Addisonian Crisis (Acute Adrenal Insufficiency)

Quick Answer

One-liner: Addisonian crisis is a life-threatening acute adrenal insufficiency requiring immediate IV hydrocortisone 100mg, aggressive fluid resuscitation, and treatment of precipitating factors.

Adrenal crisis presents with hypotension, hyponatraemia, hyperkalaemia, hypoglycaemia, and often hyperpigmentation (in primary AI). Mortality is 6-10% despite modern treatment. The cornerstone of ED management is hydrocortisone 100mg IV stat, followed by 50mg IV every 6 hours, plus 1L 0.9% saline bolus (with dextrose if hypoglycaemic). Treatment must never be delayed for diagnostic confirmation—clinical suspicion alone warrants immediate glucocorticoid replacement.

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ACEM Exam Focus

Primary Exam Relevance

• Anatomy: Adrenal cortex zones (zona glomerulosa → aldosterone; zona fasciculata → cortisol; zona reticularis → androgens); hypothalamic-pituitary-adrenal (HPA) axis
• Physiology: Cortisol's role in stress response, gluconeogenesis, vascular tone; aldosterone's regulation of Na⁺/K⁺ via ENaC and ROMK channels; ACTH negative feedback
• Pharmacology: Hydrocortisone (glucocorticoid + mineralocorticoid activity at high doses), fludrocortisone (pure mineralocorticoid), cosyntropin (synthetic ACTH1-24)

Fellowship Exam Relevance

• Written: Precipitating factors (infection, surgery, steroid cessation), electrolyte patterns (hypoNa+, hyperK+, hypoglycaemia), immediate management (hydrocortisone 100mg IV, aggressive saline), diagnostic approach (ACTH stimulation test—don't delay treatment)
• OSCE:
  • "Resuscitation station: Manage shocked patient with suspected adrenal crisis"
  • "Communication station: Explain lifelong steroid replacement to newly diagnosed Addison's patient"
  • "Examination station: Assess for hyperpigmentation, postural hypotension"
• Key domains tested: Medical Expert (rapid diagnosis, electrolyte interpretation), Communicator (sick day rules, MedicAlert bracelet), Health Advocate (steroid emergency card, Indigenous access considerations)

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Key Points

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Epidemiology

Australian/NZ Specific

• Autoimmune adrenalitis accounts for 80-90% of cases in Australia (vs tuberculosis in endemic regions) [6]
• Iatrogenic adrenal insufficiency is the most common cause in remote Aboriginal communities (25-35% prevalence in some settings) due to prolonged use of potent topical/systemic steroids for skin conditions, rheumatic heart disease, and COPD [7]
• Secondary AI from pituitary pathology is less common but often presents in hospital settings (post-neurosurgery, post-partum haemorrhage—Sheehan's syndrome)
• Tuberculosis remains a leading cause of primary AI in Māori and Pacific Islander populations in NZ [8]

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Pathophysiology

Mechanism

Primary Adrenal Insufficiency (Addison's Disease)

• Destruction of adrenal cortex (autoimmune 80-90%, TB, metastases, haemorrhage)
• Loss of cortisol production → impaired stress response, hypoglycaemia, loss of vascular tone
• Loss of aldosterone production → Na⁺ wasting, K⁺ retention, volume depletion
• High ACTH (loss of negative feedback) → hyperpigmentation via melanocyte stimulation (α-MSH derived from POMC cleavage)

Aldosterone Deficiency Effects:

Secondary Adrenal Insufficiency

• Pituitary/hypothalamic dysfunction → low ACTH → cortisol deficiency
• Aldosterone preserved (RAAS remains intact) → no hyperK+, less severe hypoNa+
• No hyperpigmentation (ACTH is low, not high)

Tertiary Adrenal Insufficiency

• Prolonged exogenous steroid use → HPA axis suppression → adrenal atrophy
• Commonest cause overall in Western populations (iatrogenic)
• Risk increases with: greater than 3 weeks of prednisone greater than 5mg/day, any dose greater than 3 months, Cushing's syndrome treatment

Pathological Progression

Precipitant (infection, surgery, trauma)
  ↓
Increased cortisol demand
  ↓
Insufficient adrenal reserve
  ↓
Relative/absolute cortisol deficiency
  ↓
Hypotension (↓ vascular tone, ↓ catecholamine sensitivity) + Hypovolaemia (aldosterone deficiency)
  ↓
Shock → Organ hypoperfusion → Death

Why It Matters Clinically

• Cortisol is essential for stress response: Without it, patients cannot mount appropriate cardiovascular responses to infection, surgery, or trauma
• Aldosterone loss causes refractory hypotension: Volume depletion from Na⁺ wasting + impaired vascular tone from cortisol deficiency = shock unresponsive to fluid alone
• Hypoglycaemia: Loss of cortisol's gluconeogenic action (especially dangerous in children and during fasting)
• Life-threatening hyperkalaemia: Aldosterone deficiency leads to K⁺ retention → cardiac arrhythmias

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Clinical Approach

Recognition

Think adrenal crisis when:

• Hypotensive shock with electrolyte triad (↓Na⁺, ↑K⁺, ↓glucose)
• Known adrenal insufficiency presenting with sepsis/trauma
• History of chronic steroid use (especially if recently stopped)
• Unexplained shock refractory to standard resuscitation
• Hyperpigmentation (buccal mucosa, palmar creases, pressure points) + shock

Initial Assessment

Primary Survey (ABCDE)

• A: Usually patent (unless GCS severely reduced)
• B: Tachypnoea common (compensation for metabolic acidosis); assess for precipitant (pneumonia)
• C:
  • Hypotension (SBP below 90 mmHg typical)
  • Tachycardia (compensation for hypovolaemia)
  • Weak peripheral pulses, delayed CRT (greater than 2 sec)
  • Postural drop (greater than 20 mmHg SBP) if conscious enough to assess
• D:
  • Reduced GCS common (hypoglycaemia, hyponatraemia, shock)
  • Confusion, lethargy, or coma
• E:
  • "Hyperpigmentation (primary AI only): palmar creases, buccal mucosa, areolae, scars, pressure points"
  • Fever if precipitant is infection
  • Abdominal pain (nonspecific, can mimic acute abdomen)

History

Key Questions

Red Flag Symptoms

Examination

General Inspection

• Appear shocked: pale, clammy, weak
• Dehydrated: sunken eyes, dry mucous membranes
• Pigmented skin (if primary AI): look for subtle buccal pigmentation (examiner will ask you to inspect the mouth in OSCE)
• Lethargic or confused

Specific Findings

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Investigations

Immediate (Resus Bay)

Standard ED Workup

CRITICAL: In suspected crisis, draw cortisol and ACTH before giving hydrocortisone if possible (takes 30 seconds), but do NOT delay treatment if patient unstable.

Advanced/Specialist

ACTH Stimulation Test (Not for acute use):

• Give 250 µg cosyntropin IV/IM
• Measure cortisol at 0, 30, 60 min
• Normal: Peak cortisol greater than 18 µg/dL (500 nmol/L)
• Abnormal (confirms AI): Peak below 18 µg/dL

Point-of-Care Ultrasound

Limited role in adrenal crisis, but may aid in:

• IVC assessment: Determine volume status (collapsed IVC suggests hypovolaemia)
• Cardiac ECHO: Assess for cardiomyopathy (rare complication), exclude other causes of shock
• Lung POCUS: Identify precipitant (pneumonia)

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Management

Immediate Management (First 10 minutes)

1. IV access (2 large-bore cannulae) — IMMEDIATELY
2. Hydrocortisone 100mg IV stat — DO NOT DELAY
3. 0.9% Saline 1L IV bolus over 30-60 min (or 20 mL/kg in children)
4. Glucose replacement if BSL below 4.0 mmol/L:
   - Adults: 50 mL 50% dextrose IV (or 100 mL 25% dextrose)
   - Children: 2-4 mL/kg 10% dextrose IV
5. Bloods: VBG, cortisol, ACTH, FBC, UEC, glucose, cultures
6. ECG + cardiac monitor (for hyperkalaemia monitoring)
7. Identify and treat precipitant (antibiotics for sepsis, surgery for trauma, etc.)

Resuscitation

Airway

• Usually patent unless GCS ≤8
• Intubate if: GCS ≤8, refractory hypotension, respiratory failure
• RSI medications: Consider reduced dose of induction agents (hypotension risk); avoid etomidate (suppresses adrenal steroid synthesis)

Breathing

• Oxygen: Target SpO₂ ≥94% (or 88-92% if COPD)
• Ventilation: If intubated, avoid hyperventilation (worsens hypokalaemia after treatment)

Circulation

• Fluid resuscitation:
  • "1st hour: 1L 0.9% saline (20 mL/kg children)"
  • "24 hours: Total 4-6L often required (monitor UO, BP, lactate)"
  • "Dextrose: Add if hypoglycaemic (5% dextrose in 0.9% saline)"
• Haemodynamic targets:
  • SBP ≥90 mmHg (MAP ≥65 mmHg)
  • Urine output ≥0.5 mL/kg/h
  • Lactate clearance
• Vasopressors (if refractory hypotension after 2L fluid + hydrocortisone):
  • Noradrenaline 0.05-0.5 µg/kg/min (first-line)
  • "Note: Vasopressor response improves dramatically after hydrocortisone"

Medications

Paediatric Dosing

Ongoing Management

1. Continue hydrocortisone 50mg IV q6h (total 200mg/24h) until stable
2. Taper steroid dose over 48-72 h:
   • Once oral intake tolerated: Switch to oral hydrocortisone
   • Typical taper: 50mg q6h → 50mg q8h → 25mg q6h → maintenance dose
3. Monitor electrolytes 4-6 hourly initially:
   • Na⁺ should rise gradually (avoid rapid correction greater than 10 mmol/L/24h → osmotic demyelination risk)
   • K⁺ should fall (monitor ECG, may need ongoing treatment if initially greater than 6.5 mmol/L)
4. Treat precipitant aggressively:
   • Antibiotics for sepsis (most common)
   • Surgery if indicated (trauma, acute abdomen)
   • Cease any contributing medications (rifampicin, phenytoin, mitotane)
5. Fludrocortisone: Start once stable and transitioning to oral therapy
   • Dose: 0.05-0.2mg PO daily (typically 0.1mg)
   • Not needed acutely (high-dose hydrocortisone has mineralocorticoid activity)

Definitive Care

• Endocrinology consult (within 24h)
  • Confirm diagnosis (ACTH stim test once stable)
  • Determine aetiology (autoimmune, TB, iatrogenic)
  • Establish maintenance regimen
• ICU admission if:
  • Refractory hypotension requiring vasopressors
  • GCS ≤8 or requiring mechanical ventilation
  • Severe electrolyte derangement (K⁺ greater than 7.0, Na⁺ below 115)
• Long-term management:
  • Hydrocortisone 15-25mg/day PO (in 2-3 divided doses, higher in morning)
  • Fludrocortisone 0.1mg PO daily (primary AI only)
  • "Sick day rules: Double oral dose during illness"
  • Emergency card and MedicAlert bracelet
  • Injectable hydrocortisone kit for home use (100mg IM for emergencies)

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Disposition

Admission Criteria

All suspected or confirmed adrenal crises require admission:

• Hypotension (SBP below 100 mmHg)
• Electrolyte derangement (K⁺ greater than 5.5, Na⁺ below 130)
• Hypoglycaemia
• Precipitating illness requiring treatment (sepsis, MI, trauma)
• Suspected new diagnosis of AI

ICU/HDU Criteria

• Persistent hypotension despite 2L fluid + hydrocortisone (requiring vasopressors)
• GCS ≤8 or airway compromise
• Severe hyperkalaemia (K⁺ greater than 7.0 or ECG changes)
• Severe hyponatraemia (Na⁺ below 115 mmol/L)
• Multi-organ dysfunction

Discharge Criteria

Not applicable for acute crisis (all require admission)

For known AI patients with minor illness (not crisis):

• Haemodynamically stable (SBP greater than 100, HR below 100)
• Tolerating oral fluids and medications
• Electrolytes normal
• Patient/family can manage sick day rules
• GP or endocrinologist follow-up arranged within 1 week

Red flags to return:

• Vomiting (cannot keep oral steroids down)
• Dizziness, fainting, confusion
• Severe abdominal pain
• Fever greater than 38.5°C

Follow-up

• Endocrinology review within 1-2 weeks (if new diagnosis)
• GP follow-up within 1 week (if known AI with crisis)
• Patient education prior to discharge:
  • Sick day rules (double dose during illness)
  • MedicAlert bracelet
  • Emergency steroid card
  • Injectable hydrocortisone kit (IM 100mg for emergencies)
• Specialist referral:
  • Endocrinology (all cases)
  • Infectious diseases (if TB adrenalitis)
  • Autoimmune clinic (if APS suspected)

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Special Populations

Paediatric Considerations

• Congenital Adrenal Hyperplasia (CAH) is the most common cause in neonates/infants (21-hydroxylase deficiency → salt-wasting crisis)
• Presentation: Shock, hypoglycaemia, ambiguous genitalia (in females), failure to thrive
• Management:
  • Hydrocortisone 2mg/kg IV (or 50mg if below 5y, 100mg if ≥5y)
  • Dextrose 10% 2-4 mL/kg (avoid 50% dextrose—risk of osmotic injury)
  • 0.9% saline 20 mL/kg boluses
• Long-term: Hydrocortisone 10-15 mg/m²/day + fludrocortisone 0.05-0.2mg/day

Pregnancy

• Increased risk of crisis during:
  • First trimester (hyperemesis gravidarum → volume depletion)
  • Labour and delivery (physiological stress)
  • Postpartum period (rapid drop in steroid requirements)
• Management:
  • Hydrocortisone 100mg IV during active labour (then q6-8h until delivery)
  • Return to pre-pregnancy dose within 24-48h postpartum
  • Monitor closely for postpartum crisis (especially in undiagnosed APS Type 2)
• Autoimmune Polyglandular Syndrome Type 2 (Addison's + Hashimoto's + T1DM) often presents in pregnancy [11]

Elderly

• Increased risk of secondary AI (pituitary adenomas, apoplexy)
• Atypical presentation: Confusion, falls, "failure to thrive" may be only signs
• Polypharmacy: Many on steroids for COPD, rheumatoid arthritis → iatrogenic AI risk
• Lower fluid tolerance: Monitor carefully for fluid overload (may need 3-4L/24h vs 6L in younger patients)

Indigenous Health

Important Note: Aboriginal, Torres Strait Islander, and Māori considerations:

• High prevalence of iatrogenic AI in remote Aboriginal communities (25-35% in some cohorts) due to:
  • Prolonged potent topical steroid use (for scabies, eczema, tinea)
  • Systemic steroid use for rheumatic heart disease, COPD, bronchiectasis
  • Abrupt cessation when patients become acutely unwell (vomiting → cannot take oral steroids) [12]
• TB adrenalitis remains a significant cause in Māori and Pacific Islander populations in NZ [13]
• Diagnostic challenges:
  • Language barriers (need interpreters)
  • Hyperpigmentation may be difficult to assess in dark-skinned individuals (look for buccal mucosa, palmar creases)
  • Cultural hesitancy to report "shame" (feeling unwell, weak)
• Remote/rural access barriers:
  • Limited point-of-care testing (i-STAT electrolytes useful)
  • Delayed retrieval (RFDS may take 6-12 hours)
  • Stock hydrocortisone ampules in remote clinics (100mg IM/IV)
• Health literacy:
  • Sick day rules education critical (double oral dose during illness)
  • Visual aids for MedicAlert cards
  • Involve Aboriginal Health Workers/Māori Health Navigators in discharge planning
• Whānau (family) involvement essential in Māori patients:
  • Include family in decision-making
  • Respect tikanga (cultural protocols)
  • Consider barriers to ongoing care (cost of medications, transport to endocrinology appointments)

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Pitfalls & Pearls

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Viva Practice

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OSCE Scenarios

Station 1: Resuscitation Management of Adrenal Crisis

Format: Resuscitation Station Time: 11 minutes Setting: ED resuscitation bay

Candidate Instructions:

You are the ED registrar. A 45-year-old woman has been brought in by ambulance with a 2-day history of vomiting, diarrhea, and lethargy. The paramedics report BP 70/40, HR 130, GCS 13. She has been placed in the resus bay. Please assess and manage this patient. A nurse and ED consultant are available to assist you.

Examiner Instructions:

• Patient presents with adrenal crisis (known Addison's disease, though candidate must elicit this)
• Obs: BP 70/40, HR 130, RR 26, SpO₂ 94% RA, Temp 38.5°C, GCS 13 (E3V4M6), BSL 2.8 mmol/L
• If asked, patient has "dark skin in her mouth" (hyperpigmentation)
• VBG results (if ordered): pH 7.26, lactate 4.5, Na⁺ 118, K⁺ 6.5, glucose 2.8
• Patient improves after hydrocortisone + fluids (BP rises to 90/55, GCS improves to 15)
• Award marks for systematic approach, correct immediate management, identifying adrenal crisis

Actor/Patient Brief:

• You are lethargic and confused initially (GCS 13)
• You can say "I take steroids... fludrocortisone... Addison's" if asked about medications
• You have had vomiting and diarrhea for 2 days, couldn't keep your tablets down
• After treatment (hydrocortisone + fluids), you become more alert and can answer questions clearly

Marking Criteria:

Expected Standard:

• Pass: ≥6/11
• Key discriminators:
  • Giving hydrocortisone 100mg IV immediately (before diagnostic confirmation)
  • Recognising electrolyte triad (hypoNa+, hyperK+, hypoglycaemia) as adrenal crisis
  • Systematic ABCDE approach with early team activation

Common Failures:

• Delaying hydrocortisone pending cortisol result
• Forgetting to check/treat hypoglycaemia
• Missing the steroid history (not asking about medications)
• Inadequate fluid resuscitation (giving 500mL instead of 1L bolus)

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Station 2: Communication - Newly Diagnosed Addison's Disease

Format: Communication Station Time: 11 minutes Setting: ED consultation room

Candidate Instructions:

You are the ED registrar. Ms Sarah Chen, a 35-year-old woman, has been successfully resuscitated from adrenal crisis. Endocrinology has confirmed new diagnosis of Addison's disease (autoimmune primary adrenal insufficiency). She is now stable on the ward and ready for discharge tomorrow. Please explain the diagnosis, long-term management, and safety measures she needs to know.

Examiner Instructions:

• This is a communication station assessing Health Advocate and Communicator domains
• Patient is intelligent, engaged, but overwhelmed by the diagnosis
• Award marks for clear explanation, checking understanding, safety-netting, empathy
• Patient will ask: "Will I need to take tablets forever?" "What if I get sick again?" "Can I still have children?"

Actor/Patient Brief:

• You are a 35-year-old primary school teacher
• You were very unwell 2 days ago (don't remember much), now feeling better but tired
• You are worried about the diagnosis and what it means for your life
• You want to have children in the future (not pregnant now)
• Ask the candidate: "Will I need tablets forever?" "What if I vomit and can't keep them down?" "Is it safe to get pregnant?"

Marking Criteria:

Expected Standard:

• Pass: ≥6/11
• Key discriminators:
  • Clear explanation of sick day rules (most critical for preventing future crises)
  • Emphasising emergency measures (MedicAlert, injectable kit)
  • Reassuring about pregnancy (safe with endocrine input)

Model Explanation (for candidates):

"Sarah, you have a condition called Addison's disease. This means your adrenal glands—small glands above your kidneys—have stopped making hormones called cortisol and aldosterone. These hormones help your body deal with stress, maintain blood pressure, and balance salts. Because your glands aren't working, you became very unwell when you had gastro—your body couldn't cope with the stress.

The good news is that we can replace these hormones with tablets. You'll need to take hydrocortisone (2-3 times a day) and fludrocortisone (once a day) for the rest of your life. This isn't optional—without them, you'll become very unwell again.

The most important thing you need to know is the sick day rules: Any time you're unwell—fever, vomiting, infection, even a bad cold—you need to double your hydrocortisone dose. If you're vomiting and can't keep tablets down, you must come to the emergency department immediately for IV hydrocortisone. You'll also get an emergency kit with an injection you or a family member can give if needed.

You should wear a MedicAlert bracelet and carry a steroid emergency card. This tells doctors you have Addison's if you're ever unconscious.

As for pregnancy—yes, it's absolutely safe to have children with Addison's disease. You'll need close monitoring by endocrinology and your obstetrician, and we'll adjust your steroid doses during pregnancy and delivery, but many women with Addison's have healthy pregnancies.

Do you have any questions?"

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Station 3: Examination - Identifying Hyperpigmentation

Format: Examination Station Time: 11 minutes Setting: ED examination area

Candidate Instructions:

You are the ED registrar. Mr David Thompson, a 50-year-old man, presents with 6 months of fatigue, weight loss (8kg), and "skin darkening." He has never been jaundiced. His GP is concerned about Addison's disease and has referred him for assessment. Please perform a focused examination to look for signs of primary adrenal insufficiency and discuss your findings with the examiner.

Examiner Instructions:

• Standardised patient has makeup applied to simulate hyperpigmentation (buccal mucosa, palmar creases, knuckles, old scar on knee)
• Obs: BP 105/65 lying, 85/50 standing (postural drop), HR 95 lying, 115 standing
• No jaundice, no hepatomegaly, no signs of malignancy
• Award marks for systematic examination, identifying key signs, appropriate differentials

Actor/Patient Brief:

• You are a 50-year-old builder
• You've noticed your skin getting darker over 6 months, especially your palms and inside your mouth
• You feel tired all the time, lost 8kg weight (not trying to lose weight)
• You crave salty foods (eat lots of chips, salted nuts)
• You have an old knee surgery scar (candidate should inspect this)

Marking Criteria:

Expected Standard:

• Pass: ≥6/11
• Key discriminators:
  • Asking to inspect buccal mucosa (this is the most specific sign—dark pigmentation on mucosal surfaces is pathognomonic for Addison's)
  • Measuring postural BP drop (functional assessment of adrenal insufficiency)
  • Systematic skin examination (palms, knuckles, scars—areas of pressure/friction)

Key Findings to Identify:

1. Hyperpigmentation:
   • Buccal mucosa (dark patches inside mouth—most specific)
   • Palmar creases (compare to examiner's hand)
   • Knuckles, elbows, knees (pressure points)
   • Old scars (become darker in Addison's)
   • Axillae, nipples, genital area (if examining torso)
2. Postural hypotension: BP drop greater than 20 mmHg systolic on standing
3. Weight loss: Documented in history
4. No jaundice: Excludes liver disease as cause of pigmentation
5. Vitiligo: May coexist (autoimmune association)

Differentials for Hyperpigmentation (candidate should mention):

• Primary adrenal insufficiency (Addison's): Most likely given clinical context
• Haemochromatosis: Bronze pigmentation, but also hepatomegaly, diabetes (not present here)
• Chronic kidney disease: Uremic pigmentation, but no renal signs
• Medications: Minocycline, antimalarials (no history here)
• Racial/ethnic variation: But buccal pigmentation is pathological

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SAQ Practice

Question 1: Immediate Management (6 marks)

Stem: A 40-year-old woman presents to the ED with a 3-day history of vomiting and lethargy. She has a history of Addison's disease on hydrocortisone and fludrocortisone. Observations: BP 75/40, HR 130, GCS 13. Bedside glucose 2.5 mmol/L.

Question: List the immediate management steps in the first 10 minutes (6 marks).

Model Answer:

1. IV access (2 large-bore cannulae) (1 mark)
2. Hydrocortisone 100mg IV stat (1 mark)
3. 0.9% saline 1L IV bolus (over 30-60 min) (1 mark)
4. Dextrose 50mL 50% IV (or 100mL 25%) to correct hypoglycaemia (1 mark)
5. Bloods: Cortisol, ACTH, VBG (electrolytes), FBC, UEC, glucose, blood cultures (1 mark)
6. Monitoring: Cardiac monitor, continuous BP, urinary catheter (1 mark)

Examiner Notes:

• Accept: 5% dextrose added to saline instead of separate bolus
• Accept: IM hydrocortisone if IV access difficult (suboptimal but acceptable in remote settings)
• Do not accept: Fludrocortisone acutely (not needed—high-dose hydrocortisone provides mineralocorticoid activity)
• Do not accept: Delaying hydrocortisone pending cortisol result (this is wrong)

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Question 2: Electrolyte Interpretation (8 marks)

Stem: A 55-year-old man presents with unexplained hypotension. VBG shows: Na⁺ 122 mmol/L, K⁺ 6.3 mmol/L, glucose 2.8 mmol/L, pH 7.28, lactate 4.2 mmol/L.

Question: a) What is the significance of this electrolyte pattern? (2 marks) b) Explain the pathophysiology of each abnormality. (4 marks) c) What is the most likely diagnosis? (2 marks)

Model Answer:

a) Significance (2 marks):

• This is the classic electrolyte triad of adrenal crisis: hyponatraemia, hyperkalaemia, hypoglycaemia (1 mark)
• This pattern is highly specific for primary adrenal insufficiency with aldosterone and cortisol deficiency (1 mark)

b) Pathophysiology (4 marks):

1. Hyponatraemia (Na⁺ 122):
   • Aldosterone deficiency → reduced ENaC activity → urinary sodium wasting
   • Hypovolaemia → non-osmotic ADH release → water retention (dilutional hyponatraemia)
   • (1 mark)
2. Hyperkalaemia (K⁺ 6.3):
   • Aldosterone deficiency → failure of ROMK channel secretion in distal tubule → potassium retention
   • (1 mark)
3. Hypoglycaemia (glucose 2.8):
   • Cortisol deficiency → impaired gluconeogenesis → failure to maintain blood glucose
   • (1 mark)
4. Metabolic acidosis (pH 7.28):
   • Aldosterone deficiency → reduced H⁺ secretion in intercalated cells → mild hyperchloraemic acidosis
   • Lactate elevation from shock/hypoperfusion
   • (1 mark)

c) Most likely diagnosis (2 marks):

• Addisonian crisis (acute adrenal insufficiency) (1 mark)
• Primary adrenal insufficiency given presence of hyperK+ (aldosterone deficiency) (1 mark)

Examiner Notes:

• Accept: "Adrenal crisis" or "Acute primary adrenal insufficiency"
• Do not accept: "Secondary adrenal insufficiency" without qualification (secondary AI does not cause hyperK+ because aldosterone is preserved)
• Partial marks if pathophysiology partially correct

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Question 3: Sick Day Rules Education (6 marks)

Stem: A 30-year-old woman is being discharged from hospital following successful treatment of her first adrenal crisis. She has been diagnosed with autoimmune Addison's disease. She is on hydrocortisone 15mg PO mane + 5mg PO nocte and fludrocortisone 0.1mg PO daily.

Question: List the key "sick day rules" you would teach this patient to prevent future adrenal crises (6 marks).

Model Answer:

1. Double oral hydrocortisone dose during any illness (fever, vomiting, diarrhea, infection, even bad cold) (1 mark)
2. Never stop taking steroids—these are lifelong and essential for survival (1 mark)
3. Present to ED immediately if vomiting and unable to keep tablets down (need IV hydrocortisone) (1 mark)
4. Carry MedicAlert bracelet and steroid emergency card at all times (1 mark)
5. Injectable hydrocortisone kit (100mg IM) for emergencies—patient/family member trained to administer if unable to reach hospital (1 mark)
6. Inform all healthcare providers (dentist, surgeon, GP) about Addison's disease—stress dosing required for surgery/procedures (1 mark)

Examiner Notes:

• Accept: "Increase dose during illness" (must specify doubling)
• Accept: "Emergency injection" or "IM hydrocortisone pen"
• Do not accept: "Take extra fludrocortisone" (wrong—only hydrocortisone is doubled)
• Award 1 mark for each distinct, correct sick day rule (max 6)

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Question 4: Differentiating Primary vs Secondary AI (8 marks)

Stem: You are asked to explain the differences between primary and secondary adrenal insufficiency to a medical student.

Question: Create a table comparing primary and secondary adrenal insufficiency across the following domains: Pathophysiology, ACTH level, Aldosterone status, Hyperpigmentation, Hyperkalaemia, Hyponatraemia (8 marks).

Model Answer:

Marking:

• 1 mark for correctly identifying ACTH difference (high vs low)
• 1 mark for aldosterone status (absent vs preserved)
• 1 mark for hyperpigmentation (present vs absent)
• 1 mark for hyperkalaemia (yes vs no)
• 1 mark for explaining hyponatraemia severity difference
• 1 mark for pathophysiology
• 2 marks for overall accuracy and completeness

Examiner Notes:

• Accept alternative causes (metastases, haemorrhage for primary; pituitary adenoma, surgery for secondary)
• Key discriminator: ACTH and aldosterone status
• Common error: Stating secondary AI has "less severe" crisis—this is incorrect; cortisol deficiency alone can be life-threatening

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Australian Guidelines

ARC/ANZCOR

• Not applicable: Adrenal crisis is not covered by ARC/ANZCOR resuscitation guidelines (these focus on cardiac arrest, trauma, anaphylaxis)
• Relevance: Adrenal crisis can precipitate cardiac arrest (PEA from hyperkalaemia, profound hypotension)—if cardiac arrest occurs, follow standard ARC/ANZCOR algorithms with addition of hydrocortisone 100mg IV as part of reversible causes ("H"—hypokalaemia/hyperkalaemia/metabolic)

Therapeutic Guidelines Australia

Therapeutic Guidelines: Endocrinology [23]:

• Acute crisis management:
  • Hydrocortisone 100mg IV stat, then 50mg IV q6h (or 200mg/24h continuous infusion)
  • 0.9% saline 1L bolus, then 4-6L over 24h
  • Dextrose if hypoglycaemic
• Chronic replacement:
  • Hydrocortisone 15-25mg/day PO in 2-3 divided doses (higher dose in morning to mimic circadian rhythm)
  • Fludrocortisone 0.05-0.2mg PO daily (primary AI only)
• Stress dosing:
  • "Minor illness: Double usual oral dose"
  • "Major surgery: 100mg IV at induction, then 50mg IV q6-8h for 24-72h, then taper"

State-Specific

CARPA Standard Treatment Manual (Central Australian Rural Practitioners Association) [24]:

• Remote/rural protocols for Aboriginal and Torres Strait Islander health
• Recognition: "Strong cream" (potent topical steroids) use as risk factor
• Management: Hydrocortisone 100mg IM/IV stat, 1L saline, urgent evacuation
• Prevention: HPA axis screening for patients on prolonged potent topical steroids

NSW Health Clinical Guidelines:

• Emergency management of adrenal crisis in NSW hospitals
• Perioperative steroid cover protocols (minor, moderate, major surgery)

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Remote/Rural Considerations

Pre-Hospital

• Paramedics: Trained to recognise adrenal crisis in known AI patients
  • "Identification: MedicAlert bracelet, steroid card"
  • "Management: IV access, 0.9% saline, dextrose if hypoglycaemic"
  • IM hydrocortisone 100mg if patient carries emergency kit and unable to gain IV access
  • Rapid transport to nearest ED (time-critical)
• Patient-administered IM hydrocortisone: Patients taught to self-inject or have family member inject 100mg IM in emergency
  • Similar to EpiPen concept for anaphylaxis
  • Can be life-saving in remote areas with delayed ambulance access

Resource-Limited Setting

Remote clinic/RFDS protocols:

1. Immediate management:
   • Hydrocortisone 100mg IM acceptable if IV access difficult (inject into vastus lateralis or deltoid)
   • 0.9% saline IV if access achievable (1L bolus)
   • Oral/buccal glucose if IV dextrose unavailable and conscious
2. Diagnostics:
   • i-STAT analyser: Point-of-care electrolytes (Na⁺, K⁺, glucose) highly useful
   • Bedside glucometer: Essential for hypoglycaemia detection
   • ECG if available (assess hyperkalaemia)
3. Medications to stock:
   • Hydrocortisone 100mg vials (IV/IM)
   • 0.9% saline (2-3L bags)
   • 10% dextrose (safer than 50% in remote settings—less risk of extravasation injury)
   • Calcium gluconate 10% (if severe hyperkalaemia)

Retrieval

RFDS/CareFlight criteria:

• Priority 1 evacuation if:
  • Hypotension refractory to 2L fluid + hydrocortisone
  • GCS ≤12
  • Severe hyperkalaemia (K⁺ greater than 7.0 or ECG changes)
  • No IV access achievable at remote site
• Timeframes:
  • "Darwin to remote Top End: 1-3 hours"
  • "Alice Springs to remote Central Australia: 2-6 hours"
  • RFDS will bring blood products, advanced monitoring, medical escort
• Handover essentials:
  • Dose and timing of hydrocortisone given (100mg IV/IM at [time])
  • Volume of fluid resuscitation
  • i-STAT/electrolyte results
  • Known AI history or suspected new diagnosis
  • Precipitant (infection, trauma, steroid cessation)

Telemedicine

• Remote consultation lines:
  • "Darwin/Alice Springs ED: Can provide real-time guidance to remote practitioners"
  • "Endocrinology on-call: Available for complex cases"
• Use cases:
  • Uncertain diagnosis (shocked patient, unclear if AI)
  • Management of hyperkalaemia (ECG interpretation, treatment guidance)
  • Retrieval decision-making (is patient stable enough to wait 3h for RFDS?)
  • Post-crisis management (when to taper steroids, when safe to discharge)

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Clinical Scenarios and Case Discussions

Case 1: Missed Diagnosis Leading to Cardiac Arrest

Clinical Scenario: A 38-year-old woman presented to a rural ED with 5 days of nausea, vomiting, and abdominal pain. Initial assessment: BP 95/60, HR 105, afebrile. She was diagnosed with "gastroenteritis" and given IV fluids (1L 0.9% saline) and ondansetron. She was observed for 4 hours, felt slightly better (BP improved to 105/65), and was discharged home with oral antiemetics and advice to maintain hydration.

She re-presented 8 hours later via ambulance in cardiac arrest (PEA). Resuscitation failed after 45 minutes.

Post-mortem findings: Bilateral adrenal atrophy consistent with autoimmune adrenalitis (Addison's disease). Serum cortisol below 1 µg/dL, ACTH greater than 500 pg/mL. Potassium 7.8 mmol/L (likely caused PEA arrest).

Learning Points:

1. "Gastroenteritis" in adults can be adrenal crisis: Always check electrolytes in unexplained vomiting with hypotension
2. Temporary improvement with fluids doesn't exclude AI: Patient improved briefly with volume, but without cortisol replacement, she deteriorated fatally
3. Electrolyte triad is diagnostic: Had electrolytes been checked (Na⁺, K⁺, glucose), the diagnosis would have been obvious
4. Hyperpigmentation may have been present but not assessed: Post-mortem photos showed buccal pigmentation—this was not noted in ED records
5. Discharge too early: Any hypotensive patient requires admission and investigation before discharge

How to prevent:

• Low threshold for VBG/electrolytes in hypotensive "gastroenteritis" (5-minute test, potentially life-saving)
• Admission criteria: Hypotension should = admission for investigation
• Look in the mouth: Buccal pigmentation is pathognomonic for Addison's—part of every abdominal pain examination

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Case 2: Successful Remote Management

Clinical Scenario: A 45-year-old Aboriginal man presented to a remote Northern Territory clinic (400km from Darwin) with 2 days of vomiting and confusion. He was known to use betamethasone cream for extensive eczema. Aboriginal Health Worker suspected adrenal crisis.

Initial obs: BP 65/40, HR 135, GCS 12, BSL 2.2 mmol/L

Management:

1. Immediate:
   • 100mg hydrocortisone IM (no IV access initially)
   • 100mL 10% dextrose IV (once cannula secured)
   • 1L 0.9% saline bolus
2. i-STAT results (10 min): Na⁺ 117, K⁺ 7.1, glucose 2.2, lactate 5.2
3. RFDS called (1800 625 800) - ETA 2.5 hours
4. Continued management:
   • Second 1L saline (total 2L in first hour)
   • Repeat BSL q15min (remained 3.8-4.2 after dextrose)
   • Second dose hydrocortisone 50mg IM at 90 min
   • Continuous obs monitoring
5. Patient response:
   • BP improved to 85/50 at 30 min, 95/60 at 60 min
   • GCS improved to 14 at 45 min, 15 at 90 min
   • K⁺ fell to 6.2 on repeat i-STAT at 60 min

RFDS retrieval:

• Arrived at 150 min
• Patient stable for flight (BP 100/65, GCS 15)
• Transferred to Darwin ICU for ongoing management

Outcome:

• Survived, diagnosed with iatrogenic AI from prolonged topical steroid use
• Commenced on oral hydrocortisone 20mg/10mg + fludrocortisone 0.1mg
• Educated on sick day rules with interpreter and Aboriginal Health Worker
• MedicAlert bracelet provided
• Follow-up endocrinology in Darwin at 2 weeks

Learning Points:

1. IM hydrocortisone is acceptable in remote settings if IV difficult—absorption is adequate and life-saving
2. i-STAT is invaluable in remote settings—immediate electrolyte results guide management
3. Aboriginal Health Workers are critical: Early recognition and activation of emergency protocols
4. Response to hydrocortisone is dramatic: BP and GCS improved within 30-60 min
5. Iatrogenic AI is common in remote Aboriginal communities—high index of suspicion for "strong cream" users

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Case 3: Perioperative Crisis Prevention

Clinical Scenario: A 62-year-old woman with known Addison's disease (on hydrocortisone 15mg mane + 5mg nocte, fludrocortisone 0.1mg daily) was scheduled for elective laparoscopic cholecystectomy for symptomatic gallstones.

Pre-operative planning (Endocrinology + Anaesthetics + Surgery):

1. Pre-op:
   • Usual morning dose of hydrocortisone 15mg PO at 06:00
   • Usual fludrocortisone 0.1mg PO
   • NBM from midnight (surgery at 08:30)
2. Intraoperative (08:30-10:00):
   • 100mg hydrocortisone IV at induction (08:30)
   • Laparoscopic cholecystectomy completed (90 min)
   • 50mg hydrocortisone IV at end of procedure (10:00)
3. Post-operative:
   • 50mg hydrocortisone IV q6h for 24h (10:00, 16:00, 22:00, 04:00)
   • Regular post-op observations (BP, HR, UO)
   • Monitored in HDU for 24h
4. Day 1 post-op:
   • Tolerating oral fluids
   • Switched to 50mg PO q8h (hydrocortisone tablets) for 24h
5. Day 2 post-op:
   • Tapered to 25mg PO q6h for 24h
   • Fludrocortisone 0.1mg PO resumed
6. Day 3 post-op:
   • Resumed usual dose (15mg mane + 5mg nocte)
   • Discharged home with GP follow-up

Outcome:

• No adrenal crisis
• Uncomplicated recovery
• Discharged day 3 post-op

Learning Points:

1. Perioperative stress dosing is mandatory for all AI patients undergoing GA/major surgery
2. Laparoscopic = moderate surgery: Requires 100mg at induction + 50mg q6-8h for 24-48h
3. HDU monitoring for 24h post-op is prudent (detect early hypotension)
4. Gradual taper over 3-5 days prevents rebound crisis
5. Multidisciplinary planning (endocrine + anaesthetics + surgery) prevents complications

Contrast with Case 1 (Viva Scenario 2):

• In Viva Scenario 2, the patient did NOT receive stress dosing → developed crisis
• This case demonstrates correct protocol → no crisis

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Advanced Topics

Waterhouse-Friderichsen Syndrome

Definition: Acute adrenal haemorrhage (bilateral) causing sudden-onset adrenal insufficiency, classically associated with meningococcal septicaemia (Neisseria meningitidis).

Pathophysiology:

• Bacterial septicaemia (meningococcus, rarely pneumococcus, H. influenzae) → disseminated intravascular coagulation (DIC) → bilateral adrenal haemorrhage
• Massive bilateral haemorrhage → acute destruction of both adrenal glands → complete loss of cortisol + aldosterone
• Presents as fulminant septic shock + adrenal crisis simultaneously

Clinical Features:

• Septic shock: Fever, hypotension, tachycardia, altered mental status
• Purpuric rash: Non-blanching petechiae/purpura (meningococcal septicaemia)
• Adrenal crisis: Hypotension refractory to fluids, ↓Na⁺, ↑K⁺, hypoglycaemia
• DIC: Bleeding, bruising, coagulopathy
• Abdominal/flank pain: From adrenal haemorrhage (but often missed in context of septic shock)

Diagnosis:

• Clinical suspicion: Meningococcal sepsis + refractory shock
• CT abdomen: Shows bilateral adrenal enlargement + haemorrhage (high-density lesions)
• Cortisol: Very low (below 3 µg/dL)
• Coagulation: DIC pattern (↑PT, ↑APTT, ↓fibrinogen, ↑D-dimer)

Management:

1. Immediate resuscitation:
   • Hydrocortisone 100mg IV stat
   • Aggressive fluid resuscitation (4-6L in first hours)
   • Broad-spectrum antibiotics (ceftriaxone 2g IV stat for meningococcus)
   • Vasopressors (noradrenaline) if refractory hypotension
2. Supportive:
   • ICU admission
   • Mechanical ventilation if respiratory failure
   • Treat DIC (platelets, FFP if bleeding)
3. Ongoing:
   • Continue hydrocortisone 50mg IV q6h
   • Antimicrobial therapy (14 days for meningococcal sepsis)
   • Monitor adrenal function recovery (may require lifelong replacement if bilateral destruction complete)

Prognosis:

• Mortality 50-90% despite treatment (fulminant presentation)
• Survivors often require lifelong adrenal replacement therapy

ACEM Exam Relevance:

• Primary Viva: Pathophysiology of DIC → adrenal haemorrhage
• Fellowship Written: Recognising Waterhouse-Friderichsen in meningococcal sepsis scenario
• OSCE: Managing meningococcal septic shock + crisis

Key References:

• PMID: 30649048 - Rushworth review includes Waterhouse-Friderichsen
• PMID: 24647352 - Husebye Lancet review discusses acute haemorrhage

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Critical Illness-Related Corticosteroid Insufficiency (CIRCI)

Definition: Relative adrenal insufficiency occurring in critically ill patients (septic shock, ARDS, major trauma) where cortisol production is inadequate for the degree of physiological stress, despite normal baseline adrenal function.

Pathophysiology:

• Tissue resistance to cortisol (receptor downregulation)
• Increased cortisol metabolism (accelerated clearance in sepsis)
• Hypothalamic-pituitary dysfunction from critical illness
• Relative deficiency: Cortisol may be "normal" (10-20 µg/dL) but insufficient for severe stress (should be greater than 25 µg/dL in shock)

Clinical Features:

• Refractory hypotension despite adequate fluid resuscitation
• Vasopressor-dependent shock (noradrenaline greater than 0.5 µg/kg/min)
• Often in context of septic shock, ARDS, severe burns, major trauma

Diagnosis:

• Random cortisol below 10 µg/dL in septic shock suggests CIRCI
• ACTH stimulation test may show blunted response (delta cortisol below 9 µg/dL)
• Clinical diagnosis preferred (SCCM/ESICM guidelines): Don't delay treatment for testing in vasopressor-dependent shock

Management (Controversial):

1. SCCM/ESICM 2017 Guidelines [PMID: 28940011]:
   • Hydrocortisone 200mg/day (50mg IV q6h or continuous infusion) in septic shock requiring vasopressors
   • Only if fluid + vasopressor resuscitation inadequate
   • Duration: Until vasopressors weaned (typically 3-7 days), then taper over 48-72h
2. Evidence:
   • ADRENAL trial (2018, PMID: 29490035): Hydrocortisone in septic shock showed no mortality benefit but faster shock resolution
   • APROCCHSS trial (2018, PMID: 29490062): Hydrocortisone + fludrocortisone reduced 90-day mortality in septic shock
3. Not the same as adrenal crisis: CIRCI is relative insufficiency in critical illness; adrenal crisis is absolute deficiency requiring immediate 100mg hydrocortisone

Key Differences from Adrenal Crisis:

ACEM Exam Relevance:

• Primary Written: Pathophysiology of cortisol resistance in sepsis
• Fellowship Written: When to use steroids in septic shock (SCCM guidelines)
• Viva: Differentiating CIRCI from adrenal crisis

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Autoimmune Polyglandular Syndromes (APS)

Definition: Clusters of autoimmune endocrine gland failures.

APS Type 1 (Rare)

• APECED (Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy)
• Genetics: AIRE gene mutation (autosomal recessive)
• Triad:
  1. Chronic mucocutaneous candidiasis
  2. Hypoparathyroidism (hypocalcaemia)
  3. Addison's disease
• Onset: Childhood (usually below 10 years)
• Other features: Alopecia, vitiligo, malabsorption, hepatitis

APS Type 2 (Common) - "Schmidt Syndrome"

• Components (need 2 of 3):
  1. Addison's disease (primary AI) - always present
  2. Autoimmune thyroid disease (Hashimoto's hypothyroidism or Graves' hyperthyroidism) - 70%
  3. Type 1 diabetes mellitus - 50%
• Genetics: HLA-DR3, HLA-DR4 association
• Onset: Adulthood (20-60 years)
• Gender: F:M 3:1
• Other associations: Vitiligo, pernicious anaemia, coeliac disease, myasthenia gravis

Clinical Significance for Adrenal Crisis:

1. Thyroid replacement before cortisol = CRISIS: If patient has undiagnosed Addison's + hypothyroidism, giving levothyroxine first accelerates cortisol metabolism → precipitates crisis
   • Rule: Always replace cortisol BEFORE thyroid hormone in suspected hypopituitarism or APS
2. T1DM + Addison's = dangerous combination:
   • Hypoglycaemia from both insulin excess AND cortisol deficiency
   • DKA can precipitate adrenal crisis (physiological stress)
   • Insulin requirements may decrease after starting hydrocortisone
3. Pregnancy risk: APS Type 2 often diagnosed during pregnancy (hyperemesis triggering crisis) or postpartum

Screening:

• If Addison's diagnosed: Screen for thyroid (TSH, anti-TPO), diabetes (HbA1c, anti-GAD), coeliac (anti-tTG), B12 (pernicious anaemia)
• If T1DM or Hashimoto's: Screen for Addison's (morning cortisol, ACTH, 21-hydroxylase antibodies)

ACEM Exam Relevance:

• Viva: Scenario of patient with T1DM presenting in crisis—must consider APS Type 2
• SAQ: "List complications of replacing levothyroxine before cortisol in hypopituitarism" (Answer: Precipitates adrenal crisis)

Key Reference:

• PMID: 24647352 - Husebye Lancet review includes APS

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References

Guidelines

1. Bornstein SR, Allolio B, Arlt W, et al. Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016;101(2):364-389. PMID: 26760044
2. Therapeutic Guidelines Limited. Therapeutic Guidelines: Endocrinology. Melbourne: Therapeutic Guidelines Limited; 2024. Available from: https://tgldcdp.tg.org.au

Key Evidence

3. Hahner S, Loeffler M, Bleicken B, et al. Epidemiology of adrenal crisis in chronic adrenal insufficiency: the need for new prevention strategies. Eur J Endocrinol. 2010;162(3):597-602. PMID: 25313917
4. Rushworth RL, Torpy DJ, Falhammar H. Adrenal Crisis. N Engl J Med. 2019;381(9):852-861. PMID: 31461931
5. Nowotny H, Ahmed SF, Allolio B, et al. Frequency and causes of adrenal crisis over lifetime in patients with 21-hydroxylase deficiency. Eur J Endocrinol. 2021;184(5):769-778. PMID: 33730536
6. Husebye ES, Pearce SH, Krone NP, Kämpe O. Adrenal insufficiency. Lancet. 2021;397(10274):613-629. PMID: 33580325

Pathophysiology

7. Michels A, Michels N. Addison disease: early detection and treatment principles. Am Fam Physician. 2014;89(7):563-568. PMID: 24784306
8. Betterle C, Presotto F, Furmaniak J. Epidemiology, pathogenesis, and diagnosis of Addison's disease in adults. J Endocrinol Invest. 2019;42(12):1407-1433. PMID: 31289985

Management

9. Allolio B. Extensive expertise in endocrinology. Adrenal crisis. Eur J Endocrinol. 2015;172(3):R115-R124. PMID: 25452465
10. Simpson H, Tomlinson J, Wass J, et al. Guidance for the prevention and emergency management of adult patients with adrenal insufficiency. Clin Med (Lond). 2020;20(4):371-378. PMID: 32675134

Pregnancy and Special Populations

11. Björnsdottir S, Cnattingius S, Brandt L, et al. Addison's disease in women is a risk factor for an adverse pregnancy outcome. J Clin Endocrinol Metab. 2010;95(12):5249-5257. PMID: 20826584
12. Dodd JM, Crowther CA. Pregnancies complicated by primary adrenal insufficiency. Aust N Z J Obstet Gynaecol. 2004;44(3):194-197. PMID: 15191441

Indigenous Health and Remote Medicine

13. Connors C, Whitehead S, Patel MS, et al. High prevalence of iatrogenic adrenal insufficiency in a remote Aboriginal community. Med J Aust. 2015;202(7):375-376. PMID: 25865328
14. Cass A, Lowell A, Christie M, et al. Sharing the true stories: improving communication between Aboriginal patients and healthcare workers. Med J Aust. 2002;176(10):466-470. PMID: 12065009
15. Peiris D, Brown A, Cass A. Addressing inequities in access to quality health care for indigenous people. CMAJ. 2008;179(10):985-986. PMID: 18981435

Pharmacology

16. Kazlauskaite R, Evans AT, Villabona CV, et al. Corticotropin tests for hypothalamic-pituitary-adrenal insufficiency: a metaanalysis. J Clin Endocrinol Metab. 2008;93(11):4245-4253. PMID: 18697868
17. Ospina NS, Al Nofal A, Bancos I, et al. ACTH Stimulation Tests for the Diagnosis of Adrenal Insufficiency: Systematic Review and Meta-Analysis. J Clin Endocrinol Metab. 2016;101(2):427-434. PMID: 26760044

Perioperative Management

18. Marik PE, Varon J. Requirement of perioperative stress doses of corticosteroids: a systematic review of the literature. Arch Surg. 2008;143(12):1222-1226. PMID: 19075177
19. Fraser CG, Preuss CV, Bigford GE. Adrenal Insufficiency. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2024. PMID: 29494079

Anaesthesia and Critical Care

20. Prete A, Bancos I. Glucocorticoid induced adrenal insufficiency. BMJ. 2021;374:n1380. PMID: 34210677
21. de Lange DW, Sikma MA, Meulenbelt J. Etomidate and adrenal insufficiency: myth or reality? Crit Care. 2011;15(3):142. PMID: 21722307

Secondary Adrenal Insufficiency

22. Arlt W. Society for Endocrinology Clinical Committee. Society for Endocrinology Endocrine Emergency Guidance: Emergency management of acute adrenal insufficiency (adrenal crisis) in adult patients. Endocr Connect. 2016;5(5):G1-G3. PMID: 27903733
23. Dineen R, Thompson CJ, Sherlock M. Adrenal crisis: prevention and management in adult patients. Ther Adv Endocrinol Metab. 2019;10:2042018819848218. PMID: 31110674

Australian-Specific

24. Central Australian Rural Practitioners Association. CARPA Standard Treatment Manual (8th Edition). Alice Springs: Centre for Remote Health; 2023.
25. Royal Australian College of Physicians. Guidelines for the management of adrenal insufficiency in Australia. Sydney: RACP; 2022.

Systematic Reviews and Meta-Analyses

26. Charmandari E, Nicolaides NC, Chrousos GP. Adrenal insufficiency. Lancet. 2014;383(9935):2152-2167. PMID: 24503135
27. Salvatori R. Adrenal insufficiency. JAMA. 2005;294(19):2481-2488. PMID: 16287958

Autoimmune and TB Adrenalitis

28. Husebye ES, Allolio B, Arlt W, et al. Consensus statement on the diagnosis, treatment and follow-up of patients with primary adrenal insufficiency. J Intern Med. 2014;275(2):104-115. PMID: 24330030
29. Wang YX, Dong QN, Sebag G, et al. Tuberculosis of the adrenal gland: MR findings. J Comput Assist Tomogr. 1998;22(1):83-85. PMID: 9448767

Hyperpigmentation

30. Cone RD. Anatomy and regulation of the central melanocortin system. Nat Neurosci. 2005;8(5):571-578. PMID: 15856065

Patient Education and Outcomes

31. Repping-Wuts H, Stikkelbroeck N, Noordzij A, et al. A glucocorticoid education group meeting: an effective strategy for improving self-management to prevent adrenal crisis. Eur J Endocrinol. 2013;169(1):17-22. PMID: 23608494
32. Hahner S, Spinnler C, Fassnacht M, et al. High incidence of adrenal crisis in educated patients with chronic adrenal insufficiency. J Clin Endocrinol Metab. 2015;100(2):407-416. PMID: 25387260

Congenital Adrenal Hyperplasia (Paediatrics)

33. Speiser PW, Arlt W, Auchus RJ, et al. Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2018;103(11):4043-4088. PMID: 30272171

Critical Illness-Related Corticosteroid Insufficiency (CIRCI)

34. Annane D, Pastores SM, Arlt W, et al. Critical illness-related corticosteroid insufficiency (CIRCI): a narrative review from a Multispecialty Task Force of the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM). Intensive Care Med. 2017;43(12):1781-1792. PMID: 28940011

Fludrocortisone

35. Arlt W, Allolio B. Adrenal insufficiency. Lancet. 2003;361(9372):1881-1893. PMID: 12788587

Long-term Outcomes

36. Erichsen MM, Løvås K, Skinningsrud B, et al. Clinical, immunological, and genetic features of autoimmune primary adrenal insufficiency: observations from a Norwegian registry. J Clin Endocrinol Metab. 2009;94(12):4882-4890. PMID: 19858318

Mortality

37. Bergthorsdottir R, Leonsson-Zachrisson M, Odén A, Johannsson G. Premature mortality in patients with Addison's disease: a population-based study. J Clin Endocrinol Metab. 2006;91(12):4849-4853. PMID: 16968806

Quality of Life

38. Løvås K, Loge JH, Husebye ES. Subjective health status in Norwegian patients with Addison's disease. Clin Endocrinol (Oxf). 2002;56(5):581-588. PMID: 12030907

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Last updated: 2026-01-24 Citation count: 38 ACEM Emergency Medicine: Addisonian Crisis