Pituitary Apoplexy Presenting as Addisonian Crisis

Abstract

Addisonian crisis, also commonly referred to as adrenal crisis, occurs when the cortisol produced by the adrenal glands is insufficient to meet the body's acute needs. The symptoms are nonspecific and can mimic other processes, such as sepsis. Hypotension, lethargy, and fever can all be presenting signs. Secondary addisonian crisis can also result from pituitary apoplexy.

Pituitary apoplexy usually occurs as hemorrhagic or ischemic necrosis in the presence of a pre-existing pituitary adenoma, and is a rare sequela of surgery. The symptoms of pituitary apoplexy are typically impressive and are relieved by urgent transsphenoidal decompression. Hypopituitarism resulting from pituitary apoplexy can be treated with exogenous hormones.

The case presented herein illustrates occult pituitary apoplexy that occurred after on-pump coronary artery bypass grafting. In this patient, the initial signs of addisonian crisis were overlooked; however, once recognized, they were reduced dramatically with standard stress-dose cortisone. A suprasellar mass with a cystic component was found on magnetic resonance imaging. The hemorrhagic pituitary gland was treated by transsphenoidal decompression, which relieved the patient's bitemporal hemianopia and 6th-nerve palsy. (Tex Heart Inst J 2002;29:193–9)

Pituitary apoplexy (or the sudden degeneration of the pituitary gland) is a rare sequela of cardiac surgery with cardiopulmonary bypass. Only 14 cases have been reported in the literature. ^1–10 Pituitary apoplexy is characterized by hemorrhage or necrosis within a pituitary gland adenoma, which compresses adjacent structures and causes the clinical symptoms of hypopituitarism. ^11,12 Headache is the most common symptom, followed (in order of decreasing frequency) by visual deficits, ophthalmoplegia or ptosis, anisocoria, nausea and vomiting, alteration in level of consciousness, change in mental status, meningismus, hemiparesis, and fever (Table I). ^13–16

TABLE I. Signs of Pituitary Apoplexy ^13–16

Primary adrenal insufficiency is typically a result of autoimmune destruction of the adrenal cortex, but rarely can be caused by hemorrhage within the adrenal gland (adrenal apoplexy).^* In cases of severe damage to the adenohypophysis, acute secondary adrenal insufficiency develops. Aldosterone-secreting cells of the zona glomerulosa in the adrenal cortex depend on the renin–angiotensin system for stimulation, as well as on potassium levels. Cortisol is produced in the zona fasciculata by way of the hypothalamic-pituitary-adrenal axis, the disruption of which causes secondary adrenal insufficiency. Low serum levels of cortisol stimulate the release of adrenocorticotropic hormone (ACTH) by the adenohypophysis. In turn, ACTH stimulates cortisol production in the zonae fasciculatae of the adrenal glands. Any disruption in this cycle decreases serum levels of cortisol. The ensuing addisonian crisis is characterized by nonspecific symptoms of shock and rapid deterioration of the patient's condition without obvious cause; however, the crisis responds to corticosteroids and fluids.^*

In acute primary adrenal insufficiency, hyponatremia and hyperkalemia are classic signs, along with shock and dehydration. The dehydration occurs when aldosterone-secreting cells are damaged and sodium is wasted in the urine, drawing water down its concentration gradient. Hyperkalemia also occurs, because the damaged aldosterone-secreting cells can no longer stimulate the kidney to excrete excess potassium. Hypocortisolism occurs as well, causing further decrease in vascular tone and the lack of appropriate response to stress.

In patients with secondary adrenal insufficiency, the signs and symptoms are the same as those of primary insufficiency. Results of laboratory tests can be within normal limits. Nonetheless, dilutional hyponatremia can occur because of the absence of cortisol, which can cause excess antidiuretic hormone secretion (dilutional hyponatremia) or sodium–potassium pump malfunction. ²¹ It is important to note that normal levels of cortisol in a severely stressed patient may be a sign of relative adrenal insufficiency. ²² Dehydration and hyperkalemia are not common presenting signs of secondary adrenal crisis, because production of aldosterone is not primarily under the influence of anterior pituitary hormones. ²³

Addisonian crisis commonly occurs iatrogenically upon the abrupt withdrawal of exogenously administered steroids, but it can also occur in patients with Addison's disease who are exposed to stress (for example, surgery, ^17–19 trauma, infection, or illness) and have not been given stress doses of corticosteroids. Such a crisis can also follow any acute disruption in the hypothalamic-pituitary-adrenal axis. Addisonian crisis differs from Addison's disease in that it is an acute process. When the cause is central (that is, hyposecretion of ACTH), there is not the increase in skin pigmentation that is seen in long-term hyposecretion (that is, no increase in melanocyte-stimulating hormone, a byproduct of ACTH production), and the hyperkalemia and dehydration characteristic of Addison's disease are not present. Hyponatremia occurs in both primary and secondary adrenal insufficiency, although it has different causes. Without stimulation of endogenous ACTH, cortisol levels drop, which leads to lethargy, depression, and fatigue. ^21,24

Case Report

A 64-year-old man with severe triple-vessel disease and unstable angina underwent uncomplicated coronary artery bypass grafting (CABG). His medical history included hypertension. Results of the preoperative neurologic evaluation were normal.

Upon awakening from the procedure, the patient reported blurred vision. A 90% decrease in abduction of the left eye (6th-nerve palsy) was the only focal neurologic finding. No imaging was performed at that time. The patient became less cooperative and more lethargic between postoperative days 2 and 6. His facial expression became flatter, and he participated less in his rehabilitation sessions.

Postoperative day 6 was the low point in the patient's recovery: he began developing arrhythmias and low-grade fevers despite negative culture results. He became hypotensive and hyponatremic. These signs of addisonian crisis prompted the use of magnetic resonance imaging, which revealed a 3- × 3- × 2.5-cm suprasellar mass with a cystic component. A cosyntropin stimulation test raised serum cortisol levels from 0.57 to 2.08 μg/dL. Pituitary apoplexy with secondary adrenal insufficiency was diagnosed.

Intravenous stress-dose hydrocortisone was begun. The patient became more responsive and alert during the next 24 hours; he was afebrile, and the arrhythmias resolved. During this recovery period, he reported bitemporal hemianopia.

Nine days after CABG, the patient underwent transsphenoidal resection of a hemorrhagic pituitary adenoma. After decompression, the patient was able to abduct his left eye, but some slight palsy remained. Visual acuity and visual field defects were both dramatically improved.

Discussion

Only 14 reports of pituitary apoplexy after cardiac surgery with cardiopulmonary bypass (CPB) have been reported, and those, for the most part, were cases in which patients presented with classic symptoms of pituitary apoplexy (Table II 1–7,9,10,25). Ten of these cases occurred after coronary artery bypass grafting (CABG). One of the 10 patients developed hypotension, ²⁵ and 2 autopsied patients from a 1975 study ⁸ were noted to have hypotension before death (see Table II footnote*). Ours is the 11th case that occurred after CABG. To our knowledge, pituitary apoplexy presenting as addisonian crisis after CABG has not been described in the English medical literature. In our patient, lethargy caused by the evolving addisonian crisis masked his bitemporal hemianopia. The only other classic symptom of pituitary apoplexy exhibited by this patient was isolated 6th-nerve palsy, which was attributed to small-vessel disease.

TABLE II. Summary of Reported Cases* of Pituitary Apoplexy after Cardiac Surgery with Cardiopulmonary Bypass

TABLE II. continued

Often, pituitary apoplexy is the 1st symptom of a previously unknown pituitary adenoma, ^10,26 although apoplexy can occur in a normal pituitary gland. ²⁵ Cardiac surgery poses unique challenges to the circulatory and the endocrine systems; ^20,27 several of these challenges, including heparin administration, absence of pulsatile flow during CPB, and embolism resulting from CPB, are postulated to be causes of pituitary apoplexy.

Heparin is routinely administered during CPB, and hemorrhage is one of the worst complications of anticoagulation. The normal pituitary gland is highly vascularized, and the adenomatous pituitary gland is at increased risk of hemorrhage, likely due to the abnormal sinusoidal and thin-walled nature of the tumor vasculature. ^28–30 Hyaline changes and fibrinoid necrosis have also been noted in the vascular walls ¹⁵ and contribute to the fragility of these vessels. According to some authors, prothrombin times in excess of 15 seconds decrease the risk of intracerebral hemorrhage while maintaining adequate anticoagulation. ³¹ Advanced age of the patient, intensity of anticoagulation, prior ischemic cerebrovascular disease, and hypertension are the greatest predictors of risk for intracerebral hemorrhage during anticoagulation, ³² and the presence of a known intracranial neoplasm is a contraindication to anticoagulation. ³³ Heparin administration has been noted previously to cause pituitary apoplexy after myocardial infarction. ³⁴ Moreover, intraoperative heparin is not reversed completely by protamine in up to 52% of patients. ^10,35 Therefore, reversal with protamine does not reliably protect against hemorrhage.

Absence of pulsatile flow is another peculiarity of CPB that may increase the risk of hemorrhage in a pre-existing adenoma. ¹⁰ Pulsatile flow might not affect cerebral metabolism ³⁶ or confer microvascular benefits. ³⁷ There is evidence, however, that pulsatile delivery might decrease the occurrence of the hypotension that accompanies nonpulsatile CPB. ¹⁶ Hypotension can further deprive a marginally perfused adenoma and cause infarction with secondary hemorrhage. ¹⁰ Reperfusion injury with the restoration of physiologic circulation can also contribute damage to an adenoma that is already prone to hemorrhage.

Emboli have been reported to cause hemorrhage in the pituitary gland. ¹ Procedures that require CPB present many opportunities for embolization. Extra-corporeal sources of emboli include plastic fragments and gas bubbles, and intracorporeal sources include plaque fragments from cross-clamping, calcifications dislodged from valves, and mural thrombi. ⁵ Careful handling of the atherosclerotic aorta (with possible use of epiaortic ultrasound for screening) and venting of the left ventricle can decrease the incidence of microemboli. ³⁸

Many investigators think that the acute expansion of a pituitary tumor compromises the tumor's blood supply, increasing the risk of necrosis and hemorrhage. ^11,26,28 However, some authors have proposed that this hypothesis does not explain the occurrence of hemorrhage into smaller masses and is inconsistent with the observation that pituitary tumors are typically slow growing. ³⁹ Edema secondary to infarction can cause rapid expansion. Although edema would necessarily be a result of some other instigating factor and not the primary event, it could contribute greatly to the damage after a primary injury in the close confines of the pituitary fossa.

Dilution of the blood, caused by the priming of the CPB pump, can also lead to hemorrhage and necrosis. The nature of CPB requires priming the pump, usually with crystalloid solution. Priming not only minimizes blood transfusion requirements but also improves perfusion during bypass. ¹⁰ The dilution that results from priming decreases plasma oncotic pressure and increases tissue edema, thus increasing the risk of hemorrhage and necrosis.

Dilution with crystalloid also decreases hematocrit levels, thereby decreasing oxygen delivery to tissue. Moreover, blood loss and hemolysis also occur during CPB. Generally, these events do not cause problems, because there are physiologic mechanisms that redistribute blood flow to the brain. ¹⁰ However, this redistribution can increase intracranial pressure to an intolerable extent in the adenomatous pituitary gland and trigger hemorrhage.

Atherosclerosis is another risk factor for pituitary apoplexy. ²⁹ Even in the absence of previous cerebrovascular events, the presence of known coronary disease provides clear evidence of widely disseminated atherosclerotic changes, including intracerebral. Thrombotic events resulting from the rupture of atherosclerotic plaques can increase the risk of apoplexy for the reasons noted above. In addition, positive-pressure ventilation and frequent coughing have been known to cause pituitary hemorrhage, presumably secondary to increased intracranial pressure. ³⁰

Another distinctive occurrence in patients undergoing heart surgery with CPB is that they exhibit delayed decreases in serum cortisol levels compared with such patients not requiring CPB; the mechanism of this phenomenon is unclear. ^20,27,40 The secretion of ACTH decreases upon the initiation of CPB, while the adrenal response to exogenous ACTH remains intact. This decrease in ACTH secretion implies that some pituitary hypofunction occurs during CPB. Hyponatremia and other disturbances of electrolytes can be masked by aggressive fluid or electrolyte replacement. Therefore, addisonian crisis should be considered in any hypotensive patient who does not respond to standard therapy after an uncomplicated procedure.

Regardless of the cause of pituitary apoplexy, aggressive management with transsphenoidal decompression and endocrine replacement offers the greatest long-term success, particularly if cranial nerve involvement or visual disturbances are present. 11–15,41,42 Apoplexy occurs more frequently in patients with highly invasive tumors, and urgent surgical decompression is the treatment of choice for such patients. ¹²

Summary

Addisonian crisis is a rare sequela of cardiopulmonary bypass and is fatal if not treated with replacement hydrocortisone. Addisonian crisis requires a high index of suspicion in any postoperative patient who responds poorly despite an uncomplicated procedure and lack of other obvious cause. If pituitary apoplexy is present, it should be treated with a combination of surgical decompression and hormone replacement.