Perioperative anaphylaxis is a rare, life‑threatening condition during anesthesia. The unique setting – multiple drugs, patient draping, and altered physiology – causes higher mortality than anaphylaxis elsewhere. This review covers evolving etiology, pathophysiology, atypical presentation, evidence‑based management, and prevention. Primary triggers include neuromuscular blocking agents, antibiotics, and latex, with emerging culprits (chlorhexidine, dyes, remimazolam). Diagnosis is challenging due to few cutaneous signs; cardiovascular collapse with low end‑tidal CO₂ is a key supportive indicator. Immediate management prioritizes epinephrine and aggressive fluids. Post‑event allergological testing (skin tests, tryptase/histamine) identifies the culprit. Prevention includes history‑taking, risk stratification, and latex‑free environments. Future directions: global surveillance, novel biomarkers (circulating microbiome), and simulation training.
Introduction
Incidence 1:2,000–1:20,000 procedures, but mortality higher than community anaphylaxis. Diagnosis difficult due to anesthesia‑induced changes, lack of patient feedback, and multiple triggers. This narrative review synthesizes recent evidence (2017–2025).
Pathophysiology and Evolving Etiology
Primarily IgE‑mediated mast cell/basophil degranulation; non‑IgE reactions also occur. Mediators cause vasodilation, capillary leak, bronchoconstriction.
Primary triggers: NMBAs (most common), β‑lactam antibiotics, latex (declining with avoidance).
Emerging triggers: Chlorhexidine, patent blue dye, remimazolam (case reports; cross‑reactivity with midazolam inconclusive).
High‑risk for latex: spina bifida, chronic bladder catheterization, healthcare workers, multiple surgeries.
Experimental: Pilot study found distinct circulating bacterial DNA (Enterobacteriaceae, Veillonellaceae) in NMBA‑allergic patients, correlating with tryptase/IgE – exploratory, needs validation.
Diagnostic Challenges and Advances
Atypical presentation: Cutaneous signs rare; initial sign often cardiovascular collapse (severe hypotension), mistaken for anesthetic effects.
Key indicator: Low ETCO₂ with hypotension – mean lowest ETCO₂ 17 mmHg in anaphylaxis vs. 32 mmHg in other causes (AUC 0.95; cutoff ~23 mmHg: 92% sensitive, 94% specific). Not specific (also hemorrhage, PE), but valuable clue.
Bronchospasm: often severe, increased airway pressure.
Serum tryptase: elevated in ~71% of perioperative hypersensitivity reactions.
Plasma histamine: early, short half‑life; sample immediately and within 1–2 hours (threshold ~1.5 ng/mL at 30 min).
Immediate Management and Post‑Event Investigation
Acute resuscitation: Stop potential triggers, 100% O₂, aggressive crystalloids, epinephrine (IM/IV titrated). Epinephrine first‑line; large volumes often needed.
Post‑stabilization:
Skin testing (prick/intradermal) – cornerstone; traditionally 4–6 weeks post‑reaction.
Drug provocation tests – for high suspicion with negative skin tests; definitive but high risk, only in expert centers.
In vitro specific IgE for latex, some NMBAs, antibiotics.
Prevention and Future Directions
Prevention: Meticulous preoperative history; risk stratification and labelling; latex‑free operating rooms. Premedication (antihistamines/corticosteroids) ineffective for latex.
Future priorities:
International registries (e.g., NAP6) for real‑time surveillance.
Validate circulating microbiome as predictive biomarker.
Pharmacovigilance for remimazolam and other new agents.
Simulation‑based team training (eye‑tracking studies show experienced providers allocate attention better).
Limitations
Narrative review; evidence for emerging triggers from case reports/small series; microbiome findings preliminary; recommendations may need local adaptation.
Conclusions
Perioperative anaphylaxis is a dynamic challenge. Masked presentation requires high suspicion, guided by profound hypotension with low ETCO₂. Acute management: swift epinephrine and volume expansion. Long‑term safety relies on systematic prevention – risk‑aware evaluation, awareness of traditional and emerging triggers, and allergen avoidance. Future: surveillance, biomarkers, novel agent evaluation, and team training.
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The study was recently published in the Exploratory Research and Hypothesis in Medicine .
Exploratory Research and Hypothesis in Medicine (ERHM) publishes original exploratory research articles and state-of-the-art reviews that focus on novel findings and the most recent scientific advances that support new hypotheses in medicine. The journal accepts a wide range of topics, including innovative diagnostic and therapeutic modalities as well as insightful theories related to the practice of medicine. The exploratory research published in ERHM does not necessarily need to be comprehensive and conclusive, but the study design must be solid, the methodologies must be reliable, the results must be true, and the hypothesis must be rational and justifiable with evidence.
