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2025 PACUPrep BCCCP Preparatory Course Relative Adrenal Insufficiency and Stress-Dose Steroid Therapy Diagnostic and Classification Criteria for RAI

Lesson 46, Topic 2

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Diagnostic and Classification Criteria for RAI

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Relative Adrenal Insufficiency: Diagnosis and Management

Diagnostic and Classification Criteria for Relative Adrenal Insufficiency

Learning Objective

Apply clinical assessment, laboratory evaluation, and severity scoring to diagnose relative adrenal insufficiency (RAI) and guide early stress-dose steroid therapy in vasopressor-dependent shock.

1. Clinical Assessment and Risk Stratification

Early recognition of relative adrenal insufficiency (RAI) depends on identifying patients with fluid-refractory hypotension and escalating vasopressor requirements. Integrating key clinical signs with severity scores helps prioritize diagnostic testing or empiric therapy.

Indications for Adrenal Function Evaluation

Persistent hypotension (Mean Arterial Pressure <65 mm Hg) after adequate fluid resuscitation (e.g., ≥30 mL/kg crystalloid).
Escalating vasopressor requirement (e.g., norepinephrine ≥0.2 µg/kg/min or equivalent) without a clear reversible cause.
New or worsening hyponatremia or unexplained hypoglycemia.
Altered mental status or profound, unexplained fatigue in the ICU setting.

Severity Scores and RAI Risk

While no dedicated RAI score exists, general critical illness severity indices can gauge urgency and risk. Higher APACHE II and SOFA scores correlate with a greater likelihood of hypothalamic-pituitary-adrenal (HPA) axis dysfunction in cohorts of patients with sepsis and trauma.

Key Pearl: The Time Factor

Any vasopressor-dependent shock state that persists beyond 4 to 6 hours, despite appropriate fluid resuscitation and source control, should raise high suspicion for RAI. This clinical milestone is a critical trigger to consider adrenal testing or the initiation of empiric stress-dose steroids.

2. Basal Cortisol Measurement

A single morning (ideally 8–9 AM) serum cortisol level provides a rapid, valuable screen of adrenal reserve. However, its interpretation must account for the profound physiological changes of critical illness, particularly altered binding proteins and assay variability.

Interpretive Thresholds for Total Cortisol in Shock

Interpretation of Random Total Cortisol Levels in Critically Ill Patients
Cortisol Level (nmol/L)	Cortisol Level (µg/dL)	Clinical Interpretation	Recommended Action
<150	<5	Suggests significant adrenal insufficiency. The adrenal gland is failing to mount a stress response.	Initiate stress-dose steroids immediately.
150–300	5–10	Indeterminate. This response may be inadequate for the degree of physiological stress.	Proceed to dynamic testing (if feasible) or initiate empiric therapy based on clinical severity.
>300	>10	Likely adequate adrenal reserve. The HPA axis is appropriately responding to stress.	RAI is unlikely. Continue to search for other causes of shock.

Note: Critical illness lowers cortisol-binding globulin (CBG), meaning total cortisol levels may underestimate the biologically active free hormone. Always use consistent assay platforms and institutional reference ranges.

3. Cosyntropin (ACTH) Stimulation Testing

The 250 µg cosyntropin stimulation test directly evaluates the adrenal gland’s responsiveness to ACTH. While considered a gold standard, its utility can be confounded by high baseline cortisol levels and the altered protein-binding state common in critical illness.

Standard-Dose (250 µg) Protocol Flow

Figure 1: The Standard-Dose Cosyntropin Stimulation Test. This protocol assesses the adrenal gland’s capacity to produce cortisol in response to a maximal stimulus.

Diagnostic Criteria for RAI

A peak cortisol level at 30 or 60 minutes that is less than 500–550 nmol/L (<18–20 µg/dL).
An incremental rise (Δ) from baseline to peak that is less than 250 nmol/L (<9 µg/dL).

Key Pearl: Treat First, Test Later

In a patient with refractory shock, do not withhold life-saving empiric hydrocortisone while awaiting the feasibility or results of a cosyntropin stimulation test. The priority is hemodynamic stabilization. If possible, draw a baseline cortisol level before administering the first dose of steroids, but do not delay therapy for this purpose if the patient is deteriorating.

4. Empiric Stress-Dose Steroid Initiation

In fluid-refractory, vasopressor-dependent shock, the empiric administration of stress-dose hydrocortisone is a critical intervention aimed at restoring vascular tone and facilitating vasopressor weaning. This therapeutic trial often precedes formal diagnostic confirmation.

Clinical Scenarios for Empiric Therapy

Progressive shock with escalating vasopressor doses despite adequate fluid resuscitation and source control.
High clinical suspicion for RAI (e.g., risk factors, suggestive labs) in a hemodynamically unstable patient.

Hydrocortisone Dosing Strategies

Intermittent Bolus: 50 mg IV every 6 hours (total 200 mg/day). This is the most common and studied regimen.
Continuous Infusion: 200 mg over 24 hours (approximately 8.3 mg/hr). This may prevent peaks in blood glucose.

Therapy duration should be tailored to shock resolution. Once vasopressors have been weaned off for 24 hours, a gradual taper of hydrocortisone should be planned.

Risk-Benefit Considerations

Potential Benefits: Faster shock reversal, reduced duration and dose of vasopressors, and a potential mortality benefit in select populations (e.g., septic shock).
Potential Risks: Hyperglycemia, immunosuppression leading to secondary infections, and potential for ICU-acquired weakness.

5. Summary of High-Yield Points

Suspect RAI in any patient with persistent hypotension and escalating vasopressor needs after adequate volume resuscitation.
A morning total cortisol <150 nmol/L (<5 µg/dL) strongly suggests RAI; >300 nmol/L (>10 µg/dL) makes it unlikely. Levels in between are indeterminate.
The standard-dose cosyntropin (250 µg) test is diagnostic for RAI if the peak cortisol is <500–550 nmol/L (<18–20 µg/dL) or the rise from baseline (Δ) is <250 nmol/L (<9 µg/dL).
Empiric hydrocortisone (200 mg/day) is indicated and should not be delayed in refractory shock while awaiting diagnostic clarity.

References

Marik PE, Zaloga GP. Adrenal insufficiency in the critically ill: a new look at an old problem. Chest. 2002;122(5):1784–1796.
Kromah F, Tyroch A, McLean S, et al. Relative adrenal insufficiency in the critical care setting: debunking the classic myth. World J Surg. 2011;35(8):1818–1823.
Marik PE, Pastores SM, Annane D, et al. Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients. Crit Care Med. 2008;36(6):1937–1949.
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.
Cooper MS, Stewart PM. Corticosteroid insufficiency in acutely ill patients. N Engl J Med. 2003;348(8):727–734.
Beuschlein F, Else T, Bancos I, 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.
Kumar R, Carr P, Wassif W. Diagnostic performance of morning serum cortisol as an alternative to short synacthen test for the assessment of adrenal reserve: a retrospective study. Postgrad Med J. 2022;98(1156):113–118.
Kazlauskaite R, Evans AT, Villabona CV, et al. Corticotropin tests for hypothalamic-pituitary-adrenal insufficiency: a meta-analysis. J Clin Endocrinol Metab. 2008;93(11):4245–4253.

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