What is the cause of neurologic symptoms in a patient with chronic obstructive pulmonary disease (COPD) who develops confusion, lethargy, and seizure after starting treatment with high flow oxygen, inhaled bronchodilators, systemic corticosteroids, and intravenous azithromycin (azithromycin) for a COPD exacerbation?

Hypercapnic Encephalopathy from Oxygen-Induced CO2 Retention

The neurologic symptoms (confusion, lethargy, and seizure) are caused by hypercapnic encephalopathy resulting from CO2 retention triggered by high-flow oxygen administration in a patient with chronic CO2 retention. 1

Pathophysiology of Oxygen-Induced Hypercapnia

The administration of high-flow oxygen to COPD patients with chronic hypercapnia causes acute worsening of CO2 retention through three mechanisms 1:

• Loss of hypoxic pulmonary vasoconstriction: High oxygen concentrations abolish the compensatory vasoconstriction in poorly ventilated lung regions, worsening ventilation-perfusion (V/Q) mismatch and increasing dead space ventilation 2, 1

• Haldane effect: Increased oxygen displaces CO2 from hemoglobin, raising blood CO2 levels 1

• Decreased respiratory drive (contrary to traditional teaching, this is the least important mechanism): While the "hypoxic drive" theory is commonly cited, V/Q mismatch is actually the primary culprit 1

Clinical Presentation

This patient's timeline is classic for oxygen-induced hypercapnic encephalopathy 1:

• Baseline state: Chronic CO2 retention (common in severe COPD with bilateral hyperinflation on chest x-ray) 3
• Acute trigger: High-flow oxygen initiated 45 minutes prior to neurologic deterioration 3, 1
• Neurologic manifestations: Confusion and lethargy progress to seizure as CO2 levels rise and pH drops, causing cerebral vasodilation, increased intracranial pressure, and altered mental status 1

Critical Management Errors to Avoid

The most dangerous pitfall is withholding oxygen entirely due to fear of hypercapnia 3, 1:

• The goal during COPD exacerbations is to maintain PaO2 >60 mmHg (8 kPa) or SpO2 >90% to prevent tissue hypoxia 3
• Prevention of tissue hypoxia supersedes CO2 retention concerns 3
• However, oxygen should be titrated rather than administered at high flow rates 1, 4

Appropriate Oxygen Management

Titrated oxygen therapy targeting SpO2 88-92% is the evidence-based approach 4:

• Start with controlled oxygen delivery (nasal cannula or Venturi mask) rather than high-flow systems 3
• Monitor arterial blood gases for PaCO2, pH, and PaO2 3
• If hypercapnia with acidemia develops despite appropriate oxygen titration, noninvasive positive pressure ventilation (NIV) should be initiated rather than withdrawing oxygen 3

Immediate Actions Required

For this patient experiencing hypercapnic encephalopathy 3:

• Reduce oxygen flow to achieve SpO2 88-92% while maintaining adequate tissue oxygenation 4
• Obtain arterial blood gas immediately to confirm hypercapnia and assess pH 3
• Initiate noninvasive ventilation if respiratory acidosis is present (pH <7.35), as NIV is strongly recommended for acute or acute-on-chronic respiratory failure in COPD exacerbations 3
• Continue bronchodilators and systemic corticosteroids as these address the underlying exacerbation 3

Why Other Treatments Are Not the Cause

The other medications initiated are appropriate and not responsible for the neurologic symptoms 3:

• Bronchodilators: Short-acting beta-agonists and anticholinergics are first-line therapy for COPD exacerbations 3
• Systemic corticosteroids: Improve lung function and shorten recovery time 3
• Azithromycin: Appropriate for purulent sputum in COPD exacerbations and reduces treatment failure 5

The timing (45 minutes after initiating high-flow oxygen) and clinical presentation (progressive encephalopathy culminating in seizure) definitively point to oxygen-induced hypercapnic encephalopathy rather than medication side effects 1.