Pathophysiology

Respiratory failure can arise from an abnormality in any of the components of the
respiratory system, including the airways, alveoli, 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.

Hypoxemic respiratory failure

The pathophysiologic mechanisms that account for the hypoxemia observed in a wide
variety of diseases are ventilation-perfusion (V/Q) mismatch and shunt. These 2
mechanisms lead to widening of the alveolar-arterial oxygen difference, which normally
is less than 15 mm Hg. With V/Q mismatch, the areas of low ventilation relative to
perfusion (low V/Q units) contribute to hypoxemia. An intrapulmonary or intracardiac
shunt causes mixed venous (deoxygenated) blood to bypass ventilated alveoli and results
in venous admixture. The distinction between V/Q mismatch and shunt can be made by
assessing the response to oxygen supplementation or calculating the shunt fraction
following inhalation of 100% oxygen. In most patients with hypoxemic respiratory
failure, these 2 mechanisms coexist.

Hypercapnic respiratory failure

At a constant rate of carbon dioxide production, PaCO2 is determined by the level of

alveolar ventilation (Va), in which VCO2 is ventilation of carbon dioxide and K is a
constant value (0.863).

(Va = K x VCO2)/PaCO2

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.

Ventilatory capacity versus demand

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.
Pathophysiologic Mechanisms in Acute Respiratory Failure

The act of respiration engages 3 processes: (1) transfer of oxygen across the alveolus, (2)
transport of oxygen to the tissues, and (3) 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.

SOURCE:): http://emedicine.medscape.com/article/167981-overview

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Acute hypoxemic respiratory failure is severe arterial hypoxemia that is refractory to

supplemental O2. It is caused by intrapulmonary shunting of blood secondary to airspace
filling or collapse. Findings include dyspnea and tachypnea. Diagnosis is by ABGs and
chest x-ray. Treatment usually requires mechanical ventilation.

Etiology

Airspace filling in acute hypoxemic respiratory failure (AHRF) may result from

• Elevated alveolar capillary hydrostatic pressure, as occurs in left ventricular

failure or hypervolemia
• Increased alveolar capillary permeability, as occurs in any of the conditions
predisposing to acute lung injury/acute respiratory distress syndrome
(ALI/ARDS)
• Blood, as seen in diffuse alveolar hemorrhage

Pathophysiology
ALI/ARDS: ALI resulting in more severe hypoxemia is known as ARDS. However,
differentiation between these two forms (see Table 1: Respiratory Failure and Mechanical
Ventilation: Definition of ALI/ARDS ) is arbitrary given that Pao2 correlates poorly
with lung pathology and clinical course.

Table 1
Definition of ALI/ARDS
• Acute onset of respiratory
failure
• Diffuse bilateral infiltrates on
chest radiograph
• Absence of left atrial
hypertension (pulmonary artery
occlusive pressure* [PAOP] ≤
18 mm Hg) or no clinical
evidence of left atrial
hypertension

• Hypoxemia, defined as
Pao2/Fio2 ≤ 300 (ALI) or ≤ 200
(ARDS)†
* If available. Pulmonary artery catheter
insertion has not been found to be
beneficial in treating patients with
ALI/ARDS.
†
Pao2 in mm Hg, Fio2 in decimal
fraction (eg, 0.5).
ALI/ARDS = acute lung injury/acute
respiratory distress syndrome; Fio2 =
fraction inspired O2; PAOP =
pulmonary artery occlusive pressure.

In ALI/ARDS, pulmonary or systemic inflammation leads to release of cytokines and

other proinflammatory molecules. The cytokines activate alveolar macrophages and
recruit neutrophils to the lungs, which in turn release leukotrienes, oxidants, platelet-
activating factor, and proteases. These substances damage capillary endothelium and
alveolar epithelium, disrupting the barriers between capillaries and airspaces. Edema
fluid, protein, and cellular debris flood the airspaces and interstitium, causing disruption
of surfactant, airspace collapse, ventilation-perfusion mismatch, shunting, and pulmonary
hypertension. The injury is distributed heterogeneously but mainly affects dependent lung
zones

Refractory hypoxemia: In both types of AHRF, flooded airspaces allow no inspired gas to
enter, so the blood perfusing those alveoli remains at the mixed venous O2 content no
matter how high the fractional inspired O2 (Fio2). This ensures constant admixture of
deoxygenated blood into the pulmonary vein and hence arterial hypoxemia. In contrast,
hypoxemia that results from ventilating alveoli that have less ventilation than perfusion
(ie, low ventilation-to-perfusion ratios as occurs in asthma or COPD and, to some extent,
patients with ARDS/ALI) is readily corrected by supplemental O2.

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Pathophysiology
The respiratory system is responsible for oxygen and carbon dioxide exchange between
the blood and the atmosphere. Respiratory failure occurs when this exchange fails and
metabolic demands for oxygen and body system acid-base stabilisation are not
maintained, creating a ventilation-perfusion mismatch.

Failure of oxygen exchange results in the development of severe hypoxaemia with

cellular anoxia and tissue asphyxia. This can occur with all forms of lung disease
including fluid filling of alveolar spaces; collapse of alveolar spaces; re-distribution of
blood flow from functioning alveolar units (shunting); loss of blood flow to alveolar
tissue (e.g., pulmonary embolism); underlying loss of pulmonary tissue (e.g.,
emphysema, trauma, fibrosis) and thickening or fluid build-up at alveolar membranes that
inhibits gas exchange (e.g., pneumonia). Chronic hypoxia in patients with chronic
respiratory failure stimulates increases in the number of circulating red blood cells
(erythrocytosis).

Failure of carbon dioxide exchange results in hypercapnic respiratory failure causing

increased carbon dioxide in arterial blood and respiratory acidosis. Carbon dioxide
accumulation leads to carbonic acid accumulation within the tissues resulting in chronic
respiratory acidosis. Renal bicarbonate retention occurs to compensate for this and results
in chronic respiratory failure.

Hypercapnic respiratory failure occurs with lung disorders that limit exchange of carbon
dioxide from the blood to the atmosphere. These lung disorders include poor ventilatory
muscle function as occurs with neuromuscular disorders (e.g., Guillain-Barre, drug over-
dose); obstruction of airways and alveoli (e.g., asthma, pulmonary oedema); secretions in
the small airways and alveoli (e.g., chronic obstructive pulmonary disease, cystic
fibrosis) and chest wall abnormalities (e.g., traumatic flail chest, kyphoscoliosis).

Respiratory factors:

• Acute pulmonary vascular occlusion can result in ventilation-perfusion mismatch

and respiratory failure due to insufficient blood flow to functioning alveoli.
Massive pulmonary artery embolisation may cause high right-sided after-load
 pressures leading to cardiac dysfunction and inability of the heart to circulate
adequate blood volume.
• Pneumothorax can lead to respiratory failure if there is not enough lung reserve to
compensate for the collapsed lung or lung segment. This would typically occur in
the setting of pre-existing pulmonary dysfunction. Bi-lateral pneumothoraces can
cause catastrophic respiratory failure and rapid cardiac arrest.
• Fluid or blood accumulation in the pleural space (pulmonary effusion) may lead
to compression of pulmonary tissues and loss of pulmonary function causing
respiratory failure. Effusion can occur secondary to infection, malignancy,
trauma, cardiac failure and collagen vascular disease as well as many other
conditions.
• Destruction or infiltration of alveoli reduces the surface area available for gas
exchange. Emphysema causes alveolar destruction and the bullae that are formed
occupy intra-thoracic space without contributing to gas exchange. Respiratory
failure results from acute or eventual loss of the baseline number of alveolar units.
Infiltration or filling of alveoli with fluid is a frequent cause of acute respiratory
failure. Conditions that cause alveolar filling include pneumonia, pulmonary
oedema and pulmonary haemorrhage. Alveolar haemorrhage can occur with
Goodpasture's syndrome, Wegener's granulomatosis and trauma. Fluid-filling of
alveoli leads to inability of these alveoli to provide gas exchange with the blood, a
condition referred to as intra-pulmonary shunting. Acute respiratory distress
syndrome resulting from trauma, hypo-perfusion or direct insult is a form of
alveolar infiltration and injury.
• Acute upper airway obstruction (e.g., from foreign body aspiration, acute
epiglottitis, anatomic abnormalities, anaphylaxis) can inhibit air flow into the
lungs and cause respiratory failure. Lower airway obstruction (e.g., from asthma,
chronic obstructive pulmonary disease, cystic fibrosis) is more common and
involves constriction or mucous blockage of intermediate size bronchioles.
• Pulmonary embolus can occur as a result of hypercoagulability from clotting
cascade diseases or abnormalities.
• Exposure to toxic fumes can lead to damage of the upper airway, lower airway or
alveoli. Industrial gases such as chlorine are an example. The most common
inhalation injury is smoke inhalation where particulate matter and gases are inter-
mixed and can cause upper airway and lower airway inflammation resulting in
respiratory failure. Toxic gases such as carbon monoxide and hydrogen sulphide
are exchanged in the lungs yet result in asphyxia by inhibiting the ability of the
blood to effectively extract oxygen from the lungs as well as causing cellular
metabolic damage (cellular asphyxia).

Non-respiratory factors:

• Poor perfusion of the brain, heart, and lungs (e.g., from haemorrhagic
hypovolaemia, dehydration hypovolaemia, septic shock, cardiogenic shock,
severe anaemia) can result in respiratory failure by reducing blood oxygenation
and depressing CNS respiratory centres.
 • Ventilation with pulmonary gas exchange is dependent on diaphragm and chest
wall muscle functioning. Neurological disorders inhibiting respiratory muscle
function limit ventilation and can cause respiratory failure. Examples include
Guillain-Barre syndrome and myasthenia gravis. Muscular dystrophy is an
example of a disorder that results in muscle function abnormalities that limit
ventilation and can result in respiratory failure.
• Opiate and sedative medicines decrease respiratory drive in the CNS with
resulting limited ventilatory effort.
• Injuries, disease or insult of the CNS can result in loss of respiratory drive and
secondary respiratory failure. Examples include infiltrating and mass cancers of
the CNS, head injury with haemorrhagic mass effect, direct brain injury,
infections, primary CNS disorders and cerebrovascular accident.

Traumatic causes

• Direct thoracic injury may result in a number of abnormalities that can lead to
respiratory failure.
• Direct brain injury can result in loss of respiratory drive.
• Spinal injury can result in loss of peripheral nerve function and the lack of ability
to ventilate.