Anaphylactic Shock: Complete Management Guide (WHO/International Guidelines)

CLINICAL SCENARIO

PART 1: PATHOPHYSIOLOGY (Brief)

Antibiotic (IV) → IgE on Mast Cells/Basophils
       ↓
   Degranulation
       ↓
  Histamine, Tryptase, Leukotrienes, Prostaglandins, PAF
       ↓
┌─────────────────────────────────────────────┐
│  Vasodilation → Hypotension                 │
│  Increased vascular permeability → Edema   │
│  Bronchospasm → Respiratory distress        │
│  Urticaria / Angioedema (skin/airway)       │
└─────────────────────────────────────────────┘

PART 2: RECOGNITION - HOW TO ASSESS (ABCDE)

Signs & Symptoms by System

Diagnostic Criteria (NIAID/FAAN - WHO endorsed)

1. Acute onset of skin/mucosal symptoms + at least one of: respiratory compromise OR hypotension/cardiovascular collapse
2. Two or more of the following occurring rapidly after allergen exposure: skin/mucosal involvement + respiratory compromise + hypotension + persistent GI symptoms
3. Hypotension alone after exposure to a known allergen

PART 3: SEVERITY GRADING - Escalation Scale (Ring & Messmer / WAO)

┌──────────────────────────────────────────────────────────────────┐
│              ANAPHYLAXIS SEVERITY GRADING                        │
├────────┬─────────────────────────────────────┬──────────────────┤
│ GRADE  │ CLINICAL FEATURES                   │ TREATMENT        │
├────────┼─────────────────────────────────────┼──────────────────┤
│  I     │ Skin only: urticaria, flush,        │ Antihistamine    │
│        │ angioedema — NO systemic symptoms   │ ± Steroids       │
├────────┼─────────────────────────────────────┼──────────────────┤
│  II    │ Mild-moderate multi-organ:          │ EPINEPHRINE IM + │
│        │ Hypotension, tachycardia,           │ Antihistamine +  │
│        │ mild bronchospasm, GI symptoms      │ Steroids + O₂    │
├────────┼─────────────────────────────────────┼──────────────────┤
│  III   │ Life-threatening:                   │ EPINEPHRINE IM   │
│        │ Severe bronchospasm, severe         │ (repeat q5 min)  │
│        │ hypotension, loss of consciousness  │ + IV Fluids +    │
│        │                                     │ O₂ + Position    │
├────────┼─────────────────────────────────────┼──────────────────┤
│  IV    │ Cardiac/Respiratory ARREST          │ CPR + IV/IO      │
│        │                                     │ Epinephrine      │
└────────┴─────────────────────────────────────┴──────────────────┘

This patient (IV antibiotic → severe anaphylaxis) = Grade III-IV emergency

PART 4: FIRST-LINE TREATMENT - WHO/International Consensus

★ ADRENALINE (EPINEPHRINE) = FIRST AND MOST IMPORTANT DRUG

"Intramuscular adrenaline is the first-line treatment for anaphylaxis - even if intravenous access is available."

PART 5: INJECTION SITE AND DOSAGE (ADR - Adrenaline)

Injection Site

         ANTEROLATERAL ASPECT OF THE THIGH
         (Middle third of outer thigh)
         
              ┌──────────────────┐
              │     OUTER THIGH  │
              │                  │
              │   ┌──────────┐   │
              │   │ INJECT   │   │
              │   │   HERE   │   │  ← Needle perpendicular to skin
              │   │ (middle  │   │     through clothing if needed
              │   │  third)  │   │
              │   └──────────┘   │
              │                  │
              └──────────────────┘
              
  Why thigh? Achieves HIGHER, FASTER peak plasma levels 
  than deltoid (arm) or subcutaneous routes.
  
  Needle: 21G (green) or 23G (blue)
  Must penetrate INTO muscle tissue

Dosage Table

• IM Adrenaline: 0.5 mg (0.5 mL of 1:1000) into anterolateral mid-thigh
• Auto-injector: EpiPen® 0.3 mg or Anapen® 0.5 mg
• Repeat in 5 minutes if no improvement

⚠️ CRITICAL: IV adrenaline with 1:1,000 solution (meant for IM) instead of 1:10,000 (for IV) is a fatal dosing error. Only trained staff should give IV adrenaline with cardiac monitoring.

PART 6: FULL MANAGEMENT ALGORITHM (WHO/RCUK Framework)

╔══════════════════════════════════════════════════════════════════╗
║           ANAPHYLAXIS MANAGEMENT ALGORITHM                       ║
╠══════════════════════════════════════════════════════════════════╣
║  STEP 1: RECOGNIZE & CALL FOR HELP                               ║
║  • Identify anaphylaxis: skin + breathing/BP/GI involvement      ║
║  • Call resuscitation team / code blue                           ║
╠══════════════════════════════════════════════════════════════════╣
║  STEP 2: REMOVE TRIGGER                                          ║
║  • STOP the IV antibiotic infusion IMMEDIATELY                   ║
║  • Leave IV access in place                                      ║
╠══════════════════════════════════════════════════════════════════╣
║  STEP 3: POSITION PATIENT                                        ║
║  • Conscious + breathing normally → SITTING (relieves breathing) ║
║  • Hypotensive → LAY FLAT + LEGS ELEVATED (Trendelenburg)        ║
║  • Vomiting → RECOVERY POSITION (left lateral)                   ║
║  • Pregnant → LEFT LATERAL TILT                                  ║
╠══════════════════════════════════════════════════════════════════╣
║  STEP 4: ★ ADRENALINE (EPINEPHRINE) - FIRST LINE ★              ║
║  • IM: 0.5 mg (0.5 mL of 1:1,000) into anterolateral thigh      ║
║  • Repeat every 5 min if A/B/C problems persist                  ║
╠══════════════════════════════════════════════════════════════════╣
║  STEP 5: OXYGEN                                                  ║
║  • High-flow O₂: 10-15 L/min via non-rebreather mask            ║
║  • Target SpO₂ > 94%                                             ║
╠══════════════════════════════════════════════════════════════════╣
║  STEP 6: IV FLUIDS                                               ║
║  • Normal saline 0.9%: 500 mL - 1000 mL rapid bolus             ║
║  • May need 3-5 liters total in severe cardiovascular shock      ║
╠══════════════════════════════════════════════════════════════════╣
║  STEP 7: SECOND-LINE DRUGS                                       ║
║  • H1 Antihistamine: Chlorphenamine 10 mg slow IV/IM             ║
║  • H2 Antihistamine: Ranitidine 50 mg IV (adjunct)               ║
║  • Corticosteroid: Hydrocortisone 200 mg IV (prevents biphasic)  ║
╠══════════════════════════════════════════════════════════════════╣
║  STEP 8: BRONCHOSPASM (if persistent)                            ║
║  • Salbutamol (albuterol) nebulizer 2.5-5 mg                     ║
║  • IV Aminophylline if refractory                                ║
╠══════════════════════════════════════════════════════════════════╣
║  STEP 9: MONITORING                                              ║
║  • Continuous ECG, SpO₂, BP, RR every 5 min                     ║
╚══════════════════════════════════════════════════════════════════╝

PART 7: ESCALATION FOR REFRACTORY ANAPHYLAXIS

REFRACTORY ANAPHYLAXIS ESCALATION:

[2x IM Adrenaline failed]
         ↓
Call CRITICAL CARE / ICU TEAM
         ↓
Switch to IV ADRENALINE INFUSION
• 1 mg in 50 mL NS → start at 0.5 mL/min (= 10 mcg/min)
• Titrate to response
• Requires continuous cardiac monitoring
         ↓
If still refractory:
• Vasopressors: Noradrenaline 0.1-1 mcg/kg/min IV
• Vasopressin 40 units IV (one dose) - useful if beta-blockers involved
• Glucagon 1-2 mg IV (if patient on beta-blockers - bypasses beta receptor block)
         ↓
If Cardiac Arrest occurs:
• CPR per ALS protocol
• Adrenaline 1 mg IV every 3-5 min
• Consider ECMO if available
         ↓
Prolonged resuscitation may be required (hours to days)

PART 8: SUMMARY - DRUG DOSES AT A GLANCE

PART 9: OBSERVATION & DISCHARGE

• Minimum 6-8 hours observation after anaphylaxis
• Biphasic reaction risk: Symptoms can recur 8-11 hours after initial episode (4-5% incidence)
• Severe cases require 24-hour observation in hospital
• On discharge:
  • Prescribe 2x EpiPen® auto-injectors for patient self-use
  • Refer to allergist for allergen identification and desensitization
  • Advise MedicAlert bracelet documenting antibiotic allergy
  • Oral prednisolone 40 mg for 3 days + oral antihistamine

KEY TAKEAWAY - MEMORY AID

A - Adrenaline FIRST (IM thigh 0.5 mg)
B - Breathing: O₂ + position
C - Circulation: IV fluids (NS)
D - Drugs: Antihistamines + Steroids
E - Escalate if not responding (IV adrenaline infusion, ICU)

Source citations: Tintinalli's Emergency Medicine 9th Ed., Table 14-4 | Resuscitation Council UK 2021 Anaphylaxis Guidelines | 2024 GA2LEN International Consensus Report | AAAAI 2023 Practice Parameter Update

Clinical Assessment: Refractory Seizures in a Known Epileptic - What to Do Next

Understanding Where This Patient Is

• Known epileptic x 6 years on Levetiracetam 500 mg BD + Midazolam nightly
• 2 seizure episodes in the past 24 hours
• You gave: IV Sodium Valproate 1g loading dose + IV Levetiracetam loading dose
• Seizures continued
• You gave: IV Midazolam 2 cc (approximately 2 mg, which is a relatively small dose)
• Seizures still occurring

IMMEDIATE NEXT STEPS (Right Now, Before Anything Else)

┌─────────────────────────────────────────────────────────────────┐
│  AIRWAY - BREATHING - CIRCULATION  →  This is a CODE situation  │
│                                                                 │
│  1. Call for Neurology + Anesthesia / ICU team NOW             │
│  2. Prepare for intubation if not already done                 │
│  3. Continuous SpO₂, ECG, BP monitoring                        │
│  4. Secure LARGE BORE IV access (x2 lines)                     │
│  5. Bedside glucose check STAT                                 │
└─────────────────────────────────────────────────────────────────┘

Your Midazolam dose was subtherapeutic

• Loading dose: 0.2 mg/kg IV (for a 60 kg patient = 12 mg IV bolus)
• The 2 mg you gave is far below the therapeutic threshold for SE

THE STATUS EPILEPTICUS MANAGEMENT LADDER

PHASE 1 (0-5 min) - You should have done this

• IV access, O₂, monitors, glucose check
• Patient protection from injury

PHASE 2 (5-20 min) - Established Status Epilepticus

You gave "2cc Midaz" - if this was 2mg IV (1mg/mL), the dose was inadequate. Midazolam at the correct SE dose is 10 mg IM or 5-10 mg IV, repeatable at 5 min intervals.

Note on your doses: Valproate 1g is a reasonable starting dose but the upper range is 20-40 mg/kg. For a 60 kg patient that is 1200-2400 mg. Check if the full dose was given slowly over the appropriate time.

PHASE 3 (>20-30 min) - REFRACTORY Status Epilepticus ← WHERE YOUR PATIENT IS NOW

PARALLEL WORKUP - WHY IS SHE STILL SEIZING?

Immediate Investigations to Order Now:

┌────────────────────────────────────────────────────────────────┐
│              MANDATORY WORKUP - DO THESE STAT                  │
├────────────────────────────────────────────────────────────────┤
│ 1. BLOOD GLUCOSE (point of care, immediate)                    │
│ 2. SERUM ELECTROLYTES: Na, K, Ca, Mg, Phosphate               │
│    - Hyponatremia, hypocalcemia, hypomagnesemia all cause      │
│      refractory seizures - CORRECT AGGRESSIVELY                │
│ 3. SERUM VALPROATE LEVEL + LEVETIRACETAM LEVEL                 │
│    - Was the patient compliant before? Sub-therapeutic?        │
│ 4. SERUM AMMONIA (if on valproate - risk of hyperammonemia)    │
│ 5. URINE DRUG SCREEN / TOXICOLOGY                              │
├────────────────────────────────────────────────────────────────┤
│              NEXT TIER (Once Stable / Intubated)               │
├────────────────────────────────────────────────────────────────┤
│ 6. MRI BRAIN (with FLAIR, DWI, contrast)                       │
│    - Look for: cortical lesion, mesial temporal sclerosis,     │
│      encephalitis (FLAIR hyperintensity), stroke, tumor        │
│    - CT brain if MRI not immediately available                 │
│ 7. CONTINUOUS EEG MONITORING                                   │
│    - Define seizure type and subclinical activity              │
│    - Guide titration of anesthetic infusion                    │
│    - Rule out non-convulsive SE when paralyzed/sedated         │
│ 8. LUMBAR PUNCTURE (after CT rules out raised ICP)             │
│    - CSF: cell count, protein, glucose, culture, PCR           │
│    - HSV encephalitis: start IV Acyclovir empirically          │
│    - Send: CSF NMDA-R antibodies, LGI1, CASPR2, GABA-B         │
│ 9. SERUM AUTOIMMUNE PANEL                                      │
│    - Anti-NMDA receptor, Anti-LGI1, Anti-CASPR2, Anti-AMPA    │
│    - Anti-GAD65, paraneoplastic panel (Anti-Hu, Anti-Yo)       │
│10. CT CHEST/ABDOMEN/PELVIS (if autoimmune suspected)           │
│    - Screen for occult malignancy (teratoma, thymoma, lymphoma)│
└────────────────────────────────────────────────────────────────┘

Why This Matters - The "New Refractory Seizures in Known Epileptic" Differential:

MOST COMMON CAUSES (Rule out systematically):

✦ MEDICATION NON-COMPLIANCE / SUBTHERAPEUTIC LEVELS
  → Check drug levels; ask about missed doses

✦ METABOLIC DERANGEMENT
  → Hyponatremia (Na < 130), hypoglycemia, hypocalcemia,
     hypomagnesemia, uremia

✦ SLEEP DEPRIVATION / INTERCURRENT ILLNESS / FEVER
  → Seizure threshold lowered; treat underlying cause

✦ DRUG INTERACTION / NEW MEDICATION
  → Any new drug started recently? Fluoroquinolones,
     antipsychotics, tramadol, isoniazid all lower seizure threshold

✦ CNS INFECTION
  → Bacterial meningitis, viral encephalitis (HSV),
     TB meningitis - DO lumbar puncture + empiric Acyclovir

✦ AUTOIMMUNE ENCEPHALITIS (KEY CONSIDERATION)
  → Anti-NMDA receptor encephalitis: most common autoimmune cause
     of refractory SE (accounts for ~40% of NORSE cases)
  → Can occur even in patients with KNOWN epilepsy
  → Symptoms: psychiatric changes, autonomic instability,
     movement disorders, refractory seizures
  → MRI: may show mesial temporal FLAIR hyperintensity
  → CSF: mild pleocytosis, elevated protein
  → EEG: "extreme delta brush" pattern is characteristic
  → TREATMENT: IV Methylprednisolone 1g/day x 5 days
                + IVIG 2 g/kg over 5 days
                + Plasmapheresis if no response

✦ STRUCTURAL LESION (NEW)
  → Stroke, bleed, tumor - needs urgent CT/MRI

✦ PNES (Psychogenic Non-Epileptic Seizures)
  → No EEG correlate, no post-ictal phase, no response to AEDs
  → Diagnosis of exclusion; video-EEG helpful

SPECIFIC FLAG: Start Empiric IV Acyclovir Now if Encephalitis Suspected

• IV Acyclovir 10 mg/kg q8h for suspected HSV encephalitis
• IV Ceftriaxone 2g q12h + IV Ampicillin 2g q4h if bacterial meningitis in differential

SUMMARY - YOUR IMMEDIATE ACTION PLAN

RIGHT NOW:
□ Call Neurology + ICU
□ Check bedside glucose STAT
□ Give adequate IV Lorazepam (4 mg IV) or repeat Midazolam properly
   (10 mg IM or 0.1-0.2 mg/kg IV)
□ Check electrolytes - correct hyponatremia/hypocalcemia/hypomagnesemia
□ Prepare for intubation

WITHIN 30 MINUTES:
□ If still seizing after 2 adequate BZD doses + valproate + levetiracetam
   → Intubate + start IV Midazolam infusion (0.2 mg/kg bolus → 0.05-2 mg/kg/h)
   OR IV Propofol 1 mg/kg bolus → infusion
   OR IV Phenobarbital 20 mg/kg

□ Order: CONTINUOUS EEG, MRI brain, LP (after CT), Autoimmune panel
□ Check: Serum valproate level, levetiracetam level, ammonia
□ Transfer: Neuro-ICU

ALSO CONSIDER ADDING (2nd antiepileptic you haven't used):
□ IV Lacosamide 200-400 mg IV (well tolerated, minimal drug interactions)
□ IV Phenobarbital 20 mg/kg (very effective, causes sedation)

IF AUTOIMMUNE ENCEPHALITIS SUSPECTED:
□ Empiric IV Methylprednisolone 1g/day + IVIG 2g/kg
   (Don't wait for antibody results - treatment delay worsens outcome)

Key Point on the Valproate + Levetiracetam Interaction

Can You Give Injection Diclofenac for Headache in This Patient?

Direct Answer: NO - Avoid Diclofenac in this patient

Reasons to AVOID Diclofenac Here

1. Drug Interaction with Sodium Valproate (Most Critical)

Diclofenac (NSAID)
        ↓
Highly protein-bound (>99% albumin binding)
        ↓
Displaces Valproate from protein binding sites
        ↓
FREE Valproate level rises → Valproate TOXICITY
(drowsiness, confusion, tremor, encephalopathy)

AND simultaneously:

NSAIDs inhibit CYP2C9
        ↓
Reduced valproate metabolism
        ↓
Further rise in valproate blood levels

2. NSAIDs Can Lower Seizure Threshold

3. Risk of Gastrointestinal Bleeding

4. Renal Risk in a Hemodynamically Compromised Patient

5. This is Post-Ictal Headache - Not a Primary Headache

What You SHOULD Give Instead

┌──────────────────────────────────────────────────────────────┐
│           SAFE ANALGESICS IN THIS PATIENT                    │
├──────────────────────────────────────────────────────────────┤
│                                                              │
│  FIRST CHOICE:                                               │
│  ✅ Paracetamol (Acetaminophen) 1g IV/oral                  │
│     - Safe with valproate and levetiracetam                 │
│     - No drug interactions in acute setting                  │
│     - No seizure threshold lowering                          │
│     - No GI or renal risk at standard doses                 │
│     - Dose: 1g IV over 15 min (or oral if patient is alert) │
│                                                              │
│  NOTE: Avoid paracetamol excess if on valproate long-term   │
│  (mild CYP interaction at high doses) - standard 1g dose    │
│  is perfectly safe                                           │
│                                                              │
├──────────────────────────────────────────────────────────────┤
│  IF HEADACHE IS SEVERE AND PATIENT IS AWAKE/ALERT:           │
│  ✅ Reassurance + oral fluids + rest                        │
│     Post-ictal headache typically resolves within           │
│     30-60 min of seizure cessation                          │
│                                                              │
├──────────────────────────────────────────────────────────────┤
│  ❌ AVOID:                                                   │
│  - Diclofenac (drug interaction + seizure threshold)        │
│  - Tramadol (DIRECTLY lowers seizure threshold)             │
│  - Ibuprofen (same NSAID concerns as diclofenac)            │
│  - Aspirin (affects platelet function + reye risk)          │
│  - Morphine/Opioids (respiratory depression with Midazolam) │
└──────────────────────────────────────────────────────────────┘

Important Clinical Reminder

Is this headache post-ictal, OR is it a sign of raised intracranial pressure / meningitis / subarachnoid hemorrhage?

• Thunderclap onset ("worst headache of life") → Urgent CT head - rule out SAH
• With fever + neck stiffness → Meningitis - LP + empiric antibiotics
• With papilloedema or focal neurology → Raised ICP - urgent CT before LP
• Post-seizure, gradual, diffuse → Post-ictal headache - Paracetamol 1g IV + reassurance