstructive Sleep Apnea

To better define the role of insufficient sleep in energy intake

and expenditure, Nedeltcheva and colleagues performed a randomized cross-over study in 10 overweight middle-aged adults
to determine whether sleep restriction will attenuate the effect
of a reduced-calorie diet on excess adiposity (27). They found
that compared with 8.5 hours of time in bed, 14 days of sleep
curtailment to 5.5 hours in bed decreased the proportion of weight
lost as fat by 55%, and was accompanied by enhanced neuroendocrine adaptation to caloric restriction, and increased hunger. In
other words, although the subjects consumed the same amount
of daily calories, reduction in sleep duration adversely affected
the fat-derived weight loss. This suggests that sleep curtailment
will attenuate the effect of reduced-calorie diets on excess adiposity, and compromise the efficacy of typical dietary interventions
for weight loss and metabolic risk reduction.
To further examine the impact of untreated OSA on glucose
control in type 2 diabetes, Aronsohn and colleagues measured
hemoglobin A1c in 60 consecutive patients with diabetes. OSA
(AHI > 5) was present in 77% of patients with type 2 diabetes
and 38% of the patients had moderate or severe OSA (AHI >
15) (28). Compared with patients without OSA, the adjusted
mean hemoglobin A1c was increased by 1.49% in patients with
mild OSA, 1.93% in moderate OSA, and 3.69% in severe OSA.
These findings complement other studies that have reported
a high prevalence of OSA in obese patients with type 2
diabetes, and highlight the urgent need for further randomized
controlled studies evaluating the role of CPAP (with objective
adherence measurements) in improving glycemic control in type
2 diabetes.

VOL 183

2011

Impact of REM-related Sleep-Disordered Breathing on

Sleepiness and Quality of Life

The prevalence of REM-related OSA based on a limited

number of small-scale studies has been quite variable, ranging
from 10 to 25% of the patient population with OSA undergoing
polysomnography in clinical sleep laboratories. Investigators
from the SHHS performed a cross-sectional analysis of 5,649
participants to determine whether obstructive respiratory events
in REM sleep are independently associated with subjective
measures of sleepiness and quality-of-life measures (29). They
found that after adjusting for non-REM AHI and other covariates, REM AHI was not associated with measures of sleepiness,
quality of life, or difficulty maintaining sleep or early awakenings.
However, the cardiometabolic impact of REM-related obstructive respiratory events was not assessed in this study. Therefore,
whether individuals with REM-related OSA should be treated
and would benefit from CPAP therapy will remain a source of
intense debate and controversy. Given the high prevalence of
REM-related OSA, further research is needed to establish
evidence-based management guidelines to appropriately treat
these frequently occurring patients.
Obstructive Sleep Apnea and Chronic Obstructive Pulmonary
Disease: the Overlap Syndrome

In a longitudinal cohort study, Marin and colleagues monitored

228 patients with overlap syndrome (chronic obstructive pulmonary disease [COPD] and OSA) treated with CPAP, 213
patients with overlap syndrome not treated with CPAP, and 210
patients with COPD but without OSA (30). All patients were
free of prior cardiovascular disease such as myocardial infarction,
heart failure, and stroke. Median follow-up was 9.4 years. After
adjusting for multiple important covariates, patients with overlap
syndrome not treated with CPAP had a higher mortality rate
(relative risk, 1.79; 95% confidence interval, 1.162.77) and were
more likely to be hospitalized for COPD exacerbations when
compared with patients with only COPD. Moreover, patients
with overlap syndrome treated with CPAP had no increased
mortality risk or COPD exacerbation risk compared with patients
with COPD only. These findings highlight the fact that untreated
OSA worsens outcomes in patients with overlap syndrome above
and beyond the anticipated effect of COPD, and that effective
treatment with CPAP is associated with improved outcomes.

PEDIATRIC SLEEP MEDICINE

Neurocognitive and Cardiovascular Consequences of
Pediatric OSA

As in adults, pediatric OSA is a prevalent condition that is

associated with multisystem disorder involvement. OSA independently increases the risk for neurocognitive deficits, reduced academic performance, and cardiovascular and metabolic
morbidities. However, the development of neuropsychological
deficits and cardiovascular morbidity is not a universal finding in
children with OSA. It also remains unclear whether those children
with evidence of one end-organ morbidity are at increased risk for
another. To further elucidate this relationship, Gozal and colleagues performed both cognitive and endothelial function tests in
87 consecutive children with OSA and 21 control subjects (31).
Approximately one-third of the children did not have neurocognitive deficits or endothelial dysfunction despite having similar
degrees of disease severity. Endothelial dysfunction was highly
predictive of neurocognitive status. Among the 50 children with
endothelial dysfunction, 80% had neurocognitive deficits, with
a degree of concordance between these two end-organ morbidities of 79.3% (P , 0.00001). This suggests that endothelial

Pulmonary, Sleep, and Critical Care Updates

and neurocognitive dysfunction may share similar pathophysiological mechanisms. Confirming the presence of endothelial
dysfunctiona substantially less labor-intensive test than neuropsychological testingmay provide a reasonable prediction
of OSA-related neurocognitive deficits. Indeed, there is a growing body of literature linking OSA with alterations in the microvasculature, including the cerebral vasculature (see above).
However, there is evidence for substantial variability in the
vascular phenotype that cannot be accounted for solely by the
usual indices of OSA severity. To better understand the reasons
behind such variability in manifesting endothelial dysfunction
in children with OSA, Kheirandish-Gozal and colleagues performed measurements of endothelial function after an overnight polysomnogram and also measured endothelial progenitor
cells in blood (32). They compared 80 children with OSA with
20 matched control subjects. As anticipated, they found significant variability in endothelial dysfunction in OSA. The novel
finding was that endothelial dysfunction in children with OSA
was closely associated with the levels of circulating endothelial
progenitor cells and with the plasma levels of stromal cell
derived factor-1, a chemokine involved in the recruitment of
progenitor cells. Thus, the ability to recruit endothelial repair
mechanisms may play a role in the variance of the endothelial
functional phenotype associated with OSA.
Treatment of Pediatric OSA

At present, adenotonsillectomy is the main form of treatment of

pediatric OSA. However, its overall efficacy in children remains
unknown. To that end, Bhattacharjee and colleagues performed
the largest multicenter retrospective study to date to quantify
the effect of adenotonsillectomy on indices of sleep-disordered
breathing, and to determine predictors of residual disease (33).
The cohort consisted of 578 children with a mean age of 6.9 6
3.8 years. Adenotonsillectomy resulted in a significant reduction
in AHI from 18.2 6 21.4 to 4.1 6 6.4 (P , 0.001). However,
only about 27% of children had complete resolution of OSA
defined as an AHI less than 1. The two most important
predictors of postoperative AHI were age and body mass index,
with presurgical AHI and asthma being significant in nonobese
children only. From this and previous studies, it becomes
apparent that despite substantial improvements after adenotonsillectomy, normalization of the respiratory patterns during sleep
is well below previous expectations. Therefore clinicians should
strongly consider obtaining a postoperative polysomnogram,
particularly in those at high risk of residual OSA such as
children above the age of 7 years and obese children. Nonobese
children should also be reevaluated if they had severe OSA at
baseline. This study underscores the need to formulate management strategies after adenotonsillectomy in children with
residual OSA. Given the suboptimal efficacy of adenotonsillectomy, there is a need to develop novel nonsurgical therapeutic
targets in children with OSA. Accordingly, Khalyfa and colleagues integrated genome-wide expression analysis with novel
bioinformatics methods to identify putative functional networks
involved in the proliferation and hypertrophy of adenotonsillar
tissues (34). Tonsillar tissues were obtained from children with
OSA and children with recurrent tonsillitis without OSA,
and in vitro studies using a mixed tonsil cell culture system
were performed. Using a systems biology approach, they identified a restricted set of candidate genes involved in adenotonsillar hypertrophy. Khalyfa and colleagues showed that
one of these genes, namely, phosphoserine phosphatase, was
more abundantly expressed in the tonsils of children with OSA,
and that in vitro pharmacological inhibition led to marked reductions in T- and B-cell lymphocyte proliferation and increased
apoptosis.

1475
Author Disclosure: B.M. has received consultancy fees from Philips/Respironics.
D.G. has received consultancy fees from Galleon Pharmaceuticals

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