SLEEP DISORDERS / Hypoventilation 85
Severinghaus J and Mitchell RA (1962) Ondine’s curse – failure of
respiratory center automaticity while awake. Clinical Research
10: 122.
Weese-Mayer DE and Berry-Kravis EM (2004) Genetics of congenital central hypoventilation syndrome. American Journal of
Respiratory and Critical Care Medicine 170: 16–21.
Hypoventilation
F Han, Beijing University, Beijing, People’s Republic of
China
& 2006 Elsevier Ltd. All rights reserved.
Abstract
Alveolar hypoventilation, defined as a partial arterial CO2 pressure (PaCO2 ) above 45 mmHg, develops in patients with breathing control defects, respiratory neuromuscular diseases, chest
wall deformity, or lung and airway disorders. The impact of
sleep on ventilation and gas exchange in these patients can be
dramatic and potentially life threatening, and often is undetected. Associated with hypercapnia is hypoxemia and sleep disturbance, leading to clinical features manifested primarily in
central nervous system and cardiovascular effects. Symptoms
usually include dyspnea, morning headache, and excessive daytime sleepiness. Clinical examination may be normal or uncover
erythrocytosis, pulmonary hypertension, cor pulmonale, or respiratory failure. Lung function tests can generally distinguish
among underlying chest diseases causing hypoventilation, and a
polysomnogram is helpful to characterize the presence of and
type of sleep disordered breathing, such as sleep apnea, hypopnea, and sleep hypoventilation. Optimum management
includes treating the underlying condition(s) and providing, as
appropriate, oxygen and/or noninvasive positive pressure
ventilation (NPPV) applied via a nasal or facial mask. Administration of NPPV only during sleep to prevent sleep-related
deterioration of ventilation often produces a dramatic improvement in daytime symptoms and blood gas levels in most cases.
Introduction
Hypoventilation is defined as an increase in partial
arterial CO2 pressure (PaCO2 ) to a level above
45 mmHg. The concomitant hypoxemia leads to
clinical sequelae such as erythrocytosis, pulmonary
hypertension, cor pulmonale, or respiratory failure,
which is referred to as hypoventilation syndrome.
Prevalence of hypoventilation is currently unknown.
The idiopathic form is rare. However, almost all disorders that result in awake hypercapnia are complicated by sleep hypoventilation. A recent study
showed that the prevalence of obesity hypoventilation syndrome (OHS) among hospitalized adults
with BMI of more than 35 is as high as 31% and is
associated with excess morbidity and mortality, but
in the majority of cases the condition has not been
recognized by cargivers.
Etiology and Pathogenesis
Hypoventilation is generally a consequence of obstructive pulmonary disease but can also develop in
patients with normal lungs. The underlying mechanisms involve a defect in the central or peripheral
respiratory control system, the respiratory neuromuscular system, or the mechanical apparatus (Table
1). In most cases, more than one mechanism is responsible. Sleep has a profound effect on hypoventilation. Pre-existing hypercapnia and hypoxemia
deteriorate during sleep, especially during the rapid
eye movement (REM) sleep stage. In some, clinically
significant hypoventilation not associated with distinct apneas and hypopneas develops only in sleep.
When chemoresponsiveness is markedly reduced or
absent, hypoventilation may develop in the absence of
chest wall, neuromuscular, or lung disease. The attenuation of the respiratory drive can be inherited or acquired. Drug use, chronic hypoxia and hypercapnia
exposure, or diseases affecting the brainstem or peripheral chemoreceptors can produce depressed chemoresponsiveness. Hypothyroidism lowers respiratory
drive and is a frequently overlooked cause of hypoventilation. However, patients with primary alveolar
hypoventilation (PAH) may have no known underlying disease. In such cases, responses to chemical
stimuli are impaired, but patients can normalize the
PaCO2 by voluntary hyperventilation while they are
awake. During sleep, with the decrease of stimulus
from the behavioral control system, there is a further
reduction in ventilation, and in particular in nonrapid
eye movement (NREM) sleep stages 3 and 4. The
defect in these patients seems to be the inability to
centrally integrate chemoreceptor signals. Congenital
central hypoventilation syndrome (CCHS) is a rare
disease of childhood. Mutations in the PHOX2B gene
may have a role in the pathogenesis of CCHS. This
pathway may operate in the pathophysiology of adult
PAH as well.
Patients with primary disorders of the spinal cord,
respiratory nerves, and respiratory muscles develop
hypoventilation because the neural output from the
brainstem respiratory center cannot always fully
compensate for the muscle weakness. Generally,
marked hypoventilation does not occur unless the
function of the diaphragm is significantly ( 80%) impaired. REM sleep is one potentially vulnerable time
for hypoventilation in these patients as there is a
generalized postural muscle atonia in accessory muscle like the sternocleidomastoid, and breathing
becomes dependent solely on diaphragm activity.
Therefore, the initial nocturnal hypoventilation and
eventual daytime respiratory failure in almost all
of the patients with neuromuscular diseases is first
86
SLEEP DISORDERS / Hypoventilation
Table 1 Disorders affecting specific components of the respiratory system
Disorder
Central control depression
Drugs
Metabolic alkalosis
Central alveolar hypoventilation
Primary alveolar hypoventilation
Chronic hypoxia/hypercapnia exposure
Hypothyroidism
Affected components of respiratory system
Narcotics, alcohol, barbiturates, benzodiazepines, anesthetics
Encephalitis, trauma, hemorrhage, tumor, stroke, degeneration,
demyelinating
Genetics
COPD, sleep disordered breathing, high altitude
Neuromuscular diseases
Spinal cord injury
Anterior horn cell diseases
Peripheral neuropathy
Myoneural junction disease
Myopathy
Postpolio syndrome, amyotrophic lateral sclerosis
Guillain–Barré, diphtheria, phrenic nerve damage
Myasthenia gravis, anticholinesterase poisoning, curare-like drugs, botulism
Duchenne muscular dystrophy, polymyositis
Mechanical apparatus disorders
Chest wall deformities
Upper airway obstruction
Lower airway and lung diseases
Kyphoscoliosis, fibrothorax, thoracoplasty, obesity hypoventilation
Sleep apnea, goiter, epiglottitis, tracheal stenosis
COPD, cystic fibrosis
evident during REM sleep. Factors contributing to
the rate of progression of hypoventilation from isolated REM events to NREM sleep, and then frank
daytime respiratory failure include the pattern of initial respiratory muscle weakness, the rate of progression of underlying disease, age, weight gain, and
development of acute respiratory infections.
Patients with diseases of the lungs, airways, or chest
wall develop alveolar hypoventilation because of the
increased work of breathing. The most common example is chronic obstructive pulmonary disease
(COPD). In addition to a substantial decrease in pulmonary function, abnormalities in ventilatory control,
reduced strength and endurance of the respiratory
muscles, and the alterations in breathing pattern are
all responsible for the development of CO2 retention.
During sleep, patients with COPD may experience
significant nocturnal O2 desaturation (NOD), either
because of increased ventilation-perfusion matching
or because of sleep-induced hypoventilation. Massive
obesity represents a mechanical load to the respiratory
system and reduces the compliance of the chest wall;
however, weight is not the sole determinant of the
occurrence of obesity hypoventilation. The majority
of obese individuals maintain a normal PaCO2 level
through a compensatory increase in respiratory drive.
Only a small proportion with reduced chemoresponsiveness retains CO2. Hypoventilation can be improved purely by increasing respiratory drive without
altering the mechanical properties of the respiratory
system. Recent studies showed that leptin-deficient
ob/ob mice demonstrate hypoventilation before the
onset of marked obesity. Such animals have an
impaired hypercapnic ventilatory response during
both wakefulness and sleep, and this abnormality exists before the development of obesity. Furthermore,
leptin infusion reverses both hypoventilation and the
hypercapnic response. In humans, serum leptin level is
as good or a better predictor than percent body fat for
the presence of hypercapnia. That sleep-disordered
breathing plays a role in daytime hypoventilation has
been suggested by the fact that obstructive sleep apnea
occurs not only in most patients with OHS, but also in
some with hypercapnia and mild obesity, and in many
cases daytime hypoventilation resolves after effective
treatment of OSA with continuous positive airway
pressure (CPAP) during sleep. How a disorder that
occurs during sleep eventually produces diurnal hypercapnia is not well defined. A key element might be
that chronic intermittent hypoxia and hypercapnia
and sleep deprivation interact to result in blunted
diurnal respiratory control. This vicious cycle results
in decrementing responsiveness of the respiratory centers, leading to daytime hypoventilation. Short-term
CPAP treatment in hypercapnic patients with OSA
will reset chemosensitivity.
Clinical Features
The fundamental disturbance in all hypoventilation
syndromes is an increase in PaCO2 and a decrease in
PaO2 . As hypercapnia and hypoxia occur in combination, it is often difficult to distinguish which is the
primary cause of the clinical presentations. The clinical features are manifested primarily in central nervous system and cardiovascular effects (Figure 1). In
SLEEP DISORDERS / Hypoventilation 87
Primary
events
Secondary
pathophysiological changes
Clinical features
Decreased
alveolar ventilation
Dyspnea
Hypercapnia
hypoxemia
HCO3−
Erythropoiesis
O2 desaturation
Apnea, hypopnea, and
hypoventilation
during sleep
Pulmonary vasoconstriction
Cerebral vasodilation
Arousal from sleep
Cyanosis, polycythemia
Pulmonary hypertension
Cor pulmonale
Peripheral edema
Morning headache
Sleep disturbance
Daytime hypersomnolence
Confusion, fatigue
Figure 1 Pathophysiological changes and clinical features in patients with hypoventilation. Adapted from Philipson EA and Sluteky AS
(2000) Hypoventilation and hyperventilation syndromes. In: Murray JF and Nadel JA (eds.) Text book of Respiratory Medicine, 3rd edn.,
pp. 2139–2152. Philadelphia: Saunders, with permission from Elsevier.
the early stage, patients with hypoventilation experience minimal, if any, respiratory discomfort. In
many cases, sleep disturbance and the effects of sleep
deprivation such as lethargy, confusion, morning
headache, fatigue, and sleepiness dominate the clinical presentation. When hypoventilation progresses,
dyspnea on exertion, followed by dyspnea at rest, is
the most frequent symptom in patients with neuromuscular diseases or mechanical apparatus disorders.
In contrast, patients with impaired chemoresponsiveness generally do not show dyspnea, and often
first come to attention due to other clinical presentations. If hypercapnia and hypoxia become more
evident, patients develop signs of cardiovascular
decompensation, including pulmonary hypertension
and right heart failure or neurocognitive dysfunction.
Other clinical features are related to the specific underlying disease. For example, significant muscle
weakness, impaired cough, and repeated lower
respiratory tract infections may occur in the course
of neuromuscular disorders.
Diagnostic Evaluation
The evaluation of a patient with hypoventilation
syndrome includes tests to determine the existence of
alveolar hypoventilation and measurements to identify the medical conditions causing hypoventilation
(Figure 2). The key diagnostic finding for hypoventilation is an elevation of PaCO2 value, which is
usually associated with hypoxemia. However, hypercapnia may not be detected in a single arterial blood
gas analysis, as patients with PAH could hyperventilate voluntarily, thus reducing the PaCO2 level to
normal, and hypercapnia occurs only during sleep in
some patients with sleep hypoventilation syndrome.
Further evidence indicating the presence of chronic
hypoventilation includes an increase in plasma
HCO3 concentration and ECG, chest X-ray,
and echocardiography findings of pulmonary hypertension and right ventricular hypertrophy. An
elevated hematocrit and hemoglobin may be present
as a complication of severe hypoxemia. History and
physical examination may initially suggest the underlying diseases causing hypoventilation, and detail
the severity of complications. Using further pulmonary function tests it should be possible to localize
the failed component of the respiratory system
responsible for hypercapnia. Minute ventilation,
occlusion pressure, and diaphragmatic electromyographic activity have been used as noninvasive measures of central respiratory drive. Impaired responses
88
SLEEP DISORDERS / Hypoventilation
Ascertain the
diagnosis of
hypoventilation
PaCO2 > 45 on ABG
pH and serum HCO3− change
Initial evaluation
History
Initial tests
Physical examination
Identify contributing factors
COPD
CHF
Obstructive sleep apnea
Hypothroidism
Neuromuscular diseases
Smoking
Alcohol
Medications
Measure BMI
Ascertain etiology
Examine upper airway
Chest X-ray
Signs of right heart failure
Signs of left heart failure
TSH
Assess end-organ effect
Musculoskeletal abnormalities
Breathing pattern to assess
diaphragm function
Neurologic examination
EKG
CBC
Echocardiogram
Etiology evaluation
Further evaluations
Polysomnogram
Identify sleep apnea hypopnea
Identify sleep hypoventilation
Pulmonary function tests
Obstructive
Evaluate for
COPD
Restrictive
Normal
Respiratory control
Respiratory drive
Measure MIP, MEP
Hypoxic response
Hypercapnic response
If abnormal
Diaphragm function
Neuromuscular abnormality
If abnormal
Central hypoventilation
PAH
OHS
Figure 2 Evaluation of patients with hypoventilation. ABG, analysis of blood gases; TSH, thyroid-stimulating hormone; EKG, electrocardiogram; CBC, complete blood count.
of these indexes to chemical stimuli during hypoxia
and hypercapnia rebreathing exist in patients with
central control defects or neuromuscular disorders;
however, the former patients can hyperventilate on
command and the latter cannot. Decrease of maximum inspiratory pressure (MIP) and maximum
expiratory pressure (MEP) indicates a global weakness of respiratory muscles. If MIP is low, then
diaphragmatic function should be assessed by measuring transdiaphragmatic pressure. Phrenic nerve
conduction assesses the integrity of the nerve-muscle
unit. Spirometry helps characterize whether the
hypoventilation resulted from a restrictive or obstructive ventilatory disorder.
Neuromuscular disease or chest wall disorders
produces restrictive patterns on spirometric testing,
manifested by a reduction in vital capacity (VC) with
a similar reduction in forced expiratory volume in 1 s
(FEV1). In contrast, COPD patients have a typical
obstructive pattern with marked reductions in FEV1
and forced vital capacity (FVC). An elevated alveolar-arterial PO2 difference [(A-a PO2 )] on blood gas
SLEEP DISORDERS / Hypoventilation 89
tests suggests a mechanical apparatus disorder, and
patients with respiratory control or neuromuscular
defects could maintain a normal A-a PO2 unless they
have significant atelectasis. Patients with hypoventilation should receive a polysomnogram to establish
whether sleep apnea and hypopnea are present. An
increase in PaCO2 during sleep of 10 mmHg from
awake supine values and sustained arterial desaturation lasting up to several minutes during sleep
not explained by apnea or hypopnea events may indicate sleep hypoventilation. Overnight monitoring
of dynamic changes of transcutaneous CO2 and
1
2
3
4
5
6
7
8
0
10
20
30
40
50
60
(a)
Sleep stage
MT
W
R
1
2
3
4
ND
21:30
22:30
23:30
00:30
01:30
02:30
03:30
04:30
Hours
1
2
3
4
5
6
7
21:30
22:30
23:30
00:30
01:30
02:30
03:30
04:30
Hours
1
2
3
4
5
6
7
05:30 06:30
8
Oxygen saturation
100
90
80
70
60
50
Des
05:30 06:06
8
(b)
Figure 3 A 62 year women with a BMI of 29 kg m 2 complained about daytime sleepiness and dyspnea. She has no history of
smoking. Blood gas analysis showed PaCO2 of 58 mmHg and PO2 of 72 mmHg. Lung function test had no remarkable findings. MIP and
MEP were in normal range. Nocturnal oximetry screening indicated the existence of sleep hypoventilation (a) without remarkable sleep
apnea, and this was confirmed by PSG testing (b).
90
SLEEP DISORDERS / Hypoventilation
nocturnal oxygen saturation by oximetry (Figure 3)
is a useful screening test before a polysomnography
(PSG) sleep study.
Treatment
In addition to the treatment of an underlying disorder, therapeutic strategies for patients with chronic
hypoventilaton syndrome aim at correcting the hypercapnia and its associated hypoxemia, which can be
achieved by either increasing alveolar ventilation or
giving supplemental oxygen.
Oxygen Therapy
As long as pH is maintained at an acceptable level,
chronic hypercapnia by itself generally has little
immediate clinical consequence. The most serious
consequence of hypoventilation is hypoxemia. The
administration of supplemental oxygen may improve
oxygenation, and prevent hypoxic sequelae. However, high concentrations of oxygen may worsen
hypercapnia, potentially to a dangerously high level,
and ventilatory support should be considered. This
happens less in patients with defects in respiratory
control than in patients with neuromuscular diseases
and mechanical apparatus disorders. In patients with
sleep hypoventilation, oxygen alone may prevent
NOD, but often results in prolonged breathing
disturbances and worse sleep quality, therefore
worsening the daytime symptoms, such as morning
headache.
Respiratory Stimulants
Medications to improve ventilatory drive have been
used with limited success in patients with alveolar
hypoventilation. The most commonly used agent
is medroxyprogesterone, which effectively lowers
PaCO2 in patients with OHS, but does not appear to
work in patients with OSA who do not have hypercapnia. Acetazolamide enhances respiratory drive
by producing a metabolic acidosis. It may have a role
in the treatment of a subgroup of patients with periodic breathing or idopathic central sleep apnea.
Theophylline administration induces a significant reduction in the frequency of central sleep apnea (CSA)
in patients with chronic heart failure (CHF), but has
an adverse effect on sleep quality, and may increase
cardiac arrhythmia.
Assisted Ventilation
In patients with severe hypoventilation, mechanical ventilation support may be required. Negative
pressure ventilation is the first form of noninvasive
ventilation. This ventilation modality is generally
effective, but can induce upper airway obstruction
in 50% of the patients. Currently positive pressure
ventilation is most often the treatment of choice. Although it could be administered by way of tracheotomy, positive pressure ventilation is usually applied
noninvasively via a nasal or facial mask. CPAP is
effective to suppress sleep apneas, but may worsen
hypercapnia in patients with respiratory muscle weakness because the patient exhales against a high mask
pressure. Bilevel ventilation (BiPAP) with a lower expiratory pressure is more comfortable and better for
correcting CO2 retention. Automatically adjusting
the CPAP (Auto-CPAP) device has the same efficacy
as CPAP on sleep apnea; however, it is not recommended to treat hypoventilation. Sometimes assisted
ventilation on its own may be insufficient to correct
hypoxemia, particularly during REM sleep; the use of
supplemental oxygen has been advocated. In most
cases, assisted ventilation is confined to sleep if
possible, as administration of such treatment only
during sleep often produces dramatic improvement of
daytime symptoms as well as the daytime blood gas
levels.
Electrophrenic or Diaphragm Pacing
Phrenic nerve stimulation has been used as an alternative to long-term mechanical ventilation in patients
with reduced respiratory drive, particularly in those
with PAH. Diaphragm pacing with laproscopically
inserted muscle electrodes has recently become available to support ventilation. Both procedures require
a functionally intact nerve-diaphragm axis; lower
motor neuron disease, phrenic neuropathy, and
respiratory muscle myopathy are contraindications
for this treatment. As occurs in negative pressure
ventilation treatment, approximately 50% of
patients undergoing phrenic or diaphragm pacing
develop upper airway obstruction during sleep.
See also: Sleep Apnea: Continuous Positive Airway
Pressure Therapy; Drug Treatments. Sleep Disorders:
Central Apnea (Ondine’s Curse).
Further Reading
American Academy of Sleep Medicine Task Force (1999) The
Report of an American Academy of Sleep Medicine Task Force
sleep related breathing disorders in adults: recommendations
for syndrome definition and measurement techniques in clinical
research. Sleep 22: 667–689.
Amiel J, Laudier B, Attie-Bitach T, et al. (2003) Polyalanine expansion and frame shift mutations of the paired-like homeobox
gene PHOX2B in congenital central hypoventilation syndrome.
Nature Genetics 33: 459–461.
Krachman S and Criner GJ (1998) Hypoventilation syndromes.
Clinics in Chest Medicine 19: 139–155.
SLEEP DISORDERS / Upper Airway Resistance Syndrome 91
Nowbar S, Burkart KM, Gonzales R, et al. (2004) Obesityassociated hypoventilation in hospitalized patients: prevalence,
effects, and outcome. American Journal of Medicine 116: 1–7.
O’Donnell CP, Tankersley CG, Polotsky VP, Schwartz AR, and
Smith PL (2000) Leptin, obesity, and respiratory function. Respiration Physiology 119: 163–170.
Phillipson EA (2003) Disorders of ventilation. In: Braunwald E
(ed.) Harrison’s Principles of Internal Medicine, 15th edn, pp.
1517–1519. Boston: McGraw-Hill.
Philipson EA and Sluteky AS (2000) Hypoventilation and hyperventilation syndromes. In: Murray JF and Nadel JA (eds.) Textbook of Respiratory Medicine, 3rd edn., pp. 2139–2152.
Philadelphia: Saunders.
Subramanian S and Strohl KP (1999) A management guideline for
obesity-hypoventilation syndromes. Sleep Breath 3: 131–138.
Weinberger SE, Schwartzstein RM, and Weiss JW (1989) Hypercapnia. New England Journal of Medicine 321: 1223–1231.
Upper Airway Resistance
Syndrome
P Lévy, R Tamisier, and JL Pépin, University
Hospital, Grenoble, France
& 2006 Elsevier Ltd. All rights reserved.
Abstract
Obstructive sleep apnea syndrome (OSAS) has been individualized as a major public health problem. Both its cardiovascular
morbidity and symptoms motivate for an accurate diagnosis and
appropriate therapeutics. The upper airway resistance syndrome
(UARS) has been described because of the hypothesis that repetitive increases in respiratory efforts that are inducing arousals (RERA) might produce a significant disease with associated
cardiovascular and cognitive morbidity. International classifications of sleep disorders in 1999 did not individualize UARS but
RERA and in 2005 recommend that it be included as part of
OSAS but not as a separate entity. In this article, the authors
attempt to describe the specificity of this syndrome that may be
relevant for both clinicians and researchers.
Since the obstructive sleep apnea syndrome (OSAS)
has been earmarked as a major public health problem, there have been many efforts in defining and
understanding this syndrome. Some evidence suggests that this disease is not limited to the patient
exhibiting obstructive apnea but includes a continuum from snoring to OSAS that may be part of a
group named sleep-disordered breathing. The upper
airway resistance syndrome (UARS) was reported by
Christian Guilleminault in 1993. This particular syndrome came into being because of the hypothesis that
repetitive increases in respiratory efforts that are
inducing arousals (RERA) might produce a significant disease with associated cardiovascular and cognitive morbidity. The definitions of sleep-disordered
breathing made by the American Academy of Sleep
Medicine (AASM) Task force in 1999 did not include
UARS as a syndrome but did define RERA. Recently
several authors have discussed the existence of this
syndrome and the morbidity that might be related
to RERA. ICSDII published in 2005 is overall in accordance with the AASM task force report published
in 1999. If baseline oxygen saturation is normal,
events including an absence of oxygen desaturation
despite a clear drop in inspiratory flow, increased
respiratory effort and a brief change in sleep state
or arousal, are defined as respiratory effort related
arousals. The UARS is a proposed diagnostic classification for patients with RERA who do not have
events that would meet definitions for apneas and
hypopneas. However, these events are presumed to
have the same pathophysiology as obstructive apneas
and hypopneas (upper airway obstruction) and are
believed to be as much of a risk factor for symptoms
of unrefreshing sleep, daytime somnolence, and
fatigue as frank apnea or hypopnea. Therefore, ICSD
II recommends that they be included as part of OSA
and not be considered as a separate entity.
Definition
The occurrence of repetitive RERA during sleep
defines the UARS. RERA is characterized by a
progressive increase in respiratory effort; this may
be assessed by direct measurement of esophageal
pressure or by another marker of respiratory effort
such as the change in pulse transit time (Figure 1).
RERA may induce both cortical and autonomic
arousal and potentially lead to cardiovascular activation. Respiratory flow, when using nasal cannula
or a pneumotachograph, exhibits only qualitative
change and is named inspiratory flow limitation.
This is of interest since inspiratory flow limitation
results from progressive increase in UA resistance
and is a useful noninvasive method to detect RERA.
The time sequence of these obstructive respiratory
events is close to what occurs with apneas and hypopneas, but the duration may be longer. This should
be distinguished from episodes of sustained stable
flow limitation occurring during slow wave sleep.
This late-flow limited aspect does not lead to repeated arousals and thus differs from RERA.
For qualifying as an individual disease, UARS
should meet the following criteria:
*
*
*
First, to exhibit specific clinical and polysomnographic diagnostic criteria.
Second, these specific criteria should not be found
in the general population.
Third, a direct relationship should be found
between this syndrome and a specific morbidity.