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This patient clearly has impaired urinary diluting capacity. The concentrated urine usually reflects a high circulating AVP level, which is clearly inappropriate for the Posm (See Figure 43-1). But since AVP release is affected by systemic hemodynamics as well as osmolality (see above), assessment of the patient's extracellular fluid volume status and hemodynamics is crucial at this juncture (See Figure 43-2).
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Euvolemic Hyponatremia
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Patients with hyponatremia as a result of pure (electrolyte-free) water excess appear clinically euvolemic because the excess water distributes throughout the total body water space; only one-third of total body water is extracellular, and only one-twelfth is intravascular. Thus, an adult patient whose total body water is expanded by 6 L, and thus has a PNa of 122 mmol/L, will have expanded the intravascular volume by only 500 mL. The only evidence of the mild intravascular volume expansion is low blood urea nitrogen and plasma uric acid concentration.9
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The paradigm of euvolemic hyponatremia with a concentrated urine is the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). SIADH is by far the most common cause of hyponatremia in patients with neurosurgical disease, accounting for over 70% of cases.2 It is characterized by elevated circulating AVP (ADH) levels that are inappropriate to vasopressin's two physiologic stimuli (ie, osmotic or hemodynamic).10 Hypotonic hyponatremia in patients with SIADH develops to the extent that water ingestion exceeds water elimination by insensible (sweat and perspiration; respiratory), gastrointestinal, and renal routes. Because the normal response to extracellular hypotonicity is the elaboration of maximally dilute urine (urine osmolality < 100 mOsm/kg), the urine need only be inappropriately concentrated (ie, > 100 mOsm/kg) to be compatible with a diagnosis of SIADH.
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Because hypothyroidism11 and glucocorticoid insufficiency12 may impair urinary dilution even with suppressed AVP, patients in whom a diagnosis of SIADH is entertained should undergo appropriate tests of thyroid and adrenocortical function (see Chapter 52).
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Once a diagnosis of SIADH is made, its cause must be established: just because a patient with SAH is found to have SIADH does not mean that the SAH is the cause. There may be another more easily remediable cause. Table 43-1 lists important causes of SIADH. They fall into five major categories: intracranial abnormalities, intrathoracic abnormalities, tumors, drugs, and idiopathic. Important adjunctive causes of SIADH in any hospitalized patient include pain, nausea, psychological stress, and, most commonly, medications.
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Hypovolemic Hyponatremia
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The urinary diluting impairment in hypovolemia is mediated both by decreased delivery of fluid to the diluting segments of the nephron and by baroreceptor stimulation of vasopressin release. Thus, the volume-contracted patient cannot excrete electrolyte-free water normally, and even in the face of modest water ingestion may become hyponatremic.
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The cause of the volume contraction (negative sodium balance) usually is obvious (eg, hemorrhage, vomiting, diarrhea, diuretics). When it is not, the urine sodium concentration can be helpful in distinguishing between renal and extrarenal solute losses. Renal losses (eg, as a result of diuretic medications) are usually reflected by sodium wasting, and extrarenal (gastrointestinal, skin, “ third space,” or hemorrhagic) losses are usually accompanied by sodium conservation (urine sodium concentration < 10 mmol/L). Exceptions occur in the recovery phase after diuretic therapy, when the kidney has regained its capacity to respond to the volume depletion, and in metabolic alkalosis due to vomiting. In the latter situation, urinary sodium excretion is obligated by the bicarbonaturia, but the urine chloride concentration tends to be very low and is the best indicator of extracellular volume depletion.13, 14
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Renal salt wasting—in this setting more commonly called cerebral salt wasting (CSW)—may be responsible for hypovolemic hyponatremia in some patients with intracranial pathology (eg, tumors, hemorrhage).15, 16 The proposed underlying pathogenesis is a failure of the kidneys to adequately reabsorb sodium, leading to volume depletion. The mechanism of hyponatremia, then, is similar to that of other hypovolemic states. The pathogenesis of the renal salt wasting is incompletely understood: putative mechanisms include impaired sympathetic efferent pathways to the kidneys from the damaged central nervous system, and excessive secretion of a circulating natriuretic factor (eg, B-type natriuretic peptide [BNP]).17 As a hyponatremic syndrome in patients with central nervous system disease, CSW is difficult to distinguish from SIADH, for several reasons. First, both are characterized by high urinary sodium excretion. Second, and particularly vexing, patients who have been diagnosed with CSW have hypo-uricemia, in contrast to most volume-depleted patients, who have hyperuricemia. The hypouricemia is thought to reflect a generalized impairment of solute reabsorption in the proximal tubule.17 Thus, the distinction of CSW from SIADH hinges completely on documentation of volume depletion. This seemingly simple determination is in fact quite complex and fraught with error.15, 18, 19, 20 Indeed, so controversial is the syndrome of CSW that some investigators think it accounts for the majority of hyponatremia in patients with central nervous system disease,15, 21 while others question its existence altogether.18, 19, 20
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The hyponatremia associated with diuretic treatment is multifactorial in origin. Insofar as diuretics produce overt volume depletion, they can cause hyponatremia by the mechanisms discussed above. Thiazide diuretics in particular have been associated with the development of acute severe, symptomatic hyponatremia, particularly in small, elderly women, in the absence of overt signs of volume depletion.22 The cause of this often precipitous syndrome remains uncertain,23 although subtle volume depletion, hypokalemia, increased thirst,24 and upregulation of aquaporin-2 water channels25 have been implicated.
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Hypervolemic Hyponatremia
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Hypervolemic hyponatremia generally is seen in patients who cannot excrete sodium normally because they have either severe renal failure or one of the pathologic edema-forming states (eg, congestive heart failure, hepatic cirrhosis, nephrotic syndrome). Patients with advanced chronic kidney disease are predisposed to hyponatremia.26 Acute oliguric renal failure or end-stage (dialysis-dependent) renal failure will be accompanied by hyponatremia to the extent that water intake exceeds insensible and gastrointestinal water elimination.
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Hyponatremia is common in the pathologic edema states, especially congestive heart failure and hepatic cirrhosis. The hormonal milieu of such patients is typical of intravascular volume depletion, even though the absolute intravascular volume typically is increased. Thus, these disorders are said to be characterized by reduced effective circulating volume.27 Because of the perceived intravascular volume depletion, renal diluting ability is compromised for reasons similar to those in hypovolemic hyponatremia.
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The patient is afebrile and breathing at 18 breaths/min. His fluid volume status is equivocal: the blood pressure is 126/68 mm Hg; the heart rate is 96 bpm at rest; there is no jugular venous distention and no dependent edema. In view of the copious urinary sodium and the possibility of subtle volume depletion, his physician entertains the diagnosis of CSW. He gives him intravenous normal saline solution at a rate of 120 mL/h. The patient is incapable of taking anything by mouth. The next day, the PNa has fallen to 118 mmol/L. The patient's mental status, which had been improving over the past few days, has now declined.