What is the role of Long-Acting Beta-Agonist (LABA)/Long-Acting Muscarinic Antagonist (LAMA) combination in managing acute exacerbation of Chronic Obstructive Pulmonary Disease (COPD) in patients requiring Intensive Care Unit (ICU) admission?

LABA/LAMA Combination in Acute COPD Exacerbation Requiring ICU Admission

Direct Recommendation

Continue LABA/LAMA maintenance therapy at the prescribed dose during acute COPD exacerbations requiring ICU admission, and add short-acting bronchodilators for acute symptom relief. 1

Rationale for Continuation During Acute Exacerbation

• Long-acting bronchodilators provide sustained bronchodilation that remains beneficial even during acute exacerbations, and discontinuing maintenance therapy increases the risk of prolonged recovery time and subsequent exacerbations. 1

• Stopping LABA/LAMA during exacerbations removes the foundation of bronchodilation and may worsen clinical outcomes in critically ill patients. 1

• The recommendation to continue LABA/LAMA during exacerbations is supported by Level A evidence from GOLD guidelines for long-acting bronchodilators as cornerstone therapy. 1

Acute Phase Management Algorithm

Step 1: Maintain Foundation Therapy

• Continue current LABA/LAMA maintenance therapy at the prescribed dose without interruption. 1

Step 2: Add Acute Relief Medications

• Add short-acting bronchodilators (short-acting beta-agonists and/or short-acting muscarinic antagonists) for immediate symptom relief during the exacerbation. 1

Step 3: Initiate Systemic Therapy

• Initiate systemic corticosteroids for moderate to severe exacerbations requiring ICU admission. 1
• Consider antibiotics if there are signs of bacterial infection (increased sputum purulence, volume, or dyspnea). 1

Post-Exacerbation Therapy Escalation Strategy

For patients who exacerbated despite LABA/LAMA therapy, escalation is indicated based on specific phenotypes:

High Eosinophil Phenotype (≥300 cells/μL) or Asthma-COPD Overlap:

• Escalate to LABA/LAMA/ICS triple therapy after recovery from the acute exacerbation. 1
• Triple therapy reduces mortality risk in high-risk patients with moderate to high symptom burden (CAT ≥10, mMRC ≥2) and impaired lung function (FEV1 <80% predicted). 2

Chronic Bronchitis Phenotype with FEV1 <50% Predicted:

• Consider adding roflumilast to LABA/LAMA therapy. 1
• Roflumilast reduces exacerbations in patients with chronic bronchitis phenotype and history of hospitalization for exacerbation. 1

Former Smokers with Recurrent Exacerbations:

• Consider adding macrolide therapy (e.g., azithromycin) to LABA/LAMA, weighing risks of antimicrobial resistance and cardiac effects. 1

Patients Already on Triple Therapy Who Continue to Exacerbate:

• Add macrolide maintenance therapy if a former smoker, with moderate certainty of benefit in reducing exacerbation rates. 1
• Add roflumilast if chronic bronchitic phenotype is present. 1

Critical Pitfalls to Avoid

Do Not Discontinue LABA/LAMA During ICU Admission:

• This is the most common error—removing the foundation of bronchodilation during acute illness worsens outcomes and prolongs recovery. 1

Do Not Add ICS Indiscriminately After Exacerbations:

• ICS increases pneumonia risk without clear benefit in low-eosinophil patients (<300 cells/μL). 1
• Triple therapy causes higher incidence of pneumonia (odds ratio 1.52,95% CI 1.16-2.00) compared to LABA/LAMA alone. 3

Do Not Step Down from Triple Therapy in High-Risk Patients:

• The Canadian Thoracic Society weakly recommends against stepping down from LABA/LAMA/ICS to LABA/LAMA in high-risk patients, as withdrawal may increase exacerbation risk, particularly in those with eosinophils ≥300 cells/μL. 1

Evidence Quality and Strength

• LABA/LAMA combination demonstrates superior efficacy in preventing subsequent exacerbations and improving patient-reported outcomes compared to single bronchodilators or LABA/ICS combinations, particularly in high-risk patients. 1

• Triple therapy (LABA/LAMA/ICS) significantly decreased the incidence of exacerbations (rate ratio 0.73,95% CI 0.64-0.83) and mortality (odds ratio 0.66,95% CI 0.50-0.87) compared to LABA/LAMA in symptomatic moderate to severe COPD patients with history of exacerbations. 3

• The Canadian Thoracic Society provides strong recommendation with moderate certainty evidence that triple combination therapy reduces mortality over LABA/LAMA dual therapy in high-risk patients with moderate to high symptom burden and impaired lung function. 2