Likely Cause of Death in Secondary Adrenal Insufficiency on Hydrocortisone Replacement
The patient most likely died from adrenal crisis precipitated by inadequate stress-dose glucocorticoid coverage during the acute physiological stress of chemotherapy and immunotherapy, compounded by possible gastrointestinal illness preventing oral medication absorption. 1, 2
Understanding the Critical Pathophysiology
Patients with secondary adrenal insufficiency cannot mount an appropriate cortisol stress response and require 2-3 times their maintenance hydrocortisone dose during illness, infection, or major physiological stress. 3, 4 The combination of recent chemotherapy and immunotherapy represents profound physiological stress that demands stress-dose glucocorticoid coverage—typically hydrocortisone 50-100 mg every 6-8 hours or 200 mg/24 hours as continuous infusion. 5, 1
Why Standard Replacement Fails During Stress
- Standard maintenance hydrocortisone dosing (15-25 mg daily) is physiologically inadequate during acute illness, infection, or cancer treatment. 4, 6
- Pro-inflammatory cytokines released during infection or chemotherapy-induced inflammation can impair glucocorticoid receptor function, effectively creating functional glucocorticoid deficiency even with normal cortisol levels. 2
- Gastrointestinal symptoms (nausea, vomiting, diarrhea) prevent oral medication absorption, creating acute glucocorticoid withdrawal. 2, 7
Immunotherapy as a Specific Risk Factor
Pembrolizumab and other immune checkpoint inhibitors can cause or worsen adrenal insufficiency, with incidence of 0.98-1.3%, and this patient's recent immunotherapy exposure created additional vulnerability. 8 The combination of pre-existing secondary adrenal insufficiency with immunotherapy-induced endocrinopathy represents a particularly high-risk scenario for adrenal crisis. 8
The Fatal Cascade of Adrenal Crisis
Adrenal crisis presents with profoundly impaired well-being, hypotension unresponsive to fluids alone, nausea, vomiting, fever, and altered mental status—and carries a mortality rate of 0.5 per 100 patient-years despite being highly treatable. 2, 7
Clinical Progression Leading to Death
- Infection or chemotherapy-induced inflammation triggers increased cortisol requirements that cannot be met. 2, 7
- Lack of adequate cortisol during stress enhances pro-inflammatory cytokine release (particularly TNF-alpha) and increases sensitivity to their toxic effects. 2
- Hypotension develops and becomes refractory to fluid resuscitation alone, requiring both hydrocortisone 100 mg IV and aggressive saline infusion (1 L in first hour). 1, 2
- Without immediate parenteral hydrocortisone administration, cardiovascular collapse progresses to death within hours to days. 1, 6
Critical Gaps in Management That Likely Occurred
The patient was discharged home on maintenance-dose hydrocortisone without adequate stress-dose instructions, emergency injectable hydrocortisone kit, or recognition of impending crisis. 3, 1
Specific Management Failures
- No stress-dose protocol: Patient should have been instructed to double or triple hydrocortisone dose (to 30-75 mg daily) during chemotherapy and any intercurrent illness. 3, 4
- No emergency kit: Every patient with adrenal insufficiency must have parenteral hydrocortisone 100 mg IM for self-administration with training. 1, 7
- No medical alert identification: Patient should have worn medical alert bracelet indicating adrenal insufficiency to trigger emergency stress-dose treatment. 3, 1
- Inadequate patient education: Current education strategies are insufficiently effective at preventing adrenal crisis, which occurs in approximately 50% of patients after diagnosis. 2, 7
Why Death Occurred at Home Rather Than Hospital
Patients and families often fail to recognize early warning signs of adrenal crisis (profound weakness, nausea, confusion) and delay seeking emergency care until cardiovascular collapse is irreversible. 2, 7
- Symptoms of impending crisis (exhaustion, nausea, dizziness) are non-specific and easily attributed to chemotherapy side effects rather than adrenal emergency. 9, 7
- Without immediate IV hydrocortisone 100 mg and saline resuscitation, mortality from adrenal crisis is extremely high. 1, 6
- The 6-day timeline suggests progressive deterioration from inadequate stress coverage, possibly with superimposed infection or gastrointestinal illness preventing oral medication absorption. 2, 7
Additional Contributing Factors
Secondary adrenal insufficiency patients may have concurrent hypothyroidism or other pituitary hormone deficiencies that compound the risk during physiological stress. 3, 4
- If thyroid hormone replacement was initiated without adequate corticosteroid coverage, this could precipitate acute adrenal crisis. 3, 4
- Chemotherapy-induced nausea medications or other drug interactions may have affected hydrocortisone absorption or metabolism. 3
- Dehydration from chemotherapy-induced nausea/vomiting combined with inadequate mineralocorticoid effect (secondary AI patients have intact aldosterone but may still develop relative insufficiency during stress) contributed to cardiovascular collapse. 1, 2
What Should Have Prevented This Death
This death was preventable with proper stress-dose protocols, emergency preparedness, and recognition of high-risk scenarios. 1, 2, 7
Essential Preventive Measures
- Stress-dose protocol during chemotherapy: Hydrocortisone should have been increased to 50-75 mg daily during active cancer treatment. 4, 1
- Emergency injectable kit: Patient needed hydrocortisone 100 mg IM with clear instructions to self-administer for severe nausea, vomiting, or profound weakness. 1, 7
- Medical alert identification: Bracelet indicating adrenal insufficiency ensures emergency personnel administer stress-dose steroids immediately. 3, 1
- Clear crisis recognition: Patient and family should have been educated that unexplained hypotension, collapse, severe nausea/vomiting, or profound weakness requires immediate emergency department presentation for IV hydrocortisone. 1, 2