Adrenal Hemorrhage

Although the precise mechanisms leading to adrenal hemorrhage are unclear in nontraumatic cases, available evidence has implicated adrenocorticotropic hormone (ACTH), adrenal vein spasm and thrombosis, and the normally limited venous drainage of the adrenal in the pathogenesis of this condition.

The adrenal gland has a rich arterial supply, in contrast to its limited venous drainage, which is critically dependent on a single vein. Furthermore, in stressful situations, ACTH secretion increases, which stimulates adrenal arterial blood flow that may exceed the limited venous drainage capacity of the organ and lead to hemorrhage.

In addition, adrenal vein spasm induced by high catecholamine levels secreted in stressful situations and by adrenal vein thrombosis induced by coagulopathies may lead to venous stasis and hemorrhage. Adrenal vein thrombosis has been found in several patients with adrenal hemorrhage, and it may occur in association with sepsis, heparin-induced thrombocytopenia,[7] primary antiphospholipid antibody syndrome, or disseminated intravascular coagulation (DIC).

Regardless of the precise mechanisms, extensive, bilateral adrenal hemorrhage commonly leads to acute adrenal insufficiency and adrenal crisis, unless it is recognized and treated promptly.

Frequency

United States

Adrenal hemorrhage has been reported in 0.3-1.8% of unselected cases in autopsy studies, although extensive bilateral adrenal hemorrhage may be present in 15% of individuals who die of shock.

Mortality/Morbidity

Acute adrenal insufficiency (adrenal crisis) may occur in association with extensive, bilateral adrenal hemorrhage, and it is uniformly fatal if unrecognized and untreated. In contrast, unilateral adrenal hemorrhage is not associated with acute adrenal insufficiency.

Patients with adrenal hemorrhage may die because of underlying disease or diseases associated with adrenal hemorrhage, despite treatment with stress-dose glucocorticoids. Overall, adrenal hemorrhage is associated with a 15% mortality rate, which varies according to the severity of the underlying illness predisposing to adrenal hemorrhage. For example, patients with Waterhouse-Friderichsen syndrome (adrenal hemorrhage occurring in sepsis, most frequently meningococcal) have a 55-60% mortality rate.[8]

Chronic adrenal insufficiency occurs in most patients who survive extensive, bilateral adrenal hemorrhage, necessitating long-term glucocorticoid replacement. In contrast, the need for mineralocorticoid replacement is variable. Androgen replacement therapy may also be beneficial in women with chronic adrenal insufficiency. Rare case reports exist of patients who had complete recovery of adrenal function after an episode of extensive, bilateral adrenal hemorrhage and acute adrenal insufficiency.

Sex

Extensive, bilateral adrenal hemorrhage is more common in males (male-to-female ratio of 2:1), probably reflecting a male predilection for several of the underlying conditions associated with adrenal hemorrhage.

Age

Although adrenal hemorrhage may occur in people of any age, most patients with nontraumatic, extensive, bilateral adrenal hemorrhage are aged 40-80 years at the time of the acute event. In contrast, patients with traumatic adrenal hemorrhage typically are in the second to third decade of life.

Most patients with Waterhouse-Friderichsen syndrome are in the pediatric age group, although adults have infrequently been affected.

Adrenal hemorrhage in neonates is a well-described entity and has even been diagnosed in utero. A full discussion of this entity is beyond the scope of this review.

Symptoms of adrenal hemorrhage are nonspecific; they include abdominal, lumbar, pelvic, or thoracic pain and symptoms of acute adrenal insufficiency, such as fatigue, anorexia, nausea, and vomiting. Symptoms associated with the underlying condition(s) also may be present. Rarely, adrenal hemorrhage is entirely asymptomatic, presenting as an incidental finding on imaging studies.

Pain that is nonspecific in location and quality is the most consistent feature of adrenal hemorrhage.

• Nonspecific pain occurred in 65-85% of published cases.

• It can occur predominantly in the epigastrium, flank, upper or lower back, pelvis, or precordium or elsewhere in the thorax.

• Left shoulder pain may occur in association with abdominal pain, likely because of diaphragmatic irritation.

Fatigue, weakness, dizziness, arthralgias, myalgias, anorexia, nausea, vomiting, and diarrhea, which are present in approximately 50% of extensive, bilateral adrenal hemorrhage cases, are indicative of acute adrenal insufficiency.

Symptoms of the underlying condition(s) predisposing to adrenal hemorrhage may be present. For example, patients with Waterhouse-Friderichsen syndrome often experience prodromic, nonspecific symptoms, including malaise, headache, dizziness, cough, arthralgias, and myalgias.

Adrenal hemorrhage may be present in approximately 2 of 1000 newborn infants and may arise spontaneously or in association with birth trauma, asphyxia, sepsis, or hemorrhagic diathesis.

Physical findings in patients with adrenal hemorrhage are nonspecific and vary depending on the extent of adrenal hemorrhage, the bleeding rate, and the underlying cause, as well as according to whether the adrenal hemorrhage is bilateral or unilateral.

Fever (ie, temperature >38ºC) is present in 50-70% of patients with adrenal hemorrhage, representing the most frequent finding in adrenal hemorrhage.

• In reported cases, temperature may range from low-grade fever to high fever with chills.

• In the setting of adrenal hemorrhage, fever may be associated with adrenal insufficiency, the hematoma itself, or the underlying cause of adrenal hemorrhage.

Tachycardia has been reported in approximately 40-50% of patients early in the course of extensive, bilateral adrenal hemorrhage, and without aggressive therapy, it may progress to shock.

Orthostatic hypotension is present in approximately 20% of patients with extensive, bilateral adrenal hemorrhage. This is an early finding that, if there is no specific intervention, usually leads to supine hypotension and shock.

Because shock occurs only late in the course of extensive, bilateral adrenal hemorrhage, its absence should not be used to exclude this diagnosis.

• In addition to acute adrenal insufficiency, shock in patients with extensive, bilateral adrenal hemorrhage may be caused by 1 or more underlying conditions, including sepsis, cardiovascular causes (commonly myocardial infarction and pulmonary embolism), or hypovolemia.

• In Waterhouse-Friderichsen syndrome, activation of several cytokine mediators appears to lead to sepsis and shock. Whether acute adrenal insufficiency has a significant role in the pathogenesis of the Waterhouse-Friderichsen syndrome remains unclear and debatable.

Hypertension has been reported rarely in patients with unilateral adrenal hemorrhage; in one patient it was accompanied by headache and dizziness, leading to an erroneous diagnosis of pheochromocytoma.

Weight loss is very uncommon, but it may occur in cases of adrenal hemorrhage that are recognized several weeks after the event. These patients have a subacute presentation of adrenal insufficiency in association with adrenal hemorrhage, instead of acute adrenal crisis.

Skin hyperpigmentation has been reported rarely in adrenal hemorrhage cases. Its presence indicates late recognition of adrenal insufficiency in association with adrenal hemorrhage.

A characteristic skin rash with a typical evolution occurs in approximately 75% of patients with Waterhouse-Friderichsen syndrome.

• In its early stages, the rash consists of small, pink macules or papules.

• These are rapidly followed by petechial lesions, which gradually transform into large, purpuric, coalescent plaques in late stages of the disease.

Signs of acute abdomen, including guarding, rigidity, or rebound tenderness, have been reported in 15-20% of patients. This relative paucity of physical findings on abdominal examination is likely secondary to the retroperitoneal location of the adrenals.

Confusion and disorientation are present in 20-40% of patients. These findings are also nonspecific, because they may be associated with acute adrenal insufficiency or with the underlying condition(s) precipitating adrenal hemorrhage.

Bilateral adrenal hemorrhage

In at least 50% of cases, bilateral adrenal hemorrhage is associated with an acute, stressful illness (eg, infection, congestive heart failure, myocardial infarction, complications of pregnancy) or event (eg, surgery or invasive procedure). Other frequent associations include hemorrhagic diatheses (eg, anticoagulant use, thrombocytopenia), thromboembolic disease (including antiphospholipid antibody syndrome), blunt trauma, and ACTH therapy. In addition, bilateral adrenal hemorrhage has been reported in patients with tuberculosis, amyloidosis, or metastatic tumors involving the adrenals, including lung adenocarcinoma. A multicenter, hospital-based, case-control study identified thrombocytopenia, heparin exposure, and sepsis as the major risk factors for the development of bilateral adrenal hemorrhage.

• Infections associated with extensive, bilateral adrenal hemorrhage are diverse; they include sepsis, wound infections, pneumonia, pseudomembranous colitis, influenza, varicella, and malaria.

• Waterhouse-Friderichsen syndrome (purpura fulminans) represents hemorrhagic necrosis of several organs, including adrenal hemorrhage, in the setting of overwhelming sepsis. The syndrome frequently is characterized by a distinctly hemorrhagic skin rash. Although Waterhouse-Friderichsen syndrome originally was recognized in association with meningococcal disease, which still accounts for 80% of cases, the syndrome also has been associated with other bacterial pathogens, including Streptococcus pneumoniae, group A beta-hemolytic streptococci, Neisseria gonorrhoeae, Escherichia coli, Klebsiella pneumoniae, Haemophilus influenzae (group B), Salmonella choleraesuis, Pasteurella multocida, Acinetobacter calcoaceticus, and Plesiomonas shigelloides.[9]

• Congestive heart failure, myocardial infarction, inflammatory bowel disease, acute pancreatitis, and cirrhosis also have been associated with bilateral adrenal hemorrhage.[10]

• Obstetric causes of bilateral adrenal hemorrhage include toxemia of pregnancy, spontaneous abortion, antepartum or postpartum hemorrhage, twisted ovarian cyst (in pregnancy), and primary antiphospholipid antibody syndrome. Spontaneous adrenal hemorrhage during pregnancy has rarely been described.[11]

• Coronary artery bypass graft surgery, hip joint replacement, intracranial surgery, and hepatic arterial chemoembolization are procedures associated with bilateral adrenal hemorrhage.[12] Heparin-induced thrombocytopenia may predispose to adrenal hemorrhage in some of these patients.

• Hemorrhagic diatheses, including anticoagulant use, thrombocytopenia, and vitamin K deficiency have been associated with approximately one third of bilateral adrenal hemorrhage cases. Heparin use accounts for the majority of cases of anticoagulant-associated, bilateral adrenal hemorrhage. In such cases, bilateral adrenal hemorrhage occurs despite the fact that the activated partial thromboplastin time is almost invariably therapeutic, and adrenal hemorrhage represents an isolated event without evidence of bleeding elsewhere. Heparin-induced thrombocytopenia (HIT) was found to underlie several bilateral adrenal hemorrhage cases, although the precise role of HIT in the pathogenesis of heparin-induced adrenal hemorrhage has not been fully elucidated.[13]

• Arterial (eg, pulmonary embolism, cerebrovascular disease, peripheral arterial embolism) and venous (eg, deep venous thrombosis, superficial thrombophlebitis) causes have been associated with bilateral adrenal hemorrhage in one third of cases. Antiphospholipid antibody syndrome (either primary or secondary to systemic lupus erythematosus) has been associated with bilateral adrenal hemorrhage.[14, 15, 16]

• Blunt trauma of diverse etiologies, ranging from motor vehicle accidents to a truck ride over a bumpy road, has been associated with bilateral adrenal hemorrhage.

• Underlying adrenal pathologic conditions, including granulomatous diseases, amyloidosis, and metastatic cancer (eg, lung or gastric adenocarcinoma), have been associated with bilateral adrenal hemorrhage.

• Treatment with ACTH for multiple sclerosis or inflammatory bowel disease has in some cases been associated with bilateral adrenal hemorrhage.

• Case studies have indicated that an association exists between coronavirus disease 2019 (COVID-19) and adrenal hemorrhage. A report by Frankel et al described a woman aged 66 years who, along with COVID-19, had primary adrenal insufficiency resulting from bilateral adrenal hemorrhage. In addition, she had renal vein thrombosis and a past history of primary antiphospholipid antibody syndrome. The investigators suggested that the combination of COVID-19 (which has been associated with coagulopathy and thromboembolic events) and antiphospholipid antibody syndrome led to the adrenal hemorrhage.[17] Another case study, by Álvarez-Troncoso et al, reported test results in a man aged 70 years indicative of both COVID-19 and bilateral adrenal hemorrhage.[18]

Unilateral adrenal hemorrhage

Unilateral adrenal hemorrhage most frequently is caused by blunt abdominal trauma (traumatic adrenal rupture), but it also has occurred in liver transplant recipients and in patients with primary adrenal or metastatic tumors. In addition, unilateral adrenal hemorrhage is associated, albeit infrequently, with otherwise uncomplicated pregnancy, neurofibromatosis 1, or long-term nonsteroidal anti-inflammatory drug (NSAID) use. There have been rare reports of idiopathic, spontaneous, unilateral adrenal hemorrhage.

In a retrospective study of 23 patients with adrenal hemorrhage (including 22 with a unilateral condition), Karwacka et al reported that risk factors could not be determined in 13 patients, while risk factors in the rest of the cohort included trauma (5 patients), sepsis (1 patient; bilateral adrenal hemorrhage), concomitant neoplastic disease (2 patients), both anticoagulant drug use and lung cancer (1 patient), and both trauma and chronic oral anticoagulation (1 patient).[19]

• Unilateral adrenal hemorrhage secondary to blunt trauma more often involves the right adrenal. Liver hematomas and rib fractures commonly occur in these patients as well. Unilateral adrenal hemorrhage occurs in 2% of patients with penetrating trauma.

• Right adrenal hemorrhage was found in 2% of liver transplant recipients in one study, and it also was reported in 10% of children dying early after orthotopic liver transplantation. In these patients, intraoperative ligation of the right adrenal vein, performed after a limited resection of the recipient's inferior vena cava, has sometimes resulted in venous infarction and adrenal hemorrhage.

• Unilateral adrenal hemorrhage was described in patients with primary adrenal or metastatic tumors, representing hemorrhagic tumor infarction. Primary adrenal tumors associated with adrenal hemorrhage include adrenal adenomas, adrenocortical carcinomas, and pheochromocytomas. In addition, adrenal hemorrhage has been described in patients with metastatic hepatocellular carcinoma or with lung or gastric adenocarcinoma.[20]

• In isolated cases, unilateral adrenal hemorrhage may occur in association with long-term NSAID, otherwise uncomplicated pregnancy, and neurofibromatosis 1.[21]

• Idiopathic, unilateral adrenal hemorrhage is a rare entity that either may have an acute presentation (eg, idiopathic adrenal rupture) or may present as an asymptomatic adrenal mass.[22]

Complete blood count (CBC) and differential generally are obtained to assist with therapeutic decisions, although these test results are nonspecific.

• A significant decrease in hematocrit (at least 4%) or hemoglobin (at least 2 g/dL) occurs in approximately one half of patients with bilateral adrenal hemorrhage.

• Leukocytosis frequently occurs in patients with adrenal hemorrhage, and it may be associated with the underlying cause of adrenal hemorrhage. Eosinophilia is present in only a small percentage of patients with adrenal hemorrhage.

Serum electrolytes, blood urea nitrogen (BUN), creatinine, and plasma glucose may be of limited diagnostic use, but they also should be obtained to assist with patient management.

• Hyponatremia, hyperkalemia, and prerenal azotemia are present in approximately 50% of patients with extensive, bilateral adrenal hemorrhage. Mild hypercalcemia may rarely occur. Although the combination of low serum sodium and high serum potassium is suggestive of adrenal insufficiency in the appropriate clinical setting, their absence never should exclude this diagnosis.

• Hypoglycemia may occur in patients with adrenal hemorrhage and adrenal insufficiency, but it rarely is severe.

Serum cortisol, plasma ACTH, serum aldosterone, and plasma renin activity (PRA) always should be obtained in suspected adrenal hemorrhage cases, because they provide important information on adrenal function.

• In an acutely ill patient, the combination of increased plasma ACTH and low, or even low-normal (ie, < 13 mcg/dL), serum cortisol is highly suggestive of glucocorticoid deficiency due to primary adrenal insufficiency. Conversely, a serum cortisol of over 25 mcg/dL in an acutely ill patient excludes glucocorticoid deficiency. The combination of low serum aldosterone and increased PRA suggests mineralocorticoid deficiency.

• In order to provide useful diagnostic information, blood samples for these tests should be obtained before glucocorticoid administration, because several exogenous glucocorticoids (hydrocortisone and prednisone, but not dexamethasone) cross-react with endogenous cortisol in radioimmunoassay.

• Because results are not available immediately, these tests are not helpful in the acute setting, but they provide retrospective diagnostic information.

The short cosyntropin (Cortrosyn) stimulation test confirms the diagnosis of adrenal insufficiency.

• This test involves the bolus intravenous or intramuscular administration of the ACTH analog cosyntropin (Cortrosyn, 250 mcg) and serum collection 1 hour after cosyntropin administration for cortisol assay. A peak serum cortisol of over 20 mcg/dL (1 h after cosyntropin administration) indicates normal adrenal response in a nonstressed individual.

• Although the normal adrenal response to cosyntropin has not been defined precisely in acutely ill patients, individuals with bilateral adrenal hemorrhage and clinical evidence of adrenal insufficiency have a markedly blunted adrenal response, according to the above criteria, in this test.

• Measurement of the aldosterone response to cosyntropin (Cortrosyn) administration has been advocated in order to assess mineralocorticoid reserve. Serum samples are obtained immediately before and 30 minutes after the administration, as above, of intravenous cosyntropin. Either a peak serum aldosterone of over 16 ng/dL or a rise in serum aldosterone of at least 4 ng/dL indicates a normal adrenal response.

• Although the short cosyntropin (Cortrosyn) stimulation test is the criterion standard for the diagnosis of adrenal insufficiency, its performance may not be practical in the acute setting, particularly in a hypotensive or otherwise unstable patient. In these cases, only basal cortisol and ACTH levels need to be obtained before urgent glucocorticoid administration, and the more definitive Cortrosyn stimulation test can be performed after the patient has been stabilized. Alternatively, because the presence of dexamethasone does not interfere with cortisol immunoassays, this medication can be administered to stabilize the condition of a patient with suspected adrenal insufficiency, before the short Cortrosyn stimulation test is performed.

• Because the results of the short cosyntropin (Cortrosyn) stimulation test are not available immediately, this test is not helpful in the acute setting to guide management decisions, but it provides retrospective confirmation of adrenal insufficiency.

CT scanning

Computed tomography (CT) scanning of the adrenals (thin slice) is the study of choice for demonstrating adrenal hemorrhage in the acute setting.[4]  However, it is practical only in hemodynamically stable patients.

CT scanning of patients with adrenal hemorrhage shows adrenal enlargement that may be asymmetrical in cases of bilateral adrenal hemorrhage. The glands become rounded or oval shaped and have high attenuation (50-90 Hounsfield units) without contrast enhancement in the acute setting.

In cases of unilateral, traumatic adrenal hemorrhage, a streaky appearance of the perirenal fat frequently is observed posterior to the gland.[24] This finding is not specific to traumatic adrenal hemorrhage, because it also has been observed in patients with adrenal hemorrhage and metastatic tumors to the adrenals. Extension of the hemorrhage into the perirenal space, with perinephric hematoma formation, has been observed in patients with metastatic disease.

Associated findings may include a mixed-density, inhomogeneous mass in patients with primary or metastatic cancer. Significant contrast enhancement further suggests the presence of an associated lesion (such as pheochromocytoma or metastatic tumor).

Several weeks after the acute adrenal hemorrhage, CT scanning shows a gradual decrease in adrenal size and attenuation. In addition, the adrenals may have a cystic appearance.

Several months after the acute event, CT scanning of the adrenals shows progressive atrophy, with the variable appearance of calcifications. The presence of adrenal calcifications does not invariably indicate a previous episode of adrenal hemorrhage, because this finding also is associated with adrenal cysts, adrenocortical adenomas and carcinomas, pheochromocytomas, neuroblastomas (only in children), metastatic tumors, and granulomatous diseases, including tuberculosis and histoplasmosis.

A study by Tan and Sutherland suggested that signs of adrenal congestion (adrenal gland thickening, periadrenal fat stranding) on CT scanning can predict subsequent nontraumatic adrenal hemorrhaging. The study involved four patients with nontraumatic adrenal hemorrhage, who were compared with 12 randomly selected intensive care patients.[25]

Recognizing that adrenal hematomas with a masslike configuration can be mistaken for adrenal neoplasms, leading to surgical resection, Rowe et al described the CT-scan characteristics of five adrenal hematomas. The lesions were well-defined, with an ovoid morphology, an average maximum diameter of 8.9 cm, and greatly varying attenuation on noncontrast CT scan. Peripheral enhancement in four of the hematomas was either thin and somewhat uniform or heterogeneous and irregular. The five lesions did not invade periadrenal fat or adjacent organs.[26]

CT scans are shown below.

Computed tomographic (CT) scans of the abdomen show normal adrenal glands several months before the onset of hemorrhage (upper panel) and enlarged adrenals 2 weeks after an acute episode of bilateral adrenal hemorrhage (lower panel). The attenuation of the adrenal glands, indicated by arrows, is increased after the acute event. Reproduced from Rao RH, Vagnucci AH, Amico JA: Bilateral massive adrenal hemorrhage: early recognition and treatment. Ann Intern Med. Feb 1 1989;110(3):227-35 with permission from the journal.

MRI

Magnetic resonance imaging (MRI) may be used to help exclude the presence of malignant tumors or pheochromocytomas, and it may provide an estimate of the age of the hematoma.[5, 6]  Less experience with the use of MRI in adrenal hemorrhage exists in comparison with CT scanning.

Acutely (ie, 24-72 h after onset), the adrenals are enlarged. Adrenal hemorrhage appears isointense with normal liver and muscle on T1-weighted images and appears hyperintense to the liver on T2-weighted images. Stranding of the perirenal and even subcutaneous fat has been observed in T2-weighted images in traumatic adrenal hemorrhage cases.

Subacutely (ie, approximately 3-7 d after onset), adrenal hemorrhage shows intermediate intensity on T1- and T2-weighted images. This appearance has been associated with the presence of deoxyhemoglobin in the adrenal hemorrhagic area. In addition, a hyperintense ring frequently is observed outlining the adrenals (on T1- and T2-weighted images). This hyperintense ring gradually may fill in centrally, and it appears to be secondary to the presence of free methemoglobin.

At a more chronic stage (ie, several wk after onset), MRI shows a decrease in adrenal size. In addition, adrenal hemorrhagic areas become hyperintense with a hypointense rim on T1- and T2-weighted images. The centrally located, high signal intensity may be secondary to the presence of free methemoglobin, and the hypointense rim has been associated with the presence of hemosiderin-laden macrophages in the fibrous capsule. Furthermore, necrotic areas in the adrenal hemorrhagic area may create a more heterogeneous appearance, with areas of low signal intensity on T1-weighted images.

In a suspected adrenal hemorrhage case, the lack of enhancement after gadolinium–diethylenetriamine penta-acetic acid (Gd-DTPA) administration and the above-outlined evolution of the appearance of the adrenals confirm the diagnosis of adrenal hemorrhage and help to exclude the presence of tumor.

Ultrasonography

Ultrasonographic examination of the adrenals (including Doppler ultrasonography) is quite helpful in neonatal adrenal hemorrhage cases, and it may reveal the presence of adrenal hemorrhage in utero.

In older children or adults, ultrasonographic examination may be employed at the bedside, although it is operator dependent and may be limited by large body habitus.

Ultrasonographic imaging of adrenal hemorrhage reveals hyperechoic masses that contain a central echogenic area in the adrenal glands. Several weeks after the acute event, the central echogenicity associated with adrenal hemorrhage decreases as the hematomas become cystic.

A study by Piskunowicz et al indicated that neonatal adrenal hemorrhages can be distinguished from malignant adrenal lesions via contrast-enhanced ultrasonography (CEUS). For example, by revealing contrast signals within even the smallest vessels, CEUS can aid in differentiating a vascular mass from a hemorrhage. Moreover, the modality can be useful in blood flow assessment, owing to its high temporal and spatial resolution.[27]

Percutaneous biopsy is helpful in establishing the presence of metastatic disease in cases of adrenal hemorrhage in which suggestive features appear on CT scans.

Examination of the adrenals in adrenal hemorrhage cases typically reveals extensive hemorrhagic necrosis involving all 3 adrenal cortical cell layers, in addition to adrenal medullary cell necrosis. The hemorrhage may extend into the perirenal fat and the perirenal space.

Other common findings include adrenal vein thrombosis and the retrograde migration of medullary cells into the zona fasciculata. In contrast, vasculitis rarely has been observed in cases of adrenal hemorrhage, suggesting that it has a limited role in the pathogenesis of adrenal hemorrhage.

At a more chronic stage, the hematoma becomes organized as a fibrous capsule that forms around the adrenal hemorrhagic area. Hemosiderin-laden macrophages are present in the capsule and digest cell debris. In the months following acute adrenal hemorrhage, fibrous tissue gradually replaces the hemorrhagic areas.

In patients with suspected acute adrenal hemorrhage, evaluation should take place in an inpatient setting, because acute adrenal insufficiency may occur. However, most of these patients are acutely ill and already are in the hospital at the time of acute adrenal hemorrhage.

In asymptomatic patients presenting with an adrenal mass or calcifications, outpatient evaluation is appropriate.

Medical therapies are used to replace adrenal function, to provide vital function support as needed, to treat the underlying condition(s), and to correct fluid, electrolyte, and red cell mass deficits.

Adrenalectomy (open or laparoscopic) may be performed.

• Surgery generally is not required in cases of nontraumatic adrenal hemorrhage, except in patients with primary adrenal tumors or in rare cases, of extensive retroperitoneal hemorrhage secondary to adrenal hemorrhage.

• In traumatic adrenal hemorrhage cases, surgery may be necessary for the treatment of associated injuries, the exploration of penetrating wounds, or the control of bleeding.

Consultations include the following:

• Endocrinologist

• Interventional radiologist

• Urologist or surgeon

• Cardiologist, infectious diseases specialist, or other specialists as needed, to optimize the management of the underlying condition(s)

Critically ill patients with suspected adrenal hemorrhage are kept on nothing by mouth (NPO) status.

Patients with acute adrenal hemorrhage also may be kept NPO, depending on the presence of symptoms, such as vomiting.

In cases of chronic adrenal hemorrhage complicated by adrenal insufficiency, patients must maintain adequate hydration and salt intake. Liberal salt intake is contraindicated in the presence of hypertension, congestive heart failure, or renal failure.

Patients with suspected acute adrenal hemorrhage are kept on bed rest.

Activity is unrestricted after resolution of the acute event; however, patients must receive appropriate adrenal replacement therapy. Depending on the underlying condition(s), activity restrictions may still be necessary.

Immediately after a serum sample (for cortisol assay) has been obtained, but without awaiting biochemical confirmation, glucocorticoids should be urgently administered to patients with suspected acute, bilateral adrenal hemorrhage in order to prevent or treat acute adrenal insufficiency.

In acutely ill patients, supportive therapy and specific treatments for the underlying condition(s) must be provided urgently as well.

After the acute adrenal hemorrhagic event, long-term glucocorticoid replacement with or without mineralocorticoid replacement therapy may be necessary, based on the results of adrenal function testing.

Class Summary

Administered in a stress-dose regimen, these medications adequately replace glucocorticoid hormone requirements in patients with suspected acute, bilateral adrenal hemorrhage whose adrenal function may be compromised. After discharge, oral prednisone, hydrocortisone, or dexamethasone commonly is used. Only the former 2 glucocorticoids possess some mineralocorticoid properties, whereas dexamethasone is devoid of any such activity.

Hydrocortisone (Solu-Cortef, Hydrocortone, Hydrocort)

Intravenous hydrocortisone, in conjunction with supportive measures, frequently is used and averts or adequately treats acute adrenal crisis.

Prednisone (Deltasone, Meticorten, Orasone)

After discharge, oral prednisone commonly is used for maintenance. Possesses some mineralocorticoid properties.

Dexamethasone (Decadron, AK-Dex)

In conjunction with supportive measures, it is used frequently and averts or adequately treats acute adrenal crisis. Preferred if a Cortrosyn stimulation test is planned soon after the patient has been stabilized, because it does not interfere in a cortisol assay. After discharge, dexamethasone commonly is used for maintenance.

9-alpha-fludrocortisone (Florinef)

May be indicated in patients with a history of bilateral, extensive adrenal hemorrhage in order to replace mineralocorticoid hormone requirements, based on results of adrenal function testing. Therapy is unnecessary in (acutely ill) patients receiving more than 100 mg of hydrocortisone daily, because this dose also provides adequate mineralocorticoid replacement.

Follow up to monitor adequacy and adverse effects of adrenal replacement therapy.

• Glucocorticoid adverse effects include iatrogenic Cushing syndrome, linear growth retardation, and hypothalamic-pituitary axis suppression.

• Mineralocorticoid adverse effects include edema, hypertension, hypokalemia, and alkalosis.

Follow-up evaluation with the short cosyntropin (Cortrosyn) stimulation test is used to assess recovery of adrenal function. This test can be performed 24 hours after the last dose of hydrocortisone or prednisone replacement.

If acute adrenal hemorrhage is considered likely, admit the patient to the medical or surgical intensive care unit (MICU or SICU) as indicated for treatment, including glucocorticoid replacement, supportive therapy, and treatment of the underlying disease(s).

Admit patients for elective adrenalectomy for suspected primary adrenal tumor.

Treatments using medications include glucocorticoid and mineralocorticoid replacement therapies. Glucocorticoid therapy should be provided routinely in the acute stage of extensive, bilateral adrenal hemorrhage without awaiting biochemical confirmation of adrenal insufficiency.

In the acute setting, supportive therapy with mechanical ventilation, intravenous fluid administration, and pressor therapy may be necessary to provide vital function support.

Specific therapy for any underlying disease(s) must be provided acutely, including antibiotics for sepsis. The use of heparin and fresh frozen plasma has been advocated in DIC cases but remains controversial.

Patients with chronic adrenal insufficiency must temporarily increase their glucocorticoid replacement dose (2-3 times above baseline for as long as 3-5 d) in case of minor acute illness or injury. This is known as using sick-day rules.

At the time of acute illness or major surgery, patients with chronic adrenal insufficiency should receive hydrocortisone (50-100 mg IV tid) with rapid tapering to maintenance, as the general condition permits.

In the outpatient setting, the need for continued glucocorticoid and mineralocorticoid replacement should be reassessed periodically by adrenal function testing, as previously outlined.

In women with adrenal insufficiency, androgen replacement therapy, including dehydroepiandrosterone (DHEA; 25-50 mg PO qd), improves libido.[28] Although available in over-the-counter preparations, DHEA has not, at the time of this writing, been approved by the Food and Drug Administration for use in women with adrenal insufficiency.

Transfer may be indicated for further diagnostic testing or surgery, although it is not practical in unstable patients.

Avoid volume depletion and salt restriction in the presence of chronic adrenal insufficiency, unless these are required for the treatment of coexisting conditions, such as congestive heart failure.

Acute adrenal insufficiency (adrenal crisis) may occur only in cases of extensive, bilateral adrenal hemorrhage. The proportion of patients with bilateral adrenal hemorrhage who develop acute adrenal insufficiency is unknown and remains controversial.

Extensive retroperitoneal hemorrhage secondary to adrenal hemorrhage is very uncommon, although it has been reported.

Chronic adrenal insufficiency may occur and previously was thought to be permanent. Reports of recovery of adrenal function in patients with documented adrenal insufficiency associated with an episode of extensive, bilateral adrenal hemorrhage suggest that periodic adrenal function testing of these patients is indicated.

The acute case fatality rate associated with extensive, bilateral adrenal hemorrhage is approximately 15% and varies according to the severity of underlying illness.

In Waterhouse-Friderichsen syndrome, the case fatality rate is 55-60%, particularly when the diagnosis is delayed. Death occurs from sepsis, despite appropriate antibiotic, glucocorticoid, and supportive treatment.

Recovery of adrenal function in patients with chronic adrenal insufficiency associated with adrenal hemorrhage is possible, although it appears to occur infrequently.[29, 16]

A retrospective study by Monticone et al found that in cases of adrenal hemorrhage resulting from adrenal vein sampling, used to determine whether primary aldosteronism is unilateral or bilateral, patients tended to have good outcomes, with little or no effect on adrenal function. The study included 24 patients.[30]

Patients with chronic adrenal insufficiency must wear an appropriate identification tag or bracelet.

These patients must increase (double or triple) their dose of glucocorticoid replacement with minor illness or injury, according to sick-day rules.

If patients with chronic adrenal insufficiency are unable to keep liquids and medications down, or if they suffer a major illness or injury, they must self-inject with hydrocortisone 100 mg intramuscularly and promptly seek medical attention.