A patient on an ACE inhibitor who periodically takes deep breaths—could this be ACE‑inhibitor‑induced angioedema or cough, and how should it be evaluated and managed?

Evaluation and Management of Periodic Deep Breaths in a Patient on ACE Inhibitor

Periodic deep breaths in a patient taking an ACE inhibitor most likely represent ACE inhibitor-induced cough rather than angioedema, and the ACE inhibitor should be discontinued and replaced with an ARB. 1, 2

Distinguishing ACE Inhibitor-Induced Cough from Angioedema

Clinical Features of ACE Inhibitor-Induced Cough

• ACE inhibitor-induced cough is dry, non-productive, and associated with a persistent tickling or scratching sensation in the throat, which can manifest as periodic deep breaths as the patient attempts to clear the sensation 1, 2
• The cough occurs in 5-35% of patients taking ACE inhibitors and is a class effect due to accumulation of bradykinin and substance P 1, 2
• Onset can occur within hours of the first dose or be delayed for weeks to months after starting therapy 2

Clinical Features of ACE Inhibitor-Induced Angioedema

• Angioedema presents with visible edema of the face, lips, tongue, uvula, and upper airways, not simply periodic deep breaths 3, 4
• Angioedema occurs in only 0.1-1.0% of patients taking ACE inhibitors, making it far less common than cough 3, 5, 4
• Angioedema is a medical emergency requiring immediate airway assessment and potential intubation or tracheotomy in severe cases 3, 6, 5

Diagnostic Confirmation Algorithm

Step 1: Rule Out Angioedema

• Examine for visible swelling of the face, lips, tongue, or oropharynx 3, 4
• If any visible edema is present, treat as angioedema emergency (see below) 3, 5

Step 2: Exclude Alternative Causes of Respiratory Symptoms

• Rule out pulmonary edema from heart failure decompensation by checking for orthopnea, paroxysmal nocturnal dyspnea, rales, and elevated jugular venous pressure 7, 1
• Exclude respiratory infections, chronic lung disease, and post-nasal drip before attributing symptoms to the ACE inhibitor 7, 2

Step 3: Confirm ACE Inhibitor-Induced Cough

• The diagnosis is confirmed by demonstrating cough resolution within 1-4 weeks after ACE inhibitor discontinuation (though it may take up to 3 months in some patients) 1, 2, 8
• Recurrence of cough within days after re-exposure to another ACE inhibitor confirms the diagnosis 1, 8

Management Algorithm

Immediate Action: Discontinue ACE Inhibitor

• Discontinue the ACE inhibitor immediately regardless of when the cough started relative to medication initiation 1, 2, 8
• Do not substitute another ACE inhibitor, as cough is a class effect and will almost invariably recur 1

First-Line Replacement: Switch to an ARB

• ARBs are the preferred alternative with equivalent cardiovascular benefits but dramatically lower cough incidence (2-3% versus 7.9% with ACE inhibitors) 1, 2, 8

Recommended ARB Dosing:

ARB	Initial Dose	Maximum Dose
Losartan	25 mg once daily	50-100 mg once daily
Candesartan	4-8 mg once daily	32 mg once daily
Valsartan	20-40 mg twice daily	160 mg twice daily

1, 8

Monitoring After ARB Switch

• Monitor blood pressure, renal function (creatinine), and potassium within 1-2 weeks after ARB initiation 1, 8
• Acceptable creatinine increase is up to 50% above baseline or 266 μmol/L (3 mg/dL), whichever is smaller 7
• Acceptable potassium level is ≤5.5 mmol/L 7

Expected Timeline for Cough Resolution

• Typical resolution occurs within 1-4 weeks after ACE inhibitor cessation 1, 2, 8
• Extended resolution may require up to 3 months in some patients 1, 2

Critical Pitfalls to Avoid

Common Mistake: Continuing ACE Inhibitor Despite Troublesome Cough

• While mild, tolerable cough may be managed conservatively given the mortality benefit of ACE inhibitors, persistent or bothersome cough that interferes with sleep or quality of life requires discontinuation 7, 1
• ACE inhibitor-induced cough does not always require treatment discontinuation, but when troublesome, switching to an ARB is recommended 7

Rare but Important: Angioedema Risk with ARBs

• Although rare (<1%), angioedema has been reported with ARBs in patients who previously experienced ACE inhibitor-related angioedema 1, 8
• Use caution during initial ARB treatment and counsel patients to seek immediate care if facial or tongue swelling develops 1, 8

Emergency Management if Angioedema is Present

Immediate Airway Management

• The primary focus for ACE inhibitor-induced angioedema is airway management, with consideration for early intubation or tracheotomy in severe cases 3, 6, 5
• Approximately 25% of patients with angioedema require intubation for airway protection 5
• Patients should be monitored in an intensive care unit to ensure the possibility of early intubation 6

Pharmacotherapy Considerations

• Corticosteroids and antihistamines are insufficient and unreliable in severe ACE inhibitor-induced angioedema 6, 9, 4
• In the absence of high-quality evidence, no specific medication therapy is definitively recommended 3, 9
• Icatibant (bradykinin B2 receptor antagonist) has shown some efficacy in one study, but results are conflicting 9, 4
• Fresh frozen plasma or C1 inhibitor concentrate infusion have shown some efficacy in case reports 9, 4

Definitive Action

• Immediately discontinue the ACE inhibitor 3, 5
• Do not rechallenge with any ACE inhibitor 3, 4