01.31.13 -- (pulm) obesity-hypoventilation syndrome -- paula carvalho, md

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 disorder…recognizing 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,

• “He’s gone to sleep again!”

• “A very extraordinary boy”, said Mr. Pickwick,

“He’s always asleep! Goes on errands fast asleep and snores as he waits at the table.”

• “But I’m proud of that boy…

wouldn’t part with him on any

account…he’s 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 don’t 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 HCO3- SaO2 > 90% and normal HCO3- Routine

Major elective surgery Emergency surgery

ABG Potential difficult airway

PSG/CPAP Post-extubation PAP therapy

Echocardiogram 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