Mechanisms, causes, and effects of hypercapnia

INTRODUCTION — Hypercapnia, defined as an elevation in the arterial carbon dioxide tension, is commonly encountered during the evaluation of patients with dyspnea and/or altered sensorium. Understanding the mechanisms, causes, and effects of hypercapnia is critical to its management.

The relevant physiology of ventilatory control, mechanisms, causes, and effects of hypercapnia are presented in this topic review. The evaluation and treatment of patients with acute hypercapnia are presented separately. (See "The evaluation, diagnosis, and treatment of the adult patient with acute hypercapnic respiratory failure".)

FORMULA FOR ARTERIAL CARBON DIOXIDE TENSION — The partial pressure of carbon dioxide in arterial blood (PaCO₂) is directly proportional to the rate of carbon dioxide (CO₂) production (VCO₂) by oxidative metabolism and indirectly proportional to the rate of CO₂ elimination by the lung (alveolar ventilation; V_A). Alveolar ventilation is the component of the expired minute volume that reaches perfused alveoli, and is in turn determined by minute ventilation (V_E) and the ratio of dead space (V_D) to tidal volume (V_T) or V_D/V_T.

The following calculation is used to determine the PaCO₂:

PaCO₂ = (k) x VCO₂/[V_E(1 - V_D/V_T)]

MECHANISMS AND ETIOLOGIES OF HYPERCAPNIA — Based upon the formula for the partial pressure of arterial carbon dioxide (PaCO₂) (see 'Formula for arterial carbon dioxide tension' above), factors that increase carbon dioxide (CO₂) production (eg, fever), reduce minute ventilation (eg, sedative-induced hypoventilation), and/or increase dead space (eg, chronic obstructive pulmonary disease exacerbation) may elevate the PaCO₂. It has been estimated that intrinsic lung diseases that increase dead space are responsible for the majority of cases of hypercapnic respiratory failure, while a smaller proportion are due to extra-pulmonary conditions (eg, sedatives, neuromuscular or thoracic cage disorders) [1]. Unless a patient has limited pulmonary reserve, increased CO₂ production does not result in clinically important hypercapnia. Etiologies associated with hypercapnia are listed in the table.

Decreased minute ventilation/global hypoventilation

Mechanism — Minute ventilation (V_E) is determined by respiratory rate (RR) and tidal volume (V_T) (V_E  =  RR  x  V_T). Both RR and V_T in turn are determined by central and peripheral factors.

●Central and neural control - The central respiratory center in the medulla comprises respiratory pacer cells, and receives stimulatory signals from central and peripheral chemoreceptors (respond to changes in hydrogen ion concentration, PaCO₂ (figure 1), and partial pressure of arterial oxygen [PaO₂] (figure 2)), as well as mechanoreceptors and thermal receptors in the upper airway and lung (respond to mechanical stimuli such as stretch, or changes in temperature related to flow). Respiratory drive is also uniquely responsive to behavioral and cognitive inputs from the cortex (eg, anxiety and pain). These signals are integrated centrally into a combined output to the muscles of respiration to ultimately affect V_E.

●Muscles of respiration - The muscles of respiration (eg, diaphragm, intercostal muscles, sternocleidomastoids, scalenes, trapezii) can affect V_E by altering RR as well as depth and duration of inspiration (affects V_T). In the presence of muscular weakness, patients typically adopt a rapid shallow breathing pattern. This leads to increased VD/VT and, while total ventilation may be the same or even increased compared to normal, alveolar ventilation is reduced.

●Thoracic cage compliance - Minute ventilation is also influenced by thoracic cage compliance such that despite adequate central respiratory drive and peripheral muscle function, limitations in lung expansion (which reduce V_T) can occur in patients with thoracic cage dysfunction (eg, thoracoplasty). While initially RR will increase to compensate for a reduction in V_T (to maintain resting alveolar ventilation), eventually RR will fall as fatigue ensues (eg, during times of stress or exercise) due to the mechanical work of breathing at a given load or disease progression; similar consequences of muscle fatigue may occur in patients with severe airway resistance (eg, asthma, chronic obstructive pulmonary disease [COPD]) who cannot increase ventilation sufficiently in the setting of acute changes in airway resistance to maintain a normal partial pressure of arterial carbon dioxide (PaCO₂). As with neuromuscular disease, a rapid-shallow breathing pattern increases V_D/V_T and reduces alveolar ventilation for any given total ventilation. If the patient is not able to increase total ventilation sufficiently to compensate for the increased V_D/V_T ratio, hypercapnia will ensue.

Thus, reduction in either central respiratory drive (won't breathe) or peripheral muscle, nerve, airway, and thoracic cage function (can't breathe) will affect V_E and result in global hypoventilation or normal total ventilation with increased V_D/V_T leading to a reduced alveolar ventilation and hypercapnia. In patients with underlying problems with the ventilatory pump, a superimposed gas exchange problem or increased CO₂ production may lead to hypercapnia. (See "Control of ventilation" and 'Etiologies' below and "Respiratory muscle weakness due to neuromuscular disease: Clinical manifestations and evaluation", section on 'Inadequate ventilation'.)

In contrast to respiratory rate, tidal volume and total ventilation cannot be readily estimated at the bedside. When a patient hypoventilates, PaO₂ drops roughly in proportion to the rise in PaCO₂ as dictated by the alveolar gas equation:

PAO₂ is alveolar partial pressure of oxygen, FiO₂ is the fraction of oxygen in the inspired gas, Patm is barometric pressure, Pwater vapor reflects the fact that the gas that reaches the alveolus is fully humidified by the airways, and R is the respiratory quotient (ie, the ratio of CO₂ produced for each molecule of oxygen consumed by metabolism). The first part of the equation reflects the partial pressure of oxygen in inspired gas. As an example, at altitude the barometric pressure is reduced and PAO₂ is consequently reduced, which will lead to hypoxemia. The second part of the equation represents alveolar ventilation, given the relationship between PaCO₂ and alveolar ventilation noted above. If alveolar ventilation is reduced, the oxygen diffusing into the blood from the alveolus is not rapidly replenished (nor is the CO₂ diffusing into the alveolus from the blood being removed normally); consequently, there is less oxygen in the alveolus (and more CO₂), and less oxygen in the blood. As CO₂ rises in the alveolus, the diffusion gradient for CO₂ between the pulmonary capillaries and the alveolus diminishes, which means less CO₂ is removed from the capillary blood, which is returned to the left heart and pumped out to the body; the result may be hypercapnia.

Thus, when a patient presents with hypoxemia, it is important for the clinician to consider the possibility of hypoventilation as a cause of hypoxemia before starting supplemental oxygen. Consequently, high level of clinical suspicion for global hypoventilation is necessary to prompt an arterial blood gas for the early detection, prevention, and treatment of hypercapnia. The clinical evaluation and treatment of hypercapnia is discussed in detail separately. (See "The evaluation, diagnosis, and treatment of the adult patient with acute hypercapnic respiratory failure".)

Etiologies — A reduction in the total V_E with constant CO₂ production and dead space will invariably lead to hypercapnia (see 'Formula for arterial carbon dioxide tension' above). The cause of global hypoventilation can arise anywhere along the axis from the respiratory control center in the medulla, the upper motor neurons, the spinal cord (anterior horn cells), the lower motor neurons (ie, phrenic nerve), neuromuscular junction, or the respiratory muscle (diaphragm, intercostal muscles, scalenes, sternocleidomastoids, trapezii) (table 1). (See 'Decreased minute ventilation/global hypoventilation' above.)

Examples include:

●Decreased respiratory drive (won't breathe) - Any major physiologic, anatomic, or pharmacologic insult to the respiratory control center in the medulla will dampen respiratory drive and can result in hypercapnia. This includes sedative overdose (eg, narcotic or benzodiazepine), encephalitis, major stroke, central and obstructive sleep apnea, primary and central alveolar hypoventilation syndromes, brainstem disease, metabolic alkalosis, hypothyroidism, hypothermia, and other causes that are listed in the table (table 1). (See "Control of ventilation".)

●Decreased respiratory nerve and muscle function and/or decreased thoracic cage function (can't breathe) – Many neuromuscular disorders are associated with global hypoventilation, particularly during conditions of stress (eg, infection, dehydration) that ordinarily induce a compensatory increase in minute ventilation. Examples include cervical spine injury (above C3) with diaphragmatic paresis/paralysis, amyotrophic lateral sclerosis, poliomyelitis, Guillain-Barré syndrome, phrenic nerve injury or neuropathy, myopathy due to hypo- and hyperthyroidism, myasthenia gravis, critical illness polymyoneuropathy, muscular dystrophy, and polymyositis. Additional rare causes including drugs, toxins, and poisons are listed in the table (table 1). (See "Respiratory complications in the adult patient with chronic spinal cord injury" and "Diagnostic evaluation of adults with bilateral diaphragm paralysis" and "Diagnosis of amyotrophic lateral sclerosis and other forms of motor neuron disease" and "Guillain-Barré syndrome in adults: Pathogenesis, clinical features, and diagnosis" and "Clinical manifestations of myasthenia gravis" and "Neuromuscular weakness related to critical illness" and "Duchenne and Becker muscular dystrophy: Clinical features and diagnosis" and "Clinical manifestations of dermatomyositis and polymyositis in adults".)

Rarely, severe hypophosphatemia or hypomagnesemia may induce inspiratory muscle myopathy that can lead to hypercapnia. (See "Hypophosphatemia: Clinical manifestations of phosphate depletion" and "Hypomagnesemia: Clinical manifestations of magnesium depletion".)

Thoracic cage disorders are also a frequently forgotten cause of hypercapnia and include kyphoscoliosis and thoracoplasty, flail chest, ankylosing spondylitis, and pectus excavatum. Although hypoventilation, typically as a consequence of reduced compliance of the chest wall or disruption of the linkage between chest wall and lung motion, is one mechanism through which hypercapnia can occur in patients with thoracic cage disorders, the etiology is likely multifactorial and may involve central control of breathing as well as ventilation/perfusion (V/Q) mismatch. (See "Chest wall diseases and restrictive physiology" and "Clinical manifestations of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults".)

Increased dead space

Mechanism — Dead space (V_D) reflects the non-gas-exchanging parts of the lung.

It comprises the following (figure 3):

●Anatomical dead space – The anatomical dead space consists of the space between the upper airways and the terminal bronchioles, across which O₂ and CO₂ cannot physically be exchanged. In general, the anatomical dead space (in milliliters) is approximately equal to the patient's body weight in pounds. An individual's pattern of breathing, primarily the size of the inspiration, determines the proportion of the breath that is allocated to the anatomic dead space, ie, it changes the V_D/V_T. If the anatomic dead space is 150 mL and one takes a 450 mL breath, the V_D/V_T is 0.33 (assuming minimal alveolar dead space); if one then changes the breathing pattern so that the tidal volume is 300 mL, the VD/VT is now 0.5. If total ventilation is unchanged, hypercapnia will result.

●Alveolar dead space – The alveolar dead space reflects reduced perfusion to alveoli that are ventilated. Thus, dead space (positive ventilation but no perfusion) is on the opposite spectrum of V/Q mismatch from shunt (no ventilation but positive perfusion). An increase in alveolar dead space is the main mechanism that underlies hypercapnia in patients with parenchymal lung disease (eg, COPD, pneumonia, interstitial fibrosis) and pulmonary vascular disease. Conditions that increase dead space to result in hypercapnia are discussed below. (See 'Etiologies' below and 'Chronic obstructive pulmonary disease' below.)

●Physiological dead space – The combination of anatomic and alveolar dead space is called physiological dead space.

Etiologies — Rapid shallow breathing can contribute to hypercapnia by increasing the dead space to tidal volume ratio, because the anatomic dead space in the central airways comprises a larger proportion of the smaller tidal breath. Increased alveolar dead space is mostly seen in patients with intrinsic lung disease that affects the gas-exchanging component of the lung (table 1).

Increases in alveolar dead space can be due to pulmonary capillary compression (extrinsic obstruction) from overinflated lung (eg, too much positive pressure with mechanical ventilation) or destruction of pulmonary capillaries (emphysema, interstitial fibrosis, pulmonary vasculitis). In most cases, the initial increase in dead space stimulates minute ventilation in an attempt to normalize PaCO₂, so that many patients with these disorders are initially normocapnic. It is only when this compensatory mechanism is impaired (usually because of problems with the ventilatory pump, such as muscle weakness or increased airway resistance) or because the extent of the disease is so great that hyperventilation of the remaining normal alveoli is inadequate to compensate for the dead space, that increased dead space will result in clinically relevant hypercapnia (eg, patients with severe or endstage lung disease). (See 'Increased dead space' above.)

Increased V_D (ie, areas of high V/Q) is thought to be the main mechanism that contributes to the development of hypercapnia in patients with COPD, the details of which are discussed separately [2]. It should be noted that the relatively linear relationship between PaCO₂ and CO₂ content of the blood often allows hyperventilation of the normal lung units to compensate for diseased units with high V/Q; thus, patients with mild to moderate V/Q abnormalities may be hypoxemic but not hypercapnic. (See 'Chronic obstructive pulmonary disease' below.)

Increased production of carbon dioxide — CO₂ production is a product of oxidative metabolism. Increased CO₂ production is rarely the primary cause of hypercapnia because the usual response to increased CO₂ production is an increased V_E, which eliminates excess CO₂ to maintain a normal PaCO₂. However, an increase in CO₂ production can partially contribute to an elevated PaCO₂, when the ability to increase alveolar ventilation (V_A) is limited (eg, severe COPD exacerbation, respiratory muscle weakness; ie, conditions that increase dead space or prevent the normal compensatory increase in global ventilation).

CO₂ production rises with fever, thyrotoxicosis, increased catabolism (sepsis, steroids), overfeeding, exercise and metabolic acidosis (table 1).

Chronic obstructive pulmonary disease — Increased V_D (ie, areas of high V/Q) is thought to be the main mechanism that contributes to the development of hypercapnia in patients with COPD [2]. While some patients can compensate by increasing their V_E and redistributing perfusion to improve V/Q matching, (eg, the classic normocapnic "pink puffer"), some patients cannot compensate and develop chronic hypercapnia (eg, the classic "blue bloater"). Other patients with COPD will develop hypercapnia with an exacerbation or in response to supplemental oxygen, which reverts to normal once the exacerbation resolves (reversible hypercapnia) or oxygen is weaned, respectively. The mechanisms that explain hypercapnia in COPD are as follows:

Hypercapnia at baseline/during exacerbations — Factors contributing to the increased dead space (increased ventilation relative to perfusion) and the consequent development of hypercapnia in COPD at baseline or during exacerbations (in the absence of oxygen) include destruction of capillaries by emphysema, airflow obstruction leading to hyperinflation, and reduced lung compliance at high lung volumes [3]. In addition, the breathing pattern in patients with COPD and hypercapnia is different from that found in their normocapnic counterparts; hypercapnic patients tend to have lower tidal volumes and an increased respiratory rate, which increases V_D/V_T [4-6]. As an example, in one prospective study, no difference in baseline minute ventilation was observed in 20 patients with COPD when compared with normal controls [7]. However, during an exacerbation, patients with COPD exhibited an increased respiratory rate, lower tidal volume, and increased respiratory drive (as measured by mouth occlusion pressure) when compared to normal controls.

The lower tidal volumes in patients with COPD are the consequence of several factors. Respiratory drive, as measured by mouth occlusion pressure or inspiratory flow rate appears to be high [4,7]; this may result in a shortened inspiratory time. Because of increased expiratory resistance, expiratory time must be prolonged to allow the individual to return to functional residual capacity (ie, relaxation volume, when the outward recoil of the chest wall is equal and opposite to the inward recoil of the lung) (figure 4). The mechanisms of this abnormal breathing pattern remain unclear but likely include hypoxemia [6], stimulation of pulmonary irritant and J receptors by coexisting chronic bronchitis [4,5], and cognitive factors relating to respiratory discomfort. In addition, inspiratory capacity is reduced when respiratory rate increases due to dynamic hyperinflation [8]. (See "Disorders of ventilatory control" and "Dynamic hyperinflation in patients with COPD".)

Oxygen-induced hypercapnia — Some (but not all) patients with COPD develop hypercapnia when given supplemental oxygen, the mechanism of which has been clarified since the early 1980s. Importantly, the potential development of hypercapnia should not preclude the administration of oxygen to patients with COPD who are hypoxemic, since withholding it can be potentially harmful (the combination of an acute respiratory acidosis and hypoxemia may lead to cardiac arrhythmias and myocardial dysfunction). The mechanism of oxygen-induced hypercapnia in COPD is discussed in this section. The safe administration of oxygen to this population is discussed separately. (See "The evaluation, diagnosis, and treatment of the adult patient with acute hypercapnic respiratory failure", section on 'Titration of oxygen'.)

It was originally thought that patients with COPD rely on their hypoxemic ventilatory drive due to a blunted sensitivity to CO₂ (ie, pH), and that hypercapnia in this setting resulted from "removal" of hypoxemic drive with a consequent reduction in alveolar ventilation. In general, the control of breathing is dependent upon central drive (inspiratory neurons in the medulla) when asleep, and the reticular activating system when awake (see "Control of ventilation"). It is now thought that the major reason for oxygen-induced hypercapnia in patients with COPD is worsening of ventilation/perfusion mismatch leading to increased dead space; while the administration of oxygen does diminish hypoxic ventilatory drive, its contribution to the acute rise in PaCO₂ when supplemental oxygen is administered is relatively minor. Decreased binding affinity of hemoglobin for carbon dioxide (the Haldane effect) in the presence of oxygen also contributes [7,9]. The following studies support this theory [7,9-14]:

●In one prospective study, 20 patients with COPD were compared with normal controls [7]. When patients were given supplemental oxygen at 5 L/min during an exacerbation, minute ventilation dropped by only 14 percent due to a small decrease in respiratory rate without a change in tidal volume. However, this reduction in minute ventilation could not account for the entire increase in PaCO₂; further analysis led to the conclusion that hypercapnia was primarily due to an increase in the dead space to tidal volume ratio. Although ventilatory drive decreased in response to supplemental oxygen, it remained three times greater than in normal controls, suggesting that respiratory drive is not eliminated by the administration of supplemental oxygen in this population.

●Another prospective study examined the effects of administration of a FiO₂ of 1 on patients with chronically stable COPD [9]. All patients had an initial decrease in minute ventilation of approximately 18 percent, which then returned to approximately 93 percent of baseline after 12 minutes, despite continued oxygen administration. The initial decrease in minute ventilation was due to reductions in both tidal volume and respiratory rate. After 15 minutes of oxygen administration, the PaCO₂ increased by an average of 23 mmHg, which was due to three components:

•Increased dead space – The largest component of acute hypercapnia (11 mmHg, 48 percent) was due to an increase in dead space ventilation (ie, areas of high V/Q). This probably reflects worsening of V/Q matching due to a loss of hypoxic pulmonary vasoconstriction (HPV) (ie, redirection of blood flow from relatively well-ventilated units to poorly ventilated units). HPV normally serves to improve the matching between blood flow and ventilation. This compensatory response improves V/Q matching and decreases physiologic dead space. The effect of loss of HPV is most pronounced in patients with a low initial PaO₂. The importance of V/Q mismatching has been confirmed in other studies [10].

•Haldane effect – An additional 7 mmHg (30 percent) rise in PaCO₂ was attributed to decreased hemoglobin affinity for CO₂ (the Haldane effect) [10]. The Haldane effect refers to the rightward displacement of the CO₂-hemoglobin dissociation curve in the presence of increased oxygen saturation (figure 5). This occurs because oxyhemoglobin binds CO₂ less avidly than deoxyhemoglobin; thus, addition of oxygen to the blood displaces CO₂ from hemoglobin thereby increasing the amount of CO₂ dissolved in blood, which in turn determines PaCO₂ [11]. The Haldane effect is most pronounced when the arterial oxygen saturation (SaO₂) changes most per mmHg of PaO₂ (ie, on the steep part of the oxygen-hemoglobin dissociation curve), which is between a PaO₂ of 20 and 60 mmHg (figure 6).

•Decreased minute ventilation – Only about 5 mmHg (22 percent) could be directly attributed to the small (7 percent) decrease in minute ventilation.

The relative contributions of a reduction in minute ventilation, the Haldane effect, and changes in V/Q matching have been confirmed by computer models of gas exchange and pulmonary hemodynamics [12].

●A third study of 22 patients with exacerbations of COPD reported a reduction in minute ventilation in response to 100 percent oxygen in those who developed hypercapnia (CO₂ retainers), when compared with those who remained normocapnic (non-retainers; 1.8 versus 0 L change in minute ventilation [V_E]) [13]. However, a limitation of this study is the definition of CO₂ retention as an increase in PaCO₂ of 3 mmHg, which is likely clinically insignificant. Additionally, both CO₂ retainers and non-retainers had mean PaO₂ levels >54 mmHg. This would minimize the role of hypoxic pulmonary vasoconstriction and the Haldane effect, both of which are more prominent at lower partial pressures of oxygen.

The FiO₂ associated with different flow rates with nasal cannula depends upon the patient's total minute ventilation (the greater the ventilation, the lower the FiO₂ for any given flow rate because the individual is entraining larger volumes of "room air" thereby diluting the supplemental oxygen; alternatively, with lower minute ventilation, the supplemental oxygen comprises a greater portion of the inspired gas). In addition, the stimulation of flow receptors by inspiratory gas in the nasopharynx reduces respiratory drive independently of changes in PaO₂. Consequently, the FiO₂ may rise as ventilation falls, which could lead to a cycle that results in progressive hypercapnia.

The anxiolytic and anti-dyspneic effects of supplemental oxygen can promote sleep, particularly in patients who arrive in the emergency department sleep-deprived. The onset of sleep is associated with loss of the drive to breathe associated with the reticular activating system. When the awake and behavioral influences on breathing present during wakefulness are absent, respiration is sustained solely by metabolic control mechanisms. This can result in progressive hypercapnia [15,16].

Importantly, abrupt removal of supplemental oxygen may cause the PaO₂ to fall to a level lower than when oxygen therapy was begun. The development of hypoxemia in this setting is more rapid than the resolution of hypercapnia (CO₂ stores in the body are large due to the ability of CO₂ to diffuse into a range of tissues), and subsequent tissue hypoxia can potentially cause or worsen metabolic acidosis [17]. Thus, the acute withdrawal of oxygen is not recommended. The titration of oxygen in hypercapnic patients is discussed separately. (See "The evaluation, diagnosis, and treatment of the adult patient with acute hypercapnic respiratory failure", section on 'Titration of oxygen'.)

EFFECTS OF HYPERCAPNIA — The end-organ effects of hypercapnia are discussed in this section. The clinical manifestations due to these end-organ effects are discussed separately. (See "The evaluation, diagnosis, and treatment of the adult patient with acute hypercapnic respiratory failure", section on 'Clinical features of hypercapnia'.)

Cerebral effects — Acute hypercapnia may produce the following effects on the brain [18,19]:

●An initial increase in respiratory drive followed by a depressed level of consciousness (also known as carbon dioxide [CO₂] narcosis) and reduced respiratory drive

●An increase in cerebral blood flow and intracranial pressure

Together, these effects can eventually progress to seizures, coma, and death.

The effects on consciousness are poorly understood but may be due to increases in brain glutamine and gamma-aminobutyric acid (GABA), as well as reductions in glutamate and aspartate. These changes may negatively impact the level of consciousness and depress minute ventilation and inspiratory drive [20].

The degree of acute hypercapnia required to provoke these responses is variable. Eucapnic individuals do not exhibit a depressed level of consciousness until the partial pressure of arterial carbon dioxide (PaCO₂) is greater than 75 to 80 mmHg (10 to 10.6 kPa), while patients with chronic hypercapnia may not develop symptoms until the PaCO₂ rises acutely to greater than 90 to 100 mmHg. In addition, patients with chronic hypercapnia have a compensatory loss of hydrogen ions from the kidney, associated with a rise in the plasma bicarbonate concentration. As a result, a larger elevation in PaCO₂ is required to produce the same reduction in pH. This feature can be used during arterial blood gas analysis to distinguish acute from acute-on-chronic and chronic hypercapnia, the details of which are discussed separately. (See "The evaluation, diagnosis, and treatment of the adult patient with acute hypercapnic respiratory failure", section on 'Arterial blood gas analysis' and "The evaluation, diagnosis, and treatment of the adult patient with acute hypercapnic respiratory failure", section on 'Differential diagnosis'.)

Cardiorespiratory effects — Patients with mild acute hypercapnia frequently complain of dyspnea, which is thought to be due to the initial compensatory increase in respiratory drive induced by elevated levels of arterial CO₂ and the associated acidemia (stimulation of peripheral and central chemoreceptors). In addition, hypercapnia may result in reduced myocardial and diaphragmatic contractility, which can progress to cardiovascular instability, arrhythmia, cardiac or respiratory arrest, and death.

Physiologic effects — One of the physiologic effects of hypercapnia (and/or acidosis) includes a shift of the oxyhemoglobin dissociation curve to the right, leading to increased release of oxygen to tissues (Bohr effect). However, arterial oxygenation as reflected by the partial pressure of arterial oxygen (PaO₂) is rarely significantly affected.

Metabolic effects — Hypercapnia produces a respiratory acidosis as determined by the equation [H⁺]  =  24  x  PaCO₂/HCO₃^-, where H⁺ is the hydrogen ion concentration in nEq/L and HCO₃^- is the concentration of bicarbonate in mEq/L. Excess amounts of CO₂ combine with water (H₂O) to form carbonic acid (H₂CO₃), which, in turn, rapidly dissociates to form H⁺ and HCO₃^-. Importantly, serum bicarbonate levels rise slightly with an acute respiratory acidosis because of the carbonic acid reaction. This reaction occurs within red blood cells and is an important means by which the body buffers an acute respiratory acidosis; the proton formed binds to the negative charges of the hemoglobin and the bicarbonate ion exits the red cell. Bicarbonate is not an effective buffer for a respiratory acidosis. Administration of bicarbonate to a patient with acute hypercapnia leads to an increase in CO₂; if the patient is already unable to increase ventilation to maintain a normal PaCO₂, the reaction will shift back to the production of a proton and a molecule of bicarbonate.

There are multiple clinical effects of acidosis, including cardiovascular instability/arrest, hypotension, and cerebral depression as well as decreased binding of calcium to albumin (ie, increase serum ionized calcium levels) and an extracellular shift of potassium. Frank hyperkalemia is rare. (See "Simple and mixed acid-base disorders".)

SUMMARY AND RECOMMENDATIONS

●Hypercapnia is defined as an elevation in the arterial carbon dioxide tension (PaCO₂). The carbon dioxide level in arterial blood is directly proportional to the rate of carbon dioxide (CO₂) production (VCO₂) by oxidative metabolism and indirectly proportional to the rate of CO₂ elimination by the lung (alveolar ventilation; V_A). Alveolar ventilation is, in turn, determined by minute ventilation (V_E) and the ratio of dead space (V_D) to tidal volume (V_T). (See 'Formula for arterial carbon dioxide tension' above.)

●Hypercapnia is due to factors that reduce minute ventilation, increase physiologic dead space, and/or increase CO₂ production. Intrinsic lung diseases that increase dead space are responsible for most cases of hypercapnic respiratory failure, while a smaller proportion are due to extra pulmonary conditions (eg, sedatives, neuromuscular or thoracic cage disorders). Unless a patient has limited pulmonary reserve, conditions that increase CO₂ production will not result in clinically important hypercapnia. Etiologies associated with hypercapnia are listed in the table (table 1). (See 'Mechanisms and etiologies of hypercapnia' above.)

●Acute hypercapnia may produce a depressed level of consciousness, increased cerebral blood flow and intracranial pressure, and reduced myocardial and diaphragmatic contractility. Other effects include increased release of oxygen to tissues and a respiratory acidosis. Severe hypercapnic acidosis eventually results in coma, cardiac or respiratory arrest, and death. Normal individuals do not exhibit a depressed level of consciousness until the PaCO₂ is greater than 75 to 80 mmHg (10 to 10.6 kPa), while patients with chronic hypercapnia may not develop symptoms until the PaCO₂ rises acutely to greater than 90 to 100 mmHg (11.9 to 13.3 kPa). (See 'Effects of hypercapnia' above.)