Anaphylaxis — IM Adrenaline, Refractory Anaphylaxis, Biphasic

📕 1 · Tintinalli's Emergency Medicine, 9th Ed

Tintinalli's Summary — Adrenaline Is the Only Drug That Saves Lives

"Anaphylaxis is a clinical diagnosis, and its treatment is intramuscular epinephrine — given early, given into the anterolateral thigh, and repeated as needed. Antihistamines and corticosteroids are adjuncts at best; they treat the hives, not the patient. The deaths from anaphylaxis are deaths of delay — delay in recognising the syndrome, delay in giving epinephrine, and the catastrophic error of sitting the hypotensive patient upright."

Tintinalli's Emergency Medicine: A Comprehensive Study Guide, 9th Ed. McGraw-Hill 2020. Chapter: Anaphylaxis & Acute Allergic Reactions.

The Core Message (Tintinalli's)

Epinephrine (adrenaline) is first-line and the only intervention shown to reduce mortality. There is no absolute contraindication in true anaphylaxis.
Route is intramuscular, not subcutaneous or IV bolus in most cases — IM into the anterolateral thigh (vastus lateralis) achieves faster, higher, more reliable peak levels than the deltoid or SC route.
Diagnosis is clinical — do not wait for tryptase or any test. The combination of acute onset + skin/mucosal involvement + airway/breathing/circulation compromise (or a known allergen exposure with hypotension) is enough.
Antihistamines and steroids do NOT treat airway obstruction or shock — they relieve cutaneous symptoms only and must never delay adrenaline.

⚡ The One Number to Remember

0.5 mg IM adrenaline = 0.5 mL of 1:1000 into the anterolateral thigh, repeat every 5 minutes as needed. (Paediatric: 0.01 mg/kg, max 0.5 mg.) 1:1000 IM — never 1:1000 IV.

📘 2 · Rosen's Emergency Medicine, 10th Ed

Rosen's — Pathophysiology & Why Adrenaline Works

🔬 How anaphylaxis causes collapse

TriggerAllergen re-exposure → cross-links IgE on mast cells & basophils

Degranulation → histamine, tryptase, leukotrienes, prostaglandins, PAF

↑ vascular permeability + vasodilatationdistributive shock, angio-oedema — up to 35% volume shift in 10 min

Bronchial smooth-muscle constriction + mucusbronchospasm, upper-airway oedema

Preload-dependent "empty ventricle" physiology

Pathological stateAirway obstruction + distributive shock → cardiorespiratory collapse

"Anaphylaxis is a systemic type I hypersensitivity reaction in which IgE-mediated (or non-IgE) mast cell and basophil degranulation releases histamine, tryptase, leukotrienes and prostaglandins. The result is a triad of increased vascular permeability, vasodilatation, and bronchoconstriction — producing distributive shock, angioedema, and bronchospasm, sometimes within minutes. Up to 35% of the circulating volume can shift into the interstitium within ten minutes."

Rosen's Emergency Medicine: Concepts and Clinical Practice, 10th Ed. Elsevier 2023. Chapter: Anaphylaxis.

📘 Rosen's — The Three Actions of Adrenaline

Adrenaline reverses every limb of the pathophysiology simultaneously — which is why no other drug substitutes for it:

α₁ agonism → vasoconstriction: reverses vasodilatation and capillary leak, raises BP, reduces mucosal/laryngeal oedema
β₁ agonism → inotropy & chronotropy: supports cardiac output
β₂ agonism → bronchodilatation and (importantly) stabilises mast cells/basophils, reducing further mediator release

The early administration matters because once profound shock and the "empty heart" develop, IM absorption falls and the window to act narrows.

📘 Rosen's — The "Empty Ventricle" & Why Positioning Kills

In anaphylactic distributive shock, venous return is critically dependent on preload. Sitting the patient up or standing them up can cause sudden pulseless electrical activity — the "empty inferior vena cava / empty ventricle" syndrome — because the vasodilated, volume-depleted circulation cannot maintain venous return against gravity. Fatalities have occurred within seconds of a patient being moved to an upright position. Keep the patient supine with legs elevated (or in the left lateral position if vomiting / pregnant); sit up only if breathing is the dominant problem and they are not hypotensive.

📘 Rosen's — Biphasic Reactions

A biphasic reaction is the recurrence of symptoms (typically 1–10 hours, occasionally up to 72 h) after apparent resolution, without re-exposure to the allergen. Incidence ~3–20%. Risk factors: severe initial presentation, delayed or repeated adrenaline doses, and a wide pulse pressure at presentation. This is the rationale for a period of observation after treatment — though routine prolonged admission is no longer mandated for all.

📋 3 · Guidelines, Diagnosis & Indian Context

WAO 2020 / Resuscitation Council UK 2021 — Diagnostic Criteria

Anaphylaxis Is Likely When ANY ONE Is Met (WAO 2020)

Criterion 1: Acute onset (minutes–hours) with skin/mucosal involvement (hives, itch, swollen lips/tongue/uvula) AND at least one of: respiratory compromise (dyspnoea, wheeze, stridor, hypoxaemia) OR reduced BP / end-organ dysfunction (collapse, syncope, incontinence).
Criterion 2: Acute onset of two or more of the following after exposure to a likely allergen — skin/mucosal, respiratory, cardiovascular, OR persistent GI symptoms (crampy pain, vomiting).
Criterion 3: Reduced BP after exposure to a known allergen for that patient (age-specific hypotension or >30% drop).

RCUK 2021 — Key Practice Changes

Antihistamines are now third-line — only for cutaneous symptoms after stabilisation; non-sedating oral cetirizine preferred over IV chlorphenamine. No longer routine emergency drugs
Corticosteroids are NO LONGER recommended routinely — evidence does not support that they prevent biphasic reactions, and they may delay discharge. Removed from the routine algorithm
Refractory anaphylaxis (no improvement after 2 IM doses) → start an adrenaline infusion with senior/critical care help.

Risk-Stratified Observation Before Discharge (RCUK 2021)

Minimum 2 hours after symptom resolution for a good responder to a single dose. Minimum 6 hours if 2 doses needed or previous biphasic reaction. 12 hours / admit if severe (required >2 doses, severe asthma, ongoing reaction, presented late at night, or poor access to emergency care). Discharge with an adrenaline auto-injector + 2 written prescriptions, allergen avoidance advice, and allergy clinic referral.

🇮🇳 Indian ED Context

Auto-injectors (EpiPen) are largely unavailable/unaffordable in India — most EDs draw up adrenaline from 1:1000 ampoules. Teach at-risk patients/families to recognise anaphylaxis and seek care; pre-filled syringes or clear ampoule-drawing instructions are the practical substitute.

Common triggers in India: drugs (β-lactams, NSAIDs, IV contrast, neuromuscular blockers), foods (peanut, tree nuts, shellfish, sesame), Hymenoptera stings, and snakebite antivenom reactions (anaphylactoid — see the Snakebite topic; manage with adrenaline, slow/stop ASV, then resume).

Drug-induced anaphylaxis during anaesthesia/procedures is under-recognised — sudden hypotension + high airway pressures + rash under drapes is anaphylaxis until proven otherwise.

💊 4 · Drug Doses & Tables

Drug Reference — Anaphylaxis

IM Adrenaline (1:1000) by Age

Adult & >12 y

0.5 mg

0.5 mL of 1:1000 IM

Child 6–12 y

0.3 mg

0.3 mL of 1:1000 IM

Child 6 mo–6 y

0.15 mg

0.15 mL of 1:1000 IM

Infant <6 mo

0.1–0.15 mg

0.01 mg/kg IM

Drug	Role	Dose	Notes
Adrenaline IM (1:1000)	FIRST-LINE — all anaphylaxis	0.5 mg (0.5 mL) anterolateral thigh; repeat q5 min	No absolute contraindication; the only mortality-reducing drug
Adrenaline infusion	Refractory (≥2 IM doses)	Start ~0.05–0.1 µg/kg/min, titrate to BP (e.g. 1 mg in 100 mL → 10 µg/mL)	Needs continuous monitoring; ideally CVC but peripheral acceptable while establishing
IV crystalloid bolus	Distributive shock / hypotension	1–2 L (20 mL/kg paeds) 0.9% saline / balanced fluid, rapid; repeat	Large volumes often needed (capillary leak); reassess
High-flow oxygen	All — airway/breathing	15 L/min non-rebreathe; titrate to SpO₂ ≥94%	Prepare for early airway management if stridor/laryngeal oedema
Salbutamol neb	Bronchospasm not relieved by adrenaline	5 mg nebulised, repeat/continuous	Adjunct; does not replace adrenaline
Glucagon	Adrenaline-resistant (β-blocker patients)	1–2 mg IV/IM q5 min, then infusion 5–15 µg/min	Bypasses β-receptor; warn re: vomiting/aspiration
Cetirizine (PO)	THIRD-LINE — cutaneous only	10 mg PO after stabilisation	RCUK 2021 prefers oral non-sedating over IV chlorphenamine
Corticosteroid	NOT routine (RCUK 2021)	Hydrocortisone 200 mg IV only if refractory/asthma component	No proven prevention of biphasic reactions

⚠️ IM vs IV Adrenaline — The Fatal Confusion

IM 1:1000 is the default. IV adrenaline (1:10,000, titrated, with cardiac monitoring) is for profound shock / peri-arrest / cardiac arrest only, by experienced clinicians. Giving an IV bolus of 1:1000, or an IV "push dose" by mistake, can cause hypertensive crisis, arrhythmia, myocardial ischaemia and death. When in doubt: IM, anterolateral thigh, 0.5 mg.

🗂 5 · Clinical Flowchart

Step-by-Step Management Algorithm

Recognise & call for help

Sudden ABC compromise + skin/mucosal change ± known/likely trigger → treat as anaphylaxis.
Remove trigger if possible (stop the drug/IV infusion, remove stinger).
Call for senior/resus help early.

Adrenaline IM + position supine

Adrenaline 0.5 mg IM (1:1000) anterolateral thigh — immediately.
Lie the patient flat, legs raised (left lateral if vomiting/pregnant). Do NOT sit or stand them up.
High-flow O₂; establish monitoring (SpO₂, ECG, BP).

Repeat & resuscitate

Repeat IM adrenaline every 5 min if no improvement.
IV access × 2; rapid crystalloid bolus 1–2 L for hypotension.
Nebulised salbutamol for persistent bronchospasm; nebulised adrenaline for stridor/upper-airway oedema.

Refractory (≥2 doses, still unwell)

Start adrenaline infusion, titrate to response; involve critical care.
β-blocked patient not responding → glucagon.
Prepare for early intubation if progressive airway oedema — get the most experienced operator, plan for a surgical airway (difficult airway).

Observe, then discharge with a plan

Risk-stratified observation (2 / 6 / 12 h) per RCUK 2021.
Serial tryptase (at presentation, ~1–2 h, and >24 h baseline) helps confirm — but never delays treatment.
Adrenaline auto-injector / ampoule-draw plan + allergen avoidance + allergy referral.

🔬 6 · Refractory Anaphylaxis & Special Cases

Difficult Scenarios

Refractory Anaphylaxis

Defined as anaphylaxis not responding to 2 appropriate IM adrenaline doses. Start an adrenaline infusion, give aggressive IV fluids, and consider a second vasopressor (noradrenaline/vasopressin) for refractory distributive shock. Consider methylene blue (1–2 mg/kg) as a rescue in vasoplegia unresponsive to catecholamines. ECMO has been used in catastrophic refractory cases.

The β-Blocked Patient

Patients on beta-blockers may be resistant to adrenaline and develop refractory hypotension/bronchospasm. Glucagon 1–2 mg IV q5 min then 5–15 µg/min infusion bypasses the β-receptor (activates adenylate cyclase directly). Anticipate vomiting — protect the airway.

Airway Oedema — Plan for the Difficult Airway

Progressive hoarseness, stridor, tongue/lip/uvular swelling = impending airway loss. Intubate early, awake/with the most experienced operator, smaller tube, and a prepared surgical airway (scalpel-bougie-tube). Do not wait for complete obstruction — repeated laryngoscopy attempts can convert a difficult airway into a "can't intubate, can't oxygenate" emergency.

📘 Pregnancy & Perioperative

Pregnancy: same adrenaline dosing; position left lateral to relieve aortocaval compression; anaphylaxis threatens both mother and foetus — treat aggressively. Perioperative anaphylaxis (NMBAs, antibiotics, chlorhexidine, latex): often presents as sudden hypotension + bronchospasm/high airway pressures under anaesthesia; mast cell tryptase and later allergy testing are essential to identify the culprit.

❌ 7 · Common Mistakes

Common Mistakes in Anaphylaxis

❌ Mistake 1 — Giving Antihistamines/Steroids Instead of Adrenaline

The commonest and most dangerous error. Antihistamines and steroids do nothing for airway oedema or shock and have no role as the primary treatment. Adrenaline IM is first-line and must be given within minutes — every other drug is an adjunct.

❌ Mistake 2 — Sitting the Hypotensive Patient Upright

Moving a vasodilated, volume-depleted patient to a sitting/standing position can cause immediate PEA arrest ("empty ventricle"). Keep them supine with legs elevated; deaths have been documented seconds after standing a patient up to "help them breathe".

❌ Mistake 3 — Wrong Route/Concentration of Adrenaline

Subcutaneous adrenaline absorbs too slowly; IV 1:1000 bolus can be fatal. Use IM 1:1000 into the anterolateral thigh. Reserve IV adrenaline (1:10,000, titrated, monitored) for peri-arrest by experienced staff.

❌ Mistake 4 — Withholding Adrenaline Over Cardiac Fears

There is no absolute contraindication to adrenaline in true anaphylaxis — the risk of under-treating exceeds the risk of the drug. Hesitation in the elderly or those with cardiac disease costs lives; give it IM and monitor.

❌ Mistake 5 — Under-Resuscitating Volume

Up to a third of circulating volume can extravasate within minutes. Hypotension often needs 1–2 L (or more) of crystalloid alongside adrenaline. Treating the BP with adrenaline alone, without fluids, leaves the patient under-filled.

❌ Mistake 6 — Discharging Without Adrenaline & a Plan

Failing to provide an adrenaline auto-injector/ampoule plan, written allergen avoidance advice, and allergy referral leaves the patient unprotected against the next (potentially fatal) exposure. Also counsel on biphasic reactions and when to return.

📑 8 · References

References

Tintinalli JE, Ma OJ, Yealy DM et al. Tintinalli's Emergency Medicine: A Comprehensive Study Guide, 9th Ed. Chapter: Anaphylaxis, Allergy & Acute Allergic Reactions. McGraw-Hill; 2020.
Walls RM, Hockberger RS, Gausche-Hill M et al. Rosen's Emergency Medicine: Concepts and Clinical Practice, 10th Ed. Chapter: Anaphylaxis. Elsevier; 2023.
Cardona V, Ansotegui IJ, Ebisawa M et al. World Allergy Organization Anaphylaxis Guidance 2020. World Allergy Organ J 2020;13:100472.
Resuscitation Council UK. Emergency treatment of anaphylaxis: Guidelines for healthcare providers. 2021 (updated).
Muraro A, Worm M, Alviani C et al. (EAACI). EAACI guidelines: Anaphylaxis (2021 update). Allergy 2022;77:357–377.
Shaker MS, Wallace DV, Golden DBK et al. Anaphylaxis — a 2020 practice parameter update (Joint Task Force, AAAAI/ACAAI). J Allergy Clin Immunol 2020;145:1082–1123.
Cameron P, Little M, Mitra B, Deasy C. Textbook of Adult Emergency Medicine, 5th Ed. Anaphylaxis. Elsevier; 2019.