Respiratory Failure

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.

Respiratory physiology

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.

Gas exchange

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).

Alveolar ventilation

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:

V_A = K × VCO₂/ PaCO₂

where K is a constant (0.863), V_A 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:

P_AO₂ = FiO₂ × (P_B – PH₂ O) – P_ACO₂/R

where P_A O₂ is alveolar PO₂, FiO₂ is fractional concentration of oxygen in inspired gas, P_B is barometric pressure, PH₂O is water vapor pressure at 37°C, P_ACO₂ 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 P_AO₂ 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

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

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:

Q_S/Q_T = (C_CO₂ – C_aO₂)/C_CO₂ – C_vO₂)

where Q_S/Q_T is the shunt fraction, C_CO₂ is capillary oxygen content (calculated from ideal P_AO₂), C_aO₂ is arterial oxygen content (derived from PaO₂ by using the oxygen dissociation curve), and C_vO₂ 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/V_A

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:

• COPD
• Pneumonia
• Pulmonary edema
• Pulmonary fibrosis
• Asthma
• Pneumothorax
• Pulmonary embolism
• Pulmonary arterial hypertension
• Pneumoconiosis
• Granulomatous lung diseases
• Cyanotic congenital heart disease
• Bronchiectasis
• Acute respiratory distress syndrome (ARDS)
• Fat embolism syndrome
• Kyphoscoliosis
• Obesity

Common causes of type II (hypercapnic) respiratory failure include the following:

• COPD
• Severe asthma
• Drug overdose
• Poisonings
• Myasthenia gravis
• Polyneuropathy
• Poliomyelitis
• Primary muscle disorders
• Porphyria
• Cervical cordotomy
• Head and cervical cord injury
• Primary alveolar hypoventilation
• Obesity-hypoventilation syndrome
• Pulmonary edema
• ARDS
• Myxedema
• Tetanus

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. ^[1] Moss and Mannino reported worse outcome for African Americans with ARDS than for whites after adjustment for case mix. ^[2] 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. ^[5] Although cessation exacerbates the mortality, predischarge initiation of beta-blockers is also associated with an improved 1-year mortality.