Metabolic Emergencies

Adrenal Failure

Jean Rosiak

DEFINITION

• Condition in which the adrenal gland is unable to produce adequate amounts of cortical hormones in response to physiological demands

˚ Glucocorticoids are required for normal function of all cells in the body and are secreted from the adrenal cortex in large quantities during times of physiological stress to maintain homeostasis.

• Potentially lethal complication that can lead to deterioration of cardiovascular status and death if untreated

EPIDEMIOLOGY

• Bilateral adrenal metastasis: 8.6%-27% overall incidence at autopsy; only 4% become symptomatic

˚ Breast cancer 58%

˚ Malignant melanoma 50%

˚ Lung cancer 42%

˚ Non-Hodgkin lymphoma 25%

• Radiation dose >5,000 cGy to pituitary: 18%-35% incidence of adrenal insufficiency (AI) after 5-15 years

PATHOPHYSIOLOGY

• Adrenal failure results from destruction or dysfunction of the hypothalamic-pituitary-adrenal axis.

• Primary AI/adrenal failure:

˚ Caused by processes that damage the adrenal glands or by drugs that block cortisol synthesis

• Secondary AI/adrenal failure

˚ Results from processes that reduce the secretion of corticotropin-releasing hormone (CRH) by the hypothalamus or adrenocorticotropin hormone (ACTH) by the pituitary gland as a result of pituitary or hypothalamic conditions

˚ Most common cause of secondary adrenal insufficiency is abrupt discontinuation of long-term administration of glucocorticoids.

• Causes of AI/adrenal failure:

˚ Consequence of sudden withdrawal of exogenous corticosteroids

˚ Bilateral adrenal hemorrhage or venous thrombosis

˚ Adrenal tumor or metastatic involvement

˚ Pituitary hemorrhage or tumor

˚ Autoimmune disorders

˚ Medications inhibiting cytochrome P-450 isoenzymes necessary for adrenal steroidogenesis:

Ketoconazole

Aminoglutethimide

Megestrol acetate (used to increase appetite in cachectic patients)

˚ Infections:

Tuberculosis

Acquired immunodeficiency syndrome (AIDS)

Meningococcemia

Histoplasmosis

SIGNS AND SYMPTOMS

• More than 80%-90% of both adrenal glands must be nonfunctioning before clinical signs result

˚ May not be symptomatic unless severe stress is induced

• Slow onset:

˚ Chronic fatigue

˚ Joint pain/muscle cramps

˚ Anorexia/unintentional weight loss

˚ Abdominal pain

˚ Nausea

˚ Diarrhea

• Acute symptoms

˚ Fever

˚ Tachycardia

˚ Loss of vasomotor tone

˚ Hypotension, acute shock

˚ Cardiovascular collapse

˚ Death

• Primary AI (associated with lack of aldosterone and cortisol)

˚ Salt craving

˚ Dehydration resulting from renal salt wasting

˚ Postural hypotension

˚ Electrolyte abnormalities: hyperkalemia, hyponatremia

˚ Hyperpigmentation of skin and buccal mucosa (ACTH related)

• Secondary AI

˚ Pallor

˚ Amenorrhea/diminished libido

˚ Scanty axillary and pubic hair

˚ Headache and visual symptoms

CANCERS ASSOCIATED WITH DISORDER

• Breast cancer

• Malignant melanoma

• Lung cancer

• Non-Hodgkin lymphoma

• Medication-induced adrenal insufficiency

˚ Prostate cancer treated with ketoconazole

˚ Prostate or breast cancer treated with aminoglutethimide

˚ Cachexia treated with megestrol acetate

DIAGNOSTIC TESTS

• Early morning serum cortisol and ACTH levels

˚ Serum cortisol level peaks in the early morning hours.

• Cortisol level >18 mcg/dL = normal adrenal function

• Cortisol level <3 mcg/dL = adrenal insufficiency

˚ Cortisol level may be falsely low in patients with albumin level <2.5 g/dL.

˚ ACTH level elevated in primary AI

˚ ACTH level low or normal (when cortisol level decreased) in secondary AI

• ACTH stimulation test: evaluate for adrenal insufficiency (on the basis of inability of adrenal gland to respond acutely to injection of ACTH by secreting cortisol)

˚ Draw baseline cortisol level.

˚ Administer cosyntropin 0.25 mg (250 mcg) intravenously (IV).

˚ Draw cortisol levels at 30 and 60 minutes after dose.

Failure to increase serum cortisol at least 5 mcg/dL above baseline and at least to a level of 15 mcg/dL at either 30 or 60 minutes is diagnostic of adrenal insufficiency.

Serum cortisol level of >18 mcg/dL at either time point is a normal response.

• Serum potassium

˚ Elevated in primary AI

˚ Normal in secondary AI

• Serum sodium: decreased

• Serum glucose level: decreased

DIFFERENTIAL DIAGNOSIS

• Primary adrenal failure (Addison’s disease)

˚ Autoimmune adrenalitis

˚ Infection: tuberculosis, AIDS-related infections

• Secondary adrenal failure

˚ Pituitary adenomas

TREATMENT

• Prompt replacement of corticosteroids

˚ Glucocorticoid: main form of therapy for all forms of adrenal failure

Hydrocortisone 10-12.5 mg/m²/day: usually given as 20 mg orally every morning and 10 mg orally every evening

May require lower dose, particularly in secondary AI

Smallest dose that improves symptoms is recommended.

Short half-life mimics normal cortisol circadian rhythm.

˚ Stress-dose steroids before any surgical procedure

Hydrocortisone 5 mg/hr IV during surgery

For first 24 hours after surgery, a total of 150-200 mg is administered.

Taper by 50% per day if the postoperative period is without complications.

˚ Stress-dose steroids: sepsis, fever >38° C, dental procedures, invasive procedures (gastroscopy, colonoscopy, cystoscopy, bronchoscopy)

Maximal recommended dose is 50 mg every 8 hours.

˚ Mineralocorticoid: needed in addition to glucocorticoids in patients with primary AI

Required for patients with concomitant aldosterone deficiency resulting in persistent hyperkalemia

Fludrocortisone 0.05-0.2 mg daily, usually in a single dose

Dose is adjusted according to symptoms

PATIENT TEACHING

• Patient and caregiver awareness regarding the condition and appropriate treatment is important.

• Wear a medical alert bracelet or necklace stating the need for glucocorticoids in event of an emergency.

• Go to the emergency department if experiencing multiple episodes of vomiting or diarrhea.

FOLLOW-UP

• Consider endocrinology consultation.

• Hydrocortisone may be needed during periods of stress.

• Monitor symptoms for signs of crisis.

BIBLIOGRAPHY

Choi C.H., Tiu S.C., Shek C.C., et al. Use of low-dose corticotropin stimulation test for the diagnosis of secondary adrenocortical insufficiency. Hong Kong Medical Journal. 2002;8:427–434.

Dirix L.Y., van Oosterom A.T. Metabolic complications: Adrenocortical insufficiency. In: Souhami R.L., Tannock I., Hohenberger P., et al. Oxford textbook of oncology. 2nd ed. Oxford: Oxford University Press; 2002:923–925.

Dorin R.I., Qualls C.R., Crapo L.M. Diagnosis of adrenal insufficiency. Annals of Internal Medicine. 2003;139:194–204.

Gonzalez H., Nardi O., Annane D. Relative adrenal failure in the ICU: An identifiable problem requiring treatment. Critical Care Clinics. 2006;22:105–118.

McCullough D.M. Adrenal gland disorders. In: Buttaro T.M., Trybulski J., Bailey P.P., et al. Primary care: A collaborative practice. 2nd ed. St. Louis: Mosby; 2003:990–993.

Nieman L.K. Dynamic evaluation of adrenal hypofunction. Journal of Endocrinological Investigation. 2003;26:74–82.

O’Connor T., Trump D.L. Endocrine complications. In: Abeloff M.D., Armitage J.O., Niederhuber J.E., et al. Clinical oncology. 3rd ed. St. Louis: W. B. Saunders; 2004:1287–1294.

Salvatori R. Adrenal insufficiency. Journal of the American Medical Association. 2005;294:2481–2488.

Stempkowski L.M. Adrenal metastasis. In: Camp-Sorrell D., Hawkins R.A. Clinical manual for the oncology advanced practice nurse. Pittsburgh, PA: Oncology Nursing Press; 2000:529–533.

Strohl R.A. Radiation therapy. In: Miaskowski C., Buchsel P. Oncology nursing: Assessment and clinical care. St. Louis: Mosby; 1999:75.

Torrey S.P. Recognition and management of adrenal emergencies. Emergency Medicine Clinics of North America. 2005;23:687–702.

Hypercalcemia

Jean Rosiak

DEFINITION

• Serum calcium >11 mg/dL or ionized calcium is >1.35 mmol/L.

• Rate of calcium mobilization from bone exceeds renal threshold for calcium excretion.

• Prognostic factor for survival of less than 1 year (median survival 3 months)

EPIDEMIOLOGY

• 10%-20% overall incidence in adult patients with advanced cancer (0.5%-1% in children)

• Adult T-cell lymphoma/leukemia: 50%

• Multiple myeloma: 20%-40%

• Breast cancer: 17%-40%

• Squamous cell lung cancer: 35%

PATHOPHYSIOLOGY

• Calcium is essential in maintaining cell membrane permeability (transmission of nerve impulses, cardiac contractility), bone formation, normal clotting mechanisms, regulating numerous cellular processes affecting multiple organ systems.

• 99% of calcium is stored in bone.

• Bone is a constantly changing tissue; continual process of bone remodeling: bone formation and resorption.

˚ Osteoblasts: responsible for bone formation by secreting a specialized extracellular matrix that subsequently mineralizes

˚ Osteoclasts: responsible for bone resorption/breakdown by releasing a proteolytic enzyme that dissolves bone matrix, releasing calcium into the extracellular space

• Hypercalcemia results when more calcium is resorbed from bone than deposited in bone, and renal excretion of excessive calcium is impaired.

• Local osteolytic hypercalcemia (20%-30%)

˚ Tumor cells infiltrating bone (bone metastasis) secrete local cytokines that directly stimulate osteoclasts and inhibit osteoblasts.

˚ Results in release of calcium into the extracellular fluid/systemic circulation

• Humoral hypercalcemia of malignancy (80%)

˚ Systemic cytokines secreted by tumor cells

Promotes release of calcium and phosphate from bone

Increases calcium reabsorption in the kidney

Parathyroid hormone–related protein (PTHrP): principal mediator of cancer-related hypercalcemia in patients with solid tumors

SIGNS AND SYMPTOMS

• Can be vague and attributable to other conditions

• Gastrointestinal:

˚ Anorexia, nausea, vomiting

˚ Constipation, ileus, abdominal pain

• Musculoskeletal:

˚ Fatigue, muscle weakness

˚ Bone pain

˚ Pathological fractures

• Renal:

˚ Polyuria, polydipsia, nocturia

˚ Oliguric renal failure, azotemia

• Neurological:

˚ Restlessness, apathy

˚ Mental status changes/disorientation

˚ Lethargy: can progress to stupor and coma

• Cardiovascular:

˚ Hypertension

˚ Electrocardiographic (ECG) changes

• Death can result if hypercalcemia is untreated.

CANCERS ASSOCIATED WITH DISORDER

• Multiple myeloma (usually the result of local factors in bone secreted by tumor)

• Solid tumors (usually the result of systemic factors associated with tumor)

˚ Breast, lung, renal, prostate, and head and neck cancer

DIAGNOSTIC TESTS

• Serum calcium

˚ Normal calcium level: 8.5-10.5 mg/dL

˚ Mild hypercalcemia: <12 mg/dL

˚ Moderate hypercalcemia: 12-14 mg/dL

˚ Severe hypercalcemia: >14-16 mg/dL

˚ Life-threatening hypercalcemia: >16 mg/dL

• Ionized serum calcium: >1.35 mmol/L

• Serum albumin

˚ Decreased albumin level may give false-normal calcium value.

˚ Corrected calcium level = total serum calcium (mg/dL) + (4.0 − serum albumin [g/dL]) × 0.8

• Parathyroid hormone level (measured with immunoradiometric assay)

˚ Elevated in primary hyperparathyroidism

˚ Usually low in malignancy

• PTHrP

˚ Level greater than 1 pmol/L is specific indicator of malignancy.

DIFFERENTIAL DIAGNOSIS

• Primary or secondary hyperparathyroidism

• Renal failure

• Paget’s disease of bone

• Medications (thiazides, lithium, large doses of vitamins A or D)

TREATMENT

Pharmacologic Management

• Only effective long-term management is to treat the underlying disease.

• Continuing management requires pharmacologic measures to inhibit bone resorption and promote renal calcium excretion.

• Immediate goal is to restore fluid and electrolyte balance.

• Hydration: 1-2 L of isotonic (0.9%) saline solution over 2 hours (may administer 100-250 mL/hr for 24-48 hours)

˚ Hydration results in approximately 2 mg/dL decrease in serum calcium level.

˚ Clinical improvement usually seen within 24 hours; effect is temporary.

• Diuresis: furosemide 20-40 mg intravenously (IV) every 12 hours

˚ Enhances calcium excretion

˚ Thiazide diuretics contraindicated because they inhibit urinary excretion of calcium

• Bisphosphonates: one of the most effective therapies for hypercalcemia

˚ Inhibit normal and pathological bone resorption by effects on osteoclasts

˚ May inhibit adhesion of tumor cells to bone matrix

˚ Administered IV because of poor oral absorption

˚ Pamidronate (Aredia) 90 mg IV over 2-24 hours (60-mg dose can be used in patients with lower calcium levels)

Response rate: 90% within 3-4 days

Duration of response: 7-30 days

˚ Zoledronate (Zometa) 4 mg IV over 15 minutes every 3-4 weeks

Response rate: more than 90% within 4-10 days

Duration of response: 4-6 weeks

• Gallium nitrate 200 mg/m²/day as a 5-day continuous infusion (100 mg/m²/day may be considered in patients with mild hypercalcemia and minimal symptoms)

˚ Inhibits bone resorption and stimulates bone formation

˚ Inhibits tubular calcium reabsorption and parathyroid hormone (PTH) secretion

˚ Response rate: 72%-82%

˚ Duration of response: 6-8 days

˚ More effective than bisphosphonates in treating hypercalcemia in patients with tumors of epidermoid histology (high-level PTHrP expression)

• Mithramycin (Plicamycin) 25 mcg/kg IV over 3-6 hours

˚ Blocks ribonucleic acid (RNA) synthesis in osteoclasts

˚ Response rate: 30%-50% within 12 hours, with maximum effect at 48 hours

˚ Duration of response: several days, requiring repeated doses every 3-7 days

• Calcitonin 4-8 International Units/kg intramuscularly or subcutaneously every 6-8 hours

˚ Inhibits osteoclast-mediated bone resorption

˚ Promotes urinary calcium and sodium excretion

˚ Decreases serum calcium within 2-6 hours

˚ Duration of response: 24-72 hours

˚ Resistance to effects develop within a few days of instituting therapy.

• Corticosteroids: prednisone 40-60 mg/day orally or hydrocortisone 100-150 mg IV every 12 hours

˚ Decrease calcium resorption from the gastrointestinal tract

˚ Inhibits bone resorption and increases urinary calcium excretion

˚ Not a first-line treatment: complications of long-term steroid use limit its usefulness

˚ May take 1-2 weeks for calcium-lowering effect

• Dialysis

PATIENT TEACHING

• Educate the patient and caregiver regarding sign and symptoms of hypercalcemia.

• Importance of maintaining hydration:1-3 L of fluid per day unless contraindicated

• Importance of maintaining activity: immobility can worsen hypercalcemia.

FOLLOW-UP

• Monitor serum calcium or ionized calcium level.

• Monitor renal function/hydration status.

• Be alert for signs and symptoms of recurrent hypercalcemia.

BIBLIOGRAPHY

Body J.J. Hypercalcemia of malignancy. Seminars in Nephrology. 2004;24:48–54.

Davidson T.G. Conventional treatment of hypercalcemia of malignancy. American Journal of Health-System Pharmacy. 2001;58:S8–S15.

Fojo A.T. Metabolic emergencies: Hypercalcemia and cancer. In: DeVita V., Hellman S., Rosenberg S.A. Cancer principles and practice. Philadelphia: Lippincott Williams & Wilkins; 2005:2297–2299.

Hutton E. Evaluation and management of hypercalcemia. Journal of the American Academy of Physician Assistants. 2005;18:30–35.

Leyland-Jones B. Treating cancer-related hypercalcemia with gallium nitrate. Journal of Supportive Oncology. 2004;2:509–516.

Li E.C., Davis L.E. Zoledronic acid: A new parenteral bisphosphonate. Clinical Therapeutics. 2003;25:2669–2708.

Miaskowski C. Hypercalcemia. In: Oncology nursing: An essential guide for patient care. Philadelphia: W. B. Saunders; 1997:230.

Miaskowski C. Oncologic emergencies: Hypercalcemia. In: Miaskowski C., Buchsel P. Oncology nursing: Assessment and clinical care. St. Louis: Mosby; 1999:223–227.

National Cancer Institute. Hypercalcemia (PDQ). Retrieved June14, 2006, from http://www.cancer.gov/cancertopics/pdq/supportivecare/hypercalcemia/healthprofessional/allpages, 2005.

Richerson M.T. Electrolyte imbalances: Hypercalcemia. In: Yarbro C.H., Frogge M.H., Goodman M. Cancer symptom management. 3rd ed. Sudbury, MA: Jones & Bartlett; 2004:440–446.

Shuey K.M. Hypercalcemia of malignancy: Part I. Clinical Journal of Oncology Nursing. 2004;8:209–210.

Shuey K.M., Brant J.M. Hypercalcemia of malignancy: Part II. Clinical Journal of Oncology Nursing. 2004;8:321–323.

Smith W.J. Hypocalcemia/hypercalcemia. In: Camp-Sorrell D., Hawkins R.A. Clinical manual for the oncology advanced practice nurse. Pittsburgh: Oncology Nursing Press; 2000:849–858.

Wickham R.S. Hypercalcemia. In: Yarbro C.H., Frogge M.H., Goodman M., et al. Cancer nursing: principles and practice. 5th ed. Sudbury, MA: Jones & Bartlett; 2000:776–791.

Williams J. Oncology complications and paraneoplastic syndromes: Hypercalcemia. In: Buttaro T.M., Trybulski J., Bailey P.P., et al. Primary care: A collaborative practice. 2nd ed. St. Louis: Mosby; 2003:1209–1210.

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