Angioedema

ACE-Inhibitor–Induced Angioedema (ACEi-AE)

ACE-inhibitor–induced angioedema is bradykinin-mediated, so the traditional histamine-directed triad (epinephrine ± antihistamines ± glucocorticoids) offers little benefit. Management therefore hinges on early airway protection plus bradykinin-targeted therapy.

Key points for ACEi-AE at the bedside (“ABCs + B-kinin blockers”)

1. Airway first: Maintain a low threshold for awake fiber-optic or video-assisted intubation when voice change, tongue-base swelling, or rapid progression are present.
2. Stop the ACE inhibitor and list it as a permanent allergy.
3. Preferred pharmacologic options (start as soon as the airway is secure or judged stable):

Sequence	Drug (dose / route)	Rationale & evidence
1	Icatibant 30 mg SC (may repeat × 2 at ≥ 6 h intervals)	Bradykinin B2-receptor antagonist; RCT showed median symptom resolution 2 h vs 8 h with steroids/antihistamine.
2	C1-esterase inhibitor concentrate 20 IU kg⁻¹ IV	Replaces C1-INH, dampening kallikrein/FXII activity; supportive case series.
3	Fresh-frozen plasma (FFP) 1–2 units IV (up to 4 units)	Provides ACE and other kininases that degrade bradykinin; relief typically ≤ 4 h but includes transfusion risks.
4	Tranexamic acid 1 g IV push / 10 min	Antifibrinolytic that indirectly limits bradykinin generation; evidence limited but appears safe as rescue.

If you must combine therapies, give FFP before C1-INH to avoid neutralising the concentrate.

4. Adjuncts: Nebulised epinephrine for stridor while preparing the definitive airway. Use the histaminergic bundle (IM epinephrine, diphenhydramine, famotidine, methylprednisolone) only if an allergic trigger has not yet been ruled out.

Diagnostic work-up & differential diagnosis at presentation

Suspected type	Triggers & history	Typical distribution / onset	Urticaria?	Key labs / tests	Distinguishing points & first-line acute therapy
Histaminergic / anaphylactic	Food, stings, drugs, contrast	Seconds–minutes	Yes	Serum tryptase (peak ≈ 1–2 h)	Responds to IM epinephrine; usually resolves < 24 h.
ACE-inhibitor (bradykinin)	Any time during ACEi therapy (risk highest first 30 days)	Hours; tongue, lips, larynx	No	No confirmatory lab; consider C4 to exclude HAE	Does not respond to histamine-directed meds; treat as above.
Hereditary angioedema (C1-INH types I/II/III)	Family history; childhood onset; estrogen sensitivity	Skin, GI, airway; lasts 2–5 days	Usually no	Low C4 during attack; low or dysfunctional C1-INH	Responds to C1-INH, icatibant, ecallantide; TXA useful prophylaxis.
Acquired C1-INH deficiency	Age > 40; lymphoproliferative / autoimmune disease	Similar to HAE	No	Low C1-INH and low C1q	Treat underlying disorder + C1-INH or icatibant.
Other drug-related (ARB, tPA, DPP-4-i, NSAID)	Temporal link to drug	Similar to ACEi or histaminergic	Variable	Guided by mechanism (tryptase or complement)	Withdraw culprit; manage per bradykinin or histamine pathway.
Idiopathic non-histaminergic	Recurrent; no clear trigger	Face / extremities	No	Normal labs	Often steroid-resistant; consider bradykinin blockade if severe.

Treatment options by angioedema mechanism

Mechanism	First-line	Proven adjuncts	Second / rescue	Long-term prophylaxis
Histamine-mediated	IM epinephrine 0.3–0.5 mg q5 min prn	Diphenhydramine 25–50 mg; famotidine 20 mg; methylprednisolone 125 mg	Airway support	Allergen avoidance; omalizumab for chronic idiopathic.
Bradykinin-mediated (ACEi-AE)	Icatibant 30 mg SC	C1-INH 20 IU kg⁻¹ IV	FFP 1–2 U; TXA 1 g IV; ecallantide 30 mg SC	Avoid ACEi; avoid DPP-4-i or mTOR inhibitors if possible.
HAE (acute)	C1-INH, icatibant, ecallantide	FFP if above unavailable	TXA 1 g IV	Lanadelumab; berotralstat; C1-INH prophylaxis.
HAE / acquired (prophylaxis)	Lanadelumab 300 mg SC q2–4 wk	C1-INH 1,000 IU IV twice weekly	TXA 1 g PO bid	Treat lymphoid / autoimmune driver (acquired).

Practical take-aways

• Tranexamic acid 1 g IV and FFP 1–2 units are acceptable rescue therapies for ACEi-AE when icatibant or C1-INH is unavailable. Current data show safety but inconclusive efficacy for TXA, and only small case series for FFP—use when benefits outweigh risks.
• Always anticipate a difficult airway; progression can be deceptively rapid.
• Once the episode resolves, counsel the patient never to restart an ACE inhibitor and to carry documentation of the reaction.

*Lines marked with an asterisk indicate off-label or lower-quality evidence interventions.*