Respiratory Failure

Respiratory failure is a syndrome that develops when the respiratory system is unable to maintain oxygenation and/or ventilation. Respiratory failure may be acute or chronic and is classified as hypoxemic, hypercapnic, or a combination of the two. A number of etiologies exist, including diseases of the lungs, cardiovascular, and nervous system. Patients with respiratory failure may present with dyspnea, tachypnea, and altered mentation. The diagnosis is made with arterial blood gas and supplemented with laboratory and imaging studies to elicit an etiology. Management involves treating the underlying cause, supplemental oxygen administration, and mechanical ventilation for severe cases.

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Definition and Classification

Definition

Respiratory failure is a syndrome that develops when the respiratory system is unable to maintain oxygenation and/or ventilation.

Classification

Respiratory failure may be classified based on: 

The time course:

  • Acute respiratory failure: occurs within minutes to hours.
  • Chronic respiratory failure: 
    • Occurs over months to years 
    • Often due to a chronic lung disease process

The underlying issue:

  • Hypoxemic respiratory failure (type 1): 
    • Most common form of respiratory failure
    • Results from a ↓ ability to oxygenate the blood
  • Hypercapnic respiratory failure (type 2):
    • Results from a ↓ ability to eliminate carbon dioxide (CO₂) 
    • ↓ pH of the blood → respiratory acidosis

Etiology

Etiology of hypoxemic respiratory failure

  • Right-to-left shunt:
    • Pulmonary edema (cardiogenic and noncardiogenic)
    • Pneumonia
    • Pulmonary hemorrhage
    • Aspiration
    • Atelectasis
    • ARDS
  • V/Q mismatch:
    • Pulmonary embolism
    • Asthma
    • Chronic obstructive pulmonary disease (COPD)
    • Cystic fibrosis
    • Interstitial lung disease
    • Pulmonary hypertension
  • Low inspired oxygen: high altitude
  • Hypoventilation:
    • Sedative medications
    • Neuromuscular conditions

Etiology of hypercapnic respiratory failure

  • Diminished respiratory drive:
    • Sedative medications (opioids, benzodiazepines)
    • Brain stem lesions (affecting the central respiratory center)
    • Multiple sclerosis
    • Hypothermia
  • Impaired respiratory muscle function:
    • Guillain–Barré syndrome
    • Myasthenia gravis
    • Amyotrophic lateral sclerosis
    • Multiple sclerosis
    • Botulism
    • Tetanus
    • Spinal cord lesions
    • Muscle fatigue (seen with hypoxemic respiratory failure)
    • Malnutrition
    • Myopathy
  • Airway obstruction:
    • COPD
    • Asthma
    • Obstructive sleep apnea
    • Cystic fibrosis
    • Airway edema
  • Diminished lung elasticity:
    • Alveolar edema
    • Pneumonia
    • Atelectasis
    • ARDS
  • Diminished chest wall elasticity:
    • Pleural effusion
    • Obesity
    • Kyphoscoliosis
    • Abdominal distention
    • Pneumothorax

Pathophysiology

Right-to-left shunt

  • Blood is shunted from the right side of the lung to the left side without oxygenation.
  • Deoxygenated blood mixes with oxygenated blood → ↓ arterial pressure of O₂
  • This can be caused by:
    • Cardiac shunting (e.g., congenital malformations of the heart that allow blood to bypass the respiratory system) 
    • Pulmonary shunting (e.g., fluid fills the alveoli, preventing oxygen diffusion)
  • Note: 100% oxygen administration will not change oxygenation.

Diagram of a right-to-left shunt resulting in hypoxemia:
A cardiac or pulmonary issue causes deoxygenated blood to skip gas exchange. When this later mixes with oxygenated blood, the arterial pressure of O2 is reduced.
PA: alveolar partial pressure
PI: inspired partial pressure
Pv: venous partial pressure
Ppv: pulmonary venous partial pressure

Image by Lecturio.

Ventilation-to-perfusion inequality

A mismatch between ventilation and perfusion occurs from a disease process resulting in either:

  • Low V/Q ratio:
    • May occur from:
      • Diminished oxygen entry into alveoli with normal blood flow 
      • Overperfusion of alveoli with normal ventilation (e.g., diversion of blood flow)
    • Results in: 
      • Hypoxemia 
      • Hypercapnia
  • High V/Q ratio:
    • Results from diminished blood flow to alveoli with normal ventilation
    • Ventilation is wasted.
    • Must be severe for gas exchange to be affected

Note: 100% oxygen administration can correct oxygenation in V/Q mismatch.

Clinical Presentation

General signs and symptoms

  • Vitals:
    • Tachypnea
    • Tachycardia
  • Dyspnea
  • Diaphoresis
  • Altered mental status:
    • Restlessness and anxiety
    • Confusion
    • Somnolence
    • Coma

Hypoxemia

  • Fatigue (inability to speak in complete sentences)
  • Use of accessory muscles of respiration
  • Cyanosis

Cyanosis on a patient’s face due to hypoxemia

Image: “Clinical signs of chronic hypoxaemia” by Maximilian Patzig et al. License: CC BY 4.0, edited by Lecturio.

Hypercapnia

  • Headache
  • Asterixis
  • Change in breathing pattern:
    • Shallow
    • Irregular
    • Gasping

Diagnosis

Arterial blood gas

An arterial blood gas (ABG) analysis is required in the diagnosis of respiratory failure. It measures and calculates components in arterial blood:

  • Measured:
    • pH
    • Partial pressure of oxygen (PaO₂)
    • Partial pressure of CO₂ (PaCO₂)
  • Calculated:
    • Bicarbonate (HCO₃)
    • Base excess
    • Oxygen saturation (SaO₂)

Criteria

The following parameters are used to define hypoxemic and hypercapnic respiratory failure:

Hypoxemic respiratory failure:

  • PaO₂ < 60 mmHg on a supplemental O₂ concentration ≥ 50% 
  • PaO₂ < 40 mmHg with any O₂ concentration
  • SaO₂ < 90%

Hypercapnic respiratory failure:

  • PaCO₂ > 50 mmHg
  • In patients with chronic hypercapnia:
    • PaCO₂ acutely above a patient’s normal baseline
    • Concurrent ↓ in pH < 7.3

Alveolar–arterial gradient

Once hypoxemic respiratory failure is established, the alveolar–arterial (A-a) gradient can be used to help in understanding the potential underlying etiology.

  • Defined as the difference between the oxygen concentration in the alveoli (PAO2) and arterial blood (PaO₂):
    • A-a gradient = PAO₂ – PaO₂ 
    • PAO₂: calculated from the alveolar gas equation
    • PaO₂: measured in an ABG
  • Interpretation:
    • Normal: 5–10 mmHg
    • Increased in etiologies that cause:
      • Right-to-left shunting
      • V/Q mismatch

Supporting workup

The following can be done to evaluate for potential causes of respiratory failure. The workup should be tailored to the patient’s presentation and clinical suspicion.

Laboratory evaluation:

  • CBC
    • Anemia
    • Polycythemia → seen in chronic respiratory failure
    • ↑ WBC → infection
  • Troponin and BNP → cardiogenic pulmonary edema
  • Blood and sputum cultures → pneumonia
  • Creatine kinase → myositis
  • Urine drug screen → sedation from opioids or benzodiazepines

Pulmonary function tests:

  • More useful in chronic respiratory failure
  • Used for assessing and monitoring the severity of obstructive and restrictive lung disease
  • Predictive of ventilatory failure in patient with neuromuscular disease

Imaging:

  • Chest X-ray:
    • Atelectasis
    • Pneumonia
    • Pulmonary edema
    • ARDS
    • Pleural effusion
    • Pneumothorax
  • CT chest:
    • Pulmonary embolism
    • Interstitial lung disease
    • Pulmonary hemorrhage

Management

Management of respiratory failure is supportive and focuses on maintaining adequate oxygenation and ventilation until the underlying condition can be treated.

Supplemental oxygen

General principles:

  • In hypoxemic respiratory failure, use the lowest concentration of oxygen that provides sufficient oxygenation to avoid oxygen toxicity.
  • In hypercapnic respiratory failure, excessive administration of oxygen may result in V/Q mismatch and loss of the hypoxemic respiratory drive.

Options:

  • Nasal cannula:
    • Used in mild hypoxemia
    • Low flow
    • Provides low amounts of oxygen (24%–50%)
  • Simple face mask: 
    • Slightly higher flow than nasal cannula
    • Delivers low to moderate amounts of oxygen (40%–60%)
  • Venturi mask: 
    • Especially helpful when overoxygenation is a potential concern
    • Delivers a known concentration of oxygen (24%–60%)
  • Nonrebreather mask:
    • Used for severe hypoxemia, often as a transition to other ventilatory measures
    • Contains a reservoir bag for oxygen
    • Requires a higher flow
    • Allows high concentrations of oxygen (60%–90%)
    • Exhaled air is released through a 1-way valve (prevents re-inhalation).
  • High-flow nasal cannula:
    • Provides high volumes of oxygen (up to approximately 100%)
    • Humidified
    • Can provide a small amount of positive pressure

Noninvasive positive-pressure ventilation (NPPV)

Noninvasive positive-pressure ventilation provides ventilatory support without placing an artificial airway.

Indications:

  • Ideally for conscious patients 
  • Moderate to severe hypoxemia or hypercapnia
  • Increased respiratory effort and tachypnea:
    • Accessory muscle use, pursed-lip breathing
    • Goal is to prevent fatigue.

Best suited for:

  • Pulmonary edema
  • COPD

Options:

  • BiPAP:
    • Most commonly used form of NPPV
    • Provides positive inspiratory pressure (assists with active inhalation)
    • Delivers constant PEEP
    • Used acutely for hypoxemic and hypercapnic failure
  • CPAP (continuous positive airway pressure):
    • Delivers essentially constant PEEP
    • Used for hypoxemic failure
    • Patients may use long term for sleep apnea.

Invasive ventilation

Indications: 

  • Severe respiratory distress 
  • Patient is obtunded and is unable to protect the airway (absent gag or cough reflex).
  • Severe hypoxemia 
  • Severe hypercapnia (especially for a pH < 7.2)
  • Worsening condition despite NPPV support
  • Impending respiratory fatigue

General principles:

  • Applies positive pressure breaths
  • Volumes and pressures given are dependent on the resistance and compliance of the airways.

Parameters:

  • To improve oxygenation:
    • ↑ Fraction of inspired oxygen (FiO₂)
    • ↑ PEEP
  • To improve ventilation:
    • ↑ Respiratory rate 
    • ↑ Tidal volume

ECMO

ECMO is an advanced therapy utilizing prolonged cardiopulmonary bypass to oxygenate blood and remove CO₂.

  • Considered in respiratory failure that remains refractory despite mechanical ventilation (e.g., ARDS)
  • Can be done only at specialized centers with a dedicated, multidisciplinary team

Diagram of venovenous ECMO for respiratory failure:
The patient is put on a cardiopulmonary bypass circuit, where venous blood is extracted, oxygenated, and returned to the body.
IVC: inferior vena cava
SVC: superior vena cava

Image: “ECMO for isolated respiratory failure” by Van Meurs et al., Extracorporeal Life Support Organization. License: CC BY 2.5

References

  1. Shebl E, Burns B. (2020). Respiratory failure. [online] StatPearls. Retrieved March 28, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK526127/
  2. Castro, D., Patil, S.M., Keenaghan, M. (2021). Arterial blood gas. [online] StatPearls. Retrieved March 28, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK536919/
  3. Brinkman, J.E., Sharma, S. (2020). Physiology, pulmonary. [online] StatPearls. Retrieved March 28, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK482426/
  4. Hickey, S.M., Giwa, A.O. (2020). Mechanical ventilation. [online] StatPearls. Retrieved March 29, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK539742/
  5. Patel, B.K. (2020). Acute hypoxemic respiratory failure (AHRF, ARDS). [online] MSD Manual Professional Version. Retrieved March 28, 2021, from https://www.msdmanuals.com/professional/critical-care-medicine/respiratory-failure-and-mechanical-ventilation/acute-hypoxemic-respiratory-failure-ahrf,-ards
  6. Patel, B.K. (2020). Ventilatory failure. [online] MSD Manual Professional Version. Retrieved March 28, 2021, from https://www.msdmanuals.com/professional/critical-care-medicine/respiratory-failure-and-mechanical-ventilation/ventilatory-failure
  7. Kaynar, A.M., Sharma, S. (2020). Respiratory failure. In Pinksy, M. R. (Ed.), Medscape. Retrieved March 28, 2021, from https://emedicine.medscape.com/article/167981-overview
  8. Soo Hoo, G.W. (2020). Noninvasive ventilation. In Mosenifar, Z. (Ed.), Medscape. Retrieved March 29, 2021, from https://emedicine.medscape.com/article/304235-overview

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