Chapter 43: Disorders of Water Homeostasis: Hypo- and Hypernatremia

Critically ill patients are prone to a wide variety of fluid, electrolyte, and acid-base disorders. Two of those disorders are of particular relevance to patients with critical neurologic illness: hyponatremia and hypernatremia. These are by far the most common electrolyte abnormalities in patients with central nervous system disease and have the most pressing diagnostic and therapeutic implications. This chapter therefore will focus exclusively on these disorders. Interested readers will find a recent, more comprehensive discussion of fluid, electrolyte, and acid-base abnormalities in critically ill patients elsewhere.¹

Hypo- and hypernatremia are manifestations of impaired water homeostasis. They occur frequently in patients with central nervous system disease² and are associated with increased morbidity and mortality rates.^{3, 4}

Plasma sodium concentration (P_Na) normally varies very little. This tight regulation of the P_Na depends on the following elements: (1) modulation of pituitary secretion of arginine vasopressin (AVP; also known as antidiuretic hormone, or ADH) over a wide range in response to physiologic stimuli, (2) kidneys that are capable of responding to circulating AVP by varying the urine concentration, (3) intact thirst, and (4) access to water.

The normal response to water ingestion (of sufficient magnitude to lower the plasma osmolality even slightly) is the excretion of maximally dilute urine (urine osmolality < 100 mOsm/kg). The underlying physiologic sequence is as follows: the plasma hypo-osmolality is sensed by the cells comprising the hypothalamic osmostat. These hypothalamic nuclei then proportionately reduce their synthesis of AVP, leading to diminished AVP release into the circulation by the posterior pituitary. The lower circulating AVP concentration causes less vasopressin receptor type 2 (V₂ receptor) stimulation of the epithelial cells lining the renal collecting duct. This, in turn, results in the insertion of proportionately fewer water channels into the collecting duct, creating a more water-impermeable conduit, which allows excretion of the dilute urine elaborated by the more proximal segments of the nephron.⁵

Conversely, plasma hyperosmolality leads to higher circulating AVP concentration and proportionately higher water permeability of the collecting duct, and the excretion of a concentrated urine.⁵

Figure 43-1 shows the relationship between plasma osmolality, plasma AVP concentration, and urine osmolality. The normal “set point” is a plasma osmolality of about 285 mOsm/kg. Notice that the minimum urine osmolality is about 50 mOsm/kg, and the maximum about 1200 mOsm/kg.⁶ When plasma osmolality rises beyond 290 to 295 mOsm/kg, the thirst center of the hypothalamus is stimulated. At that point, neurologically intact individuals with access to water will drink until the plasma osmolality returns to normal.⁶

It is important to recognize that plasma osmolality is not the only determinant of AVP synthesis and release. Low arterial blood pressure and low effective arterial volume powerfully stimulate AVP release.⁶ This baroreceptor-mediated AVP release is teleologic, since water retention is an important component in the defense against hypovolemia. So primal is this circulatory defense that the baroreceptor stimulation predominates over any osmolal effect on AVP release.⁶ Thus, a volume-contracted or hypotensive individual will have high circulating AVP levels even if his or her plasma osmolality is low. In addition, circulating AVP levels rise with pain, stress, nausea, hypoxia, hypercapnia, and a variety of medications.⁶

Hyponatremia (P_Na < 135 mmol/L) is seen in approximately 3% of hospitalized patients and as many as 30% of patients in intensive care units.³ Among neurosurgical patients, the incidence of significant hyponatremia (P_Na < 130 mmol/L) is about 14%, with subarachnoid hemorrhage patients having the highest incidence (almost 20%).²

Although sodium is the vastly predominant solute in the extracellular space, hyponatremia may coexist with a normal, high, or low plasma osmolality.

Isotonic hyponatremia (also known as factitious or pseudohyponatremia) is a laboratory artifact seen in the setting of marked hypertriglyceridemia or paraproteinemia, when the sodium measurement method involves a predilution step.⁷ The hyponatremia per se is of no clinical importance except as a clue to its pathogenesis.

Hypertonic hyponatremia results from the presence in extracellular fluid of abnormal amounts of osmotically effective solutes other than sodium (eg, glucose, mannitol, or glycerol). The osmotic pressure exerted by the nonsodium solute leads to redistribution of water from the intracellular to the extracellular fluid compartment, resulting in dilution of the extracellular sodium mass and resultant hyponatremia. The hyponatremia is real (not pseudo-), but it is accompanied by hypertonicity and a decrease in cellular volume due to cellular dehydration, and thus carries no pathophysiologic importance in itself.

Hypotonic hyponatremia, by far the most common type of hyponatremia, is caused by an inability of the kidney to excrete sufficient electrolyte-free water to match water intake. It is this form of hyponatremia in which the hyponatremia itself is of clinical concern, for reasons detailed below.

Based on this differential diagnosis, the diagnostic algorithm for hyponatremia (Figure 43-2) begins with an assessment of the plasma osmolality (P_osm). This may be estimated by the following formula:

where P_gluc is the plasma glucose concentration and BUN is blood urea nitrogen concentration, both in mg/dL. If there is a suspicion that an unmeasured, osmotically effective solute may be present in the plasma (eg, mannitol or glycerol), the P_osm should be measured directly.

The normal P_osm is 280 to 285 mOsm/kg. This patient thus has hypotonic hyponatremia. This occurs either because the normal diluting capacity of the kidney is overwhelmed by excessive water intake or because the diluting capacity of the kidney is impaired. The former condition is characterized by excretion of a maximally dilute urine (U_osm < 100 mOsm/kg H₂O), and the latter is not. The classic example of the former condition is primary polydipsia, seen most commonly in patients with schizophrenia.⁸ There are no reported cases of primary polydipsia in association with stroke, either hemorrhagic or ischemic.

This patient clearly has impaired urinary diluting capacity. The concentrated urine usually reflects a high circulating AVP level, which is clearly inappropriate for the P_osm (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).

Euvolemic Hyponatremia

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 P_Na 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

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.

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).

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.

Hypovolemic Hyponatremia

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.

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}

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}

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.

Hypervolemic Hyponatremia

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.

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.

The magnitude of the decline in the patient's P_Na implies that there was a gain of electrolyte-free water of about 2 L. By definition, normal saline solution contains no electrolyte-free water. The kidney, however, is capable of generating electrolyte-free water and returning it to the circulation, a process that has been called desalination.²⁸ This happens when the patient is excreting a large amount of electrolyte in a concentrated urine (under the influence of high circulating AVP)—exactly the case with our patient. In essence, the patient receives an isotonic saline solution, excretes a hypertonic saline solution, and returns the reabsorbed water to the circulation, further diluting his plasma sodium. In our patient's case, this could have been predicted by the recognition that his urine electrolyte concentration greatly exceeded his plasma electrolyte concentration.²⁹

The clinical manifestations of hyponatremia are largely attributed to intracellular volume expansion (cellular edema), which occurs only when hyponatremia is associated with hypotonicity. Intracellular volume expansion is of greatest consequence in the brain, where it is translated into increased intracranial pressure because of the rigid calvarium.³⁰

The pathophysiology of hypotonic hyponatremia has important implications for its management. Most cells—especially brain cells—have adaptive mechanisms for mitigating tonicity-related volume changes.³⁰ Cell volume peaks 1 to 2 hours after the onset of acute hypotonicity. Thereafter, solute and water are lost from cells, and cell volume returns toward normal. After several days of sustained hypotonicity, cell volume is restored nearly to normal.³⁰

The morbidity and mortality associated with hypotonic hyponatremia are influenced by several factors, including the magnitude and rate of development of the hyponatremia, the patient's age and gender, and the nature and severity of any underlying diseases.³⁰ The very young and very old, women, and alcoholics appear to be at particular risk.³¹ Cell-volume adaptation to hypotonicity may be deficient in premenopausal women, who suffer more frequent and more severe neurologic consequences than men with equivalent degrees of hypotonicity.³²

Neurologic symptoms usually do not occur until the P_Na falls below 125 mmol/L, although death from acute hyponatremia has been reported at 128 mmol/L.³³ The earliest symptoms include anorexia, nausea, and malaise. Between 120 and 110 mmol/L, headache, lethargy, confusion, agitation, and obtundation may be seen. More severe symptoms (seizures, coma) may occur with levels below 110 mmol/L.³⁴ Focal neurologic findings are unusual but do occur, and cerebral herniation has been described in severe cases, especially in young women following surgery.³² In that setting, hypoxemia is common and often is associated with noncardiogenic pulmonary edema.³⁵ Hypoxia appears to exacerbate the cerebral damage in hyponatremia.³⁶

Although symptoms generally resolve with correction of the hypotonicity, permanent neurologic deficits may occur, particularly in acute severe hypotonicity, when the brain's volume-regulatory defenses may be overwhelmed.³² Profound hypotonicity that develops in less than 24 hours may be associated with residual neurologic deficits and has a 50% mortality rate in some populations.³² In contrast, when hypotonicity develops more gradually, symptoms are both less common and less severe. Indeed, patients with chronic hyponatremia, even in the range of 115 to 120 mmol/L, may be completely asymptomatic.³⁰ Recent evidence suggests, however, that even chronic, mild, asymptomatic hyponatremia is associated with inattention, gait disturbances, falls, and fractures.^{37, 38, 39} Thus, if hyponatremia is present upon presentation of a patient with traumatic brain injury after a fall, the hyponatremia may have led to the fall.

Our patient's mental status has deteriorated as his P_Na has fallen. In this situation, a causal link should be presumed. Indeed, there is some evidence that hyponatremia in patients with SAH increases the risk of cerebral infarction, presumably by exacerbating cerebral edema.⁴⁰ Thus, the hyponatremia should be treated urgently.

The therapy of symptomatic hyponatremia, irrespective of cause, is directed at raising extracellular fluid tonicity to shift water out of cells, thereby ameliorating cerebral edema. Severe symptomatic hypotonic hyponatremia can be treated in two ways. The traditional treatment uses hypertonic (3%) saline (sodium concentration 513 mmol/L). The volume of 3% saline required can be estimated by the following formula:

where TBW is the total body water. Our patient weighs 70 kg and thus is estimated to have a total body water volume of 42 L (60% of body weight). If we want to raise the P_Na by 8 mmol/L over the next 24 hours (to 126 mmol/L), then the amount of sodium we need to administer is 8 × 42, or 336 mmol. Therefore, 336 ÷ 513 or 0.66 L of 3% saline would be required in the first 24 hours, or 27 mL/h. It is important to recognize that the calculation provides only a very rough guideline. It does not account for other gains or losses of sodium or water. The P_Na must, therefore, be monitored frequently during treatment to adjust the rate of correction. If the rate of correction begins to exceed the target rate, the hypertonic saline infusion should be stopped; rarely, it may be necessary to administer water (enterally or intravenously [IV]) or even desmopressin in order to prevent overly rapid correction or overcorrection.⁴¹ Rapid extracellular volume expansion with hypertonic saline may precipitate pulmonary edema, particularly in patients with underlying heart disease. Thus, patients receiving 3% saline should be assessed frequently for evidence of volume overload. One may administer a loop diuretic if necessary, recognizing that this will enhance electrolyte-free water clearance and accelerate the correction.

Conivaptan may be considered an alternative treatment for severe, symptomatic hyponatremia, although it has never been studied for this indication.⁴² Conivaptan is a vasopressin receptor antagonist with both the V_1A and V₂ receptor antagonist effects. V_1A receptors mediate AVP-induced vasoconstriction, and V₂ receptors mediate AVP-induced water reabsorption in the renal collecting duct, thus augmenting electrolyte-free water excretion (aquaresis).⁴³ Conivaptan was the first aquaretic agent approved for use in the United States. It is approved for intravenous infusion in patients with euvolemic hyponatremia, and it causes an increase in electrolyte-free water excretion in a high percentage of treated patients.⁴⁴ When given in the recommended dosage (20 mg IV over 30 minutes, followed by 20 to 40 mg/d to a maximum of 40 mg/d), the average rate of rise in the P_Na is about 4 mmol/L in the first 24 hours.⁴⁴ Side effects, including hypotension, appear to be no more common than in the placebo group, except for mild infusion-site reactions. Despite its theoretical appeal, its use has several drawbacks. First, it is metabolized by, and competitively inhibits, hepatic CYP3A4, creating the opportunity for numerous drug interactions. Second, it is quite expensive (over $300 per 20 mg⁴⁵), especially when compared with the nominal cost of hypertonic saline. Finally, and most important, if there is any possibility of CSW, the underlying volume depletion will only be exacerbated by conivaptan. Particularly in view of this last consideration, I strongly recommend using hypertonic saline to treat symptomatic hyponatremia in patients with intracranial pathology.

The rate of correction of the P_Na in severe hyponatremia must be carefully regulated. Overly rapid correction, particularly in patients with chronic hyponatremia (2-3 days' duration) in whom cell volume adaptations may be complete, can lead to the osmotic demyelination syndrome,^{46, 47} presumably as a result of cellular dehydration. The osmotic demyelination syndrome is associated with a variety of sometimes irreversible neurologic deficits (eg, dysarthria, dysphagia, behavioral disturbances, ataxia, quadriplegia, coma), which typically develop 3 to 10 days after treatment.⁴⁸ Additional risk factors for osmotic demyelination include hypokalemia, malnutrition, alcoholism, advanced age, and female sex.⁴⁹ The recommended maximum rate of correction, based on numerous studies over decades, is about 0.5 mmol/L per hour, 10 to 12 mmol/L in the first 24 hours, and no more than 18 mmol/L in the first 48 hours.⁴² In profound, symptomatic hyponatremia, one may target a rate of correction in the first hour or two of 1 mmol/L per hour, but the 24- and 48-hour targets should not be exceeded.

Because euvolemic hyponatremia represents pure water excess, treatment depends on inducing negative water balance: restricting water intake to less than the daily water output. Water output includes renal and extrarenal losses. Patients with SIADH excrete little or no electrolyte-free water in the urine. Indeed, sometimes (and in our patient's case) the kidney generates electrolyte-free water (essentially increasing water intake) by extracting it from the glomerular filtrate and returning it to the circulation, such desalination signaled by the fact that the sum of the cation concentration in the urine exceeds that in the plasma.²⁹ In this situation, even limiting water intake to less than the amount of insensible water losses (approximately 10 mL/kg body weight per day) will be unlikely to cause the P_Na to rise. Thus, most patients with SIADH require interventions to increase their urinary electrolyte-free water excretion.

A high-protein diet may enhance electrolyte-free water excretion in patients with SIADH by increasing urinary excretion of urea. Enforcing a high-protein diet in ill patients is difficult, but it is possible if they are fed by enteral tube. Similarly, oral administration of urea has been shown to normalize the P_Na over the long term in patients with SIADH,⁵⁰ but urea for this purpose is unavailable in the United States.

Demeclocycline is a tetracycline antibiotic that incidentally causes nephrogenic diabetes insipidus in about 70% of patients, increasing electrolyte-free water excretion by inhibiting vasopressin-mediated water reabsorption in the collecting duct.⁴² Onset of action is 3 to 5 days with a dose of 300 mg two to four times daily. Demeclocycline is contraindicated in patients with renal disease, hepatic cirrhosis, or congestive heart failure because drug-related renal insufficiency has been described in these situations.⁵¹

Conivaptan (see earlier) is for short-term (4 days) parenteral use only, and is therefore not useful for long-term management of patients with SIADH. Tolvaptan, a selective V₂ receptor blocker, is available for long-term oral use, and is efficacious in a majority of patients with hyponatremia of various causes, including SIADH.⁵² The starting dose is 15 mg daily, and the dose may be increased to 30 mg on day 2 and 60 mg on day 3. Clinical trials lasting 30 days showed that about 2% of patients exceeded the recommended rate of correction of P_Na.^{52, 53} This may be of particular concern in patients who cannot sense thirst or who have limited access to water, so the P_Na must be monitored daily when initiating therapy. No cases of osmotic demyelination syndrome were reported.^{52, 53} Like conivaptan, tolvaptan is metabolized by CYP3A4, so many drug interactions are possible. The current average wholesale cost of tolvaptan is about $300 a day.

Hypernatremia is common in critically ill patients, being present on admission in about 9% of patients and developing during the course of the ICU stay in another 6%.⁵⁴ Sustained hypernatremia develops in patients whose water output exceeds their input. Water ingestion can defend against the development of hypernatremia even when water losses are prodigious. For that reason, hypernatremia occurs most commonly in patients who are incapacitated: those who have impaired thirst sensation, who cannot access water, or who cannot express their need for water (eg, infants and patients with neurologic impairments). Thus, the development of hypernatremia in hospitalized patients is considered to be iatrogenic, reflecting an incomplete understanding of the factors that lead to hypernatremia.⁵⁴ The increased mortality rate seen in patients with hypernatremia⁵⁴ may be due to their underlying vulnerabilities⁵⁵ or an effect of the hypernatremia itself.⁵⁶ In patients in the neurologic ICU, severe hypernatremia (P_Na > 160 mmol/L) appears to be an independent predictor of death.⁵⁷

The P_Na reflects the ratio of body sodium content to total body water. Thus, hypernatremia (P_Na > 145 mmol/L) can result from loss of pure water alone, loss of hyponatricⁱ fluid, or a gain of sodium or hypernatric fluid. These will tend to be associated with euvolemia, hypovolemia, and hypervolemia, respectively. It is important to distinguish among these paths to hypernatremia since they have diagnostic and therapeutic implications (Figure 43-3).

Euvolemic Hypernatremia

Hypernatremic patients who appear euvolemic most likely have pure water loss as an explanation for their hypernatremia. This is because the water is lost from all body compartments proportionately; only one-twelfth of the water loss is intravascular. For example, a 60-kg woman with a 3-L pure water loss would experience an intravascular loss of only 250 mL (clinically imperceptible), but would develop a P_Na of 155 mmol/L.ⁱⁱ Pure water can be lost either through the skin and respiratory tract (so-called insensible losses) or in urine.

Insensible losses amount to about 10 mL/kg body weight per day under normal environmental conditions in an afebrile individual with a normal respiratory rate. A hot environment, fever, or rapid respiratory rate may double that rate.⁶ Note that a patient on a mechanical ventilator using humidified gas will lose no water through the respiratory tract.

The loss of large amounts of dilute, electrolyte-free water in the urine is typical of diabetes insipidus (DI). Diabetes insipidus may be central (CDI) or nephrogenic (NDI) depending on whether the defect is in vasopressin release from the posterior pituitary or in the renal response to circulating vasopressin, respectively. The causes of DI are shown in Table 43-2. Most cases of CDI, especially those following trauma or intracranial surgery, are self-limited, lasting 3 to 5 days. Of special interest to neurointensivists is a classic triphasic syndrome that may be seen following severe head trauma or pituitary surgery^{58, 59}:

1. Initially, there is abrupt cessation of vasopressin release from the posterior pituitary, accompanied by polyuria.

2. About a week later, an antidiuretic phase ensues, characterized by urinary concentration and water retention with a tendency toward hyponatremia, lasting 2 to 14 days. This appears to result from the release of stored vasopressin from the degenerating hypothalamic neurons.

3. Persistent CDI recurs when the vasopressin stores are depleted.

Regardless of the cause, conscious and competent patients with DI of either type usually have a P_Na within the normal range because their water ingestion matches their urinary water output. They develop hypernatremia only with water deprivation, owing to mental or physical incapacity and/or neglect. An awareness of the causes of DI, a careful history, and familiarity with the differential diagnosis of polyuria will prevent hypernatremia in these circumstances.

Hypovolemic Hypernatremia

The loss of salt and water, with the water loss greater than the sodium loss, will lead to hypernatremia and volume depletion, manifested by orthostatic or persistent hypotension and tachycardia, and evidence of organ underperfusion (eg, acute renal failure, lactic acidosis). For example, if the 60-kg woman whose P_Na rose to 155 mmol/L (see above) had lost the equivalent of half-isotonic saline instead of pure water, her intravascular volume would have contracted by 750 mL, enough to cause at least orthostatic hypotension and tachycardia.

A common cause of hypovolemic hypernatremia is the loss of gastrointestinal fluids. Most gastrointestinal fluids have an electrolyte concentration below that of plasma: the concentration of sodium plus potassium in stool is roughly constant at 110 to 120 mmol/L over a wide range of stool volume.⁶⁰ Gastric fluid has an even lower electrolyte concentration: about 40 to 50 mmol/L total cation concentration.⁶¹ Diuresis, either osmotic (glucose, mannitol, or urea induced) or medication induced, causes the loss of urine with an electrolyte concentration less than that of plasma, leading to volume contraction and hypernatremia. The loss of sweat, which contains some sodium, can cause hypovolemic hypernatremia in individuals who exercise vigorously in a hot environment. If the cause of the fluid loss is not apparent from the history or the physical examination, a urinary chloride concentration less than 10 mmol/L in the face of hypovolemic hypernatremia suggests that the electrolyte loss is extrarenal (cutaneous or gastrointestinal).

Hypervolemic Hypernatremia

Hypervolemic hypernatremia is relatively uncommon and often results from the administration of hypertonic sodium salts to patients without free access to water. Patients show signs of extracellular volume expansion (eg, hypertension, edema, congestive heart failure, and pulmonary edema). In infants, this syndrome has been caused by erroneous preparation of dietary formula using salt instead of sugar; in adult outpatients, it may be caused by ingestion of a concentrated salt solution, usually for its emetic effect.⁶²

In hospitalized adults, hypervolemic hypernatremia is most often iatrogenic, caused by intravenous administration of undiluted sodium bicarbonate (formulated at 1 mEq/mL or 1000 mmol/L) or sodium chloride (3% [513 mmol/L] or 23.5% [4019 mmol/L]). In patients with neurosurgical disease, it is caused by parenteral administration of hypertonic saline solutions to reduce intracranial pressure and possibly decrease inflammation.^{63, 64}

i. Hyponatric and hypernatric are used here to refer to a fluid with a sodium concentration less than or greater than that of plasma, respectively.

ii. The expected change in the serum sodium concentration is calculated as follows: [initial total body water volume] × [initial sodium concentration] ÷ [final total body water volume]; 30 L × 140mmol/L ÷ 27 L = 155 mmol/L.

The patient therefore appears euvolemic, so the most likely explanation for her hypernatremia is pure electrolyte-free water loss. (The amount of sodium in the hypertonic saline she received was 128 mmol, equivalent to about 830 mL of normal saline solution. This would be unlikely to cause significant fluid overload in a patient with normal heart and kidney function, although it exacerbated her hypernatremia.) The differential diagnosis at this point includes renal (DI) and extrarenal water loss (See Figure 43-3). The polyuria in her case suggests urinary water loss. A simple confirmatory test is the U_osm: if it is lower than the P_osm in the face of hyperosmolality, that would signal inappropriate urinary dilution (See Figure 43-1), consistent with DI. A high U_osm would be consistent with appropriate urinary concentration in the face of extrarenal water loss.

The patient has hypernatremia due to inadequate urinary concentration (DI). The differential diagnosis at this point includes inadequate circulating AVP levels (central or hypothalamic DI), in this setting due to the intracranial pathology, or renal resistance to appropriate concentrations of circulating AVP (nephrogenic or NDI). These can be distinguished by observing the effect of exogenous AVP on U_osm. The standard protocol consists of administering 5 units of aqueous vasopressin or 4 μg of desmopressin (DDAVP) subcutaneously, and measuring the U_osm every 30 minutes for 2 hours. Patients with NDI will show very little if any increase in U_osm (< 10% change), whereas patients with CDI will have a significant increase in U_osm, typically greater than 50%.⁶ (The gray area between a 10% and 50% increase in U_osm may be seen in patients with partial central DI.)

The patient apparently has NDI. In this setting, the most likely underlying cause is the patient's use of lithium. Twenty to 85% of patients taking lithium long-term will develop NDI.^{65, 66} As long as they have intact thirst and access to water, patients with DI (central or nephrogenic) typically have P_Na in the normal range since they drink enough to match their urinary water losses. When deprived of water, such patients will quickly dehydrate, as our patient did.

The clinical manifestations of hypernatremia are attributable to osmotically driven intracellular volume contraction and are proportional to the magnitude and rate of rise of the P_Na. To counteract cellular volume contraction, cells begin to adapt within minutes by allowing the influx of electrolytes, thus mitigating cell shrinkage. When hypernatremia lasts more than a few hours, brain cells generate new organic osmolytes. This leads to further water movement back into brain cells, restoring cell volume nearly to normal after about 3 days.⁶⁷ Thus, chronic progressive hypernatremia is associated with fewer and milder symptoms than acute severe hypernatremia. Patients with hypernatremia tend to present with weakness, lethargy, and confusion. Seizure and coma may supervene. Acute severe hypernatremia in infants and small children is associated with intracranial bleeding,⁶⁸ presumably caused by brain shrinkage and traction on the penetrating vessels. There is some controversy, however, as to whether the hypernatremia in that situation is the cause or the effect of the intracranial hemorrhage.⁶⁹

For patients with pure water losses (euvolemic), therapy has two goals: (1) reduction and/or replacement of ongoing water losses and (2) replacement of the existing water deficit.

The reduction of the urinary water losses that accompany lithium-associated NDI is best accomplished with amiloride, with or without cyclooxygenase (COX) inhibitors.⁶⁶ Because amiloride and most COX inhibitors are orally administered, treatment of NDI in the critically ill patient often consists of water administration (see below) until he or she is able to take medications by mouth. (Furthermore, a COX inhibitor would be contraindicated in a patient such as ours with an intracranial hemorrhage.)

If the urinary water losses had been due to CDI and not NDI, an antidiuretic hormone preparation would be the treatment of choice to reduce ongoing water losses. Several formulations are available (Table 43-3). In the acute (postsurgical or posttraumatic) setting, l-arginine vasopressin may be used either subcutaneously or intravenously, although the latter route may be associated with hypertension and coronary spasm and should therefore be used with extreme caution.⁷⁰ The advantage of vasopressin in this setting is its short half-life, which allows the physician to repeatedly assess the need for continued hormone replacement, especially when the disorder may be self-limited. DDAVP is a synthetic analogue of vasopressin that has no vasoconstrictor properties, and thus avoids the risks of hypertension and myocardial ischemia.

Once the ongoing water losses have been addressed, the current body water deficit can be estimated by the following formula:

where TBW is total body water in liters (estimated as about 0.5 × lean body weight [kg] in women and 0.6 × lean body weight in men). For example, our patient is a 60-kg woman with a P_Na of 155 mmol/L. She is estimated to have a total body water deficit of 30 (1 — 0.90) or 3 L. This formula provides only a rough estimate of the water deficit.

The rate of water replacement should be proportional to the rapidity with which the hypernatremia developed.⁶⁷ Thus, if the hypernatremia had developed over only a few hours (such as in our patient, or in postsurgical or posttraumatic DI), it can be corrected just as quickly. On the other hand, hypernatremia of more than a day's duration (or of unknown duration) must be corrected slowly in order to avoid inducing cerebral edema. In that setting, one should aim to correct half the water deficit in the first 24 hours, and the remainder over the next 24 to 48 hours.

Water is best administered enterally, as tap water. If that route is unavailable, 5% dextrose in water (D5W) may be used, with the understanding that the capacity to metabolize glucose is limited to about 15 g/h in a critically ill adult.⁷¹ Thus, even in nondiabetic patients, the administration of more than 300 mL/h of D5W is likely to result in hyperglycemia, which may be relatively resistant to insulin administration. The hyperglycemia will exacerbate urinary water losses by causing an osmotic diuresis. Half-normal (0.45%) saline may be a good alternative, as long as one recognizes that only half the administered volume is electrolyte-free water, and that the sodium load may cause unwanted volume expansion.

For the hypernatremic patient who presents with obvious volume depletion—manifested by hypotension, tachycardia, and evidence of impaired tissue perfusion—normal (0.9%) saline should be given intravenously, regardless of the degree of hypernatremia. This is consistent with the first principles of emergency and critical care, prioritizing the adequacy of the circulation. Only after the extracellular volume deficit has been largely corrected may the clinician direct his or her attention to the total body water deficit (see earlier).

Patients with hypervolemic hypernatremia need reduction in their extracellular and intravascular volume before their water deficit can be corrected. Failure to do so will exacerbate the volume overload. For patients with adequate renal function, this may be accomplished with the use of diuretic drugs. Loop diuretics tend to cause the excretion of an isotonic urine. Replacement of that urine volume with pure water will allow correction of the hypervolemia and the hypernatremia simultaneously.

Because of the imprecision of the estimation formulas and the failure of the foregoing analysis to take account of other fluids and electrolytes both administered and lost, it is imperative that the plasma electrolytes be monitored frequently during the correction of hypernatremia, especially because cerebral edema may develop with overly rapid correction.