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Anaphylaxis Management

Algorithm

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1. Immediate Recognition

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2. First-Line: Epinephrine (No Absolute Contraindications)

• Repeat every 5–10 minutes — up to 30% require more than one dose
• IM thigh provides peak plasma concentration in ~8 min vs. ~34 min for subcutaneous; SC route is no longer recommended
• For refractory/protracted cases: IV epinephrine infusion titrated to BP
• Beta-blocker patients: glucagon 1–5 mg IV bolus over 5 min, then infusion at 5–15 µg/min (reverses refractory bronchospasm and hypotension)

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3. Simultaneous Supportive Measures

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4. Airway Management

• Endotracheal intubation may be needed
• If laryngeal edema is not rapidly responsive to epinephrine → cricothyroidotomy or tracheotomy
• Inhaled β-agonists (e.g., salbutamol) for persistent bronchospasm

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5. Second- and Third-Line Adjuncts

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6. Biphasic Anaphylaxis

• Protracted initial reaction
• Hypotension or airway involvement
• Unknown trigger
• Receiving IV epinephrine or >1 dose of IM epinephrine
• Poor outpatient social support

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7. Observation and Disposition

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8. Discharge Instructions

1. Prescription for self-injectable epinephrine (EpiPen) × 2 devices — with demonstrated training
2. Written emergency action plan
3. Allergen avoidance counseling
4. Referral to allergist/immunologist for formal evaluation, trigger identification (skin testing, specific IgE), and consideration of immunotherapy

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Diagnostic Notes

• Anaphylaxis remains a clinical diagnosis
• Serum tryptase: peaks at ~1 hour, detectable up to 4 hours — most useful in hymenoptera-induced cases (may be normal in food-induced)
• Serum histamine: peaks within 1 hour
• Labs are not required before treatment

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Anaphylaxis — Comprehensive Overview

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Definition

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Epidemiology

• Lifetime incidence in adults: 2–8%; higher in children (food allergy is more prevalent)
• ~1,500–2,000 deaths/year in the United States
• Fatal anaphylaxis is rare (<1% of cases), but medication-induced fatalities are rising
• ~50% of reactions occur at home; 15% at a medical facility
• Only ~30% of patients receive epinephrine in the prehospital setting; 50–70% receive it in the ED

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Pathophysiology

Classical (IgE-Mediated) Pathway

1. Sensitization: Initial allergen exposure → antigen-presenting cells activate Th2 lymphocytes → IL-4/IL-13 drive B-cell class switching → allergen-specific IgE produced
2. Sensitized state: IgE binds high-affinity receptors (FcεRI) on mast cells and basophils — patient is now sensitized
3. Re-exposure: Multivalent allergen cross-links IgE–FcεRI complexes → receptor aggregation → mast cell degranulation
4. Mediator release:
   • Pre-formed (immediate): histamine, tryptase, chymase, heparin
   • Newly synthesized (minutes): prostaglandin D₂, leukotriene C₄, platelet-activating factor (PAF)
   • Late-phase (hours): cytokines/chemokines (IL-4, IL-5, IL-13, TNF-α)

Non-IgE-Mediated (Anaphylactoid) Pathway

• NSAIDs/aspirin: arachidonic acid pathway disruption → excess leukotrienes
• Radiocontrast media, opioids, vancomycin: direct mast cell degranulation (complement activation or MRGPRX2 receptor)
• Complement activation (C3a, C5a → anaphylatoxins) — can trigger identical clinical picture

Net Effect of Mediators

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Triggers (Causes)

IgE-Mediated

Non-IgE-Mediated

Note on penicillin: <10% of those with a reported penicillin allergy are truly allergic on skin testing. Cross-reactivity with cephalosporins exists but is low (1–8%).

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Risk Factors for Severity and Mortality

• Extremes of age (infants: under-recognition; elderly: reduced physiologic reserve)
• Cardiovascular disease, asthma, mastocytosis
• Beta-blocker or ACE inhibitor use (blunts epinephrine response; ACE inhibitors impair bradykinin degradation)
• Hereditary α-tryptasemia (increased mast cell burden; present in ~5% of population)
• Upright posture at symptom onset (reduces venous return — "empty ventricle" syndrome → cardiac arrest)
• Delayed epinephrine administration
• Previous anaphylactic episode

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Clinical Features

Absence of skin findings does not exclude anaphylaxis — and these cases (no urticaria/flushing) are associated with higher fatality.

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Diagnostic Criteria (NIAID/FAAN)

1. Acute onset of skin/mucosal involvement PLUS respiratory compromise or hypotension
2. Two or more of the following after allergen exposure: skin/mucosal involvement, respiratory compromise, hypotension, persistent GI symptoms
3. Hypotension alone after exposure to a known allergen for that patient

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Diagnosis

• Serum tryptase: peaks ~1 hour after onset, detectable up to 4 hours; best yield in hymenoptera-induced; may be normal in food-induced anaphylaxis
• Serum histamine: peaks within 1 hour (narrow window)
• Specific IgE / skin testing: performed after the acute episode, not in the acute setting

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Differential Diagnosis

• Vasovagal syncope (bradycardia; no urticaria/angioedema)
• Flushing syndromes: carcinoid, red-man syndrome, pheochromocytoma
• Non-histaminergic angioedema: hereditary angioedema (HAE), ACE inhibitor-induced angioedema
• Airway obstruction: epiglottitis, foreign body, croup
• Other shock states: cardiogenic, septic, hemorrhagic
• Panic attack, vocal cord dysfunction

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Management

Algorithm

Step 1 — Immediate Actions (Simultaneous)

• Remove/stop the trigger (stop infusion, remove stinger)
• Call for help; activate emergency response
• Position: supine + legs elevated; if vomiting/airway compromise → comfortable position; pregnancy → left lateral decubitus
• IV access, continuous cardiac monitoring + pulse oximetry
• High-flow 100% oxygen

Step 2 — Epinephrine (First-Line, No Absolute Contraindications)

• Repeat every 5–10 min (up to 30% need >1 dose)
• IM lateral thigh: peak plasma in ~8 min vs. ~34 min subcutaneously — SC route no longer recommended
• There are no absolute contraindications to epinephrine in anaphylaxis

Step 3 — Fluids

• Aggressive IV crystalloid bolus for hypotension/distributive shock

Step 4 — Refractory Cases

Step 5 — Adjuncts (Second/Third Line — Do NOT Delay Epinephrine)

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Biphasic Reaction

• A second anaphylactic wave without re-exposure, occurring 1–72 hours after resolution (most within 8 hours)
• Incidence ~5%
• More likely with: protracted initial reaction, hypotension, airway involvement, unknown trigger, delayed epinephrine, >1 epi dose required

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Disposition

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Discharge Planning

1. Self-injectable epinephrine (EpiPen) × 2 devices + demonstrated training on use
2. Written emergency action plan
3. Allergen avoidance education
4. Referral to allergist/immunologist for:
   • Skin testing / specific IgE to identify trigger
   • Consideration of allergen immunotherapy (especially venom-induced)

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Special Situations

Hereditary Angioedema (non-histaminergic — does NOT respond to epi/antihistamines)

ACE Inhibitor–Induced Angioedema

• Bradykinin-mediated (impaired degradation)
• Treatment mainly supportive; consider HAE agents if airway threatened

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Anaphylaxis — Comprehensive Overview

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Definition

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Epidemiology

• Lifetime incidence in adults: 2–8%
• ~1,500–2,000 deaths/year in the United States; foods and insect stings each account for ~100 deaths/year
• Fatal anaphylaxis is rare (<1% of cases)
• ~50% of reactions occur at home; 15% at a medical facility
• Only ~30% of patients receive epinephrine prehospital; 50–70% receive it in the ED

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Pathophysiology

Classical — IgE-Mediated

1. Sensitization: Allergen exposure → Th2 activation → B-cell class switching → allergen-specific IgE produced and bound to FcεRI on mast cells/basophils
2. Re-exposure: Multivalent allergen cross-links IgE–FcεRI → receptor aggregation → mast cell degranulation
3. Mediator release:

Non-IgE-Mediated (Anaphylactoid)

• NSAIDs/aspirin: COX-1 inhibition → arachidonic acid shunting → excess leukotrienes
• Radiocontrast media, opioids, vancomycin: direct MRGPRX2 receptor activation or complement (C3a/C5a)
• Exercise-induced: often requires co-trigger (food)

Net Mediator Effects

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Triggers

IgE-Mediated

Non-IgE-Mediated

Penicillin allergy is over-reported — <10% of patients with a reported history are truly allergic on skin testing.

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Risk Factors for Severity & Mortality

• Beta-blocker or ACE inhibitor use (epinephrine resistance; impaired bradykinin clearance)
• Asthma, mastocytosis, hereditary α-tryptasemia (~5% of population)
• Extremes of age; cardiovascular disease
• Upright posture at onset → reduced venous return → "empty ventricle" cardiac arrest
• Delayed epinephrine, previous anaphylactic episode
• Unknown trigger

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Clinical Features

Absence of skin findings does not exclude anaphylaxis — and cases without urticaria carry higher fatality.

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Diagnostic Criteria (NIAID/FAAN)

1. Acute onset of skin/mucosal involvement + respiratory compromise or hypotension
2. Two or more of: skin/mucosal involvement, respiratory compromise, hypotension, persistent GI symptoms — after allergen exposure
3. Hypotension alone after exposure to a known allergen for that patient

Labs

• Serum tryptase: peaks ~1 h, detectable up to 4 h; best for hymenoptera-induced; may be normal in food-induced
• Serum histamine: peaks within 1 h (narrow window)
• Labs are never required before starting treatment

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Differential Diagnosis

• Vasovagal syncope (bradycardia, no urticaria)
• Non-histaminergic angioedema: HAE, ACE inhibitor–induced
• Flushing syndromes: carcinoid, pheochromocytoma, red-man syndrome
• Airway obstruction: epiglottitis, foreign body
• Other shock states: cardiogenic, septic, hemorrhagic
• Panic attack, vocal cord dysfunction

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Management

Algorithm

Step 1 — Simultaneous Immediate Actions

• Remove/stop the trigger
• Supine + legs elevated (left lateral decubitus if pregnant)
• IV access, cardiac monitoring, pulse oximetry
• High-flow 100% O₂

Step 2 — Epinephrine (First-Line; No Absolute Contraindications)

• Repeat every 5–10 min — up to 30% need >1 dose
• IM lateral thigh: peak plasma ~8 min vs. ~34 min SC — SC route no longer recommended
• Antihistamines and corticosteroids must never precede or replace epinephrine

Step 3 — IV Fluids

• Aggressive crystalloid bolus for hypotension

Step 4 — Refractory Management

Step 5 — Adjuncts (Do NOT delay epinephrine for these)

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Biphasic Anaphylaxis

• Second reaction without re-exposure, occurring 1–72 hours after initial resolution (most within 8 h)
• Incidence ~5%
• Higher risk with: protracted initial episode, hypotension or airway involvement, unknown trigger, >1 epinephrine dose, delayed initial treatment

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Disposition

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Discharge Planning

1. Self-injectable epinephrine (EpiPen) ×2 + training
2. Written emergency action plan
3. Allergen avoidance counseling
4. Referral to allergist/immunologist (skin testing, specific IgE, possible immunotherapy)

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Special Topic: Non-Histaminergic Angioedema (HAE)

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Heat Stroke — Comprehensive Overview

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Definition

1. Core temperature >40°C (>104°F)
2. Central nervous system dysfunction (altered mental status, seizures, coma)
3. Multiorgan involvement

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Classification: Two Types

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Pathophysiology

• Heat generation overwhelms heat dissipation (radiation, conduction, convection, evaporation)
• Core temperature rises → direct cellular thermotoxicity to brain, liver, kidneys, endothelium
• Cerebellum is highly sensitive to heat (ataxia is an early sign)
• High temperature → endothelial injury → DIC cascade, increased vascular permeability, capillary leak
• Liver: centrilobular necrosis (enzyme peaks 24–72 h after insult; usually reversible)
• Rhabdomyolysis (especially EHS) → myoglobinuria → acute renal failure
• Neurologic injury is proportional to peak temperature × duration of exposure

Cardiovascular Effects

• Hyperdynamic circulation: tachycardia (up to 180 bpm), low peripheral vascular resistance, high cardiac output
• Skin vasodilation to dissipate heat → elevated CVP with right-sided cardiac dilation → high-output heart failure
• Hypotension in severe cases

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Risk Factors & Precipitating Medications

• Advanced age, extremes of age
• Cardiovascular disease, diabetes, obesity
• Prior heat illness, dehydration, skin disorders (reduced sweating)
• Alcohol/drug use
• Acclimatization failure

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Clinical Features

• Core temperature >40°C (>104°F)
• CNS dysfunction — can range from confusion, irritability, bizarre behaviour, hallucinations, ataxia → combativeness, seizures, decerebrate posturing, coma

• Tachycardia (up to 180 bpm), hypotension
• Hot skin — absence of sweating is not a required criterion (sweating present in >50% of cases)
• Tachypnoea, hyperventilation → pCO₂ often <20 mmHg
• Signs of end-organ damage: jaundice, oliguria, bleeding

Note: Ataxia is an early neurologic sign due to cerebellar heat sensitivity.

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Diagnosis

Workup (directed at end-organ damage & excluding differentials)

• CBC — thrombocytopenia (DIC)
• CMP — electrolytes (hypo/hypernatremia, hypokalemia, hyperkalemia in ARF), glucose, LFTs (centrilobular necrosis), creatinine
• ABG — respiratory alkalosis; lactic acidosis in EHS
• Coagulation panel (PT/PTT/fibrinogen) — DIC
• CPK + myoglobin — rhabdomyolysis
• Urinalysis — myoglobinuria, proteinuria
• ECG — arrhythmia
• CT head / LP — to exclude meningitis, CVA, intracranial haemorrhage if diagnosis unclear

Differential Diagnosis

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Management

Prehospital

1. Remove from hot environment immediately
2. Remove clothing
3. Check point-of-care glucose
4. Begin cooling (spray water + fan, or wet towels/ice packs)
5. IV normal saline bolus 1–2 L if hypotensive
6. Transport urgently

ED Resuscitation

• Standard ABCs — airway management, oxygen
• IV access × 2, continuous monitoring
• Electronic rectal thermometer / oesophageal thermometer / urinary catheter thermistor for accurate core temperature monitoring
• IV fluids: rate titrated to maintain adequate urine output; use invasive monitoring in elderly/cardiac patients
• Check glucose — treat hypoglycaemia

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Cooling Techniques

• First-line: short-acting benzodiazepines
• Second-line: phenothiazines (use cautiously — lower seizure threshold, anticholinergic effects impair sweating, cause hypotension)

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Managing Complications

Hypotension

• First: IV fluid bolus 20 mL/kg
• If CVP reaches 12–14 mmHg and hypotension persists → dopamine or dobutamine
• Avoid norepinephrine (α-adrenergic vasoconstriction redirects blood away from skin → impairs cooling)

Seizures

• Benzodiazepines (first-line)
• Cooling itself reduces seizure threshold
• Barbiturates (phenobarbital) for refractory seizures

Rhabdomyolysis / Renal Failure

• Aggressive IV fluid hydration
• Target urine output >1 mL/kg/hr (>200–300 mL/hr)
• Alkalinise urine with sodium bicarbonate (controversial) to prevent myoglobin precipitation
• Dialysis for severe ARF

DIC / Coagulopathy

• FFP, cryoprecipitate, platelets as indicated
• Treat underlying heat stroke (cooling is primary therapy)

Complications Summary Table

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Prognosis

• Hypotension on arrival
• Altered coagulation
• Lactic acidosis
• Need for endotracheal intubation on arrival
• Advanced age
• Delayed cooling

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Prevention

• Acclimatisation (10–14 days of gradual heat exposure)
• Adequate hydration before and during exertion
• Avoid exercise during peak heat hours
• Light-coloured, loose-fitting clothing
• Awareness of high-risk medications (see table above)
• Cooling stations and buddy systems in high-risk settings (military, endurance sports, elderly in heatwaves)

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