Anaphylaxis
IgE-mediated systemic allergic reaction. Epinephrine is the ONLY first-line treatment -everything else is adjunctive. The most common mistake: giving diphenhydramine and steroids instead of epinephrine. Epi first, always.
🔍 Overview
Diagnostic Criteria -Any ONE of Three
- Criterion 1: Acute onset (minutes–hours) of skin/mucosal involvement (hives, flushing, angioedema) PLUS respiratory compromise (dyspnea, stridor, wheeze, hypoxia) OR hypotension/end-organ dysfunction
- Criterion 2: ≥ 2 of the following after exposure to LIKELY allergen: skin/mucosal symptoms, respiratory compromise, hypotension, persistent GI symptoms (cramping, vomiting)
- Criterion 3: Hypotension alone after exposure to KNOWN allergen for that patient
Up to 20% of anaphylaxis has NO skin findings. Don't wait for hives to give epinephrine. Isolated hypotension or bronchospasm after allergen exposure = anaphylaxis.
Common Triggers
- Foods: peanuts, tree nuts, shellfish, milk, eggs (#1 cause in children)
- Medications: antibiotics (penicillin, cephalosporins), NSAIDs, contrast dye, anesthetic agents (#1 cause in perioperative setting)
- Insect stings: Hymenoptera (bee, wasp, hornet) -#1 cause of fatal anaphylaxis in adults
- Latex
- Idiopathic (~20% -no identifiable trigger)
Biphasic Anaphylaxis
Up to 20% of anaphylaxis cases have a biphasic reaction -recurrence of symptoms 1–72 hours after initial resolution (most within 8–10h). This is why ALL patients require a minimum 4–6 hour observation period, and severe reactions warrant 12–24h observation. Steroids (methylprednisolone 125 mg IV) are given empirically to prevent biphasic reactions, though evidence is limited.
Clinical Example
Case
28F with known shrimp allergy presents from a restaurant with lip swelling, diffuse urticaria, audible wheezing, and BP 82/48 within 15 minutes of eating shellfish. HR 124, SpO₂ 91% on RA. This is anaphylaxis (Criterion 2: skin + respiratory + hypotension after known allergen).
🚨 Management
Treatment Protocol
EPINEPHRINE is the ONLY first-line treatment. There is NO contraindication to epinephrine in anaphylaxis -not age, not pregnancy, not cardiac disease. The risk of NOT giving epi is always greater than the risk of giving it. IM Epinephrine Pharmacokinetics Trial, 2004 WAO, 2020
| Step | Drug | Dose | Notes |
|---|---|---|---|
| 1. EPINEPHRINE | Epinephrine 1:1000 (1 mg/mL) GIVE FIRST | 0.3–0.5 mg IM (0.3–0.5 mL) in anterolateral thigh. Repeat q5–15 min if no improvement. | IM (not SubQ) -faster absorption IM Epinephrine Pharmacokinetics Trial, 2004. Anterolateral thigh (not deltoid) -better blood flow. Autoinjector: EpiPen 0.3 mg adult, 0.15 mg pediatric (< 30 kg). Most common error: not giving epi, giving it too late, or giving it SubQ. WAO Anaphylaxis Guidelines, 2020 |
| 2. Position | Supine with legs elevated (improves venous return). If vomiting → recovery position. If respiratory distress → sitting up. Do NOT have the patient stand or sit upright if hypotensive -can cause fatal "empty ventricle syndrome." | ||
| 3. IV access + fluids | NS bolus | 1–2 L rapid bolus (20 mL/kg peds) | Anaphylaxis causes massive vasodilation + capillary leak → distributive shock. Aggressive fluids needed. |
| 4. Adjuncts | Diphenhydramine 50 mg IV + famotidine (Pepcid) 20 mg IV | H1 + H2 blockers | Adjunctive ONLY -do NOT give instead of epinephrine. Antihistamines treat hives but do NOT reverse bronchospasm or hypotension. |
| 5. Steroids | Methylprednisolone 125 mg IV | Or dexamethasone 10 mg IV | Does NOT help acute anaphylaxis (takes 4–6h to work). May prevent biphasic reaction (occurs in ~5–20%, usually 1–72h later) Biphasic Anaphylaxis Review, 2015. Observe ≥ 4–6h after resolution. |
| Refractory | Epinephrine drip | 1–10 mcg/min IV | If ≥ 2 doses of IM epi fail → start epi drip. Glucagon 1–5 mg IV if on beta-blockers (epi may be ineffective due to β-blockade). Vasopressin for refractory hypotension. |
IM epinephrine is the ONLY life-saving treatment. Antihistamines and steroids are ADJUNCTS -they do NOT treat anaphylaxis. Delay in epinephrine = death.
NEVER give IV epinephrine push for anaphylaxis (unless cardiac arrest). IV push epi in a patient with a pulse causes fatal arrhythmias. Use IM or IV drip only.
Updated Practice: Old teaching: give IV Benadryl and steroids first, then epi if not improving. WRONG -epinephrine is FIRST, immediately. Every minute of delay increases mortality. WAO, 2020
🧪 Workup
Laboratory Workup
- Tryptase level -draw within 1–2h of onset (peaks at 1h). Confirms mast cell degranulation. A normal tryptase does NOT rule out anaphylaxis.
- CBC -baseline hematocrit, WBC
- BMP -renal function, electrolytes (epinephrine can cause hypokalemia)
- ECG -arrhythmias from epinephrine administration or myocardial involvement (Kounis syndrome -allergic MI)
- Trigger identification -detailed timeline of exposures (food, drugs, insect stings, latex, exercise)
- Allergist referral -4–6 weeks post-event for skin-prick testing and component testing
Clinical diagnosis. Do NOT delay treatment waiting for labs. Tryptase is confirmatory, not diagnostic. If it looks like anaphylaxis, treat like anaphylaxis.
📋 On Rounds
Why give glucagon in anaphylaxis for patients on beta-blockers?
Epinephrine works primarily through β₁ (increased HR, contractility) and β₂ (bronchodilation, vasodilation in muscle) receptors. In patients on beta-blockers, these receptors are occupied/blocked → epinephrine is less effective → refractory anaphylaxis. Glucagon bypasses the β-receptor entirely -it activates adenylyl cyclase directly via the glucagon receptor → increases cAMP → positive inotropy + chronotropy + smooth muscle relaxation.
Why is IM epinephrine given in the anterolateral thigh and not the deltoid?
The anterolateral thigh (vastus lateralis) provides faster and higher peak epinephrine absorption than the deltoid, with peak plasma levels at ~8 minutes vs ~34 minutes for subcutaneous. This is because the thigh has rich vasculature and large muscle mass for IM absorption. Never give epi IV push for anaphylaxis (unless in cardiac arrest) -IV bolus can cause fatal arrhythmia. The dose is 0.3–0.5 mg of 1:1000 (1 mg/mL) IM, repeat q5–15 min.
A patient had an anaphylactic reaction 4 hours ago and feels fine. Can you discharge them?
Observe for biphasic reaction. Biphasic anaphylaxis occurs in 1-20% of cases (most estimates ~5%), typically 1-72 hours after the initial reaction (most within 8-10h). Risk factors for biphasic: severe initial reaction, delayed epinephrine, required > 1 dose of epi, unknown trigger. Minimum observation: 4-6 hours for mild reactions.
What are the diagnostic criteria for anaphylaxis?
Anaphylaxis is diagnosed when any 1 of 3 criteria is met: (1) Acute skin/mucosal involvement (hives, flushing, angioedema) + respiratory compromise (wheeze, stridor, hypoxia) OR hypotension. (2) ≥ 2 of the following after exposure to a likely allergen: skin/mucosal symptoms, respiratory compromise, hypotension, persistent GI symptoms (cramping, vomiting). (3) Hypotension alone after exposure to a known allergen for that patient.
Clinical Examples
📋 Case 1, Antibiotic-Induced Anaphylaxis
Patient: 42F, no known drug allergies. First dose IV piperacillin-tazobactam. Within 15 min: diffuse urticaria, lip swelling, wheeze, BP 72/38.
Key findings: Skin + respiratory + hypotension after allergen. HR 128, SpO2 91%, stridor developing.
Management:
- Epinephrine 0.5 mg IM anterolateral thigh (1:1000), FIRST, do not delay
- Stop offending antibiotic immediately
- NS 1-2L bolus; diphenhydramine 50 mg IV + famotidine 20 mg IV
- Methylprednisolone 125 mg IV; albuterol neb for bronchospasm
- Repeat epi q5-15 min if no improvement; epi drip if refractory
Teaching point: Most deaths from anaphylaxis result from delayed or withheld epinephrine. IM epinephrine has NO absolute contraindications. Antihistamines treat hives but do NOT reverse hypotension or airway obstruction. WAO, 2020
📋 Case 2, Refractory Anaphylaxis on Beta-Blockers
Patient: 67M, PMH CAD on metoprolol 100 mg BID. Bee sting 20 min ago. Flushing, tongue swelling, wheeze, BP 68/40, HR 52.
Key findings: Refractory hypotension despite 2 IM epi doses. HR blunted by beta-blocker.
Management:
- Glucagon 1-5 mg IV bolus, then 5-15 mcg/min, bypasses beta-receptor
- Epinephrine IV drip 1-10 mcg/min (ICU monitoring)
- Aggressive IVF 2-3L; have suction ready (glucagon causes vomiting)
Teaching point: Beta-blockers blunt the cardiac response to epinephrine. Glucagon bypasses the beta-receptor via direct adenylyl cyclase activation, producing positive inotropy and chronotropy independent of beta-receptors.
📋 Case 3, Biphasic Anaphylaxis
Patient: 25F with peanut allergy. Accidental exposure 6h ago. Initial reaction treated with EpiPen. Resolved. Now: recurrent urticaria, throat tightness, wheezing.
Key findings: Biphasic anaphylaxis (~5% of cases, within 1-72h). Risk factors: severe initial reaction, > 1 epi dose needed, delayed treatment.
Management:
- Repeat epinephrine 0.5 mg IM immediately
- Admit for extended observation (12-24h minimum)
- Continue H1 + H2 blockers and steroids
- Discharge with EpiPen, allergist referral, action plan, medical alert bracelet
Teaching point: Biphasic reactions are why all anaphylaxis patients need minimum 4-6h observation (12-24h if severe). All patients need an EpiPen prescription and allergist referral at discharge.
📣 Sample Presentation
One-Liner
"Ms. Williams is a 35-year-old who developed diffuse urticaria, throat tightness, wheezing, and hypotension (BP 78/42) within 10 minutes of IV cefazolin administration. Consistent with anaphylaxis."
Key Points to Cover on Rounds
Anaphylaxis to cefazolin (probable cephalosporin allergy). Epinephrine 0.5 mg IM anterolateral thigh given × 1 → BP improved to 102/64. Additional: diphenhydramine 50 mg IV, famotidine 20 mg IV, methylprednisolone 125 mg IV, NS 1L bolus. Wheezing resolved with albuterol neb. Observed for biphasic reaction × 6 hours -no recurrence. Tryptase level drawn at 1h. Allergy documented: cephalosporins → anaphylaxis. EpiPen prescribed. Plan: allergist referral, avoid cephalosporins and high-cross-reactivity penilcillins, discharge with anaphylaxis action plan.
💊 Medications
Anaphylaxis Medications
| Drug | Dose | Route | Role |
|---|---|---|---|
| Epinephrine (1:1000) | 0.3–0.5 mg | IM anterolateral thigh | FIRST-LINE -repeat q5–15 min. No contraindications in anaphylaxis. |
| Diphenhydramine | 50 mg | IV | H1 blocker -adjunct for urticaria/pruritus. Does NOT treat hypotension or bronchospasm. |
| Famotidine (Pepcid) | 20 mg | IV | H2 blocker -adjunct. Combined H1+H2 blockade more effective than H1 alone. |
| Methylprednisolone | 125 mg | IV | Prevents biphasic reaction (theoretical -weak evidence). Takes 4–6h to work. NOT for acute treatment. |
| Albuterol | 2.5 mg neb | Nebulized | For bronchospasm refractory to epinephrine. Continuous neb if severe. |
| Glucagon | 1–5 mg bolus, then 5–15 mcg/min | IV | For patients on beta-blockers. Bypasses β-receptor blockade → direct cAMP activation. Side effect: vomiting. |
| Epinephrine drip | 1–10 mcg/min | IV infusion | Refractory anaphylaxis (failed ≥2 IM doses). ICU-level monitoring required. |
⚡ Summary
Summary
Epinephrine Is the Only First-Line Treatment
0.3 to 0.5 mg IM of 1:1000 into the anterolateral thigh, repeated every 5 to 15 min as needed. Everything else is adjunctive. The commonest fatal mistake is giving diphenhydramine and steroids instead of epinephrine. Antihistamines treat hives; they do not treat airway edema, bronchospasm or shock.
There Is No Contraindication
Not age, not pregnancy, not coronary disease. The risk of withholding epinephrine always exceeds the risk of giving it, and delay is the strongest predictor of death in fatal anaphylaxis. Hesitating in an elderly cardiac patient is the exact situation in which the drug is most needed.
Never IV Push Epinephrine in a Patient With a Pulse
IV push causes fatal arrhythmia and hypertensive crisis. Use IM, and escalate to an IV infusion if IM doses fail, titrated under monitoring. IV push is reserved for cardiac arrest. This is one of the highest-consequence route errors in acute medicine.
Up to 20% Have No Skin Findings
Do not wait for hives. Isolated hypotension, or isolated bronchospasm, after exposure to a known or likely allergen is anaphylaxis and is treated as such. The diagnostic criteria are met by any one of three patterns, and only one of them requires skin or mucosal involvement.
Position and Resuscitate at the Same Time
Lay the patient flat with the legs elevated, unless they are vomiting or in respiratory distress. Sitting a hypotensive anaphylaxis patient up, or letting them stand, has caused sudden death from the empty ventricle syndrome. Give aggressive IV fluid, since massive capillary leak means these patients need liters, and remove the trigger where possible.
Know the Refractory Cases
Patients on beta blockers may not respond to epinephrine; give glucagon 1 to 5 mg IV, which bypasses the beta receptor to raise cyclic AMP. Add a vasopressor infusion for persistent hypotension, and prepare for a difficult airway early, since angioedema progresses fast and late intubation may be impossible.
Adjuncts Have a Role, Just Not the First One
H1 and H2 antihistamines for cutaneous symptoms, bronchodilators for bronchospasm, and steroids, historically given to prevent biphasic reactions though the evidence for that is weak. None of them substitutes for epinephrine, and none should delay it.
Observe, Then Prescribe and Refer
Biphasic reactions occur in up to 20%, typically within 4 to 12 h, so observe for 4 to 6 h, longer after severe reactions or repeated epinephrine doses. Discharge with two epinephrine autoinjectors, a demonstration of how to use them, and an anaphylaxis action plan, plus allergy referral. A serum tryptase drawn within 1 to 3 h can confirm the diagnosis retrospectively when the presentation was ambiguous.
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