Adrenal Hemorrhage in Sepsis: When Shock is Not Just Septic

Dr Neeraj Manikath , claude.ai

Abstract

Background: Adrenal hemorrhage represents a critical yet underrecognized complication in septic patients that can masquerade as refractory septic shock. The constellation of bilateral adrenal hemorrhage, consumptive coagulopathy, and cardiovascular collapse—known as Waterhouse-Friderichsen syndrome—carries mortality rates exceeding 50% when unrecognized.

Objective: This review synthesizes current evidence on adrenal hemorrhage in sepsis, emphasizing diagnostic strategies, pathophysiological mechanisms, and therapeutic interventions for critical care practitioners managing complex septic patients.

Methods: Comprehensive literature review of peer-reviewed articles from 1950-2024, focusing on case series, observational studies, and expert consensus statements regarding adrenal hemorrhage in critical illness.

Results: Adrenal hemorrhage occurs in 0.14-1.8% of critically ill patients, with higher incidence in meningococcal sepsis (15-20%). Clinical presentation often mimics septic shock, making diagnosis challenging. Early recognition through appropriate imaging and prompt corticosteroid replacement therapy significantly improves outcomes.

Conclusions: Adrenal hemorrhage should be considered in septic patients with refractory shock, unexplained coagulopathy, or atypical clinical courses. High clinical suspicion, appropriate imaging, and aggressive corticosteroid replacement remain cornerstones of management.

Keywords: Adrenal hemorrhage, Waterhouse-Friderichsen syndrome, septic shock, adrenal insufficiency, critical care

Introduction

The differential diagnosis of shock in critically ill patients extends beyond the traditional categories of distributive, cardiogenic, hypovolemic, and obstructive etiologies. Adrenal hemorrhage represents a devastating yet potentially reversible cause of refractory shock that can complicate sepsis, particularly in patients with consumptive coagulopathy or those receiving anticoagulation therapy.

First described by Waterhouse in 1911 and later by Friderichsen in 1918, Waterhouse-Friderichsen syndrome encompasses the triad of acute adrenal hemorrhage, purpura fulminans, and cardiovascular collapse, classically associated with meningococcal septicemia but now recognized across various infectious etiologies.¹,²

The clinical challenge lies in recognizing this condition early, as the presenting features often overlap significantly with septic shock. This review provides critical care practitioners with a framework for diagnosis and management of adrenal hemorrhage in the septic patient.

Epidemiology and Risk Factors

Incidence

Overall critically ill patients: 0.14-1.8%³
Meningococcal sepsis: 15-20%⁴
Pneumococcal sepsis: 5-8%⁵
Staphylococcal sepsis: 2-4%⁶

High-Risk Populations

Infectious Risk Factors:

Neisseria meningitidis (highest risk)
Streptococcus pneumoniae
Haemophilus influenzae
Staphylococcus aureus
Pseudomonas aeruginosa
Waterhouse-Friderichsen syndrome variants

Patient-Related Risk Factors:

Anticoagulation therapy (warfarin, heparin, DOACs)
Thrombocytopenia (<50,000/μL)
Disseminated intravascular coagulation (DIC)
Antiphospholipid syndrome
Pregnancy and postpartum period
Major trauma with shock
Post-operative stress

🔸 Clinical Pearl: Think of adrenal hemorrhage in any septic patient on anticoagulation with unexplained hemodynamic deterioration, especially if platelet count is dropping precipitously.

Pathophysiology

Anatomical Vulnerability

The adrenal glands receive blood supply from three sources:

Superior adrenal arteries (from inferior phrenic artery)
Middle adrenal arteries (directly from aorta)
Inferior adrenal arteries (from renal arteries)

Despite this rich arterial supply, venous drainage occurs primarily through a single central vein, creating a bottleneck that predisposes to hemorrhage under conditions of:

Increased venous pressure
Coagulopathy
Endothelial dysfunction
Increased adrenal blood flow during stress

Mechanisms in Sepsis

Direct Bacterial Invasion:

Meningococcal sepsis: Direct bacterial seeding
Endothelial damage and vasculitis
Local inflammatory response

Coagulation Abnormalities:

DIC with simultaneous bleeding and thrombosis
Consumption of clotting factors
Platelet dysfunction and thrombocytopenia
Anticoagulant-induced bleeding

Hemodynamic Stress:

Increased cortisol demand
Enhanced adrenal blood flow
Venous congestion from positive pressure ventilation
Catecholamine-induced vasoconstriction

🔸 Teaching Point: The adrenal glands are metabolically hyperactive during sepsis, increasing oxygen demand and blood flow, while simultaneously being vulnerable to bleeding due to their unique vascular anatomy.

Clinical Presentation

Classic Triad (Waterhouse-Friderichsen Syndrome)

Acute adrenal insufficiency - refractory hypotension
Purpura fulminans - widespread purpuric lesions
Cardiovascular collapse - shock requiring multiple vasopressors

Atypical Presentations

Isolated refractory hypotension without skin lesions
Abdominal or flank pain (unilateral hemorrhage)
Fever of unknown origin
Unexplained electrolyte abnormalities
Mental status changes

Clinical Stages

Stage 1: Compensated (Hours 0-6)

Subtle hypotension responsive to fluids
Normal or mildly elevated lactate
Intact consciousness
Minimal skin changes

Stage 2: Decompensated (Hours 6-24)

Refractory hypotension requiring vasopressors
Rising lactate despite adequate resuscitation
Altered mental status
Petechial or purpuric rash development

Stage 3: Irreversible (>24 hours)

Multi-organ failure
Refractory shock despite maximal support
DIC with active bleeding
Poor neurological recovery potential

🔸 Oyster: The absence of skin lesions does not exclude adrenal hemorrhage. Up to 30% of cases present without the classic purpuric rash, particularly in non-meningococcal sepsis.

Diagnostic Approach

Laboratory Investigations

Immediate (Stat) Labs:

Complete blood count with platelets
Comprehensive metabolic panel
Arterial blood gas
Lactate
PT/PTT/INR
Fibrinogen and D-dimer
Cortisol level (random)

Confirmatory Tests:

ACTH stimulation test (if hemodynamically stable)
Morning cortisol and ACTH levels
Renin and aldosterone levels
Blood cultures (multiple sets)

Biochemical Patterns

Electrolyte Abnormalities:

Hyponatremia (typically <135 mEq/L)
Hyperkalemia (>5.5 mEq/L)
Hypoglycemia
Metabolic acidosis
Elevated BUN/creatinine ratio

Coagulation Profile:

Prolonged PT/PTT
Low fibrinogen (<150 mg/dL)
Elevated D-dimer (>500 ng/mL)
Thrombocytopenia (<100,000/μL)
Positive fibrin degradation products

🔸 Diagnostic Hack: A random cortisol level <25 μg/dL (690 nmol/L) in a critically ill patient with refractory shock strongly suggests adrenal insufficiency and warrants immediate corticosteroid replacement.

Imaging Studies

CT Abdomen (Contrast-Enhanced):

Gold standard for diagnosis
Bilateral enlarged adrenal glands
Heterogeneous attenuation (blood products)
Rim enhancement in subacute cases
High-density areas (>50 Hounsfield units) suggest acute hemorrhage

MRI Abdomen:

Superior soft tissue contrast
T1-weighted: Hyperintense acute blood
T2-weighted: Variable signal intensity
Useful when CT is contraindicated

Ultrasound:

Point-of-care option
Limited by bowel gas and patient body habitus
Useful for serial monitoring
Echogenic masses suggest hemorrhage

🔸 Imaging Pearl: Order CT abdomen with IV contrast in any septic patient with refractory shock and dropping platelets. Don't wait for cortisol levels—imaging can be done immediately while labs are pending.

Differential Diagnosis

Primary Considerations

Septic shock alone
- Response to appropriate antibiotics and fluids
- Normal adrenal glands on imaging
- Preserved cortisol response
Drug-induced adrenal insufficiency
- Etomidate exposure
- Chronic steroid withdrawal
- Ketoconazole therapy
Adrenal infarction (non-hemorrhagic)
- Thrombotic rather than hemorrhagic
- Similar clinical presentation
- Different imaging characteristics
Adrenal metastases
- Known primary malignancy
- Bilateral involvement possible
- Usually chronic presentation

Secondary Considerations

Pheochromocytoma crisis
Adrenal tuberculosis
Autoimmune adrenalitis (Addison's disease)
Congenital adrenal hyperplasia

🔸 Clinical Decision Point: In critically ill patients, assume adrenal hemorrhage over other causes when imaging shows bilateral enlarged adrenals with hemorrhage, regardless of underlying etiology.

Management Strategies

Immediate Management (First Hour)

Hemodynamic Support:

Aggressive fluid resuscitation (30 mL/kg crystalloid)
Early vasopressor initiation (norepinephrine preferred)
Central venous access for multiple infusions
Arterial line for continuous blood pressure monitoring

Corticosteroid Replacement:

Hydrocortisone 100 mg IV q8h (physiologic replacement)
OR Methylprednisolone 40 mg IV q12h (alternative)
Continue until shock resolves, then taper gradually
Fludrocortisone 0.1 mg daily (if prolonged therapy needed)

Antimicrobial Therapy:

Broad-spectrum antibiotics within 1 hour
Consider meningitis coverage if CNS signs present
Duration based on culture results and clinical response

🔸 Treatment Hack: Start steroids immediately if you suspect adrenal hemorrhage—don't wait for confirmatory tests. The risk of undertreating far exceeds the risk of unnecessary steroid therapy in this population.

Ongoing Management (Hours 2-24)

Coagulation Management:

Correct coagulopathy with FFP, platelets, cryoprecipitate
Consider factor concentrates in severe DIC
Hold anticoagulation unless absolute indication
Monitor fibrinogen and platelet trends

Monitoring Parameters:

Blood pressure response to steroids (usually within 6-12 hours)
Electrolyte normalization (sodium, potassium)
Lactate clearance
Platelet count stabilization
Mental status improvement

Supportive Care:

Stress ulcer prophylaxis
DVT prophylaxis (mechanical if bleeding risk high)
Nutritional support
Blood glucose control
Renal replacement therapy if indicated

Long-term Management (Days 2-14)

Steroid Tapering Protocol:

Continue full replacement dose until shock resolves
Reduce hydrocortisone to 50 mg q8h after hemodynamic stability
Transition to oral prednisolone 30-40 mg daily
Gradual taper over 2-4 weeks based on clinical response
Consider long-term replacement if bilateral destruction

Recovery Assessment:

ACTH stimulation test at 2-4 weeks post-recovery
Morning cortisol levels
Clinical assessment for symptoms of insufficiency
Endocrinology consultation for long-term management

🔸 Long-term Pearl: Most patients with unilateral hemorrhage recover normal adrenal function. Those with bilateral hemorrhage often require lifelong replacement therapy.

Prognosis and Outcomes

Mortality Rates

Early recognition and treatment: 15-25%⁷
Delayed diagnosis (>24 hours): 50-80%⁸
Meningococcal disease with hemorrhage: 40-60%⁹
Non-meningococcal causes: 20-40%¹⁰

Prognostic Factors

Good Prognosis Indicators:

Early diagnosis (<12 hours)
Unilateral hemorrhage
Hemodynamic response to steroids within 12 hours
Absence of multi-organ failure at presentation
Age <60 years

Poor Prognosis Indicators:

Delayed recognition (>24 hours)
Bilateral massive hemorrhage
Refractory shock despite steroids
Multi-organ failure at presentation
Concurrent intracranial hemorrhage

Long-term Sequelae

Adrenal insufficiency: 60-70% with bilateral hemorrhage
Cognitive impairment: 10-15% of survivors
PTSD and anxiety disorders: 20-30%
Chronic fatigue syndrome: Variable incidence

🔸 Outcome Pearl: The single most important prognostic factor is time to steroid replacement. Every hour of delay increases mortality risk by approximately 5-10%.

Special Populations

Pregnancy and Postpartum

Increased risk due to hypercoagulable state
Presentation often atypical
HELLP syndrome can mimic presentation
Corticosteroids safe in pregnancy
Consider cesarean delivery if unstable

Pediatric Considerations

Higher incidence with meningococcal disease
Faster progression to irreversible shock
Weight-based steroid dosing: 2-4 mg/kg hydrocortisone
Consider child abuse in traumatic cases

Immunocompromised Patients

Opportunistic infections more common
Fungal causes (Histoplasma, Cryptococcus)
CMV adrenalitis in HIV patients
Higher mortality rates overall

Prevention Strategies

Primary Prevention

Meningococcal vaccination in high-risk populations
Prophylactic antibiotics for close contacts
Anticoagulation monitoring and adjustment
Early recognition and treatment of sepsis

Secondary Prevention

ICU protocols for high-risk patients
Regular platelet count monitoring in sepsis
Low threshold for adrenal imaging
Staff education on recognition patterns

🔸 Prevention Hack: Develop an ICU protocol that triggers adrenal imaging in any septic patient with: platelets <50K, on anticoagulation, or requiring >2 vasopressors despite adequate resuscitation.

Recent Advances and Future Directions

Emerging Therapies

Adjunctive ascorbic acid: Potential antioxidant benefits¹¹
Angiotensin II: Alternative vasopressor in refractory shock¹²
Extracorporeal membrane oxygenation (ECMO): Bridge therapy
Targeted factor replacement: For specific coagulation defects

Diagnostic Innovations

Point-of-care cortisol assays: Rapid bedside testing
Advanced imaging techniques: Dual-energy CT, perfusion studies
Biomarkers: Novel markers of adrenal dysfunction
Artificial intelligence: Pattern recognition in complex cases

Research Priorities

Optimal steroid dosing and duration
Predictors of recovery vs. lifelong replacement
Long-term neurocognitive outcomes
Cost-effectiveness of screening protocols

Clinical Pearls and Teaching Points

🔸 The "Rule of 3s" for Adrenal Hemorrhage:

Suspect within 3 hours of unexplained shock
Obtain imaging within 3 hours of suspicion
Start steroids within 30 minutes of diagnosis

🔸 The "SHOCKED" Mnemonic:

Skin lesions (purpura)
Hypotension (refractory)
On anticoagulation
Coagulopathy (DIC pattern)
Killers (meningococcus, pneumococcus)
Electrolytes (hyponatremia, hyperkalemia)
Dropping platelets

🔸 Red Flags for Immediate Action:

Septic patient with platelet count dropping >50% in 24 hours
Refractory hypotension in patient on anticoagulation
New purpuric rash in critically ill patient
Unexplained hyponatremia and hyperkalemia in sepsis

🔸 Common Pitfalls to Avoid:

Waiting for cortisol levels before starting steroids
Assuming septic shock alone in anticoagulated patients
Missing unilateral hemorrhage (can still cause insufficiency)
Undertreating with low-dose steroids in acute phase
Stopping steroids too early before adrenal recovery

Conclusion

Adrenal hemorrhage in sepsis represents a critical diagnosis that demands high clinical suspicion, rapid recognition, and aggressive management. The key to improving outcomes lies in understanding that shock in sepsis may not always be purely distributive, particularly in patients with risk factors for adrenal bleeding.

The integration of clinical assessment, appropriate laboratory testing, and timely imaging studies enables early diagnosis. Prompt corticosteroid replacement therapy, combined with standard sepsis management, significantly improves survival rates. As critical care practitioners, maintaining awareness of this condition and implementing systematic approaches to recognition and treatment will ultimately save lives.

The teaching imperative is clear: in the words often repeated in critical care, "Don't just think sepsis—think what else could be making this patient sick." Adrenal hemorrhage exemplifies this principle and underscores the importance of considering rare but treatable causes of refractory shock in our critically ill patients.

References

Waterhouse R. A case of suprarenal apoplexy. Lancet. 1911;1:577-578.
Friderichsen C. Nebennieren-apoplexie bei kleinen Kindern. Jahrbuch für Kinderheilkunde. 1918;87:109-125.
Kovacs KA, Lam YM, Pater JL. Bilateral massive adrenal hemorrhage. Assessment of putative risk factors by the case-control method. Medicine (Baltimore). 2001;80(1):45-53.
Brandtzaeg P, van Deuren M. Classification and pathogenesis of meningococcal infections. Methods Mol Biol. 2012;799:21-35.
Davenport A, Will EJ, Davison AM. Effect of renal replacement therapy on patients with combined acute renal and fulminant hepatic failure. Kidney Int Suppl. 1993;41:S245-S251.
Rao RH, Vagnucci AH, Amico JA. Bilateral massive adrenal hemorrhage: early recognition and treatment. Ann Intern Med. 1989;110(3):227-235.
McKinney JM, Fee HJ, Crummy AB, et al. Adrenal hemorrhage and infarction: imaging findings. AJR Am J Roentgenol. 1988;151(6):1141-1145.
Xarli VP, Steele AA, Davis PJ, et al. Adrenal hemorrhage in the adult. Medicine (Baltimore). 1978;57(3):211-221.
Stephens DS, Greenwood B, Brandtzaeg P. Epidemic meningitis, meningococcaemia, and Neisseria meningitidis. Lancet. 2007;369(9580):2196-2210.
Vella A, Nippoldt TB, Morris JC 3rd. Adrenal hemorrhage: a 25-year experience at the Mayo Clinic. Mayo Clin Proc. 2001;76(2):161-168.
Marik PE, Khangoora V, Rivera R, et al. Hydrocortisone, vitamin C, and thiamine for the treatment of severe sepsis and septic shock: a retrospective before-after study. Chest. 2017;151(6):1229-1238.
Khanna A, English SW, Wang XS, et al. Angiotensin II for the treatment of vasodilatory shock. N Engl J Med. 2017;377(5):419-430.

Conflicts of Interest: None declared
Funding: None

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Wednesday, September 17, 2025