Anaphylaxis in the ICU · ICU Topics

Cinematic ICU scene of a patient in anaphylactic shock with a widespread urticarial rash and angioedema, an adrenaline autoinjector and an IV adrenaline infusion running, a cardiac monitor showing tachycardia and hypotension, clinical-blue lighting, no faces, no text — FigureAnaphylaxis — IM adrenaline 0.5 mg into the anterolateral thigh is first-line, repeated every five minutes. For the refractory or beta-blocked patient, an IV adrenaline infusion and glucagon (which bypasses the beta-receptor) are the rescue. Observe for the biphasic reaction (5-20 per cent) for 6-12 hours.

[1] [1]

Diagnostic criteria

Educational schematic of anaphylaxis pathophysiology: allergen IgE crosslinking, mast cell degranulation histamine tryptase leukotrienes, vasodilation leak bronchospasm angioedema — FigureAnaphylaxis mediators — mast-cell degranulation releases histamine, tryptase and leukotrienes that drive shock, bronchospasm and angioedema within minutes.

[1] [2]

Management

[1]

Anaphylaxis management protocol

1. IM ADRENALINE 0.5 mg (500 mcg) — FIRST-LINE

Give IMMEDIATELY. Site: anterolateral thigh (vastus lateralis — best absorption). Dose: 0.5 mg (0.5 mL of 1:1000). REPEAT every 5 minutes if no improvement (up to 3 doses). Do NOT delay for IV access or investigations. IM is preferred over IV for initial treatment (safer, effective).<Cite id="2" />

2. Position and oxygen

SUPINE with legs elevated (maximises venous return). Do NOT sit up or stand (empty vena cava syndrome — catastrophic hypotension). Oxygen 15 L/min via non-rebreather mask. If airway compromised from angioedema: early intubation by experienced operator.

3. IV fluid resuscitation

1-2 large-bore IV cannulae. Crystalloid bolus: 20 mL/kg rapidly (may need 1-2 L). Anaphylactic shock causes massive vasodilation + capillary leak + third-space losses. Continue fluids guided by response.

4. Second-line agents

Antihistamines: chlorphenamine 10 mg IV (H1 blocker — helps urticaria/itch but NOT first-line for airway/circulation). Ranitidine/famotidine 20 mg IV (H2 blocker — adjunctive). Corticosteroids: hydrocortisone 200 mg IV (may prevent biphasic reaction but no definitive evidence). These do NOT substitute for adrenaline.

5. Refractory anaphylaxis — IV adrenaline

If 2-3 doses IM adrenaline + fluids are ineffective: start IV adrenaline infusion. Bolus: 50 mcg IV over 5 min (dilute 1 mL of 1:1000 in 10 mL saline). Infusion: 0.05-0.1 mcg/kg/min, titrate up. Consider vasopressin if refractory. ICU admission for monitoring.<Cite id="3" />

6. Beta-blocked patient — GLUCAGON

Patients on beta-blockers may not respond to adrenaline (beta-receptor blocked). Give GLUCAGON 3-5 mg IV over 5 min, then infusion 5-15 mcg/min. Glucagon bypasses the beta-receptor — activates adenylate cyclase directly, increasing cAMP. Also treat bradycardia from beta-blockade.

7. Investigations

Tryptase: send at 1-2h (peak), 24h, and baseline (after recovery). Elevated mast cell tryptase confirms anaphylaxis (vs vasovagal). Allergy referral for identification of trigger (skin prick testing, specific IgE). Check: FBC, U&E, lactate, ABG.

8. Observe for biphasic reaction

5-20% of anaphylaxis cases have a biphasic reaction (recurrence 1-72h after initial recovery). Observe for 6-12 hours (longer if severe, needed IM adrenaline x2+, or beta-blocked). Discharge with adrenaline auto-injector (EpiPen) and allergy referral.

[4]

Common triggers

ICU-specific triggers

Peri-procedural

Neuromuscular blocking agents: rocuronium, suxamethonium (#1 perioperative)
Antibiotics: penicillins, cephalosporins, vancomycin
Radiocontrast media
Chlorhexidine (increasingly recognised — catheters, skin prep)
Latex (less common now — latex-free environment)
Ethylene oxide (sterilising agent)
Patent Blue dye (sentinel lymph node biopsy)

General triggers

Community

Foods: nuts (peanut, tree nuts), shellfish, eggs, milk
Medications: NSAIDs, antibiotics
Insect stings: bee, wasp
Exercise-induced
Idiopathic (no trigger identified in 20-30%)

Sugammadex reversal for rocuronium anaphylaxis

Exam practice

SAQ — Perioperative anaphylaxis

10 minutes · 10 marks

A 55-year-old woman receives IV co-amoxiclav and rocuronium for induction of anaesthesia for elective cholecystectomy. Within 2 minutes she becomes hypotensive (BP 65/35), tachycardic (HR 130), develops widespread urticaria, and has audible wheeze with SpO2 falling to 85%.

[1]

Clinical pearls

High-yield anaphylaxis points for the CICM/FFICM exam

IM adrenaline 0.5 mg is FIRST-LINE — anterolateral thigh, repeat every 5 min. Do NOT delay.[2]
Supine with legs elevated — never sit/stand (empty vena cava syndrome = death).
Beta-blocked patient: give glucagon 3-5 mg IV — bypasses beta-receptor.[3]
IV adrenaline for refractory: infusion 0.05-0.1 mcg/kg/min. Use only if IM adrenaline + fluids ineffective.
Biphasic reactions in 5-20% — observe 6-12h. Longer if severe or beta-blocked.[4]
Tryptase: send at 1-2h (peak), 24h, and baseline. Elevated confirms anaphylaxis.
Antihistamines and steroids are SECOND-LINE — they do NOT substitute for adrenaline.
Neuromuscular blockers are #1 cause of perioperative anaphylaxis (rocuronium, suxamethonium).
Chlorhexidine is increasingly recognised as a cause of perioperative anaphylaxis.
Sugammadex 16 mg/kg can reverse rocuronium-triggered anaphylaxis (encapsulates NMBA).
IV fluids: 1-2 L crystalloid rapidly — anaphylaxis causes massive vasodilation + capillary leak.
Skin involvement absent in 10-20% — do NOT wait for rash if presentation is classic.
Allergy referral on discharge — skin prick testing to identify trigger.
Adrenaline auto-injector (EpiPen) on discharge — teach patient to use.

Red flags

NIAID/FAAN diagnostic criteria — the three criteria in detail

The NIAID/FAAN second symposium (Sampson 2006) criteria remain the international standard for diagnosing anaphylaxis and are required knowledge for the CICM/FFICM exam.[5] Anaphylaxis is highly likely when any one of three clinical criteria is fulfilled. The criteria exist because anaphylaxis is under-diagnosed — relying on "rash plus collapse" misses the 10–20% of cases without cutaneous features.[24]

[1]

NIAID/FAAN Criterion 2 — two-or-more organ systems after a likely allergen

Two or more of the following occur rapidly (minutes to several hours) after exposure to a likely allergen for that patient:

Skin/mucosal involvement
Respiratory compromise
Reduced BP or associated symptoms
Persistent gastrointestinal symptoms (crampy abdominal pain, vomiting, diarrhoea) [1]

Worked example: a known asthmatic receives IV contrast for CT. Within 10 minutes she develops vomiting, widespread itch and stridor with normal BP. → Criterion 2 met (skin + respiratory + GI, after a likely allergen). → Treat as anaphylaxis. [1]

Pearl: the GI criterion is the discriminator that distinguishes Criterion 2 from Criterion 1 — persistent abdominal pain/vomiting in isolation is not anaphylaxis, but combined with another system it is.

[1] [1]

When the NIAID/FAAN criteria are NOT met — recognise the mimics

True anaphylaxis mimics

Look-alikes

Vasovagal syncope — pallor (NOT flush), bradycardia, no urticaria/itch, resolves supine
Asthma exacerbation — isolated bronchospasm, no hypotension or urticaria
Panic attack — subjective dyspnoea with normal SpO2/BP, no urticaria
Carcinoid syndrome — episodic flush/diarrhoea/bronchospasm (not acute collapse)
Mastocytosis — recurrent unexplained anaphylaxis; persistently elevated baseline tryptase
Hereditary angioedema — complement C4 low, no urticaria, bradykinin-mediated (NOT histamine)
Scombroid — histamine fish poisoning with flush (NOT IgE-mediated, responds to antihistamines)

Red flags that favour anaphylaxis

Treat as anaphylaxis

Sudden cardiovascular collapse within minutes of a drug/food/sting
Angioedema (lip/tongue/uvula swelling) + any other system
Bilateral wheeze + hypotension after an exposure
Hypotension refractory to fluids in the perioperative window
Pulse >130 and SBP <90 with a temporal trigger
When in doubt, give IM adrenaline — the harm of omission > harm of an unnecessary dose

Brown's severity grading — guides who needs ICU

Brown's 3-grade severity grading (anaphylaxis)

Grade 1 — mild

Skin only

Generalised urticaria, erythema, angioedema WITHOUT other system involvement
Rarely needs adrenaline — observe and consider oral antihistamine
ED observation usually sufficient; ICU rarely needed

Grade 2 — moderate

Skin + one system

Skin features PLUS respiratory (dyspnoea/wheeze), cardiovascular (tachycardia, dizziness, SBP 90–110), or GI symptoms
Standard IM adrenaline 0.5 mg; usually responds
ED/HDU observation 6–12 h for biphasic risk

Grade 3 — severe

Life-threatening

Hypoxia (SpO2 <92%), cyanosis, hypotension (SBP <90), collapse, neurological (confusion/loss of consciousness)
IM adrenaline + IV fluids; often needs multiple adrenaline doses, IV adrenaline infusion, ICU admission
ICU admission mandatory — high risk of refractory course and biphasic recurrence

[1]

ICU-specific triggers — in depth

The ICU and perioperative environment is a high-density allergen landscape — patients are exposed to dozens of parenteral agents within minutes, and parenteral exposure produces a faster, more severe reaction than oral.[12] Below are the ICU-relevant triggers that must be considered for every collapse in ICU/ theatre.

Beta-lactam antibiotics

Beta-lactam anaphylaxis — the ICU staples

Penicillins (benzylpenicillin, amoxicillin, co-amoxiclav, flucloxacillin, piperacillin-tazobactam) and cephalosporins (cefuroxime, ceftriaxone, cefazolin) are the most commonly administered ICU antibiotics and a leading drug trigger of anaphylaxis. Cross-reactivity between penicillins and cephalosporins is much lower than historically taught — modern data place it at ~1–2%, driven by side-chain similarity rather than the core beta-lactam ring. Piperacillin-tazobactam is a particularly high-risk perioperative antibiotic in NAP6.[9]

Key ICU points:

Anaphylaxis typically occurs within 5–30 minutes of IV administration (faster than oral)
A reported "penicillin allergy" on the chart is wrong in ~90% of cases — but never ignore it during an acute reaction; treat empirically and refer for formal testing
Monobactams (aztreonam) and carbapenems (meropenem) have very low cross-reactivity with penicillins — often safe alternatives after allergy workup
Vancomycin is NOT a beta-lactam and can usually be used when beta-lactam allergy is confirmed

[1]

Vancomycin — "red man syndrome" vs true anaphylaxis

Vancomycin: red man syndrome is NOT IgE-mediated anaphylaxis

Vancomycin causes two distinct reactions every ICU trainee must distinguish: [1]

Red man syndrome (RMS) — rate-dependent direct mast-cell degranulation causing histamine release. Presents with flush, erythema, pruritus (neck/upper body), sometimes mild hypotension. Slowing or stopping the infusion (give over ≥60 min, 1 g) and antihistamines treat it. Not IgE-mediated, no tryptase rise (usually), not life-threatening, can re-challenge at slower rate.
True vancomycin IgE anaphylaxis — rare. Cardiovascular collapse, bronchospasm, angioedema within minutes. Treat with IM adrenaline. Confirmed on skin testing. Avoid vancomycin permanently and use teicoplanin/daptomycin/linezolid. [1]

Pearl: if a patient flushes during a fast vancomycin infusion, slow/stop the infusion and give antihistamine — this is usually RMS, not anaphylaxis. If they become hypotensive with bronchospasm, give IM adrenaline regardless.

[1]

Neuromuscular blocking agents — the #1 perioperative trigger

NMBAs: the dominant perioperative anaphylaxis trigger (NAP6)

Neuromuscular blocking agents are the single commonest cause of perioperative anaphylaxis, accounting for ~50–60% of cases in NAP6.[9][10] NMBAs cause anaphylaxis through IgE antibodies directed against substituted ammonium groups on the molecule — a structural motif shared by all NMBAs, which explains cross-reactivity between chemically dissimilar agents.[13]

Rocuronium — most frequently implicated (highest UK market share; NAP6 #1 culprit). Onset within 1–5 minutes of IV dose.
Suxamethonium (succinylcholine) — historically the leading trigger; still high-risk due to its depolarising structure. Often causes the most explosive reactions.
Vecuronium, atracurium, cisatracurium, mivacurium — all reported; atracurium/cisatracurium have a lower relative risk in some series.
Cross-reactivity between NMBAs is ~60–75% — a patient reactive to one NMBA may react to any. Skin testing of multiple agents guides future safe options. [1]

ICU/take-home: any cardiovascular or bronchospastic collapse within 5 minutes of induction should be assumed to be NMBA (or antibiotic) anaphylaxis until proven otherwise.[12]

NSAIDs

[1]

Radiocontrast media

[1]

Latex

Blood products and transfusion reactions

Transfusion-related reactions in ICU — distinguish from anaphylaxis

Blood products can cause several reactions that mimic anaphylaxis: [1]

Anaphylactic transfusion reaction — IgA-deficient patient with anti-IgE/IgA antibodies receiving IgA-containing blood → true IgE anaphylaxis. Rare but catastrophic. Treat with IM adrenaline. Use washed/deglycerolised or IgA-deficient donor products subsequently.
TRALI (transfusion-related acute lung injury) — donor anti-leucocyte antibodies → bilateral pulmonary oedema within 6 h. Not anaphylaxis — no urticaria, no tryptase rise. Treat supportively (oxygen, lung-protective ventilation, avoid diuresis).
TACO (transfusion-associated circulatory overload) — volume overload → pulmonary oedema. Not anaphylaxis.
Febrile non-haemolytic / urticarial — pre-storage leucodepletion has made these rare; respond to antihistamine and pause. [1]

Pearl: anaphylaxis within minutes of a blood product unit = stop the transfusion, IM adrenaline, send mast-cell tryptase and a clotted sample for anti-IgA. Suspect IgA deficiency if reaction is recurrent or severe.

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Other ICU/perioperative triggers worth knowing

Less common but high-yield ICU triggers

Chestnut triggers

Often missed

Chlorhexidine — increasingly recognised; central line dressings, chlorhexidine-impregnated CVCs, urinary catheters, oral rinses. Can cause anaphylaxis on mucosal contact. Check dressings in unexplained ICU anaphylaxis
Patent Blue / Isosulfan Blue dye — sentinel lymph node biopsy; vivid blue urticaria easily missed
Protamine — heparin reversal in cardiac surgery; rapid IV bolus → catastrophic vasoplegia/anaphylaxis
Ethylene oxide — sterilising agent on disposable equipment; bovine/porcine proteins in surgical haemostats
Colloid plasma expanders — gelatins (Gelofusine, Haemaccel) and dextrans can trigger non-IgE anaphylactoid reactions
Aprotinin, fluorescein, indocyanine green, methylene blue itself, oxytocin, iron dextran infusion

[12]

Perioperative anaphylaxis — NAP6 in depth

NAP6 (6th National Audit Project of the Royal College of Anaesthetists, 2018) is the definitive UK epidemiological study of perioperative anaphylaxis and required knowledge for the exam.[9][10] Every FFICM/CICM candidate should be able to quote its headline findings.

NAP6 (2018) — UK 6th National Audit Project, perioperative anaphylaxis (PMID 29935569, 29935567)

Source

Royal College of Anaesthetists 6th National Audit Project — UK-wide prospective case capture of all Grade 3–5 perioperative anaphylaxis events (2016)

Incidence

~1 in 10,000 anaesthetics (similar to historical UK and French data)

Triggers

NMBAs ~50–60% (rocuronium #1), antibiotics ~33% (teicoplanin and co-amoxiclav over-represented), chlorhexidine ~9%, Patent Blue dye ~4%, latex <1%

Mortality

3.8% death or brain damage (Grade 5) — higher than non-perioperative anaphylaxis

Adrenaline delays

Adrenaline was delayed or under-dosed in the majority of fatal/near-fatal cases — the single most cited preventable failure

Key recommendation

All suspected perioperative anaphylaxis MUST be referred to a specialist allergy clinic; serial tryptase mandatory; never re-expose without workup

Clinical bottom line

NMBAs (especially rocuronium) are the #1 perioperative trigger; antibiotic anaphylaxis is rising (teicoplanin); adrenaline delay kills — give IM adrenaline EARLY and in adequate dose

[1]

Perioperative anaphylaxis — the unique challenges

Perioperative anaphylaxis differs from community anaphylaxis in ways that change management: [1]

Drapes hide the rash — cutaneous signs are missed in 30–40% of cases; the presenting sign is often unexplained hypotension or bronchospasm under anaesthesia
Multiple simultaneous exposures — induction agent, NMBA, antibiotic, opioid, chlorhexidine prep, latex, dye, contrast may all be given within 5 minutes — identifying the culprit requires structured tryptase sampling and later skin testing
Volatile agents and positive-pressure ventilation mask bronchospasm; tachycardia from surgical stimulus masks hypotension
Pregnancy increases risk (caesarean section, suxamethonium, oxytocin, Syntocinon)
Cardiac surgery is a distinct high-risk environment — protamine, aprotinin, blood products, cold agglutinins, gelatins
Referral is mandatory — every suspected case to a specialist perioperative allergy clinic for skin prick/intradermal testing and specific IgE at 4–6 weeks post-event (earlier testing gives false negatives; later testing may lose sensitivity)[12]

Tryptase sampling protocol

Mast-cell tryptase sampling after suspected anaphylaxis

Sample 1 — ASAP (ideally within 1–2 h)

Take the first serum tryptase as soon as feasible after the event, ideally within the **1–2 h peak window**. Mast-cell tryptase rises within 30 min, peaks at **1–2 h**, and falls back to baseline by **4–6 h** (sometimes up to 24 h). A peak tryptase > (1.2 × baseline) + 2 mcg/L supports anaphylaxis (the 1.2 + 2 rule).<Cite id="12" />

Sample 2 — at 4 h (or convalescence)

A second sample at ~4 h (or as the patient stabilises) captures the falling phase. A **normal** tryptase does **NOT** exclude anaphylaxis — mast-cell degranulation can be localised (food-triggered reactions often have normal tryptase). The **delta** (rise above baseline) matters more than the absolute value.

Sample 3 — baseline (≥24 h after full recovery)

A baseline tryptase taken at least 24 h after complete recovery (or at the allergy clinic visit) lets you interpret the acute rise. A **persistently elevated baseline tryptase (>11.4 mcg/L, especially >20)** raises the possibility of **mastocytosis / clonal mast-cell disorder** — these patients have recurrent unexplained anaphylaxis and need bone-marrow workup.

Interpretation

Acute tryptase >25 mcg/L (or a rise >2 mcg/L above baseline per the 1.2+2 rule) supports mast-cell activation. Send samples **clotted (serum) gold-top tube**, 1–2 mL, room temperature. Always pair with the **clinical picture** — tryptase is supportive, not diagnostic.

Trigger identification — at 4–6 weeks

Refer to a specialist allergy / perioperative allergy clinic. Skin-prick testing, intradermal testing and specific serum IgE performed at **4–6 weeks** post-event (to avoid false-negatives during the refractory mast-cell period immediately after the event, and to allow recovery of skin reactivity). NAP6 recommends every case is referred — under-referral was a major quality finding.<Cite id="9" />

Refractory anaphylaxis — escalation beyond IM adrenaline

Refractory anaphylaxis is defined (Delphi consensus, Dribin 2020) as anaphylaxis unresponsive to adequate initial treatment — typically 2–3 doses of IM adrenaline plus IV crystalloid.[8][3] Management requires escalating to IV catecholamine infusions and, if these fail, non-adrenergic rescue agents.[18]

Refractory anaphylaxis — stepwise pharmacological escalation

Ensure adequate IM adrenaline — at least 2 doses of 0.5 mg IM, 5 min apart. Most "refractory" cases are simply under-dosed.
IV crystalloid boluses — repeated 20 mL/kg aliquots; anaphylaxis produces massive capillary leak (often 5–7 L of third-space loss in severe cases).
IV adrenaline infusion — the standard second-line. Bolus 50 mcg IV over 5 min (diluted: 1 mL of 1:1000 in 10 mL saline), then infusion 0.05–0.5 mcg/kg/min titrated to SBP >90 / MAP >65. Prepare: 1 mg (1 mL of 1:1000) in 100 mL saline = 10 mcg/mL; or 4 mg in 250 mL = 16 mcg/mL.[3]
Glucagon — if patient is beta-blocked and not responding to adrenaline. 3–5 mg IV over 5 min, then infusion 5–15 mcg/min. Bypasses the beta-receptor entirely (acts via Gs protein → adenylate cyclase → cAMP). Also treats the bradycardia of beta-blockade.[20]
Vasopressin / terlipressin — non-adrenergic V1 agonist. 2–10 units IV bolus, infusion 0.01–0.04 U/min. Useful when alpha-receptors are down-regulated or the patient is on high-dose catecholamines. Animal data show similar haemodynamic efficacy to adrenaline.[17][18]
Methylene blue — inhibits the NO–cGMP vasoplegic pathway that drives refractory vasodilation. 1–2 mg/kg IV over 5 min, may repeat; infusion 0.25–2 mg/kg/h. Increasingly reported as salvage therapy for catecholamine-resistant vasoplegic anaphylaxis.[18]
Extracorporeal support (VA-ECMO / VV-ECMO) — last-line rescue for refractory cardiovascular collapse (VA-ECMO) or refractory bronchospasm (VV-ECMO). Case series now support ECMO as a bridge in truly refractory cases.[21][22]

Rescue agents for refractory anaphylaxis — when to use which

IV adrenaline infusion

First refractory step

Indication: not responding to 2× IM adrenaline + fluids
Dose: 0.05–0.5 mcg/kg/min titrated; bolus 50 mcg IV (diluted)
Mechanism: alpha-1 vasoconstriction + beta-1 inotropy + beta-2 bronchodilation
Watch: tachyarrhythmia, myocardial ischaemia, lactate rise — requires arterial line and ICU monitoring

Glucagon

Beta-blocked patient

Indication: anaphylaxis in a patient on beta-blockers refractory to adrenaline
Dose: 3–5 mg IV over 5 min, then 5–15 mcg/min infusion
Mechanism: bypasses the beta-receptor — Gs protein → adenylate cyclase → cAMP
Watch: nausea/vomiting (give antiemetic), hyperglycaemia — does NOT replace adrenaline, used IN ADDITION

Vasopressin / terlipressin

Catecholamine-resistant vasoplegia

Indication: refractory vasodilatory shock despite catecholamines
Dose: 2–10 units IV bolus; infusion 0.01–0.04 U/min
Mechanism: V1 receptor vasoconstriction — independent of adrenergic pathway
Watch: peripheral/splanchnic ischaemia, hyponatraemia — adjunct, not replacement

Methylene blue

NO-mediated vasoplegia

Indication: catecholamine-resistant vasoplegic shock (case reports; not first-line)
Dose: 1–2 mg/kg IV over 5 min, repeatable; infusion 0.25–2 mg/kg/h
Mechanism: inhibits soluble guanylate cyclase → blocks NO-cGMP vasodilation
Watch: serotonin syndrome risk with SSRIs/MAOIs; SpO2 readout falls to ~85% (spectral interference, not desaturation); DO NOT use with VV/VA-ECMO circuit priming concerns

ECMO (VA / VV)

Last-resort salvage

Indication: refractory cardiac arrest / circulatory failure (VA-ECMO) or refractory bronchospasm (VV-ECMO) despite full pharmacological therapy
Modality: VA-ECMO for circulatory support; VV-ECMO for gas exchange in refractory bronchospasm
Evidence: case reports/series — protamine anaphylaxis, peanut anaphylaxis, NMBA anaphylaxis
Watch: anticoagulation, limb ischaemia, transfer to ECMO centre — only at experienced centres

[3] [18]

Why is methylene blue rational in anaphylaxis?

Biphasic reactions — observation period

A biphasic reaction is recurrence of anaphylaxis symptoms 1–72 hours after the initial event resolves, with no new allergen exposure. The reported incidence varies widely (5–20%) depending on case definition and population; modern meta-analyses suggest ~5% overall, higher in severe presentations.[4][7]

Lee 2015 — Time of onset and predictors of biphasic anaphylactic reactions: meta-analysis (PMID 25680923)

Source

Systematic review and meta-analysis — Journal of Allergy and Clinical Immunology in Practice

Biphasic rate

~4.6–5% across studies (range 1–23%); most recurrences within 10 h, nearly all within 24 h

Predictors

Severity of initial reaction (need for >1 adrenaline dose), delayed adrenaline (>60 min), wide pulse pressure, unknown trigger, beta-blocker/ACE-inhibitor use

Fatal biphasic reactions

Rare but reported — usually in patients with severe initial reaction or comorbidity

Clinical bottom line

Most biphasic reactions occur within the first 10 hours — an observation window of 6–12 h captures the majority; longer for high-risk features

[1]

Kim 2019 — Duration of observation for detecting biphasic reaction: meta-analysis (PMID 30763927)

Source

Meta-analysis — International Archives of Allergy and Immunology

Key finding

To detect 95% of biphasic reactions, an observation period of ~**48 h** would be required — but most (>95%) occur within the first 24 h

Practical cut-off

Observation to **6–12 h** captures the great majority; extending to 24 h only for high-risk patients

Risk-stratified observation

Mild (grade 1): can discharge early. Moderate (grade 2): observe 6–12 h. Severe (grade 3), multiple adrenaline doses, beta-blocked, or unknown trigger: observe 24 h or admit

Clinical bottom line

No single observation window captures 100% of biphasic reactions — risk-stratify. ICU admission reserved for severe/refractory or those needing ongoing vasopressors

[1]

Biphasic reaction — who needs longer observation?

Factors that mandate longer observation (≥24 h or ICU admission):

Severe initial reaction requiring 2 or more doses of IM adrenaline, or any IV adrenaline
Refractory course needing vasopressor infusion or methylene blue/glucagon/vasopressin
Beta-blocker or ACE-inhibitor therapy (interferes with compensation)
Pre-existing cardiovascular/respiratory disease
Unknown trigger (cannot counsel avoidance)
Massive mast-cell load — mastocytosis, baseline tryptase elevated
Delayed initial adrenaline (>60 min from symptom onset)
Children with food-triggered reactions (higher biphasic rate in some series) [1]

Most biphasic reactions occur within 10 hours; virtually all within 24 hours. The traditional "observe everyone 6–12 h" is being replaced by risk-stratified observation.[4][6][23]

Recommended observation period by risk stratification

Low risk — discharge early

Grade 1 / mild

Single-system reaction (e.g. skin only) that fully resolves with one dose of IM adrenaline
No biphasic risk factors; trigger identified and avoidable
Discharge at 4–6 h with adrenaline auto-injector, written action plan, allergy referral

Moderate risk — observe 6–12 h

Grade 2

Two-system involvement, resolved with 1 dose IM adrenaline, normal haemodynamics after
No IV adrenaline, no vasopressors; no high-risk comorbidity
ED/HDU observation; discharge with auto-injector + plan if no recurrence

High risk — observe ≥24 h / ICU

Grade 3 / refractory

Severe reaction: hypoxia, hypotension, or any IV adrenaline/vasopressor use
2 or more IM adrenaline doses; beta-blocked patient; mastocytosis
ICU admission for haemodynamic monitoring and ongoing vasopressor titration
Discharge only after stable off all catecholamines for >12 h

[8] [23]

ICU management protocol — ongoing care after initial resuscitation

Once the patient reaches ICU after initial resuscitation, the focus shifts to haemodynamic support, ventilatory support, monitoring for biphasic recurrence, and trigger identification. [1]

ICU management protocol for anaphylaxis — first 24 hours

1. Airway and breathing

Maintain intubation if angioedema was severe or airway was threatened — extubate only when swelling clearly receding (often 12–24 h). Lung-protective ventilation if bronchospasm/atelectasis. Bronchodilator (salbutamol nebs/IV) for ongoing bronchospasm — note IV salbutamol can cause lactic acidosis and tachycardia that mimic ongoing anaphylaxis.

2. Circulation — vasopressor titration

Arterial line + central access. Titrate adrenaline/noradrenaline to MAP >65. If persistent vasoplegia despite escalating catecholamines → add vasopressin (0.01–0.04 U/min) and/or methylene blue (1–2 mg/kg). Reassess intravascular volume with POCUS IVC / dynamic indices — anaphylactic capillary leak often needs **3–7 L** crystalloid over 12–24 h, with albumin in refractory cases.<Cite id="18" /><Cite id="19" />

3. Glucagon if beta-blocked

If the patient is on beta-blockers and bradycardic/refractory → glucagon 3–5 mg IV bolus then 5–15 mcg/min infusion. Watch for vomiting (give ondansetron). Continue adrenaline as well — glucagon is adjunctive.<Cite id="20" />

4. Adjunctive therapy

H1 blocker (chlorphenamine 10 mg IV q8h or oral cetirizine 10 mg); H2 blocker (famotidine 20 mg IV q12h — note ranitidine withdrawn); corticosteroid (hydrocortisone 200 mg IV q6h for 24–48 h — evidence for biphasic prevention is weak but commonly given). These DO NOT treat the acute airway/circulation — they are for symptomatic itch and (theoretically) biphasic prevention.

5. Serial tryptase and investigation

Send tryptase at baseline (on ICU), 4 h, and convalescent. Check FBC, U&E, lactate, ABG, troponin (Kounis syndrome — type II vasospastic ACS from mast-cell mediators), IgE, specific IgE to suspected triggers. Arrange specialist allergy clinic referral at 4–6 weeks for skin testing.<Cite id="12" />

6. Monitor for biphasic recurrence

Continuous cardiac/SpO2 monitoring, hourly observations for first 12 h. Any new urticaria, hypotension, or bronchospasm → repeat IM adrenaline and escalate. Most biphasic reactions occur within the first 10 h — vigilance is highest during this window.<Cite id="4" /><Cite id="6" />

7. De-escalation

Once stable off catecholamines for >6–12 h with no new features, step down to HDU/ward. Continue H1/H2 blocker for 48–72 h. Arrange adrenaline auto-injector (EpiPen 0.3 mg, or Anapen) — at least 2 devices — and structured patient education before discharge.

8. Discharge planning

Written anaphylaxis action plan, 2 adrenaline auto-injectors, MedicAlert bracelet, training of patient and family in auto-injector use. Specialist allergy clinic referral (mandatory after perioperative anaphylaxis per NAP6). Document the suspected trigger clearly and flag in the electronic record.<Cite id="9" /><Cite id="23" />

Special situations

Anaphylaxis in special populations — ICU nuances

Pregnancy

Maternal + foetal

Left lateral tilt (avoid aortocaval compression); IM adrenaline dose UNCHANGED (no contraindication)
Higher incidence in caesarean section — suxamethonium, oxytocin, antibiotics, chlorhexidine all candidates
Foetal distress common — continuous CTG; consider early delivery if peri-arrest
Try to identify trigger before next pregnancy/paediatric anaesthesia (NMBAs cross placenta rarely relevant acutely)

Cardiac disease / Kounis syndrome

Coronary vasospasm

Mast-cell mediators cause coronary vasospasm and plaque erosion — "allergic ACS"
ECG and troponin mandatory; treat anaphylaxis FIRST (adrenaline) then standard ACS therapy
Adrenaline can worsen ischaemia — use lowest effective dose; nitrate/morphine as adjunct
Beta-blockers relatively contraindicated in active anaphylaxis — withhold; consider glucagon early if already on beta-blocker

Elderly / comorbid

Polypharmacy

Beta-blockers, ACE-inhibitors, diuretics all impair compensation — have glucagon ready
Reduced physiological reserve → decompensate faster; lower threshold for ICU
Higher risk of adrenaline-induced myocardial ischaemia/arrhythmia — titrate carefully
Antihistamine anticholinergic effects compound delirium

Mastocytosis

Clonal mast-cell disorder

Recurrent unexplained anaphylaxis with elevated baseline tryptase (>20 mcg/L)
Reactions often WITHOUT an identifiable trigger; venom (Hymenoptera) is the classic elicitor
Pre-medicate procedures with H1/H2 blockers and steroids; have adrenaline infusion ready
Refer for bone-marrow biopsy and KIT D816V mutation testing

[1]

Additional exam practice

SAQ — Refractory perioperative anaphylaxis and methylene blue

12 minutes · 10 marks

A 68-year-old man undergoes elective aortic valve replacement. After protamine reversal of heparin at the end of bypass, he develops sudden profound hypotension (MAP 35), bronchospasm with peak airway pressures rising from 25 to 55 cmH2O, and widespread erythema. He has received 3 doses of IM adrenaline (0.5 mg each), 2 L of crystalloid, and is now on a noradrenaline infusion at 0.5 mcg/kg/min. MAP remains 45 with bronchospasm persisting. He takes metoprolol 50 mg daily.

[1]

SAQ — Tryptase sampling and NAP6 referral

10 minutes · 10 marks

A 45-year-old woman undergoes emergency laparotomy for perforated diverticulitis. After induction with propofol, fentanyl, rocuronium and co-amoxiclav, she develops profound hypotension (BP 60/30), bronchospasm and widespread urticaria. She is resuscitated with IM adrenaline (×2), IV fluids and IV chlorphenamine/hydrocortisone, and is stabilised in ICU. It is now 90 minutes since the event.

[1]

Additional clinical pearls

Advanced anaphylaxis pearls — refractory, perioperative, and exam traps

NIAID/FAAN Criterion 3 (known allergen + hypotension alone) is the criterion that catches "no-rash anaphylaxis" — never wait for urticaria in the vasopleptic patient with a known trigger.[5]
Cross-reactivity between NMBAs is ~60–75% — they share a substituted ammonium epitope. Skin-test multiple agents to find a safe one.[13]
NAP6 #1 trigger is rocuronium (not suxamethonium as historically taught); teicoplanin and co-amoxiclav are the #1 antibiotics.[9][10]
Red man syndrome is rate-dependent, NOT IgE — slow the vancomycin infusion and give antihistamine; do not label the patient "vancomycin-allergic" without testing.[12]
Tryptase peaks at 1–2 h — if you only send one sample, send it then. Always pair with a baseline (≥24 h later) to interpret the rise; use the 1.2 × baseline + 2 mcg/L delta rule.
Glucagon for beta-blocked anaphylaxis works via a different Gs-protein pathway (bypasses the blocked beta-receptor → direct adenylate cyclase activation). Dose: 3–5 mg IV over 5 min then 5–15 mcg/min.[20]
Vasopressin is the rational second-line when catecholamine receptors are exhausted — V1-mediated vasoconstriction independent of the adrenergic pathway.[17]
Methylene blue blocks the NO–cGMP vasoplegic pathway; watch for spurious SpO2 ~85% (spectral interference, not real desaturation) and serotonin syndrome with SSRIs/MAOIs.[18]
VA-ECMO is the salvage rescue for refractory circulatory failure; VV-ECMO for refractory bronchospasm — case reports only, but growing.[21][22]
Kounis syndrome = "allergic ACS" — mast-cell mediators cause coronary vasospasm; treat the anaphylaxis first, then standard ACS therapy.
ACE-inhibitors (not just beta-blockers) impair compensation and increase severity — consider withholding in the workup.
Anaphylaxis needs 3–7 L of fluid in severe cases — massive capillary leak; reassess volume with POCUS IVC, give albumin if refractory.[19]
Antihistamines and steroids do NOT save lives in anaphylaxis — only adrenaline does. Never delay adrenaline for adjuncts.[15]
IV salbutamol for refractory bronchospasm can cause lactic acidosis and tachycardia that mimic ongoing anaphylaxis — interpret with care.
Pregnant patient: left lateral tilt, IM adrenaline dose unchanged (adrenaline is NOT contraindicated in pregnancy — anaphylaxis kills mother and foetus, adrenaline saves both).
Mastocytosis should be suspected in any patient with recurrent unexplained anaphylaxis and baseline tryptase >20 mcg/L — refer for KIT D816V and bone marrow biopsy.
Chlorhexidine is the silent ICU trigger — central line dressings, chlorhexidine-impregnated CVCs, urinary catheters, oral rinses. Strip the dressings in unexplained ICU anaphylaxis.[12]
"Iodine/seafood allergy" is NOT a contraindication to contrast — the allergens are unrelated; this myth causes unnecessary steroid pre-medication and imaging delay.
Every suspected perioperative anaphylaxis MUST be referred to a specialist allergy clinic (NAP6) — under-referral was a major quality failure.[9]
Anaphylaxis mortality is ~0.05–2% in community series, but 3–4% in perioperative series (NAP6) — higher acuity, sicker patients, hidden rashes.[14]

Red flags — extended

Refractory and perioperative anaphylaxis red flags

Refractory anaphylaxis = no response to 2× IM adrenaline + fluids → escalate to IV adrenaline infusion, then glucagon (if beta-blocked), vasopressin, methylene blue, and finally ECMO.[3][8]
Beta-blocked or ACE-inhibitor patient: anticipate refractory course — have glucagon 3–5 mg IV drawn up; beta-blockade abolishes adrenaline's beta-1/2 effects.[20]
Perioperative collapse within 5 min of induction: assume NMBA or antibiotic anaphylaxis — drapes hide the rash; hypotension + bronchospasm under anaesthesia IS anaphylaxis until proven otherwise.[12]
Send tryptase EARLY (within 1–2 h) — the peak is narrow and a missed sample cannot be re-collected. Always pair with a convalescent baseline.[12]
Methylene blue causes spurious SpO2 ~85% — do NOT chase this with more oxygen; verify with an arterial gas.[18]
Kounis syndrome — any anaphylaxis patient with chest pain or ECG changes: get troponin and ECG; treat anaphylaxis first, then standard ACS therapy.
Mastocytosis — recurrent unexplained anaphylaxis + baseline tryptase >20 mcg/L → refer for bone marrow biopsy and KIT mutation testing.
Biphasic reactions can occur 1–72 h later — most within 10 h. Severe reactions, multiple adrenaline doses, beta-blocked, or unknown trigger mandate ≥24 h observation or ICU.[4][6]
Never re-expose a perioperative anaphylaxis patient without formal allergy workup at 4–6 weeks — under-investigation is a recurring NAP6 quality failure.[9]
Pregnant patient — left lateral tilt; IM adrenaline dose UNCHANGED; anaphylaxis is more dangerous to mother and foetus than adrenaline.[11]

Drug-trigger red flags in ICU

Protamine at end of cardiac bypass → sudden vasoplegia/bronchospasm = protamine anaphylaxis until proven otherwise. Have adrenaline/vasopressin ready.[21]
Vancomycin flush during rapid infusion → likely red man syndrome (rate-dependent) — slow infusion, antihistamine; NOT IgE. Differentiate from true vancomycin anaphylaxis (bronchospasm, hypotension) which needs adrenaline.
Co-amoxiclav / teicoplanin / piperacillin-tazobactam are the highest-risk ICU antibiotics in NAP6.[9]
NSAIDs — assume cross-reactivity across the whole non-selective class; paracetamol and COX-2 inhibitors are the safe alternatives.[12]
Chlorhexidine — hidden in dressings, lubricants, mouthwashes, impregnated CVCs; consider in any unexplained ICU anaphylaxis.[12]
Blood product within minutes of anaphylaxis → stop the transfusion, IM adrenaline, send clotted sample for anti-IgA antibodies (IgA-deficient recipient).[12]

References

[1]Brown SG Anaphylaxis: clinical concepts and research priorities Emerg Med Australas, 2006.PMID 16669942
[2]Shaker MS, Wallace DV, Golden DBK, et al. Anaphylaxis-a 2020 practice parameter update, systematic review, and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) analysis J Allergy Clin Immunol, 2020.PMID 32001253
[3]Pouessel G, Dribin TE, Tacquard C, et al. Management of Refractory Anaphylaxis: An Overview of Current Guidelines Clin Exp Allergy, 2024.PMID 38866583
[4]Lee S, Bellolio MF, Hess EP, et al. Time of Onset and Predictors of Biphasic Anaphylactic Reactions: A Systematic Review and Meta-analysis J Allergy Clin Immunol Pract, 2015.PMID 25680923
[5]Sampson HA, Munoz-Furlong A, Campbell RL, et al. Second symposium on the definition and management of anaphylaxis: summary report--Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium J Allergy Clin Immunol, 2006.PMID 16461139
[6]Kim TH, Yoon SH, Choi YH, et al. Duration of Observation for Detecting a Biphasic Reaction in Anaphylaxis: A Meta-Analysis Int Arch Allergy Immunol, 2019.PMID 30763927
[7]Lee S, Sadosty AT, Campbell RL Update on biphasic anaphylaxis Curr Opin Allergy Clin Immunol, 2016.PMID 27253484
[8]Dribin TE, Sachs PE, Scharf SM, et al. Persistent, refractory, and biphasic anaphylaxis: A multidisciplinary Delphi study J Allergy Clin Immunol, 2020.PMID 32853640
[9]Harper NJN, Cook TM, Garcez T, et al. Anaesthesia, surgery, and life-threatening allergic reactions: management and outcomes in the 6th National Audit Project (NAP6) Br J Anaesth, 2018.PMID 29935569
[10]Cook TM, Harper NJN, Garcez T, et al. Anaesthesia, surgery, and life-threatening allergic reactions: epidemiology and clinical features of perioperative anaphylaxis in the 6th National Audit Project (NAP6) Br J Anaesth, 2018.PMID 29935567
[11]Kemp HI, Cook TM, Thomas M, Harper NJN UK anaesthetists' perspectives and experiences of severe perioperative anaphylaxis: NAP6 baseline survey Br J Anaesth, 2017.PMID 28498889
[12]Ebo DG, Clarke RC, Mertes PM, et al. Acute Management, Diagnosis, and Follow-Up of Suspected Perioperative Hypersensitivity Reactions in Flanders 2001-2018 J Allergy Clin Immunol Pract, 2019.PMID 30857939
[13]Dejoux D, Gatineau-Sailliant G, De Chaisemartin L, et al. Neuromuscular blocking agent induced hypersensitivity reaction exploration: an update Eur J Anaesthesiol, 2023.PMID 36301083
[14]Pouessel G, Lucet Y, Dorkenoo A, et al. Anaphylaxis mortality in the perioperative setting: Epidemiology, elicitors, risk factors and knowledge gaps Clin Exp Allergy, 2024.PMID 38168878
[15]Sheikh A, Shehata YA, Brown SG, Simons FE Adrenaline for the treatment of anaphylaxis: cochrane systematic review Allergy, 2009.PMID 19178399
[16]Gouel-Cheron A, Harpan A, Mertes PM, Longrois D Management of anaphylactic shock in the operating room Presse Med, 2016.PMID 27208918
[17]Zheng F, Barthel G, Collange O, et al. Epinephrine, compared with arginine vasopressin, is associated with similar haemodynamic effects but significantly improved brain oxygenation in the early phase of anaphylactic shock in rats: An experimental study Eur J Anaesthesiol, 2015.PMID 26244468
[18]Heyman HM, Chappell TL, DeBeer DA, et al. Vasoplegic Syndrome and Noncatecholamine Therapies 2026.PMID 38261707
[19]Russell JA, Lee T Vasopressor Therapy in the Intensive Care Unit Semin Respir Crit Care Med, 2021.PMID 32820475
[20]Thomas M, Crawford I Best evidence topic report. Glucagon infusion in refractory anaphylactic shock in patients on beta-blockers Emerg Med J, 2005.PMID 15788828
[21]Oda Y, Hayashida K, Matsuda N, et al. Rescuing Protamine Anaphylaxis Refractory to Adrenaline Using Extracorporeal Membrane Oxygenation JACC Case Rep, 2025.PMID 40118612
[22]Garcia-Mendez JP, Lancheros PA, Jaimes JP, et al. VV-ECMO as a lifesaving measure for refractory bronchospasm in anaphylactic shock: A case report Perfusion, 2025.PMID 41021782
[23]Gorham NP, Wang J, Samaan Z Anaphylaxis:: After the Emergency Department Immunol Allergy Clin North Am, 2023.PMID 37394253
[24]Wallace DV Knowledge gaps in the diagnosis and management of anaphylaxis Ann Allergy Asthma Immunol, 2023.PMID 37209836

[1] [1]

Diagnostic criteria

[1] [2]

Management

[1]

Anaphylaxis management protocol

1. IM ADRENALINE 0.5 mg (500 mcg) — FIRST-LINE

2. Position and oxygen

3. IV fluid resuscitation

4. Second-line agents

5. Refractory anaphylaxis — IV adrenaline

6. Beta-blocked patient — GLUCAGON

7. Investigations

8. Observe for biphasic reaction

[4]

Common triggers

ICU-specific triggers

Peri-procedural

Neuromuscular blocking agents: rocuronium, suxamethonium (#1 perioperative)
Antibiotics: penicillins, cephalosporins, vancomycin
Radiocontrast media
Chlorhexidine (increasingly recognised — catheters, skin prep)
Latex (less common now — latex-free environment)
Ethylene oxide (sterilising agent)
Patent Blue dye (sentinel lymph node biopsy)

General triggers

Community

Foods: nuts (peanut, tree nuts), shellfish, eggs, milk
Medications: NSAIDs, antibiotics
Insect stings: bee, wasp
Exercise-induced
Idiopathic (no trigger identified in 20-30%)

Sugammadex reversal for rocuronium anaphylaxis

Exam practice

SAQ — Perioperative anaphylaxis

10 minutes · 10 marks

[1]

Clinical pearls

High-yield anaphylaxis points for the CICM/FFICM exam

IM adrenaline 0.5 mg is FIRST-LINE — anterolateral thigh, repeat every 5 min. Do NOT delay.[2]
Supine with legs elevated — never sit/stand (empty vena cava syndrome = death).
Beta-blocked patient: give glucagon 3-5 mg IV — bypasses beta-receptor.[3]
IV adrenaline for refractory: infusion 0.05-0.1 mcg/kg/min. Use only if IM adrenaline + fluids ineffective.
Biphasic reactions in 5-20% — observe 6-12h. Longer if severe or beta-blocked.[4]
Tryptase: send at 1-2h (peak), 24h, and baseline. Elevated confirms anaphylaxis.
Antihistamines and steroids are SECOND-LINE — they do NOT substitute for adrenaline.
Neuromuscular blockers are #1 cause of perioperative anaphylaxis (rocuronium, suxamethonium).
Chlorhexidine is increasingly recognised as a cause of perioperative anaphylaxis.
Sugammadex 16 mg/kg can reverse rocuronium-triggered anaphylaxis (encapsulates NMBA).
IV fluids: 1-2 L crystalloid rapidly — anaphylaxis causes massive vasodilation + capillary leak.
Skin involvement absent in 10-20% — do NOT wait for rash if presentation is classic.
Allergy referral on discharge — skin prick testing to identify trigger.
Adrenaline auto-injector (EpiPen) on discharge — teach patient to use.

Red flags

NIAID/FAAN diagnostic criteria — the three criteria in detail

[1]

NIAID/FAAN Criterion 2 — two-or-more organ systems after a likely allergen

Two or more of the following occur rapidly (minutes to several hours) after exposure to a likely allergen for that patient:

Skin/mucosal involvement
Respiratory compromise
Reduced BP or associated symptoms
Persistent gastrointestinal symptoms (crampy abdominal pain, vomiting, diarrhoea) [1]

[1] [1]

When the NIAID/FAAN criteria are NOT met — recognise the mimics

True anaphylaxis mimics

Look-alikes

Vasovagal syncope — pallor (NOT flush), bradycardia, no urticaria/itch, resolves supine
Asthma exacerbation — isolated bronchospasm, no hypotension or urticaria
Panic attack — subjective dyspnoea with normal SpO2/BP, no urticaria
Carcinoid syndrome — episodic flush/diarrhoea/bronchospasm (not acute collapse)
Mastocytosis — recurrent unexplained anaphylaxis; persistently elevated baseline tryptase
Hereditary angioedema — complement C4 low, no urticaria, bradykinin-mediated (NOT histamine)
Scombroid — histamine fish poisoning with flush (NOT IgE-mediated, responds to antihistamines)

Red flags that favour anaphylaxis

Treat as anaphylaxis

Sudden cardiovascular collapse within minutes of a drug/food/sting
Angioedema (lip/tongue/uvula swelling) + any other system
Bilateral wheeze + hypotension after an exposure
Hypotension refractory to fluids in the perioperative window
Pulse >130 and SBP <90 with a temporal trigger
When in doubt, give IM adrenaline — the harm of omission > harm of an unnecessary dose

Brown's severity grading — guides who needs ICU

Brown's 3-grade severity grading (anaphylaxis)

Grade 1 — mild

Skin only

Generalised urticaria, erythema, angioedema WITHOUT other system involvement
Rarely needs adrenaline — observe and consider oral antihistamine
ED observation usually sufficient; ICU rarely needed

Grade 2 — moderate

Skin + one system

Skin features PLUS respiratory (dyspnoea/wheeze), cardiovascular (tachycardia, dizziness, SBP 90–110), or GI symptoms
Standard IM adrenaline 0.5 mg; usually responds
ED/HDU observation 6–12 h for biphasic risk

Grade 3 — severe

Life-threatening

Hypoxia (SpO2 <92%), cyanosis, hypotension (SBP <90), collapse, neurological (confusion/loss of consciousness)
IM adrenaline + IV fluids; often needs multiple adrenaline doses, IV adrenaline infusion, ICU admission
ICU admission mandatory — high risk of refractory course and biphasic recurrence

[1]

ICU-specific triggers — in depth

Beta-lactam antibiotics

Beta-lactam anaphylaxis — the ICU staples

Key ICU points:

Anaphylaxis typically occurs within 5–30 minutes of IV administration (faster than oral)
A reported "penicillin allergy" on the chart is wrong in ~90% of cases — but never ignore it during an acute reaction; treat empirically and refer for formal testing
Monobactams (aztreonam) and carbapenems (meropenem) have very low cross-reactivity with penicillins — often safe alternatives after allergy workup
Vancomycin is NOT a beta-lactam and can usually be used when beta-lactam allergy is confirmed

[1]

Vancomycin — "red man syndrome" vs true anaphylaxis

Vancomycin: red man syndrome is NOT IgE-mediated anaphylaxis

Vancomycin causes two distinct reactions every ICU trainee must distinguish: [1]

Red man syndrome (RMS) — rate-dependent direct mast-cell degranulation causing histamine release. Presents with flush, erythema, pruritus (neck/upper body), sometimes mild hypotension. Slowing or stopping the infusion (give over ≥60 min, 1 g) and antihistamines treat it. Not IgE-mediated, no tryptase rise (usually), not life-threatening, can re-challenge at slower rate.
True vancomycin IgE anaphylaxis — rare. Cardiovascular collapse, bronchospasm, angioedema within minutes. Treat with IM adrenaline. Confirmed on skin testing. Avoid vancomycin permanently and use teicoplanin/daptomycin/linezolid. [1]

[1]

Neuromuscular blocking agents — the #1 perioperative trigger

NMBAs: the dominant perioperative anaphylaxis trigger (NAP6)

Rocuronium — most frequently implicated (highest UK market share; NAP6 #1 culprit). Onset within 1–5 minutes of IV dose.
Suxamethonium (succinylcholine) — historically the leading trigger; still high-risk due to its depolarising structure. Often causes the most explosive reactions.
Vecuronium, atracurium, cisatracurium, mivacurium — all reported; atracurium/cisatracurium have a lower relative risk in some series.
Cross-reactivity between NMBAs is ~60–75% — a patient reactive to one NMBA may react to any. Skin testing of multiple agents guides future safe options. [1]

ICU/take-home: any cardiovascular or bronchospastic collapse within 5 minutes of induction should be assumed to be NMBA (or antibiotic) anaphylaxis until proven otherwise.[12]

NSAIDs

[1]

Radiocontrast media

[1]

Latex

Blood products and transfusion reactions

Transfusion-related reactions in ICU — distinguish from anaphylaxis

Blood products can cause several reactions that mimic anaphylaxis: [1]

Anaphylactic transfusion reaction — IgA-deficient patient with anti-IgE/IgA antibodies receiving IgA-containing blood → true IgE anaphylaxis. Rare but catastrophic. Treat with IM adrenaline. Use washed/deglycerolised or IgA-deficient donor products subsequently.
TRALI (transfusion-related acute lung injury) — donor anti-leucocyte antibodies → bilateral pulmonary oedema within 6 h. Not anaphylaxis — no urticaria, no tryptase rise. Treat supportively (oxygen, lung-protective ventilation, avoid diuresis).
TACO (transfusion-associated circulatory overload) — volume overload → pulmonary oedema. Not anaphylaxis.
Febrile non-haemolytic / urticarial — pre-storage leucodepletion has made these rare; respond to antihistamine and pause. [1]

[1]

Other ICU/perioperative triggers worth knowing

Less common but high-yield ICU triggers

Chestnut triggers

Often missed

Chlorhexidine — increasingly recognised; central line dressings, chlorhexidine-impregnated CVCs, urinary catheters, oral rinses. Can cause anaphylaxis on mucosal contact. Check dressings in unexplained ICU anaphylaxis
Patent Blue / Isosulfan Blue dye — sentinel lymph node biopsy; vivid blue urticaria easily missed
Protamine — heparin reversal in cardiac surgery; rapid IV bolus → catastrophic vasoplegia/anaphylaxis
Ethylene oxide — sterilising agent on disposable equipment; bovine/porcine proteins in surgical haemostats
Colloid plasma expanders — gelatins (Gelofusine, Haemaccel) and dextrans can trigger non-IgE anaphylactoid reactions
Aprotinin, fluorescein, indocyanine green, methylene blue itself, oxytocin, iron dextran infusion

[12]

Perioperative anaphylaxis — NAP6 in depth

NAP6 (2018) — UK 6th National Audit Project, perioperative anaphylaxis (PMID 29935569, 29935567)

Source

Royal College of Anaesthetists 6th National Audit Project — UK-wide prospective case capture of all Grade 3–5 perioperative anaphylaxis events (2016)

Incidence

~1 in 10,000 anaesthetics (similar to historical UK and French data)

Triggers

NMBAs ~50–60% (rocuronium #1), antibiotics ~33% (teicoplanin and co-amoxiclav over-represented), chlorhexidine ~9%, Patent Blue dye ~4%, latex <1%

Mortality

3.8% death or brain damage (Grade 5) — higher than non-perioperative anaphylaxis

Adrenaline delays

Adrenaline was delayed or under-dosed in the majority of fatal/near-fatal cases — the single most cited preventable failure

Key recommendation

All suspected perioperative anaphylaxis MUST be referred to a specialist allergy clinic; serial tryptase mandatory; never re-expose without workup

Clinical bottom line

NMBAs (especially rocuronium) are the #1 perioperative trigger; antibiotic anaphylaxis is rising (teicoplanin); adrenaline delay kills — give IM adrenaline EARLY and in adequate dose

[1]

Perioperative anaphylaxis — the unique challenges

Perioperative anaphylaxis differs from community anaphylaxis in ways that change management: [1]

Drapes hide the rash — cutaneous signs are missed in 30–40% of cases; the presenting sign is often unexplained hypotension or bronchospasm under anaesthesia
Multiple simultaneous exposures — induction agent, NMBA, antibiotic, opioid, chlorhexidine prep, latex, dye, contrast may all be given within 5 minutes — identifying the culprit requires structured tryptase sampling and later skin testing
Volatile agents and positive-pressure ventilation mask bronchospasm; tachycardia from surgical stimulus masks hypotension
Pregnancy increases risk (caesarean section, suxamethonium, oxytocin, Syntocinon)
Cardiac surgery is a distinct high-risk environment — protamine, aprotinin, blood products, cold agglutinins, gelatins
Referral is mandatory — every suspected case to a specialist perioperative allergy clinic for skin prick/intradermal testing and specific IgE at 4–6 weeks post-event (earlier testing gives false negatives; later testing may lose sensitivity)[12]

Tryptase sampling protocol

Mast-cell tryptase sampling after suspected anaphylaxis

Sample 1 — ASAP (ideally within 1–2 h)

Sample 2 — at 4 h (or convalescence)

Sample 3 — baseline (≥24 h after full recovery)

Interpretation

Trigger identification — at 4–6 weeks

Refractory anaphylaxis — escalation beyond IM adrenaline

Refractory anaphylaxis — stepwise pharmacological escalation

Ensure adequate IM adrenaline — at least 2 doses of 0.5 mg IM, 5 min apart. Most "refractory" cases are simply under-dosed.
IV crystalloid boluses — repeated 20 mL/kg aliquots; anaphylaxis produces massive capillary leak (often 5–7 L of third-space loss in severe cases).
IV adrenaline infusion — the standard second-line. Bolus 50 mcg IV over 5 min (diluted: 1 mL of 1:1000 in 10 mL saline), then infusion 0.05–0.5 mcg/kg/min titrated to SBP >90 / MAP >65. Prepare: 1 mg (1 mL of 1:1000) in 100 mL saline = 10 mcg/mL; or 4 mg in 250 mL = 16 mcg/mL.[3]
Glucagon — if patient is beta-blocked and not responding to adrenaline. 3–5 mg IV over 5 min, then infusion 5–15 mcg/min. Bypasses the beta-receptor entirely (acts via Gs protein → adenylate cyclase → cAMP). Also treats the bradycardia of beta-blockade.[20]
Vasopressin / terlipressin — non-adrenergic V1 agonist. 2–10 units IV bolus, infusion 0.01–0.04 U/min. Useful when alpha-receptors are down-regulated or the patient is on high-dose catecholamines. Animal data show similar haemodynamic efficacy to adrenaline.[17][18]
Methylene blue — inhibits the NO–cGMP vasoplegic pathway that drives refractory vasodilation. 1–2 mg/kg IV over 5 min, may repeat; infusion 0.25–2 mg/kg/h. Increasingly reported as salvage therapy for catecholamine-resistant vasoplegic anaphylaxis.[18]
Extracorporeal support (VA-ECMO / VV-ECMO) — last-line rescue for refractory cardiovascular collapse (VA-ECMO) or refractory bronchospasm (VV-ECMO). Case series now support ECMO as a bridge in truly refractory cases.[21][22]

Rescue agents for refractory anaphylaxis — when to use which

IV adrenaline infusion

First refractory step

Indication: not responding to 2× IM adrenaline + fluids
Dose: 0.05–0.5 mcg/kg/min titrated; bolus 50 mcg IV (diluted)
Mechanism: alpha-1 vasoconstriction + beta-1 inotropy + beta-2 bronchodilation
Watch: tachyarrhythmia, myocardial ischaemia, lactate rise — requires arterial line and ICU monitoring

Glucagon

Beta-blocked patient

Indication: anaphylaxis in a patient on beta-blockers refractory to adrenaline
Dose: 3–5 mg IV over 5 min, then 5–15 mcg/min infusion
Mechanism: bypasses the beta-receptor — Gs protein → adenylate cyclase → cAMP
Watch: nausea/vomiting (give antiemetic), hyperglycaemia — does NOT replace adrenaline, used IN ADDITION

Vasopressin / terlipressin

Catecholamine-resistant vasoplegia

Indication: refractory vasodilatory shock despite catecholamines
Dose: 2–10 units IV bolus; infusion 0.01–0.04 U/min
Mechanism: V1 receptor vasoconstriction — independent of adrenergic pathway
Watch: peripheral/splanchnic ischaemia, hyponatraemia — adjunct, not replacement

Methylene blue

NO-mediated vasoplegia

Indication: catecholamine-resistant vasoplegic shock (case reports; not first-line)
Dose: 1–2 mg/kg IV over 5 min, repeatable; infusion 0.25–2 mg/kg/h
Mechanism: inhibits soluble guanylate cyclase → blocks NO-cGMP vasodilation
Watch: serotonin syndrome risk with SSRIs/MAOIs; SpO2 readout falls to ~85% (spectral interference, not desaturation); DO NOT use with VV/VA-ECMO circuit priming concerns

ECMO (VA / VV)

Last-resort salvage

Indication: refractory cardiac arrest / circulatory failure (VA-ECMO) or refractory bronchospasm (VV-ECMO) despite full pharmacological therapy
Modality: VA-ECMO for circulatory support; VV-ECMO for gas exchange in refractory bronchospasm
Evidence: case reports/series — protamine anaphylaxis, peanut anaphylaxis, NMBA anaphylaxis
Watch: anticoagulation, limb ischaemia, transfer to ECMO centre — only at experienced centres

[3] [18]

Why is methylene blue rational in anaphylaxis?

Biphasic reactions — observation period

Lee 2015 — Time of onset and predictors of biphasic anaphylactic reactions: meta-analysis (PMID 25680923)

Source

Systematic review and meta-analysis — Journal of Allergy and Clinical Immunology in Practice

Biphasic rate

~4.6–5% across studies (range 1–23%); most recurrences within 10 h, nearly all within 24 h

Predictors

Severity of initial reaction (need for >1 adrenaline dose), delayed adrenaline (>60 min), wide pulse pressure, unknown trigger, beta-blocker/ACE-inhibitor use

Fatal biphasic reactions

Rare but reported — usually in patients with severe initial reaction or comorbidity

Clinical bottom line

Most biphasic reactions occur within the first 10 hours — an observation window of 6–12 h captures the majority; longer for high-risk features

[1]

Kim 2019 — Duration of observation for detecting biphasic reaction: meta-analysis (PMID 30763927)

Source

Meta-analysis — International Archives of Allergy and Immunology

Key finding

To detect 95% of biphasic reactions, an observation period of ~**48 h** would be required — but most (>95%) occur within the first 24 h

Practical cut-off

Observation to **6–12 h** captures the great majority; extending to 24 h only for high-risk patients

Risk-stratified observation

Mild (grade 1): can discharge early. Moderate (grade 2): observe 6–12 h. Severe (grade 3), multiple adrenaline doses, beta-blocked, or unknown trigger: observe 24 h or admit

Clinical bottom line

No single observation window captures 100% of biphasic reactions — risk-stratify. ICU admission reserved for severe/refractory or those needing ongoing vasopressors

[1]

Biphasic reaction — who needs longer observation?

Factors that mandate longer observation (≥24 h or ICU admission):

Severe initial reaction requiring 2 or more doses of IM adrenaline, or any IV adrenaline
Refractory course needing vasopressor infusion or methylene blue/glucagon/vasopressin
Beta-blocker or ACE-inhibitor therapy (interferes with compensation)
Pre-existing cardiovascular/respiratory disease
Unknown trigger (cannot counsel avoidance)
Massive mast-cell load — mastocytosis, baseline tryptase elevated
Delayed initial adrenaline (>60 min from symptom onset)
Children with food-triggered reactions (higher biphasic rate in some series) [1]

Most biphasic reactions occur within 10 hours; virtually all within 24 hours. The traditional "observe everyone 6–12 h" is being replaced by risk-stratified observation.[4][6][23]

Recommended observation period by risk stratification

Low risk — discharge early

Grade 1 / mild

Single-system reaction (e.g. skin only) that fully resolves with one dose of IM adrenaline
No biphasic risk factors; trigger identified and avoidable
Discharge at 4–6 h with adrenaline auto-injector, written action plan, allergy referral

Moderate risk — observe 6–12 h

Grade 2

Two-system involvement, resolved with 1 dose IM adrenaline, normal haemodynamics after
No IV adrenaline, no vasopressors; no high-risk comorbidity
ED/HDU observation; discharge with auto-injector + plan if no recurrence

High risk — observe ≥24 h / ICU

Grade 3 / refractory

Severe reaction: hypoxia, hypotension, or any IV adrenaline/vasopressor use
2 or more IM adrenaline doses; beta-blocked patient; mastocytosis
ICU admission for haemodynamic monitoring and ongoing vasopressor titration
Discharge only after stable off all catecholamines for >12 h

[8] [23]

ICU management protocol — ongoing care after initial resuscitation

Once the patient reaches ICU after initial resuscitation, the focus shifts to haemodynamic support, ventilatory support, monitoring for biphasic recurrence, and trigger identification. [1]

ICU management protocol for anaphylaxis — first 24 hours

1. Airway and breathing

2. Circulation — vasopressor titration

3. Glucagon if beta-blocked

4. Adjunctive therapy

5. Serial tryptase and investigation

6. Monitor for biphasic recurrence

7. De-escalation

8. Discharge planning

Special situations

Anaphylaxis in special populations — ICU nuances

Pregnancy

Maternal + foetal

Left lateral tilt (avoid aortocaval compression); IM adrenaline dose UNCHANGED (no contraindication)
Higher incidence in caesarean section — suxamethonium, oxytocin, antibiotics, chlorhexidine all candidates
Foetal distress common — continuous CTG; consider early delivery if peri-arrest
Try to identify trigger before next pregnancy/paediatric anaesthesia (NMBAs cross placenta rarely relevant acutely)

Cardiac disease / Kounis syndrome

Coronary vasospasm

Mast-cell mediators cause coronary vasospasm and plaque erosion — "allergic ACS"
ECG and troponin mandatory; treat anaphylaxis FIRST (adrenaline) then standard ACS therapy
Adrenaline can worsen ischaemia — use lowest effective dose; nitrate/morphine as adjunct
Beta-blockers relatively contraindicated in active anaphylaxis — withhold; consider glucagon early if already on beta-blocker

Elderly / comorbid

Polypharmacy

Beta-blockers, ACE-inhibitors, diuretics all impair compensation — have glucagon ready
Reduced physiological reserve → decompensate faster; lower threshold for ICU
Higher risk of adrenaline-induced myocardial ischaemia/arrhythmia — titrate carefully
Antihistamine anticholinergic effects compound delirium

Mastocytosis

Clonal mast-cell disorder

Recurrent unexplained anaphylaxis with elevated baseline tryptase (>20 mcg/L)
Reactions often WITHOUT an identifiable trigger; venom (Hymenoptera) is the classic elicitor
Pre-medicate procedures with H1/H2 blockers and steroids; have adrenaline infusion ready
Refer for bone-marrow biopsy and KIT D816V mutation testing

[1]

Additional exam practice

SAQ — Refractory perioperative anaphylaxis and methylene blue

12 minutes · 10 marks

[1]

SAQ — Tryptase sampling and NAP6 referral

10 minutes · 10 marks

[1]

Additional clinical pearls

Advanced anaphylaxis pearls — refractory, perioperative, and exam traps

NIAID/FAAN Criterion 3 (known allergen + hypotension alone) is the criterion that catches "no-rash anaphylaxis" — never wait for urticaria in the vasopleptic patient with a known trigger.[5]
Cross-reactivity between NMBAs is ~60–75% — they share a substituted ammonium epitope. Skin-test multiple agents to find a safe one.[13]
NAP6 #1 trigger is rocuronium (not suxamethonium as historically taught); teicoplanin and co-amoxiclav are the #1 antibiotics.[9][10]
Red man syndrome is rate-dependent, NOT IgE — slow the vancomycin infusion and give antihistamine; do not label the patient "vancomycin-allergic" without testing.[12]
Tryptase peaks at 1–2 h — if you only send one sample, send it then. Always pair with a baseline (≥24 h later) to interpret the rise; use the 1.2 × baseline + 2 mcg/L delta rule.
Glucagon for beta-blocked anaphylaxis works via a different Gs-protein pathway (bypasses the blocked beta-receptor → direct adenylate cyclase activation). Dose: 3–5 mg IV over 5 min then 5–15 mcg/min.[20]
Vasopressin is the rational second-line when catecholamine receptors are exhausted — V1-mediated vasoconstriction independent of the adrenergic pathway.[17]
Methylene blue blocks the NO–cGMP vasoplegic pathway; watch for spurious SpO2 ~85% (spectral interference, not real desaturation) and serotonin syndrome with SSRIs/MAOIs.[18]
VA-ECMO is the salvage rescue for refractory circulatory failure; VV-ECMO for refractory bronchospasm — case reports only, but growing.[21][22]
Kounis syndrome = "allergic ACS" — mast-cell mediators cause coronary vasospasm; treat the anaphylaxis first, then standard ACS therapy.
ACE-inhibitors (not just beta-blockers) impair compensation and increase severity — consider withholding in the workup.
Anaphylaxis needs 3–7 L of fluid in severe cases — massive capillary leak; reassess volume with POCUS IVC, give albumin if refractory.[19]
Antihistamines and steroids do NOT save lives in anaphylaxis — only adrenaline does. Never delay adrenaline for adjuncts.[15]
IV salbutamol for refractory bronchospasm can cause lactic acidosis and tachycardia that mimic ongoing anaphylaxis — interpret with care.
Pregnant patient: left lateral tilt, IM adrenaline dose unchanged (adrenaline is NOT contraindicated in pregnancy — anaphylaxis kills mother and foetus, adrenaline saves both).
Mastocytosis should be suspected in any patient with recurrent unexplained anaphylaxis and baseline tryptase >20 mcg/L — refer for KIT D816V and bone marrow biopsy.
Chlorhexidine is the silent ICU trigger — central line dressings, chlorhexidine-impregnated CVCs, urinary catheters, oral rinses. Strip the dressings in unexplained ICU anaphylaxis.[12]
"Iodine/seafood allergy" is NOT a contraindication to contrast — the allergens are unrelated; this myth causes unnecessary steroid pre-medication and imaging delay.
Every suspected perioperative anaphylaxis MUST be referred to a specialist allergy clinic (NAP6) — under-referral was a major quality failure.[9]
Anaphylaxis mortality is ~0.05–2% in community series, but 3–4% in perioperative series (NAP6) — higher acuity, sicker patients, hidden rashes.[14]

Red flags — extended

Refractory and perioperative anaphylaxis red flags

Refractory anaphylaxis = no response to 2× IM adrenaline + fluids → escalate to IV adrenaline infusion, then glucagon (if beta-blocked), vasopressin, methylene blue, and finally ECMO.[3][8]
Beta-blocked or ACE-inhibitor patient: anticipate refractory course — have glucagon 3–5 mg IV drawn up; beta-blockade abolishes adrenaline's beta-1/2 effects.[20]
Perioperative collapse within 5 min of induction: assume NMBA or antibiotic anaphylaxis — drapes hide the rash; hypotension + bronchospasm under anaesthesia IS anaphylaxis until proven otherwise.[12]
Send tryptase EARLY (within 1–2 h) — the peak is narrow and a missed sample cannot be re-collected. Always pair with a convalescent baseline.[12]
Methylene blue causes spurious SpO2 ~85% — do NOT chase this with more oxygen; verify with an arterial gas.[18]
Kounis syndrome — any anaphylaxis patient with chest pain or ECG changes: get troponin and ECG; treat anaphylaxis first, then standard ACS therapy.
Mastocytosis — recurrent unexplained anaphylaxis + baseline tryptase >20 mcg/L → refer for bone marrow biopsy and KIT mutation testing.
Biphasic reactions can occur 1–72 h later — most within 10 h. Severe reactions, multiple adrenaline doses, beta-blocked, or unknown trigger mandate ≥24 h observation or ICU.[4][6]
Never re-expose a perioperative anaphylaxis patient without formal allergy workup at 4–6 weeks — under-investigation is a recurring NAP6 quality failure.[9]
Pregnant patient — left lateral tilt; IM adrenaline dose UNCHANGED; anaphylaxis is more dangerous to mother and foetus than adrenaline.[11]

Drug-trigger red flags in ICU

Protamine at end of cardiac bypass → sudden vasoplegia/bronchospasm = protamine anaphylaxis until proven otherwise. Have adrenaline/vasopressin ready.[21]
Vancomycin flush during rapid infusion → likely red man syndrome (rate-dependent) — slow infusion, antihistamine; NOT IgE. Differentiate from true vancomycin anaphylaxis (bronchospasm, hypotension) which needs adrenaline.
Co-amoxiclav / teicoplanin / piperacillin-tazobactam are the highest-risk ICU antibiotics in NAP6.[9]
NSAIDs — assume cross-reactivity across the whole non-selective class; paracetamol and COX-2 inhibitors are the safe alternatives.[12]
Chlorhexidine — hidden in dressings, lubricants, mouthwashes, impregnated CVCs; consider in any unexplained ICU anaphylaxis.[12]
Blood product within minutes of anaphylaxis → stop the transfusion, IM adrenaline, send clotted sample for anti-IgA antibodies (IgA-deficient recipient).[12]

References

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[2]Shaker MS, Wallace DV, Golden DBK, et al. Anaphylaxis-a 2020 practice parameter update, systematic review, and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) analysis J Allergy Clin Immunol, 2020.PMID 32001253
[3]Pouessel G, Dribin TE, Tacquard C, et al. Management of Refractory Anaphylaxis: An Overview of Current Guidelines Clin Exp Allergy, 2024.PMID 38866583
[4]Lee S, Bellolio MF, Hess EP, et al. Time of Onset and Predictors of Biphasic Anaphylactic Reactions: A Systematic Review and Meta-analysis J Allergy Clin Immunol Pract, 2015.PMID 25680923
[5]Sampson HA, Munoz-Furlong A, Campbell RL, et al. Second symposium on the definition and management of anaphylaxis: summary report--Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium J Allergy Clin Immunol, 2006.PMID 16461139
[6]Kim TH, Yoon SH, Choi YH, et al. Duration of Observation for Detecting a Biphasic Reaction in Anaphylaxis: A Meta-Analysis Int Arch Allergy Immunol, 2019.PMID 30763927
[7]Lee S, Sadosty AT, Campbell RL Update on biphasic anaphylaxis Curr Opin Allergy Clin Immunol, 2016.PMID 27253484
[8]Dribin TE, Sachs PE, Scharf SM, et al. Persistent, refractory, and biphasic anaphylaxis: A multidisciplinary Delphi study J Allergy Clin Immunol, 2020.PMID 32853640
[9]Harper NJN, Cook TM, Garcez T, et al. Anaesthesia, surgery, and life-threatening allergic reactions: management and outcomes in the 6th National Audit Project (NAP6) Br J Anaesth, 2018.PMID 29935569
[10]Cook TM, Harper NJN, Garcez T, et al. Anaesthesia, surgery, and life-threatening allergic reactions: epidemiology and clinical features of perioperative anaphylaxis in the 6th National Audit Project (NAP6) Br J Anaesth, 2018.PMID 29935567
[11]Kemp HI, Cook TM, Thomas M, Harper NJN UK anaesthetists' perspectives and experiences of severe perioperative anaphylaxis: NAP6 baseline survey Br J Anaesth, 2017.PMID 28498889
[12]Ebo DG, Clarke RC, Mertes PM, et al. Acute Management, Diagnosis, and Follow-Up of Suspected Perioperative Hypersensitivity Reactions in Flanders 2001-2018 J Allergy Clin Immunol Pract, 2019.PMID 30857939
[13]Dejoux D, Gatineau-Sailliant G, De Chaisemartin L, et al. Neuromuscular blocking agent induced hypersensitivity reaction exploration: an update Eur J Anaesthesiol, 2023.PMID 36301083
[14]Pouessel G, Lucet Y, Dorkenoo A, et al. Anaphylaxis mortality in the perioperative setting: Epidemiology, elicitors, risk factors and knowledge gaps Clin Exp Allergy, 2024.PMID 38168878
[15]Sheikh A, Shehata YA, Brown SG, Simons FE Adrenaline for the treatment of anaphylaxis: cochrane systematic review Allergy, 2009.PMID 19178399
[16]Gouel-Cheron A, Harpan A, Mertes PM, Longrois D Management of anaphylactic shock in the operating room Presse Med, 2016.PMID 27208918
[17]Zheng F, Barthel G, Collange O, et al. Epinephrine, compared with arginine vasopressin, is associated with similar haemodynamic effects but significantly improved brain oxygenation in the early phase of anaphylactic shock in rats: An experimental study Eur J Anaesthesiol, 2015.PMID 26244468
[18]Heyman HM, Chappell TL, DeBeer DA, et al. Vasoplegic Syndrome and Noncatecholamine Therapies 2026.PMID 38261707
[19]Russell JA, Lee T Vasopressor Therapy in the Intensive Care Unit Semin Respir Crit Care Med, 2021.PMID 32820475
[20]Thomas M, Crawford I Best evidence topic report. Glucagon infusion in refractory anaphylactic shock in patients on beta-blockers Emerg Med J, 2005.PMID 15788828
[21]Oda Y, Hayashida K, Matsuda N, et al. Rescuing Protamine Anaphylaxis Refractory to Adrenaline Using Extracorporeal Membrane Oxygenation JACC Case Rep, 2025.PMID 40118612
[22]Garcia-Mendez JP, Lancheros PA, Jaimes JP, et al. VV-ECMO as a lifesaving measure for refractory bronchospasm in anaphylactic shock: A case report Perfusion, 2025.PMID 41021782
[23]Gorham NP, Wang J, Samaan Z Anaphylaxis:: After the Emergency Department Immunol Allergy Clin North Am, 2023.PMID 37394253
[24]Wallace DV Knowledge gaps in the diagnosis and management of anaphylaxis Ann Allergy Asthma Immunol, 2023.PMID 37209836