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Postoperative Period. Endocrine related. • Abnormalities of ADH (diabetes insipidus and the syndrome of inappropriate ADH secretion). Non-endocrine related.
Journal of Intensive Care Medicine

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:

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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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Dumont et al

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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Dumont et al

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


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].

Journal of Intensive Care Medicine 20(3); 2005

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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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Dumont et al

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