Oral intake is controlled by the thirst center, located in which of the following cerebral areas?

Journal Article

Mark J. Hannon,

1Academic Department of Endocrinology (M.J.H., F.M.F., M.S., A.A., C.J.T.), Beaumont Hospital and Royal College of Surgeons in Ireland Medical School, Dublin 9, Ireland

Search for other works by this author on:

Received:

22 November 2011

Accepted:

23 January 2012

Published:

22 February 2012

• 
  PDF
• Split View
• • Article contents
  • Figures & tables
  • Video
  • Audio
  • Supplementary Data

• Cite

  Cite

  Mark J. Hannon, Francis M. Finucane, Mark Sherlock, Amar Agha, Christopher J. Thompson, Disorders of Water Homeostasis in Neurosurgical Patients, The Journal of Clinical Endocrinology & Metabolism, Volume 97, Issue 5, 1 May 2012, Pages 1423–1433, https://doi.org/10.1210/jc.2011-3201

  Close

• • Email
  • Twitter
  • Facebook
  • More

Close

Navbar Search Filter Microsite Search Term Search

Abnormalities of salt and water balance are common in neurosurgical patients. In the national neurosciences center at our hospital, approximately 70% of endocrine consults relate to such problems. They occur either as a consequence of the underlying neurological lesion or because of the subsequent neurosurgical intervention and postoperative treatment. Hyponatremia is the commonest electrolyte abnormality seen in neurosurgical units, occurring in up to 10–50% of patients, according to the underlying condition. It is more common after subarachnoid hemorrhage (SAH), traumatic brain injury (TBI), and hypophysectomy for pituitary tumors than it is in other neurosurgical conditions such as spinal disease (1). Although diabetes insipidus is common in the acute phase following neurosurgical intervention, it is usually transient in nature, and most patients are able to maintain normal plasma sodium concentrations with oral hydration. Hypernatremia only occurs where fluid replacement is insufficient to keep up with water loss. The risk of insufficient fluid intake is higher in patients with cognitive impairment, impaired consciousness, and in the rare, but important condition of adipsic diabetes insipidus. In this review, we will explore the pathophysiology of disorders of salt and water homeostasis in neurosurgical patients and discuss a comprehensive clinical approach to diagnosing and managing these important problems.

Regulation of Water Homeostasis

In health, plasma osmolality is very closely regulated by the sophisticated interaction of the secretion and action of the antidiuretic hormone arginine vasopressin (AVP) and the sensation of thirst, which promotes water intake. Changes in plasma osmolality are detected by specialized neurons, which in mammalian species are located in the circumventricular organs of the anterior hypothalamus. When plasma osmolality rises, these neurons depolarize and, via the nucleus medianus, stimulate the synthesis of AVP in the magnocellular neurons of the paraventricular and supraoptic nuclei and the parvocellular neurons of the paraventricular nucleus. AVP is then transported in neurosecretory granules down the pituitary stalk, for storage in the posterior pituitary gland, and subsequent secretion into the systemic circulation. AVP release occurs rapidly after stimulation of the osmoreceptors. Plasma AVP binds to V2 receptors in the collecting ducts of the renal tubules, stimulating an intracellular cascade that leads to migration of vesicle-bound aquaporin-2 to the luminal membrane of the collecting duct (2). This renders the cells of the collecting duct permeable to water, allowing reabsorption of water from the urine into the blood, such that adequate urine concentration can occur. Simultaneously, the thirst center in the cerebral cortex is stimulated, promoting water intake. Thus, AVP-mediated restriction of water excretion combined with thirst-driven water intake leads to an increase in plasma water and normalization of plasma osmolality (3). Regulation of this homeostatic process is so precise that plasma osmolality rarely varies by more than 2%, once access to water is unrestricted (4). The mechanisms controlling water balance are summarized in Fig. 1. In the neurosurgical context, disturbances in water balance are usually related to either overproduction of AVP leading to excess water retention and the syndrome of inappropriate antidiuretic hormone release (SIADH) or underproduction leading to excess water loss and diabetes insipidus.

Fig. 1.

Normal regulation of salt and water balance.

Diabetes Insipidus

Diabetes insipidus occurs commonly in the acute phase of neurosurgical insults such as pituitary surgery, SAH, and TBI. The onset is usually 1 to 3 d after such an insult and manifests principally as hypotonic polyuria (5). Many neurosurgical patients have a diminished consciousness level because of brain injury, postoperative cerebral irritation, cerebral edema, sedation for airway management, or a combination of these factors. Hence, their awareness of thirst or their ability to respond to it by ingesting fluids may be diminished or absent, and they are vulnerable to the development of severe hypernatremia. It is therefore particularly important to monitor the urine output and daily plasma sodium concentrations in these patients.

Diabetes insipidus in TBI

Diabetes insipidus is a well-recognized complication of TBI (6, 7). Polyuria occurs immediately after brain injury in 22% of cases, nearly always within the first 2–3 d (8, 9). The great majority of cases resolve spontaneously, and cross-sectional studies of long-term survivors of TBI report low rates of chronic diabetes insipidus. A recent retrospective study reported chronic diabetes insipidus in only 3% of survivors of TBI (10). The only study to have formally assessed neurohypophyseal function, using water deprivation tests in 102 long-term survivors of TBI, identified diabetes insipidus in 7% of patients, a relatively high prevalence compared with other studies (11). Of note, five of seven affected patients in this study had been undiagnosed and untreated because AVP deficiency produced only partial diabetes insipidus. It is likely that in the absence of formal diagnostic assessment of AVP secretion, many patients with “subclinical” diabetes insipidus remain undiagnosed and maintain normal plasma osmolality through increased water intake. Retrospective case note analysis in the same patient cohort revealed that 22% had developed diabetes insipidus during their original hospital admission and that the risk of this occurring was closely related to the severity of head trauma (as assessed by the Glasgow Coma Scale) and the presence of cerebral edema on imaging studies.

In a prospective study of 50 patients followed sequentially at 0, 6, and 12 months after TBI, 13 (26%) developed diabetes insipidus within 10 d of head injury; nine of the 13 patients recovered within 6 months, and another patient recovered by 12 months (12). Some patients who developed diabetes insipidus in the acute phase after trauma became hypernatremic due to inadequate fluid intake, which appeared to be related to altered conscious level and cognitive impairment rather than thirst deficits per se. Although adipsic diabetes insipidus (where there is an absence of thirst in the context of normal consciousness and cognitive function) has been reported after TBI (13) in studies where thirst has been formally assessed in TBI patients, the normal process is for thirst to remain intact (11).

Diabetes insipidus in pituitary tumors

Diabetes insipidus is so rare in pituitary adenomas before surgical intervention that when it occurs in a patient with a pituitary mass, it should prompt clinical suspicion of granulomatous disease, craniopharyngioma, or another even rarer underlying diagnosis. However, diabetes insipidus does occur commonly in the early phase after pituitary surgery, with reported rates of 4–80% (13–17). Most cases are transient, with reported rates of permanent diabetes insipidus of 0.5 to 15% (13, 16–18). The risk varies according to tumor size, such that in our unit, 14% of patients undergoing microadenomectomy and 30% of those undergoing suprasellar adenomectomy developed diabetes insipidus (19). It is almost the universal policy to cover patients undergoing hypophysectomy with parenteral hydrocortisone to prevent acute hypocortisolemia, and there is evidence that those patients receiving high-dose hydrocortisone for this purpose have a higher rate of postoperative diabetes insipidus (20); this may be because free water excretion is impaired in the presence of cortisol deficiency (21), meaning that patients on an insufficient dose of parenteral hydrocortisone postoperatively may have their diabetes insipidus effectively “masked” by the presence of relative cortisol deficiency. There are some data suggesting higher rates of diabetes insipidus with ACTH-secreting tumors (22), although this is not a universal finding (23) and is contrary to our own clinical experience.

If diabetes insipidus occurs in association with a pituitary tumor, it usually results from disturbance of the hypothalamus, pituitary stalk, or the posterior pituitary gland intraoperatively. Although transection of the stalk almost always produces permanent diabetes insipidus, spontaneous resolution can occur in distal dissections of the stalk (24). Postoperative diabetes insipidus characteristically occurs within 2 d of surgery, with the abrupt onset of hypotonic polyuria and thirst (if the patient is not unconscious or cognitively impaired). Most cases resolve by the third postoperative day, with a minority progressing to persistent diabetes insipidus (25). Rarely, a triphasic response is observed, with initial diabetes insipidus resolving after 3 or 4 d, followed by a period of hyponatremia and antidiuresis, before permanent diabetes insipidus occurs up to 2 wk postoperatively. The triphasic response is discussed in more detail in Management of diabetes insipidus.

The onset of hypotonic polyuria in diabetes insipidus after pituitary surgery is invariably accompanied by the sensation of thirst. In this context, water intake is usually sufficient to replace urinary losses, such that normal plasma sodium concentrations are maintained. Systematic evaluations have shown that thirst appreciation persists in patients with diabetes insipidus after hypophysectomy (19, 26), although we have recently reported a case of adipsic diabetes insipidus after extensive surgery for a large, suprasellar prolactinoma (27).

In contrast to pituitary tumors, abnormalities of thirst are well documented in craniopharyngiomas in adult and pediatric series, both at presentation and postoperatively. Furthermore, diabetes insipidus is much more common after surgical removal of craniopharyngiomas than after removal of pituitary adenomas. In our experience, 90% of craniopharyngioma patients developed postoperative diabetes insipidus (19, 28).

Interestingly, although radiotherapy is a recognized cause of anterior pituitary dysfunction when used as a treatment for both pituitary and nonpituitary intracranial tumors, diabetes insipidus does not seem to occur (29). Data from relatively small studies implicate different radiosensitivities in adenohypophyseal compared with neurohypophyseal tissue as an explanation for this discrepancy (30).

Diabetes insipidus in SAH

Diabetes insipidus occurs acutely in 15% of cases of SAH and in one small study was associated with worse prognosis and increased mortality (31). In survivors of SAH, diabetes insipidus is usually transient, but can persist up to 3 months after discharge in up to 8% of patients (32). The incidence may be higher after hemorrhage from anterior communicating artery aneurysms, putatively because of a higher risk of compromising perfusion of the anterior hypothalamus with these lesions. Hypovolemia is a particular concern in patients with SAH because it can predispose to cerebral vasospasm and worsen outcomes. Hence, it is important to ensure adequate fluid replacement to maintain blood volume and pressure, particularly in obtunded patients in whom volitional fluid intake to replace urinary losses is significantly reduced. Surgical clipping of anterior communicating artery aneurysms can predispose to the development of adipsic diabetes insipidus, with numerous case reports documenting this association (33). Adipsic diabetes insipidus is described in detail later in this review in a separate section.

Diabetes insipidus occurs less commonly in other neurosurgical conditions, such as intracerebral hemorrhage, subdural hematoma, and brain abscess. An important clinical caveat is that in patients with adrenal insufficiency, diabetes insipidus may only arise after steroid replacement is initiated because the ability to excrete water is dependent to some extent on adequate adrenal function. Particular vigilance in relation to electrolyte levels and fluid balance is therefore mandatory in the neurosurgical patient on initiation of hydrocortisone replacement therapy.

Management of diabetes insipidus

Several diagnostic approaches to the diagnosis of diabetes insipidus in neurosurgical patients have been proposed. We find that the criteria suggested by Seckl et al. (25) for diagnosis in the early postoperative period can be applied with equal diagnostic value in all acute neurosurgical conditions. After the exclusion of confounding causes for polyuria, such as steroid-induced hyperglycemia, mannitol, or other diuretic therapy, a plasma sodium greater than 145 mmol/liter in the presence of hypotonic (urine osmolality <300 mOsm/kg) polyuria (>300 ml/h for 2 consecutive hours or >3 liters/d) is robust evidence of acute diabetes insipidus and warrants urgent and decisive action.

Most cases of diabetes insipidus in neurosurgical patients are transient, so our current practice is to administer a single parenteral (sc or im) dose of desmopressin, which is active for 6 to 12 h. Further injections are only administered if there is evidence of persisting or recurrent polyuria. It is important to diagnose and, where necessary, treat associated hypokalemia, which can cause renal resistance to desmopressin therapy. Regular desmopressin is only prescribed if there is persistent polyuria for more than 48 h. Withdrawal of desmopressin before discharge from hospital is helpful in identifying those patients who have recovered secretion of endogenous vasopressin. Advice should be given to patients and caregivers regarding the small risk of a triple phase response manifesting after discharge, such that should symptoms suggestive of hyponatremia develop, an urgent electrolyte assessment should be done and appropriate therapy initiated without delay. This is particularly relevant given the modern trend for rapid discharge from hospital after pituitary surgery or coiling of Berry aneurysms. If diabetes insipidus is persistent, oral desmopressin can be given in a dose that is proportional to the degree of vasopressin deficiency; in those with partial diabetes insipidus, a single nocturnal dose of 0.2 mg is usually sufficient to prevent nocturia, whereas those with more severe disease may need a dose of 0.2 mg twice or even thrice daily to prevent symptoms. Our own policy is to advise those patients with persistent diabetes insipidus to omit one desmopressin dose once a week to allow a hypotonic diuresis to occur and prevent the development of dilutional hyponatremia.

It is important to continue to monitor the plasma sodium concentration after starting treatment with desmopressin. Rarely, diabetes insipidus may progress to the SIADH, with the consequent development of hyponatremia. Continued desmopressin therapy in this context is inappropriate because it would exacerbate the fall in plasma sodium concentration. The underlying mechanistic basis for the transient development of SIADH after diabetes insipidus is putatively related to the release of prestored AVP from damaged neurohypophyseal cells, leading to antidiuresis and hyponatremia. Thereafter, these damaged neurons undergo gliosis and lose their functional capacity to synthesize or release AVP; permanent diabetes insipidus then ensues. This relatively unusual occurrence of initial diabetes insipidus followed by SIADH and then permanent diabetes insipidus is referred to as the triple phase response. In our experience, this occurs in less than 5% of cases of neurosurgical diabetes insipidus. Nonetheless, awareness of this potential complication is critical to avoid harming patients who have transient excess circulating AVP with additional exogenous AVP therapy.

Adipsic diabetes insipidus

Adipsic diabetes insipidus, where the absence of thirst confounds the deranged water balance, is relatively uncommon but has been reported in neurosurgical patients (19, 27, 28). This tends to occur in patients who have had clipping of an anterior communicating artery aneurysm and results from the surgery rather than the bleed itself (33, 34). It is seen less frequently now that the interventional trend is towards coiling rather than clipping of aneurysms. Studies in patients with adipsic diabetes insipidus have demonstrated dramatic rises in plasma AVP concentrations in response to nonosmotic stimuli such as hypotension and apomorphine, indicating that the supraoptic and paraventricular nuclei and the posterior pituitary were intact in these patients. These results indicate that the lesion in anterior communicating artery aneurysm patients with adipsic diabetes insipidus affects the osmoreceptors in the anterior hypothalamus (28) but spares the supraoptic and paraventricular nuclei. The vascular supply to this area is derived from small arterioles originating from the anterior communicating artery. Some reported cases of adipsic diabetes insipidus after clipping of anterior communicating artery aneurysms described radiological evidence of infarction of the anterior hypothalamus. It is likely therefore that surgical disruption of the blood supply to the osmoreceptors infarcts these nuclei, leading to failure to generate thirst or to secrete AVP in response to hyperosmolarity, despite retaining the ability to synthesize and secrete AVP in response to other nonosmotic stimuli such as hypotension (28). Thus, the most physiologically important control of water homeostasis is lost. Adipsic diabetes insipidus has also been described in patients with TBI, pituitary adenomas (27), and in non-neurosurgical conditions such as toluene exposure (28, 35, 36) and neurosarcoidosis (28, 37).

In contrast, patients with craniopharyngioma, who commonly have either adipsia or polydipsia in association with diabetes insipidus, seem to sustain more widespread hypothalamic injury, particularly after extensive surgery for large, suprasellar tumors. Adipsic diabetes insipidus after surgery for craniopharyngioma is accompanied by loss of baroregulated AVP release and is often also accompanied by other abnormalities suggestive of hypothalamic dysfunction, including polyphagia, obesity, and sleep apnea (28). Clearly, the maintenance of electrolyte and fluid balance in these patients poses particular challenges and requires expert input. Data published from our unit show a high morbidity and mortality associated with adipsic diabetes insipidus. Patients have high rates of hypothalamic abnormalities such as sleep apnea, seizures, disturbances of temperature regulation, and polyphagia leading to obesity. The sleep apnea is particularly important because we have reported deaths due to respiratory failure in this group (28). The other key clinical issue is that the development of hypernatremic dehydration is associated with thromboembolic complications consequent to the increased hematocrit. The identification of adipsic diabetes insipidus should therefore stimulate awareness of these other morbidities. If patients with adipsic diabetes insipidus are admitted to hospital for any reason, the clinical imperatives are the prevention of hypernatremic dehydration and prophylaxis against thromboembolism. We recommend the administration of fixed-dose desmopressin to limit fluid loss, with the variable infusion of hypotonic fluids to slowly reduce plasma sodium concentrations to the normal range and maintain them therein. We would also routinely use low molecular weight heparin for thromboembolic prophylaxis.

Hyponatremia

Hyponatremia is the commonest electrolyte abnormality in neurosurgical patients, occurring in up to 50% of cases depending on the underlying diagnosis (38). The incidence is higher in patients with SAH, TBI, intracranial tumors, and after hypophysectomy compared with those with spinal lesions (1) (Table 1). Neurosurgical patients are more prone to develop symptoms related to hyponatremia because of additional cerebral irritation related to their underlying pathology, raised intracranial pressure, or because of associated surgery. Additionally, in the critical care setting, many will have acidosis, hypoxia, or hypercapnia, at least in the acute phase of their illness. Therefore, some complications, such as hyponatremic seizures, may occur at higher plasma sodium concentrations than usual (39). Data from a number of studies suggest that hyponatremia is associated with increased duration of hospital stay, although not necessarily increased mortality (38–41); indeed, it appears that hypernatremia may be just as strong a predictor of mortality in neurosurgical patients (28). Although hyponatremia is an important determinant of outcome, its relevance in the neurosurgical setting is sometimes overlooked (42).

Table 1.

Incidence of significant hyponatremia (plasma sodium <130 mmol/liter) in patients admitted to the neurosurgical unit in Beaumont Hospital between January 2002 and September 2003

[Adapted from M. Sherlock et al.: Incidence and pathophysiology of severe hyponatraemia in neurosurgical patients. Postgrad Med J 85:171–175, 2009 (1), with permission. © The Fellowship of Postgraduate Medicine.]

Table 1.

Incidence of significant hyponatremia (plasma sodium <130 mmol/liter) in patients admitted to the neurosurgical unit in Beaumont Hospital between January 2002 and September 2003

[Adapted from M. Sherlock et al.: Incidence and pathophysiology of severe hyponatraemia in neurosurgical patients. Postgrad Med J 85:171–175, 2009 (1), with permission. © The Fellowship of Postgraduate Medicine.]

The differential diagnosis of hyponatremia is broad, as summarized in Table 2. The key to establishing the correct diagnosis is an accurate assessment of the volume status of the patient, to determine whether they are hypo-, eu-, or hypervolemic. Hypovolemia is most reliably diagnosed when central venous pressure (CVP) monitoring is available, but hypotension, tachycardia, and raised plasma urea are also useful parameters to consider. Hypervolemia leads to an elevated CVP and is also characterized by clinical signs of fluid overload, including peripheral and pulmonary edema as well as a positive fluid balance. In order for the diagnosis of SIADH to be made, the patient must be clinically euvolemic. Other essential diagnostic criteria for SIADH are summarized in Table 3. Of particular importance is the exclusion of adrenocortical and thyroid insufficiency, both of which can occur acutely in the neurosurgical setting (38). However, thyroid function tests in acute illnesses are often misleading because of the development of sick euthyroid syndrome. Our approach is to perform thyroid function tests only where it is felt that organic thyroid pathology is a significant possibility.

Table 3.

Essential diagnostic criteria for SIADH (76)

Table 3.

Essential diagnostic criteria for SIADH (76)

Table 2.

Differential diagnosis of neurosurgical hyponatremia

Table 2.

Differential diagnosis of neurosurgical hyponatremia

Differentiating between SIADH and cerebral salt-wasting syndrome (CSWS) poses specific diagnostic challenges; because the same insults can give rise to both problems, they are associated with significant additional morbidity, and yet the management of the two conditions is very different. SIADH occurs in a wide range of intracranial lesions, including subarachnoid, intracerebral and subdural hemorrhage, aneurysms, tumors, TBI, and space-occupying lesions. In the classical presentation, diagnosis is relatively straightforward, with a characteristic pattern of worsening hyponatremia coinciding with falling blood urea concentrations and diminished urine output secondary to antidiuresis. Some authors believe that a significant proportion of hyponatremic neurosurgical patients are incorrectly diagnosed with SIADH, when in fact they have CSWS, particularly in the context of SAH (43–45).

CSWS was first proposed in 1950 by Peters et al. (46), who described three neurological patients who developed hyponatremia and volume depletion in association with diuresis and natriuresis and who had normal hypothalamic-pituitary-adrenal axis function. They hypothesized that the cerebral disease directly attenuated renal sympathetic innervation, causing natriuresis and diuresis, with resultant hyponatremia and blood volume depletion. The notion that a separate entity to SIADH could cause neurosurgical hyponatremia was only revisited 30 yr later, when in 1981 a report emerged of 12 unselected hyponatremic patients who had SAH, intracranial aneurysm, and TBI (47). Hyponatremia developed in association with volume depletion, natriuresis, and inappropriate urine concentration in 10 of these patients. The authors concluded that the presence of hypovolemia precluded a diagnosis of SIADH and proposed cerebral salt wasting as the underlying pathology.

The concept of CSWS was not universally accepted, with some speculating that the diuresis and natriuresis simply represented escape from antidiuresis and that the underlying biochemical problem remained excess ADH secretion. However, two subsequent studies provided evidence for a syndrome which was distinct from SIADH (48, 49). In the first study, eight of 21 patients developed natriuresis and a negative sodium balance before the development of hyponatremia during recovery from SAH. All of these patients had a decline in body weight, whereas in six of them, plasma volume fell by at least 10%. In the second study, hyponatremia developed in 21 patients in association with natriuresis and low CVP measurements, and patients responded favorably to volume and sodium repletion with iv saline.

Nonetheless, others continue to challenge the existence of cerebral salt wasting, citing a lack of clear evidence of volume depletion and renal salt wasting in reported cases (50). Our own data would support the view expressed by others (51) that cerebral salt wasting is a relatively uncommon cause of neurosurgical hyponatremia. In a retrospective survey of 1698 patients admitted to our neurosurgical unit over a 20-month period, we found that SIADH was responsible for 62% of cases of hyponatremia (plasma sodium <130 mmol/liter), as outlined in Table 4 (1). Cerebral salt wasting could only be diagnosed with confidence in 5% of cases (a considerable proportion of patients were given a diagnosis of hypovolemic hyponatremia due to insufficient CVP data; as a result, CSWS may have been underdiagnosed). We do not agree, however, that cerebral salt wasting simply represents an escape from antidiuresis. The dramatic diuresis and natriuresis in cerebral salt wasting is very different from the modest responses observed in escape from antidiuresis in SIADH secondary to pulmonary disease, for example. In addition, we have also followed prospectively a number of patients admitted to our neurosurgical unit who have developed hyponatremia. We have found that there is an initial rise in plasma natriuretic peptides in these patients, which leads to natriuresis, diuresis, contraction of blood volume, and a secondary rise in plasma AVP, possibly due to baroreceptor stimulation. A typical biochemical profile from a representative patient (a 39-yr-old male who was admitted after TBI) is shown in Table 5. It is clear that the peak plasma concentrations of brain natriuretic peptide and atrial natriuretic peptide preceded the plasma sodium nadir, whereas the peak plasma AVP levels occurred later, coinciding with the nadir CVP reading.

Table 4.

Etiology of 187 cases of hyponatremia (plasma sodium <130 mmol/liter) documented in 1698 admissions to Beaumont Hospital neurosurgical unit between January 2002 and September 2003

DDAVP, 1-Desamino-8-d-AVP; SSRI, selective serotonin reuptake inhibitors. [Adapted from M. Sherlock et al.: Incidence and pathophysiology of severe hyponatraemia in neurosurgical patients. Postgrad Med J 85:171–175, 2009 (1), with permission. © The Fellowship of Postgraduate Medicine.]

Table 4.

Etiology of 187 cases of hyponatremia (plasma sodium <130 mmol/liter) documented in 1698 admissions to Beaumont Hospital neurosurgical unit between January 2002 and September 2003

DDAVP, 1-Desamino-8-d-AVP; SSRI, selective serotonin reuptake inhibitors. [Adapted from M. Sherlock et al.: Incidence and pathophysiology of severe hyponatraemia in neurosurgical patients. Postgrad Med J 85:171–175, 2009 (1), with permission. © The Fellowship of Postgraduate Medicine.]

Table 5.

Sequential changes in hormonal, urine volume, urine sodium, and CVP parameters in a 39-yr-old male patient who developed hyponatremia after admission with TBI

BNP, Brain natriuretic peptide; ANP, atrial natriuretic peptide; pNa+, plasma sodium.

Table 5.

Sequential changes in hormonal, urine volume, urine sodium, and CVP parameters in a 39-yr-old male patient who developed hyponatremia after admission with TBI

BNP, Brain natriuretic peptide; ANP, atrial natriuretic peptide; pNa+, plasma sodium.

Hyponatremia in TBI

Approximately 15% of patients recovering from TBI develop hyponatremia in the acute recovery phase (52). In over 80% of these cases, hyponatremia is due to SIADH. The natural history is for resolution of hyponatremia after recovery from the acute insult (11). Although ACTH deficiency occurs in approximately 15% of head injury cases in the acute recovery phase (8), hyponatremia is only rarely due to glucocorticoid deficiency in this context (11). Notwithstanding this, cases of ACTH-deficiency-induced acute severe hyponatremia after TBI have been described, and so this diagnosis must always be borne in mind (53). Indications that a patient with a biochemical picture otherwise typical of SIADH might be ACTH deficient include hypoglycemia and hypotension. Chronic hyponatremia after head injury is rare and is often due to drugs such as carbamazepine, rather than the injury itself. Prospective data on a cohort of 50 patients with TBI showed that 14% had acute hyponatremia, but none had hyponatremia at 6 or 12 months after TBI (12). More recent data from our unit (unpublished) has again shown that approximately 15% of patients develop hyponatremia immediately afterward, but this almost never progresses to chronicity and is much less common than hypernatremia in this patient cohort.

Hyponatremia after SAH

In a cohort of over 300 patients recovering from SAH, 57% developed mild hyponatremia (<135 mmol/liter), whereas 20% developed moderate to severe hyponatremia (<130 mmol/liter) (39). In contrast to other studies, this large series identified SIADH as the commonest cause of hyponatremia, occurring in 62% of cases; however, the study was dependent on a retrospective case note analysis, and full ascertainment of all essential diagnostic information was not available in all patients. Hyponatremia was unrelated to the anatomical site of hemorrhage but was more common after intervention with either craniotomy and clipping or neuroradiological coiling. Surprisingly, hyponatremia was not any more common after surgical intervention compared with endovascular coiling. Although there was no statistically significant increase in mortality in the hyponatremic group, their duration of hospital stay was doubled. The finding that SIADH was the commonest cause of hyponatremia in patients with SAH contrasted with a number of smaller prospective studies documenting elevated atrial natriuretic peptide concentrations after SAH. However, not all patients in these studies developed hyponatremia, despite the elevation in natriuretic peptide concentrations (54–56). SAH has recently been implicated in the development of hypopituitarism. A recent systematic review suggested that 47% of patients showed evidence of anterior hypopituitarism after SAH (57). Specific studies have shown that up to 40% of patients develop some degree of ACTH deficiency between 12 and 72 months after hemorrhage (58, 59). Rates of hypopituitarism tend to be higher in patients who are tested sooner after SAH, with up to 50% having some degree of pituitary insufficiency if tested within 3 months of their hemorrhage (32). In relation to the immediate postoperative period, fewer studies have formally tested ACTH secretion, relying instead on basal cortisol levels (60, 61). Recently completed prospective work from our own unit has aimed to determine the relative contribution of adrenal insufficiency to the etiology of hyponatremia immediately after SAH. Analysis of 100 patients with nontraumatic aneurysmal SAH showed that 49% developed acute hyponatremia, with the majority of cases of hyponatremia (approximately 70%) after SAH caused by SIADH; however, up to 10% of cases may have been due to acute glucocorticoid insufficiency. Most patients (approximately 72%) developed hyponatremia in the first 3 d after SAH, and none had persistent hyponatremia when followed up at 6 months after discharge (62).

Management of hyponatremia in the neurosurgical patient

As always, the key to managing hyponatremia in this setting is an accurate diagnosis of the underlying cause. Although we consider assessment of blood volume status to be of vital importance, this is often difficult in the neurosurgical setting. The cardinal clinical parameters that are usually used to estimate blood volume, such as blood pressure and blood urea, are more difficult to interpret in this setting. Hypotension may be secondary to sepsis or glucocorticoid deficiency rather than hypovolemia. Blood pressure may be elevated by iv fluids, inotropes, or raised intracranial pressure in a patient who remains volume deplete. Measurement of CVP is an excellent surrogate of circulating blood volume, but it is relatively invasive and so is not appropriate to all clinical scenarios.

We find a useful strategy is to construct a detailed flow chart, collating changes in plasma sodium in relation to changes in blood urea, blood pressure, and hourly fluid balance calculations. Where hyponatremia coincides with a progressive increase in urine volume, a fall in blood pressure, and a rise in blood urea (in the absence of diuretic therapy), the diagnosis of cerebral salt wasting should be considered. In contrast, falling plasma sodium concentration in a patient who is euvolemic and has a falling blood urea and low urine output would suggest a diagnosis of SIADH, which would then need to be confirmed by fulfilling the criteria in Table 3.

The diagnosis of ACTH deficiency in an acutely ill patient with hyponatremia is often far from straightforward. We routinely measure a 0900 h plasma cortisol concentration in all hyponatremic patients who have biochemical and blood volume data to suggest SIADH. In the presence of hypotension and/or hypoglycemia, we would empirically commence iv glucocorticoids pending laboratory analyses. In those in whom there is no strong clinical suspicion of ACTH deficiency, glucocorticoid treatment is only commenced if the 0900 h cortisol is less than 18 μg/dl (500 nmol/liter). It should be noted, however, that the diurnal variation of plasma cortisol is usually lost in critical illness, and so cortisol measurement may not necessarily have to take place at 0900 h. It is our policy to measure cortisol at 0900 h because this is the time point for which we have the best control values. A recent review advocated a random plasma cortisol cutoff of approximately 15 μg/dl (414 nmol/liter) for the diagnosis of ACTH deficiency in intensive care patients (with normal serum binding proteins) (63). The Critical Care Medicine Taskforce has recommended a very conservative random total plasma cortisol cutoff of 9.94 μg/dl (276 nmol/liter) for the formation of this diagnosis (64). However, this recommendation is intended to cover all intensive care patients, and there is a lack of normative data in neurosurgical patients upon which to base a higher cutoff. In addition, it seems unlikely that plasma cortisol concentrations of 18–25 μg/dl (500–700 nmol/liter) are sufficiently severe to contribute to the development of hyponatremia. In dynamic pituitary testing, these levels would be considered a “pass.” All patients diagnosed with ACTH deficiency in the acute phase of their neurosurgical illness are reassessed with dynamic pituitary function testing between 3 and 6 months into their recovery period, because prospective studies in TBI patients indicate that acute hormone deficiencies tend to recover by this stage (12, 65). Long-term glucocorticoid therapy is only continued in patients who fail dynamic pituitary testing.

Treatment with iv sodium chloride solution is the specific therapy for cerebral salt wasting (66). It is often necessary to give large volumes to keep up with urinary losses. It is important to avoid misdiagnosing SIADH with “escape” as cerebral salt wasting because treatment with iv saline may worsen diuresis and natriuresis in SIADH and escape. Because CSWS is invariably self-limiting, aggressive treatment with iv fluids is usually only required for a few days (67). However, some believe that the majority of cases of cerebral salt wasting are a consequence of inappropriate treatment of SIADH with iv saline (51, 68). In the context of SAH, for example, there is often a tendency to aggressively hydrate patients because of concerns about cerebral vasospasm, despite no evidence that aggressive hydration prevents this (69, 70). Arguably a better strategy to prevent vasospasm would be the maintenance of adequate blood pressure, using pressors if necessary, given that the treatment of choice for SIADH is fluid restriction. Although the instinct for endocrinologists in this setting is to limit fluid intake to less than 1200 ml/d, neurosurgeons might be more inclined to perceive the contraction of extracellular fluid volume as a trigger for vasoconstriction and worsening cerebral edema. Often, limitation of fluid intake to 2 liters of iv 0.9% sodium chloride daily is as much as neurosurgeons are prepared to contemplate. Indeed, this approach is not without merit because half of patients with SIADH will respond favorably to 2 liters/d of normal saline (71).

These are complex issues that again require multidisciplinary expertise, with a tailored approach to the management of individual patients, and there are no published data on the treatment of hyponatremia in this setting. In those with acute, severe, symptomatic hyponatremia, hypertonic saline is indicated. Other treatments that have been used in SIADH have no evidence base in the neurosurgical setting. Demeclocycline, although well established in the management of SIADH, has an unpredictable response rate and erratic onset of action; it can also lead to nephrotoxicity and a photosensitive skin rash. Lithium is an even more problematic treatment for SIADH, with very erratic response rates and a wide range of side effects. Urea has been shown to be effective (72) but is not widely available and is very unpalatable. Sodium tablets, fludrocortisone, and loop diuretics have all been used for SIADH in this setting, but there is little evidence base and no physiological rationale for their use. The recent availability of selective vasopressin-2 receptor antagonists (the vaptan class of drugs) represents an exciting new development in the management of SIADH. Although no data are yet available in the neurosurgical setting, the vaptans have shown that they can induce a gradual, well-controlled rise in plasma sodium to normal levels and maintain them there without any risk of central pontine myelinolysis (73, 74). Further studies in neurosurgical patients are needed before this class of medications can be recommended as first-line therapy for SIADH in this setting. Of note, most cases of neurosurgical hyponatremia are self limiting and do not require long-term treatment (75).

Conclusions

It is clear that disorders of water homeostasis are among the most important metabolic disturbances in neurosurgical patients. Diabetes insipidus is usually relatively straightforward to diagnose and treat, but care must be taken to discontinue treatment if and when the condition resolves. The clinician must also be able to rapidly recognize adipsic diabetes insipidus because these patients can progress rapidly to profound hypernatremia, intravascular volume depletion, coma, and death.

With regard to hyponatremia, the majority of cases seen in patients with TBI are due to SIADH, but in SAH the situation is much less straightforward. The differentiation between SIADH, CSWS, and acute ACTH deficiency poses specific diagnostic challenges and is based primarily on excellent clinical acumen and the correct interpretation of basic biochemical values. Because the consequences of inappropriate therapy for hyponatremia are profound, it is imperative that a systematic and well-informed approach is taken to the diagnosis and management of disordered salt and water balance in these patients.

Acknowledgments

Disclosure Summary: None of the authors have any conflict of interest to declare.

Abbreviations

 

• AVP

 

• CSWS

  cerebral salt-wasting syndrome

 

• CVP

 

• SAH

 

• SIADH

  syndrome of inappropriate antidiuretic hormone release

 

• TBI

References

1.

Sherlock

M

2009

Incidence and pathophysiology of severe hyponatraemia in neurosurgical patients.

Postgrad Med J

85

:

171

–

175

2.

Knoers

NV

1995

The clinical importance of the urinary excretion of aquaporin-2.

N Engl J Med

332

:

1575

–

1576

3.

Thompson

CJ

1986

The osmotic thresholds for thirst and vasopressin release are similar in healthy man.

Clin Sci (Lond)

71

:

651

–

656

4.

Robertson

GL

1982

Neurogenic disorders of osmoregulation.

Am J Med

72

:

339

–

353

5.

Thompson

CJ

1989

Polyuric states in man.

Baillieres Clin Endocrinol Metab

3

:

473

–

497

6.

Griffin

JM

1976

Diabetes insipidus caused by craniofacial trauma.

J Trauma

16

:

979

–

984

7.

Notman

DD

1980

Permanent diabetes insipidus following head trauma: observations on ten patients and an approach to diagnosis.

J Trauma

20

:

599

–

602

8.

Agha

A

2004

Neuroendocrine dysfunction in the acute phase of traumatic brain injury.

Clin Endocrinol (Oxf)

60

:

584

–

591

9.

Wong

MF

1998

Diabetes insipidus in neurosurgical patients.

Ann Acad Med Singapore

27

:

340

–

343

10.

Boughey

JC

2004

Diabetes insipidus in the head-injured patient.

Am Surg

70

:

500

–

503

11.

Agha

A

2004

Posterior pituitary dysfunction after traumatic brain injury.

J Clin Endocrinol Metab

89

:

5987

–

5992

12.

Agha

A

2005

The natural history of post-traumatic neurohypophysial dysfunction.

Eur J Endocrinol

152

:

371

–

377

13.

Kreutzer

J

2001

Surgical management of GH-secreting pituitary adenomas: an outcome study using modern remission criteria.

J Clin Endocrinol Metab

86

:

4072

–

4077

14.

Ciric

I

1997

Complications of transsphenoidal surgery: results of a national survey, review of the literature, and personal experience.

Neurosurgery

40

:

225

–

236

;

discussion 236–237

15.

Dumont

AS

2005

Postoperative care following pituitary surgery.

J Intensive Care Med

20

:

127

–

140

16.

Partington

MD

1994

Pituitary adenomas in childhood and adolescence. Results of transsphenoidal surgery.

J Neurosurg

80

:

209

–

216

17.

Semple

PL

1999

Complications in a contemporary series of patients who underwent transsphenoidal surgery for Cushing's disease.

J Neurosurg

91

:

175

–

179

18.

Black

PM

1987

Incidence and management of complications of transsphenoidal operation for pituitary adenomas.

Neurosurgery

20

:

920

–

924

19.

Smith

D

2004

Abnormal regulation of thirst and vasopressin secretion following surgery for craniopharyngioma.

Clin Endocrinol (Oxf)

61

:

273

–

279

20.

Rajaratnam

S

2003

Hydrocortisone dose and postoperative diabetes insipidus in patients undergoing transsphenoidal pituitary surgery: a prospective randomized controlled study.

Br J Neurosurg

17

:

437

–

442

21.

Green

HH

1970

On the role of antidiuretic hormone in the inhibition of acute water diuresis in adrenal insufficiency and the effects of gluco- and mineralocorticoids in reversing the inhibition.

J Clin Invest

49

:

1724

–

1736

22.

Nemergut

EC

2005

Predictors of diabetes insipidus after transsphenoidal surgery: a review of 881 patients.

J Neurosurg

103

:

448

–

454

23.

Kristof

RA

2002

Endocrinological outcome following first time transsphenoidal surgery for GH-, ACTH-, and PRL-secreting pituitary adenomas.

Acta Neurochir (Wien)

144

:

555

–

561

24.

Nishizawa

S

2006

Spontaneous resolution of diabetes insipidus after pituitary stalk sectioning during surgery for large craniopharyngioma. Endocrinological evaluation and clinical implications for surgical strategy.

Neurol Med Chir (Tokyo)

46

:

126

–

134

25.

Seckl

JR

1987

Neurohypophyseal peptide function during early postoperative diabetes insipidus.

Brain

110

:

737

–

746

26.

Thompson

CJ

1987

Thirst in diabetes insipidus: clinical relevance of quantitative assessment.

Q J Med

65

:

853

–

862

27.

Sherlock

M

2006

Adipsic diabetes insipidus following pituitary surgery for a macroprolactinoma.

Pituitary

9

:

59

–

64

28.

Crowley

RK

2007

Clinical insights into adipsic diabetes insipidus: a large case series.

Clin Endocrinol (Oxf)

66

:

475

–

482

29.

Borson-Chazot

F

2006

Pituitary deficiency after brain radiation therapy.

Ann Endocrinol (Paris)

67

:

303

–

309

30.

Nishioka

H

2001

Histological changes in the hypofunctional pituitary gland following conventional radiotherapy for adenoma.

Histopathology

38

:

561

–

566

31.

Qureshi

AI

2002

Prognostic significance of hypernatremia and hyponatremia among patients with aneurysmal subarachnoid hemorrhage.

Neurosurgery

50

:

749

–

755

;

discussion 755–756

32.

Aimaretti

G

2004

Traumatic brain injury and subarachnoid haemorrhage are conditions at high risk for hypopituitarism: screening study at 3 months after the brain injury.

Clin Endocrinol (Oxf)

61

:

320

–

326

33.

McIver

B

1991

Adipsic hypothalamic diabetes insipidus after clipping of anterior communicating artery aneurysm.

BMJ

303

:

1465

–

1467

34.

Baylis

PH

1980

Plasma vasopressin response to hypertonic saline infusion to assess posterior pituitary function.

J R Soc Med

73

:

255

–

260

35.

Gurewitz

R

1986

Recurrent hypothermia, hypersomnolence, central sleep apnea, hypodipsia, hypernatremia, hypothyroidism, hyperprolactinemia and growth hormone deficiency in a boy—treatment with clomipramine.

Acta Endocrinol Suppl (Copenh)

279

:

468

–

472

36.

Teelucksingh

S

1991

Hypothalamic syndrome and central sleep apnoea associated with toluene exposure.

Q J Med

78

:

185

–

190

37.

Tabuena

RP

2004

Diabetes insipidus from neurosarcoidosis: long-term follow-up for more than eight years.

Intern Med

43

:

960

–

966

38.

Fraser

JF

2006

Hyponatremia in the neurosurgical patient: epidemiology, pathophysiology, diagnosis, and management.

Neurosurgery

59

:

222

–

229

39.

Sherlock

M

2006

The incidence and pathophysiology of hyponatraemia after subarachnoid haemorrhage.

Clin Endocrinol (Oxf)

64

:

250

–

254

40.

Stelfox

HT

2008

The epidemiology of intensive care unit-acquired hyponatraemia and hypernatraemia in medical-surgical intensive care units.

Crit Care

12

:

R162

41.

Waikar

SS

2009

Mortality after hospitalization with mild, moderate, and severe hyponatremia.

Am J Med

122

:

857

–

865

42.

Finucane

FM

2006

Cerebral aneurysms.

N Engl J Med

355

:

2703

43.

Betjes

MG

2002

Hyponatremia in acute brain disease: the cerebral salt wasting syndrome.

Eur J Intern Med

13

:

9

–

14

44.

Isotani

E

1994

Alterations in plasma concentrations of natriuretic peptides and antidiuretic hormone after subarachnoid hemorrhage.

Stroke

25

:

2198

–

2203

45.

Tomida

M

1998

Plasma concentrations of brain natriuretic peptide in patients with subarachnoid hemorrhage.

Stroke

29

:

1584

–

1587

46.

Peters

JP

1950

A salt-wasting syndrome associated with cerebral disease.

Trans Assoc Am Physicians

63

:

57

–

64

47.

Nelson

PB

1981

Hyponatremia in intracranial disease: perhaps not the syndrome of inappropriate secretion of antidiuretic hormone (SIADH).

J Neurosurg

55

:

938

–

941

48.

Sivakumar

V

1994

Management of neurosurgical patients with hyponatremia and natriuresis.

Neurosurgery

34

:

269

–

2674

;

discussion 274

49.

Wijdicks

EF

1985

Volume depletion and natriuresis in patients with a ruptured intracranial aneurysm.

Ann Neurol

18

:

211

–

216

50.

Oh

MS

1999

Cerebral salt-wasting syndrome. We need better proof of its existence.

Nephron

82

:

110

–

114

51.

Singh

S

2002

Cerebral salt wasting: truths, fallacies, theories, and challenges.

Crit Care Med

30

:

2575

–

2579

52.

Moro

N

2007

Hyponatremia in patients with traumatic brain injury: incidence, mechanism, and response to sodium supplementation or retention therapy with hydrocortisone.

Surg Neurol

68

:

387

–

393

53.

Agha

A

2005

Post-traumatic hyponatraemia due to acute hypopituitarism.

QJM

98

:

463

–

464

54.

McGirt

MJ

2004

Correlation of serum brain natriuretic peptide with hyponatremia and delayed ischemic neurological deficits after subarachnoid hemorrhage.

Neurosurgery

54

:

1369

–

1373

;

discussion 1373–1374

55.

Sayama

T

2000

High incidence of hyponatremia in patients with ruptured anterior communicating artery aneurysms.

Neurol Res

22

:

151

–

155

56.

Tsubokawa

T

2003

[Clinical significance of natriuretic peptides in patients with aneurysmal subarachnoid hemorrhage].

No To Shinkei

55

:

953

–

960

57.

Schneider

HJ

2007

Hypothalamopituitary dysfunction following traumatic brain injury and aneurysmal subarachnoid hemorrhage: a systematic review.

JAMA

298

:

1429

–

1438

58.

Kreitschmann-Andermahr

I

2004

Prevalence of pituitary deficiency in patients after aneurysmal subarachnoid hemorrhage.

J Clin Endocrinol Metab

89

:

4986

–

4992

59.

Tanriverdi

F

2007

High risk of pituitary dysfunction due to aneurysmal subarachnoid haemorrhage: a prospective investigation of anterior pituitary function in the acute phase and 12 months after the event.

Clin Endocrinol (Oxf)

67

:

931

–

937

60.

Mangieri

P

2003

Evaluation of pituitary and thyroid hormones in patients with subarachnoid hemorrhage due to ruptured intracranial aneurysm.

Arq Neuropsiquiatr

61

:

14

–

19

61.

Savaridas

T

2004

Cortisol dynamics following acute severe brain injury.

Intensive Care Med

30

:

1479

–

1483

62.

Hannon

MJ

Hyponatraemia in aneurysmal subarachnoid haemorrhage is due to the syndrome of inappropriate antidiuresis and acute glucocorticoid deficiency

.

Program of the 93rd Annual Meeting of The Endocrine Society

,

Boston, MA

,

2011

(Abstract OR16-5)

63.

Arafah

BM

2006

Hypothalamic pituitary adrenal function during critical illness: limitations of current assessment methods.

J Clin Endocrinol Metab

91

:

3725

–

3745

64.

Marik

PE

2008

Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: consensus statements from an international task force by the American College of Critical Care Medicine.

Crit Care Med

36

:

1937

–

1949

65.

Agha

A

2005

The natural history of post-traumatic hypopituitarism: implications for assessment and treatment.

Am J Med

118

:

1416

66.

Revilla-Pacheco

FR

2005

Cerebral salt wasting syndrome in patients with aneurysmal subarachnoid hemorrhage.

Neurol Res

27

:

418

–

422

67.

Cerdà-Esteve

M

2008

Cerebral salt wasting syndrome: review.

Eur J Intern Med

19

:

249

–

254

68.

Carlotti

AP

2001

A method to estimate urinary electrolyte excretion in patients at risk for developing cerebral salt wasting.

J Neurosurg

95

:

420

–

424

69.

Muench

E

2007

Effects of hypervolemia and hypertension on regional cerebral blood flow, intracranial pressure, and brain tissue oxygenation after subarachnoid hemorrhage.

Crit Care Med

35

:

1844

–

1851

70.

Rinkel

GJ

2004

Circulatory volume expansion therapy for aneurysmal subarachnoid haemorrhage.

Cochrane Database Syst Rev

4

:

CD000483

71.

Musch

W

1998

Treating the syndrome of inappropriate ADH secretion with isotonic saline.

QJM

91

:

749

–

753

72.

Soupart

A

2007

Treatment of hyponatraemia by urea decreases risks of brain complications in rats. Brain osmolyte contents analysis.

Nephrol Dial Transplant

22

:

1856

–

1863

73.

Schrier

RW

2006

Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia.

N Engl J Med

355

:

2099

–

2112

74.

Berl

T

2010

Oral tolvaptan is safe and effective in chronic hyponatremia.

J Am Soc Nephrol

21

:

705

–

712

75.

Agha

A

2006

Anterior pituitary dysfunction following traumatic brain injury (TBI).

Clin Endocrinol (Oxf)

64

:

481

–

488

76.

Verbalis

JG

1989

Hyponatraemia.

Baillieres Clin Endocrinol Metab

3

:

499

–

530

Copyright © 2012 by The Endocrine Society

Copyright © 2012 by The Endocrine Society

Citations

Views

Altmetric

Email alerts

More on this topic

Related articles in PubMed

Citing articles via

• Latest

• Most Read

• Most Cited

More from Oxford Academic

Which hormone stimulates the thirst mechanism?

Which of the following electrolytes is the primary determinant of extracellular fluid ECF osmolality?

What is the main determinant of extracellular fluid osmolarity?

Which of the following electrolytes are the main determinants of extracellular volume?