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Definition of Respiratory Failure

Respiratory dysfunction refers to the failure of gas exchange, i.e., decrease in arterial oxygen tension, PaO2, lower than 60 mm Hg (hypoxemia). It may or may not accompany hypercapnia, a PaCO2 higher than 50 mm Hg (decreased CO2 elimination).

Normal Physiology of Respiration

In normal individuals, the “alveolar” oxygen tension PAO2 remains close to 100 mmHg, while alveolar carbon-dioxide tension PACO2 is maintained close to 40 mmHg.

There is a small difference of 5-10 mmHg between “Alveolar (A)” and “arterial (a)” oxygen tension because around 2% of the systemic cardiac output bypasses the pulmonary circulation (physiologic shunt) and is not oxygenated.

The resulting mix of a small amount of deoxygenated blood makes the PO2 of arterial blood (PaO2) slightly lower than that of alveolar air (PAO2). A normal A-a gradient is about < 10 mmHg. If the A-a gradient is normal, it means there is no defect in the diffusion of gases. The A-a gradient helps to outline the different causes of respiratory failure.

Gas exchange in the alveolus

Image: “Gas exchange in the alveolus” by domdomegg. License: CC-BY 4.0

At steady-state, the rate of carbon dioxide production within the body is constant. The PACO2 depends on and is ‘inversely proportional’ to the ventilation, so the increased ventilation will lead to decreased PACO2, and decreased ventilation will cause increased PACO2.

The alveolar oxygen tension, PAO2, depends on the concentration of inhaled oxygen (FIO2), and alveolar carbon-dioxide tension (PACO2), as in the following equation:

                         PAO2    =     FIO2 × (PB – PH2 O) – PACO2/R

PAO2: Alveolar PO2           FIO2: Fractional concentration of oxygen in inspired gas
PB: Barometric pressure  PH2O: water vapor pressure at 37°C
PACO2: Alveolar PCO2     R: Respiratory exchange ratio.

Types of Respiratory Failure

There are two types of respiratory failure that are classified using arterial blood gases (ABG) analysis:

Type I is characterized by:

  • Hypoxemia (PaO2 less than 60 mmHg)
  • Without hypercapnia, normal or low PaCO2 (PaCO2 less than 50 mmHg)
  • Usually occurs due to a significant ventilation-perfusion mismatch

Type II is characterized by:

  • Hypoxemia (PaO2 less than 60 mmHg) and
  • Increased hypercapnia (PaCO2 more than 50 mmHg)
  • Usually occurs due to hypoventilation

Respiratory failure may be further classified as an acute or chronic onset.

Acute respiratory failure occurs within minutes and hours and is usually an emergency. It is characterized by life-threatening changes in arterial blood gases, and the body’s acid-base status, eg., tension pneumothorax, pulmonary embolism, acute respiratory distress syndrome, anaphylactic reactions.

Chronic respiratory failure occurs gradually over weeks and months. It is less dramatic and not always readily apparent. The kidneys usually compensate and normalize the body’s acid-base status by altering bicarbonate and acid excretion. Polycythemia, chronic obstructive pulmonary disease, and pneumoconiosis may also occur.

Pathophysiology of Hypoxemia

Hypoxemia is a decrease in arterial PO2, while hypoxia is decreased oxygen delivery to the tissues. Patients may develop hypoxia in the presence of normal PaO2, as in cases of carbon monoxide poisoning or decreased hemoglobin (anemia).Respiratory failure

There are five important pathophysiological causes of hypoxemia and respiratory failure.

1. Hypoventilation

The minute ventilation depends on the respiratory rate and the tidal volume, which is the amount of inspired air during each normal breath at rest.

Minute ventilation     =    Respiratory rate     x     Tidal volume

The normal respiratory rate is about 12 breaths per minute, and the normal tidal volume is about 500 mL. Therefore, the minute respiratory volume normally averages about 6 L/min.

Hypoventilation occurs when there is a decrease in the respiratory rate and/or tidal volume so that a lower amount of air is exchanged per minute. There will be decreased oxygen entry within the alveoli and the arteries, leading to decreased PaO2. As already described, the PaCO2 is inversely proportional to the ventilation. Hence, hypoventilation will lead to increased PaCO2.

The alveolar-arterial gradient will be normal and less than 10 mmHg since there is no defect in the diffusion of gases. In these cases, increasing the ventilation and/or increasing the oxygen concentration will correct the deranged blood gases.

2. Diffusion Impairment

In diffusion impairment, there is a structural problem within the lung. There may be decreased surface area (as in emphysema), or increased thickness of alveolar membranes (as in fibrosis and restrictive lung diseases) that impairs the diffusion of gases across the alveoli, leading to an increased alveolar-arterial gradient. In an increased A-a gradient, the alveolar PO2 will be normal or higher, but arterial PO2 will be lower. The greater the structural problem, the greater the alveolar-arterial gradient will be.

Since the diffusion of gases is directly proportional to the concentration of gases; therefore increasing the concentration of inhaled oxygen will correct PaO2, but the increased A-a gradient will be present as long as the structural problem is present.

3. Pulmonary Shunt

In pulmonary shunt, also known as right-to-left shunt, the venous deoxygenated blood from the right side enters the left side of the heart and systemic circulation without getting oxygenated within the alveoli. In simple words, shunt refers to “normal perfusion, poor ventilation.” The lungs have a normal blood supply, but ventilation is decreased or absent, resulting in failure to exchange gases with the incoming deoxygenated blood. The ventilation/perfusion ratio is or near to zero.

For example, in atelectasis, the collapsed lung is not ventilated, and the blood within that segment fails to oxygenate. In cyanotic heart diseases, the blood from right side bypasses (shunts) the lungs and enters the left side, causing hypoxemia and cyanosis.

The A-a gradient increases as deoxygenated blood enter the arterial (systemic) circulation, decreasing the arterial oxygen tension, PaO2.

Since venous blood does not oxygenate in the pulmonary shunt, therefore increasing the oxygen concentration does not correct the hypoxemia. The blood will bypass the lungs, no matter how high the oxygen concentration. This failure to increase PaO2 after oxygen administration is a very important point and helps with a differential diagnosis between impaired diffusion and other causes of hypoxemia that resolve with supplemental oxygen.

4. Ventilation – Perfusion (V/Q) Mismatch

V/Q is the ratio of alveolar ventilation (V) to pulmonary blood flow (Q). Matching ventilation and perfusion is essential for achieving the adequate exchange of oxygen and carbon dioxide within the alveoli. The V/Q ratio in normal individuals is around 0.8, but this ratio alters if there are significant ventilation or perfusion defects.

Within the lung, all the alveoli do not have uniform ventilation and perfusion. They tend to vary due to the effects of gravity. At the apex of the lung, alveoli are large and completely inflated, while they are small at the bases. Similarly, the blood supply is more at the base of the lung than at the apex. This creates physiological ventilation (V) – perfusion (Q) mismatch between different alveoli.

The decreased V/Q ratio (< 0.8) may occur either from decreased ventilation (airway or interstitial lung disease) or from over-perfusion. In these cases, the blood is wasted because it fails to properly oxygenate. In extreme conditions, when ventilation decreases significantly, and V/Q approaches zero, it will behave as a pulmonary shunt.

The increased V/Q ratio (> 0.8) usually occurs when perfusion is decreased (a pulmonary embolism prevents blood flow distal to obstruction) or over-ventilation. The air is wasted in these cases and is unable to diffuse within the blood. In extreme conditions, when perfusion decreases significantly, and V/Q approaches 1, the alveoli will act as dead space, and no diffusion of gases occurs.

Therefore, the increased mismatch in ventilation and perfusion within the lung impairs gas exchange processes, ultimately leading to hypoxemia and respiratory failure.

5. High Altitude

At high altitudes, the barometric pressure (PB) decreases, which will lead to decreased alveolar PO2 as in the equation:

PAO2    =     FIO2 × (PB – PH2 O) – PACO2/R

The decreased alveolar PAO2 will lead to decreased arterial PaO2 and hypoxemia, but the A-a gradient remains normal since there is no defect within the gas exchange processes. Under these conditions, additional oxygen (increasing the FIO2) increases the PAO2 and corrects the hypoxemia.

When a person suddenly ascends to the high altitude, the body responds to the hypoxemia by hyperventilation, causing respiratory alkalosis. The concentrations of 2, 3-diphosphoglycerate (DPG) are increased, shifting the oxygen-hemoglobin dissociation curve to the right.

Chronically, the acclimatization takes place, and the body responds by increasing the oxygen-carrying capacity of the blood (polycythemia). The kidneys excrete bicarbonates and maintain the pH within normal limits.

Causes of Hypoxemia
Cause PaO2 A-a gradient PaO2 response to supplemental oxygen
Hypoventilation Decreased Normal Increases
Diffusion Impairment Decreased Increased Increases
Shunt Decreased Increased Does not increase.
V/Q Mismatch Decreased Increased Usually increases (depends on V/Q mismatch type)
High Altitude Decreased Normal Increases

Pathophysiology of Hypercapnia

Hypercapnia occurs when carbon-dioxide tension (PCO2) increases to more than 50 mmHg. As explained above, at a steady-state, the rate of carbon dioxide production within the body is constant. The PACO2 depends on and is inversely proportional to ventilation, so decreased ventilation will cause increased PACO2 and vice versa. Therefore, hypercapnia (along with hypoxemia, Type II respiratory failure) occurs, usually due to conditions that decrease ventilation.Main symptoms of carbon dioxide toxicity

For example:

  • Reduced central respiratory drive, e.g.,, opioid overdose or head injury
  • Upper airway obstruction (foreign body, edema, infection)
  • Late severe acute asthma, COPD
  • Peripheral neuromuscular diseases, e.g., Guillain–Barre syndrome, myasthenia gravis, botulism
  • Respiratory muscle fatigue

Treatment of Respiratory Failure

Patients with acute respiratory failure have an increased risk of hypoxic tissue damage and should be admitted to a respiratory/intensive care unit. The patient’s airway, breathing, and circulation (ABCs) must be assessed and managed first, similar to all emergencies.

The first goal is to correct hypoxemia and/or prevent tissue hypoxia by maintaining an arterial oxygen tension (PaO2) of 60 mm Hg or arterial oxygen saturation (SaO2) greater than 90%. Usually, initially providing supplemental oxygen and mechanical ventilation, which is provided by facial mask (non-invasive) or by tracheal intubation, is effective.

Specific respiratory failure treatment depends on the underlying cause. Therefore, we should try to identify the underlying pathophysiologic disturbances that led to respiratory failure and correct them by providing specific treatment, such as steroids and bronchodilators for COPD and asthma, antibiotics for pneumonia, and heparin for pulmonary embolism.

Mechanical Ventilation Goals

Mechanical ventilation has two principal goals:

  1. Increase PaO2 by increasing the concentration of inhaled oxygen (FIO2) and positive end-expiratory pressure (PEEP).
  2. Decrease PaCO2 by increasing the ventilation by adjusting the tidal volume and respiratory rate of the mechanical ventilators.

Mechanical ventilation is also an appropriate therapy for respiratory muscle fatigue because it rests the respiratory muscles.

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