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Sodium abnormalities in the neurosurgical patient
Current Anaesthesia & Critical Care (2002) 13, 153^158 c 2002 Elsevier Science Ltd. All rights reserved. doi:10.1054/cacc.394, available online at http://www.idealibrary.com on
FOCUS ON: NEUROINTENSIVE CARE
Sodium abnormalities in the neurosurgical patient T. Bookallil* and R. Ruggierw *John Hunter Hospital, Lookout Road, New Lambton Hts 2305, Australia and wAtkinson Morley’s Hospital, Copse Hill, Wimbledon SW20 0NE, UK
KEYWORDS sodium, hyponatremia, hypernatremia, diabetes insipidus, atrial natriuretic factor, vasopressin
Summary The most frequently seen electrolyte disturbance in patients with central nervous system lesions involves sodium.This usually results from disturbed water regulation.Hyponatraemia and hypo-osmolalityis found commonly in the neurosurgical population, particularly following subarachnoid haemorrhage.If inadequately managed, it can produce signi¢cant morbidity and mortality. Assessment of the clinical presentation and subsequent management requires a thorough understanding of the underlying pathophysiology. A diuretic and naturetic state develops with profound loss of both salt and water. Cerebral salt wasting is a clinical entity found in the neurosurgical intensive care unit.Its pathophysiologyis stillunclear, however, atrialnatriuretic factorisprobably involved. It is important that it is di¡erentiated from the less-common syndrome of inappropriate antidiuretic hormone because £uid restriction in cerebral salt wasting can resultin extracellular volume depletion and subsequentcerebral hypoperfusion, predisposing to ischaemic de¢cit with vasospasm. Avoidance of hypovolaemia is essential, and initially, the treatment is to replace the urine output with isotonic saline.However, if the urinary sodium concentration exceeds 150 mmol/l, then hypertonic (3%) saline becomes necessary. Symptomatic hyponatraemia is a medical emergency and should be managed aggressively in the intensive care unit. Rapid correction of hyponatraemia is safe provided the increase in serum sodium is not greater than 25 mmol/l in 48 h. Diabetes insipidus should be suspected in any neurosurgical patient who is polyuric. The ¢ndings are increased serum sodium and osmolality, and high volume, dilute urine. Careful £uid management is required, replacing urine output, and considering the horc 2002 Elsevier Science Ltd. mone analogue DDAVP when urinary losses exceed 250 ml/h. All rights reserved.
HYPONATRAEMIA Hyponatraemia is a clinical entity found frequently within a neurosurgical intensive care unit. The neuroendocrine axis plays a signi¢cant part in the regulation of sodium metabolism.This article outlines the multiple factors that can produce hyponatraemia, placing emphasis on the contention arising over the existence of cerebral salt wasting (CSW) as opposed to the syndrome of inappropriate antidiuretic hormone (SIADH). There is also debate arising over the relationship between the age and gender of the patient, degree and time of onset of hyponatraemia and the development of clinical features and long-term morbidity and mortality. Further address is given regarding the contribution of too rapid correction of hyponatraemia and the development of clinical Correspondence to: TB. 0953-7112/02/$ - see front matter
morbidity and mortality relating to central pontine myelinosis. Hyponatraemia occurs within the general hospital population with an incidence of 1%.1 It occurs more commonly within the neurosurgical population associated with numerous pathologies including head injury, intracranial infections, tumours and haemorrhage. The incidence in patients with subarachnoid haemorrhage has been reported to be as high as 30%.2 While hyponatraemia is de¢ned as a serum sodium concentration less than 135 mmol/l, clinical features are seldom seen when the serum sodium is greater than 125 mmol/l and are generally seen with a sodium less than 120 mmol/l.3 The clinical features of hyponatraemia relate to its e¡ects on the central nervous system, primarily the development of cerebral oedema, raised intracranial pressure and cerebral hypoxia.
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PATHOPHYSIOLOGICAL MECHANISMS Hyponatraemia is the result of a net gain in free water or net loss of monovalent cations (sodium and potassium) at a concentration greater than that of plasma. Hyponatraemia in this discussion is de¢ned as hypotonic (hypo-osmolar). It should be di¡erentiated from isotonic hyponatremia (seen in hyperproteinaemia and hyperlipidaemia) and hypertonic (seen in hyperglycaemia, excessive administration of mannitol, sorbitol and other impermeant solutions). Gain of free water means that free water intake minus insensible losses (normally 600 ml/24 h) exceeds free water loss, where free water loss equals the di¡erence between urine output and osmolar clearance. Osmolar clearance equals the volume of urine required to excrete the daily solute load, at an osmolality equivalent to plasma.4 The ability of the kidney to produce a net gain of free water depends on the delivery of solute to the loop of Henle and distal convoluted tubule, the adequate function of these segments and the action of antidiuretic hormone. Loss of monovalent cations at a concentration su⁄cient to decrease plasma concentration occurs less commonly. The causes can be divided into renal salt wasting and non-renal salt wasting. Antidiuretic hormone (ADH) is produced in the hypothalamus and stored in the posterior pituitary gland. It is released in response to increased plasma osmolality and decreased plasma volume. Its release is also moderated by drugs, stress, ageing and disease states.The main actions of ADH are antidiuresis, vasoconstriction and enhancement of coagulation. Its antidiuretic function, which directly regulates free water excretion, is mediated via V2 receptors in the collecting ducts of the kidney. In binding to the receptor, it activates adenylate cyclase, producing cAMP, which leads to the opening of microtubular passages, via protein kinases, allowing the £ow of water along osmotic gradients out of the tubular lumen. Serum osmolality represents the number of particles in a given mass of water, usually expressed as millimoles per kilogram of water. These particles can be described as either osmotically active, meaning they do not readily cross a semi-permeable membrane, or osmotically inactive which readily cross. Examples of osmotically active particles in extracellular £uid are sodium, glucose and mannitol. Examples of osmotically inactive particles are urea and alcohol.The signi¢cance of this point is that osmotically inactive particles readily di¡use down osmotic gradients between intra- and extracellular £uid causing minimal £uid shifts, whereas osmotically active particles create an osmotic gradient between £uid compartments along which there are £uid shifts across semipermeable membranes. Tonicity describes the relative concentra-
CURRENT ANAESTHESIA & CRITICAL CARE
tion of osmotically active particles, and this is behind the body’s regulatory mechanisms for water homeostasis. The brain regulates water retention and tonicity of the body’s £uid compartments via a negative feedback system involving the thirst response and ADH secretion with its subsequent action on the kidney. The thirst response is not well understood, but is thought to involve an increase in extracellular tonicity and subsequent decrease in intracellular volume. Also involved are neuroendocrine re£exes, ADH, angiotensin II and pharyngeal distension. Secretion of ADH increases, in response to shrinkage of neuroendocrine cells in the hypothalamus, as a result of increased extracellular tonicity. An increase in 3% above normal plasma osmolality (from 285 to 294 Mosm/kg), provided this represents an increase in osmotically active particles, induces the maximal thirst response and maximal secretion of ADH resulting in maximally concentrated urine of up to 4 times the concentration of plasma. Therefore, the development of a di¡erential between the tonicity of intra- and extracellular compartments will result in movements of solutes and water between the compartments to re-establish equilibrium. So where there is hypotonic extracellular £uid, there will be an initial in£ux of water into the cells.This will result in stimulation of the Na/K ATPase pump, which is involved in the extrusion of sodium and potassium from the cells. If these mechanisms are adequate, then osmotic equilibrium can be obtained between compartments, without swelling of the cells. If not, there will be cellular swelling. Most organ systems are able to tolerate cellular swelling to a degree, however, the central nervous system is very sensitive, and an increased intracellular volume of as little as 5% can be associated with signi¢cant morbidity and mortality.5 The brain has several mechanisms to respond to increased cellular swelling and subsequent raised intracranial pressure. Firstly, as discussed above, there is extrusion of osmotically active cations. Secondly, there is a increase in resorption of cerebrospinal £uid and cerebral blood £ow. If, however, there is persistent uncorrected hyponatraemia and extracellular hypotonicity, there will be continued cellular swelling and progressive increase in intracranial pressure. This will lead to pressure necrosis and tentorial herniation leading to respiratory depression, hypoxia and further cerebral ischaemia. The development of brain injury as a sequel to hyponatraemia is not, as previously suspected, determined by the extent or rate of onset of hyponatraemia. It has, however, been demonstrated to be associated with systemic hypoxaemia, pre-existing liver disease, alcoholism, menstruating women and structural brain defects.6 Causes of hyponatraemia are listed in Table 1.
SODIUM ABNORMALITIES IN THE NEUROSURGICAL PATIENT
Table 1 Causes of hyponatraemia Loss of monovalent cations K Renal K Idiosyncratic response to thiazide diuretics K Renal tubular acidosis K Adrenal insu⁄ciency K Salt losing nephritis K Cerebral salt wasting K
Non-renal Emesis K Diarrhoea K Burns K Pancreatitis K
Gain of free water K Iatrogenic K Inappropriate administration of hypotonic £uids K Drugs K Renal failure K Cardiac failure K Hepatic failure Neurogenic polydipsia Syndrome of inappropriate ADH
CLINICAL PRESENTATIONOF HYPONATRAEMIA Clinical features of hyponatraemia are rarely seen with serum sodium concentration greater than 125 mmol/l. All features are related to the central e¡ects of hyponatraemia. Early features include lethargy, cramps, headache, nausea and vomiting. Advanced features include decreased responsiveness to painful and verbal stimuli, delirium and incontinence. End stage features include seizures, coma, respiratory arrest and death.7
CEREBRAL SALT WASTING AND SYNDROMEOF INAPPROPRIATE ADH Cerebral salt wasting (CSW) was ¢rst described in19508 as a renal loss of sodium during intracranial disease resulting in hyponatraemia and decreased extracellular volume. However, following the identi¢cation of the syndrome of inappropriate antidiuretic hormone (SIADH) it was, for many years, considered a misnomer for SIADH or at best, a rare clinical entity. In SIADH, which is frequently associated with intracranial pathology,9 there is physiologically an inappropriate increase in ADH activity, leading to increased renal resorption of water and a dilutional hyponatraemia. However, recent evidence suggests that CSW is a clinical syndrome distinct from SIADH. The signi¢cance of this di¡erentiation relates to the management of these separate entities. For example, a patient with CSW who is salt and water depleted, if treated by water restriction (the standard treatment
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for asymptomatic SIADH), would become further volume depleted, which may increase the possibility of cerebral infarction, as has been shown in patients with subarachnoid haemorrhage.10 On the other hand, managing a patient with SIADH with volume replacement and salt (the standard treatment for CSW), may exacerbate cerebral oedema. Currently, we do not understand completely the pathophysiological mechanisms by which intracranial pathology leads to CSW. It is felt that neural and hormonal mechanisms play a role. It has been postulated that blood-born natriuretic factors are involved, and experiments have shown natriuresis following intraventricular infusion of hypertonic saline in rats with denervated kidneys.11 Atrial natriuretic peptide (ANP) was ¢rst found in atrial muscle, where its release is mediated by stretch receptors. Its physiological e¡ects are diuresis, natriuresis, vasodilation and suppression of the renin ^angiotensin system.12 While it has been isolated in the brain, its concentration there is 10 000 times less than in the heart,13 and the brain is thought to regulate ANP release via the autonomic nervous system. Several studies have shown that there is a correlation between intracranial pathology and elevated ANP.14,15 However, there are con£icting reports on the relationship between serum ANP levels and sodium levels, and while involved in the pathophysiology of CSW, ANP does not explain the whole picture. Di¡erentiating SIADH from CSW in the clinical setting can be di⁄cult. In addition, there can be concomitant SIADH and CSW. In subarachnoid haemorrhage, an initial elevation in ADH and ANP may be followed by a persistence of ANP and a clinical picture of CSW. In the neurosurgical ICU setting, in addition to intracranial pathology, there are other sources for elevated ADH (e.g. pain, stress, drugs) which further complicate the picture. In both SIADH and CSW there is hyponatremia, decreased serum osmolality, inappropriately normal or high urine osmolality, high urine sodium (420 mmol), however in CSW this can exceed 200 mmol. They di¡er in several measurable ways. Extracellular volume in CSW is low but normal or high in SIADH. Extracellular volume status can be assessed by simple measures such as daily weights, strict £uid balance and measuring postural changes in blood pressure and heart rate. Laboratory investigations such as hematocrit, serum protein and urea nitrogen:creatinine ratio are subject to multiple variables and are of limited use for determining extracellular volume in the critical care setting. Invasive measurement of central venous pressure and pulmonary capillary wedge pressure, have also been used. It has been suggested that measurement of serum urate and fractional excretion of urate16 can be useful. Initially serum urate is low and fractional excretion of urate is high in SIADH and CSW. However, following £uid restriction and correction of hyponatraemia, both are
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normal in SIADH but unchanged in CSW.This method is limited because it requires the challenge of £uid restriction and poses the risk of cerebral infarction in patients with subarachnoid haemorrhage.
MANAGEMENTOF HYPONATRAEMIA The asymptomatic patient need not be managed aggressively. In assessing the asymptomatic patient, regard must be made to the underlying mechanism (e.g. drugs, hormones) and this should be corrected if possible. If the patient is euvolaemic or hypervolaemic, then water restriction can be imposed (usually1l/24 h).This will bring about an increase in serum sodium, rarely exceeding 1.5 mmol/24 h.17 If, however, the patient is salt depleted (with or without volume depletion), then appropriate replacement of salt and water (either orally or intravenously) is necessary, according to the volume status and serum sodium of the patient. When the patient is symptomatic, more aggressive treatment is necessary.This usually involves the use of hypertonic saline (usually 3% or 514 mmol/l). A loop diuretic may be added if the patient is volume overloaded. Isotonic saline is considered where the patient is volume depleted. The aim of treatment should be to increase the serum sodium concentration by 1mmol/h. The end-points are either that the patient becomes asymptomatic, serum sodium reaches 130 mmol/l or that the total increase in serum sodium is 25 mmol. Serum sodium should not increase by more than 25 mmol in the ¢rst 48 h.18,19 Ideally, the patient should be monitored in the ICU setting, with appropriate supportive measures. Serum electrolytes should be measured every 2 h. Calculating the infusion rate to achieve the above rate of increase in serum sodium requires assessment of the total body water. This can be made by considering the patient’s age, gender, body habitus and weight. Generally, males have higher total body water as a percentage of weight than females. Total body water as a percentage decreases with age. The mean adult total body water is approximately 50%. Therefore, for a 70 kg male whose serum sodium is 110 mmol, to correct this over 24 h to 130 mmol, his total body water can be estimated to be 70 0:5 ¼ 35 l: Therefore, sodium required for correction is 35ð130 110Þ ¼ 700 mmol: Therefore, rate of infusion of hypertonic saline (514 mmol/l) is 700=514=24ðhÞ ¼ 56 ml=h: This rate should be adjusted according to measured serum sodium.
OUTCOMES OF HYPONATRAEMIA As stated above, the development of serious morbidity and mortality from hyponatraemia does not appear to be related to the degree or duration of hyponatraemia, but is instead related to other factors such as hypoxia and female sex hormones. By understanding the role of Na/K ATPase in the adaptive mechanism of cells to hyponatraemia, we can better appreciate the role of hypoxia in the development of brain damage in hyponatraemia. The generation of ATP within cells via oxidative phosphorylation requires oxygen.Therefore, hypoxaemia leads to decreased e¡ectiveness of cellular extrusion of sodium via the Na/K ATPase pump. Subsequently, there is increased intracellular sodium, increased cellular swelling leading to raised intracranial pressure (ICP).20 If this is allowed to progress, the end result is seizures, coma and respiratory arrest. Subsequent hypoxia, if inadequately managed, leads to a self-perpetuating situation and death rapidly ensues.21 Hypoxia also increases the production of ADH. In addition to its systemic e¡ects to increase hyponatraemia, ADH acts on the AQP4 channels in the neural and glial cells of the brain,22 which allows the in£ux of water thereby worsening cellular swelling. Additionally, it is thought that ADH may cause cerebral hypoperfusion by increasing vascular tone, further exacerbating tissue hypoxia.23 The role of sex hormones in the development of brain damage is thought to be related to the inhibitory e¡ect of both progesterone and oestrogen on the Na/K ATPase pump.24 In addition, it has been suggested that sex hormones increase the circulating levels of ADH.25 A point of much conjecture is whether there is an association between the rapid correction of hyponatraemia and the development of central pontine myelinolysis. This is a distinct clinical entity diagnosed either radiologically with CTscan or MRI, or histopathologically by the presence in the pons of demyelinating lesions and the absence of extra pontine areas of myelinolysis. Central pontine myelinosis has been reported in animal testing to be associated with rapid correction of hyponatraemia. However, this association has not been clearly demonstrated in humans. In a retrospective analysis of reported cases of central pontine myelinosis associated with hyponatraemia, it was found that most cases did not ¢t the diagnostic criteria as the lesions were di¡use, often extrapontine, areas of demyelination. In virtually all cases, there was either an hypoxic episode, rapid correction of sodium greater than 25 mmol/l in 48 h, or concomitant systemic illnesses such as burns, alcoholism and liver disease, all of which are known to be associated with cerebral myelinolysis.26,27 It has been shown, prospectively, that rapid correction of hyponatraemia (mean 1.6 mmol/l/h) can be performed without morbidity or mortality.18
SODIUM ABNORMALITIES IN THE NEUROSURGICAL PATIENT
HYPERNATRAEMIA Hypernatraemia (Table 2) is the result of net water loss relative to sodium loss. When considering neurosurgical intensive care, special consideration must be given to osmotic diuresis and diabetes insipidus. Mannitol is an osmotic diuretic, used in the management of an acute rise in intracranial pressure. Mannitol is a sugar alcohol of mannose and is administered as a 20% solution containing 549 mmol/l. It achieves its pharmacological e¡ect by increasing serum osmolality, thereby drawing water out of the swollen brain and decreasing intracranial pressure. In the kidney, mannitol is ¢ltered freely at the glomerulus, but there is no tubular reabsorption.This produces an osmotic load, which draws water out. The increased £ow of ¢ltrate through the proximal tubule leads to increased load-dependent reabsorption of sodium in the distal tubule and increased excretion of potassium. The net result is water loss, increased serum sodium and osmolality and decreased potassium.
DIABETES INSIPIDUS Diabetes insipidus (Table 3) is characterized by polyuria and polydipsia. It may be accompanied by elevated serum sodium and osmolality, if water intake is inadequate to cover losses.The urine is typically dilute with an osmolality of 50 ^150 mmol/kg. Diabetes insipidus can be either neurogenic or nephrogenic.28 The neurogenic causes all involve disruption of the hypothalamus and decreased production of ADH. If the cause of diabetes insipidus is neurogenic, it will respond to DDAVP; however, nephrogenic diabetes insipidus will not. The remainder of this discussion refers only to neurogenic diabetes insipidus. The typical time of onset of diabetes insipidus is 1^3 days following the initial insult (usually trauma or surgery).The duration depends on the nature and reversibility of the pathology. For example, it is common to see transient diabetes insipidus (lasting approximately 1
Table 2 Causes of hypernatraemia Iatrogenic K Inappropriate £uid therapy Excessive insensible losses K Emesis K Diarrhoea K Sweating Excessive renallosses K Osmotic diuresis K Diabetes insipidus K Renal failure
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Table 3 Causes of diabetes insipidus Neurogenic K Trauma K Cerebrovascular disease K Neoplasia K Neurosurgery K Raised ICP K Idiopathic Nephrogenic K Chronic renal failure K Elevated calcium K Drugs e.g. lithium K Excess water intake
week) following neurosurgical procedures that involve traction of the pituitary stalk due to oedema of the hypothalamus. However, if there is destruction of the hypothalamus, diabetes insipidus will be permanent. The diagnosis should be suspected in any neurosurgical patient who is polyuric. Serum and urine electrolyte changes, as above, support the diagnosis.
MANAGEMENTOF DIABETES INSIPIDUS There are two components to management: 1. Maintain strict £uid balance. In the conscious patient, tolerating feeds, the patient’s oral intake may su⁄ce. However, in the obtunded patient, as often found in ICU, intravenous intake, calculated hourly according to urine output is necessary. Electrolytes should be monitored at least once daily. 2. DDAVP (desmopressin acetate) is a long-acting synthetic analogue of vasopressin. Its action is largely con¢ned to V2 receptors in the collecting ducts of the kidney. It should be considered, in diagnosed diabetes insipidus, when urine output exceeds 250 ml/h.29 Dosage is 1^2 mcg iv/sc or 10 mcg nasal spray as required. Care must be taken in patients who have developed acute diabetes insipidus because of the potentially variable and transient nature of this disturbance.
REFERENCES 1. Chung H M, Kluge R, Schrier R W, Anderson R J. Postoperative hyponatremia. A prospective study. Arch Intern Med 1986; 146(2): 333–336.
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2. Fox J L, Falik J L, Shalhoub R J. Neurosurgical hyponatremia: the role of inappropriate antidiuresis. J Neurosurg 1971; 34(4): 506– 514. 3. Arieff A I. Central nervous system manifestations of disordered sodium metabolism. Clin Endocrinol Metab 1984; 13(2): 269–294. 4. Fraser C L, Arieff A I. Epidemiology, pathophysiology, and management of hyponatremic encephalopathy. Am J Med 1997; 102(1): 67–77. 5. Arieff A I, Kozniewska E, Roberts T P, Vexler Z S, Ayus J C, Kucharczyk J. Age, gender, and vasopressin affect survival and brain adaptation in rats with metabolic encephalopathy. Am J Physiol 1995; 268(5 Part 2): R1143–R1152. 6. Ayus J C, Wheeler J M, Arieff A I. Postoperative hyponatremic encephalopathy in menstruant women. Ann Intern Med 1992; 117(11): 891–897. 7. Leaf A. The clinical and physiologic significance of the serum sodium concentration. N Engl J Med 1962; 267: 24–30, 77–85. 8. Peters J P, Welt L G, Sims E A H. A salt wasting syndrome associated with cerebral disease. Trans Assoc Am Physicians 1950; 63: 57–64. 9. Lester M C, Nelson P B. Neurological aspects of vasopressin release and the syndrome of inappropriate secretion of antidiuretic hormone. Neurosurgery 1981; 8(6): 735–740. 10. Wijdicks E F, Vermeulen M, Hijdra A, van Gijn J. Hyponatremia and cerebral infarction in patients with ruptured intracranial aneurysms: is fluid restriction harmful? Ann Neurol 1985; 17(2): 137–140. 11. Beasley D, Malvin R L, Mouw D R. CNS-induced natriuresis and renal hemodynamics in conscious rats. Am J Physiol 1983; 245(6): F763–F771. 12. Espiner E A. Physiology of natriuretic peptides. J Intern Med 1994; 235(6): 527–541. 13. de Bold A J, Borenstein H B, Veress A T, Sonnenberg H. A rapid and potent natriuretic response to intravenous injection of atrial myocardial extract in rats. Life Sci 1981 Jan; 28(1): 89–94. 14. Diringer M, Ladenson P W, Stern B J, Schleimer J, Hanley D F. Plasma atrial natriuretic factor and subarachnoid hemorrhage. Stroke 1988; 19(9): 1119–1124. 15. Yamaki T, Tano-oka A, Takahashi A, Imaizumi T, Suetake K, Hashi K. Cerebral salt wasting syndrome distinct from the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Acta Neurochir (Wien) 1992; 115(3–4): 156–162. 16. Maesaka JK, Gupta S, Fishbane S. Cerebral salt-wasting syndrome: does it exist? Nephron 1999; 82(2): 100–109. 17. Arieff A I. Management of hyponatraemia. Br Med J 1993; 307(6899): 305–308.
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18. Ayus J C, Krothapalli R K, Arieff A I. Treatment of symptomatic hyponatremia and its relation to brain damage. A prospective study. N Engl J Med 1987; 317(19): 1190–1195. 19. Ayus J C, Krothapalli R K, Armstrong D L, Norton H J. Symptomatic hyponatremia in rats: effect of treatment on mortality and brain lesions. Am J Physiol 1989; 257(1 Part 2): F18–F22. 20. Vexler Z S, Ayus J C, Roberts T P, Fraser C L, Kucharczyk J, Arieff A I. Hypoxic and ischemic hypoxia exacerbate brain injury associated with metabolic encephalopathy in laboratory animals. J Clin Invest 1994; 93(1): 256–264. 21. Arieff A I. Hyponatremia, convulsions, respiratory arrest, and permanent brain damage after elective surgery in healthy women. N Engl J Med 1986; 314(24): 1529–1535. 22. Jung J S, Bhat R V, Preston G M, Guggino W B, Baraban J M, Agre P. Molecular characterization of an aquaporin cDNA from brain: candidate osmoreceptor and regulator of water balance. Proc Natl Acad Sci USA 1994; 91(26): 13 052–13 056. 23. Okada K, Caramelo C, Tsai P, Schrier R W. Effect of inhibition of Na+/K(+)-adenosine triphosphatase on vascular action of vasopressin. J Clin Invest 1990; 86(4): 1241–1248. 24. Fraser C L, Swanson R A. Female sex hormones inhibit volume regulation in rat brain astrocyte culture. Am J Physiol 1994; 267(4 Part 1): C909–C914. 25. Share L. Control of vasopressin release: an old but continuing story. News Physiol Sci 1996; 11: 7–13. 26. Tien R, Arieff A I, Kucharczyk W, Wasik A, Kucharczyk J. Hyponatremic encephalopathy: is central pontine myelinolysis a component? Am J Med 1992; 92(5): 513–522. 27. Ayus J C, Arieff A I. Pathogenesis and prevention of hyponatremic encephalopathy. Endocrinol Metab Clin N Am 1993; 22(2): 425– 446. 28. Robertson G L, Aycinena P, Zerbe R L. Neurogenic disorders of osmoregulation. Am J Med 1982; 72(2): 339–353. 29. Cobb W E, Spare S, Reichlin S. Neurogenic diabetes insipidus: management with dDAVP (1-desamino-8-D arginine vasopressin). Ann Intern Med 1978; 88(2): 183–188.
FURTHER READING Harrigan M R.Cerebral salt wasting syndrome: a review. Neurosurgery 1996 38(1): 152^160. Maesaka J K,Gupta S, Fishbane S.Cerebral salt-wasting syndrome: does it exist? Nephron 1999; 82(2): 100 ^109.
FOCUS ON: NEUROINTENSIVE CARE
Sodium abnormalities in the neurosurgical patient T. Bookallil* and R. Ruggierw *John Hunter Hospital, Lookout Road, New Lambton Hts 2305, Australia and wAtkinson Morley’s Hospital, Copse Hill, Wimbledon SW20 0NE, UK
KEYWORDS sodium, hyponatremia, hypernatremia, diabetes insipidus, atrial natriuretic factor, vasopressin
Summary The most frequently seen electrolyte disturbance in patients with central nervous system lesions involves sodium.This usually results from disturbed water regulation.Hyponatraemia and hypo-osmolalityis found commonly in the neurosurgical population, particularly following subarachnoid haemorrhage.If inadequately managed, it can produce signi¢cant morbidity and mortality. Assessment of the clinical presentation and subsequent management requires a thorough understanding of the underlying pathophysiology. A diuretic and naturetic state develops with profound loss of both salt and water. Cerebral salt wasting is a clinical entity found in the neurosurgical intensive care unit.Its pathophysiologyis stillunclear, however, atrialnatriuretic factorisprobably involved. It is important that it is di¡erentiated from the less-common syndrome of inappropriate antidiuretic hormone because £uid restriction in cerebral salt wasting can resultin extracellular volume depletion and subsequentcerebral hypoperfusion, predisposing to ischaemic de¢cit with vasospasm. Avoidance of hypovolaemia is essential, and initially, the treatment is to replace the urine output with isotonic saline.However, if the urinary sodium concentration exceeds 150 mmol/l, then hypertonic (3%) saline becomes necessary. Symptomatic hyponatraemia is a medical emergency and should be managed aggressively in the intensive care unit. Rapid correction of hyponatraemia is safe provided the increase in serum sodium is not greater than 25 mmol/l in 48 h. Diabetes insipidus should be suspected in any neurosurgical patient who is polyuric. The ¢ndings are increased serum sodium and osmolality, and high volume, dilute urine. Careful £uid management is required, replacing urine output, and considering the horc 2002 Elsevier Science Ltd. mone analogue DDAVP when urinary losses exceed 250 ml/h. All rights reserved.
HYPONATRAEMIA Hyponatraemia is a clinical entity found frequently within a neurosurgical intensive care unit. The neuroendocrine axis plays a signi¢cant part in the regulation of sodium metabolism.This article outlines the multiple factors that can produce hyponatraemia, placing emphasis on the contention arising over the existence of cerebral salt wasting (CSW) as opposed to the syndrome of inappropriate antidiuretic hormone (SIADH). There is also debate arising over the relationship between the age and gender of the patient, degree and time of onset of hyponatraemia and the development of clinical features and long-term morbidity and mortality. Further address is given regarding the contribution of too rapid correction of hyponatraemia and the development of clinical Correspondence to: TB. 0953-7112/02/$ - see front matter
morbidity and mortality relating to central pontine myelinosis. Hyponatraemia occurs within the general hospital population with an incidence of 1%.1 It occurs more commonly within the neurosurgical population associated with numerous pathologies including head injury, intracranial infections, tumours and haemorrhage. The incidence in patients with subarachnoid haemorrhage has been reported to be as high as 30%.2 While hyponatraemia is de¢ned as a serum sodium concentration less than 135 mmol/l, clinical features are seldom seen when the serum sodium is greater than 125 mmol/l and are generally seen with a sodium less than 120 mmol/l.3 The clinical features of hyponatraemia relate to its e¡ects on the central nervous system, primarily the development of cerebral oedema, raised intracranial pressure and cerebral hypoxia.
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PATHOPHYSIOLOGICAL MECHANISMS Hyponatraemia is the result of a net gain in free water or net loss of monovalent cations (sodium and potassium) at a concentration greater than that of plasma. Hyponatraemia in this discussion is de¢ned as hypotonic (hypo-osmolar). It should be di¡erentiated from isotonic hyponatremia (seen in hyperproteinaemia and hyperlipidaemia) and hypertonic (seen in hyperglycaemia, excessive administration of mannitol, sorbitol and other impermeant solutions). Gain of free water means that free water intake minus insensible losses (normally 600 ml/24 h) exceeds free water loss, where free water loss equals the di¡erence between urine output and osmolar clearance. Osmolar clearance equals the volume of urine required to excrete the daily solute load, at an osmolality equivalent to plasma.4 The ability of the kidney to produce a net gain of free water depends on the delivery of solute to the loop of Henle and distal convoluted tubule, the adequate function of these segments and the action of antidiuretic hormone. Loss of monovalent cations at a concentration su⁄cient to decrease plasma concentration occurs less commonly. The causes can be divided into renal salt wasting and non-renal salt wasting. Antidiuretic hormone (ADH) is produced in the hypothalamus and stored in the posterior pituitary gland. It is released in response to increased plasma osmolality and decreased plasma volume. Its release is also moderated by drugs, stress, ageing and disease states.The main actions of ADH are antidiuresis, vasoconstriction and enhancement of coagulation. Its antidiuretic function, which directly regulates free water excretion, is mediated via V2 receptors in the collecting ducts of the kidney. In binding to the receptor, it activates adenylate cyclase, producing cAMP, which leads to the opening of microtubular passages, via protein kinases, allowing the £ow of water along osmotic gradients out of the tubular lumen. Serum osmolality represents the number of particles in a given mass of water, usually expressed as millimoles per kilogram of water. These particles can be described as either osmotically active, meaning they do not readily cross a semi-permeable membrane, or osmotically inactive which readily cross. Examples of osmotically active particles in extracellular £uid are sodium, glucose and mannitol. Examples of osmotically inactive particles are urea and alcohol.The signi¢cance of this point is that osmotically inactive particles readily di¡use down osmotic gradients between intra- and extracellular £uid causing minimal £uid shifts, whereas osmotically active particles create an osmotic gradient between £uid compartments along which there are £uid shifts across semipermeable membranes. Tonicity describes the relative concentra-
CURRENT ANAESTHESIA & CRITICAL CARE
tion of osmotically active particles, and this is behind the body’s regulatory mechanisms for water homeostasis. The brain regulates water retention and tonicity of the body’s £uid compartments via a negative feedback system involving the thirst response and ADH secretion with its subsequent action on the kidney. The thirst response is not well understood, but is thought to involve an increase in extracellular tonicity and subsequent decrease in intracellular volume. Also involved are neuroendocrine re£exes, ADH, angiotensin II and pharyngeal distension. Secretion of ADH increases, in response to shrinkage of neuroendocrine cells in the hypothalamus, as a result of increased extracellular tonicity. An increase in 3% above normal plasma osmolality (from 285 to 294 Mosm/kg), provided this represents an increase in osmotically active particles, induces the maximal thirst response and maximal secretion of ADH resulting in maximally concentrated urine of up to 4 times the concentration of plasma. Therefore, the development of a di¡erential between the tonicity of intra- and extracellular compartments will result in movements of solutes and water between the compartments to re-establish equilibrium. So where there is hypotonic extracellular £uid, there will be an initial in£ux of water into the cells.This will result in stimulation of the Na/K ATPase pump, which is involved in the extrusion of sodium and potassium from the cells. If these mechanisms are adequate, then osmotic equilibrium can be obtained between compartments, without swelling of the cells. If not, there will be cellular swelling. Most organ systems are able to tolerate cellular swelling to a degree, however, the central nervous system is very sensitive, and an increased intracellular volume of as little as 5% can be associated with signi¢cant morbidity and mortality.5 The brain has several mechanisms to respond to increased cellular swelling and subsequent raised intracranial pressure. Firstly, as discussed above, there is extrusion of osmotically active cations. Secondly, there is a increase in resorption of cerebrospinal £uid and cerebral blood £ow. If, however, there is persistent uncorrected hyponatraemia and extracellular hypotonicity, there will be continued cellular swelling and progressive increase in intracranial pressure. This will lead to pressure necrosis and tentorial herniation leading to respiratory depression, hypoxia and further cerebral ischaemia. The development of brain injury as a sequel to hyponatraemia is not, as previously suspected, determined by the extent or rate of onset of hyponatraemia. It has, however, been demonstrated to be associated with systemic hypoxaemia, pre-existing liver disease, alcoholism, menstruating women and structural brain defects.6 Causes of hyponatraemia are listed in Table 1.
SODIUM ABNORMALITIES IN THE NEUROSURGICAL PATIENT
Table 1 Causes of hyponatraemia Loss of monovalent cations K Renal K Idiosyncratic response to thiazide diuretics K Renal tubular acidosis K Adrenal insu⁄ciency K Salt losing nephritis K Cerebral salt wasting K
Non-renal Emesis K Diarrhoea K Burns K Pancreatitis K
Gain of free water K Iatrogenic K Inappropriate administration of hypotonic £uids K Drugs K Renal failure K Cardiac failure K Hepatic failure Neurogenic polydipsia Syndrome of inappropriate ADH
CLINICAL PRESENTATIONOF HYPONATRAEMIA Clinical features of hyponatraemia are rarely seen with serum sodium concentration greater than 125 mmol/l. All features are related to the central e¡ects of hyponatraemia. Early features include lethargy, cramps, headache, nausea and vomiting. Advanced features include decreased responsiveness to painful and verbal stimuli, delirium and incontinence. End stage features include seizures, coma, respiratory arrest and death.7
CEREBRAL SALT WASTING AND SYNDROMEOF INAPPROPRIATE ADH Cerebral salt wasting (CSW) was ¢rst described in19508 as a renal loss of sodium during intracranial disease resulting in hyponatraemia and decreased extracellular volume. However, following the identi¢cation of the syndrome of inappropriate antidiuretic hormone (SIADH) it was, for many years, considered a misnomer for SIADH or at best, a rare clinical entity. In SIADH, which is frequently associated with intracranial pathology,9 there is physiologically an inappropriate increase in ADH activity, leading to increased renal resorption of water and a dilutional hyponatraemia. However, recent evidence suggests that CSW is a clinical syndrome distinct from SIADH. The signi¢cance of this di¡erentiation relates to the management of these separate entities. For example, a patient with CSW who is salt and water depleted, if treated by water restriction (the standard treatment
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for asymptomatic SIADH), would become further volume depleted, which may increase the possibility of cerebral infarction, as has been shown in patients with subarachnoid haemorrhage.10 On the other hand, managing a patient with SIADH with volume replacement and salt (the standard treatment for CSW), may exacerbate cerebral oedema. Currently, we do not understand completely the pathophysiological mechanisms by which intracranial pathology leads to CSW. It is felt that neural and hormonal mechanisms play a role. It has been postulated that blood-born natriuretic factors are involved, and experiments have shown natriuresis following intraventricular infusion of hypertonic saline in rats with denervated kidneys.11 Atrial natriuretic peptide (ANP) was ¢rst found in atrial muscle, where its release is mediated by stretch receptors. Its physiological e¡ects are diuresis, natriuresis, vasodilation and suppression of the renin ^angiotensin system.12 While it has been isolated in the brain, its concentration there is 10 000 times less than in the heart,13 and the brain is thought to regulate ANP release via the autonomic nervous system. Several studies have shown that there is a correlation between intracranial pathology and elevated ANP.14,15 However, there are con£icting reports on the relationship between serum ANP levels and sodium levels, and while involved in the pathophysiology of CSW, ANP does not explain the whole picture. Di¡erentiating SIADH from CSW in the clinical setting can be di⁄cult. In addition, there can be concomitant SIADH and CSW. In subarachnoid haemorrhage, an initial elevation in ADH and ANP may be followed by a persistence of ANP and a clinical picture of CSW. In the neurosurgical ICU setting, in addition to intracranial pathology, there are other sources for elevated ADH (e.g. pain, stress, drugs) which further complicate the picture. In both SIADH and CSW there is hyponatremia, decreased serum osmolality, inappropriately normal or high urine osmolality, high urine sodium (420 mmol), however in CSW this can exceed 200 mmol. They di¡er in several measurable ways. Extracellular volume in CSW is low but normal or high in SIADH. Extracellular volume status can be assessed by simple measures such as daily weights, strict £uid balance and measuring postural changes in blood pressure and heart rate. Laboratory investigations such as hematocrit, serum protein and urea nitrogen:creatinine ratio are subject to multiple variables and are of limited use for determining extracellular volume in the critical care setting. Invasive measurement of central venous pressure and pulmonary capillary wedge pressure, have also been used. It has been suggested that measurement of serum urate and fractional excretion of urate16 can be useful. Initially serum urate is low and fractional excretion of urate is high in SIADH and CSW. However, following £uid restriction and correction of hyponatraemia, both are
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normal in SIADH but unchanged in CSW.This method is limited because it requires the challenge of £uid restriction and poses the risk of cerebral infarction in patients with subarachnoid haemorrhage.
MANAGEMENTOF HYPONATRAEMIA The asymptomatic patient need not be managed aggressively. In assessing the asymptomatic patient, regard must be made to the underlying mechanism (e.g. drugs, hormones) and this should be corrected if possible. If the patient is euvolaemic or hypervolaemic, then water restriction can be imposed (usually1l/24 h).This will bring about an increase in serum sodium, rarely exceeding 1.5 mmol/24 h.17 If, however, the patient is salt depleted (with or without volume depletion), then appropriate replacement of salt and water (either orally or intravenously) is necessary, according to the volume status and serum sodium of the patient. When the patient is symptomatic, more aggressive treatment is necessary.This usually involves the use of hypertonic saline (usually 3% or 514 mmol/l). A loop diuretic may be added if the patient is volume overloaded. Isotonic saline is considered where the patient is volume depleted. The aim of treatment should be to increase the serum sodium concentration by 1mmol/h. The end-points are either that the patient becomes asymptomatic, serum sodium reaches 130 mmol/l or that the total increase in serum sodium is 25 mmol. Serum sodium should not increase by more than 25 mmol in the ¢rst 48 h.18,19 Ideally, the patient should be monitored in the ICU setting, with appropriate supportive measures. Serum electrolytes should be measured every 2 h. Calculating the infusion rate to achieve the above rate of increase in serum sodium requires assessment of the total body water. This can be made by considering the patient’s age, gender, body habitus and weight. Generally, males have higher total body water as a percentage of weight than females. Total body water as a percentage decreases with age. The mean adult total body water is approximately 50%. Therefore, for a 70 kg male whose serum sodium is 110 mmol, to correct this over 24 h to 130 mmol, his total body water can be estimated to be 70 0:5 ¼ 35 l: Therefore, sodium required for correction is 35ð130 110Þ ¼ 700 mmol: Therefore, rate of infusion of hypertonic saline (514 mmol/l) is 700=514=24ðhÞ ¼ 56 ml=h: This rate should be adjusted according to measured serum sodium.
OUTCOMES OF HYPONATRAEMIA As stated above, the development of serious morbidity and mortality from hyponatraemia does not appear to be related to the degree or duration of hyponatraemia, but is instead related to other factors such as hypoxia and female sex hormones. By understanding the role of Na/K ATPase in the adaptive mechanism of cells to hyponatraemia, we can better appreciate the role of hypoxia in the development of brain damage in hyponatraemia. The generation of ATP within cells via oxidative phosphorylation requires oxygen.Therefore, hypoxaemia leads to decreased e¡ectiveness of cellular extrusion of sodium via the Na/K ATPase pump. Subsequently, there is increased intracellular sodium, increased cellular swelling leading to raised intracranial pressure (ICP).20 If this is allowed to progress, the end result is seizures, coma and respiratory arrest. Subsequent hypoxia, if inadequately managed, leads to a self-perpetuating situation and death rapidly ensues.21 Hypoxia also increases the production of ADH. In addition to its systemic e¡ects to increase hyponatraemia, ADH acts on the AQP4 channels in the neural and glial cells of the brain,22 which allows the in£ux of water thereby worsening cellular swelling. Additionally, it is thought that ADH may cause cerebral hypoperfusion by increasing vascular tone, further exacerbating tissue hypoxia.23 The role of sex hormones in the development of brain damage is thought to be related to the inhibitory e¡ect of both progesterone and oestrogen on the Na/K ATPase pump.24 In addition, it has been suggested that sex hormones increase the circulating levels of ADH.25 A point of much conjecture is whether there is an association between the rapid correction of hyponatraemia and the development of central pontine myelinolysis. This is a distinct clinical entity diagnosed either radiologically with CTscan or MRI, or histopathologically by the presence in the pons of demyelinating lesions and the absence of extra pontine areas of myelinolysis. Central pontine myelinosis has been reported in animal testing to be associated with rapid correction of hyponatraemia. However, this association has not been clearly demonstrated in humans. In a retrospective analysis of reported cases of central pontine myelinosis associated with hyponatraemia, it was found that most cases did not ¢t the diagnostic criteria as the lesions were di¡use, often extrapontine, areas of demyelination. In virtually all cases, there was either an hypoxic episode, rapid correction of sodium greater than 25 mmol/l in 48 h, or concomitant systemic illnesses such as burns, alcoholism and liver disease, all of which are known to be associated with cerebral myelinolysis.26,27 It has been shown, prospectively, that rapid correction of hyponatraemia (mean 1.6 mmol/l/h) can be performed without morbidity or mortality.18
SODIUM ABNORMALITIES IN THE NEUROSURGICAL PATIENT
HYPERNATRAEMIA Hypernatraemia (Table 2) is the result of net water loss relative to sodium loss. When considering neurosurgical intensive care, special consideration must be given to osmotic diuresis and diabetes insipidus. Mannitol is an osmotic diuretic, used in the management of an acute rise in intracranial pressure. Mannitol is a sugar alcohol of mannose and is administered as a 20% solution containing 549 mmol/l. It achieves its pharmacological e¡ect by increasing serum osmolality, thereby drawing water out of the swollen brain and decreasing intracranial pressure. In the kidney, mannitol is ¢ltered freely at the glomerulus, but there is no tubular reabsorption.This produces an osmotic load, which draws water out. The increased £ow of ¢ltrate through the proximal tubule leads to increased load-dependent reabsorption of sodium in the distal tubule and increased excretion of potassium. The net result is water loss, increased serum sodium and osmolality and decreased potassium.
DIABETES INSIPIDUS Diabetes insipidus (Table 3) is characterized by polyuria and polydipsia. It may be accompanied by elevated serum sodium and osmolality, if water intake is inadequate to cover losses.The urine is typically dilute with an osmolality of 50 ^150 mmol/kg. Diabetes insipidus can be either neurogenic or nephrogenic.28 The neurogenic causes all involve disruption of the hypothalamus and decreased production of ADH. If the cause of diabetes insipidus is neurogenic, it will respond to DDAVP; however, nephrogenic diabetes insipidus will not. The remainder of this discussion refers only to neurogenic diabetes insipidus. The typical time of onset of diabetes insipidus is 1^3 days following the initial insult (usually trauma or surgery).The duration depends on the nature and reversibility of the pathology. For example, it is common to see transient diabetes insipidus (lasting approximately 1
Table 2 Causes of hypernatraemia Iatrogenic K Inappropriate £uid therapy Excessive insensible losses K Emesis K Diarrhoea K Sweating Excessive renallosses K Osmotic diuresis K Diabetes insipidus K Renal failure
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Table 3 Causes of diabetes insipidus Neurogenic K Trauma K Cerebrovascular disease K Neoplasia K Neurosurgery K Raised ICP K Idiopathic Nephrogenic K Chronic renal failure K Elevated calcium K Drugs e.g. lithium K Excess water intake
week) following neurosurgical procedures that involve traction of the pituitary stalk due to oedema of the hypothalamus. However, if there is destruction of the hypothalamus, diabetes insipidus will be permanent. The diagnosis should be suspected in any neurosurgical patient who is polyuric. Serum and urine electrolyte changes, as above, support the diagnosis.
MANAGEMENTOF DIABETES INSIPIDUS There are two components to management: 1. Maintain strict £uid balance. In the conscious patient, tolerating feeds, the patient’s oral intake may su⁄ce. However, in the obtunded patient, as often found in ICU, intravenous intake, calculated hourly according to urine output is necessary. Electrolytes should be monitored at least once daily. 2. DDAVP (desmopressin acetate) is a long-acting synthetic analogue of vasopressin. Its action is largely con¢ned to V2 receptors in the collecting ducts of the kidney. It should be considered, in diagnosed diabetes insipidus, when urine output exceeds 250 ml/h.29 Dosage is 1^2 mcg iv/sc or 10 mcg nasal spray as required. Care must be taken in patients who have developed acute diabetes insipidus because of the potentially variable and transient nature of this disturbance.
REFERENCES 1. Chung H M, Kluge R, Schrier R W, Anderson R J. Postoperative hyponatremia. A prospective study. Arch Intern Med 1986; 146(2): 333–336.
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2. Fox J L, Falik J L, Shalhoub R J. Neurosurgical hyponatremia: the role of inappropriate antidiuresis. J Neurosurg 1971; 34(4): 506– 514. 3. Arieff A I. Central nervous system manifestations of disordered sodium metabolism. Clin Endocrinol Metab 1984; 13(2): 269–294. 4. Fraser C L, Arieff A I. Epidemiology, pathophysiology, and management of hyponatremic encephalopathy. Am J Med 1997; 102(1): 67–77. 5. Arieff A I, Kozniewska E, Roberts T P, Vexler Z S, Ayus J C, Kucharczyk J. Age, gender, and vasopressin affect survival and brain adaptation in rats with metabolic encephalopathy. Am J Physiol 1995; 268(5 Part 2): R1143–R1152. 6. Ayus J C, Wheeler J M, Arieff A I. Postoperative hyponatremic encephalopathy in menstruant women. Ann Intern Med 1992; 117(11): 891–897. 7. Leaf A. The clinical and physiologic significance of the serum sodium concentration. N Engl J Med 1962; 267: 24–30, 77–85. 8. Peters J P, Welt L G, Sims E A H. A salt wasting syndrome associated with cerebral disease. Trans Assoc Am Physicians 1950; 63: 57–64. 9. Lester M C, Nelson P B. Neurological aspects of vasopressin release and the syndrome of inappropriate secretion of antidiuretic hormone. Neurosurgery 1981; 8(6): 735–740. 10. Wijdicks E F, Vermeulen M, Hijdra A, van Gijn J. Hyponatremia and cerebral infarction in patients with ruptured intracranial aneurysms: is fluid restriction harmful? Ann Neurol 1985; 17(2): 137–140. 11. Beasley D, Malvin R L, Mouw D R. CNS-induced natriuresis and renal hemodynamics in conscious rats. Am J Physiol 1983; 245(6): F763–F771. 12. Espiner E A. Physiology of natriuretic peptides. J Intern Med 1994; 235(6): 527–541. 13. de Bold A J, Borenstein H B, Veress A T, Sonnenberg H. A rapid and potent natriuretic response to intravenous injection of atrial myocardial extract in rats. Life Sci 1981 Jan; 28(1): 89–94. 14. Diringer M, Ladenson P W, Stern B J, Schleimer J, Hanley D F. Plasma atrial natriuretic factor and subarachnoid hemorrhage. Stroke 1988; 19(9): 1119–1124. 15. Yamaki T, Tano-oka A, Takahashi A, Imaizumi T, Suetake K, Hashi K. Cerebral salt wasting syndrome distinct from the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Acta Neurochir (Wien) 1992; 115(3–4): 156–162. 16. Maesaka JK, Gupta S, Fishbane S. Cerebral salt-wasting syndrome: does it exist? Nephron 1999; 82(2): 100–109. 17. Arieff A I. Management of hyponatraemia. Br Med J 1993; 307(6899): 305–308.
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18. Ayus J C, Krothapalli R K, Arieff A I. Treatment of symptomatic hyponatremia and its relation to brain damage. A prospective study. N Engl J Med 1987; 317(19): 1190–1195. 19. Ayus J C, Krothapalli R K, Armstrong D L, Norton H J. Symptomatic hyponatremia in rats: effect of treatment on mortality and brain lesions. Am J Physiol 1989; 257(1 Part 2): F18–F22. 20. Vexler Z S, Ayus J C, Roberts T P, Fraser C L, Kucharczyk J, Arieff A I. Hypoxic and ischemic hypoxia exacerbate brain injury associated with metabolic encephalopathy in laboratory animals. J Clin Invest 1994; 93(1): 256–264. 21. Arieff A I. Hyponatremia, convulsions, respiratory arrest, and permanent brain damage after elective surgery in healthy women. N Engl J Med 1986; 314(24): 1529–1535. 22. Jung J S, Bhat R V, Preston G M, Guggino W B, Baraban J M, Agre P. Molecular characterization of an aquaporin cDNA from brain: candidate osmoreceptor and regulator of water balance. Proc Natl Acad Sci USA 1994; 91(26): 13 052–13 056. 23. Okada K, Caramelo C, Tsai P, Schrier R W. Effect of inhibition of Na+/K(+)-adenosine triphosphatase on vascular action of vasopressin. J Clin Invest 1990; 86(4): 1241–1248. 24. Fraser C L, Swanson R A. Female sex hormones inhibit volume regulation in rat brain astrocyte culture. Am J Physiol 1994; 267(4 Part 1): C909–C914. 25. Share L. Control of vasopressin release: an old but continuing story. News Physiol Sci 1996; 11: 7–13. 26. Tien R, Arieff A I, Kucharczyk W, Wasik A, Kucharczyk J. Hyponatremic encephalopathy: is central pontine myelinolysis a component? Am J Med 1992; 92(5): 513–522. 27. Ayus J C, Arieff A I. Pathogenesis and prevention of hyponatremic encephalopathy. Endocrinol Metab Clin N Am 1993; 22(2): 425– 446. 28. Robertson G L, Aycinena P, Zerbe R L. Neurogenic disorders of osmoregulation. Am J Med 1982; 72(2): 339–353. 29. Cobb W E, Spare S, Reichlin S. Neurogenic diabetes insipidus: management with dDAVP (1-desamino-8-D arginine vasopressin). Ann Intern Med 1978; 88(2): 183–188.
FURTHER READING Harrigan M R.Cerebral salt wasting syndrome: a review. Neurosurgery 1996 38(1): 152^160. Maesaka J K,Gupta S, Fishbane S.Cerebral salt-wasting syndrome: does it exist? Nephron 1999; 82(2): 100 ^109.