Sodium is the most copious extracellular (EC) cation and is the most important osmotically active constituent of the EC fluid. Changes in serum sodium represent changes in salt and water balance. Therefore, a careful assessment of the patient's osmolality and volume status are vital to appropriately evaluate the patient with either hypernatremia or hyponatremia.
Hyponatremia is one of the most common electrolyte disorders in hospitalized patients, with a reported prevalence of 30% to 40%. It has been observed in 14% of patients upon admission to the ICU and in 30% of patients in the critical care setting.1,2 This diagnosis is associated with statistically significantly increased mortality, length of hospital stay, admission to the ICU, and cost for hospitalization.3 An algorithm for evaluating the patient with hyponatremia is proposed in Figure 27–1.
Clinical approach to the patient with hyponatremia.
Pseudohyponatremia and Hyperosmolar Hyponatremia
The first step in the evaluation of a hyponatremic patient is to obtain a serum osmolality in order to identify those patients with pseudohyponatremia and those who have hyperosmolar hyponatremia. As its name implies, pseudohyponatremia refers to a spuriously low-measured serum sodium value. In the presence of severe hyperlipidemia and paraproteinemia, the water phase of serum becomes displaced by these particles, and when flame photometry or indirect potentiometry is used to the measure sodium, the values are reported as spuriously low. Measuring serum sodium by direct potentiometry should remove this problem. Patients with pseudohyponatremia require no further treatment.
The presence of exogenously or endogenously derived osmotically active particles in serum will cause hyperosmolar hyponatremia. In normal homeostasis, water will shift across the cell membrane to equalize the osmolality between the intracellular (IC) and EC spaces. When there are osmotically active particles in the EC space, large volumes of water can transfer from the IC, causing a true dilutional hyponatremia. Patients who undergo procedures, such as hysteroscopies or transurethral resections of bladder tumor (TURBTs) are exposed to glycine containing fluids. Glycine is an osmotically active particle. Because large volumes of these solutions are instilled into the body cavity during surgical procedures, the high intravesical pressures can cause glycine to be absorbed into the venous circulation. Subsequent translocation of free water from the IC to the EC space will cause a dilutional hyponatremia. A similar process occurs in the presence of other osmotically active particles, such as mannitol and in the setting of hyperglycemia.4 Importantly, the patient with hyperosmolar hypernatremia should never receive hypertonic saline as part of the management of hyponatremia, even if they have mental status changes associated with hypernatremia, since hypertonic saline will only exacerbate the hyperosmolar state. A renal consultation should be obtained since these patients may require hemodialysis (HD).
Most patients will fall into the remaining category of hypo-osmolar hyponatremia. Since disorders of serum sodium are best approached as disorders of relative concentrations of salt and water, all hyponatremic patients, whether they are volume overloaded, euvolemic or hypervolemic, have an excess of total body water relative to total body sodium. Therefore, an assessment of the patient's volume status helps to define the primary disorder in this category of patients. Be mindful that the presence of edema does not accurately identify a patient as hypervolemic. Deep venous thrombosis, inferior vena cava (IVC) clots, and lymphatic or venous obstruction from pelvic masses can all produce lower extremity edema. However, these patients may have a state of diminished effective intravascular volume due to diminished venous return to the right atrium from the primary disease process. Since patients in the ICU can have nonvolume mediated causes of tachycardia and dry mucous membranes, whenever possible, it can be very helpful to check orthostatic vital signs at the bedside to assess the volume status in patients who is not frankly hypotensive. A patient is considered to be orthostatic if the heart rate increases more than 20 beats/min or the systolic blood pressure drops more than 10 mm Hg from the supine to upright position. Patients should be allowed spend 2 to 3 minutes in the sitting and standing position before the vitals are checked to allow for appropriate autoregulation.
Hypovolemic hyponatremia—This scenario can be observed in patients on diuretics, or who have diarrhea, excessive sweating (marathon runners), or insensible losses from the skin (burn victims). A similar scenario can be observed in the intubated ICU patient because the positive intrathoracic pressures generated by mechanical ventilation will impair cardiac filling. The volume deficit in these patients will cause activation of the baroreceptors, the release of antidiuretic hormone (ADH), and activation of the renin angiotensin aldosterone system and the sympathetic nervous system. The end result of triggering these pathways is the retention of free water and salt. ADH and angiotensin are also dipsogens and will stimulate thirst. Consequently, there will be net retention of free water and salt, but a relative excess of free water retention. These patients typically have “prerenal” indices—a urine sodium less than 20 mEq/L, urine osmolarity more than 500 mOsm and a fractional excretion of sodium (FENa) less than 1%. Since diuretics can affect urine sodium excretion, for patients who have received diuretics within the preceding 24 hours, the fractional excretion of urea (FEurea) can be checked instead. A FEurea of <15% suggests volume contraction.
A more complex presentation of hypovolemic hypovolemia occurs with renal salt wasting and cerebral salt wasting. Renal salt wasting has been described following exposure to chemotherapeutic agents (cisplatin and ifosfamide) and anti-infectives (amphotericin, trimethoprim-sulfamethoxazole, and amikacin).5 Cerebral salt wasting has been described following CNS trauma, neurosurgery, and traumatic brain injury. In contrast to the previously described group of hypovolemic patients, those individuals with salt wasting syndromes tend to have polyuria and will have inappropriately high urine sodium and osmolality values and the FENa can be more than 1%. Similar urine values can be observed in patients with the syndrome of inappropriate ADH release (SIADH) which is discussed in the section on normovolemic hyponatremia. However, the patient with SIADH, by definition, is euvolemic.
Appropriate treatment for salt wasting syndromes is isotonic normal saline (0.9% NS), which can be delivered as a bolus or infusion, depending on the severity of the volume depletion. Some patients with severe salt wasting may require hypertonic saline solutions (2% or 3% NS) to replace the amount of salt being lost in the urine.
There is a subset of critically ill patients who appear volume overloaded on exam, but have diminished effective arterial blood flow and who are hypotensive or orthostatic on exam. Patients with hepatorenal syndrome, systemic inflammatory response syndrome, and those who are “third spacing” (rhabdomyolysis and pancreatitis) will have prerenal indices. In hepatorenal syndrome, increased nitric oxide levels results in preferential pooling of blood in the splanchnic circulation, resulting in diminished effective intraarterial blood volume (EABV) to other vital organs, including the kidneys.6 These patients can be frankly hypotensive in the presence of substantial edema on exam. In systemic inflammatory response syndrome, although the pathophysiology is not well delineated, several cytokines pathways, which include tumor necrosis factor, nitric oxide, and interleukins appear to be responsible for the substantial capillary leak and diminished EABV. These patients may require significant amounts of crystalloid and/or colloid fluids to expand their intravascular volume.
Hypervolemic hyponatremia—This group of visibly volume overloaded patients have excessive amounts of total body free water and sodium, with relatively more free water than sodium in the EC space. Classically, patients with congestive heart failure, cirrhosis, nephrotic syndrome (NS), and pregnancy fall into this category. In the case of a normal pregnancy, serum sodium declines up to 5 mEq/L below normal values because ADH is released at a lower set point. Hyponatremia in pregnancy is physiologic and does not require correction.7 On the other hand, the hyponatremia associated with congestive heart failure and cirrhosis is best treated with the use of loop diuretics. Thiazide diuretics should be avoided in the setting of hyponatremia because they can actually cause hyponatremia. This is because thiazides impeded the ability of the collecting tubules to maximally concentrate urine and will, therefore, cause overall retention of free water.
Normovolemic hyponatremia—The 2 physiologic stimuli for ADH release are an elevated serum osmolality and a diminished plasma volume. Therefore, in the setting of a low-serum osmolarity and a normal plasma volume, there is no physiologic stimulus for ADH release. There are, however, numerous nonphysiologic stimuli for ADH, and these stimuli are prevalent in the ICU. Pain, nausea, drugs (catecholamines, chemotherapy, antidepressants, and diuretics), and any lung or CNS disease can cause inappropriate release of ADH. The postoperative state is also associated with inappropriate ADH release, and potentially severe hyponatremia can develop in patients receiving hypotonic intravenous (IV) solutions in the perioperative period. Death and permanent neurologic deficits in the setting of postoperative hyponatremia is more commonly observed in menstruating women and pre pubertal children.8 Adrenal and thyroid deficient states are also associated with SIADH. Figure 27–1 lists some causes of SIADH that can be encountered in the ICU setting.
The defining feature of the SIADH state is the presence of inappropriately concentrated urine in the setting of a low-serum osmolality and a normal plasma volume. The urine sodium is > 20 mEq/L and the FENa is more than 1%.
Importantly, administering 0.9% NS to a patient with SIADH will actually worsen the hyponatremia. Because these patients have a normal plasma volume, there is no stimulus for the kidney to retain the 9 g of sodium contained in each liter of 0.9% NS. However, the presence of ADH will cause the renal tubules to retain the IL of water. This free water retention will dilute and further lower the serum sodium. Inappropriately administering 0.9% NS to patients with SIADH who have a very low serum sodium values or abruptly lowing the sodium significant amounts can precipitate hyponatremic seizures. Therefore, 0.9% NS without furosemide or any hypotonic fluids (D5W, 1/2NS) are all contraindicated in the setting of SIADH.
Several approaches can be employed to correct the imbalance between sodium and water concentration in the setting of SIADH. Patients can be asked to restrict their fluid intake to 1 to 1.5 L of free water per day and can be given NaCl tablets. These interventions may be limited in the ICU patient since the often require IV medications and cannot tolerate oral medications. In this case, 0.9% NS given along with furosemide or hypertonic saline (2% or 3%) alone can be used to increase the serum sodium concentration. Usual doses of furosemide in patients with normal renal function are 10 to 20 mg/d and can be give IV or orally. Higher doses of furosemide may be required in patients with renal function. Vasopressin-2 (V2) receptor antagonists are the newest class of agents which can be used in the management of hypervolemic and euvolemic hyponatremia. V2 receptor antagonists will block ADH-mediated insertion of aquaporin channels at the apical membrane of the renal collecting duct cells and will ultimately result in free water losses in the urine. Conivaptan is an IV formulation (20 mg infused over 30 minutes as a loading dose, followed by a continuous infusion of 20 mg over 24 hours) and tolvaptan can be given to patients who are able to take oral medications (initial dose is 15 mg once daily can increase to 30 mg once daily after 24 hours). Any combination of fluid restriction, NaCl tablets, furosemide, and/or a V2 receptor antagonist can be used to achieve a normal serum sodium value. Conivaptan and tolvaptan have been shown to reliably increase serum sodium by 6 to 8 mEq/L with a 48 hours period and have the advantage of not producing the hypokalemia and metabolic alkalosis that can result from treatment with diuretics.9
If nausea, vomiting and pain are inappropriately stimulating ADH, then appropriate use of antiemetics and pain medications can diminish these nonphysiologic stimuli for ADH release. Any of the culprit medications that have been implicated as a cause of hyponatremia (see Figure 27–1) should be discontinued if it is safe to do so. For patients with adrenal or thyroid deficient states, hormone replacement therapy will be necessary to correct the hyponatremia.
Clinical Manifestations and Management of Severe Hyponatremia
The clinical signs and symptoms of hyponatremia are in large part manifestations of increased intracerebral pressure due to brain edema. When the serum sodium and serum osmolality are lower than that within the brain cells, water will shift into the brain cells. Since the skull is a fixed cavity, it cannot expand to accommodate this increase in brain volume. Some clinical signs of increased intracranial pressure include nausea, confusion vomiting, a decline in mental status, ataxia, and seizures. When hyponatremic encephalopathy develops, the associated mortality rate is as high as 20%.8 If the brain volume markedly exceeds the skull volume, frank herniation of the brainstem and death can occur. There are adaptive mechanisms in place to mitigate brain edema in the setting of hyponatremia. However, when the serum sodium drops too rapidly relative to the ability of the brain to adapt to the change in osmolality, clinical signs, and symptoms will develop. This explains why one patient can present with seizures and another can appear asymptomatic at equivalent serum sodium values.
The brain's adaptive mechanisms are essentially aimed at decreasing its water content back to normal by extruding solute. In rat models, Na2+ and Cl– are extruded via the Na2+ and Cl– channels present in the cell membrane within 30 minutes of induction of hyponatremia. These electrolyte losses are maximal at around 3 hours. After longer periods of persistent hyponatremia, organic osmolytes such as glutamate, creatine, and taurine exit the brain cell.10 These compensatory adaptations explain why rapid correction of chronic hyponatremia leads to rapid egress of water from the brain cell. In mild cases, dehydration of the brain tissue occurs, and in severe cases, osmotic demyelination can occur. The current recommendation for correcting chronic hyponatremia or hyponatremia of unknown duration is to correct the serum sodium no more than 10-12 mEq/L within the first 24 hours, and at a rate of no more than 10 to 12 mEq/L within the first 24 hours, and generally, at a rate of no more than 0.5 mEq/L/h.11
Treatment for mild hyponatremia is discussed in the aforementioned sections. When symptomatic hyponatremic develops (mental status changes, seizures, and coma), and when serum sodium levels are very low (less than 115 mEq/L), patients needs to be closely monitored with repeated neurologic evaluations and frequent monitoring of their serum sodium values while they receive 3% NS to correct the sodium deficit. One of the numerous online resources available to calculate the sodium deficit is http://www.mdcalc.com/sodium-deficit-in-hyponatremia/, or the sodium deficit can be calculated using the equation: Sodium deficit = total body water × (desired serum Na − actual serum Na), where total body water is total body weight (kg) × 0.5. Each IL of 3% NS contains 512 mEq of sodium. Importantly, the severely symptomatic patient with hyperosmolar hyponatremia should not receive 3% NS. Administration of a hypertonic solution in this setting is contraindicated as it will worsen the hyperosmolar state. This category of patients may require urgent dialysis. Patients with significant hypovolemia should be treated with boluses of NS until a euvolemic state is achieved. Thereafter, the rate of correction of the serum sodium should not exceed 10 to 12 mEq/L in a 24 hours period.
The incidence of hypernatremia in the general hospital population is only 1%. The reported incidence in the ICU population ranges from 10% to 26%, and it is most commonly hospital acquired.12 When hypernatremia is acquired in the ICU, the adjusted hazard ratio for ICU mortality increased twofold in patients with mild hypernatremia (> 145 mEq/L) and 2.67-fold in patients with moderate to severe hypernatremia (> 150 mEq/L).13
Hypernatremia arises when there is a relative or absolute free water deficit so patients are either hypervolemic or hypovolemic, respectively. Normally, a rise in serum sodium, and consequent rise in serum osmolarity causes ADH release, which is a potent stimulus for thirst. Patients with an intact thirst mechanism and access to free water are able to maintain normal serum sodium levels notwithstanding considerable urine outputs in hyperosmolar states from hyperglycemia or diabetes insipidus. By contrast, ICU patients oftentimes have an impaired thirst response, impaired access to free water or restricted fluid intake.
Administration of sodium bicarbonate, trisodium citrate, hypertonic saline, or other fluids containing an excess of solute relative to free water results in hypervolemic hypernatremia.
Conditions that cause excessive amounts of free water losses via the kidneys include central and nephrogenic diabetes insipidus (CDI and NDI, respectively). Acquired causes of NDI include amphotericin, foscarnet, lithium, hypokalemia, and hypercalcemia. Hyperglycemia and mannitol cause an osmotic diuresis and hyperalimentation solutions can also produce diuresis due to urea generation. Nonrenal free water losses can occur via the gastrointestinal (GI) tract (nasogastric suction, diarrhea, and vomiting), skin (burns, hyperthermia, open wounds, and drains), and from the respiratory tract in intubated patients.
Clinical Manifestations and Management
The clinical signs of hypernatremia are the result of shrinkage of the brain away from the skull and the mechanical stress that this causes on blood vessels, which can lead to ischemia and hemorrhage. Symptoms include agitation, lethargy, seizures, and coma. When hypernatremia develops rapidly, osmotic demyelination can occur.
The goals in treating hypernatremia include (1) identifying correcting any reversible factors (hypercalcemia, hypokalemia hypertonic solutions); (2) correcting volume depletion if present; and (3) replacing the calculated free water deficit. Additionally, if compatible, all IV medications should be administered in hypotonic solutions (1/2 NS or D5W). In hypervolemic patients, thiazides can be used to decrease edema as well as the serum sodium. In patients with polyuria due to partial NDI or CDI, arginine vasopressin administration will permit free water retention in the kidneys and correction of the sodium to a normal value permitting free water retention in the kidneys. In the hypovolemic patient with hemodynamic compromise, isotonic NS can be given to first correct the volume deficit and to ward off hemodynamic collapse. Thereafter, hypotonic solutions (1/2 NS or D5W) can be used with the goal of correcting 1/2 the free water deficit in the initial 24 hours period, and the remaining deficit over the ensuing 48 to 72 hours. The free water deficit can be calculated using the formula: Water deficit = 0.5 Wt (kg) [Serum Na/140-1]. Ongoing losses should be considered when replacing the water deficit. The serum sodium should not decrease by more than 0.5 mEq/L/h. Overly rapid correction of hypernatremia can cause increased intracranial pressure and the signs associated with hyponatremia (see section on hyponatremia).