Obesity-Hypoventilation Syndrome

Paula Carvalho, M.D., F.C.C.P.

Section Head, Pulmonary and Critical Care Medicine
Boise VA Medical Center
and
Professor of Medicine
University of Washington

Learning Objectives:
The complex physiology of OHS!
This is a sneaky disorderrecognizing the
clinical features is essential for diagnosis.
A rational approach to evaluation.
Rational approaches to treatment.

The Obesity-Hypoventilation Syndrome (OHS)

A review of respiratory control
The pathophysiology of OHS
Central respiratory drive in OHS
The response to hypoxemia and hypercapnia
The contribution of sleep-disordered breathing in OHS
The role of leptin

Obesity-Hypoventilation Syndrome:

A disease entity that is distinct from

simple obesity and
obstructive sleep apnea!

The Posthumous Papers of the Pickwick Club:

Damn that boy! said the old gentleman,
Hes gone to sleep again!
A very extraordinary boy, said Mr. Pickwick,
Hes always asleep! Goes on errands fast
asleep and snores as he waits at the table.
But Im proud of that boy
wouldnt part with him on any
accounthes a natural
curiosity!

Charles Dickens, 1836

120 years later

Extreme obesity associated with alveolar
hypoventilation: A Pickwickian Syndrome
Burwell CS, Am J Med 1956;21:811-818

Obesity-Hypoventilation Syndrome (OHS):

Definition:
Obesity (body mass index 30 kg/m2).
Chronic awake alveolar hypoventilation:
arterial carbon dioxide tension >/= 45 mmHg and
oxygen tension < 70 mmHg.

The absence of other conditions that can cause

hypoventilation.

Obesity-Hypoventilation Syndrome (OHS):

Definition:
Obesity (body mass index 30 kg/m2).
Chronic awake alveolar hypoventilation (arterial carbon
dioxide tension >/= 45 mmHg and oxygen tension < 70
mmHg).
The absence of other conditions that can cause
hypoventilation.
Such as: Severe parenchymal lung disease
Congenital central hypoventilation syndrome
Kyphoscoliosis
Severe hypothyroidism
Neuromuscular disease

Obesity-Hypoventilation Syndrome:
Prevalence

Who knows?
We dont look for it as much as we should.

Obesity-Hypoventilation Syndrome:
Prevalence

Best estimates:
US population:
0.15-0.3%
Sleep labs:
11-20%
Bariatric surgery programs: 7-22%
Mokhlesi B et al., Respir Care 55:1347, 2010.
Laaban JP et al., Chest 127:710, 2005.
Lecube A et al., Obes Surg 20:454, 2010.

What is hypoventilation?
Ventilation changes with the amount of CO2
being produced by the body to keep arterial
PCO2 ~ 40 mm Hg.
Hypoventilation:
Ventilation is reduced to a level that is inadequate to
eliminate the CO2 being produced by the body.
Mild hypoventilation normally occurs during normal sleep
(PCO2 = 43 to 45 mm Hg)

Control of Ventilation

The overall picture of ventilatory control:

Ventilatory control: Where are the receptors?

Respiratory tract: Vagal mediation
Lung parenchyma:
Slowly-adapting pulmonary stretch receptors and
muscle spindles:
Changes in lung volume

Rapidly-adapting receptors:
Irritants and changes in lung volume

Ventilatory control: Where are the receptors?

Respiratory tract: Vagal mediation
Lung parenchyma:
Slowly-adapting pulmonary stretch receptors and
muscle spindles:
Changes in lung volume

Rapidly-adapting receptors:
Irritants and changes in lung volume
cough, goblet cell activation, bronchospasm

Ventilatory control: Where are the receptors?

Respiratory tract: Vagal mediation
Bronchi and bronchioles:
Receptors are activated by stretch or compression of the
lung, and impulses travel via the vagus nerve to the
respiratory centers in the brain.

The Hering-Breuer reflexes help regulate the

rhythmic ventilation of the lung and prevent
overdistention or extreme deflation.

Ventilatory control: Where are the receptors?

Respiratory tract: Vagal mediation
Bronchi and bronchioles:
Receptors are activated by stretch or compression of the
lung, and impulses travel via the vagus nerve to the
respiratory centers in the brain.

The Hering-Breuer reflexes help regulate the

rhythmic ventilation of the lung and prevent
overdistention or extreme deflation.

pons

inspiratory nuclei

Obesity-Hypoventilation Syndrome
OHS is a diagnosis of exclusion, and other causes of
hypoventilation should be considered:

Obstructive or restrictive parenchymal diseases

Musculoskeletal causes of chest wall restriction

Neuromuscular weakness
Severe hypothyroidism
Congenital central hypoventilation
Arnold-Chiari type II malformations

Ventilatory control: Where are the receptors?

Trachea
Chest wall
Pulmonary vessels
Nose!
The nose has flow sensors that respond to the
temperature change during the inflow of air and stimulate
upper airway muscle activation.

Receptors in the respiratory system:

The peripheral chemoreceptors:

The carotid and aortic bodies are the primary peripheral
chemoreceptors.
Primarily sense oxygen tension, but also respond to hypercapnia and
acidosis.
The carotid bodies are most important in adults.
The aortic chemoreceptors significantly lose function after infancy.
Neural outflow from the carotid bodies travels through cranial nerve IX to
the brain centers, where excitatory neurotransmitters are released that
result in increased ventilation.
Response of the carotid bodies to hypoxemia PLUS hypercapnia is
synergistic, not additive.

Other receptors?
Peripheral chemoreceptors in muscles?
Patients with congenital central hypoventilation syndrome
do not respond to a hypercapnic challenge, but increase
their ventilation with exercise.
?changes in pH in the extracellular fluid of exercising
muscle cause increases in ventilation during aerobic
exercise?

A review of ventilatory control:

The receptors

A review of ventilatory control:

The receptors

The central chemoreceptors:

Central nervous system chemoreceptors are located
on the ventral surface of the medulla oblongata and
mid-brain.

Medullary chemoreceptors respond immediately to

changes in pH.
CO2 is lipid-soluble and crosses the blood-brain
barrier rapidly.
PaCO2 affects interstitial fluid pH
sensed by the central chemoreceptors
immediate effects on ventilation

What happens at the neuronal level:

Where is the respiratory control center?

The respiratory control center is located in the
medulla oblongata.
There are a group of pacemaker neurons that
rhythmically depolarize, fire, and repolarize, and
can be altered by various afferent inputs.
The efferent input is translated into the
respiratory drive.

The central respiratory centers:

Two respiratory control centers have been
identified in the pons:
The apneustic center:
Appears to promote inspiration by stimulating
the inspiratory neurons in the medulla.
The pneumotaxic center:
Inhibits inspiration by inhibiting the apneustic
center.

The respiratory controllers:

The central controllers and chemoreceptors:

The central respiratory centers:

The medulla drives the breathing
frequency, inspiratory time, and
expiratory time. Lesions of the
brainstem may cause characteristic
abnormalities in breathing pattern.
Ataxic breathing, which is irregular,
can occur with medullary lesions.

Apneustic breathing, characterized

by sustained inspiration, can occur
with pontine lesions.

The respiratory center: Convenient locations

Integration of receptor input:

The respiratory cycle:

PaO2 and PaCO2 during the respiratory cycle:

Pathophysiology of
Obesity-Hypoventilation Syndrome

OHS and usual eucapnic obesity:

How do we tell them apart?

Patients with OHS present with:

Severe upper airway obstruction

Restrictive chest physiology
Pulmonary hypertension
Blunted central respiratory drive

OHS and usual eucapnic obesity:

How do we tell them apart?

Patients with OHS present with:

Severe upper airway obstruction

Restrictive chest physiology
Pulmonary hypertension
Blunted central respiratory drive
daytime hypercapnia

OHS and usual eucapnic obesity:

How do we tell them apart?

Patients with OHS present with:

Severe upper airway obstruction

Restrictive chest physiology
Pulmonary hypertension
Blunted central respiratory drive

who cares?

OHS and usual eucapnic obesity:

How do we tell them apart?

Patients with OHS present with:

Severe upper airway obstruction

Restrictive chest physiology
Pulmonary hypertension
Blunted central respiratory drive

Significantly increased morbidity!

OHS and usual eucapnic obesity:

How do we tell them apart?

Patients with OHS present with:

Severe upper airway obstruction

Restrictive chest physiology
Pulmonary hypertension
Blunted central respiratory drive
Significantly increased morbidity

Significantly increased mortality!

Survival curves: OHS vs. eucapnic obese patients

Nowbar S et al. Am J Med 2004; 116:1

Obesity-Hypoventilation Syndrome:

A potentially treatable condition

Obesity-Hypoventilation Syndrome:
Proposed mechanisms

Impaired respiratory mechanics:

Impaired compensation to acute
hypercapnia:
Leptin resistance:

Obesity-Hypoventilation Syndrome:
Proposed mechanisms

Impaired respiratory mechanics:

Obesity
Impaired compensation to acute
hypercapnia:
Disruption of central control
Leptin resistance:
Central hypoventilation

OHS: Abnormalities in respiratory control

Obesity-Hypoventilation Syndrome (OHS):

Hypoventilation in patients with obesity
hypoventilation syndrome (OHS) is due to
multiple obesity-related physiologic abnormalities
and conditions including:
Abnormalities in respiratory control.
Sleep-disordered breathing and resulting metabolic
derangements.
Respiratory system mechanics and increased work of
breathing.
Ventilation/perfusion mismatching.
Leptin resistance.

OHS: Abnormalities in respiratory control

OHS: Abnormalities in respiratory control

Patients with OHS have a decreased ventilatory response to

hypercapnia when compared with other patients with high PaCO2,

Sampson et al. Am J Med 1983;75:81-90.

OHS: Abnormalities in respiratory control

Patients with OHS have a decreased ventilatory response to

hypercapnia when compared with other patients with high PaCO2,

This is corrected in most patients with positive airway

pressure.
Sampson et al. Am J Med 1983;75:81-90.

OHS: Abnormalities in respiratory control

Patients with OHS have a decreased ventilatory response to
hypoxemia when compared with obese control subjects.

Han et al. Chest 2001; 119:1814-1819.

OHS: Abnormalities in respiratory control

Patients with OHS have a decreased ventilatory response to
hypoxemia when compared with obese control subjects.
The hypoxic response in the subjects with OHS improved
significantly after 2 weeks of treatment with positive airway
pressure, and normalized at 5 weeks as compared with controls.
Han et al. Chest 2001; 119:1814-1819.

Mokhlesi B. Respir Care 2010;55:1347

OHS: Abnormalities in respiratory control

The result:
In OHS, defects in central respiratory drive are responsible
for alveolar hypoventilation in due to blunted hypoxic and
hypercapnic responses.
This is REVERSIBLE in most patients with effective
treatment.
These findings suggest that central defects are present in
OHS, but are not the sole cause of the syndrome.

OHS: Sleep-disordered breathing

Sleep-disordered breathing in OHS can be due to:
Central hypoventilation

(~10%)

Sleep hypoventilation is defined as a 10 mm Hg increase in

sleeping PaCO2 versus wakefulness, or oxygen desaturation
during sleep unexplained by obstructive apneas or hypopneas.

Obstructive sleep apnea (~ 90%)

Upper airway obstruction during sleep resulting in recurrent
hypopneas or apneic episodes.

Banerjee D, et al. Chest 2007; 131:1678.

Berger KI et al. J Appl Physiol 2000; 88:257

OHS: Sleep-disordered breathing

PaCO2 rises during each episode of airflow obstruction and during
episodes of impaired ventilation.
Patients who develop OHS are unable to normalize their PaCO2
between such respiratory events.
Increased PaCO2 causes a decrease in pH and leads to increased
renal bicarbonate retention.
The bicarbonate levels often remain elevated, as the kidney does
not completely eliminate bicarbonate during the day.
Once bicarbonate is elevated, ventilation is depressed due to a
blunted ventilatory response to hypercapnia while awake.

OHS: Sleep-disordered breathing

The result:
Imbalances in acid-base homeostasis lead to
chronic hypoventilation and hypercapnia during
both the day and night.

OHS: Abnormalities in respiratory control

OHS: Abnormalities in respiratory control

OHS: Respiratory muscle function

Patients with OHS generate equivalent transdiaphragmatic
pressures (Pdi) during a hypercapnic trial as compared with
eucapnic obese patients.
Patients with OHS do not have evidence of diaphragmatic
fatigue or neuromuscular uncoupling during a hypercapnic
trial.
Sampson et al. Am J Med 1983; 75:81-90.

OHS: Respiratory muscle function

Results:
Patients with OHS appear to have intact
diaphragmatic strength.

Respiratory muscle weakness is not

thought to be a primary cause for the alveolar
hypoventilation seen in OHS

OHS: Work of breathing

In OHS, there is an increased work of breathing to
move the excess weight on the thoracic wall and
abdomen.
The respiratory muscles have the capacity to
compensate for these altered lung mechanics.
Sharp et al. J Clin Invest 1964; 43:728-739.

OHS: Work of breathing

Conclusions:
Although obesity increases the work of breathing,
the respiratory muscles have the capacity to
compensate for these abnormalities.
Although there are abnormalities in
lung mechanics with OHS, these do not
contribute significantly to the pathogenesis
of OHS.

OHS: Ventilation-perfusion mismatch

The physiologic alterations in obesity result in
decreased ventilation in the lower lobes.
There is an increase in vascular perfusion to the
lower lobes due to increased pulmonary blood
volume.
Koenig SM. Am J Med Sci 2001; 321:249.

OHS: The role of leptin

Leptin is a satiety hormone produced by
adipocytes which has been implicated in the
pathogenesis of OHS.
The functions of leptin:
a) Acts on the hypothalamus to inhibit eating.

b) Stimulates ventilation.

OHS: Evidence for leptin resistance

As weight increases, so does CO2 production.
Obese, hypercapnic patients have elevated leptin levels,
and leptin resistance appears to be associated with a
decreased ventilatory response to hypercapnia.
Increased leptin levels may be a compensatory response
to leptin resistance.
Makinodan et al. Respiration 2008; 75:257-264.
Considine et al. N Engl J Med 1996; 334:292-295

OHS and leptin: The vicious cycle

A rational approach to evaluation:

Suspected OHS
Clinical screening
Check SaO2 and serum HCO3- level
High risk for OHS

Low risk for OHS

SaO2 < 90% and elevated HCO3Major elective surgery

ABG
PSG/CPAP
Echocardiogram

SaO2 > 90% and normal HCO3-

Routine

Emergency surgery

Potential difficult airway

Post-extubation PAP therapy
Vigilance for opioid-induced ventilatory impairment

Prevalence of OHS is higher in patients with OSA and extreme obesity

Mokhlesi B, et al. Proc Am Thorac Soc. 2008; 5:218.

Obesity Hypoventilation Syndrome: Conclusions

In OHS, defects in central respiratory drive are responsible for
alveolar hypoventilation.
There is a decreased response to hypoxemia and hypercapnia.
Sleep-disordered breathing worsens acid-base homeostasis and
leads to further hypoventilation.
Respiratory muscle function appears to be normal, although obesity
increases the work of breathing.
Changes in lung physiology due to obesity cause imbalance in
ventilation/perfusion relationships.
Leptin resistance appears to decrease the ventilatory response to
hypercapnia.

Obesity Hypoventilation Syndrome: Conclusions

There is an epidemic of obesity, and the prevalence of
OHS is likely to increase.
Most cases of OHS are unrecognized, and the mortality
is high.
A high degree of suspicion and appropriate screening
helps identify these cases.
Positive airway therapy is the mainstay of treatment!
Early diagnosis and treatment appears to be quite
beneficial and may decrease morbidity and mortality!

VA Medical Center, Boise, Idaho