Definition and Physiology

In health the arterial level of carbon dioxide (Pa_CO2) is maintained between 37 and 43 mmHg at sea level. All disorders of ventilation result in abnormal measurements of Pa_CO2. This chapter reviews chronic ventilatory disorders that are reflected in abnormal Pa_CO2.

The continuous production of CO₂ by cellular metabolism necessitates its efficient elimination by the respiratory system. The relationship between CO₂ production and Pa_CO2 is described by the equation, Pa_CO2 = (k)(V._CO2)/V. A, where V. _CO2 represents the carbon dioxide production, k is a constant and V. A is fresh gas alveolar ventilation. V. A can be calculated as minute ventilation x(1-Vd/Vt), where the dead space fraction Vd/Vt represents the portion of a tidal breath that remains within the conducting airways at the conclusion of inspiration and does not, therefore, contribute to alveolar ventilation. As such, all disturbances of Pa_CO2 must reflect altered CO₂ production, minute ventilation, or dead space fraction.

Diseases that alter V. _CO2 are often acute (sepsis, burns, or pyrexia, for example), and their contribution to ventilatory abnormalities and/or respiratory failure is reviewed elsewhere. Chronic ventilatory disorders typically involve inappropriate levels of minute ventilation or increased dead space fraction. Characterization of these disorders requires a review of the normal respiratory cycle.

The spontaneous cycle of inspiration and expiration is automatically generated in the brainstem. Two groups of neurons located within the medulla are particularly important: the dorsal respiratory group (DRG) and the ventral respiratory column (VRC). These neurons have widespread projections, including the descending projections into the contralateral spinal cord, where they perform many functions. They initiate activity in the phrenic nerve/diaphragm, project to the upper airway muscle groups and spinal respiratory neurons, and innervate the intercostal and abdominal muscles that participate in normal respiration. The DRG acts as the initial integration site for many of the afferent nerves relaying information about the partial pressure of arterial oxygen (Pa_O2), Pa_CO2, pH, and blood pressure from the carotid and aortic chemoreceptors and baroreceptors to the central nervous system (CNS). In addition, the vagus nerve relays information from stretch receptors and juxtapulmonary-capillary receptors in the lung parenchyma and chest wall to the DRG. The respiratory rhythm is generated within the VRC, as well as the more rostrally located parafacial respiratory group (pFRG), which is particularly important for the generation of active expiration. One particularly important area within the VRC is the so-called pre-Bötzinger complex. This area is responsible for the generation of various forms of inspiratory activity, and lesioning of the pre-Bötzinger complex leads to the complete cessation of breathing. The neural output of these medullary respiratory networks can be voluntarily suppressed or augmented by input from higher brain centers and the autonomic nervous system. During normal sleep there is an attenuated response to hypercapnia and hypoxemia resulting in mild nocturnal hypoventilation that corrects upon awakening.

Once neural input has been delivered to the respiratory pump muscles, normal gas exchange requires an adequate amount of respiratory muscle strength to overcome the elastic and resistive loads of the respiratory system (Fig. N-1A. In health, the strength of the respiratory muscles readily accomplishes this, and normal respiration continues indefinitely. Reduction in respiratory drive or neuromuscular competence or substantial increase in respiratory load can diminish minute ventilation, resulting in hypercapnia (Fig. N-1B). Alternatively, if normal respiratory muscle strength is coupled with excessive respiratory drive, then alveolar hyperventilation ensues and leads to hypocapnia (Fig. N-1C).

Hypoventilation

Clinical Features

Diseases that reduce minute ventilation or increase dead space fall into four major categories: parenchymal lung and chest wall disease, sleep disordered breathing, neuromuscular disease, and respiratory drive disorders (Fig. N-1B). The clinical manifestations of hypoventilation syndromes are nonspecific (Table N-1) and vary depending on the severity of hypoventilation, the rate at which hypercapnia develops, the degree of compensation for respiratory acidosis, and the underlying disorder. Patients with parenchymal lung or chest wall disease typically present with shortness of breath and diminished exercise tolerance. Episodes of increased dyspnea and sputum production are hallmarks of obstructive lung diseases, such as chronic obstructive pulmonary disease (COPD), whereas progressive dyspnea and cough are common in interstitial lung diseases. Excessive daytime somnolence, poor quality sleep, and snoring are common among patients with sleep-disordered breathing. Sleep disturbance and orthopnea are also described in neuromuscular disorders. As neuromuscular weakness progresses, the respiratory muscles, including the diaphragm, are placed at a mechanical disadvantage in the supine position due to the upward movement of the abdominal contents. New-onset orthopnea is frequently a sign of reduced respiratory muscle force generation. More commonly, however, extremity weakness or bulbar symptoms develop prior to sleep disturbance in neuromuscular diseases, such as amyotrophic lateral sclerosis (ALS) or muscular dystrophy. Patients with respiratory drive disorders do not have symptoms distinguishable from other causes of chronic hypoventilation.

Table N-1 Signs and Symptoms of Hypoventilation

Dyspnea during activities of daily living

Orthopnea in diseases affecting diaphragm function

Poor quality sleep

Daytime hypersomnolence

Early morning headaches

Anxiety

Impaired cough in neuromuscular diseases

The clinical course of patients with chronic hypoventilation from neuromuscular or chest wall disease follows a characteristic sequence: An asymptomatic stage where daytime Pa_O2 and Pa_CO2 are normal, followed by nocturnal hypoventilation, initially during rapid eye movement (REM) sleep and later in non-REM sleep. Finally, if vital capacity drops further, daytime hypercapnia develops. Symptoms can develop at any point along this time course and often depend on the pace of respiratory muscle functional decline. Regardless of cause, the hallmark of all alveolar hypoventilation syndromes is an increase in alveolar P_CO2 (PA_CO2) and, therefore, in Pa_CO2. The resulting respiratory acidosis eventually leads to a compensatory increase in plasma bicarbonate concentration. The increase in PA_CO2 results in an obligatory decrease in PA_O2, often resulting in hypoxemia. If severe, the hypoxemia manifests clinically as cyanosis and can stimulate erythropoiesis, thereby inducing secondary erythrocytosis. The combination of chronic hypoxemia and hypercapnia may also induce pulmonary vasoconstriction, leading eventually to pulmonary hypertension, right-ventricular hypertrophy, and right heart failure.

Diagnosis

Elevated plasma bicarbonate in the absence of volume depletion is suggestive of hypoventilation. An arterial blood gas demonstrating elevated Pa_CO2 with a normal pH confirms chronic alveolar hypoventilation. The subsequent evaluation to identify an etiology should initially focus on whether the patient has lung disease or chest wall abnormalities. Physical examination, imaging studies (chest x-ray and/or CT scan), and pulmonary function tests are sufficient to identify most lung/chest wall disorders leading to hypercapnia. If these evaluations are unrevealing, then the clinician should screen for obstructive sleep apnea (OSA), the most frequent sleep disorder leading to chronic hypoventilation. Several screening tools have been developed to identify patients at risk for OSA. The Berlin Questionnaire has been validated in a primary care setting and identifies patients likely to have OSA. The Epworth Sleepiness Scale (ESS) and the STOP-Bang questionnaire have not been validated in outpatient primary care settings but are quick and easy to use. The ESS measures daytime sleepiness, with a score of ≥10 identifying individuals who warrant additional investigation. The STOP-Bang survey has been used in preoperative clinics to identify patients at risk of having OSA. In this population, it has 93% sensitivity and 90% negative predictive value.

If the ventilatory apparatus (lung, airways, chest wall) is not responsible for chronic hypercapnia, then the focus should shift to respiratory drive and neuromuscular disorders. There is an attenuated increase in minute ventilation in response to elevated CO₂ and/or low O₂ in respiratory drive disorders. These diseases are difficult to diagnose and should be suspected when patients with hypercapnia are found to have normal respiratory muscle strength, normal pulmonary function, and normal alveolar-arterial P_O2 difference. Hypoventilation is more marked during sleep in patients with respiratory drive defects, and polysomnography often reveals central apneas, hypopneas, or hypoventilation. Brain imaging (CT scan or MRI) can sometimes identify structural abnormalities in the pons or medulla that result in hypoventilation. Chronic narcotic use or significant hypothyroidism can depress the central respiratory drive and lead to chronic hypercapnia, as well.

Respiratory muscle weakness has to be profound before lung volumes are compromised and hypercapnia develops. Typically, physical examination reveals decreased strength in major muscle groups prior to the development of hypercapnia. Measurement of maximum inspiratory and expiratory pressures or forced vital capacity (FVC) can be used to monitor for respiratory muscle involvement in diseases with progressive muscle weakness. These patients also have increased risk for sleep-disordered breathing, including hypopneas, central and obstructive apneas, and hypoxemia. Nighttime oximetry and polysomnography are helpful in better characterizing sleep disturbances in this patient population.

Treatment: Hypoventilation

Nocturnal noninvasive positive-pressure ventilation (NIPPV) has been used successfully in the treatment of hypoventilation and apneas, both central and obstructive, in patients with neuromuscular and chest wall disorders. Nocturnal NIPPV has been shown to improve daytime hypercapnia, prolong survival, and improve health-related quality of life when daytime hypercapnia is documented. ALS guidelines recommend nocturnal NIPPV if symptoms of hypoventilation exist AND one of the following criteria is present: Paco₂ ≥45 mmHg; nocturnal oximetry demonstrates oxygen saturation ≤88% for 5 consecutive minutes; maximal inspiratory pressure <60 cm H₂O; and FVC <50% predicted. However, at present there is inconclusive evidence to support preemptive nocturnal NIPPV use in all patients with neuromuscular and chest wall disorders who demonstrate nocturnal, but not daytime, hypercapnia. Nevertheless, at some point the institution of full-time ventilatory support with either pressure or volume-preset modes is required in progressive neuromuscular disorders. There is less evidence to direct the timing of this decision, but ventilatory failure requiring mechanical ventilation and chest infections related to ineffective cough are frequent triggers for the institution of full-time ventilatory support.

Treatment of chronic hypoventilation from lung or neuromuscular diseases should be directed at the underlying disorder. Pharmacologic agents that stimulate respiration, such as medroxyprogesterone and acetazolamide, have been poorly studied in chronic hypoventilation and should not replace treatment of the underlying disease process. Regardless of the cause, excessive metabolic alkalosis should be corrected, as plasma bicarbonate levels elevated out of proportion to the degree of chronic respiratory acidosis can result in additional hypoventilation. When indicated, administration of supplemental oxygen is effective in attenuating hypoxemia, polycythemia, and pulmonary hypertension.

Phrenic nerve or diaphragm pacing is a potential therapy for patients with hypoventilation from high cervical spinal cord lesions or respiratory drive disorders. Prior to surgical implantation, patients should have nerve conduction studies to ensure normal bilateral phrenic nerve function. Small case series suggest that effective diaphragmatic pacing can improve quality of life in these patients.

Hypoventilation Syndromes

Obesity Hypoventilation Syndrome

The diagnosis of obesity hypoventilation syndrome (OHS) requires: body mass index (BMI) ≥30 kg/m², sleep-disordered breathing and chronic daytime alveolar hypoventilation, defined as Pa_CO2 ≥45 mmHg, and Pa_O2 < 70 mmHg in the absence of other known causes of hypercapnia. In almost 90% of cases, the sleep-disordered breathing is in the form of OSA. Several international studies in different populations confirm that the overall prevalence of obstructive sleep apnea syndrome, defined by an apnea hypopnea index ≥5 AND daytime sleepiness, is approximately 3–4% in middle-aged men and 2% in middle-aged women. Thus, the population at risk for the development of OHS continues to rise as the worldwide obesity epidemic persists. Although no population-based prevalence studies of OHS have been performed, some estimates suggest there may be as many as 500,000 individuals with OHS in the United States.

Several studies suggest that severe obesity (BMI >40 kg/m²) and severe OSA apnea-hypopnea index [(AHI) >30 events per hour] are risk factors for the development of OHS. The pathogenesis of hypoventilation in these patients is multifactorial and incompletely understood. Defects in central respiratory drive have been demonstrated in OHS patients but often improve with treatment. This suggests central defects may not be the primary disturbance that leads to chronic hypercapnia. The treatment of OHS is similar to that for OSA: weight reduction and continuous positive airway pressure (CPAP) therapy during sleep. CPAP improves daytime hypercapnia and hypoxemia in the majority of patients with OHS. There is not conclusive evidence to suggest that bilevel positive airway pressure (BiPAP) is superior to CPAP. Bilevel positive airway pressure should be reserved for patients not able to tolerate high levels of CPAP support or patients that remain hypoxemic despite resolution of obstructive respiratory events.

Central Hypoventilation Syndrome

This syndrome can present later in life or in the neonatal period where it is often called Ondine’s curse or congenital central hypoventilation syndrome (CCHS). Abnormalities in the gene encoding PHOX2b, a transcription factor with a role in neuronal development, have been implicated in the pathogenesis of congenital central hypoventilation syndrome. Regardless of the age of onset, these patients have absent respiratory response to hypoxia or hypercapnia, mildly elevated Pa_CO2 while awake, and markedly elevated Pa_CO2 during non-REM sleep. Interestingly, these patients are able to augment their ventilation and “normalize” Pa_CO2 during exercise. These patients typically require NIPPV or mechanical ventilation as therapy and should be considered for phrenic nerve or diaphragmatic pacing at centers with experience performing these procedures.

Hyperventilation

Clinical Features

Hyperventilation is defined as ventilation in excess of metabolic requirements (CO₂ production) leading to a reduction in Pa_CO2. The physiology of patients with chronic hyperventilation is poorly understood, and there is no typical clinical presentation. Symptoms can include dyspnea, paresthesias, tetany, headache, dizziness, visual disturbances, and atypical chest pain. Because symptoms can be so diverse, patients with chronic hyperventilation present to a variety of health care providers, including internists, neurologists, psychologists, psychiatrists, and pulmonologists.

It is helpful to think of hyperventilation as having initiating and sustaining factors. Some investigators believe that an initial event leads to increased alveolar ventilation and a drop in Pa_CO2 to ~20 mmHg. The ensuing onset of chest pain, breathlessness, paresthesia, or altered consciousness can be alarming. The resultant increase in minute volume to relieve these acute symptoms only serves to exacerbate symptoms that are often misattributed by the patient and health care workers to cardiopulmonary disorders. An unrevealing evaluation for causes of these symptoms often results in patients being anxious and fearful of additional attacks. It is important to note that anxiety disorders and panic attacks are NOT synonymous with hyperventilation. Anxiety can be both an initiating and sustaining factor in the pathogenesis of chronic hyperventilation, but these are not necessary for the development of chronic hypocapnia.

Diagnosis

Respiratory symptoms associated with acute hyperventilation can be the initial manifestation of systemic illnesses such as diabetic ketoacidosis. Causes of acute hyperventilation need to be excluded before a diagnosis of chronic hyperventilation is considered. Arterial blood gas sampling that demonstrates a compensated respiratory alkalosis with a near-normal pH, low Pa_CO2 and low calculated bicarbonate are necessary to confirm chronic hyperventilation. Other causes of respiratory alkalosis, such as mild asthma, need to be diagnosed and treated before chronic hyperventilation can be considered. A high index of suspicion is required as increased minute ventilation can be difficult to detect on physical examination. Once chronic hyperventilation is established, a sustained 10% increase in alveolar ventilation is enough to perpetuate hypocapnia. This increase can be accomplished with subtle changes in the respiratory pattern, such as occasional sigh breaths or yawning two to three times per minute.

Treatment: Hyperventilation

There are few well-controlled treatment studies of chronic hyperventilation because of its diverse features and the lack of a universally accepted diagnostic process. Clinicians often spend considerable time identifying initiating factors, excluding alternative diagnoses and discussing the patient’s concerns and fears. In some patients, reassurance and frank discussion about hyperventilation can be liberating. Identifying and eliminating habits that perpetuate hypocapnia, such as frequent yawning or sigh breathing, can be helpful. Some evidence suggests that breathing exercises and diaphragmatic retraining may be beneficial for some patients. The evidence for using medications to treat hyperventilation is scant. Beta-blockers may be helpful in patients with sympathetically mediated symptoms, such as palpitations and tremors.