Adrenal Glands

Anatomy

The adrenal glands are paired, retroperitoneal structures located cranial and medial to the cranial pole of each kidney. The right adrenal gland lies dorsolateral to, and is intimately associated with, the caudal vena cava. The left adrenal gland is more caudal in location. The phrenicoabdominal vein courses over the ventral surface of each adrenal gland, while the phrenicoabdominal artery lies on the dorsal surface of the gland. The adrenal arterial blood supply is derived from branches of the aorta and phrenic, renal, accessory renal, phrenicoabdominal, and lumbar arteries. Venous drainage is into the caudal vena cava and renal and phrenicoabdominal veins. Malignant adrenal tumors sometimes invade these venous structures.

The adrenal gland consists of two separate endocrine components with distinct embryonic origins. The cortex is derived from the celomic epithelium and is of mesodermal origin. Histologically, the cortex is divided into an outer zona glomerulosa, the chief site of aldosterone production, and the zona fasciculata and the inner zona reticularis, which together are responsible for the production of glucocorticoids and sex hormones. The medulla is derived from the sympathetic ganglia and is ectodermal in origin. The adrenal medulla produces catecholamines, epinephrine, and norepinephrine.

Glucocorticoids

Physiology

The production of glucocorticoids is regulated via the hypothalamic-pituitary-adrenal axis. Corticotrophin-releasing hormone (CRH) is a 41 amino acid peptide hormone. CRH is secreted by neurons in the anterior portion of the paraventricular nuclei of the hypothalamus. CRH is delivered to the pituitary gland via a portal circulation and acts to stimulate the secretion of adrenocorticotrophic hormone (ACTH) from the anterior pituitary gland (adenohypothesis). ACTH is a 39 amino acid peptide hormone derived from a large precursor molecule, proopiomelanocortin. The primary function of ACTH is to stimulate the secretion of glucocorticoids from the adrenal cortex. Cortisol is the major glucocorticoid produced. Circulating cortisol and synthetic glucocorticoids produce a negative feedback inhibition of the hypothalamus and pituitary, thus inhibiting ACTH secretion. During severe stress, such as pain, trauma, acute hypoglycemia, and surgery, the suppressive effects of glucocorticoids are overridden, resulting in increased secretion of CRH, ACTH, and glucocorticoids.

Hyperadrenocorticism

Hyperadrenocorticism (Cushing’s syndrome) is caused by chronic exposure to excessive concentrations of glucocorticoids. Of dogs with naturally occurring hyperadrenocorticism, 80% to 85% have pituitary-dependent hyperadrenocorticism (PDH). PDH causes excessive production of ACTH resulting in bilateral adrenocortical hyperplasia and excessive secretion of glucocorticoids. The majority of dogs with PDH have a small pituitary adenoma (microadenoma); 10% to 20% of dogs with PDH have large pituitary adenomas (macroadenoma). These tumors can compress and invade the overlying hypothalamus, resulting in clinical signs such as dullness, listlessness, inappetance, and disorientation, which can progress to neurologic signs such as aimless wandering, ataxia, head pressing, circling, and seizures. Pituitary carcinomas are rare in dogs.

Functional primary adrenocortical tumors secrete excessive amounts of cortisol independent of pituitary control. The excess gluocorticoid production suppresses hypothalamic CRH and plasma ACTH concentrations, resulting in cortical atrophy of the contralateral adrenal gland. Functional adrenocortical tumors commonly retain ACTH receptors and respond to exogenous ACTH administration by secreting cortisol. Histologic differentiation of adrenocortical adenomas and carcinomas is challenging; it would appear that the two tumor types occur with approximately equal frequency in dogs. Cases of simultaneous occurrence of PTH and an adrenocortical tumor or pheochromocytoma have been reported, as have bilateral adrenocortical tumors and simultaneous occurrence of an adrenocortical tumor and a pheochromocytoma. Naturally occurring hyperadrenocorticism should be differentiated from the iatrogenic form caused by chronic glucocorticoid therapy.

Signalment

The median age of dogs with naturally occurring hyperadrenocorticism is 11 [4]. years [1]; the disease is uncommon in dogs younger than 6 years of age. Hyperadrenocorticism is seen in a variety of breeds, with poodles, daschunds, various terrier breeds and German shepherd dogs being commonly represented. Approximately 75% of dogs with PDH weigh less than 20 kg, whereas 45% 50% of dogs with a functional adrenocortical tumor weigh more than 20 kg [1]. Females account for 55% to 60% of dogs with PDH and 60% to 65% of dogs with a functional adrenocortical tumor [1]. Hyperadrenocorticism is rarely diagnosed in cats. There are reports of cats with clinical signs of hyperadrenocorticism caused by a progesterone-secreting adrenal tumor.

History and Physical Examination Findings

Hyperadrenocorticism is one of the most common endocrinopathies in dogs. The clinical signs are largely attributable to chronic glucocorticoid excess, resulting in gluconeogenic, immune-suppressive, anti-inflammatory, protein catabolic, and lipolytic effects. Clinical signs include polydipsia and polyuria, polyphagia, bilateral symmetric alopecia and other skin abnormalities (hyperpigmentation, comedone formation, thin skin, thin hair coat, and calcinosis cutis), pendulous abdomen (owing to hepatomegaly, muscle wasting, and intra-abdominal fat accumulation), muscle weakness, muscle atrophy, panting, heat intolerance, and anestrous or testicular atrophy. The number and severity of clinical signs vary markedly. PDH and a functional adrenocortical tumor cannot be differentiated based on clinical signs.

Medical Complications Associated with Hyperadrenocorticism

1. Hypertension
2. Pyelonephritis
3. Diabetes mellitus
4. Pulmonary thromboembolism

Clinicopathologic Findings

CBC: Excess glucocorticoids produce a stress leukogram in most dogs, consisting of a mature neutrophilia, lymphopenia, eosinopenia, and monocytosis.

Biochemistry profile: The most common abnormality is increased serum alkaline phosphatase (ALP) activity (a result in part of the induction of a glucocorticoid isoenzyme unique to dogs). Alanine aminotransferase (ALT) activity may also be increased associated with a steroid hepatopathy. Mild to moderate increases in cholesterol and triglyceride concentrations are common, and serum bile acid concentrations may be elevated. Serum bilirubin and albumin concentrations are usually within the reference ranges. Glucose concentration varies, with approximately 10% of dogs developing overt diabetes mellitus (interestingly, up to 80% of cats with hyperadrenocorticism are diabetic). Blood urea nitrogen and serum creatinine concentrations may be low as a result of diuresis.

Urinalysis: Urine specific gravity is often low, although most dogs retain an ability to concentrate urine with water deprivation. Urinary tract infections occur in 40% to 50% [2]. Proteinuria is common, associated with urinary tract infection or glomerular leakage. Glucosuria may occur if the renal glucose threshold is exceeded.

Thyroid function tests: Decreased basal serum T4 and/or T3 concentrations are common.

Diagnostic Imaging

Thoracic radiography: Mineralization of the tracheobronchial tree and pulmonary parenchyma is a nonspecific finding that is more common in dogs with hyperadrenocorticism. Radiographs should be evaluated for signs of pulmonary metastases and pulmonary thromboembolism.

Abdominal radiography: Findings include hepatomegaly, obesity, and mineralization of soft tissue structures. Adrenal gland mineralization occurs in approximately 50% of adrenocortical tumors.

Abdominal ultrasonography: Dogs with PDH usually have relatively equal sized adrenal glands with normal or enlarged dimensions. In dogs with a functional adrenocortical tumor, the affected adrenal gland is usually enlarged and irregular with mixed echogenicity, and a normal or atrophied adrenal gland is usually observed on the contralateral side. Compression or invasion of the phrenicoabdominal vein and/or caudal vena cava may have occurred, and intra-abdominal metastases may be present. The liver is generally enlarged with increased echogenicity, and urinary calculi and dilated renal pelvises (caused by pyelonephritis) may be present.

CT or MRI: Used to rule out a pituitary macroadenoma. Abdominal imaging may provide additional information on adrenal anatomy, intra-abdominal metastases, and vascular invasion.

Adrenal Function Tests

Screening tests are used to confirm the diagnosis of hyperadrenocorticism.

Basal plasma cortisol concentration: As cortisol is released episodically, this test has virtually no diagnostic value.

Urine cortisol:creatinine ratio: This test adjusts for fluctuating plasma concentrations of cortisol. Has high sensitivity but low specificity; may thus be a good test for ruling out hyperadrenocorticism.

ACTH stimulation test: This measures the response of the adrenal glands to maximal ACTH stimulation. It has a sensitivity of 60 to 85% and a specificity of 85 to 90% [3]. It cannot differentiate PDH from a functional adrenocortical tumor. This is the only test that can identify dogs with iatrogenic hyperadrenocorticism and is the only test in veterinary medicine for monitoring response to therapy.

Low-dose dexamethasone suppression (LDDS) test: Dexamethasone is a synthetic glucocorticoid that does not cross react in the cortisol assay. In normal dogs, the cortisol concentration decreases 2 to 3 hours after dexamethasone administration, whereas dogs with hyperadrenocorticism do not experience suppressed cortisol concentrations. For the LDDS test, dexamethasone is administered (0.01 mg/kg IV) and blood samples collected 4 and 8 hours later. The sensitivity of the test at 8 hours after administration is 85 to 95% and the specificity is 70 to 75% [3].

Differentiating tests are used to differentiate PDH from a functional adrenocortical tumor.

High-dose dexamethasone suppression (HDDS) test: After administration of a high dose of dexamethasone (0.1 mg/kg IV), approximately 75% of dogs with PDH have suppressed cortisol concentrations, whereas in dogs with a functional adrenocortical tumor, even large doses of dexamethasone should not suppress plasma cortisol concentrations [3].

Endogenous plasma ACTH concentration: In dogs with a functional adrenocortical tumor, the hypothalamic-pituitary axis is suppressed and the ACTH concentration is low or undetectable, whereas dogs with PDH usually have an ACTH concentration above the reference range.

Surgery

Adrenalectomy: Surgical removal is the treatment of choice for adrenal tumors. During surgery, hemostasis is a definite challenge. Adrenal tumors can cause a tumor thrombus in the caudal vena cava. In most dogs with a caval thrombus, the tumor invades the phrenicoabdominal vein and extends into the caudal vena cava [4]. This results in a pedunculated caval thrombus based around the insertion of the phrenicoabdominal vein that can be removed by temporary caval occlusion and a venotomy centered around the insertion of the phrenicoabdominal vein. After unilateral adrenalectomy, cortisol secretion from the contralateral, atrophied adrenal gland is suppressed and glucocorticoid supplementation is needed during and following surgery. Aldosterone secretion from the contralateral adrenal gland is usually adequate, although electrolyte concentrations should be closely monitored and mineralocorticoid therapy instituted if hyperkalemia and/or hyponatremia are observed. Bilateral adrenalectomy necessitates lifelong glucocorticoid and mineralocorticoid supplementation.

Dogs with hyperadrenocorticism are hypercoagulable and at increased risk of experiencing pulmonary thromboembolism after surgery; therefore, these patients should be maintained on anticoagulant regimens following surgery. Other surgical considerations include impaired wound healing, a greater propensity for wound infection, impaired respiratory function, and hypertension. Postoperative mortality rates are relatively high (21-28%) [4,5]. Other serious postoperative complications include pancreatitis, pneumonia, sepsis, and acute renal failure.

Hypophysectomy: Transsphenoidal hypophysectomy is the treatment of choice for humans with PDH and has been shown to be an effective treatment in dogs with PDH [6,7]. Potential intraoperative complications include hemorrhage from the arterial circle during exploration of the fossa. Following hypophysectomy, dogs require lifelong therapy with glucocorticoids and thyroxine. Diabetes insipidus is normally transient, requiring short-term treatment with vasopressin. Reduced tear production is frequently reversible. Estimated survival rates at 2 and 4 years were 76% and 68%, and 2- and 4-year estimated relapse-free fractions were 75% and 58% [7].

Medical Therapy

Mitotane (o,p’-DDD, Lysodren): Mitotane is a potent adrenolytic drug that causes selective destruction of the zona fasciculata and zona reticularis (site of glucocorticoid production) while sparing the zona glomerulosa (site of mineralocorticoid production). The drug is most commonly used to induce and maintain a state of partial adrenocortical destruction, with the goal of restricting glucocorticoid production to amounts needed for daily life. The ACTH stimulation test is used to monitor therapy. It can also be used to induce complete adrenocortical destruction, a state that requires lifelong glucocorticoid and mineralocorticoid therapy. The results of using mitotane in cats with hyperadrenocorticism have been disappointing.

Trilostane: Trilostane is an orally administered competitive inhibitor of the enzyme 3β-hydroxysteroid dehydrogenase. This enzyme converts pregnenolone to progesterone and 17-hydroxypregnenolone to 17-hydroxyprogesterone in the adrenal cortex. Trilostane thus inhibits the production of cortisol, aldosterone, and androstenedione. Similar to the use of mitotane, the aim is to restrict cortisol production and the dose of drug is altered based on the results of ACTH stimulation testing. Trilostane has been used successfully to manage PDH and functional adrenocortical tumors in dogs. Trilostane is reported to ameliorate the signs of feline hyperadrenocorticism.

Ketoconazole: Ketoconazole is a fungistatic drug that blocks several P-450 enzyme systems. It produces reversible inhibition of the synthesis of glucocorticoids and androgens, while sparing mineralocorticoid production. Trilostane has largely replaced ketoconazole for the management of hyperadrenocorticism. The use of ketoconazole in cats with hyperadrenocorticism has produced mixed results.

Mineralocorticoids

Physiology

The production of mineralocorticoids is primarily regulated by the renin-angiotensin system. Renin is produced by the juxtraglomerular cells, which surround the afferent arterioles of the renal glomeruli. The juxtaglomerular cells monitor renal perfusion. Volume depletion and hypotension stimulate renin production. Renin acts on a plasma α2-globulin produced by the liver, releasing angiotensin I. Converting enzyme in the lung converts angiotensin I to angiotensin II, a potent vasoconstrictor and the primary stimulant for aldosterone production. The primary site of action of aldosterone is the renal tubule, where it promotes the resorption of sodium and water and the excretion of potassium. This results in expansion of the extracellular fluid volume, and removes the stimulus for renin production.

Hyperaldosteronism

Primary hyperaldosteronism (Conn’s syndrome) is caused by autonomous secretion of aldosterone by a tumor of the zona glomerulosa layer of the adrenal cortex. Hyperaldosteronism results in sodium retention, expansion of the extracellular fluid volume, and hypertension. The production of renin is suppressed. Increased potassium excretion leads to progressive depletion of body potassium and the development of hypokalemia and hypokalemic metabolic alkalosis.

The condition is rare in cats and dogs. Clinical signs include weakness, which may be episodic, cervical ventroflexion (cats), lethargy, polyuria, and/or polydipsia. The most common clinicopathologic abnormality is moderate-to-severe hypokalemia. The sodium concentration may be normal or slightly elevated. Definitive diagnosis requires demonstrating an inappropriately elevated aldosterone concentration with a low renin concentration. Adrenalectomy is the treatment of choice in animals with no detectable metastases. Medical therapy consists of potassium supplementation and spironolactone (an aldosterone antagonist) administration.

Adrenocortical Insufficiency

Hypoadrenocorticism is a syndrome that results from deficient secretion of glucocorticoids and/or mineralocorticoids by the adrenal cortices. Primary hypoadrenocorticism (Addison’s disease) is caused by the destruction of more than 90% of adrenocortical tissue. Primary hypoadrenocorticism is rare in the dog and cat. The most common cause is idiopathic adrenocortical insufficiency, which is most likely a result of immune-mediated destruction of the adrenal cortices. Iatrogenic hypoadrenocorticism is a possible complication of mitotane therapy in dogs with hyperadrenocorticism. Although mitotane usually spares the zona glomerulosa and thus mineralocorticoid production, some dogs experience a permanent, complete adrenocortical failure. Other causes of primary hypoadrenocorticism include bilateral adrenalectomy, hemorrhage or infarction of the adrenal glands, granulomatous or neoplastic destruction of the adrenal glands, amyloidosis, and trauma. Secondary hypoadrenocorticism is caused by deficient production of ACTH, resulting in impaired secretion of glucocorticoids by the adrenal cortices; the production of mineralocorticoids is spared.

Deficiency of glucocorticoids causes a decreased tolerance to stress, including a reduced ability to mount a stress response to surgery. Other signs include inappetance, vomiting, diarrhea, abdominal pain, and lethargy. Aldosterone deficiency impairs the patient’s ability to conserve sodium and water and causes a failure to excrete potassium, resulting in hyponatremia and hyperkalemia. Hyponatremia induces lethargy, depression, and nausea, whereas hyperkalemia results in muscle weakness and impaired cardiac conduction. These patients experience hypovolemia, hypotension, reduced cardiac output, and impaired renal perfusion.

Signalment

Female dogs account for approximately 70% of cases [8]. Hypoadrenocorticism can be diagnosed in dogs of any age, but is most common in young and middle-aged dogs. No breed predilection has been identified.

History and Physical Examination Findings

Acute hypoadrenocorticism (Addisonian crisis) causes hypovolemic shock. Dogs present in a state of collapse or they collapse when stressed, with a weak pulse, profound bradycardia, vomiting, diarrhea, dehydration, and hypothermia. The chronic form of hypoadrenocorticism causes vague, non-specific, and often episodic clinical signs. Signs include lethargy, anorexia, weight loss, vomiting, diarrhea, obtundation, shaking or shivering, muscle fasciculations, muscle weakness, and polyuria/polydipsia.

Clinicopathologic Findings

CBC: Changes can include lymphocytosis, eosinophilia, and a mild nonregenerative anemia.

Biochemistry profile: The most common abnormalities noted include hyponatremia, hyperkalemia, prerenal azotemia, and metabolic acidosis. The normal sodium:potassium ratio is 27:1 to 40:1; most patients with hypoadrenocorticism have a ratio below 25:1. In approximately 10% of dogs with primary hypoadrenocorticism, the serum electrolyte concentrations are within the reference ranges at initial examination.

Electrocardiographic Findings

Hyperkalemia impairs electrical conduction in the heart. An ECG can be used to evaluate patients with hypoadrenocorticism. As a rough guide:

Adrenal Function Tests

ACTH stimulation test: The gold standard for diagnosing hypoadrenocorticism. The resting cortisol concentration is low or non detectable with a subnormal or negligible cortisol response to ACTH.

Endogenous plasma ACTH concentration: Used to differentiate primary from secondary hypoadrenocorticism. Dogs with primary hypoadrenocorticism have a markedly elevated ACTH concentration (owing to a lack of negative feedback of cortisol), whereas those with secondary hypoadrenocorticism have low or undetectable concentrations of ACTH.

Medical Therapy

Acute primary hypoadrenocorticism: Initial therapy consists of aggressive intravenous fluid therapy using normal saline (0.9% sodium chloride) at an initial rate of 60 to 80 ml/kg/hour for 1 to 2 hours. Urine output and, if possible, central venous pressure should be monitored. This therapy will correct the hypovolemia and hyponatremia. The serum potassium concentration decreases owing to dilution and improved renal perfusion, and specific therapy for hypokalemia is usually not required. Other therapies for hyperkalemia include intravenous glucose administration (addition of 5% dextrose to intravenous fluids), which can be combined with insulin therapy and intravenous calcium administration.

Intravenous glucocorticoid therapy (hydrocortisone sodium succinate, prednisolone sodium succinate, or dexamethasone sodium phosphate) is initiated early during treatment of acute hypoadrenocorticism. Mineralocorticoid therapy is not essential for the management of an Addisonian crisis, but administration of a mineralocorticoid is usually initiated.

Chronic primary hypoadrenocorticism: During maintenance therapy, a mineralocorticoid is administered. Fludrocortisone acetate (15 mg/kg PO once daily, adjusting the dose to keep the serum sodium and potassium concentrations within the reference ranges) has mainly mineralocorticoid effects, although it retains some glucocorticoid activity. Desoxycorticosterone pivalate (DOCP; 2.2 mg/kg IM or SQ every 25 days) has no glucocorticoid activity and should be combined with a low dose of prednisone or prednisolone (0.1-0.2 mg/kg/day).

Prognosis

The long-term prognosis for the management of hypoadrenocorticism is excellent with appropriate maintenance therapy. Animals should receive supplemental doses of glucocorticoids during periods of stress, such as when undergoing anesthesia and surgery.

Adrenal Medulla

Physiology

The adrenal medulla is essentially a large sympathetic ganglion that lacks postganglionic fibers. Catecholamines are the primary secretory product of chromaffin cells. Catecholamines are synthesized from the amino acid tyrosine. The first step in catecholamine synthesis, the conversion of L-tyrosine to L-DOPA, involves the enzyme tyrosine hydroxylase, and is the rate-limiting step. Secretory products are stored in cytoplasmic vesicles in the chromaffin cells. Stimulation of the chromaffin cell results in exocytosis of the vesicles and expulsion of their contents. The end product of catecholamine synthesis is predominately epinephrine in humans and dogs, and norepinephrine in cats. The half-life of catecholamines in the circulation is short (minutes). Catecholamine catabolism is mediated by two enzymes, catecholamine-O-methyltransferase (COMT) and monoamine oxidase (MAO). The predominant metabolite is vanillylmandelic acid (VMA), which, along with the catecholamines, is excreted in the urine.

Pheochromocytoma

Pheochromocytoma is a catecholamine-producing tumor derived from the chromaffin cells of the adrenal medulla. Neoplastic transformation of the chromaffin cells results in loss of regulatory control of catecholamine release. In the fetus, chromaffin cells are widely distributed and form paraganglia. Most extra-adrenal chromaffin cells involute after birth, although remnants remain, and tumors of the extra-adrenal chromaffin cells, paraganglionomas, are reported. A substantial portion of dogs with a pheochromocytoma also have another malignancy. Pheochromocytomas can occur in human patients with multiple endocrine neoplasia type 2 (MEN2) syndrome, and a similar syndrome has been reported in dogs.

History and Physical Examination Findings

Clinical signs are often vague and episodic. Clinical signs may relate to either excessive circulating catecholamine concentrations or the presence of an abdominal mass. The most common signs in dogs are weakness and collapse. Signs related to catecholamine excess include tachycardia and arrhythmias, panting, anxiety, pacing, seizures, blindness (from retinal hemorrhage), polyuria and polydipsia, vomiting, diarrhea, and anorexia. Signs related to the adrenal mass include hemoabdomen (associated with tumor rupture) and Budd-Chiari syndrome (owing to obstruction of the caudal vena cava producing ascites and hind limb edema and weakness). In some dogs, the pheochromocytoma is diagnosed as an incidental finding, for instance during performance of abdominal ultrasonography for an unrelated reason.

Clinicopathologic Findings

CBC and biochemistry panel: Findings are nonspecific.
Urinalysis: Proteinuria owing to hypertensive glomerulopathy may be present, as well as hyposethenuria or isothenuria.
Catecholamine concentrations: The measurement of basal plasma catecholamine concentrations and the urine concentrations of catecholamines and catecholamine metabolites is not routinely performed in veterinary medicine.

Arterial Blood Pressure Determination

Catecholamine secretion and systemic hypertension tend to be episodic in patients with a pheochromocytoma.

Diagnostic Imaging

Abdominal ultrasonography: Pheochromocytomas appear as adrenal gland mass lesions with variable echogenicity. The patient should also be assessed for the presence of intraabdominal metastases and vascular invasion.
CT or MRI: Abdominal imaging may provide additional information on adrenal anatomy, intraabdominal metastases, and vascular invasion.

Treatment

Adrenalectomy is the treatment of choice. Patients with a pheochromocytoma are a challenge to anesthetize. Dogs in which a pheochromocytoma is suspected are placed on phenoxybenzamine at least 2 weeks prior to surgery. Phenoxybenzamine is an α-adrenergic blocking drug with a long duration of action. It is considered the drug of choice for preoperative management of hypertension as it binds noncompetitively with the receptor, and thus, surges of catecholamine release cannot override the inhibition. A relatively high dose of phenoxybenzamine is recommended (up to 2.5 mg/kg b.i.d. PO). Management of hypertension prior to surgery allows reexpansion of the intravascular plasma volume by removing the vasoconstrictive effects of high catecholamine concentrations. Intraoperative hypertension is managed by intravenous administration of phentolamine, a short-acting, competitive α-adrenergic blocking drug (loading dose 0.1 mg/kg; CRI 1-2 μg/kg/min). Intraoperative hypotension is managed by decreasing the dose of or discontinuing phentolamine; administration of phenylephrine; or rapid expansion of the vascular volume by administration of crystalloid fluid, plasma volume expanders, or blood products. Phenylephrine is a short-acting α1-adrenergic agonist that can displace phentolamine from the receptor. Esmolol, a short-acting β1-adrenergic blocking drug, is administered intravenously (loading dose 0.1 mg/kg; CRI 50-70 μg/kg/min) in those cases with persistent tachycardia despite adequate α-adrenergic blockade and vascular volume expansion. Medications that stimulate catecholamine release should be avoided, including ketamine, morphine, and halothane. Moderate surface-induced hypothermia (esophageal temperature of 32°C) is recommended in case temporary caval occlusion is required.