Respiratory Failure: Background, Pathophysiology, Etiology

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:

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

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:

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.