2025 PACUPrep BCCCP Preparatory Course Relative Adrenal Insufficiency and Stress-Dose Steroid Therapy Foundational Principles: Epidemiology, Pathophysiology, and Risk Factors
Relative Adrenal Insufficiency: Epidemiology, Pathophysiology, and Risk Factors

Relative Adrenal Insufficiency: Epidemiology, Pathophysiology, and Risk Factors

Objectives Icon A target symbol, representing a learning goal.

Lesson Objective

Summarize the epidemiology and incidence of Relative Adrenal Insufficiency (RAI) in critically ill patients.

1. Definition and Epidemiology of Relative Adrenal Insufficiency

Relative Adrenal Insufficiency (RAI), now more commonly termed critical illness–related corticosteroid insufficiency (CIRCI), describes a state where the cortisol activity is inadequate to meet the profound metabolic and inflammatory demands of severe systemic stress. This functional insufficiency contributes directly to hemodynamic instability and refractory shock.

Diagnostic Criteria and Incidence

Diagnosis is based on a combination of clinical context (e.g., refractory shock) and biochemical testing, though the latter is often debated. The incidence varies significantly depending on the patient population and the diagnostic criteria used.

Diagnostic Thresholds and Incidence of CIRCI in Critical Illness
Category Biochemical Criteria Reported Incidence
Diagnostic Threshold Random total cortisol ≤10 µg/dL Highly specific but insensitive
Stimulation Test Δ cortisol <9 µg/dL after 250-µg cosyntropin Commonly used in clinical trials
Septic Shock Cohorts Varies with definition 30–50%
Surgical ICU Patients Suboptimal cosyntropin response Up to 40%
Major Trauma Patients Varies with definition ~20–30%

High-Risk Cohorts

Recognition of CIRCI has increased following the publication of consensus guidelines. The risk is significantly elevated in patients with:

  • Multi-organ dysfunction (e.g., ARDS, hepatic failure, renal replacement therapy).
  • Pre-existing conditions like pituitary disease or HIV.
  • A history of chronic or recent high-dose steroid use.
Clinical Pearl Icon A lightbulb, symbolizing an idea or clinical pearl. Clinical Pearl

Suspect RAI in any septic shock patient requiring vasopressors after ≥1 hour of adequate fluid resuscitation. While biochemical tests are useful, total cortisol assays can be misleading due to changes in binding proteins. The clinical response to empiric steroids (e.g., vasopressor weaning) is often the most practical diagnostic indicator.

2. Pathophysiology and HPA Axis Dysfunction

In critical illness, the finely tuned hypothalamic-pituitary-adrenal (HPA) axis is disrupted at multiple levels. This dysfunction, combined with altered cortisol metabolism, results in a state of functional glucocorticoid insufficiency despite potentially normal or elevated serum cortisol levels.

HPA Axis Dysfunction in Critical Illness A flowchart illustrating the Hypothalamic-Pituitary-Adrenal (HPA) axis. The normal pathway shows the hypothalamus releasing CRH, stimulating the pituitary to release ACTH, which causes the adrenal cortex to produce cortisol. In critical illness, cytokines like TNF-α and IL-1β inhibit the hypothalamus and pituitary, and peripheral glucocorticoid receptors become resistant, leading to functional adrenal insufficiency. HPA Axis in Critical Illness Hypothalamus (CRH) Pituitary (ACTH) Adrenal Cortex (Cortisol) Proinflammatory Cytokines (TNF-α, IL-1β) Glucocorticoid Receptor Resistance Negative Feedback
Figure 1: Pathophysiology of CIRCI. Critical illness disrupts the HPA axis through two primary mechanisms: (1) Proinflammatory cytokines suppress the release of CRH and ACTH, blunting the central stress response. (2) Peripheral tissues develop glucocorticoid receptor resistance, impairing cortisol’s ability to modulate inflammation and support vascular tone, even with normal serum levels.
Key Points Icon A document with a checkmark, indicating key takeaways. Key Pathophysiologic Points
  • Impaired Signaling: Proinflammatory cytokines (TNF-α, IL-1β) directly inhibit CRH and ACTH release, while prolonged high cortisol levels can cause receptor desensitization.
  • Altered Metabolism: In critical illness, cortisol’s half-life is often prolonged due to reduced clearance. Furthermore, levels of cortisol-binding globulin (CBG) decrease, increasing the fraction of “free” (active) cortisol. This makes interpretation of total cortisol levels challenging.
  • Therapeutic Rationale: A “stress dose” of exogenous hydrocortisone (e.g., 200 mg/day) is intended to overcome receptor resistance and bypass defects in the HPA signaling cascade, restoring adequate glucocorticoid effect at the tissue level.

3. Risk Factors and Precipitating Conditions

The development of CIRCI is multifactorial, stemming from the acute insult, underlying patient comorbidities, chronic medication exposure, and broader social determinants of health.

Major Precipitants and Comorbidities

  • Acute Illness: Sepsis and septic shock are the most common triggers. Prolonged ICU stays, multi-organ failure, and major trauma are also strong precipitants.
  • Chronic Steroid Use: Use of prednisone >10 mg/day (or equivalent) for more than a week can suppress the HPA axis for months. This risk persists even after the steroids are discontinued, necessitating perioperative stress-dose coverage.
  • Underlying Disease: Conditions like diabetes mellitus and cardiovascular disease may blunt the normal stress response. HIV and pre-existing pituitary disorders can directly impair cortisol synthesis.

Social Determinants of Health

Patient-level factors can significantly influence risk and outcomes. Low health literacy may delay the recognition of an impending adrenal crisis in steroid-dependent patients. Limited access to care can prevent at-risk individuals from obtaining emergency hydrocortisone kits and medical alert identification.

Editor’s Note IconA pencil editing a document, indicating an editorial note. Editor’s Note: Gaps in Evidence

There is insufficient high-quality evidence to provide definitive guidance on perioperative stress-dosing and tapering protocols for patients with chronic steroid-induced HPA axis suppression. A comprehensive clinical guideline would need to address:

  • Evidence-based perioperative stress-dose regimens tailored to the level of surgical stress.
  • The expected time course of HPA axis recovery after steroid withdrawal.
  • Optimal monitoring strategies (e.g., morning cortisol, ACTH stimulation) during steroid tapering.
Clinical Pearl IconA lightbulb, symbolizing an idea or clinical pearl. Clinical Pearl

Always inquire about all forms of exogenous steroid exposure, including oral, inhaled, topical, and intra-articular preparations. For patients with known adrenal insufficiency or long-term steroid use, proactive education, including providing steroid emergency cards and training on self-injection of hydrocortisone, is a critical, life-saving intervention.

4. Clinical Presentation and Recognition

The clinical presentation of CIRCI is often masked by the underlying critical illness. The hallmark sign is refractory hypotension, but other nonspecific systemic symptoms are common. Early recognition and empiric treatment are crucial for improving outcomes.

Case Vignette

A 60-year-old man with septic shock remains on norepinephrine 0.1 µg/kg/min after 4 hours of resuscitation with 30 mL/kg of crystalloid fluids. His random total cortisol level is 18 µg/dL. Empiric hydrocortisone 50 mg IV every 6 hours is initiated, leading to rapid weaning and discontinuation of vasopressors within 12 hours.

Hemodynamic and Systemic Signs

  • Hemodynamic Instability: The most prominent feature is vasopressor-dependent hypotension despite adequate fluid resuscitation (euvolemia). A rapid and significant reduction in vasopressor requirements after steroid initiation is highly suggestive of CIRCI.
  • Nonspecific Features: Patients may exhibit fatigue, anorexia, unexplained fever, or confusion. Electrolyte abnormalities like hyponatremia (due to non-osmotic ADH release) can occur, but hyperkalemia is rare in CIRCI (unlike in primary adrenal failure). Hypoglycemia can be a late finding.

Diagnostic Red Flags

  • Persistent or worsening lactic acidosis despite otherwise appropriate resuscitation.
  • A new or escalating requirement for vasopressors to maintain mean arterial pressure.
  • If the patient is stable enough, a cosyntropin stimulation test can be considered, but this should never delay empiric therapy in a patient with refractory shock.
Clinical Pearl IconA lightbulb, symbolizing an idea or clinical pearl. The “Treat First” Principle

In a patient with suspected RAI and refractory shock, the immediate priority is hemodynamic stabilization. Start empiric hydrocortisone 50 mg IV q6h (or a 100 mg bolus followed by a 200 mg/24h infusion) immediately. Diagnostic testing can be performed concurrently or after the patient is stabilized, but treatment should not be withheld pending results.

References

  1. Bornstein SR et al. Diagnosis and treatment of primary adrenal insufficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2016;101(2):364–389.
  2. Kromah F et al. Relative adrenal insufficiency in the critical care setting: debunking the classic myth. World J Surg. 2011;35(8):1818–1823.
  3. Annane D et al. Guidelines for the diagnosis and management of critical illness–related corticosteroid insufficiency (CIRCI) in critically ill patients. Crit Care Med. 2017;45(12):2078–2088.
  4. Boonen E et al. Reduced cortisol metabolism during critical illness. N Engl J Med. 2013;368(15):1477–1488.
  5. Broersen LHA et al. Adrenal insufficiency in corticosteroid use: systematic review and meta-analysis. J Clin Endocrinol Metab. 2015;100(6):2171–2180.
  6. Beuschlein F et al. European Society of Endocrinology and Endocrine Society joint clinical guideline: diagnosis and therapy of glucocorticoid-induced adrenal insufficiency. J Clin Endocrinol Metab. 2024;109(7):1657–1683.
  7. Hahner S et al. High incidence of adrenal crisis in educated patients with chronic adrenal insufficiency: a prospective study. J Clin Endocrinol Metab. 2015;100(1):407–416.
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