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Postoperative Care Following Pituitary Surgery Aaron S. Dumont, Edward C. Nemergut, II, John A. Jane, Jr and Edward R. Laws, Jr J Intensive Care Med 2005; 20; 127 DOI: 10.1177/0885066605275247 The online version of this article can be found at: http://jic.sagepub.com/cgi/content/abstract/20/3/127

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ANALYTIC REVIEWS

Postoperative Care Following Pituitary Surgery Aaron S. Dumont, MD Edward C. Nemergut II, MD John A. Jane Jr, MD Edward R. Laws Jr, MD

Patients undergoing surgery for pituitary tumors represent a heterogeneous population each with unique clinical, biochemical, radiologic, pathologic, neurologic, and/ or ophthalmologic considerations. The postoperative management of patients following pituitary surgery often occurs in the context of a dynamic state of the hypothalamic– pituitary–end organ axis. Consequently, a significant component of the postoperative care of these patients focuses on vigilant screening and observation for neuroendocrinologic perturbations such as varying degrees of hypopituitarism and disorders of water balance (diabetes insipidus and the syndrome of inappropriate antidiuretic hormone). Additionally, one must be cognizant of other potential complications specific to the transsphenoidal approach for tumor removal including cerebrospinal fluid leakage and meningitis. This review addresses the postoperative management of patients undergoing pituitary surgery with an emphasis on careful screening and recognition of complications. Key words: pituitary surgery; postoperative management; pituitary adenoma; diabetes insipidus; syndrome of inappropriate antidiuretic hormone; endocrinopathies; replacement therapy; meningitis

Patients with tumors of the pituitary gland are commonly encountered, representing approximately 10% of diagnosed brain neoplasms (and found in more than 10% of individuals incidentally at autopsy) [1-5]. Pituitary tumors encompass a diverse spectrum of disease, and perturbations of the endocrine system are frequent. Individuals harborFrom the Departments of Neurological Surgery, Radiology, Neuroscience, Anesthesiology and Medicine, University of Virginia School of Medicine, Charlottesville, VA. Received Feb 2, 2004, and in revised form Aug 6, 2004. Accepted for publication Sep 28, 2004. Address correspondence to Edward R. Laws Jr, MD, University of Virginia Health System, P.O. Box 800212, Charlottesville, VA 22908, or e-mail: [email protected]. Dumont AS, Nemergut EC, Jane JA, Laws ER. Postoperative care following pituitary surgery. J Intensive Care Med. 2005;20: 127-140. DOI: 10.1177/0885066605275247

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ing nonfunctioning tumors may develop varying degrees of hypopituitarism and/or hyperprolatinemic states (secondary to “stalk effect” or loss of tonic inhibition of prolactin secretion). Additionally, hormone-secreting tumors can result in pathologic syndromes (such as acromegaly and Cushing’s disease) with resultant adverse effects across multiple organ systems that may ultimately result in demise without treatment. The above notwithstanding, pituitary tumors may also produce neurologic deficits through insidious mass effect on adjacent structures including the optic chiasm or through an acute hemorrhagic event as in apoplexy. The successful surgical management of patients harboring pituitary tumors requires a multidisciplinary approach and is critically dependent on perioperative care. The nature and diversity of pathology encountered and the propensity for multiplesystem involvement must be carefully considered. Patients with functioning tumors resulting in acromegaly, Cushing’s disease, and thyrotoxicosis (secondary to growth hormone–secreting adenoma, adrenocorticotropic hormone [ACTH]–secreting adenoma, and thyroid stimulation hormone– secreting adenoma, respectively) each present specific challenges with their own inherent perioperative management considerations. In addition, the possibility of a dynamic state of the hypothalamic– pituitary–end organ axis in the postoperative period exists. As such, a significant component of postoperative care is devoted to vigilant screening for neuroendocrine abnormalities (such as hypopituitarism and disorders of water balance) with appropriate intervention when necessary. There are also other potential complications seen with transsphenoidal surgery such as cerebrospinal fluid (CSF) leakage and meningitis that must also be considered. The ensuing discussion will review the postoperative management of patients undergoing pituitary surgery emphasizing systematic but individualized postoperative management.

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Postoperative Considerations Postoperative management is critical to the overall successful treatment of patients with pituitary tumors. Assessment of the hypothalamic– pituitary–end organ axis and screening for specific abnormalities coupled with monitoring for relatively uncommon nonendocrine complications (such as visual loss, CSF leakage, meningitis, stroke) occurring in less than 2% of patients [6-9] are central constituents of postoperative care (Table 1).

Table 1. Complications to Monitor in the Early

Postoperative Period Endocrine related • Abnormalities of ADH (diabetes insipidus and the syndrome of inappropriate ADH secretion) Non-endocrine related • Visual loss/other cranial neuropathies • CSF leakage/meningitis • Stroke or other neurologic abnormalities ADH = antidiuretic hormone; CSF = cerebrospinal fluid.

Table 2. Summary of Postoperative Screening

Routine Postoperative Screening and General Postoperative Management The main objective of routine postoperative screening following pituitary surgery is to assess the integrity of the hypothalamic-pituitary axis, which may be in a dynamic state of flux following surgery (either attributable to removal of functioning tumors with a resultant decrease in abnormal hormone secretion or attributable to inadvertent surgical trauma), and to rule out important surgical complications (Table 2). Following completion of surgery and extubation in the operating room, patients are typically taken to the recovery room for close observation until they are completely awake. Shortly following surgery, patients are carefully assessed neurologically (emphasizing visual fields and acuity), and the nasal and abdominal wounds (if present from fat graft harvest) are inspected. A basic metabolic profile is sent and other specific tests are ordered as indicated (serum cortisol in patients with Cushing’s disease and complete blood count if intraoperative blood loss was significant) to serve as initial postoperative reference studies. The most common patient complaint after transsphenoidal surgery is headache. Pain may be treated with narcotics, nonsteroidal drugs such as ketorolac, or acetaminophen. A recent retrospective review of transsphenoidal surgery in our institution revealed a vast range of postoperative narcotic requirements, with some narcotic-naïve patients requiring more than 30 mg morphine in the first 2 postoperative hours and others requiring very little, if any, narcotic analgesia. One possible explanation is built on the fact that the pituitary gland has the greatest concentration of βendorphins in the brain. It is possible that in some patients, surgical manipulation of the gland may contribute to pain relief. Nevertheless, as noted above, narcotics should be used with great care in 128

Daily complete blood count and serum prolactin levels Disorders of water balance • Clinical data (eg, voracious thirst) • Strict input and output recording • Daily serum chemistries and serum osmolarities (more frequently, if indicated) • Urine specific gravities every 4 hours Hypothalamic-pituitary-adrenal axis • Signs and symptoms of cortisol deficiency (anorexia, nausea/vomiting, headache, myalgias, hypotension, etc) • If no preoperative abnormality—serum cortisol checked at 6:00 AM on PODs 2 and 3 (after stress dose steroids have been stopped on morning of POD 1) • If preoperative hypopituitarism—no screening (patients placed on stress dose steroids and tapered to maintenance dosage) • Cushing’s disease—serum cortisol levels every 6 hours (no perioperative steroid coverage is routinely provided) Acromegaly—serum growth hormone levels on POD 1 and 2 Screening for surgical complications • Focused history and thorough physical exam including wounds, visual fields, acuity, etc • If CSF leak suspected, fluid sent for tau transferrin and head CT performed to assess for pneumocephaly POD = postoperative day; CSF, cerebrospinal fluid; CT, computed tomography.

any patient with a history of obstructive sleep apnea. Nausea and vomiting are also very common postoperative complications in patients undergoing neurosurgical procedures, with nearly 40% of patients reporting some such complaint [10]. Given the high risk for vomiting in patients undergoing this procedure and the detrimental effect of vomiting on intracranial pressure, we routinely provide all patients with pharmacologic prophylaxis. No randomized controlled studies exist in this specific Journal of Intensive Care Medicine 20(3); 2005

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Postoperative Care Following Pituitary Surgery

patient population to guide therapy toward any specific drug or drug class. As such, we tend to select drugs after considering patient-specific risk factors [11]. Patients are then triaged for close postoperative observation. At our institution, patients are cared for in the specialized neuroendocrine center (a section of the neurosurgical floor), which uses an experienced team well versed in the care of such patients [12]. A select few patients are transferred to the neurosurgical intensive care unit if complications arise during surgery or if complicated concomitant medical issues are present. At our institution, complete blood counts and prolactin (when preoperative elevation exists secondary to “stalk effect” or functioning tumor) are typically measured daily in the immediate postoperative period. Abnormalities of antidiuretic hormone (ADH) secretion and subsequent disorders of water balance are among the most common complications seen following pituitary surgery and will be discussed in detail below. The perioperative assessment of the hypothalamicpituitary-adrenal (HPA) axis and administration of glucocorticoids are controversial, with practices varying between institutions [12-16]. Patients with Cushing’s disease will be discussed separately below. There is general consensus that patients with preoperative cortisol deficiency are treated with stress dose steroids perioperatively (preoperatively and postoperatively) [12, 13, 16-18], typically 50 to 100 mg of intravenous hydrocortisone every 6 hours. Induction of anesthesia is a potent stress to the HPA axis [19], and adequate coverage with stress dose steroids “on call” to the operating room is critical. Hydrocortisone is then administered orally and tapered down to the patient’s preoperative regimen (typically 20 mg in the morning and 10 mg in the evening for hydrocortisone, or 5 mg in the morning and 2.5 mg in the evening for prednisone). No perioperative testing of the HPA axis is undertaken at this point. Controversy exists concerning the management of patients without (or with low probability of having) preoperative cortisol deficiency [6, 12-15, 17, 18]. Some institutions routinely administer perioperative steroids to patients without preoperative cortisol deficiency undergoing transsphenoidal surgery, whereas other institutions do not [6, 12-15, 17, 18]. The basis for stress dose steroid administration in the perioperative period is based on the assumption that the surgical procedure may disturb the HPA axis to some degree resulting in the possibility of inadequate

ACTH secretion. Those in favor of this theory provide brief stress dose steroid coverage in the immediate perioperative period that is subsequently withdrawn, at which time the HPA axis is assessed. Routine administration of steroids is simple, is relatively innocuous, and obviates the need for additional serial serum cortisol levels. Advocates of the alternative strategy of withholding steroids have achieved equally satisfactory results [13, 14, 16, 20]. Patients typically undergo serial serum cortisol level determinations and are monitored closely for clinical signs and symptoms of cortisol deficiency (hypotension, malaise, anorexia, nausea, myalgias, tachycardia, unexplained hyponatremia, problems with thermoregulation, etc). At our institution, our practice has been to administer hydrocortisone in stress doses with the last dose given on the morning of postoperative day 1. Cortisol levels are then routinely measured on the mornings of postoperative days 2 and 3. In general, patients with 2 consecutive cortisol values of 8 µg/dL or less receive replacement with hydrocortisone, and ongoing needs for cortisol replacement are evaluated in follow-up. Postoperative assessment of cortisol levels in patients with Cushing’s disease is different from that described above. The ultimate objective of postoperative assessment of the status of cortisol production in the patient with Cushing’s disease is to categorize the effectiveness of surgery (i.e., whether remission was achieved). There is significant variation across centers in outcome assessment and the classification of cases as surgically induced remission or surgical failure [21-26]. Laboratory investigation ultimately aims to document extirpation of an ACTH-producing adenoma through demonstration of either restoration of normal HPA axis function or absence of endogenous cortisol production [21]. At our institution we do not administer perioperative corticosteroids to patients with Cushing’s disease because of their native nonphysiologic hypercortisolemic state. We have documented that exogenous steroid medication is not required until after the determination of remission [21]. Instead, we carefully clinically and biochemically monitor cortisol levels beginning immediately following surgery. Serum cortisol levels are subsequently drawn every 6 hours (at 12:00, 18:00, 00:00, and 06:00). Signs and symptoms of hypocortisolemia were addressed earlier. When clinical signs and symptoms of hypocortisolemia are accompanied by low serum cortisol levels (usually less than 2 µg/dL), replacement hydrocortisone is administered and surgical remission is docu-

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mented. Serum cortisol levels likely decrease sharply following successful surgery because unregulated hypersecretion of ACTH by the adenoma suppresses endogenous release of corticotrophin releasing factor and ACTH through feedback inhibition. Postoperative assessment of patients with acromegaly following tumor removal also poses several specific considerations. Growth hormone levels are measured on the morning of postoperative days 1 and 2. These allow prompt comparison with preoperative levels; however, we have reported stringent criteria for ascertainment of remission at the 6-week postoperative visit (namely, glucosesuppressed nadir less than 1.0 µg/L, a normal sexand age-adjusted insulin-like growth factor-1 level, and postoperative random growth hormone levels of 2.5 µg/L or less) [27]. As will be discussed below, patients with acromegaly develop brisk, physiologic postoperative diuresis following successful tumor removal during which treatment for presumptive DI should be avoided. As patients with acromegaly often have macroglossia and hypertrophied soft tissues of the upper airway, sleep apnea is common in this population. Patients with acromegaly receive a nasal trumpet down the right nostril placed intraoperatively under the operating microscope, in addition to standard nasal packing. This is removed the next morning with the nasal packing. In our experience with surgical management of more than 550 patients with acromegaly, the incidence of postoperative airway issues has not been significantly different from that seen in the general population of patients undergoing surgery for pituitary tumors. Evaluation of the pituitary-thyroid axis is carefully undertaken preoperatively. Replacement is started when appropriate. Patients with known hypothyroidism continue their preoperative replacement dosage following surgery and are reevaluated at their first postoperative follow-up visit. Patients without preoperative hypothyroidism are not screened in the immediate postoperative period; however, they are evaluated at their first postoperative follow-up visit. For patients who undergo a total hypophysectomy (eg, for recurrent Cushing’s disease), thyroid replacement therapy is started in the immediate postoperative period and thyroid studies are performed in follow-up several weeks later. Patients may be normalized soon after surgery and begin ambulating. Patients typically have nasal dressings (“rocket”-type nasal packing), which are

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removed the following morning. They are usually discharged on postoperative day 2 or 3. Patients undergoing an “extended” transsphenoidal skull base approach to sellar and parasellar tumors are managed slightly differently [28]. These patients have a lumbar drain postoperatively for 48 hours (whereas none of our other patients have postoperative lumbar drains). Their nasal dressings also remain in place for 48 hours. These patients undergo a routine postoperative computed tomography (CT) scan. The postoperative screening procedures for this subset of patients are otherwise similar to procedures used with patients undergoing standard transsphenoidal tumor resection. Although we routinely performed CT scans of patients undergoing standard transsphenoidal surgery in the past [29], we have since abandoned this practice secondary to a paucity of impact on perioperative care and overall inferiority compared with high-resolution postoperative magnetic resonance imaging [30]. We now only perform CT scans routinely in patients undergoing an “extended” transsphenoidal skull base approach to examine for pneumocephaly and postoperative complications in and around the resection cavity. A baseline CT scan can then be used for comparison to document resolution of pneumocephaly in instances where a CSF leak may be suspected. Postoperative CT scanning in patients undergoing standard transsphenoidal surgery is reserved for situations where a CSF leak is strongly suspected and in instances of severe postoperative headache without other explanation. The onset of new neurologic deficits (such as diplopia or visual loss) may also be an indication for a postoperative CT scan, although immediate visual loss can be addressed by prompt surgical exploration without imaging, as discussed under the surgical complications section. Alternatively, CT scanning for neurologic deficit may be supplanted by magnetic resonance imaging with its superior resolution and multiplanar definition. The use of prophylactic antibiotics has not been rigorously studied in the setting of transsphenoidal surgery, and the paucity of quality data has left this issue to the discretion of the surgical team. We routinely administer prophylactic antibiotics before skin incision and continue its use until the nasal packing is removed. Nafcillin or clindamycin for patients with penicillin allergy has typically been administered. With this regimen, infection rates have been acceptable (rate of meningitis less than 1%) [31].

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Postoperative Care Following Pituitary Surgery

Disorders of Water Balance— Abnormalities of ADH Secretion Disorders of water balance secondary to disturbances in secretion of ADH are among the most common acute perioperative complications of transsphenoidal surgery [32-37]. Abnormalities in ADH secretion resulting in postoperative diabetes insipidus and the syndrome of inappropriate ADH (SIADH) have been reported in 0.5% to 25% of cases (and sometimes higher) [18, 27, 33, 35, 38-40] and 9% to 25% of cases [18, 33, 34, 37], respectively. Additionally, postoperative abnormalities in ADH secretion appear to be independent of tumor type [33, 41]. Antidiuretic hormone is a nonapeptide that is derived from the processing of a larger polypeptide [42, 43]. It is synthesized predominantly in magnocellular neurons of the supraoptic and paraventricular nuclei of the hypothalamus [44-47]. Axonal processes of these ADH-producing neurons coalesce to form the supraopticohypophyseal tract, which terminates in the posterior lobe of the pituitary gland. Antidiuretic hormone is packaged in neurosecretory granules and transported anterogradely to the posterior lobe, where it matures into its fully functional form. Clinically, the absence of ADH leads to the familiar scenario of excretion of large volumes of dilute urine. The basis for this lies in the fact that the renal collecting tubules have limited water absorptive capacity in the absence of ADH. Circulating ADH released from the posterior pituitary binds to specific V2 receptors on the renal collecting tubules, leading to signal transduction that culminates in activation of a cyclic adenosine monophosphate kinase cascade that promotes insertion of aquaporin (water channels) into the cell membrane from their preformed location in the cytosol. Aquaporin channels facilitate the passive resorption of water (through a concentration gradient established by a countercurrent mechanism earlier in the nephron) [48, 49]. Furthermore, ADH promotes a pathway for urea to be reabsorbed from the medullary urine into the interstitium to further bolster interstitial osmolality [50-53]. Collectively, ADH increases water resorption in terminal segments of the nephron by increasing water permeability and strengthening interstitial-lumen osmolality gradients through promotion of urea transport. Secretion of ADH is principally governed by plasma osmolality [54-57] and effective circulating volume [55, 58-60]. Osmolality, in turn, is primarily

dependent on sodium concentration (the principal extracellular cation). Osmoreceptors in the hypothalamus monitor plasma osmolarity and through regulation of ADH secretion maintain homeostasis (osmolarity of 280-290 mOsm/L). When plasma osmolarity increases, ADH secretion is increased in a relatively linear manner whereas decreases in osmolarity maximally suppress ADH release [5457]. Baroreceptors in the left atrium and carotid artery monitor effective circulating volume and can potently stimulate ADH secretion with a decrease in circulating volume of at least 8% to 10% [58-60] via glosopharyngeal and vagus nerve–mediated stimulation of the supraoptic and paraventricular nuclei [61]. Other factors play minor modulatory roles in ADH secretion, such as angiotensin II and atrial natriuretic peptide, and will not be discussed further. Changes in plasma osmolarity may stimulate thirst osmoreceptors, particularly once plasma osmolarity exceeds 290 mOsm/L. This mechanism is a carefully designed homeostatic safeguard as rising plasma osmolarity stimulates thirst, which subsequently evokes a behavior (water intake) that abrogates development of significant plasma hyperosmolarity [57, 62]. Postoperative diabetes insipidus. Diabetes insipidus (DI) resulting from absent or inadequate ADH secretion is characterized by polyuria and polydipsia in the setting of dilute urine (Table 3) [63-66]. If water excretion exceeds intake, hypovolemia, hypotension, and elevated serum osmolarity and sodium result. Serum sodium and osmolarity may remain normal if intake matches output (typically the case in awake and alert adults with intact thirst mechanisms). Pituitary surgery may produce DI through disturbing any component of the ADH pathway (hypothalamus, pituitary stalk, or posterior lobe of pituitary gland). Diabetes insipidus is a common early perioperative complication and fortunately is often transient. Early postoperative DI (first 24 hours) developed in 31% of 1571 patients undergoing transsphenoidal surgery, whereas 17% had persistent DI at 3 days and 6% had persistent DI 1 week following surgery [67]. The overall reported incidence of transient DI varies widely [18, 27, 32, 33, 35, 38-40] affecting 4% to 80% of patients following surgery, whereas permanent diabetes insipidus is seen in 0.5% to 15% [7, 27, 39, 40]. Postoperative DI typically manifests in the first 24 or 48 hours following pituitary surgery. There are varying degrees of severity of postoperative DI

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Table 3. Diabetes Insipidus (Practical

Considerations in Setting of Postoperative Pituitary Patientsa) Clinical signs and symptoms • Polyuria, polydipsia, thirst (with craving for ice-cold fluids), typically beginning in the first 24-48 hours following surgery • High volumes (4-18 L/d) of dilute urine • Significant hypovolemia rare in setting of alert patient with intact thirst mechanism; some weight loss may be apparent Laboratory data • Normal or increased serum sodium • Normal or increased serum osmolarity • Urine specific gravity usually <1.005 • Use caution in patients with diabetes mellitus, those on diuretics, and those with acromegaly, and distinguish from normal postoperative diuresis Treatment • Individualized (depending on severity/duration) • Expectant management if mild and well compensated • DDAVP for symptomatic relief (titrated to avoid hyponatremia and overshoot) • Frequent electrolyte monitoring DDAVP = desmopressin a Fluid deprivation is seldom performed and the diagnosis of central diabetes insipidus is based on practical considerations in the context of the postoperative period following pituitary surgery.

depending on the extent of disturbance to the hypothalamic-neurohypophysis axis; however, commonalities transcend all presentations. There is usually the abrupt onset of polyuria along with accompanying thirst and polydipsia. The urine is dilute (specific gravity less than 1.005) and voluminous (4-18 L/d, the latter of which represents the mean volume of glomerular filtrate reaching the collecting ducts in the total absence of ADH) [68, 69]. Thirst in these patients includes a characteristic craving for ice-cold fluids [63, 70]. Because the majority of patients in the postoperative period following transsphenoidal surgery are awake, are alert with intact thirst mechanisms, and have adequate access to fluid intake, the development of significant volume depletion and hyperosmolarity is relatively uncommon as a presentation (although it may be seen in pediatric and very elderly patients and in any patient with altered level of consciousness). Screening for DI is an important component of postoperative management. Daily weights (at the same time and on the same scale) are recorded. Although Foley catheters are not routinely used,

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fluid intake and output are carefully recorded and patients are questioned regarding thirst. There is no specific hourly guideline for urine output; however, urine output greater than 250 cc per hour for 2 consecutive hours has been a reasonable indicator supporting the diagnosis of DI. Urine output alone, however, cannot be considered in isolation and treatment cannot be based solely on this. Daily serum chemistries and osmolarities are sent (with serum sodium and osmolarity evaluated more frequently as indicated) and urine specific gravities are analyzed every 4 hours after the patient voids. Collectively, these data provide serial information regarding body fluid balance. For example, an increasing serum sodium, increasing serum osmolarity, decreasing urine specific gravity with large volume output, and decreasing weight in the setting of voracious thirst herald the onset of DI. Clinical factors and biochemical data secure the diagnosis of DI. Thirst, polyuria, polydipsia, and decreasing daily weight are important clinical characteristics. Serum hyperosmolarity and hypernatremia coupled with high-volume urine with low specific gravity are important supportive biochemical data. Adult patients who are awake, alert, and allowed to drink ad libitum typically do not develop hypernatremia above 150 mmol/L because of osmotic stimulation of thirst drive that in turn results in behavior to increase fluid intake to keep up with losses. Diabetes insipidus may follow 1 of 3 clinical courses, namely transient, permanent, or triphasic. In the first course, DI is a transient phenomenon beginning within 24 to 48 hours of surgery and abating by the third day. This course may result from release of biologically inert precursors, temporary disruption of ADH producing neurons secondary to edema, or perturbation in the vascular supply to the stalk and posterior lobe [66, 68, 71]. In a second variant, transient DI is seen as before; however, persistent DI follows as preformed stores of ADH are depleted [72, 73]. In the third course, a triphasic pattern is seen as described in the classic work of Fisher and Ingram [74]. The first phase manifests abruptly within 24 hours of surgery and lasts 1 to 3 days. It is similar to the transient course described above and is generally thought to result from the same underlying pathology (neuronal shock leading to diminished or absent ADH release or release of biologically inert precursors or derivatives) [66, 68, 71, 72]. An interphase of antidiuresis develops around 1 week following surgery resulting from neuronal degeneration and release of remaining stores of ADH [66, 68, 71, 72]. Urine

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Postoperative Care Following Pituitary Surgery

output tapers and urine is concentrated, leaving the patient vulnerable to hyponatremia and hypoosmolarity. Following this second phase (lasting 114 days), permanent DI appears because the magnocellular neurons of the supraoptic and paraventricular neurons have degenerated [66, 68, 71, 72]. Permanent DI is fortunately relatively uncommon. Complete removal of the posterior pituitary gland [75] or total hypophysectomy does not necessarily lead to permanent DI. It appears that at least 90% of magnocellular neurons in the supraoptic and paraventricular nuclei must bilaterally degenerate (via damage sufficiently high in the supraopticohypophyseal tract [pituitary stalk]) to produce permanent DI [74, 76, 77]. Treatment of DI is individualized to each patient. The general aim of treatment is to ensure restoration and/or maintenance of osmotic homeostasis. Depending on the severity and duration of DI, specific treatment aims to reduce urine output and replete/maintain intravascular and intracellular volume. As noted above, DI is most commonly a transient event. As long as the patient is awake and alert, with intact thirst mechanisms and access to fluid, and serum sodium and osmolarity remain acceptably stable, no specific treatment is required. Close monitoring of fluid balance and serum electrolytes is mandatory. Specific treatment of DI may be undertaken with a synthetic analogue of ADH, desmopressin (DDAVP) [78]. Desmopressin works quickly and effectively without undesirable pressor effects [66, 68, 71, 72]. It can be administered orally, subcutaneously, intranasally, and occasionally intravenously (although this is unnecessary in stable patients). At our institution, DDAVP is administered as a single dose if there is a significant discrepancy in fluid intake and output, if serum sodium is increasing (above 145), and when excessive urine output significantly interferes with sleep. An initial dose of 1 µg of DDAVP can be administered subcutaneously and usually is effective in controlling postoperative DI. Alternatively, a 0.1-mg tablet of DDAVP can be administered orally. The oral formulation has been effective in our experience and remains our first-line treatment. When DDAVP is administered, close monitoring of urine output and serum electrolytes is mandatory. The risk of hyponatremia from DDAVP treatment remains, and it is important not to “overshoot” with DDAVP therapy. We have generally refrained from treatment of DI in people with serum sodium values less than 145 mmol/L. It is important to distinguish DI from some commonly encountered processes frequently seen in

the postoperative pituitary patient. First, many patients undergo a relatively brisk postoperative diuresis in response to intravenous fluid administration perioperatively. In these patients, serum sodium is typically low to normal and patients’ body weights may be above preoperative levels. Urine specific gravities are usually above 1.005. This is a self-limited, homeostatic response that normalizes fluid balance and should not be treated. Second, patients with inadequately controlled diabetes may have high urine output associated with glycosuria. The urine osmolarity and specific gravity may be falsely increased (secondary to increased glucose solute load). Additionally, serum sodium levels may be artificially low if glucose levels are high, and determination of serum sodium levels in these patients mandates concomitant assessment of serum glucose levels. This condition may obviously occur in any patient with diabetes mellitus but is not uncommon in patients with impaired glucose tolerance secondary to functioning tumors as in those with known Cushing’s disease or acromegaly. In these instances, blood glucose must be aggressively corrected. This may correct the problem of polyuria or may unmask underlying DI, which may then be appropriately managed. Third, patients with acromegaly demonstrate a robust physiologic diuresis following successful tumor resection, and early treatment with DDAVP should be avoided [12]. Postoperative hyponatremia—syndrome of inappropriate antidiuretic hormone. Hyponatremia following pituitary surgery is a common and important complication of pituitary surgery that manifests in a delayed fashion [33-35, 37, 79]. It occurs in 9% to 25% of patients [18, 33, 34, 37]. In most instances, despite hypo-osmolarity and an expanded effective circulating volume, secretion of ADH or an analogue peptide is not suppressed [80-82]. Indeed, hypo-osmolar, hyponatremic patients have failed to appropriately suppress ADH secretion [34, 35, 83, 84]. Additionally, experimental removal of the posterior pituitary gland in animals has prevented the development of hyponatremia in similar settings [85]. Taken collectively, these data suggest that inappropriate antidiuretic hormone release is responsible for the observed hyponatremia [33-35, 83-86]. Furthermore, emerging data demonstrate that other factors may play a role including excess natriuresis secondary to the action of a nonatrial natriuretic peptide, inappropriately normal thirst and fluid intake, and low dietary sodium intake [33]. In SIADH, free water intake exceeds free

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water excretion, and consequently increased urinary excretion of sodium is observed in the context of inappropriately concentrated urine [87-89]. Diagnosis of hyponatremia following pituitary surgery is often a biochemical one, although depending on the rapidity of onset and severity, symptoms can arise. The basis for laboratory diagnosis of SIADH resulting in hyponatremia is contingent on demonstration of low serum sodium in the context of a hypo-osmolar serum, hyperosmolar urine, and euvolemic state (Table 4). The serum sodium is less than 135 mmol/L along with a low serum uric acid (reflecting underlying renal loss of uric acid) with excess sodium excretion in the urine (greater than 40 mmol/L) [18, 90]. As mentioned, SIADH is characterized by a general euvolemic (or mildly hypervolemic) state and should be distinguished from cases of hyponatremia associated with volume contraction. In SIADH, blood urea nitrogen (BUN) and serum creatinine are normal and serum uric acid is generally low. In contrast, patients who are volume contracted may have elevated BUN and creatinine, and serum uric acid levels may be increased. Urine sodium concentration is usually less than 10 to 15 mmol/L, and fractional excretion of sodium is less than 1%. Although postoperative hyponatremia may be entirely asymptomatic and diagnosed incidentally, symptoms can arise particularly when the decrease in serum sodium is rapid and large in magnitude. Symptoms often first appear after the patient has been discharged home (1 week following surgery on average). Delerium, agitation, headache, anorexia, nausea/vomiting, and lethargy may be seen. With rapid and severe decreases in sodium level (less than 115 mmol/L), seizures can occur [91-93]. Postoperative hyponatremia may be attributable to a host of other processes that must be considered in establishing the etiology and planning therapy. The delayed onset of SIADH-related hyponatremia should be recalled, because many other causes of postoperative hyponatremia are seen earlier. Adrenal insufficiency is an important cause of hyponatremia and one that is eminently treatable. Although this is carefully screened for in the perioperative period, it is perhaps the most important differential diagnosis to entertain in the approach to the hyponatremic patient following pituitary surgery. Cortisol deficiency results in an impaired ability to excrete free water (cortisol inhibits ADH secretion, whereas a relative or absolute absence of cortisol results in an increase in ADH secretion) [80, 94, 95]. To confirm the diagnosis when suspected,

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Table 4. Syndrome of Inappropriate Secretion of

ADH (Practical Considerations in Setting of Postoperative Pituitary Patient) Clinical signs and symptoms • Variable depending on severity and rapidity of symptom onset • May include headache, delirium, agitation, anorexia, nausea/vomiting, seizures, lethargy (or may be asymptomatic) • Euvolemic without peripheral edema • Typically seen after discharge (1 week following surgery on average) Laboratory data • Hyponatremia • Serum hypo-osmolarity • Other causes ruled out (normal thyroid, cortisol, glucose levels and normal renal function) • Inappropriately concentrated urine Treatment • Individualized (depending on severity/duration) • Fluid restriction often adequate • Hypertonic saline or urea if severe and symptomatic • Frequent electrolyte monitoring ADH = antidiuretic hormone.

a serum cortisol level is drawn followed by immediate replacement with appropriate intravenous corticosteroid. Aldosterone deficiency under these circumstances may also be contributory [96]. In humans with SIADH, aldosterone usually remains normal despite decreased renin levels, thereby contributing to avoidance of excessive urinary loss of salts [97-100]. However, in patients with adrenal insufficiency (secondary to deficient ACTH drive), aldosterone levels are often low [96]. Moreover, with appropriate cortisone replacement, the hyponatremia corrects and aldosterone levels normalize [96]. Hypothyroidism is another important consideration in patients with hyponatremia following pituitary surgery. This is also screened for preoperatively but is still important to consider because it may occur in patients who are partially treated. Although the mechanism by which hypothyroidism produces hyponatremia is not entirely clear, decreased cardiac output (with stimulation of baroreceptors leading to increased ADH release), decreased clearance of ADH, or resetting of the osmostat may all contribute [101-104]. This is also easily treatable once the diagnosis is established. “Pseudo” hyponatremia may be seen in cases of poorly controlled serum glucose as in patients with Cushing’s disease, acromegaly, or long-standing diabetes. Hyperglycemia provides an osmotic load in the intravascular compartment that

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draws water from the intracellular space leading to dilutional hyponatremia [105]. Cerebral salt wasting, most often associated with severe intracranial pathology including subarachnoid hemorrhage [106-110], is a rare potential cause of hyponatremia following pituitary surgery [111, 112]. The key distinction to be made is that patients with cerebral salt wasting are clinically hypovolemic compared with the euvolemic or slightly hypervolemic status of patients with SIADH. Patients with cerebral salt wasting may have abnormally elevated BUN greater than creatinine, increased hematocrit, and increased serum uric acid [107, 108, 110]. Cerebral salt wasting is treated with volume restoration (fluid restriction may be harmful). Other less common causes such as drugs, pulmonary disorders, and excessive fluid administration (particularly those with 5% dextrose) should also be considered but will not be discussed further here [113-115]. Treatment of hyponatremia is aimed at the underlying cause. The overall goal is to correct sodium and plasma osmolality, which must be accomplished in the context of the temporal evolution and severity of hyponatremia with consideration of comorbidities (such as renal failure). We have generally adopted a similar strategy for prevention of hyponatremia that Olson and colleagues [33] advocated; in our discharge instructions to patients we recommend mild fluid restriction (drinking only when clearly thirsty), attention to adequate salt intake, and awareness of symptoms of hyponatremia in the first couple of weeks following transsphenoidal surgery. If hyponatremia develops and SIADH is diagnosed, fluid restriction remains an important part of therapy [33, 37]. In patients with mild and asymptomatic hyponatremia, fluid restriction is the only treatment necessary. We often initiate a fluid restriction to 1000 cc of total fluid intake per day with a minimum of once daily serum electrolyte monitoring. Serum sodium should correct over the next several days and if a trend to correction is not seen with 1000 cc of total fluid restriction, the fluid restriction is adjusted to 600 cc per day or less. Mild cases of hyponatremia may be managed on an outpatient basis, but certainly symptomatic or severe hyponatremia warrants inpatient admission. Sodium supplementation may also be added [18, 107, 108, 116], although definitive effectiveness has not been proven. In patients with severe, symptomatic hyponatremia (usually sodium less than 120 with headache, nausea/vomiting, and altered mental status), hypertonic saline (3% or 1.8% saline) can be added to fluid restriction to quickly but partially restore

serum sodium. Hyponatremia in the setting of pituitary surgery is more of an acute event rather than a chronic process; however, the possibility of excessively rapid correction must be considered to prevent central pontine myelinolysis. Correction in this setting should proceed at a rate not exceeding 1 mmol/L/h, and if chronic hyponatremia is present, correction should not exceed 0.5 mmol/L/h [117-119]. Hypertonic saline should be discontinued after partial correction and resolution of symptoms and is usually not necessary for longer than 12 to 24 hours. Frequent careful monitoring of fluid and electrolyte status is an essential component of therapy, and we examine serum electrolytes every 6 to 12 hours.

Surgical Complications and Complications Avoidance Complications are a reality of virtually every major surgical procedure performed. Understanding complications qualitatively and quantitatively, coupled with minimizing their occurrence, is essential to counseling patients and conducting the procedures themselves. Endocrine complications have been dealt with above, and the ensuing discussion will emphasize surgical complications and their avoidance. In a comprehensive survey conducted by Ciric and colleagues [32], endocrine complications were, not surprisingly, the most common complications overall (19% and 18% of patients developed anterior pituitary insufficiency and diabetes insipidus, respectively). Cerebrospinal fluid fistulas were reported in 4% of patients, whereas other major surgical complications including visual loss, meningitis, carotid artery injury, and hypothalamic injury were reported in 1% to 2% of cases. Overall mortality was just under 1%. Of note, there was an apparent inverse relationship between experience of the treating group and the likelihood of complications. Our overall results also reveal that transsphenoidal surgery is generally safe but carries the risk of rare but serious complications. Mortality in our overall series is less than 0.5%, with major complications (CSF leak, meningitis, stroke, vascular injury, and visual loss) occurring in 1.5% and minor complications (sinus disease, septal perforations, epistaxis, wound hematomas, and infections) in 6.5% [6]. However, complications vary according to patient population, with some diseases portending significantly higher complication rates. For instance, in a series of 105 patients with Cushing’s

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disease whom we treated, mortality and permanent morbidity occurred in 0.9% and 1.8% of patients, respectively [39]. The overall rate of complications was 13.3%, including 4 patients with deep venous thrombosis and 1 patient with pneumonia. Injury to the carotid artery is a known but fortunately rare complication of transsphenoidal surgery [120]. Following stabilization in the operating room, patients with injury of the carotid artery typically undergo postoperative angiography to evaluate for pseudoaneurysm formation. If a pseudoaneurysm is visualized, it may be treated with endovascular therapy or open surgery if endovascular therapy is not feasible. Close neurologic and hemodynamic monitoring in the intensive care unit is mandatory postoperatively. In cases of unexpected visual loss or cranial neuropathy in the immediate perioperative period, we have relied on early reexploration (most often revealing hemorrhage or excessive sellar packing). New neurologic signs and symptoms not initially apparent following surgery are evaluated with urgent imaging studies (ideally magnetic resonance imaging with its superior, multiplanar anatomic definition). Patients are expected to have some nasal discharge following surgery in the early perioperative period. When excessive drainage of clear fluid is encountered or the patient reports a salty taste in the back of the throat associated with postnasal discharge, a CSF fistula must be excluded. The drainage is often worse with bending forward and is associated with a headache (which may or may not be positional). We collect the drainage in a tube and send it to our laboratory to check for tau protein (β2-transferrin, a specific CSF marker [121]). β2Transferrin is usually a reliable marker for CSF, but false-positive diagnoses can occur in the setting of certain systemic diseases such as alcoholism and severe liver disease, and false-negative results can occur in samples in which a minimal amount of CSF is mixed with blood and/or mucous [122]. Other CSF markers such as prostaglandin-D synthase (also known as β2-trace protein) and a CSF variant of transthyretin have been investigated [122]; however, experience is limited and tests for these proteins are not widely available in hospital laboratories. Where clinical suspicion is high, we may also obtain a head CT to evaluate for pneumocephaly (which would support a diagnosis of CSF leakage). A cisternogram or similar procedure may be performed if the diagnosis is equivocal; however, this has rarely been necessary in our

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experience. Cerebrospinal fluid leakage in the postoperative period is treated with immediate reexploration and repair. Reliance on lumbar drainage has not been adopted at our institution, because repacking in the early postoperative period is simple and almost uniformly successful in isolation, obviating the anxiety and additional hospital stay mandated with prolonged lumbar drainage and bed rest. Follow-up with a CT scan may be performed to document resolution of pneumocephaly after repair. Meningitis occurs in 3% or less of patients undergoing transsphenoidal surgery [31, 123]. Although it has been incompletely studied, intraoperative CSF leakage has been identified as a risk factor for development of postoperative meningitis [123]. Classic signs and symptoms of meningitis such as severe headache, meningismus, photophobia, and fever may be present. Patients may also demonstrate less dramatic symptomatology but may complain of persistent nasal discharge. A workup for CSF leak should be undertaken as outlined above including a CT scan to evaluate for pneumocephaly or other postoperative complication. A lumbar puncture may be performed and analyzed for CSF cell count, glucose, protein, lactic acid, Gram stain, and culture. Measurement of opening pressure and evaluation for respiratory variation along with Queckenstedt’s test (compression of 1 and then both jugular veins) can be performed. Low opening pressure, absent respiratory variation, and response to jugular vein compression may herald the presence of a CSF fistula. Following appropriate imaging, a lumbar puncture should be performed in anyone for whom meningitis is a diagnostic consideration. When clinical suspicion of meningitis is high, empiric antibiotic coverage should be initiated immediately following lumbar puncture. We have used vancomycin and cefepime (or ceftriaxone) for empiric coverage and make appropriate adjustments once the culture results and sensitivities are available. Duration of therapy is typically 14 to 21 days depending on organism and clinical circumstance. At least 1 repeat lumbar puncture is performed to document clearing of the CSF and appropriate response to antibiotic administration. Epistaxis following removal of packing can occur, although it is quite rare. This most often resolves spontaneously. Persistent epistaxis can be investigated by endoscopy performed by an ear, nose, and throat physician. If a superficial bleeding vessel is identified, it can be treated appropriately.

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With more significant hemorrhage uncontrollable or unidentifiable by the ear, nose, and throat physician, angiography and potential embolization can be performed (eg, with significant bleeding from a sphenopalatine artery), although this has rarely been performed. Inadvertent removal of nasal packing in the immediate perioperative period can occur but is difficult because of the tightly fitting and lowprofile nature of the materials used. If this occurs, however, we have generally managed this expectantly. We have not had to reinsert the original packing material, although occasionally light, intranasal packing with gauze can be performed if necessary.

Conclusions Pituitary tumors are commonly encountered, and patients with these lesions comprise a heterogeneous population of patients with different subsets possessing their own unique, inherent characteristics that merit individualized attention. Surgical management of pituitary tumors has advanced considerably over time from its early beginnings to its present highly refined but continually evolving state. Fortunately, the postoperative care of patients following pituitary surgery has also enjoyed significant advancements. The perioperative assessment of patients undergoing pituitary surgery aims to collect all available clinical, radiologic, pathologic, neurologic, ophthalmologic, and radiologic data to guide a given patient’s care. Patients with nonfunctioning tumors and those with Cushing’s disease, acromegaly, or thyrotoxicosis secondary to functioning tumors have specific perioperative considerations that must be attended to. In addition, postoperative care of patients following pituitary surgery may occur in the context of a dynamic functional state of the hypothalamic–pituitary–end organ axis. Knowledge of potential complications, their management, and strategies for avoidance are important components of postoperative care. Transsphenoidal surgery can be performed successfully and safely and critically depends on excellent postoperative care.

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