What are the causes of acute respiratory failure?

Causes of Acute Respiratory Failure

Acute respiratory failure results from either failure of oxygenation (Type 1/hypoxemic) or failure of ventilation (Type 2/hypercapnic), with distinct underlying pathophysiological mechanisms and clinical causes that require different management approaches. 1

Classification Framework

Acute respiratory failure is fundamentally divided into two types based on arterial blood gas abnormalities:

• Type 1 (Hypoxemic): PaO₂ <8 kPa with normal or low PaCO₂, representing failure to maintain adequate oxygenation despite normal ventilatory effort 1
• Type 2 (Hypercapnic): PaCO₂ >6.0 kPa (45 mmHg), often with concurrent hypoxemia, representing failure of the ventilatory pump 1

Type 1 Respiratory Failure: Primary Causes

Pathophysiological Mechanisms

The fundamental mechanisms driving Type 1 failure include:

• Intrapulmonary shunting: Blood bypasses ventilated alveoli entirely, flowing through completely unventilated or fluid-filled lung units 1
• Ventilation-perfusion (V/Q) mismatch: Imbalance between ventilation and perfusion in different lung regions 2
• Diffusion impairment: Impaired gas exchange across the alveolar-capillary membrane 2

Acute Respiratory Distress Syndrome (ARDS)

ARDS is the prototypical cause of severe Type 1 respiratory failure, characterized by bilateral pulmonary infiltrates, increased pulmonary vascular permeability, and severe hypoxemia. 1

• Triggered by diverse insults including sepsis, pneumonia, aspiration of gastric contents, trauma, and pancreatitis 1, 3
• Classified by severity: mild (PaO₂/FiO₂ 200-300 mmHg), moderate (100-200 mmHg), or severe (≤100 mmHg) 1
• Mortality remains approximately 30-40% despite advances in supportive care 1, 3
• Pathological specimens reveal diffuse alveolar damage with both alveolar epithelial and lung endothelial injury 3

Pneumonia and Sepsis

• Community-acquired and hospital-acquired pneumonia cause alveolar filling with inflammatory exudate, creating shunt physiology 1
• Sepsis causes a spectrum of respiratory abnormalities ranging from subclinical changes to full ARDS 1
• Sepsis-related mechanisms include increased dead space ventilation, respiratory muscle dysfunction, decreased thoracic compliance, and bronchoconstriction 1
• Both increased physiological dead-space and intrapulmonary shunting drive tachypnea and elevated minute ventilation 1

Cardiogenic and Non-Cardiogenic Pulmonary Edema

• Pulmonary edema fills alveoli with fluid, creating shunt physiology and severe V/Q mismatch 1
• Can develop from increased pulmonary vascular permeability, increased hydrostatic pressures from resuscitation, and lowered oncotic pressure 1

Pulmonary Embolism

• Causes V/Q mismatch through increased dead space ventilation 1
• Results in hypoxemia from multiple mechanisms including shunt and V/Q mismatch 4

Type 2 Respiratory Failure: Primary Causes

Chronic Obstructive Pulmonary Disease (COPD) Exacerbations

COPD exacerbations account for the majority of Type 2 respiratory failures and represent the most common indication for non-invasive ventilation. 1, 5

Pathophysiological Mechanisms in COPD

• Alveolar hypoventilation: Minute ventilation insufficient relative to CO₂ production 1
• Dynamic hyperinflation: Flow-limited expiration prevents lung emptying to relaxation volume, creating intrinsic PEEP (PEEPi) that acts as an inspiratory threshold load 1, 5
• Increased airway resistance: Elevated work of breathing with greater energy consumption by inspiratory muscles 1, 5
• Inspiratory muscle dysfunction: Impaired muscle function related to mechanical disadvantage from hyperinflation 1, 5
• V/Q abnormalities: Worsen during acute exacerbations 5

Precipitants of COPD Exacerbations

• Acute viral infections (rhinovirus, coronavirus, influenza B, parainfluenza) found in approximately one-third of episodes 5
• Bacterial infections or overgrowth with Streptococcus pneumoniae, Moraxella catarrhalis, and Haemophilus influenzae 5
• Molecular typing shows acute exacerbations frequently associated with new strains of preexisting organisms 5

Neuromuscular Disorders

Neuromuscular diseases cause progressive ventilatory pump failure and can present with acute-on-chronic hypercapnic respiratory failure. 1, 5

• Amyotrophic lateral sclerosis (ALS), muscular dystrophy, and myasthenia gravis are primary causes 1
• In some conditions (acid maltase deficiency, ALS), diaphragm involvement precedes locomotor disability with presentation as acute-on-chronic hypercapnia 5
• Bulbar muscle involvement in muscular dystrophies causes sleep-disordered breathing from combined respiratory muscle weakness and upper airway obstruction 5
• Bulbar dysfunction renders voluntary cough less effective, compounding respiratory failure 5

Chest Wall Deformities

• Severe chest wall deformity (scoliosis, thoracoplasty) causes restrictive mechanics limiting ventilation 5
• Presentation often occurs with advanced chronic hypercapnia when vital capacity falls below 1 L 5

Obesity Hypoventilation Syndrome

• Combines restrictive mechanics from chest wall loading with central drive abnormalities 1
• Results in chronic hypoventilation with acute decompensation during intercurrent illness 5

Cystic Fibrosis

• Acute hypercapnic respiratory failure in CF typically precipitated by infection, pneumothorax, or hemoptysis 5
• Secretion clearance is a major issue that may render NIV ineffective or poorly tolerated 5
• Chronic disease markers (BMI decline, colonizing organisms) are more relevant than FEV1 decline in assessing outcome 5

Acute-on-Chronic Respiratory Failure

An insidious decline in health may not be medically recognized as respiratory failure until acute decompensation occurs, particularly in restrictive lung diseases and neuromuscular conditions. 5

• Acute presentations often triggered by infection when vital capacity is <1 L 5
• Unlike COPD, recurrent critical episodes in neuromuscular disease do not preclude intervening good life quality and prolonged survival 5
• Compensatory mechanisms (renal bicarbonate retention) develop in chronic hypercapnia, altering baseline physiology 1

Common Clinical Pitfalls

Diagnostic Challenges

• Standard chest radiographs are poor predictors of oxygenation defect severity or clinical outcome in ARDS 1
• Classic ARDS findings may be asymmetric, patchy, or focal rather than diffuse bilateral infiltrates 1
• Some neuromuscular patients present before formal diagnosis has been made (Limb Girdle muscular dystrophy, Myotonic Dystrophy) 5

Management Errors

• Administering high-flow oxygen without monitoring CO₂ can precipitate CO₂ narcosis and respiratory arrest in Type 2 respiratory failure 1
• Delaying NIV initiation when pH <7.35 and PaCO₂ >6.0 kPa misses the therapeutic window 1
• Confusing thrombocytosis (common in COPD exacerbations) with polycythemia secondary to chronic hypoxemia 6

Special Considerations by Etiology

Infection-Related Considerations

• In COPD exacerbations with increased sputum purulence and/or volume, bacterial infection should be suspected and antibiotics considered 5
• Viral respiratory infections predispose airways to bacterial superinfection by interfering with mucociliary clearance and impairing bacterial killing by pulmonary macrophages 5
• In CF, outcome following invasive mechanical ventilation is worse than with NIV, especially when infection is the precipitant 5

Cardiovascular Comorbidities

• Approximately 26% of deaths in patients with moderate to severe COPD are due to cardiovascular causes 7
• Both ischemic and hemorrhagic strokes are increased in COPD patients, with 40% of stroke cases attributable to smoking 7
• Systematic evaluation of cardiovascular comorbidities is recommended in all COPD patients as they share common pathobiological pathways 7