Obesity Hypoventilation Syndrome

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Chapter 62 Obesity Hypoventilation Syndrome

Gimbada B. Mwenge, Daniel Rodenstein

Obesity hypoventilation syndrome is a disorder characterized by the presence of daytime compensated respiratory acidosis (i.e., hypercapnia with normal pH and increased serum bicarbonate), in patients in whom no cause of ventilatory failure can be identified. These patients cannot ensure a normal minute ventilation even in the resting state, although clinical evaluation will rule out disorders associated with decreased muscle force (neuromuscular diseases), abnormal muscle geometry (e.g., kyphoscoliosis), severe airway obstruction and abnormal ventilation-perfusion relationships (e.g., chronic obstructive pulmonary disease [COPD], emphysema), or parenchymal abnormalities (e.g., interstitial lung diseases). In these patients, with performance of a respiratory maneuver consisting of serial deep inspirations, subsequently the arterial carbon dioxide tension (PaCO₂) normalizes, and in those in whom hypoxia is present, oxygen saturation (SaO₂) rises by 4% to 6% in less than 2 minutes. Of note, however, they do not sustain adequate minute ventilation and remain hypercapnic, with the kidneys compensating to maintain a normal pH. Another clinical element quite evident is that such persons are obese, frequently morbidly obese, with body mass index (BMI) values in excess of 35 kg/m². It is the association of pathologic obesity and daytime hypercapnia that defines the obesity hypoventilation syndrome.

When these patients are studied in a sleep laboratory, it becomes clear that they are afflicted with some form of sleep-disordered breathing pattern. The vast majority of patients have a moderate to severe form of obstructive sleep apnea (OSA), with a minority showing no obstructed breathing but simply sleep-related hypoxia and hypercapnia (long periods of SaO₂ below 90% and an increase in PaCO₂ of about 10 mm Hg developing overnight). The diagnosis of obesity hypoventilation syndrome can be reached with certainty only when other causes of daytime hypercapnia have been excluded.

Epidemiology

The prevalence of obesity hypoventilation syndrome in the general population remains unknown. In the United States, it has been estimated to be between 0.15% and 0.3%. A study conducted in obese hospitalized patients with a BMI greater than 35 kg/m² found a prevalence of 31%. Among patients with OSA, previous European studies (France, Italy, Greece, and Spain) found occurrence rates for obesity hypoventilation syndrome of 9% to 17%. Studies from the United States found a prevalence of greater than 20% in this patient group.

The gender ratio for obesity hypoventilation syndrome remains uncertain: Even if the prevalence seems to be higher in men, some studies found a higher proportion of the cases in women. All reported data come from selected cohorts of hospitalized patients or from sleep laboratories.

Risk Factors

Several conditions seem to predispose an obese person to development of the obesity hypoventilation syndrome. Undisputedly, in comparison with patients with OSA, patients diagnosed with this syndrome seem to be more obese, and they have more severe OSA. The main cause of obesity is well recognized to be an excess of food intake in relation to the energy expenditure requirements of the organism, resulting in the constitution of an energy stock essentially in the form of fat deposits. According to worldwide epidemiologic data, the prevalence of obesity is increasing everywhere, and this trend seems to be related essentially to a rapid change in eating habits, themselves influenced by technologic changes and food industry policies. Whether this reflects an improvement in the standard of living is a matter of debate.

The health consequences of obesity should prompt implementation of educational strategies to promote adequate behavioral changes in eating habits. Nevertheless, at the individual level, genetic factors may have an influence on the development of obesity, depending on the balance between what can be termed “catabolic” and “anabolic” genes. More than 250 genes have been identified that have a more or less important influence on the final handling of the energetic balance. The clinical importance of each genetic variant, however, is not yet well appreciated. Only a few monogenetic causes of obesity have been described in humans, the best example being mutations in the gene coding for the melanocortin 4 receptor. It has to be stressed, however, that obesity will not develop if access to food is compromised, or if energy expenditure exceeds energy absorption.

An apnea-hypopnea index (AHI) greater than 50, as measured by the number of apneic or hypopneic episodes per hour of sleep, also seems to be a risk factor for obesity hypoventilation syndrome, because 25% of patients with such AHIs in several studies had the syndrome. Oxygen saturation nadir levels below 60% during polysomnography and moderate to severe restriction found on pulmonary function testing also are predictors for the syndrome, with odds ratios of 4 and 10, respectively. Finally, some studies found that patients with obesity hypoventilation syndrome had greater neck, waist, and hip circumferences and a larger waist-to-hip ratio than their counterparts with OSA.

Pathophysiology

Obese patients, both eucapnic and hypercapnic, have significant reductions in functional residual capacity and expiratory reserve volume with preservation of inspiratory capacity and often normal or slightly reduced total lung capacity. But obesity is not, however, the only determinant of hypoventilation, because only a third of morbidly obese persons develop hypercapnia. Some differences between eucapnic obese and hypercapnic subjects have been recognized and are summarized next.

Reduced Muscle Strength

The maximal inspiratory and expiratory pressures are normal in eucapnic morbidly obese patients but may be reduced in patients with obesity hypoventilation syndrome, although this is not a universal finding.

Central Respiratory Drive

Many studies found that patients with obesity hypoventilation syndrome do not hyperventilate to the same degree as morbidly obese patients without the syndrome when rebreathing CO₂. This deficit corrects in most patients after normalization of PaCO₂. In patients with severe OSA but without hypercapnia, the hypercapnic ventilatory response does not change with continuous positive airway therapy (CPAP). The reversibility of the blunted central drive suggests that this is a secondary phenomenon of the syndrome (and necessary for its persistence), but not the origin of it.

Obstructive Sleep Apnea

OSA may play a role in the pathogenesis of chronic hypercapnia in those patients, because in most cases, treatment of OSA corrects the hypercapnia. Indeed, to compensate for the effect of intermittent periodic breathing and resultant acute hypercapnia, normal subjects as well as patients with OSA will increase their tidal volume in the first breath after an apnea (hyperventilation). With physiologic differences in ventilatory responses between subjects, however, an overload in CO₂ could result. The duration of the apneas also could contribute: When apneic episode duration becomes three times longer than the breathing interval, CO₂ tends to accumulate despite maximal tidal volume, because there is insufficient time for adequate hyperventilation events (Figure 62-1). In addition, hypercapnia could blunt the ventilatory responses: The initial ventilation after an apneic episode is directly related to the volume of CO₂ loaded during the preceding respiratory event and thus represents an index of CO₂ ventilatory response. Hypercapnic patients demonstrated depression of this index of ventilatory compensation compared with that in eucapnic patients. It has been shown that the apnea-to-interapnea duration ratio is greater in hypercapnic patients than in eucapnic patients.

Figure 62-1 Five-minute tracing from a diagnostic polysomnography study. Top to bottom: Two electrooculograms (EOG); chin electromyogram (EMG1); three electroencephalograms (C3-A2, C4-A1, C3-O1); electrocardiogram (ECG); leg movement electromyograms (EMG2, EMG3); snoring recordings (PHONO); oronasal flow with a thermocouple (NAF1); nasal flow (NAF2P); abdominal and thoracic movement from inductive plethysmographic bands (VAB, VTH); and oxygen saturation measurement with pulse oximetry (SaO₂). The subject is in stage 2 non-REM sleep. Note the absence of nasal flow and persistent abdominal and thoracic movements with falls in oxygen saturation, with successive obstructive apneas ending with loud snoring and leg movements (with one exception). REM, rapid eye movement.

One study also has shown impaired CO₂ homeostasis after respiratory events may be mediated by opioids or opioid receptors, because endorphin blockade changed this pattern. Increased cerebrospinal fluid beta-endorphin activity with return to normal values has been reported in subjects with OSA. This finding could explain hypercapnia on awakening after a night full of apneic episodes. To understand why in a period of wakefulness free of apnea the PaCO₂ does not normalize, the role of the renal system has to be considered. Hypercapnia leads to respiratory acidosis, which activates the process of renal compensation.

To elucidate the mechanisms that are involved in the development of hypercapnia in patients with OSA, Norman and co-workers have proposed, using a computer model, some hints for prediction of the transition from acute hypercapnia during sleep-disordered breathing (apnea, hypopnea, and hypoventilation) to chronic daytime hypercapnia. In their model, when the ventilatory CO₂ response and renal HCO₃⁻ excretion were normal, increases in PaCO₂ and HCO₃⁻ did not develop. The bicarbonate excretion during the day compensated for that retained during the night. When CO₂ ventilatory response was very low, however, the model demonstrated a modest rise in PaCO₂ and HCO₃⁻ measured during the awake state over multiple days. Similarly, when renal HCO₃⁻ excretion rate was lowered to simulate chloride deficiency, the model demonstrated a modest rise in daytime PaCO₂ and HCO₃⁻. The combination of low CO₂ response and low renal HCO₃⁻ excretion rate produced a synergistic effect on the degree of elevation of daytime PaCO₂. These workers suggested that hypercapnia results from an imbalance between the period of CO₂ loading (short = apnea or hypopnea; long = hypoventilation) and inadequate compensation both during sleep and during the awake state. This pulmonary-renal interaction may contribute to the development and perpetuation of chronic daytime hypercapnia, which will lead to a blunted respiratory drive for the next sleep cycle (Figure 62-2).

Figure 62-2

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