Was untreated adrenal insufficiency a contributing factor in the death of a patient with a history of chemotherapy and immunotherapy, who presented with sepsis, perforated bowel, hypocortisolism, and anemia?

Was Untreated Adrenal Insufficiency a Contributing Factor in This Patient's Death?

Yes, untreated adrenal insufficiency very likely contributed to this patient's death, particularly given the combination of sepsis, perforated bowel, documented hypocortisolism, and history of immunotherapy—all of which create a perfect storm for adrenal crisis that is fatal without immediate hydrocortisone replacement.

Why Adrenal Insufficiency Was Likely Contributory

The Fatal Triad in This Case

• Septic shock with documented hypocortisolism is associated with 26% mortality at 90 days when adrenal insufficiency is present versus 10% when absent 1
• Relative adrenal insufficiency in critically ill patients is associated with higher risk of sepsis, septic shock, circulatory dysfunction, and new bacterial infections 1
• Adrenal crisis has a documented mortality rate, with two deaths occurring during crisis in a prospective 2-year follow-up of 423 patients 1
• The all-cause mortality risk ratio for patients with adrenal insufficiency is 2.19 for men and 2.86 for women, with excess mortality attributable to cardiovascular, malignant, and infectious diseases 2

Immunotherapy as a Direct Precipitant

• Cancer immunotherapy can cause secondary adrenal insufficiency through direct hypothalamic-pituitary damage 3
• Surgical episodes (perforated bowel requiring surgery) are documented precipitating factors for adrenal crisis 1, 2
• Sepsis itself is the most common precipitant of adrenal crisis in patients with underlying adrenal insufficiency 2

The Clinical Presentation Matches Adrenal Crisis

• Hypotension refractory to fluids and vasopressors without clear causation is a cardinal sign of adrenal insufficiency in critically ill patients 4, 5
• The documented hypocortisolism in the setting of septic shock represents inadequate cortisol response to maximal physiologic stress 1
• Any patient with unexplained hypotension who has received cancer treatment should be presumed to have adrenal insufficiency until proven otherwise 3

What Should Have Been Done

Immediate Treatment Protocol

• Hydrocortisone 100 mg IV bolus should have been administered immediately without waiting for diagnostic confirmation 3, 6
• This should be followed by continuous infusion of 200 mg/24 hours or 50 mg IV every 6 hours 1, 6
• Treatment should NEVER be delayed for diagnostic procedures—mortality is high if untreated 3, 6
• Fluid resuscitation with 0.9% saline at 1 L/hour (at least 2L total) should accompany steroid administration 3

The Evidence for Treatment in Septic Shock

• Hydrocortisone (50 mg IV every 6 hours or 200 mg infusion for 7 days or until ICU discharge) is recommended for refractory shock requiring high-dose vasopressors based on the ADRENAL and APROCCHSS trials, which documented earlier shock reversal and potential mortality benefit 1
• The Surviving Sepsis Campaign recommends intravenous hydrocortisone <400 mg/day for ≥3 days for patients with septic shock not responsive to fluid and moderate to high-dose vasopressor therapy 1, 6
• Treatment should continue for at least 3-5 days at full dose before considering a taper 6

Critical Diagnostic Clues That Were Present

Laboratory Findings Consistent with Adrenal Crisis

• Hyponatremia is present in 90% of newly diagnosed adrenal insufficiency cases 3
• Anemia is a documented hematologic manifestation of adrenal crisis 2
• The documented hypocortisolism in the context of septic shock represents inadequate adrenal response 1

The ACTH Stimulation Test Is Irrelevant Here

• The ACTH stimulation test should NOT be used to identify which patients with septic shock should receive hydrocortisone 1, 6
• The CORTICUS trial demonstrated that responders and nonresponders to ACTH testing had similar clinical outcomes with steroid treatment 1
• In unstable patients with volume-resistant hypotension, treatment should be given immediately without waiting for test results 6

Common Pitfalls That May Have Occurred

Failure to Recognize High-Risk Population

• Approximately 7 in 1,000 people are prescribed long-term corticosteroid therapy, creating a population 100 times larger than those with intrinsic adrenal insufficiency and at substantial risk for adrenal crisis 3
• All routes of glucocorticoid administration (including inhaled, topical, intranasal, and intra-articular) can suppress the hypothalamo-pituitary-adrenal axis 1, 3
• Cancer treatment with chemotherapy and immunotherapy places patients at high risk for adrenal insufficiency 3

Delaying Treatment for Diagnostic Confirmation

• The nonspecific presentation (hypotension, altered mental status, gastrointestinal symptoms) often leads to delayed recognition 4, 5
• Waiting for cortisol levels or ACTH stimulation test results in a hemodynamically unstable patient is a fatal error 3, 6
• The absence of hyperkalemia (which occurs in only ~50% of cases) cannot rule out adrenal insufficiency 3

Inadequate Dosing or Duration

• Some clinicians may have used dexamethasone instead of hydrocortisone, but hydrocortisone 200-300 mg/day is the preferred corticosteroid in septic shock 5
• Treatment must continue for at least 3 days at full dose, not just a single stress dose 1, 6
• Tapering should only begin when vasopressors are no longer required, not on a fixed schedule 1, 6

The Bottom Line

In a patient with chemotherapy/immunotherapy history presenting with septic shock, perforated bowel, and documented hypocortisolism, the failure to immediately administer hydrocortisone 100 mg IV followed by 200 mg/24 hour infusion represents a critical missed opportunity that very likely contributed to mortality. The evidence is clear that relative adrenal insufficiency in septic shock increases mortality from 10% to 26%, and that hydrocortisone treatment improves shock reversal and potentially mortality 1. The combination of multiple precipitating factors (sepsis, surgery, immunotherapy) with documented inadequate cortisol response makes untreated adrenal insufficiency a highly probable contributor to this patient's death 1, 2, 3.