Critical Systems Failure Leading to Patient Death
The patient died from unrecognized and untreated adrenal insufficiency (cortisol 1.8 µg/dL) that progressed to adrenal crisis, compounded by checkpoint inhibitor-induced hypophysitis and the immunosuppressive/metabolic stress of carboplatin chemotherapy—a preventable death caused by a 5-day delay in reviewing a critically abnormal laboratory result.
Why the Cortisol Result Was Not Reviewed for 5 Days
Systems-Level Failures
Critical laboratory values require immediate notification protocols. A morning cortisol of 1.8 µg/dL is diagnostic of severe adrenal insufficiency and represents a life-threatening emergency requiring same-day recognition and treatment 1, 2.
Laboratory information systems should flag cortisol <5 µg/dL as a critical value requiring immediate physician notification, as values <9 µg/dL with clinical illness are diagnostic of primary adrenal insufficiency 1, 2.
Common institutional failures include: inadequate critical value notification systems, lack of automated alerts for endocrine emergencies, results routed to incorrect providers, weekend/holiday coverage gaps, and absence of fail-safe mechanisms for life-threatening laboratory abnormalities 1.
Clinical Context Requiring Immediate Action
Any patient on checkpoint inhibitors with unexplained hypotension, collapse, nausea, vomiting, or hyponatremia must have cortisol checked emergently and empiric hydrocortisone 100 mg IV administered immediately without waiting for results 1, 3.
Checkpoint inhibitor-induced hypophysitis occurs in 0.1-18% of patients and can present with nonspecific symptoms including exhaustion, hyponatremia, and headache—making early recognition challenging but critical 3.
Treatment of suspected adrenal crisis should NEVER be delayed for diagnostic procedures—mortality is high if untreated, and empiric hydrocortisone must be given immediately when adrenal insufficiency is suspected 4, 1.
Mechanism of Death on Day 5 After Chemotherapy and Immunotherapy
Checkpoint Inhibitor-Induced Hypophysitis
Checkpoint inhibitors cause destructive hypophysitis leading to ACTH deficiency and secondary adrenal insufficiency, which can evolve rapidly from initial presentation to severe corticotroph deficiency 5, 3.
Hypophysitis typically presents with nonspecific symptoms (fatigue, headache, nausea) that are easily attributed to cancer or chemotherapy rather than recognized as endocrine emergency 3.
The combination of ipilimumab and nivolumab carries higher risk of immune-related endocrinopathies than single-agent therapy, with hypophysitis occurring in up to 18% of patients on combination regimens 5, 3.
Carboplatin-Induced Metabolic Stress
Carboplatin chemotherapy creates severe physiologic stress requiring 2-3 times normal cortisol production—a demand that cannot be met in patients with adrenal insufficiency 1.
Chemotherapy-induced nausea, vomiting, and anorexia further deplete cortisol reserves and precipitate adrenal crisis in patients with underlying hypoadrenalism 1.
The combination of checkpoint inhibitors and platinum chemotherapy creates a "perfect storm" of immune-mediated pituitary destruction plus metabolic stress exceeding the patient's cortisol production capacity 5, 3, 6.
Progression to Fatal Adrenal Crisis
Untreated adrenal insufficiency progresses to adrenal crisis characterized by severe hypotension/shock, altered mental status, severe vomiting/diarrhea, hyponatremia, hyperkalemia, and hypoglycemia 1.
Adrenal crisis is a medical emergency with high mortality if not recognized and treated immediately with IV hydrocortisone 100 mg bolus plus aggressive saline resuscitation at 1 L/hour 4, 1.
The 5-day delay allowed progression from compensated adrenal insufficiency to decompensated crisis—during which time the patient likely developed refractory hypotension, cardiovascular collapse, and multi-organ failure 4, 1.
Specific Pathophysiology of Death
Severe hypotension refractory to vasopressors occurs in adrenal crisis because cortisol is required for vascular responsiveness to catecholamines—without cortisol, blood pressure cannot be maintained despite maximal vasopressor support 4, 1.
Hyponatremia and hypoglycemia cause cerebral edema, seizures, and altered mental status progressing to coma 4, 1.
Cardiovascular collapse and shock lead to multi-organ failure including acute kidney injury, hepatic dysfunction, and ultimately cardiac arrest 4, 1.
Critical Pitfalls That Led to This Death
Failure to Recognize High-Risk Clinical Scenario
Any patient taking checkpoint inhibitors who develops unexplained hypotension should be presumed to have adrenal insufficiency until proven otherwise and treated empirically with stress-dose hydrocortisone 1, 3.
Checkpoint inhibitor-induced hypophysitis can present with thyroiditis followed by corticotroph deficiency—the sequence seen in reported cases where pituitary findings were preceded by thyroid dysfunction 5.
Failure to Implement Stress-Dose Steroids
Patients receiving chemotherapy with known or suspected adrenal insufficiency require stress-dose hydrocortisone 100-150 mg daily during treatment to prevent crisis 1.
The standard approach is hydrocortisone 100 mg IV immediately, then 50 mg IV every 6 hours during acute illness or major physiologic stress 1.
Absence of Monitoring Protocols
Patients on checkpoint inhibitors should have baseline and interval monitoring of TSH, free T4, cortisol, and ACTH at each infusion visit to detect endocrinopathies early 3.
Clinical warning signs requiring immediate cortisol assessment include new-onset fatigue, hypotension, hyponatremia, nausea/vomiting, or headache in checkpoint inhibitor-treated patients 3.
How This Death Could Have Been Prevented
Immediate Recognition and Treatment
A cortisol of 1.8 µg/dL should have triggered immediate notification to the treating oncologist with recommendation for emergency hydrocortisone 100 mg IV bolus 1, 2.
Empiric treatment should have been initiated on day 1 when the cortisol was drawn, not waiting 5 days for review—any patient sick enough to warrant cortisol testing is sick enough to treat empirically 1.
Institutional Safeguards
Critical laboratory value policies must include cortisol <5 µg/dL as requiring immediate (within 1 hour) physician notification with documented read-back 1, 2.
Electronic health record alerts should fire when cortisol results <5 µg/dL are resulted in patients on checkpoint inhibitors or chemotherapy 1, 3.
Mandatory endocrine consultation protocols should be triggered for all patients on checkpoint inhibitors who develop hypotension, hyponatremia, or unexplained clinical deterioration 1, 3.
Patient Safety Measures
All patients starting checkpoint inhibitors should receive education about warning signs of adrenal insufficiency and instructions to seek immediate care for severe fatigue, dizziness, nausea, or vomiting 3.
Patients with confirmed checkpoint inhibitor-induced hypophysitis must wear medical alert bracelets indicating adrenal insufficiency to trigger emergency stress-dose steroids 1.