CCS Integrated Cases

CCS case: anaphylaxis after medication administration

Clinical Overview and When to Suspect Anaphylaxis After Medication Administration

— Acute onset (minutes to hours) of skin/mucosal involvement (hives, flushing, lip/tongue swelling) PLUS either respiratory compromise OR hypotension/end-organ dysfunction

— Two or more of the following after exposure to a likely allergen: skin/mucosal, respiratory, hypotension, persistent GI symptoms

— Hypotension alone after exposure to a known allergen for that patient

— Beta-lactam antibiotics (penicillins, cephalosporins) — most common drug cause

— NSAIDs, aspirin (often pseudo-allergic, COX-1 mediated)

— IV contrast (iodinated > gadolinium)

— Neuromuscular blockers (rocuronium, succinylcholine) — intra-op anaphylaxis

— Monoclonal antibodies, chemotherapy (platinum agents), vancomycin (true IgE rare; vs red-man syndrome)

CCS pearl: The moment you suspect anaphylaxis, your first order is IM epinephrine 0.3–0.5 mg (1:1000) into the mid-anterolateral thigh — before you order labs, IV access, or call a consult. Delay in epinephrine is the single strongest predictor of death and biphasic reactions.

Key distinction: Anaphylactoid (non-IgE, e.g., vancomycin red-man, radiocontrast) reactions are clinically identical and treated identically — the management does not change based on mechanism.

Definition: Anaphylaxis is an acute, IgE- or non-IgE-mediated systemic hypersensitivity reaction that is rapid in onset and can cause death. Diagnosis is clinical — do not wait for labs.

NIAID/FAAN diagnostic criteria (any one of three):

Common medication triggers on Step 3 stems:

Timing clue: Symptoms typically begin within 5–60 minutes of IV drug administration; oral exposures may take longer. Biphasic reactions occur in up to 20%, usually within 1–8 hours after initial resolution.

When to suspect on CCS: Patient just received a new drug (often in the ED, infusion center, or OR) and develops urticaria, wheezing, hoarseness, hypotension, or syncope. Even isolated hypotension or bronchospasm after a known-allergen drug counts.

Presentation Patterns and Key History

— Cutaneous (~90%): urticaria, pruritus, flushing, angioedema of lips/tongue/periorbital tissue

— Respiratory (~70%): dyspnea, wheeze, stridor, hoarseness, chest tightness, cough

— Cardiovascular (~45%): hypotension, tachycardia, syncope, "feeling of impending doom"

— GI (~45%): crampy abdominal pain, nausea, vomiting, diarrhea

— Isolated hypotension after drug exposure (no rash) — common in intraoperative anaphylaxis under drapes

— Isolated laryngeal edema with stridor and no urticaria

— Beta-blocker patients may present with paradoxical bradycardia rather than tachycardia and are refractory to epinephrine — need glucagon

— Exact drug, dose, route, and time of administration

— Prior reactions to this drug or related drugs (cross-reactivity: penicillin ↔ cephalosporin ~1–2%; NSAIDs as a class)

— Atopy: asthma, eczema, allergic rhinitis (asthma is the strongest risk factor for fatal anaphylaxis)

— Concurrent medications: beta-blockers, ACE inhibitors (worsen severity and impair response to treatment)

— Mastocytosis history (recurrent unexplained anaphylaxis)

— IV drugs: seconds to 5 minutes

— IM drugs: 10–30 minutes

— Oral drugs: 30 minutes to 2 hours

— Faster onset = more severe reaction

Board pearl: A patient on a beta-blocker who develops anaphylaxis and fails to respond to two IM epi doses needs IV glucagon 1–5 mg over 5 minutes, which bypasses the beta-receptor by activating adenylate cyclase directly.

Key distinction: Urticaria alone (without respiratory, CV, or GI involvement) is not anaphylaxis and does not require epinephrine — treat with H1 antihistamine and observe. Adding epi unnecessarily is a common stem trap.

Classic tetrad (organ systems involved, in descending frequency):

Atypical/dangerous presentations to recognize on the boards:

Key history points to obtain (rapidly, in parallel with treatment):

Onset timing pattern:

Physical Exam Findings and Hemodynamic Assessment

— BP (often <90 systolic or >30% drop from baseline)

— HR (tachycardia typical; bradycardia in late shock or beta-blocked patients — Bezold-Jarisch reflex)

— RR, SpO2 (hypoxia from bronchospasm or laryngeal edema)

— Temperature usually normal (fever suggests alternative dx)

— Hoarseness, "hot potato" voice, drooling, inspiratory stridor → impending airway loss

— Tongue/uvular edema, posterior pharyngeal swelling

— Threshold to intubate is low — secure airway early before edema makes it impossible. Have surgical airway kit at bedside.

— Diffuse wheezing, prolonged expiratory phase

— Decreased breath sounds if severe bronchospasm or fatigue

— Weak thready pulse, cool clammy extremities (distributive shock with relative hypovolemia from capillary leak — up to 35% of intravascular volume lost in 10 min)

— JVP typically flat

— Generalized urticaria, flushing, angioedema (non-pitting, asymmetric)

— Absence of skin findings does not rule out anaphylaxis (~10% have none)

Hemodynamic classification:

— Mild: skin + GI only, normal vitals

— Moderate: respiratory or mild CV involvement

— Severe: hypoxia, hypotension, altered mental status, or cardiac arrest

CCS pearl: On the CCS interface, order continuous cardiac monitoring, continuous pulse oximetry, automatic BP cuff q5min, and continuous telemetry the moment you suspect anaphylaxis. Reassess vitals at the 5-minute mark after each epinephrine dose — this drives your decision to redose.

Board pearl: Anaphylactic shock = distributive + hypovolemic + cardiogenic combined. That's why epi (vasopressor + inotrope + bronchodilator) is uniquely suited as monotherapy — antihistamines alone won't fix shock.

Vitals to capture immediately:

Airway exam — highest priority:

Pulmonary:

Cardiovascular:

Skin:

GI: diffuse tenderness, hyperactive bowel sounds, vomiting

Neuro: anxiety, confusion, syncope (cerebral hypoperfusion)

Diagnostic Workup — Initial Labs and Bedside Studies

— Two large-bore (16–18g) peripheral IVs

— Normal saline 1–2 L IV bolus wide open (20 mL/kg in adults; 20 mL/kg in peds), then reassess

— Continuous SpO2, telemetry, BP q5min

— Supplemental O2 via non-rebreather to maintain SpO2 ≥94%

— 12-lead ECG — assess for ischemia (Kounis syndrome — allergic ACS from coronary vasospasm/plaque rupture), arrhythmia

— CBC, BMP, lactate, troponin (lactate as marker of tissue hypoperfusion; troponin if chest pain or ECG changes)

— ABG if respiratory distress

— Portable CXR if persistent wheeze/hypoxia to evaluate for pulmonary edema, aspiration, pneumothorax

— Serum tryptase — peaks 15 min to 3 hours post-onset; draw at presentation, 1–2 hr, and 24 hr (baseline). Elevation >11.4 ng/mL or >20% above baseline + 2 supports diagnosis.

— Tryptase often normal in food/drug-induced anaphylaxis (more sensitive for insect sting and parenteral drug). A normal tryptase does not rule out anaphylaxis.

— Persistently elevated baseline tryptase → consider systemic mastocytosis (workup with KIT D816V mutation, bone marrow biopsy outpatient)

CCS pearl: On the CCS clock, advance time in 5-minute increments during the active reaction. After stabilization, advance in 30-minute then hourly intervals. Reorder vitals and recheck the patient at each step.

Key distinction: Tryptase confirms mast cell activation but does not identify the trigger. Trigger identification requires outpatient skin testing or specific IgE 4–6 weeks after the event (mast cells must repopulate).

Anaphylaxis is a clinical diagnosis — do NOT delay epinephrine for confirmatory testing. Labs are obtained after stabilization to support diagnosis, identify complications, or evaluate differentials.

CCS initial order set after IM epi given:

Specific anaphylaxis biomarker:

Histamine levels — short half-life (<1 hr), not clinically useful

Diagnostic Workup — Confirmatory and Outpatient Studies

— Serum tryptase at 0, 1–2 hr, and 24 hr (baseline level for comparison)

— If isolated cardiac symptoms: serial troponins q3–6h to rule out Kounis syndrome (allergic ACS)

— If recurrent or refractory: consider checking C4, C1-esterase inhibitor level/function to rule out hereditary angioedema masquerading

— Refer to allergy/immunology for testing 4–6 weeks after the event (sooner = false negatives from mast cell depletion)

— Skin prick testing for suspected drug — gold standard for penicillin (PPV ~50%, NPV >97%)

— Intradermal testing if skin prick negative but suspicion high

— Specific IgE (ImmunoCAP) — useful for penicillin, latex, insulin, chymopapain

— Graded oral challenge under supervision — definitive when skin testing equivocal; gold standard for NSAID and aspirin hypersensitivity

— Not IgE-mediated in most cases — skin testing rarely useful

— Strategy is premedication for future scans (see chunk 15) plus use of iso-osmolar nonionic agent

— Test all drugs given within 1 hour of onset: NMBAs, latex, antibiotics, chlorhexidine, blue dye

— Coordinate with anesthesia for future surgical planning

— Wristband/EHR allergy alert with specific reaction described (anaphylaxis vs rash vs GI upset)

— Avoid generic "allergy" labeling — leads to inappropriate avoidance of first-line drugs

Board pearl: Penicillin allergy delabeling is a major Step 3 ambulatory care topic. ~90% of patients labeled "penicillin allergic" are not truly allergic. Confirmed low-risk patients (remote reaction, non-anaphylactic) can undergo direct oral amoxicillin challenge in clinic.

Step 3 management: After the acute event, the discharge plan must include (1) epinephrine auto-injector prescription, (2) allergy referral within 4–6 weeks, (3) written anaphylaxis action plan, (4) medical alert bracelet.

Acute-phase confirmation (in-hospital):

Outpatient allergy workup (the Step 3 longitudinal piece):

For radiocontrast reactions:

For perioperative anaphylaxis:

Documentation:

First-Line Management Logic — The Anaphylaxis Algorithm

— Stop the offending drug/infusion immediately

— IM epinephrine 0.3–0.5 mg (0.01 mg/kg, max 0.5 mg) of 1:1000 (1 mg/mL) into mid-anterolateral thigh

— Call for help; activate rapid response if inpatient

— Position patient supine with legs elevated (or left lateral if pregnant or vomiting) — Trendelenburg improves venous return; sitting upright can precipitate empty ventricle syndrome and PEA arrest

— Establish 2 large-bore IVs

— Begin NS bolus 1–2 L wide open

— Apply O2, monitors

— Reassess: if persistent symptoms → repeat IM epi q5–15 min (up to 3 doses typical)

— Start epinephrine IV infusion 0.1 mcg/kg/min, titrate to MAP ≥65

— Add adjuncts (see chunk 7)

— Consider intubation if airway compromise progressing

— Add second vasopressor: norepinephrine or vasopressin

— Glucagon 1–5 mg IV if on beta-blocker

— Methylene blue 1–2 mg/kg has been used in refractory shock

— Consider ECMO for cardiac arrest from anaphylaxis

CCS pearl: On CCS, the correct first three orders in this order are: (1) Stop the offending agent, (2) Epinephrine 0.3 mg IM, (3) Place patient supine, legs elevated. Ordering diphenhydramine or methylprednisolone first is a classic CCS scoring trap — those are adjuncts, never first-line.

Key distinction: IM > SC > IV for initial dosing. SC absorption is unreliable in shock. IV bolus epinephrine is reserved for cardiac arrest or refractory shock with continuous monitoring — bolus IV epi in awake patients causes hypertensive crisis, MI, and arrhythmia.

Board pearl: There is no absolute contraindication to epinephrine in anaphylaxis — not pregnancy, not advanced age, not CAD. The risk of withholding it exceeds the risk of giving it.

Time zero (the moment of diagnosis):

Within 5 minutes:

Within 15 minutes if refractory:

Refractory anaphylaxis (no response after 3 IM doses + fluids):

Pharmacotherapy — First-Line and Adjunctive Regimen

— IM 1:1000 (1 mg/mL): 0.3–0.5 mg adult, 0.15 mg child <30 kg, q5–15 min

— IV infusion 1:10,000 dilution: start 0.1 mcg/kg/min, titrate

— IV bolus (arrest only): 1 mg of 1:10,000 q3–5 min

— Mechanism: α1 (vasoconstriction, reverses edema), β1 (inotropy, chronotropy), β2 (bronchodilation, stabilizes mast cells)

— Normal saline 1–2 L bolus (20 mL/kg), repeat as needed; up to 4–7 L may be required due to capillary leak

— H1 antihistamine: diphenhydramine 25–50 mg IV/IM — relieves urticaria/pruritus, no effect on shock or airway

— H2 antihistamine: famotidine 20 mg IV — synergistic with H1 for cutaneous symptoms

— Corticosteroids: methylprednisolone 125 mg IV or hydrocortisone 200 mg IV — theoretical role in preventing biphasic reactions, though evidence is weak. Onset 4–6 hours.

— Inhaled β2 agonist: albuterol 2.5–5 mg nebulized for persistent bronchospasm after epi

— Glucagon 1–5 mg IV over 5 min, then 5–15 mcg/min infusion. Side effect: nausea/vomiting — protect airway.

— Norepinephrine 0.05–0.5 mcg/kg/min

— Vasopressin 0.01–0.04 U/min

— Promethazine IV (tissue necrosis if extravasates)

— Beta-blockers acutely (worsen bronchospasm)

Step 3 management: Steroids and antihistamines do not prevent biphasic anaphylaxis per current evidence (2020 GRADE recommendations) — recent guidelines actually recommend against routine corticosteroids as first-line, though they remain widely used. Boards still test their use as adjuncts.

CCS pearl: Order albuterol nebulizer 2.5 mg for any patient with persistent wheeze after epi. Order famotidine 20 mg IV alongside diphenhydramine 50 mg IV — the H1+H2 combo outperforms H1 alone for cutaneous symptoms.

Epinephrine (the only life-saving drug):

IV fluids:

Adjuncts (do not replace epi, do not give first):

For beta-blocked patients (refractory):

Vasopressors if refractory to epi infusion:

Avoid:

Procedural Management — Airway and Hemodynamic Rescue

— Early intubation indications:

– Progressive stridor, hoarseness, tongue/posterior pharyngeal edema

– Hypoxia despite O2 and bronchodilators

– Altered mental status from hypoperfusion

– Failure to respond to 2–3 epi doses

— Anticipate difficult airway: mucosal edema, bleeding, distorted anatomy. Use the most experienced operator, smaller ETT (6.0–7.0), video laryngoscopy, awake fiberoptic if time permits

— Have surgical airway ready: cricothyrotomy kit at bedside; prep neck; anesthesia + ENT consult STAT

— Avoid succinylcholine if hyperkalemia concern; rocuronium acceptable (but is itself a common trigger)

— Two large-bore peripheral IVs preferred

— If unable: intraosseous access (humeral or tibial) — do not delay epinephrine for IV

— Central line if prolonged vasopressor need, but don't delay IM epi for line placement

— Arterial line for continuous BP monitoring

— Central venous catheter for vasopressor infusion

— VA-ECMO for cardiac arrest from anaphylaxis (case reports support survival)

— Standard ACLS with prolonged resuscitation — outcomes can be good due to reversible cause

— High-volume fluids (4–8 L)

— Epinephrine bolus + infusion

— Consider thrombolysis only if PE suspected as alternate cause

— Stop contrast, treat as above; do not abort emergent indication if life-threatening (e.g., suspected aortic dissection) — proceed with premedication and alternative agent

CCS pearl: On the CCS, if you see stridor + drooling + hoarseness, immediately order "intubation, anesthesia consult stat, prepare cricothyrotomy" — waiting for "trial of more epi" while airway closes is a scoring failure.

Board pearl: Patients who arrest from anaphylaxis often have good neurologic outcomes if resuscitation is prolonged and aggressive — never give up early on a reversible cause.

Airway management — the critical procedural decision:

IV access and resuscitation:

Refractory shock procedural escalation:

Cardiac arrest from anaphylaxis:

Special procedure: if anaphylaxis during contrast for CT/cath:

Special Populations — Elderly and Renal/Hepatic Impairment

— Higher mortality from anaphylaxis (cardiovascular reserve lower, more comorbidities)

— Still get full-dose epinephrine — 0.3–0.5 mg IM. Age and CAD are NOT contraindications.

— Higher risk of epi-induced complications: arrhythmia, demand ischemia, hypertensive emergency — monitor ECG continuously, but do not withhold

— Polypharmacy concerns: beta-blockers (40% of elderly), ACE inhibitors common → more refractory reactions

— Consider lower starting dose of IV epi infusion (0.05 mcg/kg/min) and titrate cautiously

— Epinephrine is metabolized by MAO/COMT, not renally cleared — no dose adjustment

— Diphenhydramine: reduce dose in severe renal impairment (CrCl <10) due to active metabolite accumulation; consider cetirizine alternative

— Famotidine: reduce dose by 50% if CrCl <50

— Fluid resuscitation: cautious in dialysis-dependent patients — use 250–500 mL boluses with frequent reassessment; consider early dialysis support

— Epi: no adjustment

— Methylprednisolone: no adjustment but watch for hepatic encephalopathy with high-dose steroids

— Diphenhydramine: reduce dose (hepatic metabolism)

— Glucagon: caution — can cause hypoglycemia in cirrhotic patients with depleted glycogen

— Epinephrine can precipitate ischemia or pulmonary edema, but anaphylaxis itself will kill the patient faster — give epi

— Have nitro and CPAP available for post-stabilization pulmonary edema

— Cardiology consult after stabilization to assess for Kounis syndrome

Step 3 management: An 78-year-old on metoprolol with CAD develops anaphylaxis after IV ceftriaxone. Correct action: IM epinephrine 0.3 mg + glucagon 1 mg IV + fluids. Do NOT withhold epi due to age/CAD/CHF — withholding is the wrong answer every time.

Board pearl: Always ask about beta-blocker, ACE inhibitor, and tricyclic antidepressant use — all three worsen severity and impair epi response.

Elderly patients:

Renal impairment:

Hepatic impairment:

Heart failure / CAD:

Special Populations — Pregnancy and Pediatrics

— Epinephrine is first-line — Category C but unequivocally indicated. Maternal hypoperfusion causes far worse fetal outcomes than epi exposure.

— Position: left lateral decubitus (relieves aortocaval compression) rather than supine, especially >20 weeks gestation

— Continuous fetal monitoring if viable gestation (≥24 weeks)

— Common pregnancy triggers: oxytocin, β-lactams (intrapartum GBS prophylaxis), latex, NMBAs at C-section

— If maternal arrest unresponsive at 4 minutes and fetus >20 weeks: perimortem C-section at 5 minutes to improve maternal resuscitation

— Avoid: diphenhydramine in late pregnancy near delivery (sedates neonate); use cetirizine

— IM epinephrine 0.01 mg/kg of 1:1000, max 0.5 mg into mid-anterolateral thigh

— Auto-injectors: 0.15 mg for 10–25 kg, 0.3 mg for >25 kg, 0.1 mg device for infants <10 kg available

— Fluid bolus 20 mL/kg NS, repeat as needed

— Diphenhydramine 1 mg/kg (max 50 mg)

— Methylprednisolone 1–2 mg/kg

— Common pediatric drug triggers: amoxicillin, ibuprofen, vaccines (rare — anaphylaxis to vaccine ~1 per million doses; does NOT contraindicate future vaccination except to the specific component)

— Egg allergy and influenza vaccine: no longer a contraindication per CDC/ACIP — give in standard setting

— Epinephrine, antihistamines, steroids all compatible

CCS pearl: For a pregnant patient on the CCS, order left lateral tilt position, continuous fetal heart monitoring, OB consult stat alongside epinephrine. Failing to order fetal monitoring in a viable pregnancy is a scoring miss.

Key distinction: Children frequently present with predominantly respiratory symptoms (wheeze, stridor) rather than hypotension. Don't wait for hypotension to give epi in a wheezing child after drug exposure with skin findings.

Board pearl: A child with an anaphylaxis history needs two epi auto-injectors at school, an Anaphylaxis Action Plan filed with the school nurse, and 504 plan accommodations.

Pregnancy:

Pediatrics:

Breastfeeding mothers:

Complications and Adverse Outcomes

— Recurrence of symptoms 1–72 hours (typically 4–8 hr) after apparent resolution, without re-exposure

— Incidence: up to 20%, more common with delayed epinephrine, severe initial reaction, or unknown trigger

— Drives the observation period decision (see chunk 12)

— Symptoms persist >24 hours despite treatment — requires ICU admission and prolonged epi infusion

— Kounis syndrome: allergic acute coronary syndrome — three types: (1) coronary vasospasm without plaque, (2) plaque erosion/rupture, (3) stent thrombosis. Triage to cath lab if STEMI/NSTEMI criteria after stabilization.

— Arrhythmias from epinephrine: SVT, AF, VT

— Demand ischemia in CAD patients

— Stress (Takotsubo) cardiomyopathy

— ARDS from severe hypoxia and resuscitation

— Aspiration pneumonia from vomiting + altered consciousness

— Negative-pressure pulmonary edema after relief of upper airway obstruction

— Anoxic brain injury if prolonged hypoperfusion or arrest

— Seizures (rare, from hypoxia)

— Epi overdose (especially IV bolus in awake patient): hypertensive crisis, intracranial hemorrhage, MI

— Extravasation of peripheral epi infusion → local tissue necrosis (phentolamine 5–10 mg SC for infiltration)

— Fluid overload pulmonary edema in CHF patients

— Mortality 0.7–2% of cases; most deaths from delayed epinephrine or airway loss

— Risk factors for fatality: asthma, beta-blocker use, upright positioning, food/drug-induced (vs sting)

CCS pearl: After stabilization, observe inpatient with q15min vitals × 1 hour, then q30min × 2 hours, then q1h. Reactivate full anaphylaxis protocol immediately if symptoms recur — biphasic reactions require a second full dose of IM epinephrine, not just antihistamines.

Board pearl: A patient stabilized after anaphylaxis who suddenly develops chest pain and ST elevation has Kounis syndrome — treat ACS and the allergic reaction; nitrates and antiplatelets are usually safe.

Biphasic anaphylaxis:

Protracted anaphylaxis:

Cardiac complications:

Respiratory complications:

Neurologic:

Iatrogenic:

Death:

When to Escalate Care — Disposition and Admission Criteria

— Required >2 doses of epinephrine

— Refractory hypotension requiring vasopressor infusion

— Intubation or airway intervention

— Cardiac involvement (Kounis, arrhythmia, ischemia)

— Protracted symptoms >4 hours

— Pregnancy with viable fetus and significant maternal involvement

— History of asthma or severe atopy

— Delayed presentation or delayed epi administration

— Reaction to oral/injected medication with prolonged absorption (slow-release, IM depot)

— Patient lives alone or far from emergency services

— Persistent mild symptoms after initial treatment

— Single-dose epi response, complete resolution, no airway/CV involvement

— Reliable patient, lives close to ED, has support

— Auto-injector prescribed and patient demonstrates use

— Per 2020 guidelines: observation ≥1 hr after resolution for mild reactions, ≥4–6 hr for moderate, ≥12–24 hr for severe

— Allergy/Immunology — outpatient follow-up 4–6 weeks

— Anesthesia/ENT stat if airway compromise

— Cardiology if Kounis suspected or ECG changes

— OB stat if pregnant

— Pharmacy for medication reconciliation and EHR allergy update

— 0–15 min: Epi, fluids, monitors, stop drug

— 15–60 min: Reassess, redose epi PRN, adjuncts

— 1–4 hr: Observation, taper interventions

— 4–24 hr: Disposition decision, education, discharge planning

CCS pearl: Before discharging from the CCS, your final orders must include: (1) epinephrine auto-injector × 2 with refills, (2) Allergy/Immunology referral, (3) medical alert bracelet recommendation, (4) anaphylaxis action plan, (5) avoid the trigger drug + cross-reactive agents, (6) follow-up with PCP in 1 week.

Step 3 management: Discharging without an epi auto-injector is a guaranteed scoring failure.

ICU admission indications:

Floor/observation admission indications:

ED observation (4–6 hours) and discharge:

Consults to order on CCS:

Time-anchored CCS workflow:

Key Differentials — Other Hypersensitivity and Mast Cell Disorders

— Cutaneous symptoms only, no respiratory/CV/GI

— Treat with H1 antihistamine; no epi needed

— C1-esterase inhibitor deficiency (type I) or dysfunction (type II)

— Recurrent angioedema without urticaria, often abdominal pain

— Bradykinin-mediated, not histamine — does NOT respond to epi, antihistamines, or steroids

— Treatment: C1-INH concentrate, ecallantide, icatibant, or FFP if nothing else

— Triggered by ACE inhibitors, trauma, stress; family history common

— Bradykinin-mediated; can occur years after starting drug

— Tongue/lip/face edema without urticaria

— Stop ACE inhibitor permanently, switch to ARB (small cross-reactivity ~10%)

— Refractory cases: icatibant, FFP

— Recurrent flushing, hypotension, GI symptoms with elevated baseline tryptase (>20 ng/mL)

— Triggers: opioids, NSAIDs, alcohol, heat

— Workup: bone marrow biopsy, KIT D816V mutation

— Flushing, headache, diarrhea after eating spoiled tuna/mackerel

— Histamine in fish, NOT immune-mediated; responds to antihistamines

— Bradycardia + hypotension, but pale (not flushed), no urticaria, responds to supine positioning alone

— Rate-related histamine release, NOT IgE

— Slow infusion rate, pretreat with diphenhydramine; vancomycin not contraindicated

Key distinction: Anaphylaxis = histamine-mediated, treat with epinephrine. HAE and ACEi angioedema = bradykinin-mediated, do not respond to epi. Tongue swelling on an ACEi patient without urticaria → suspect bradykinin pathway.

Board pearl: Recurrent "anaphylaxis" without identifiable trigger + elevated baseline tryptase → systemic mastocytosis workup.

Acute urticaria/angioedema without anaphylaxis:

Hereditary angioedema (HAE):

ACE inhibitor-induced angioedema:

Mastocytosis / mast cell activation syndrome:

Scombroid (histamine fish poisoning):

Vasovagal syncope:

Red man syndrome (vancomycin):

Key Differentials — Non-Allergic Mimics

— Fever, leukocytosis, infectious source; hypotension and shock overlap with anaphylaxis

— No skin findings of urticaria; treatment is antibiotics + fluids + norepi

— Chest pain, ECG changes, elevated troponin

— Cool clammy skin, but no urticaria/wheeze/GI symptoms

— Beware Kounis syndrome — combination of anaphylaxis + MI

— Sudden dyspnea, hypoxia, tachycardia, hypotension

— No urticaria; often pleuritic chest pain, unilateral leg swelling

— CT angiography, anticoagulation

— Unilateral absent breath sounds, tracheal deviation

— Post-procedural (central line, thoracentesis); needle decompression

— Sudden stridor/wheeze, especially pediatric

— Unilateral findings, no skin/CV involvement

— Wheeze, dyspnea, but no urticaria/hypotension/GI

— Often known asthmatic with URI trigger

— Bronchodilators + steroids; no role for epi unless severe/refractory

— Inspiratory stridor mimicking laryngeal edema

— Younger women, anxiety, no urticaria

— Reassurance, speech therapy

— Dyspnea, tachycardia, paresthesias, normal vitals otherwise

— No skin/CV/airway findings

— Flushing, diarrhea, wheezing — but chronic and episodic, with elevated 5-HIAA

— Episodic HTN, headaches, palpitations, sweating; no urticaria

— Plasma/urine metanephrines

— Bradycardia + hypotension immediately after needle stick; pale, diaphoretic, no urticaria; resolves with supine position

Key distinction: The presence of urticaria, angioedema, or wheeze immediately after drug administration virtually clinches anaphylaxis. Isolated hypotension after drug — consider vasovagal vs anaphylaxis vs sepsis; anaphylaxis is the diagnosis if known allergen exposure.

Board pearl: A patient who passes out after IM injection with bradycardia and pale skin and recovers with supine position alone = vasovagal, not anaphylaxis. Do not give epi.

Septic shock:

Cardiogenic shock / acute MI:

Pulmonary embolism:

Tension pneumothorax:

Foreign body aspiration:

Asthma exacerbation:

Vocal cord dysfunction (paradoxical vocal fold motion):

Panic attack / hyperventilation:

Carcinoid syndrome:

Pheochromocytoma:

Vasovagal reaction post-injection:

Secondary Prevention and Discharge Medications

— Epinephrine auto-injector × 2 (EpiPen, Auvi-Q, or generic) — prescribe two pens because ~20% need second dose before EMS arrival. Refill annually.

— Oral H1 antihistamine (cetirizine 10 mg daily PRN) for breakthrough urticaria

— Oral corticosteroid (prednisone 40 mg × 3 days) optional — controversial benefit for biphasic prevention

— Albuterol MDI if bronchospasm component

— EHR allergy field updated with specific drug name, reaction (anaphylaxis), date

— Medical alert bracelet/necklace

— Written anaphylaxis action plan (AAP) provided

— Specific drug AND cross-reactive agents

— Penicillin allergy: avoid all β-lactams pending testing; if true allergy confirmed, cephalosporin cross-reactivity 1–2% (mostly 1st gen); carbapenems <1%; aztreonam safe

— NSAID allergy: avoid all NSAIDs; acetaminophen is safe; consider COX-2 selective inhibitors after allergy testing

— Contrast allergy: premedicate before future contrast: prednisone 50 mg PO at 13, 7, and 1 hr pre-procedure + diphenhydramine 50 mg 1 hr pre-procedure (Greenberger protocol)

— Drug desensitization (graded re-introduction under monitored setting) — for chemotherapy, penicillin in pregnancy with syphilis, aspirin in cardiac patients

— Performed by allergy/immunology in monitored setting

— Anaphylaxis to a vaccine component (e.g., PEG in mRNA vaccines) does not contraindicate future vaccines without that component

— Most patients with prior anaphylaxis can still receive most vaccines safely with observation

Step 3 management: A patient with penicillin anaphylaxis now diagnosed with syphilis in pregnancy must receive penicillin — desensitize her, do NOT substitute doxycycline (teratogenic) or erythromycin (poor placental transfer).

Board pearl: "Sulfa allergy" refers to sulfonamide antibiotics — patients can safely receive non-antibiotic sulfonamides (furosemide, celecoxib, sulfasalazine) — cross-reactivity is minimal.

Discharge medication list (the "anaphylaxis kit"):

Documentation and labeling:

Avoidance counseling:

For drug-allergic patients needing the trigger drug:

Vaccination considerations:

Follow-Up, Monitoring, and Counseling

— PCP visit within 1 week — medication reconciliation, review of action plan, EpiPen technique demonstration

— Allergy/Immunology consult within 4–6 weeks — formal trigger identification with skin testing, specific IgE, or oral challenge

— Cardiology follow-up in 2–4 weeks if Kounis syndrome or ECG changes occurred

— Repeat baseline tryptase at 24 hours and again at 4–6 weeks if elevated at acute event — persistent elevation > 11.4 ng/mL warrants mastocytosis workup

— Demonstrate EpiPen technique on training device — "blue to the sky, orange to the thigh" for EpiPen; through clothing OK

— Recognize early symptoms: itching, throat tightness, voice change, lightheadedness

— Use epi immediately at first sign — don't wait — and call 911 even if symptoms resolve

— Carry two auto-injectors at all times

— Check expiration dates; replace annually

— Avoid trigger and cross-reactive agents — printed list provided

— Avoid beta-blockers and ACE inhibitors if possible (use ARB, CCB, diuretic alternatives)

— Inform all providers, dentists, pharmacists of drug allergy

— Travel: carry doctor's letter for auto-injectors through airport security

— School/workplace: ensure auto-injector accessibility; AAP filed

— Annual review of action plan and auto-injector

— If recurrent unexplained anaphylaxis: consider idiopathic anaphylaxis, mastocytosis, or alpha-gal syndrome workup

— Consider omalizumab (anti-IgE) for idiopathic or refractory recurrent anaphylaxis

— Documented allergy with reaction type in EHR

— Auto-injector prescription filled

— Allergy referral completed

Step 3 management: At the 1-week PCP visit, the single most important task is to watch the patient self-administer a training auto-injector — verbal teaching alone has poor retention.

Board pearl: Always ask older patients to show you the EpiPen they carry — many carry expired devices or have forgotten how to use them.

Post-discharge cadence:

Patient education checklist (CCS-style orders):

Lifestyle and risk reduction:

Long-term outpatient monitoring:

Quality measures:

Ethical, Legal, and Patient Safety Considerations

— High-risk drugs (chemotherapy, biologics, contrast, allergen immunotherapy) require discussion of anaphylaxis risk and benefits before administration

— Document the conversation; obtain written consent where institutional policy requires

— Mislabeled allergies lead to broader-spectrum antibiotic use, increased C. difficile, more resistant organisms, higher costs, worse surgical outcomes

— Step 3 ambulatory care emphasizes delabeling: review every "allergy" at each visit; refer for testing if appropriate

— Reactions in childhood (rash with amoxicillin) often resolve and rarely represent true IgE allergy

— At every handoff (ED → floor, floor → discharge, discharge → PCP), explicitly communicate the allergy and trigger

— Update all systems: hospital EHR, pharmacy, primary care record

— Pharmacy should flag the trigger drug for future encounters

— If anaphylaxis occurred from a drug the patient was known to be allergic to (system failure), this is a sentinel event — report through institutional patient safety system, root cause analysis required

— Disclose the error to the patient transparently per ethical and JCAHO standards

— Cost barrier (>$600/2-pack brand; generic ~$150) — ensure prescription is filled; provide manufacturer coupons or generic substitution

— Underinsured patients: state programs, school stock supplies (most US states have stock epi laws)

— Federal School Access to Emergency Epinephrine Act (2013) encourages stock epinephrine in schools

— Good Samaritan laws protect bystander administration in all 50 states

— Anaphylaxis impairs capacity (hypoxia, hypoperfusion) — treat under implied consent if patient unable to refuse coherently

— Jehovah's Witnesses accept all anaphylaxis treatments (no blood products needed); never withhold treatment over misperception

Step 3 management: When a patient receives a drug they were documented as allergic to, the correct action is (1) immediate treatment, (2) transparent disclosure to patient/family, (3) sentinel event report, (4) root cause analysis — never conceal.

Informed consent for medications with anaphylaxis risk:

The "penicillin allergy" labeling problem:

Transition-of-care safety:

Mandatory error reporting:

Epinephrine auto-injector access:

Schools and public spaces:

Refusal of treatment:

Religious considerations:

High-Yield Associations and Rapid-Fire Clinical Facts

Board pearl: A child with idiopathic anaphylaxis who fails antihistamines and gets recurrent attacks → next step omalizumab.

Key distinction: Aspirin-exacerbated respiratory disease (Samter triad: asthma, nasal polyps, NSAID sensitivity) is pseudoallergic via leukotriene overproduction — desensitization possible.

Drug triggers by frequency: β-lactams > NSAIDs > contrast > NMBAs > monoclonal antibodies > chemotherapy > opioids

Penicillin cross-reactivity: 1st-gen cephalosporins ~1–2%, 2nd-gen <1%, 3rd/4th-gen negligible, carbapenems <1%, aztreonam 0% (except ceftazidime)

Carboplatin/oxaliplatin: anaphylaxis typically after 6+ exposures — desensitization protocols allow continued treatment

Vancomycin: red man syndrome ≠ anaphylaxis; slow infusion to >60 min, pretreat diphenhydramine

Contrast media: nonionic, iso-osmolar agents (iodixanol) lowest risk; gadolinium <1/10,000 risk; premedication for prior reactors

Latex allergy: banana, kiwi, avocado, chestnut cross-react (latex-fruit syndrome)

Alpha-gal syndrome: delayed anaphylaxis (3–6 hr) after red meat in patients with Lone Star tick bites; specific IgE to galactose-α-1,3-galactose

Idiopathic anaphylaxis: 20% of cases have no identified trigger; omalizumab effective

Exercise-induced anaphylaxis: often food-dependent (wheat, shellfish); avoid food 4–6 hr before exercise

Asthma is the strongest risk factor for fatal anaphylaxis — always optimize asthma control

Tryptase peaks 15 min–3 hr post-event; useful in hymenoptera and drug, often normal in food

Biphasic reactions: up to 20%, peak 4–8 hr post-resolution

Bezold-Jarisch reflex: paradoxical bradycardia in severe anaphylaxis due to empty ventricle

Kounis syndrome: anaphylaxis + ACS; treat both

MRGPRX2 receptor: non-IgE pseudo-allergy from fluoroquinolones, opioids, vancomycin, NMBAs

HAE first-line in acute attack: C1-INH concentrate, icatibant (bradykinin B2 antagonist), ecallantide (kallikrein inhibitor)

Auto-injector dose: 0.15 mg <25 kg; 0.3 mg ≥25 kg; available 3-pack only in US currently for some brands

Maximum IM epi: 0.5 mg adult, 0.3 mg pediatric per dose

Position: supine + legs elevated; never sitting upright (PEA arrest risk)

Onset times: IV seconds, IM minutes, oral 30–120 min

Mortality risk factors: asthma, delayed epi, upright position, beta-blocker

Board Question Stem Patterns

— Answer: IM epinephrine 0.3–0.5 mg into anterolateral thigh. NOT diphenhydramine, NOT methylprednisolone, NOT IV epi bolus.

— Answer: IV glucagon 1–5 mg

— Answer: IM epinephrine + left lateral decubitus + fetal monitoring

— Answer: Penicillin desensitization in monitored setting. Not doxycycline (teratogenic). Not erythromycin (poor fetal transfer).

— Answer: ACE inhibitor-induced angioedema — stop ACEi, switch to ARB (or CCB if angioedema severe). Bradykinin-mediated; does NOT respond to epi.

— Answer: Systemic mastocytosis — bone marrow biopsy, KIT D816V mutation

— Answer: Proceed with prednisone 50 mg + diphenhydramine 50 mg premedication + iso-osmolar agent. Do not delay life-threatening imaging.

— Answer: Diphenhydramine + observation. Epi not indicated for isolated urticaria.

— Answer: Alpha-gal syndrome — serum IgE to galactose-α-1,3-galactose

— Answer: Observe ≥4–6 hours, discharge with 2 epi auto-injectors, allergy referral, action plan

— Answer: Treat anaphylaxis, then disclose error transparently + file sentinel event report + root cause analysis

Board pearl: Whenever a stem mentions a drug, timing within minutes, and multisystem symptoms (skin + airway/CV/GI) → IM epinephrine is always the first answer.

Stem 1: "Within 5 minutes of receiving IV ceftriaxone, patient develops urticaria, wheezing, BP 80/40."

Stem 2: "Patient on metoprolol with anaphylaxis fails to respond to 2 doses of IM epi."

Stem 3: "Pregnant patient at 32 weeks with anaphylaxis."

Stem 4: "Patient with prior anaphylaxis to penicillin diagnosed with syphilis during pregnancy."

Stem 5: "Patient develops tongue swelling without urticaria 3 months after starting lisinopril."

Stem 6: "Recurrent flushing, hypotension after various unrelated triggers; baseline tryptase 35 ng/mL."

Stem 7: "Patient with prior mild contrast reaction needs CT with contrast for suspected dissection."

Stem 8: "Child with peanut allergy gets a hive after touching peanut residue but no other symptoms."

Stem 9: "Patient develops anaphylaxis 4 hr after eating red meat; history of tick bite last summer."

Stem 10: "ED course resolves with one epi dose; patient asymptomatic at 2 hr. Disposition?"

Stem 11: "Patient receives drug they were documented allergic to; develops anaphylaxis."

One-Line Recap

Anaphylaxis is a clinical diagnosis requiring immediate IM epinephrine 0.3–0.5 mg into the anterolateral thigh — given before labs, before antihistamines, before steroids, before consults — followed by fluids, supine positioning, adjunctive therapy, observation for biphasic reactions, and a discharge bundle of two auto-injectors, allergy referral, action plan, and trigger avoidance.

Final board pearl: Epinephrine has no absolute contraindication in anaphylaxis. The most common cause of anaphylaxis death is delayed or withheld epinephrine, not epinephrine toxicity. When in doubt, give it.

Final CCS pearl: Advance the CCS clock in 5-minute increments during the acute reaction, reassess after each intervention, and remember that disposition planning and a complete discharge order set are graded just as heavily as the resuscitation itself.

The 6 first-move orders on CCS: stop the drug → IM epi 0.3 mg thigh → supine + legs elevated (left lateral if pregnant) → O2 + monitors → 2 large-bore IVs + NS 1–2 L bolus → call for help

The 4 discharge essentials: 2 epinephrine auto-injectors, written anaphylaxis action plan, Allergy/Immunology referral within 4–6 weeks, medical alert bracelet + EHR update with specific trigger

The 3 things that will fail you on the boards: giving diphenhydramine or steroids first instead of epi, withholding epi from elderly/CAD/pregnant patients, discharging without an auto-injector and follow-up plan

The 3 mimics not to miss: ACE inhibitor angioedema (bradykinin, no urticaria, give icatibant/C1-INH/FFP, switch to ARB), hereditary angioedema (recurrent abdominal pain + facial swelling, low C4, C1-INH replacement), Kounis syndrome (anaphylaxis + ACS, treat both simultaneously)