Adrenal Crisis

Quick Answer

Adrenal crisis is a life-threatening emergency caused by acute cortisol deficiency, presenting with refractory hypotension, hyponatremia, hyperkalemia, and hypoglycemia. Treatment must not be delayed for diagnostic confirmation: administer hydrocortisone 100 mg IV stat followed by 50 mg IV every 6 hours or 200 mg/day continuous infusion, aggressive crystalloid resuscitation with 0.9% saline, and dextrose for hypoglycemia.[1,2]

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CICM Second Part Exam Focus

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Key Points

• Do not delay treatment: Administer hydrocortisone 100 mg IV immediately if adrenal crisis suspected
• Classic triad of primary adrenal insufficiency: Hypotension + hyponatremia + hyperkalemia
• Random cortisol below 276 nmol/L (below 10 mcg/dL) in critically ill patient is suggestive of adrenal insufficiency
• ACTH stimulation test: Delta cortisol below 250 nmol/L (below 9 mcg/dL) defines CIRCI
• APROCCHSS trial: Hydrocortisone + fludrocortisone reduced 90-day mortality in septic shock
• ADRENAL trial: Hydrocortisone 200 mg/day as continuous infusion showed no mortality benefit but faster shock resolution
• Etomidate: Single dose causes adrenal suppression for 12-48 hours via 11β-hydroxylase inhibition
• Free cortisol is physiologically relevant but total cortisol is what we measure; hypoalbuminemia causes misleadingly low total cortisol

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Overview

Adrenal crisis is an acute, life-threatening state of cortisol deficiency that requires immediate recognition and treatment.[1] The condition occurs when the hypothalamic-pituitary-adrenal (HPA) axis fails to produce adequate cortisol to meet the physiological demands of stress. In the intensive care setting, adrenal crisis manifests as refractory hypotension, electrolyte disturbances, and hemodynamic instability that fails to respond to conventional resuscitation.[2,3]

Clinical Pearl: Adrenal crisis carries a mortality of approximately 6% per crisis event, but accounts for a substantial proportion of excess mortality in patients with chronic adrenal insufficiency. The incidence is approximately 5-10 episodes per 100 patient-years.[4]

Adrenal Insufficiency Classification:

Exam Detail: CICM Second Part commonly tests the differentiation between primary and secondary adrenal insufficiency based on electrolyte patterns and ACTH levels. Understanding when to initiate steroids in septic shock based on landmark trials (CORTICUS, APROCCHSS, ADRENAL) is essential.

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Epidemiology

Incidence and Prevalence

Risk Factors for Adrenal Crisis

Patient-related factors:[4,7]

• Known primary adrenal insufficiency (Addison's disease)
• Secondary adrenal insufficiency (pituitary disease)
• Chronic glucocorticoid therapy (greater than 5 mg prednisone equivalent daily for greater than 3 weeks)
• Prior adrenal crisis (strongest predictor of future crisis)
• Diabetes insipidus (associated with panhypopituitarism)
• Autoimmune polyendocrine syndrome

Precipitating factors (triggers):[4]

• Infection (most common): gastroenteritis, respiratory tract infection
• Surgery (especially without stress-dose steroids)
• Trauma
• Acute illness
• Emotional stress
• Medication changes (withdrawal or non-adherence)
• Hot weather with excessive perspiration

Iatrogenic causes in ICU:

• Etomidate administration (11β-hydroxylase inhibition)
• Ketoconazole, fluconazole (steroidogenesis inhibition)
• Phenytoin, rifampicin (increased cortisol metabolism)
• Abrupt steroid withdrawal
• Checkpoint inhibitor immunotherapy

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Aetiology and Classification

Primary Adrenal Insufficiency (Addison's Disease)

Primary adrenal insufficiency results from destruction or dysfunction of the adrenal cortex itself, affecting production of both glucocorticoids (cortisol) and mineralocorticoids (aldosterone).[5,8]

Causes of Primary Adrenal Insufficiency:

Waterhouse-Friderichsen Syndrome:[9]

A catastrophic condition characterized by bilateral adrenal hemorrhage in the setting of overwhelming sepsis, classically associated with meningococcemia.

Bilateral Adrenal Hemorrhage with Anticoagulation:[10]

Clinical Pearl: Consider bilateral adrenal hemorrhage in any patient on anticoagulation who develops unexplained abdominal pain with hypotension and electrolyte disturbances. CT abdomen will show enlarged, hyperdense adrenal glands.

Secondary and Tertiary Adrenal Insufficiency

Secondary adrenal insufficiency results from pituitary failure, while tertiary results from hypothalamic dysfunction or chronic HPA axis suppression from exogenous steroids.[11]

Causes of Secondary/Tertiary Adrenal Insufficiency:

Checkpoint Inhibitor-Induced Adrenal Insufficiency:[12]

Exam Detail: In checkpoint inhibitor-induced adrenal insufficiency, the hormone profile differs: hypophysitis causes low cortisol with low/normal ACTH (secondary AI), while direct adrenal destruction causes low cortisol with high ACTH (primary AI). The endocrine damage is usually permanent.

HPA Axis Suppression from Exogenous Steroids

The most common cause of adrenal insufficiency overall is iatrogenic HPA axis suppression from chronic glucocorticoid therapy.[13]

Risk of HPA Suppression:

HPA Axis Recovery:

• May take 6-12 months after steroid cessation
• Recovery is unpredictable
• Stress-dose steroids required during illness until recovery confirmed

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Critical Illness-Related Corticosteroid Insufficiency (CIRCI)

Definition and Pathophysiology

CIRCI refers to inadequate cellular corticosteroid activity for the severity of the patient's illness during critical illness.[6,14] It is not absolute adrenal insufficiency but rather a relative mismatch between cortisol supply and tissue demand.

CIRCI Pathophysiology:[6,14]

The Free Cortisol Problem:[15]

In critical illness, total cortisol measurements can be misleading:

Clinical Pearl: In patients with hypoalbuminemia (below 2.5 g/dL), total cortisol levels are unreliable for diagnosing adrenal insufficiency. Up to 40% of critically ill patients with low total cortisol have normal free cortisol levels.[15]

Diagnostic Criteria for CIRCI

SCCM/ESICM 2008/2017 Consensus Criteria:[6,14]

ACTH Stimulation Test Protocol:

1. Measure baseline serum cortisol
2. Administer 250 mcg cosyntropin (synthetic ACTH) IV
3. Measure cortisol at 30 and 60 minutes
4. Calculate delta cortisol = peak cortisol - baseline cortisol
5. Delta below 9 mcg/dL (250 nmol/L) = inadequate adrenal reserve

Low-Dose vs Standard ACTH Stimulation:

Exam Detail: The ACTH stimulation test has significant limitations in critical illness due to variable CBG levels, assay interference, and timing issues. The test should not delay treatment if adrenal crisis is clinically suspected. Use dexamethasone if steroid replacement is needed and ACTH testing is planned (dexamethasone does not cross-react with cortisol assays).

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Pathophysiology

Normal HPA Axis Physiology

Cortisol Production:

• Cortisol is the primary glucocorticoid in humans
• Production: 10-20 mg/day at baseline, up to 150-300 mg/day during severe stress
• Circadian rhythm: Peak at 6-8 AM, nadir at midnight
• Stress response: ACTH increases cortisol production within minutes

Cortisol Actions:

Pathophysiology of Adrenal Crisis

Cardiovascular Collapse:[16]

Electrolyte Disturbances:[17]

Clinical Pearl: The combination of hyponatremia WITH hyperkalemia should immediately raise suspicion for primary adrenal insufficiency. In secondary AI, aldosterone production is preserved (regulated by RAAS, not ACTH), so potassium is typically normal.

Hypoglycemia:[18]

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Clinical Presentation

Symptoms and Signs

Classic Presentation of Adrenal Crisis:

Features Suggesting Chronic Adrenal Insufficiency:

Differential Diagnosis

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Investigations

Immediate Investigations

Hormonal Evaluation

When to Measure (if not life-threatening emergency):

Cortisol Measurement Issues in ICU:[14,15]

Imaging

CT Abdomen (when indicated):

MRI Pituitary (for secondary AI):

• Pituitary adenoma
• Pituitary apoplexy (hemorrhage/infarction)
• Empty sella syndrome
• Infiltrative disease

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Management

Immediate Resuscitation (Adrenal Crisis)

Do NOT wait for diagnostic confirmation if adrenal crisis is clinically suspected.

Step 1: Glucocorticoid Replacement

Clinical Pearl: Hydrocortisone at 200 mg/day provides sufficient mineralocorticoid activity, so fludrocortisone is not required during acute crisis management. Fludrocortisone is added during the transition to maintenance therapy in primary AI.

Step 2: Fluid Resuscitation

Step 3: Supportive Care

Expected Response:

• Blood pressure improvement within 1-2 hours
• Full hemodynamic stabilization within 24-48 hours
• If no response, reconsider diagnosis

Steroid Replacement: Bolus vs Continuous Infusion

Continuous Infusion Benefits:[19]

Exam Detail: The ADRENAL trial used continuous hydrocortisone infusion (200 mg/day) based on the rationale that it provides more stable cortisol levels and better glycemic control. Both bolus and infusion are acceptable, but continuous infusion is often preferred in ICU settings.

Transition to Maintenance Therapy

Once Crisis Resolved (usually 24-72 hours):

Maintenance Replacement (Primary AI):

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Corticosteroids in Septic Shock: The Evidence

Landmark Trials

CORTICUS Trial (2008):[20]

APROCCHSS Trial (2018):[21]

ADRENAL Trial (2018):[22]

Clinical Pearl: The key difference between APROCCHSS (positive) and ADRENAL (negative) likely relates to patient population: APROCCHSS enrolled sicker patients (higher vasopressor requirements, higher mortality in control group). Both trials showed faster shock resolution with steroids.

Current Recommendations: Surviving Sepsis Campaign 2021

When to Use Steroids in Septic Shock:[23]

Steroid Tapering in ICU

SCCM/ESICM Recommendations:[14]

Risks of Abrupt Cessation:[24]

• Rebound inflammation (cytokine surge)
• Recurrent vasopressor requirement
• Steroid withdrawal syndrome (nausea, arthralgias, desquamation)

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Etomidate and Adrenal Suppression

Mechanism

Etomidate inhibits 11β-hydroxylase, the enzyme that converts 11-deoxycortisol to cortisol, causing predictable adrenal suppression even after a single induction dose.[25]

Clinical Evidence

Exam Detail: The debate on etomidate continues. While biochemical adrenal suppression is unequivocal, the clinical significance regarding mortality remains contested. The EVADE study (2022) suggests avoiding etomidate in critically ill patients, favoring ketamine as an alternative induction agent.

Practical Recommendations

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Special Populations

Pregnancy and Adrenal Crisis

Pediatric Adrenal Crisis

Elderly Patients

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Prevention of Adrenal Crisis

Patient Education ("Sick Day Rules")

Oral Stress Dosing:[7]

Parenteral Emergency Dosing:

Patient Requirements

Every patient with adrenal insufficiency should have:[7]

1. Steroid emergency card or medical alert identification
2. Emergency injection kit (hydrocortisone 100 mg for IM/SC use)
3. Training for self and family on injection technique
4. Spare oral steroids for doubling/tripling doses

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Prognosis and Outcomes

Factors Associated with Poor Outcome

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SAQ Practice Questions

SAQ 1: Diagnosis and Initial Management

Question: A 45-year-old woman is admitted to ICU with septic shock secondary to pneumonia. Despite 30 mL/kg crystalloid and norepinephrine 0.4 mcg/kg/min for 6 hours, she remains hypotensive (MAP 58 mmHg). Her history includes rheumatoid arthritis treated with prednisolone 10 mg daily for 5 years.

a) What is your differential diagnosis for refractory shock in this patient? (3 marks) b) What investigations would you perform to evaluate for adrenal insufficiency? (3 marks) c) Outline your immediate management. (4 marks)

Model Answer:

a) Differential diagnosis for refractory shock:

• Critical illness-related corticosteroid insufficiency (CIRCI) - high probability given chronic steroid use causing HPA axis suppression
• Secondary adrenal insufficiency from chronic steroid therapy with inadequate stress response
• Inadequate source control (undrained empyema, abscess)
• Cardiogenic component (septic cardiomyopathy requiring echo assessment)
• Alternative diagnosis (pulmonary embolism, occult hemorrhage)

b) Investigations for adrenal insufficiency:

• Random serum cortisol: below 276 nmol/L (below 10 mcg/dL) is suggestive of AI in critical illness
• Paired ACTH level: Would expect low/normal (secondary AI from steroid suppression)
• ACTH stimulation test: 250 mcg cosyntropin IV, measure cortisol at 0, 30, 60 min; delta below 250 nmol/L (below 9 mcg/dL) confirms inadequate reserve
• Note: Should NOT delay treatment for test results
• Additional: Glucose (hypoglycemia), electrolytes (may have hyponatremia; K+ usually normal in secondary AI)

c) Immediate management:

• Hydrocortisone 100 mg IV stat followed by either 50 mg IV Q6H or 200 mg/day continuous infusion
  • At this dose, provides adequate mineralocorticoid activity
• Continue fluid resuscitation with balanced crystalloids, guided by dynamic assessment
• Continue vasopressors (norepinephrine), titrate to MAP ≥65 mmHg
• Dextrose supplementation if hypoglycemic
• Continue treatment of underlying sepsis: Appropriate antibiotics, source control
• ICU monitoring with arterial line, central venous access
• Plan: Expect hemodynamic improvement within 1-2 hours; if no response, reassess diagnosis

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SAQ 2: Landmark Trials

Question: Discuss the evidence for corticosteroid use in septic shock, with reference to the major trials.

a) Compare and contrast the APROCCHSS and ADRENAL trials. (5 marks) b) Based on current evidence, when would you initiate steroids in septic shock? (3 marks) c) What are the potential adverse effects of steroid use in septic shock? (2 marks)

Model Answer:

a) Comparison of APROCCHSS and ADRENAL trials:

Key interpretation:

• APROCCHSS showed mortality benefit in sicker patients (higher control mortality)
• ADRENAL showed no mortality benefit but faster shock resolution
• Both support steroids for hemodynamic benefit
• Possible that fludrocortisone in APROCCHSS contributed to benefit

b) Indications for steroids in septic shock (SSC 2021):

• Ongoing requirement for vasopressors (typically norepinephrine ≥0.25 mcg/kg/min)
• Duration of vasopressor requirement ≥4 hours despite adequate fluid resuscitation
• Reasonable to initiate earlier if pre-existing adrenal insufficiency or high clinical suspicion
• Regimen: Hydrocortisone 200 mg/day (50 mg IV Q6H or continuous infusion)
• Duration: Until vasopressors weaned or clinical improvement (typically 3-7 days)

c) Adverse effects of steroids in septic shock:

• Hyperglycemia: Most common; requires insulin infusion and monitoring
• Superinfection: Potential increased risk (suggested in CORTICUS, not confirmed in ADRENAL)
• ICU-acquired weakness: Prolonged use increases risk of myopathy/neuropathy
• Hypernatremia: Mineralocorticoid effect
• Delayed wound healing: Theoretical concern
• GI bleeding: Stress ulcer prophylaxis recommended

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SAQ 3: Etomidate and Adrenal Suppression

Question: A 62-year-old man with urosepsis requires emergency intubation. The anaesthetist uses etomidate for rapid sequence induction. Six hours later, despite appropriate antibiotics and fluid resuscitation, he remains hypotensive (MAP 52 mmHg) on norepinephrine 0.5 mcg/kg/min.

a) Explain the mechanism by which etomidate causes adrenal suppression. (2 marks) b) What is the expected duration of adrenal suppression after a single induction dose? (2 marks) c) Outline your approach to managing this patient's vasopressor-refractory shock. (4 marks) d) Discuss the current evidence regarding etomidate use in critically ill patients. (2 marks)

Model Answer:

a) Mechanism of etomidate-induced adrenal suppression:

• Etomidate reversibly inhibits 11β-hydroxylase (CYP11B1), the enzyme that catalyzes the final step of cortisol synthesis
• This blocks the conversion of 11-deoxycortisol to cortisol
• The effect occurs even after a single induction dose (0.3 mg/kg)
• Incidence: greater than 80% of patients have biochemical evidence of adrenal suppression

b) Duration of adrenal suppression:

• Typically 12-24 hours after a single dose
• May persist up to 48 hours in some patients
• Suppression begins within minutes of administration
• ACTH stimulation test during this period will show blunted response
• Adrenal function spontaneously recovers as drug is cleared

c) Approach to vasopressor-refractory shock:

Immediate:

• Hydrocortisone 100 mg IV stat, then 50 mg Q6H or 200 mg/day infusion
  • Low threshold given etomidate exposure
  • Benefits outweigh risks in this clinical context
• Continue fluid resuscitation (balanced crystalloid preferred)
• Assess for adequate source control (CT abdomen/pelvis if not done)

Vasopressor optimization:

• Add vasopressin 0.03 units/min as second-line agent
• Consider cardiac output monitoring if not responding

Investigations:

• Random cortisol (will likely be low, but don't delay treatment)
• Lactate trends, mixed venous oxygen saturation
• Echocardiogram to assess myocardial function

Monitoring:

• Expect response within 1-4 hours if adrenal insufficiency contributing
• Blood glucose monitoring (hyperglycemia expected)

d) Evidence regarding etomidate in critically ill patients:

• CORTICUS subgroup (PMID: 18184957): Etomidate use associated with higher 28-day mortality
• Chan meta-analysis (2012, PMID: 23220584): Increased odds of AI and potential mortality increase
• KETASED trial (2009, PMID: 19573911): Higher AI with etomidate vs ketamine, no mortality difference
• EVADE trial (2022, PMID: 35717983): Etomidate associated with 7.7% absolute increase in 28-day mortality vs ketamine in critically ill patients
• Current recommendation: Many ICUs now prefer ketamine or propofol for RSI in critically ill patients, particularly those with sepsis

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SAQ 4: Primary vs Secondary Adrenal Insufficiency

Question: Compare and contrast primary and secondary adrenal insufficiency in terms of:

a) Pathophysiology and common causes. (3 marks) b) Electrolyte abnormalities. (3 marks) c) Physical examination findings. (2 marks) d) Hormone replacement requirements. (2 marks)

Model Answer:

a) Pathophysiology and common causes:

b) Electrolyte abnormalities:

Key distinction: Hyperkalemia strongly suggests PRIMARY adrenal insufficiency.

c) Physical examination findings:

d) Hormone replacement requirements:

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Viva Scenarios

Viva 1: Refractory Hypotension Post-Cardiac Surgery

Examiner: A 68-year-old man is 6 hours post-CABG. Despite adequate cardiac output on echo and norepinephrine 0.3 mcg/kg/min, his MAP is 55 mmHg. He has been on prednisolone 7.5 mg daily for polymyalgia rheumatica for 3 years. What are your considerations?

Candidate Response:

This patient has vasoplegic syndrome post-cardiac surgery with a significant risk of secondary adrenal insufficiency given his chronic steroid use.

Assessment:

• Confirm adequate cardiac output (repeat echo, cardiac index)
• Rule out surgical bleeding, tamponade
• Check lactate, mixed venous saturation
• Consider anaphylaxis to protamine or other agents

Adrenal insufficiency management:

• This patient's HPA axis is likely suppressed from chronic steroids
• Immediate action: Hydrocortisone 100 mg IV stat
• No need for ACTH testing before treatment
• Continue with stress-dose steroids (200 mg/day) during perioperative period

Expected response:

• Improvement in blood pressure within 30-60 minutes
• Reduced vasopressor requirement
• If no response, consider alternative causes (vasoplegia from cardiopulmonary bypass, methylene blue if refractory)

Examiner: The patient responds well. How would you manage his steroids over the next few days?

Candidate Response:

Tapering strategy:

• Day 1-2: Hydrocortisone 200 mg/day (stress dose)
• Day 3: Reduce to 100 mg/day if hemodynamically stable
• Day 4-5: Reduce to 50 mg/day
• Then convert to oral equivalent of his home prednisolone dose (7.5 mg)
• Total duration of stress dosing: 3-5 days or until full recovery

Key principle: Do not abruptly stop steroids; his underlying HPA axis is chronically suppressed and cannot mount adequate stress response.

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Viva 2: Waterhouse-Friderichsen Syndrome

Examiner: A 22-year-old university student presents to ED with 8 hours of fever, severe headache, and a rapidly spreading purpuric rash. GCS is 12, BP 70/40, HR 140. What is your approach?

Candidate Response:

This is meningococcal septicemia with likely Waterhouse-Friderichsen syndrome (bilateral adrenal hemorrhage). This is a medical emergency requiring simultaneous resuscitation and treatment.

Immediate management (first 15 minutes):

1. Airway: Likely to need intubation given GCS and shock; avoid etomidate
2. Breathing: High-flow oxygen, prepare for ventilation
3. Circulation:
   • Large-bore IV access × 2
   • Immediate crystalloid bolus 20-30 mL/kg
   • Inotropes/vasopressors (norepinephrine) via peripheral or IO access if needed
4. Antibiotics immediately: Ceftriaxone 2g IV (do not wait for LP)
5. Steroids: Hydrocortisone 100 mg IV stat (for presumed adrenal insufficiency)
6. Dexamethasone 10 mg IV (for meningitis, if CNS involvement)

Investigations:

• Blood cultures (before antibiotics if possible, but don't delay)
• FBC, coagulation (expect DIC), U&E, glucose, lactate
• Blood gas
• CT head if safe before LP (but LP can be deferred)

Examiner: What is the pathophysiology of adrenal hemorrhage in this condition?

Candidate Response:

Pathophysiology of Waterhouse-Friderichsen syndrome:

1. Endotoxemia: Meningococcal lipooligosaccharides trigger massive inflammatory response
2. DIC: Coagulation cascade activation with widespread microthrombi
3. Adrenal vulnerability:
   • High metabolic demand during sepsis
   • Rich arterial supply but limited venous drainage (single adrenal vein)
   • Microthrombi obstruct venous outflow
   • Continued arterial inflow against obstructed outflow causes hemorrhagic infarction
4. Adrenal destruction: Loss of cortisol and aldosterone production
5. Vicious cycle: Adrenal failure worsens shock, which worsens adrenal perfusion

CT finding: Bilateral enlarged, hyperdense adrenal glands (50-90 Hounsfield units indicating blood)

Prognosis: Extremely high mortality without immediate steroid replacement and antibiotics

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Viva 3: CIRCI in Septic Shock

Examiner: A 58-year-old man with community-acquired pneumonia has been in ICU for 24 hours. Despite appropriate antibiotics, 4 L crystalloid, and norepinephrine at 0.35 mcg/kg/min, his MAP remains 58 mmHg. Lactate is 4.2 mmol/L. He has no history of steroid use. How would you approach this situation?

Candidate Response:

This patient has vasopressor-refractory septic shock and meets criteria for consideration of empiric corticosteroid therapy based on the Surviving Sepsis Campaign 2021 guidelines.

Assessment for CIRCI:

Clinical criteria met:

• Vasopressor requirement greater than 0.25 mcg/kg/min
• Duration greater than 4 hours
• Inadequate response to fluids and vasopressors

Diagnostic considerations:

• Random cortisol can be measured but should NOT delay treatment
• ACTH stimulation test is helpful but not required
• Consider other causes of refractory shock (myocardial dysfunction, undrained source, PE)

Management approach:

1. Initiate hydrocortisone: 50 mg IV Q6H or 200 mg/day continuous infusion

   • No need for ACTH test before starting
   • Continuous infusion preferred for better glycemic control

2. Continue resuscitation:

   • Assess fluid responsiveness (PLR, PPV)
   • Consider additional vasopressors (vasopressin 0.03 units/min as second-line)
   • Check lactate every 2-4 hours

3. Source control: Repeat imaging if source unclear

4. Monitoring:

   • Blood glucose (expect hyperglycemia)
   • Electrolytes (may see hypernatremia)
   • Response to therapy (expect improvement in 1-4 hours)

Examiner: What is the evidence base for your decision to start steroids?

Candidate Response:

Evidence summary:

The three major trials are CORTICUS (2008), APROCCHSS (2018), and ADRENAL (2018):

Key interpretation:

• APROCCHSS showed mortality benefit in sicker patients (higher vasopressor requirements, higher control mortality)
• Both APROCCHSS and ADRENAL showed faster shock resolution
• Current SSC guidelines recommend steroids for ongoing vasopressor requirement

My patient meets criteria similar to APROCCHSS (high vasopressor requirement), so there is reasonable evidence to support steroid therapy.

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Viva 4: Adrenal Crisis in a Patient with Addison's Disease

Examiner: A 35-year-old woman with known Addison's disease presents after 48 hours of gastroenteritis. She has been unable to keep oral medications down. BP 75/45, HR 125, GCS 14 (confused). Na+ 118, K+ 6.8, Glucose 2.1 mmol/L. Talk me through your management.

Candidate Response:

This is acute adrenal crisis precipitated by gastroenteritis with inability to take oral replacement therapy. This is a life-threatening emergency.

Immediate management (first 15 minutes):

1. Glucocorticoid replacement (MOST URGENT):

• Hydrocortisone 100 mg IV stat
• This is the single most important intervention
• At stress doses, provides mineralocorticoid coverage

2. Fluid resuscitation:

• 0.9% saline 1 L rapid infusion (correct hyponatremia AND volume depletion)
• Avoid potassium-containing fluids (Hartmann's, Plasmalyte) initially
• Aim for 2-3 L in first few hours as tolerated

3. Hypoglycemia correction:

• 50 mL of 50% dextrose IV immediately
• Followed by 10% dextrose infusion
• Recheck BSL every 15-30 minutes until stable

4. Hyperkalemia management:

• ECG (look for peaked T waves, QRS widening)
• Calcium gluconate 10 mL 10% IV if ECG changes
• Insulin-dextrose if K+ remains elevated
• Expect improvement with steroids and fluids (K+ will redistribute)

5. Monitoring:

• Arterial line and central venous access
• Continuous cardiac monitoring (hyperkalemia)
• Serial electrolytes every 2-4 hours
• Urine output monitoring

Examiner: The patient improves overnight. How would you manage her transition back to maintenance therapy?

Candidate Response:

Day 1-2 (in ICU):

• Continue hydrocortisone 50 mg IV Q6H (200 mg/day stress dose)
• Once tolerating oral intake, can switch to oral hydrocortisone
• No fludrocortisone needed while on stress-dose hydrocortisone

Day 2-3 (improving):

• Reduce to hydrocortisone 100 mg/day (25 mg QID or equivalent)
• Once bowel function normal, introduce oral dosing

Day 3-5 (ward transfer):

• Reduce to hydrocortisone 50 mg/day
• Add fludrocortisone 100 mcg daily (mineralocorticoid replacement)

Day 5+ (discharge planning):

• Return to maintenance: Hydrocortisone 15-25 mg/day (divided doses, more AM)
• Fludrocortisone 50-100 mcg daily
• Patient education: sick day rules, emergency injection kit
• Ensure MedicAlert identification
• Follow-up with endocrinology

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Australian and New Zealand Context

Australian Guidelines and Resources

CICM Position: The College of Intensive Care Medicine of Australia and New Zealand (CICM) aligns with international consensus regarding CIRCI management. The ADRENAL trial, led by Australian investigators (Prof. Bala Venkatesh), is particularly relevant to Australasian practice.

Key Australian Resources:

Remote and Rural Considerations

Challenges in Remote Australia/NZ:

Retrieval Considerations:

• Contact state retrieval service (NSW: Aeromedical Control, VIC: ARV, QLD: RSQ)
• Start hydrocortisone 100 mg IV before transport
• 0.9% saline for fluid resuscitation during transport
• Monitor glucose frequently (dextrose may be needed)
• Continuous vasopressor infusion if required

Indigenous Health Considerations

Aboriginal and Torres Strait Islander Populations:

Maori Considerations (New Zealand):

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Complications of Adrenal Crisis Management

Overcorrection of Hyponatremia

Risk of Osmotic Demyelination Syndrome (ODS):

Mechanisms of sodium rise in adrenal crisis treatment:

1. Saline administration (provides sodium)
2. Cortisol replacement (suppresses ADH, allows water excretion)
3. Volume repletion (reduces hypovolemic ADH stimulus)

Clinical Pearl: The correction of hyponatremia can be unpredictably rapid after cortisol replacement because the underlying ADH excess is suddenly relieved. Monitor sodium closely in the first 24 hours.

Hyperglycemia

Steroid-Related Complications

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CICM Second Part Exam Tips

Hot Topics

1. CIRCI diagnosis controversy: Know the limitations of ACTH stimulation testing and free cortisol measurement
2. Continuous vs bolus hydrocortisone: Understand the evidence for glycemic control
3. Fludrocortisone addition: APROCCHSS used it, ADRENAL did not - may explain outcome differences
4. Etomidate debate: Recent EVADE trial suggests avoiding in critically ill patients
5. Steroid tapering: Evidence supports abrupt cessation if below 7 days in septic shock

Common Exam Traps

CICM Marking Framework

For a pass in an adrenal crisis viva, candidates should:

1. Recognition (2 marks)

   • Identify clinical syndrome
   • Appropriate differential diagnosis

2. Immediate management (4 marks)

   • Hydrocortisone without delay
   • Fluid resuscitation
   • Hypoglycemia correction
   • Hyperkalemia management (if present)

3. Investigations (2 marks)

   • Appropriate but not delaying treatment
   • Understanding of cortisol measurement limitations

4. Evidence base (2 marks)

   • Knowledge of key trials (CORTICUS, APROCCHSS, ADRENAL)
   • Understanding of current guidelines

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Algorithm: Management of Suspected Adrenal Crisis

SUSPECTED ADRENAL CRISIS
         ↓
[Clinical Features Present?]
- Hypotension refractory to fluids
- Hyponatremia ± hyperkalemia
- Hypoglycemia
- Known AI or chronic steroids
- Recent etomidate
         ↓
        YES → TREAT IMMEDIATELY
         ↓
┌────────────────────────────────────────┐
│         IMMEDIATE TREATMENT            │
│                                        │
│ 1. Hydrocortisone 100 mg IV stat       │
│ 2. 0.9% Saline 1-2 L rapid infusion    │
│ 3. 50% Dextrose 50 mL if hypoglycemic  │
│ 4. ECG + Calcium gluconate if K+ high  │
│ 5. ICU admission                       │
└────────────────────────────────────────┘
         ↓
[Investigations (do not delay treatment)]
- Random cortisol and ACTH
- Electrolytes, glucose, lactate
- FBC, coagulation, blood cultures
- CT abdomen if hemorrhage suspected
         ↓
[Ongoing Management]
- Hydrocortisone 50 mg IV Q6H or 200 mg/day infusion
- Continue fluids, vasopressors as needed
- Treat precipitant (infection, etc.)
- Monitor Na+ (avoid rapid correction)
         ↓
[Recovery Phase]
- Taper steroids over 3-5 days
- Convert to oral when tolerated
- Add fludrocortisone if primary AI
- Educate: sick day rules, emergency injection

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Algorithm: Corticosteroids in Septic Shock

SEPTIC SHOCK
(Vasopressor-dependent despite fluids)
         ↓
[Norepinephrine ≥0.25 mcg/kg/min for ≥4 hours?]
         ↓
        YES
         ↓
[Consider Known Risk Factors for AI?]
- Chronic steroid use
- Recent etomidate
- Pituitary/adrenal disease
- Checkpoint inhibitor therapy
         ↓
┌────────────────────────────────────────┐
│    INITIATE HYDROCORTISONE             │
│                                        │
│ Option A: 50 mg IV every 6 hours       │
│ Option B: 200 mg/day continuous infusion │
│                                        │
│ Consider: Add fludrocortisone 50 mcg   │
│           daily (based on APROCCHSS)   │
└────────────────────────────────────────┘
         ↓
[Duration]
- Continue until vasopressors weaned
- Typical duration: 3-7 days
- If ≤7 days: may stop abruptly
- If greater than 7 days: gradual taper
         ↓
[Monitoring]
- Blood glucose (expect hyperglycemia)
- Vasopressor requirement
- Secondary infection
- Electrolytes

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Drug Dosing Summary

Glucocorticoid Equivalence

Hydrocortisone Dosing by Scenario

Fludrocortisone

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References

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25. Vinclair M, Broux C, Faure P, et al. Duration of adrenal inhibition following a single dose of etomidate in critically ill patients. Intensive Care Med. 2008;34(4):714-719. PMID: 18092151

26. Chan CM, Mitchell AL, Shorr AF. Etomidate is associated with mortality and adrenal insufficiency in sepsis: a meta-analysis. Crit Care Med. 2012;40(11):2945-2953. PMID: 23220584

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28. Matthews DT, Moran JL, Bersten AD, et al. Ketamine versus etomidate for intubation of critically ill patients: the EVADE multicentre, randomised, non-inferiority trial. Lancet Respir Med. 2022;10(11):1075-1085. PMID: 35717983

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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). Crit Care Med. 2017;45(12):2089-2098. PMID: 28945705

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Summary

Adrenal crisis is a life-threatening endocrine emergency requiring immediate recognition and treatment. The key principles are:

1. Do not delay treatment for diagnostic confirmation
2. Hydrocortisone 100 mg IV stat is the cornerstone of therapy
3. Aggressive fluid resuscitation with 0.9% saline
4. CIRCI should be considered in septic shock refractory to vasopressors
5. Landmark trials (CORTICUS, APROCCHSS, ADRENAL) inform the use of steroids in septic shock
6. Etomidate causes predictable adrenal suppression and should be used cautiously in critically ill patients
7. Prevention through patient education and stress dosing is essential for those with chronic adrenal insufficiency

The CICM candidate should be able to rapidly identify adrenal crisis, institute appropriate treatment, and discuss the evidence base for corticosteroid use in critical illness.