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Adrenal Hemorrhage
11 Interesting Facts of Adrenal Hemorrhage
- Adrenal hemorrhage is a rare but potentially life-threatening condition. Early recognition and prompt treatment are key in reducing morbidity and mortality in these patients
- Trauma is most common cause of adrenal hemorrhage. Other risk factors include stress due to sepsis, burns, or surgery; adrenal neoplasms; coagulopathies; infection with COVID-19; pregnancy; and neonatal stress
- Patients may present with wide range of symptoms from mild abdominal pain to cardiovascular collapse and shock
- Diagnosis is made on imaging, typically CT with IV contrast material. MRI may also be helpful in distinguishing between adrenal hematoma and neoplasm. Ultrasonography is modality of choice for pediatric population
- Begin treatment with supportive measures, including close hemodynamic monitoring and blood transfusions when appropriate
- Perform angioembolization with interventional radiology in patients with ongoing bleeding
- Surgery is reserved for patients who have bleeding that is refractory to angioembolization or who are hemodynamically unstable and require rapid control of hemorrhage
- Providers should have high clinical suspicion for adrenal insufficiency in patients with bilateral adrenal hemorrhage
- Diagnosis is made with ACTH stimulation test
- Treatment is with IV hydrocortisone
- In hemodynamically unstable patients, empiric steroid administration should not be delayed while awaiting results for diagnostic testing
Alarm Signs and Symptoms
- Hypotension, tachycardia, hypothermia, and altered mental status may be signs of impending cardiovascular collapse due to acute blood loss or adrenal crisis
- Hypertension, tachycardia, and flushing may indicate pheochromocytoma
- Palpable flank mass or presence of Grey Turner sign may indicate large retroperitoneal bleed
- Purpura fulminans may indicate Waterhouse-Friderichsen syndrome
Terminology
- Adrenal hemorrhage is a relatively uncommon condition and can be unilateral or bilateral1
- Adrenal hematoma is comprised of residual blood from hemorrhage that collects around adrenal gland(s) in the retroperitoneal space
- Acute adrenal insufficiency is the most severe complication of adrenal hemorrhage
- Characterized by inability to produce glucocorticoids and mineralocorticoids due to destruction of adrenal glands2
- Can quickly lead to cardiovascular collapse and death, highlighting importance of early recognition and treatment
Epidemiology
- Clinical manifestations of adrenal hemorrhage can range from minor asymptomatic bleeding to life-threatening hemorrhage and death
- Most information about epidemiology is limited to case series; thus, exact incidence is unclear
- Incidence ranges from 0.14% to 1.8% based on a small series of autopsies in patients hospitalized for trauma or acute illness3
- In another series of case studies, adrenal hemorrhage has been found on CT scan in 1.5% to 5% of adult patients hospitalized after blunt trauma1
- Adrenal insufficiency occurs when greater than 90% of adrenal cortex has been destroyed in each adrenal gland5
- Most cases of adrenal hemorrhage are unilateral, so adrenal insufficiency is a rare occurrence overall
- In cases of bilateral adrenal hemorrhage, rates of adrenal insufficiency are up to 50%1
Etiology
- Anatomy of adrenal gland places these organs at particularly high risk for hemorrhage (Figure 1)
- Blood flow to adrenal gland is supplied by 3 arteries (superior, middle, and inferior adrenal arteries), while a single vein (adrenal vein) is responsible for venous outflow
- Between the arteries and vein lies a complex network of capillaries and sinusoids, making the adrenal gland highly vascular
- This anatomy creates a “vascular dam” in which the adrenal gland becomes engorged with blood in states of either increased arterial inflow or obstructed venous outflow through the single adrenal vein1
- Thus, factors that cause either increased blood flow through adrenal arteries (eg, stress leading to increased catecholamine and glucocorticoid release) or decreased venous outflow (eg, obstruction caused by renal vein thrombosis) lead to significantly increased intraglandular pressure, which may lead to ischemia and can predispose patient to hemorrhage (Figure 2)8
- Causes of adrenal hemorrhage can be either primary (no obvious cause) or secondary due to inciting event. Risk factors for secondary causes include trauma, stress, adrenal neoplasms, coagulopathies, COVID-19, pregnancy, and neonatal stress (Table 1)
- View full sizeTable 1. Causes of secondary adrenal hemorrhage.Causes of secondary adrenal hemorrhageTraumaStress
- Severe infections (eg, sepsis)
- Myocardial infarction
- Burns
- Surgery
- Exogenous steroid use
- Pheochromocytoma
- Metastasis
- Myelolipoma
- Adrenocortical carcinoma
- Heparin-induced thrombocytopenia
- Autoimmune diseases
- Iatrogenic
- Inherited coagulopathies
Risk Factors
- Trauma
- Most common cause of adrenal hemorrhage, accounting for up to 80% of all cases9
- Despite this, less than 5% of all patients with blunt force trauma have adrenal hemorrhage11
- Adrenal hemorrhage from trauma is usually unilateral and is mostly seen on right side12
- Likely owing to anatomy of right adrenal vein, which empties directly into inferior vena cava (compared with left adrenal vein, which empties into left renal vein)11
- Sudden compression of inferior vena cava, as in blunt force trauma, can lead to acute rise in intra-adrenal venous pressure, particularly on right side11
- Other mechanisms of injury include direct compression of adrenal gland between spine and liver or spleen1
- Shearing of small vessels that perforate adrenal capsule may also occur due to sudden deceleration force
- Clinicians should have higher clinical suspicion for adrenal hemorrhage if there is concurrent injury to liver, ribs, kidneys, or spleen11
- Stress
- Physiologic stress can lead to increased release of catecholamines and glucocorticoids, which in turn cause both increased blood flow to adrenal glands and vasoconstriction of adrenal vein, raising intra-adrenal pressure and predisposing patient to hemorrhage3
- Conditions that lead to increased physiologic stress include:
- Severe infection (eg, sepsis)13
- Myocardial infarction14
- Burns1
- Surgery15
- Exogenous steroid use1
- Sepsis is a well-documented risk factor for adrenal hemorrhage and increases risk of adrenal hemorrhage 6-fold13
- Waterhouse-Friderichsen syndrome is a severe form of bilateral adrenal hemorrhage associated with sepsis that leads to acute adrenal crisis16
- Has traditionally been associated with sepsis caused by Neisseria meningitidis but has also been linked to Pseudomonas aeruginosa, Neisseria gonorrhoeae, Haemophilus influenzae, Escherichia coli, and Staphylococcus aureus16
- Patients with Waterhouse-Friderichsen syndrome often present with concurrent disseminated intravascular coagulation and purpura fulminans16
- Prognosis is poor, and mortality ranges between 50% to 95%17
- Adrenal neoplasms
- Account for about 20% of all cases of adrenal hemorrhage7
- Important to identify early as nature of mass may alter treatment approach6
- Pheochromocytoma
- Account for up to 48% of all cases of adrenal hemorrhage due to underlying adrenal neoplasm18
- Management of hemorrhagic pheochromocytoma poses unique clinical challenges
- Some may present with hypertension due to catecholamine storm and subsequent hypertensive crisis
- Others may present with hypotension, presumably due to destruction of pheochromocytoma resulting in sudden drop in circulating catecholamines
- Metastasis
- Seen in about 14% of all adrenal hemorrhages due to underlying adrenal neoplasm19
- Metastatic disease is typically bilateral, although adrenal hemorrhage may occur unilaterally or bilaterally19
- Common etiologies of primary neoplasm are lung, kidney, breast, and melanoma3
- Myelolipoma
- Rare, benign adrenal masses
- Bleeding is usually only associated with large tumors larger than 4 cm20
- Adrenocortical carcinoma
- These masses rarely bleed; however, important to identify because management usually requires removal of adrenal gland
- Inherited and acquired coagulopathies
- Heparin-induced thrombocytopenia
- Thought to be caused by stimulation of heparin-platelet factor 4 antibodies, leading to aggregation of platelets and creating risk of thromboembolism21
- Can lead to thrombosis of adrenal vein, subsequently leading to increased intra-adrenal pressure and ischemia, which may lead to adrenal hemorrhage
- Autoimmune diseases
- Patients with autoimmune diseases that lead to prothrombotic states (eg, systemic lupus erythematosus, antiphospholipid syndrome) are at risk for developing thrombosis of adrenal vein and subsequent adrenal hemorrhage
- Major surgery, infection, trauma, or stress may trigger thrombotic events and place these patients at higher risk for hemorrhage1
- Adrenal vein thrombosis due to antiphospholipid syndrome has been associated with severe bilateral hemorrhage and adrenal insufficiency
- A case series demonstrated that adrenal insufficiency due to adrenal hemorrhage is first clinical manifestation of antiphospholipid syndrome in about one-third of patients in study sample22
- In patients with antiphospholipid syndrome who had adrenal hemorrhage caused by thrombosis, risk of recurrent hemorrhage is estimated to be 2.9% per year5
- Iatrogenic
- Nontraumatic adrenal hemorrhage is most often associated with systemic anticoagulation or antiplatelet therapy13
- While these medications do not always directly lead to adrenal hemorrhage, systemic anticoagulation can potentiate bleeding risk when administered
- Inherited coagulopathies
- Patients with inherited diseases that lead to hypercoagulable states (eg, factor V Leiden mutations, von Willebrand disease) may be at increased risk for adrenal hemorrhage due to adrenal vein thrombosis, although cases of this in medical literature are rare
- Heparin-induced thrombocytopenia
- COVID-19
- Patients with COVID-19 are at increased risk for adrenal hemorrhage, likely owing to increased coagulation activation and thrombosis seen in these patients23
- A complete autopsy study of patients who died with severe COVID-19 showed that around 42% of patients, mostly males, had adrenal lesions25
- Most adrenal lesions detected were identified as cortical lipid degeneration, necrosis, focal inflammation, or hemorrhage
- Pregnancy
- Adrenal hemorrhage is seen in 0.14% to 1.1% of pregnancies26
- Most cases are in third trimester and present as unilateral adrenal hemorrhage27
- Cause is likely physiologic hypertrophy of adrenal cortex seen in pregnancy, predisposing it to hemorrhage
- Neonatal stress
- Adrenal hemorrhage in neonates is found in about 0.2% of newborns28
- Neonates are naturally predisposed to adrenal hemorrhage because adrenal glands are relatively larger and more vascularized in neonates than in adults29
- Risk factors for neonatal adrenal hemorrhage include:1
- Diabetic mother
- Difficult labor
- Asphyxia
- Breech delivery
- Fetal acidemia
Diagnosis
Approach to Diagnosis
- Early recognition and intervention is key for successful treatment of adrenal hemorrhage because bilateral adrenal hemorrhage can quickly lead to adrenal insufficiency, cardiovascular collapse, and death
- Adrenal hemorrhage can present with a large range of nonspecific symptoms, from mild abdominal pain to shock due to adrenal insufficiency
- Adrenal insufficiency
- Although rare, important to keep this etiology in mind when evaluating patients who present with abdominal pain, hypotension, confusion, or decreasing hemoglobin levels
Diagnostic Criteria
- Mainstay of diagnosis of adrenal hemorrhage is CT imaging with IV contrast material
- Anemia on serial laboratory tests may also suggest active hemorrhage
- Adrenal insufficiency is diagnosed using biochemical laboratory studies
Workup
History
- Most common presenting symptom of adrenal hemorrhage is vague abdominal or flank pain19
- Other nonspecific symptoms include malaise, weakness, lethargy, nausea, vomiting, and diarrhea31
- Severity of symptoms corresponds with both volume of blood lost as well as whether patient has developed acute adrenal insufficiency from a massive bilateral hemorrhage (Table 2)
- In stable patient, important to rule out history of malignancy, particularly melanoma or lung, breast, colon, and kidney cancer, because adrenal gland is common site of metastasis for these primary cancers and may be source of bleeding19
- Review all medications thoroughly, particularly any history of anticoagulation or antiplatelet medications, as these may potentiate further bleeding
- View full sizeTable 2. Prevalence of signs and symptoms of adrenal crisis.Sign or symptomProportion of patientsHypotension and shock90%Fever66%Abdominal rebound tenderness or rigidity22%Anorexia, nausea, or vomiting47%Pain in abdomen, flank, back, or chest86%Neuropsychiatric complaints (eg, confusion, disorientation)42%Caption: From Rao RH et al. Bilateral massive adrenal hemorrhage: early recognition and treatment. Ann Intern Med. 1989;110(3):227-35.
Physical Examination
Figure 1. Anatomy and blood supply of adrenal glands.From Chingkoe CM et al. The adrenal glands. In: Rumack CM et al, eds. Diagnostic Ultrasound. 5th ed. Elsevier; 2018:416-431, Figure 11.1.
Figure 2. Pathogenesis of adrenal hemorrhage.From Rao RH et al. Bilateral massive adrenal hemorrhage: early recognition and treatment. Ann Intern Med. 110(3):227-235, 1989.- Figure 3. Grey Turner sign. Note characteristic blue discoloration and location between 12th rib and hip.From Mehta SH et al. Grey Turner’s sign. Vis J Emerg Med. 2018;12:47-48, Figure 1.
- Figure 4. Purpura fulminans.From Davis MDP et al. Presentation and outcome of purpura fulminans associated with peripheral gangrene in 12 patients at Mayo Clinic. J Am Acad Dermatol. 2007;57(6):944-956, Figure 4.
Figure 5. Right adrenal hematoma.From Tublin M et al. Adrenal hemorrhage. In: Tublin M et al, eds. Imaging in Urology. Elsevier; 2018:46, Figure 1.
- Vital signs
- Patients in shock from either hemorrhage or adrenal insufficiency present with hypotension and tachycardia
- Adrenal insufficiency typically presents as progressive hypotension refractory to fluid resuscitation and vasopressor support
- Hypothermia may be present in cases of severe adrenal insufficiency
- Some patients may present with hypertension and tachycardia if they have periadrenal hematoma large enough to compress adrenal gland, causing release of cortisol and catecholamines
- Hypertension may also be present in patients with pheochromocytoma
- General
- Varying degrees of altered mental status and distress may be present depending on severity of hemorrhage or adrenal insufficiency
- Patients with pheochromocytoma may have episodic diaphoresis and flushing
- Abdomen
- Abdominal or flank tenderness is most common physical examination finding19
- Palpable flank mass may also be felt in presence of large retroperitoneal hematoma1
- Genitourinary
- In male neonates, scrotal hematoma may be present
- Occurs when retroperitoneal bleed tracks inferiorly through patent processus vaginalis and into scrotum28
- Skin
- Grey Turner sign (Figure 3)19
- Rare examination finding consisting of ecchymosis that extends down flank and thigh
- Occurs when retroperitoneal hemorrhage tracks down subcutaneous tissues throughout dependent areas
- Petechiae may be present in cases of heparin-induced thrombocytopenia
- Purpura fulminans is examination finding classically seen in Waterhouse-Friderichsen syndrome (Figure 4)
- Grey Turner sign (Figure 3)19
Laboratory Tests
- Order routine set of laboratory tests, including complete blood count and chemistry, for any patient with suspected adrenal hemorrhage
- Depending on severity of hemorrhage, serial hemoglobin or hematocrit may need to be closely monitored to assess need for resuscitation with blood products
- Patients with adrenal insufficiency will typically present with hyponatremia, hyperkalemia, hypoglycemia, and metabolic acidosis2
- Evaluate for bleeding disorders:
- Measure prothrombin time/INR and platelet count for coagulopathies
- Assess fibrinogen levels if concern exists for disseminated intravascular coagulation
- Low levels are associated with severe disseminated intravascular coagulation
- Where available, thromboelastography can provide rapid analysis of patient’s coagulation status for patients with acute hemorrhage
- To rule out functional adrenal masses:
- Screen for pheochromocytoma
- Measurement of plasma-fractionated metanephrine and normetanephrine levels is simplest way to rule out pheochromocytoma. If either are elevated, further testing of 24-hour urine metanephrine level can be performed to make accurate diagnosis of pheochromocytoma32
- In general, pheochromocytomas have plasma normetanephrine levels that are two to four-times upper limit of reference range19
- When obtaining these laboratory tests, it is important to recognize that catecholamines are typically elevated in a stressed patient and it may be difficult to distinguish physiologic stress from pheochromocytoma in patients who are acutely ill
- Screen for hypercortisolism
- Overnight dexamethasone suppression test is best method to rule out cortisol-producing adrenal mass32
- Administer 1 mg of oral dexamethasone in evening before sleep
- Check serum cortisol levels the next morning between 8 AM and 9AM
- In normal individuals, serum cortisol levels are below 1.8 mcg/dL. Cortisol levels greater than 5 mcg/dL are diagnostic of hypercortisolism
- Note that cortisol levels will be elevated in physiologically stressed patients as well as patients with cortisol-producing adrenal masses33
- In patients who are acutely ill, use ACTH levels to distinguish between elevated cortisol levels caused by physiological stress (elevated ACTH) and a functional adrenal tumor (suppressed ACTH)
- However, in these cases it is still recommended to obtain repeated cortisol level when patient has stabilized to get cortisol sample that accurately reflects patient’s baseline adrenal function19
- Overnight dexamethasone suppression test is best method to rule out cortisol-producing adrenal mass32
- Screen for pheochromocytoma
- To rule out adrenal insufficiency:
- Random cortisol level can rapidly rule out adrenal insufficiency
- Baseline cortisol levels of 9 to 25 mcg/dL are within reference range2
- In stressed individuals, cortisol levels less than 18 mcg/dL represent an inadequate response and require further investigation2
- Diagnosis of adrenal insufficiency is made using ACTH stimulation test, performed in accordance with 2016 Endocrine Society guidelines for adrenal insufficiency:34
- Administer 250 mcg of IV corticotrophin to patient and measure cortisol 30 to 60 minutes later
- Cortisol level of 18 mcg/dL or higher is considered within reference range
- Value may vary depending on assay used to determine cortisol levels; newer monoclonal antibody tests for cortisol typically read cortisol levels lower when compared with older polyclonal antibody tests from which 18 mcg/dL cutoff was derived35
- Individuals with chronic illness often have low albumin and cortisol binding globulin that lead to serum cortisol peak lower than 18 mcg/dL in individuals without adrenal insufficiency36
- Patients with adrenal insufficiency may also present with hyperkalemia, hyponatremia, hypoglycemia, and metabolic acidosis, although these are nonspecific findings and are not diagnostic
- Random cortisol level can rapidly rule out adrenal insufficiency
Imaging Studies
- CT with IV contrast
- Imaging modality of choice in adult patients when evaluating potential cases of adrenal hemorrhage (Figure 5)3
- Appearance of adrenal hemorrhage varies depending on age of hematoma37
- During acute hemorrhage, adrenal gland enlarges to a rounded or ovoid shape, with high or mixed attenuation and patchy peripheral enhancement.38 The attenuation value of blood is high (50-90 Hounsfield units), usually higher than that of simple fluid. Periadrenal fat stranding and bleeding into perinephric space may also be visualized39
- Over time, the hematoma will have less attenuation and adrenal gland will appear as a small isoattenuated gland. Most adrenal hematomas will resolve on imaging by 1 year. Some adrenal glands may become calcified due to atrophy1
- Limitation of CT imaging
- May be difficult to distinguish between adrenal hemorrhage and adrenal mass
- In addition, underlying adrenal masses may be masked by a hematoma and go unrecognized
- Clinical expertise, radiologist experience, and laboratory evaluation are helpful in interpreting these images
- MRI
- Most sensitive modality in diagnosing adrenal hemorrhage, although not routinely used in diagnosis owing to time required to perform, especially in unstable patient3
- Modality of choice in pregnant patients and others in whom ionizing radiation should be avoided
- Current recommendations from American Association of Endocrine Surgeons and American Association of Clinical Endocrinologists state that CT and MRI are equivalent imaging modalities to use in initial workup of adrenal mass32
- However, if there is uncertainty on CT imaging as to whether an adrenal lesion represents a mass or hematoma, the high signal intensity of blood products seen on MRI T1-weighted images combined with subtraction techniques make MRIs superior in differentiating adrenal hemorrhage from adrenal mass. These techniques are also useful in detecting small underlying neoplasms that are otherwise obscured by blood on CT images41
- MRI can also be used to precisely determine age of adrenal hematoma if timing of adrenal hemorrhage is in question42
- Ultrasonography
- Imaging modality of choice in pediatric population owing to need to avoid ionizing radiation in these patients
- In addition, low volume of retroperitoneal fat and relatively large adrenal glands in pediatric patients make them ideal candidates for evaluation with ultrasonography3
- May also be beneficial in rapid evaluation of adult patients who are too unstable for CT scan
- In early stages of adrenal hemorrhage, adrenal glands will appear enlarged with irregular margins. They will also appear hypoechoic30
- Later, blood may be visualized either contained within adrenal capsule or located in retroperitoneal space in cases of capsule rupture3
- Use of Doppler in these imaging studies is critical to distinguish adrenal hemorrhage from adrenal mass. Adrenal gland in acute hemorrhage will appear avascular, while adrenal neoplasms are typically hypervascular30
- Contrast-enhanced ultrasonography is also growing in popularity, particularly among pediatric patients, and may also aid in distinguishing between adrenal hemorrhage and mass43
- It is also important to rule out renal vein thrombosis, which is commonly associated with adrenal hemorrhage in neonates44
- Imaging modality of choice in pediatric population owing to need to avoid ionizing radiation in these patients
- PET-CT
- Not routinely used in diagnosis of adrenal hemorrhage
- However, if underlying adrenal mass is detected, PET-CT has 97% sensitivity and 91% specificity in determining whether mass is benign or malignant, which may impact treatment options45
- Plain radiography
- There is no role for plain film radiography in evaluation of adrenal hemorrhage
- Eggshell calcifications may be present in cases of chronic adrenal hematoma15
Differential Diagnosis
- Table 3. Differential Diagnosis: Adrenal hemorrhage or hematoma.ConditionDescriptionDifferentiated byRuptured abdominal aortic aneurysmAcute rupture and hemorrhage from abdominal aortic aneurysm. Patients may present with hypotension, tachycardia, altered mental status, and abdominal pain. Potentially devastating diagnosis associated with high mortalityAneurysmal dilation of abdominal aorta is seen on CT imaging. Contrast extravasation may be seen from aorta. Unlike adrenal hemorrhage, not associated with adrenal insufficiencyAdrenal neoplasmAdrenal neoplasms can often masquerade as adrenal hematomas; it is difficult to distinguish between them on CT imagingAdrenal neoplasms may be benign or malignant. They may also be functional (eg, pheochromocytoma, aldosteronoma, cortisol-producing adenoma) or nonfunctionalMRI is modality of choice when determining if lesion seen on CT is neoplasm or hematomaIf MRI is not available, serial CT imaging is performed. Adrenal hematomas usually shrink in size over time and typically resolve within 1 year, whereas adrenal neoplasms typically remain same size or may enlarge over timeBiochemical evaluation can be used to determine if lesion seen on imaging is functional. Serum or urine metanephrine level, aldosterone-renin ratio, and 24-hour urine cortisol can be used to screen for pheochromocytoma, aldosteronoma or cortisol-producing adenoma, respectivelyNeuroblastomaEmbryonic neuroendocrine tumors, most of which arise from adrenal glands. Most common pediatric tumor. Rarely seen in patients older than 10 years46Diagnosis can be ruled out with 24-hour urinary vanillylmandelic acid testDoppler ultrasonography is key to distinguishing between neuroblastoma and adrenal hematoma. Neuroblastomas are typically highly vascular, while no vascularity is seen in adrenal hematomaIn cases where diagnosis is unclear, serial ultrasonography may be helpful in distinguishing adrenal hematoma from neuroblastoma, as adrenal hematoma will typically resolve over timeAdrenal abscessUsually seen in disseminated bacteremia. Can be caused by large range of organisms, including Staphylococcus aureus, streptococcal species, and mycobacterium47Patients will typically present with fevers and leukocytosis. Blood cultures may also be positive for offending organismTypical imaging characteristics of abscess include peripheral enhancement on contrast CT with heterogenous material within abscess. MRI can also be used to distinguish abscess from hematomaDiagnosis is made using CT-guided aspiration of abscessAdrenal tuberculosisDisseminated tuberculosis may spread to adrenal glands, leading to adrenal enlargement and granuloma formation within adrenal glandTypically presents with bilateral adrenal involvement. Most patients have extra-adrenal manifestations, with lung being most common site. Adrenal tuberculosis may lead to chronic adrenal insufficiency in cases of bilateral adrenal involvement48
Treatment
Approach to Treatment
- In general, treatment should start with least invasive intervention possible, beginning with supportive care and followed by angioembolization of adrenal arteries if continued bleeding occurs
- Surgery is indicated if either intervention is unsuccessful or if patient is clinically unstable and needs rapid hemorrhagic control
- In cases of acute adrenal insufficiency, steroids are mainstay of treatment. In addition, some patients may require treatment with vasopressors to achieve mean arterial pressure that will provide adequate perfusion to end organs
- When adrenal crisis is suspected, initiate empiric treatment immediately, regardless of whether diagnostic workup has been completed as delayed treatment may lead to rapid deterioration, cardiovascular collapse, and possibly death34
Nondrug and Supportive Care
- Supportive care involves close hemodynamic monitoring with fluid resuscitation as needed
- If patient is taking anticoagulation or antiplatelet medications, stop them immediately because they can potentiate further bleeding
- Discuss cardiac risks of stopping antiplatelet medications with patient
- May require consultation with cardiologist
- Currently no guidelines exist on timing of restarting these medications, although in general they should be restarted as soon as safely possible
- Clinical judgment and knowledge of risks and benefits of these medications are required when deciding when they can be taken again in setting of a recent bleed
- Consider serial hemoglobin laboratory work and give blood transfusions when appropriate
- Correct any abnormalities noted in prothrombin/INR, platelet count, or fibrinogen level test results
- In particular, coagulopathies associated with elevated prothrombin time/INR can be treated rapidly with infusion of fresh frozen plasma, while low fibrinogen levels can be increased by administering cryoprecipitate49
- Repeated imaging may also be considered to evaluate for expanding hematoma if there is concern for ongoing bleeding1
Drug Therapy
- Initiate prompt empiric treatment for any patient with suspected acute adrenal insufficiency to avoid adrenal crisis. Treatment should not be delayed by diagnostic testing in patients who have hemodynamic instability
- Cornerstone of treatment for any patient with suspected acute adrenal insufficiency includes systemic steroid replacement and volume repletion in accordance with 2016 Endocrine Society clinical practice guidelines:34
- Steroid replacement
- Adults dosing
- Give adults with suspected adrenal crisis 100 mg of IV hydrocortisone immediately
- Maintenance steroid replacement includes 200 mg hydrocortisone per day (via continuous IV therapy or 6 hourly IV injections). Dosage and duration is dependent on severity of illness and magnitude of stressor
- Of note, hydrocortisone dosages greater than 50 mg per 24 hours will act as a mineralocorticoid, which will prevent hyperkalemia often seen in patients with acute adrenal insufficiency
- Prednisolone may be used as alternative if hydrocortisone is unavailable
- Dexamethasone is least-preferred alternative and should only be used if no other glucocorticoid is available
- Pediatric dosing
- Give children with suspected adrenal crisis immediate parenteral injection of 50 mg/m2 hydrocortisone
- Maintenance steroid replacement includes 50 to 100 mg/m2 hydrocortisone per day (via continuous IV therapy or 6 hourly IV injections). Dosage and duration is dependent on severity of illness and magnitude of stressor
- Adults dosing
- Aggressive fluid replacement
- Adults
- Rapid infusion of 1000 mL isotonic saline within 1 hour
- Continuous IV isotonic saline should be guided by individual patient needs
- Children
- Rapid bolus of 20 mL/kg normal saline (0.9%)
- May repeat for total of 60 mL/kg within 1 hour for shock
- Continuous IV isotonic saline should be guided by individual patient needs
- Adults
- Steroid replacement
- Other drug therapies
- Patients who are in persistent hemorrhagic shock despite resuscitation with fluid and blood products may need hemodynamic support with vasopressors
- Treat electrolyte abnormalities seen in adrenal insufficiency, especially hyperkalemia, to avoid serious cardiac complications
- If patient is suspected to have infectious source as underlying cause of adrenal hemorrhage, empiric broad spectrum antibiotics are recommended49
- Levothyroxine replacement is not required in patients with adrenal insufficiency caused by adrenal hemorrhage because hypothalamic–pituitary–adrenal axis is typically functioning appropriately at level of hypothalamus and pituitary gland in these patients; therefore, there is no disruption to thyroid hormone synthesis
- If underlying cause of adrenal hemorrhage is pheochromocytoma, initiate treatment with α-blockers before definitive surgical intervention
- There are no recommendations for standard dosing or type of α1-adrenergic blocker to use. Titrate doses with goal of mild orthostatic hypotension in patient50
- Other antihypertensives may be required as adjuncts to prevent hypertensive crisis. β-blockers should only be added after appropriate α-blockade has been achieved because unopposed β-blockade in patient with elevated levels of plasma catecholamines may lead to hypertensive crisis and can place patient at risk for heart failure and cardiovascular collapse
Treatment Procedures
- Angioembolization
- Consider embolization of blood vessels supplying adrenal glands in cases of ongoing bleeding refractory to supportive care
- In cases of bilateral adrenal hemorrhage, use angioembolization judiciously because it can lead to permanent adrenal insufficiency
- Although surgical resection of pheochromocytoma is standard of care, angioembolization is treatment of choice in hemodynamically unstable patients with pheochromocytoma who require urgent intervention
- Surgical intervention without appropriate preoperative α-blockade is associated with 45% mortality rate19
- After angioembolization, these patients still require surgical adrenalectomy to remove pheochromocytoma; however, this should be done in elective setting under appropriate α-blockade where possible50
- Surgical adrenalectomy
- Reserve for patients who have ongoing bleeding refractory to angioembolization
- Also treatment of choice in patients who present with hemodynamically instability in whom angioembolization is considered unsafe
- Also definitive management for patients who have underlying adrenocortical carcinoma or functional adrenal mass
- In patients who are hemodynamically unstable and need rapid hemostasis, open laparotomy approach is typically used. Otherwise, laparoscopic approach can be considered, depending on surgeon preference and experience
- Take extreme caution if underlying cause of adrenal hemorrhage is pheochromocytoma
- Proceeding immediately to surgery in case of occult pheochromocytoma can be catastrophic, as surgical manipulation of pheochromocytoma can lead to release of catecholamines and may cause hypertensive crisis
- Perform careful attention to imaging and biochemical evaluation to rule out underlying pheochromocytoma before considering surgery. Inability to identify pheochromocytoma before surgery is directly related to increased mortality in patients with adrenal hemorrhage51
- In patients with confirmed pheochromocytoma, perform proper α-blockade before proceeding with surgery
- Current recommendations from North American Neuroendocrine Tumor Society include initiating α-blockade 7 to 14 days before surgical intervention to avoid periprocedural cardiovascular complications52
- Use α-blockers as first line therapy to control hypertension. Calcium channel blockers may be used as second line agents in patients who have persistent hypertension on α-blockade alone52
- Historically, nonselective α-blockers (eg, phenoxybenzamine) have been used as agent of choice because they irreversibly bind to α-adrenergic receptors, although recent studies have suggested that α1-selective blockers have better postoperative hemodynamic recovery and fewer adverse effects. There is no consensus as to which particular α1-selective blocker to use52
- Coadministration of β-blockers to control tachycardia is indicated only after proper administration of α-blockers and sufficient volume expansion has occurred because unopposed stimulation of α-adrenergic receptors may lead to hypertensive crisis52
- If α-blockade is not feasible owing to ongoing bleeding and hemodynamic instability, it is recommended to perform angioembolization with interventional radiology in acute setting with definitive surgical resection deferred until patient is hemodynamically stable and appropriate α-blockade can take place50
- Table 4 summarizes periprocedural medications and doses
- View full sizeTable 4. Medications for preoperative management of pheochromocytoma.Medication classMedication nameAverage dosingSpecial considerationsSelective β1-blockersDoxazosin2-8 mg by mouth every 12-24 hoursDecreased potency compared with nonselective β-blockerPrazosin2-5 mg by mouth every 8 hoursTerazosin4-8 mg by mouth every 12-24 hoursNonselective β-blockerPhenoxybenzamine10-20 mg by mouth every 8-12 hoursExpensive; irreversible binding to α-receptorsSelective β1-blockersMetoprolol Tartrate25-50 mg by mouth every 12 hoursGoal heart rate <90/minuteAtenolol25-50 mg by mouth once or twice dailyNonselective β-blockerPropranolol20-40 mg by mouth every 8-12 hoursGoal heart rate <90/minuteCalcium channel blockersAmlodipine5-10 mg by mouth dailySecond line agent for hypertension after β-blocker administrationNifedipine30–60 mg by mouth every 12 hCaption: From Fishbein L et al. The North American Neuroendocrine Tumor Society consensus guidelines for surveillance and management of metastatic and/or unresectable pheochromocytoma and paraganglioma. Pancreas. 2021;50(4):469-493.
Admission Criteria
- In general, patients with adrenal hemorrhage warrant admission to hospital given potential for rapid decompensation
- Patients with small hematomas that are not actively bleeding and who are hemodynamically stable may be considered for outpatient observation; however, there should be a low threshold to admit any patient found to have adrenal hemorrhage
- In patients with severe adrenal hemorrhage or bilateral adrenal hemorrhage, admission to critical care unit should be strongly considered for close monitoring of hemodynamics because hemorrhagic shock and adrenal insufficiency can be fatal if not treated promptly
Follow-up
Monitoring
- Typically, once adrenal hemorrhage has resolved, patients do not require further monitoring with imaging or laboratory testing
- In instances where it is unclear whether adrenal lesion is a hematoma or neoplasm, serial imaging may be needed to track evolution of lesion19
- Hematomas will typically shrink or completely resolve over time, while neoplasms can persist or even grow in size
- Patients with underlying adrenal neoplasms may require monitoring with serial imaging to ensure that mass does not grow in size or develop features worrisome for malignancy, each of which would indicate surgical removal of mass
Prognosis
- Prognosis varies depending on underlying cause and extent of adrenal hemorrhage
- Small, unilateral hemorrhages in asymptomatic patients typically have good prognosis, while large or bilateral hemorrhages portend poor prognosis
- Overall, mortality is up to 15% in patients with adrenal hemorrhage13
- In cases of adrenal hemorrhage caused by Waterhouse-Friderichsen syndrome, mortality ranges between 50% to 95%17
Referral
- Refer patients who develop chronic adrenal insufficiency after acute adrenal hemorrhage to endocrinologist because they will require lifelong steroid replacement
References
1.Simon DR et al. Clinical update on the management of adrenal hemorrhage. Curr Urol Rep. 2009;10(1):78-83.
View In Article|Cross Reference
2.Udobi KF et al. Adrenal crisis after traumatic bilateral adrenal hemorrhage. J Trauma. 2001;51(3):597-600.
View In Article|Cross Reference
3.Badawy M et al. Adrenal hemorrhage and hemorrhagic masses; diagnostic workup and imaging findings. Br J Radiol. 2021;94(1127):20210753.
View In Article|Cross Reference
4.Xarli VP et al. Adrenal hemorrhage in the adult. Medicine (Baltimore). 1978;57(3):211-221.
View In Article|Cross Reference
5.Ramon I et al. Primary adrenal insufficiency due to bilateral adrenal hemorrhage-adrenal infarction in the antiphospholipid syndrome: long-term outcome of 16 patients. J Clin Endocrinol Metab. 2013;98(8):3179-3189.
View In Article|Cross Reference
6.Bhattacharya P et al. Haemorrhagic shock from solid tumours of the adrenal gland: a case of bleeding primary adrenal lymphoma. Ann R Coll Surg Engl. 2021;103(3):e101-e105.
View In Article|Cross Reference
7.Vella A et al. Adrenal hemorrhage: a 25-year experience at the Mayo Clinic. Mayo Clin Proc. 2001;76(2):161-168.
View In Article|Cross Reference
8.Ulrich-Lai YM et al. Chronic stress induces adrenal hyperplasia and hypertrophy in a subregion-specific manner. Am J Physiol Endocrinol Metab. 2006;291(5):e965-e973.
View In Article|Cross Reference
9.Mayo-Smith WW et al. State-of-the-art adrenal imaging. Radiographics. 2001;21(4):995-1012.
View In Article|Cross Reference
10.To’o KJ et al. Imaging of traumatic adrenal injury. Emerg Radiol. 2012;19(6):499-503.
View In Article|Cross Reference
11.Mehrazin R et al. Adrenal trauma: Elvis Presley Memorial Trauma Center experience. Urology. 2007;70(5):851-855.
View In Article|Cross Reference
12.Panda A et al. Are traumatic bilateral adrenal injuries associated with higher morbidity and mortality? A prospective observational study. J Trauma Manag Outcomes. 2015;9:6.
View In Article|Cross Reference
13.Kovacs KA et al. Bilateral massive adrenal hemorrhage. Assessment of putative risk factors by the case-control method. Medicine (Baltimore). 2001;80(1):45-53.
View In Article|Cross Reference
14.Ries MD et al. Fatal massive adrenal hemorrhage after bilateral total knee arthroplasty. J Arthroplasty. 1994;9(5):559-562.
View In Article|Cross Reference
15.Kawashima A et al. Imaging of nontraumatic hemorrhage of the adrenal gland. Radiographics. 1999;19(4):949-963.
View In Article|Cross Reference
16.Hale AJ et al. Fatal purpura fulminans and Waterhouse-Friderichsen syndrome from fulminant Streptococcus pneumoniae sepsis in an asplenic young adult. IDCases. 2016;6:1-4.
View In Article|Cross Reference
17.Carvalho R et al. Fatal Waterhouse-Friderichsen syndrome in an adult due to serogroup Y Neisseria meningitidis. BMJ Case Rep. 2021;14(2).
View In Article|Cross Reference
18.Hammond NA et al. Imaging of adrenal and renal hemorrhage. Abdom Imaging. 2015;40(7):2747-2760.
View In Article|Cross Reference
19.Marti JL et al. Spontaneous adrenal hemorrhage with associated masses: etiology and management in 6 cases and a review of 133 reported cases. World J Surg. 2012;36(1):75-82.
View In Article|Cross Reference
20.Kumar S et al. Rare adrenal gland emergencies: a case series of giant myelolipoma presenting with massive hemorrhage and abscess. Nephrourol Mon. 2015;7(1):e22671.
View In Article|Cross Reference
21.Rosenberger LH et al. Bilateral adrenal hemorrhage: the unrecognized cause of hemodynamic collapse associated with heparin-induced thrombocytopenia. Crit Care Med. 2011;39(4):833-838.
View In Article|Cross Reference
22.Espinosa G et al. Adrenal involvement in the antiphospholipid syndrome: clinical and immunologic characteristics of 86 patients. Medicine (Baltimore). 2003;82(2):106-118.
View In Article|Cross Reference
23.Frankel M et al. Bilateral adrenal hemorrhage in coronavirus disease 2019 patient: a case report. J Clin Endocrinol Metab. 2020;105(12):dgaa487.
View In Article|Cross Reference
24.Sharrack N et al. Adrenal haemorrhage as a complication of COVID-19 infection. BMJ Case Rep. 2020;13(11):e239643.
View In Article|Cross Reference
25.Freire Santana M et al. Case report: adrenal pathology findings in severe COVID-19: an autopsy study. Am J Trop Med Hyg. 2020;103(4):1604-1607.
View In Article|Cross Reference
26.Imga NN et al. Idiopathic spontaneous adrenal hemorrhage in the third trimester of pregnancy. Case Rep Med. 2013;2013:912494.
View In Article|Cross Reference
27.Singh M et al. Idiopathic unilateral adrenal hemorrhage in a term pregnant primigravida female. Radiol Case Rep. 2020;15(9):1541-1544.
View In Article|Cross Reference
28.Lai LJ et al. Neonatal adrenal hemorrhage associated with scrotal hematoma: an unusual case report and literature review. Pediatr Neonatol. 2012;53(3):210-212.
View In Article|Cross Reference
29.Demirel N et al. Adrenal bleeding in neonates: report of 37 cases. Turk J Pediatr. 2011;53(1):43-47.
View In Article|Cross Reference
30.Toti MS et al. Adrenal hemorrhage in newborn: how, when and why–from case report to literature review. Ital J Pediatr. 2019;45(1):58.
View In Article|Cross Reference
31.Bharucha T et al. Bilateral adrenal haemorrhage presenting as epigastric and back pain. JRSM Short Rep. 2012;3(3):15.
View In Article|Cross Reference
32.Zeiger MA et al. The American Association of Clinical Endocrinologists and American Association of Endocrine Surgeons medical guidelines for the management of adrenal incidentalomas. Endocr Pract. 2009;15(Suppl 1):1-20.
View In Article|Cross Reference
33.Godfrey RL et al. Bilateral adrenal haemorrhagic infarction in a patient with antiphospholipid syndrome. BMJ Case Rep. 2014;2014:bcr2014207050.
View In Article|Cross Reference
34.Bornstein SR et al. Diagnosis and treatment of primary adrenal insufficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2016;101(2):364-389.
View In Article|Cross Reference
35.Javorsky BR et al. New cutoffs for the biochemical diagnosis of adrenal insufficiency after ACTH stimulation using specific cortisol assays. J Endocr Soc. 2021;5(4):bvab022.
View In Article|Cross Reference
36.Hamrahian AH et al. Measurements of serum free cortisol in critically ill patients. N Engl J Med. 2004;350(16):1629-1638.
View In Article|Cross Reference
37.Dunnick NR et al. Imaging of adrenal incidentalomas: current status. AJR Am J Roentgenol. 2002;179(3):559-568.
View In Article|Cross Reference
38.Rowe SP et al. Computed tomography appearance of surgically resected adrenal hematomas. J Comput Assist Tomogr. 2016;40(6):892-895.
View In Article|Cross Reference
39.Karwacka IM et al. Adrenal hemorrhage: a single center experience and literature review. Adv Clin Exp Med. 2018;27(5):681-687.
View In Article|Cross Reference
40.Imachi H et al. Idiopathic unilateral adrenal hemorrhage in an elderly patient. Endocrine. 2010;37(2):249-252.
View In Article|Cross Reference
41.Charalampakis V et al. Spontaneous adrenal hemorrhage. Report of two cases and review of pathogenesis, diagnosis and management. J Surg Case Rep. 2018;2018(6):rjy129.
View In Article|Cross Reference
42.Manganaro L et al. Bilateral adrenal hemorrhage in a patient with myelodysplastic syndrome: value of MRI in the differential diagnosis. Case Rep Radiol. 2013;2013:479836.
View In Article|Cross Reference
43.Back SJ et al. Contrast-enhanced ultrasound of the kidneys and adrenals in children. Pediatr Radiol. 2021.
View In Article|Cross Reference
44.Orazi C et al. Renal vein thrombosis and adrenal hemorrhage in the newborn: ultrasound evaluation of 4 cases. J Clin Ultrasound. 1993;21(3):163-169.
View In Article|Cross Reference
45.Boland GW et al. Characterization of adrenal masses by using FDG PET: a systematic review and meta-analysis of diagnostic test performance. Radiology. 2011;259(1):117-126.
View In Article|Cross Reference
46.Khuri FJ et al. Adrenal hemorrhage in neonates: report of 5 cases and review of the literature. J Urol. 1980;124(5):684-687.
View In Article|Cross Reference
47.Sharma S et al. Tuberculous adrenal abscess presenting as adrenal insufficiency in a 4-year-old boy. J Trop Pediatr. 2019;65(3):301-304.
View In Article|Cross Reference
48.Serter R et al. Acute adrenal crisis together with unilateral adrenal mass caused by isolated tuberculosis of adrenal gland. Endocr Pract. 2003;9(2):157-161.
View In Article|Cross Reference
49.Tucci V et al. The clinical manifestations, diagnosis, and treatment of adrenal emergencies. Emerg Med Clin North Am. 2014;32(2):465-484.
View In Article|Cross Reference
50.Maruyama M et al. Spontaneous rupture of pheochromocytoma and its clinical features: a case report. Tokai J Exp Clin Med. 2008;33(3):110-115.
View In Article|Cross Reference
51.Kobayashi T et al. Spontaneous rupture of adrenal pheochromocytoma: review and analysis of prognostic factors. J Surg Oncol. 2005;90(1):31-35.
View In Article|Cross Reference
52.Fishbein L et al. The North American Neuroendocrine Tumor Society consensus guidelines for surveillance and management of metastatic and/or unresectable pheochromocytoma and paraganglioma. Pancreas. 2021;50(4):469-493.
