Regardless of the underlying cause, the clinical presentation of patients with hypoventilation (which may be literally translated as lower breathing rate) is similar. Initial stages may be asymptomatic, but complaints such as dyspnea, fatigue and increased exertion effort may be reported. In obesity hypoventilation syndrome and nocturnal hypoventilation, disturbed sleep and hypersomnolence is frequently noted, whereas infections and COPD can present with expectorating cough and high fever. Central hypoventilation syndromes in newborns and infants present with severe cyanosis and apnea, often leading to cardiorespiratory arrest [5]. Respiratory acidosis may have either a severe acute or chronic asymptomatic course. Headaches, disturbed mental state, tremor, drowsiness and asterixis are clinical hallmarks of acute respiratory acidosis [1]. Additional signs include gait disturbances, papilledema, memory loss and even stupor [1].

A detailed approach to the patient must be conducted in order to determine the underlying cause of hypoventilation. A meticulous physical examination coupled with a properly obtained patient history should provide an initial insight into the pathology, but various laboratory and imaging studies are necessary to solidify the diagnosis. Firstly, arterial blood gasses (ABGs) should be evaluated in all patients in whom dyspnea and impaired breathing rates are observed, together with a complete blood count (CBC), serum electrolytes (particularly bicarbonate), and renal function tests including creatinine and blood urea nitrogen [1]. Serum levels of thyroid hormones can be useful in excluding hypothyroidism as a potential cause. Imaging studies, such as plain radiography or chest CT are useful methods to assess the lungs and can detect elevation of hemidiaphragms or diaphragmal flattening and hyperinflation (considered as a hallmark of COPD). Spirometry is a vital diagnostic procedure in patients with suspected hypoventilation and can determine the functional capacity of the respiratory system. If the cause is not found after these tests, neuromuscular evaluation through electromyography (EMG) and measurement of transdiaphragmal pressure should be done. Polysomnography should be considered in patients who report sleep disturbances.

Correction of the underlying disorder that caused hypoventilation is the single most important therapeutic strategy. However, ensuring adequate ventilation and correction of PaCO2 and PaO2 are also vital, which is most commonly performed by instating various forms of assisted ventilation. Supplemental oxygen should be instated in all patients, whereas noninvasive positive pressure ventilation has shown to be an optimal method [8]. The necessity for more invasive methods such as endotracheal intubation or even tracheostomy may be warranted in severe cases [3]. Administration of bronchodilators and correction of electrolytes, mainly potassium, bicarbonate and chloride is important as well. NaHCO3 should, in theory, markedly increase blood pH in the setting of respiratory acidosis, but it is contraindicated in this group of patients because bicarbonate can be converted to CO2 and cross the blood brain barrier [1], thus causing marked disbalance between blood and brain pH and putting the patients at great risk for seizures. Drug-induced hypoventilation is effectively treated by flumazenil (in the case of benzodiazepine overdose) or naloxone (used in patients with opioid overdose).

It is difficult to predict the outcome of patients who develop hypoventilation and most important factors include the underlying etiology, severity of other accompanying symptoms and responsiveness to therapy. Additionally, the time of diagnosis is equally important, as milder gas-exchange disturbances can be more effectively treated. Moreover, the development of pulmonary hypertension and cor pulmonale in advanced stages of diseases can't be reversed in many patients. One of the most important complications of hypoventilation, however, is respiratory acidosis, in which profound hypercapnia, hypoxia and acidosis can lead to rapid deterioration of the patient's general condition [1].

Under physiological conditions, factors that determine adequate ventilation and gas exchange include the functionality of the respiratory muscles (the diaphragm, abdominal and the intercostals) and proper regulation by higher structures [3]. Numerous conditions can impair the activity of the chest wall, gas exchange or cause defective central nervous system breathing regulation and provoke hypoventilation [1] [2] [7] [8]:

• Neuromuscular diseases such as amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS) Guillain-Barré syndrome, myasthenia gravis, poliomyelitis and various muscular dystrophies, including Duchenne muscular dystrophy and Becker muscular dystrophy.
• Lung diseases - COPD, emphysema, chronic bronchitis and asthma.
• Chest wall deformities - scoliosis (with or without kyphosis) and fibrothorax.
• Obesity hypoventilation syndrome, in which a triad of obesity, sleep-disordered breathing and daytime hypoventilation causes significant breathing impairment [9].
• Various conditions that fall under the group central hypoventilation syndromes (examples include Arnold Chiari malformation, Prader-Willi syndrome and achondroplasia), which most commonly appear in infancy and early childhood.
• Other notable causes include hypothyroidism, drug-induced (opioids, benzodiazepines) and cystic fibrosis.

The exact prevalence and incidence rates of hypoventilation are unknown, as they appear in a myriad of conditions in variable and often unpredictable rates. Hypoventilation can be seen in patients of all ages and gender, but some conditions can be restricted to certain age groups. Central hypoventilation syndromes are almost exclusively seen in neonates or infants, some of them being present as early as birth and incidence rates of 1 in 200,000 live births indicate their rare occurrence in clinical practice [5]. Obesity hypoventilation syndrome (OHS), on the other hand, is most commonly seen in obese adults and is shown to be present in up to 0.1-0.3% of the adult population [9]. In fact, approximately 10-20% of obese individuals with obstructive sleep apnea suffer from OHS [9]. COPD and lung-related diseases have shown high prevalence rates of hypoventilation, whereas all patients who are diagnosed with neuromuscular diseases will eventually develop respiratory muscle weakness and hypoventilation.

Several mechanisms of hypoventilation have been described. Firstly, neuromuscular diseases, which are mainly characterized by progressive muscle weakness, cause hypoventilation through progressive weakening of the respiratory muscles that leads to reduced capacity for gas exchange [7]. On the other hand, COPD and other intrinsic lung diseases create much harsher conditions for normal air conduction through the bronchial tree as a result of increased amount of dead space and because the expiratory breathing effort is much higher in these patients [6]. Mechanical compression, either due to obesity or chest wall deformities [10], creates a profound load on the thorax and the respiratory muscles to carry out their function, resulting in fatigue and reduced functional capacity. Central nervous system regulation of breathing has also shown to be a target for many diseases that belong to the group of central hypoventilation syndromes, which may be either congenital or acquired [5] [11]. In congenital forms, various gene mutations have been identified, but the exact pathophysiological mechanism remains unknown. Presumably, these diseases cause defects in sensory and integration signaling, as well as functional impairment of the brain stem, the main site of breathing regulation [5]. Regardless of the causative mechanism, inability of the respiratory muscles to perform adequate inhalation and exhalation reduces PaO2 and increases the concentration of PaCO2, leading to hypoxemia and hypercapnia, respectively.

Prevention of hypoventilation can be achieved primarily through identifying the underlying cause before its clinical progression leads to severe respiratory deficits. Early recognition of symptoms and a thorough laboratory workup can significantly aid in reducing the burden of hypercapnia and hypoxemia, which are well-established as factors that severely impair the quality of life and the ability of the patient to perform daily activities. Screening of patients with sleep disorders could be advocated, as it is not uncommon for these patients to develop hypoventilation.

Hypoventilation is a clinical entity characterized by reduced alveolar ventilation with accompanying disturbances in partial pressures of O2 and CO2 (PaO2 and PaCO2, respectively) [1]. The main pathophysiological mechanisms include chest wall abnormalities and reduced capacity for thoracic expansion, weakness of respiratory muscles, mechanical alterations in airflow and bronchial resistance, but also dysregulation of breathing rates by the regulatory centers in the brain [2] [3]. As a result, elevations of PaCO2 and a decrease in PaO2 are observed, which can be detrimental if not managed adequately on time. Neuromuscular diseases, hypothyroidism, chronic obstructive pulmonary disease (COPD), obesity hypoventilation syndrome (OHS) and numerous disorders of the central nervous system (known as central hypoventilation syndromes, some of them being Arnold Chiari malformation and achondroplasia) are listed as potential causes [5] [4] [5]. Hypoventilation can also be a physiological occurrence, for ex. during sleep, when several regulatory changes lead to very small variations in PaCO2 and PaO2, but nocturnal hypoventilation can occur and present as a significant challenge for diagnosis [3]. One of the most important complications is respiratory acidosis, in which acute manifestations of headache, confusion, drowsiness, tremor and asterixis appear after extensive hypercapnia and hypoxia [1]. Other accompanying symptoms may be present, depending on the underlying cause and the initial diagnosis of hypoventilation can be made on clinical criteria. Arterial blood gas analysis (ABG), however, is a necessary diagnostic method which confirms hypercapnia and hypoxemia, while additional laboratory studies should be conducted in order to establish the underlying cause. Thyroid hormone levels and serum electrolytes should be evaluated, whereas spirometry, imaging studies such as plain radiography or computed tomography (CT) of the chest, and polysomnography, if necessary, are valuable tests that can point to the disease that triggered hypoventilation. In most cases, treatment principles rest on managing the disease that caused this respiratory disturbance [6]. Some form of ventilation therapy, however, is almost always necessary, ranging from oxygen supplementation and noninvasive positive pressure ventilation to endotracheal intubation or even tracheostomy. Because rapid deterioration of the patient's condition can occur, an early diagnosis is imperative in achieving good patient outcomes.

Hypoventilation is a clinical manifestation of numerous conditions that interfere with functions of the respiratory system. In clinical terms, hypoventilation (in literal terms, decreased rate of breathing) demarcates reduced gas-exchange in the lungs that leads to accumulation of carbon dioxide in the body, as well as lack of oxygen. Numerous conditions can cause hypoventilation:

• Lung diseases such as bronchial asthma, cystic fibrosis and chronic obstructive pulmonary disease (COPD), but also conditions that cause chest wall deformities (scoliosis and kyphosis).
• Illnesses that target the neuromuscular system such as myasthenia gravis, Duchenne muscular dystrophy, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS) and poliomyelitis
• Infections, hypothyroidism, obesity hypoventilation syndrome (OHS), drug-induced, and a group of illnesses known as central hypoventilation syndromes may all cause hypoventilation.

These conditions trigger hypoventilation by either causing weakness of the respiratory muscles, providing a much tougher task of expelling by increasing the resistance of the bronchial tree, or mechanical compression of the chest wall by obesity and other structural deformities. The end-result is inability of the lungs to perform exchange of oxygen and carbon dioxide, leading to the appearance of symptoms such as fatigue and shortness of breath, while many patients report an increased breathing effort. Numerous complications can develop, depending on the severity of disease, one of the most important being respiratory acidosis, in which severe headache, altered mental state and drowsiness may develop as a result of markedly reduced pH and oxygen in blood. To make the diagnosis, it is necessary to obtain levels of arterial blood gasses and serum electrolytes and perform a test that investigates the functional capacity of the lungs known as spirometry. Additionally, imaging techniques such as chest X-ray or computed tomography (CT scan) of the chest may be useful in confirming the underlying cause of hypoventilation. In terms of treatment, identification of the cause is, in fact, the most important step, while symptomatic management through supplemental oxygen and correction of electrolytes is mandatory. In virtually all patients, some form of ventilatory support is necessary, ranging from noninvasive oxygen therapy to intubation and assisted or total artificial ventilation. The prognosis of patients who develop hypoventilation significantly depends on the severity of symptoms at the time of diagnosis and the underlying disease, but prompt recognition can surely improve long-term outcomes.

1. Porter RS, Kaplan JL. Merck Manual of Diagnosis and Therapy. 19th Edition. Merck Sharp & Dohme Corp. Whitehouse Station, N.J; 2011.

2. Chebbo A, Tfaili A, Jones SF. Hypoventilation syndromes. Med Clin North Am. 2011;95(6):1189-202

3. Piper AJ. Nocturnal hypoventilation - identifying & treating syndromes. Indian J Med Res. 2010;131:350-365.
4. Fukusumi M, Iidaka T, Mouri A, Hamamoto Y, Kamimura M. Respiratory failure associated with hypoventilation in a patient with severe hypothyroidism. Respirol Case Rep. 2014;2(2):79-80.
5. Cielo C, Marcus CL. Central Hypoventilation Syndromes. Sleep Med Clin. 2014;9(1):105-118.
6. Brown LK. Hypoventilation syndromes. Clin Chest Med. 2010;31(2):249-70
7. Paschoal IA, Villalba Wde O, Pereira MC. Chronic respiratory failure in patients with neuromuscular diseases: diagnosis and treatment. J Bras Pneumol. 2007;33(1): 81-92.
8. Muzumdar H, Arens R. Central Alveolar Hypoventilation Syndromes. Sleep Med Clin. 2008;3(4):601-615.
9. Chau EH, Lam D, Wong J, Mokhlesi B, Chung F. Obesity hypoventilation syndrome: a review of epidemiology, pathophysiology, and perioperative considerations. Anesthesiology. 2012;117(1):188-205.
10. Kessler R, Chaouat A, Schinkewitch P, et al. The obesity-hypoventilation syndrome revisited: a prospective study of 34 consecutive cases. Chest. 2001; 120: 369-376.
11. Kc P, Martin RJ. Role of Central Neurotransmission and Chemoreception on Airway Control. Respir Physiol Neurobiol. 2010;173(3):213-222.