Respiratory failure is a syndrome in which the respiratory system fails in one or both of its gas exchange functions: oxygenation and carbon dioxide elimination. In practice, it may be classified as either hypoxemic or hypercapnic.
Hypoxemic respiratory failure (type I) is characterized by an arterial oxygen tension (PaO2) lower than 60 mm Hg with a normal or low arterial carbon dioxide tension (PaCO2). This is the most common form of respiratory failure, and it can be associated with virtually all acute diseases of the lung, which generally involve fluid filling or collapse of alveolar units. Some examples of type I respiratory failure are cardiogenic or noncardiogenic pulmonary edema, pneumonia, and pulmonary hemorrhage.
Hypercapnic respiratory failure (type II) is characterized by a PaCO2 higher than 50 mm Hg. Hypoxemia is common in patients with hypercapnic respiratory failure who are breathing room air. The pH depends on the level of bicarbonate, which, in turn, is dependent on the duration of hypercapnia. Common etiologies include drug overdose, neuromuscular disease, chest wall abnormalities, and severe airway disorders (eg, asthma and chronic obstructive pulmonary disease [COPD]).
Respiratory failure may be further classified as either acute or chronic. Although acute respiratory failure is characterized by life-threatening derangements in arterial blood gases and acid-base status, the manifestations of chronic respiratory failure are less dramatic and may not be as readily apparent.
Acute hypercapnic respiratory failure develops over minutes to hours; therefore, pH is less than 7.3. Chronic respiratory failure develops over several days or longer, allowing time for renal compensation and an increase in bicarbonate concentration. Therefore, the pH usually is only slightly decreased.
The distinction between acute and chronic hypoxemic respiratory failure cannot readily be made on the basis of arterial blood gases. The clinical markers of chronic hypoxemia, such as polycythemia or cor pulmonale, suggest a long-standing disorder.
Arterial blood gases should be evaluated in all patients who are seriously ill or in whom respiratory failure is suspected. Chest radiography is essential. Echocardiography is not routine but is sometimes useful. Pulmonary functions tests (PFTs) may be helpful. Electrocardiography (ECG) should be performed to assess the possibility of a cardiovascular cause of respiratory failure; it also may detect dysrhythmias resulting from severe hypoxemia or acidosis. Right-sided heart catheterization is controversial (see Workup).
Hypoxemia is the major immediate threat to organ function. After the patient’s hypoxemia is corrected and the ventilatory and hemodynamic status have stabilized, every attempt should be made to identify and correct the underlying pathophysiologic process that led to respiratory failure in the first place. The specific treatment depends on the etiology of respiratory failure (see Treatment).
Respiratory failure can arise from an abnormality in any of the components of the respiratory system, including the airways, alveoli, central nervous system (CNS), peripheral nervous system, respiratory muscles, and chest wall. Patients who have hypoperfusion secondary to cardiogenic, hypovolemic, or septic shock often present with respiratory failure.
Ventilatory capacity is the maximal spontaneous ventilation that can be maintained without development of respiratory muscle fatigue. Ventilatory demand is the spontaneous minute ventilation that results in a stable PaCO2.
Normally, ventilatory capacity greatly exceeds ventilatory demand. Respiratory failure may result from either a reduction in ventilatory capacity or an increase in ventilatory demand (or both). Ventilatory capacity can be decreased by a disease process involving any of the functional components of the respiratory system and its controller. Ventilatory demand is augmented by an increase in minute ventilation and/or an increase in the work of breathing.
The act of respiration engages the following three processes:
Transfer of oxygen across the alveolus
Transport of oxygen to the tissues
Removal of carbon dioxide from blood into the alveolus and then into the environment
Respiratory failure may occur from malfunctioning of any of these processes. In order to understand the pathophysiologic basis of acute respiratory failure, an understanding of pulmonary gas exchange is essential.
Respiration primarily occurs at the alveolar capillary units of the lungs, where exchange of oxygen and carbon dioxide between alveolar gas and blood takes place. After diffusing into the blood, the oxygen molecules reversibly bind to the hemoglobin. Each molecule of hemoglobin contains 4 sites for combination with molecular oxygen; 1 g of hemoglobin combines with a maximum of 1.36 mL of oxygen.
The quantity of oxygen combined with hemoglobin depends on the level of blood PaO2. This relationship, expressed as the oxygen hemoglobin dissociation curve, is not linear but has a sigmoid-shaped curve with a steep slope between a PaO2 of 10 and 50 mm Hg and a flat portion above a PaO2 of 70 mm Hg.
The carbon dioxide is transported in 3 main forms: (1) in simple solution, (2) as bicarbonate, and (3) combined with protein of hemoglobin as a carbamino compound.
During ideal gas exchange, blood flow and ventilation would perfectly match each other, resulting in no alveolar-arterial oxygen tension (PO2) gradient. However, even in normal lungs, not all alveoli are ventilated and perfused perfectly. For a given perfusion, some alveoli are underventilated, while others are overventilated. Similarly, for known alveolar ventilation, some units are underperfused, while others are overperfused.
The optimally ventilated alveoli that are not perfused well have a large ventilation-to-perfusion ratio (V/Q) and are called high-V/Q units (which act like dead space). Alveoli that are optimally perfused but not adequately ventilated are called low-V/Q units (which act like a shunt).
At steady state, the rate of carbon dioxide production by the tissues is constant and equals the rate of carbon dioxide elimination by the lung. This relation is expressed by the following equation:
VA = K × VCO2/ PaCO2
where K is a constant (0.863), VA is alveolar ventilation, and VCO2 is carbon dioxide ventilation. This relation determines whether the alveolar ventilation is adequate for metabolic needs of the body.
The efficiency of lungs at carrying out of respiration can be further evaluated by measuring the alveolar-arterial PO2 gradient. This difference is calculated by the following equation:
PAO2 = FiO2 × (PB – PH2 O) – PACO2/R
where PA O2 is alveolar PO2, FiO2 is fractional concentration of oxygen in inspired gas, PB is barometric pressure, PH2O is water vapor pressure at 37°C, PACO2 is alveolar PCO2 (assumed to be equal to PaCO2), and R is respiratory exchange ratio. R depends on oxygen consumption and carbon dioxide production. At rest, the ratio of VCO2 to oxygen ventilation (VO2) is approximately 0.8.
Even normal lungs have some degree of V/Q mismatching and a small quantity of right-to-left shunt, with PAO2 slightly higher than PaO2. However, an increase in the alveolar-arterial PO2 gradient above 15-20 mm Hg indicates pulmonary disease as the cause of hypoxemia.
Hypoxemic respiratory failure
The pathophysiologic mechanisms that account for the hypoxemia observed in a wide variety of diseases are V/Q mismatch and shunt. These 2 mechanisms lead to widening of the alveolar-arterial PO2 gradient, which normally is less than 15 mm Hg. They can be differentiated by assessing the response to oxygen supplementation or calculating the shunt fraction after inhalation of 100% oxygen. In most patients with hypoxemic respiratory failure, these 2 mechanisms coexist.
V/Q mismatch is the most common cause of hypoxemia. Alveolar units may vary from low-V/Q to high-V/Q in the presence of a disease process. The low-V/Q units contribute to hypoxemia and hypercapnia, whereas the high-V/Q units waste ventilation but do not affect gas exchange unless the abnormality is quite severe.
The low V/Q ratio may occur either from a decrease in ventilation secondary to airway or interstitial lung disease or from overperfusion in the presence of normal ventilation. The overperfusion may occur in case of pulmonary embolism, where the blood is diverted to normally ventilated units from regions of lungs that have blood flow obstruction secondary to embolism.
Administration of 100% oxygen eliminates all of the low-V/Q units, thus leading to correction of hypoxemia. Hypoxemia increases minute ventilation by chemoreceptor stimulation, but the PaCO2 generally is not affected.
Shunt is defined as the persistence of hypoxemia despite 100% oxygen inhalation. The deoxygenated blood (mixed venous blood) bypasses the ventilated alveoli and mixes with oxygenated blood that has flowed through the ventilated alveoli, consequently leading to a reduction in arterial blood content. The shunt is calculated by the following equation:
QS/QT = (CCO2 – CaO2)/CCO2 – CvO2)
where QS/QT is the shunt fraction, CCO2 is capillary oxygen content (calculated from ideal PAO2), CaO2 is arterial oxygen content (derived from PaO2 by using the oxygen dissociation curve), and CvO2 is mixed venous oxygen content (assumed or measured by drawing mixed venous blood from a pulmonary arterial catheter).
Anatomic shunt exists in normal lungs because of the bronchial and thebesian circulations, which account for 2-3% of shunt. A normal right-to-left shunt may occur from atrial septal defect, ventricular septal defect, patent ductus arteriosus, or arteriovenous malformation in the lung.
Shunt as a cause of hypoxemia is observed primarily in pneumonia, atelectasis, and severe pulmonary edema of either cardiac or noncardiac origin. Hypercapnia generally does not develop unless the shunt is excessive (> 60%). Compared with V/Q mismatch, hypoxemia produced by shunt is difficult to correct by means of oxygen administration.
Hypercapnic respiratory failure
At a constant rate of carbon dioxide production, PaCO2 is determined by the level of alveolar ventilation according to the following equation (a restatement of the equation given above for alveolar ventilation):
PaCO2 = VCO2 × K/VA
where K is a constant (0.863). The relation between PaCO2 and alveolar ventilation is hyperbolic. As ventilation decreases below 4-6 L/min, PaCO2 rises precipitously. A decrease in alveolar ventilation can result from a reduction in overall (minute) ventilation or an increase in the proportion of dead space ventilation. A reduction in minute ventilation is observed primarily in the setting of neuromuscular disorders and CNS depression. In pure hypercapnic respiratory failure, the hypoxemia is easily corrected with oxygen therapy.
Hypoventilation is an uncommon cause of respiratory failure and usually occurs from depression of the CNS from drugs or neuromuscular diseases affecting respiratory muscles. Hypoventilation is characterized by hypercapnia and hypoxemia. Hypoventilation can be differentiated from other causes of hypoxemia by the presence of a normal alveolar-arterial PO2 gradient.
These diseases can be grouped according to the primary abnormality and the individual components of the respiratory system (eg, CNS, peripheral nervous system, respiratory muscles, chest wall, airways, and alveoli).
A variety of pharmacologic, structural, and metabolic disorders of the CNS are characterized by depression of the neural drive to breathe. This may lead to acute or chronic hypoventilation and hypercapnia. Examples include tumors or vascular abnormalities involving the brain stem, an overdose of a narcotic or sedative, and metabolic disorders such as myxedema or chronic metabolic alkalosis.
Disorders of the peripheral nervous system, respiratory muscles, and chest wall lead to an inability to maintain a level of minute ventilation appropriate for the rate of carbon dioxide production. Concomitant hypoxemia and hypercapnia occur. Examples include Guillain-Barré syndrome, muscular dystrophy, myasthenia gravis, severe kyphoscoliosis, and morbid obesity.
Severe airway obstruction is a common cause of acute and chronic hypercapnia. Examples of upper-airway disorders are acute epiglottitis and tumors involving the trachea; lower-airway disorders include COPD, asthma, and cystic fibrosis.
Diseases of the alveoli are characterized by diffuse alveolar filling, frequently resulting in hypoxemic respiratory failure, although hypercapnia may complicate the clinical picture. Common examples are cardiogenic and noncardiogenic pulmonary edema, aspiration pneumonia, or extensive pulmonary hemorrhage. These disorders are associated with intrapulmonary shunt and an increased work of breathing.
Common causes of type I (hypoxemic) respiratory failure include the following:
Pulmonary arterial hypertension
Granulomatous lung diseases
Cyanotic congenital heart disease
Acute respiratory distress syndrome (ARDS)
Fat embolism syndrome
Common causes of type II (hypercapnic) respiratory failure include the following:
Primary muscle disorders
Head and cervical cord injury
Primary alveolar hypoventilation
Respiratory failure is a syndrome rather than a single disease process, and the overall frequency of respiratory failure is not well known. The estimates for individual diseases mentioned in this article can be found in the Medscape Reference articles specific to each disease.
The relationship between acute respiratory failure and race is still debated. A study by Khan et al suggested that no differences in mortality exist in patients of Asian and Native Indian descent with acute critical illness after adjusting for differences in case mix.  Moss and Mannino reported worse outcome for African Americans with ARDS than for whites after adjustment for case mix.  Future prospective association studies should yield a better knowledge of the impact of race on the outcome of respiratory failure.
The mortality associated with respiratory failure varies according to the etiology. For ARDS, mortality is approximately 40-45%; this figure has not changed significantly over the years. [3, 4] Younger patients (< 60 y) have better survival rates than older patients. Approximately two thirds of patients who survive an episode of ARDS manifest some impairment of pulmonary function 1 or more years after recovery.
Significant mortality also occurs in patients admitted with hypercapnic respiratory failure. This is because these patients have a chronic respiratory disorder and other comorbidities such as cardiopulmonary, renal, hepatic, or neurologic disease. These patients also may have poor nutritional status.
For patients with COPD and acute respiratory failure, the overall mortality has declined from approximately 26% to 10%. Acute exacerbation of COPD carries a mortality of approximately 30%. The mortality rates for other causative disease processes have not been well described.
A study by Noveanu et al suggests a strong association between the preadmission use of beta-blockers and in-hospital and 1-year mortality among patients with acute respiratory failure.  Although cessation exacerbates the mortality, predischarge initiation of beta-blockers is also associated with an improved 1-year mortality.
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