Chapter 27: Electrolyte Disorders in Critically Ill Patients

Fluid and electrolyte disorders are ubiquitous in the intensive care unit (ICU) setting. This text will focus on common clinical scenarios in the ICU and assumes a basic fund of knowledge about fluid and electrolyte disorders.

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

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.

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).

Hypo-Osmolar Hyponatremia

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.

Hypernatremia

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.

Hypervolemia Hypernatremia

Administration of sodium bicarbonate, trisodium citrate, hypertonic saline, or other fluids containing an excess of solute relative to free water results in hypervolemic hypernatremia.

Hypovolemic 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).

Approximately 98% of the body's potassium is found in the IC space. Normally, when potassium enters the circulation acutely, it is rapidly shifted to the IC space by the action of insulin and catecholamines. The kidneys are the major site for excretion of potassium and chronic potassium homeostasis. Eighty percent of potassium is excreted from the kidneys, and 90% is reabsorbed via the renal tubules. Aldosterone is the major hormone governing renal potassium excretion.¹⁴ About 15% of potassium is eliminated from the GI tract and 5% is lost in sweat.¹⁵ The major clinical manifestations potassium disorders are cardiac and neuromuscular abnormalities.

Hyperkalemia

Keeping in mind the key regulators of potassium homeostasis mentioned in the previous paragraph, a simple and effective approach to evaluating hyperkalemia is to make the following inquiries: (1) Is there is too much exogenous potassium being delivered to the patient? (2) Is there is a problem with the usual mechanism for shifting potassium into the IC space? (3) Is there is a problem with eliminating potassium via the kidneys or GI tract? A number of conditions can predispose ICU patient to developing hyperkalemia, including insulin deficiency or resistance, renal dysfunction, adrenal insufficiency, and exposures to medications that are known to derange normal potassium homeostasis.

Acute potassium loads from cell destruction in the setting tumor lysis syndrome, massive blood transfusions and rhabdomyolysis can overwhelm the normal mechanisms available to acutely shift potassium into the IC space. In patients with hyperglycemia, insulin deficiency will cause diminished influx of potassium to the IC space. Moreover, when hyperglycemia is present, in response to the osmotic gradient generated across the cell membrane by the hyperglycemia, water will shift from teh IC to the EC space to equalize the gradient across the cell membrane. By the process of solvent drag, potassium will move with the water to the EC space, further increasing serum potassium levels.

A host of medications commonly used in the ICU can (1) impair the kidney's ability to appropriately excrete potassium (triamterene, trimethoprim, pentamidine, and spironolactone); (2) inhibit the ATPase driven movement of potassium into cells (beta-blockers and digoxin; (3) inhibit aldosterone synthesis (angiotensin converting enzyme inhibitors, angiotensin 2 receptor blockers, heparin, and azole antifungals); (4) inhibit prostaglandin (nonsteroidal anti-inflammatory medications); and (5) suppress the release of low renin and consequently low aldosterone levels (cyclosporine and tacrolimus).¹⁶

Patients who are volume-depleted patient are unable to properly excrete potassium, since the delivery of sodium to the distal renal tubule is necessary for urinary potassium secretion. Patients with obstructive uropathy also have an impaired ability to excrete potassium properly. Potential sources of exogenous potassium that can go unnoticed in the ICU patient include the administration of inappropriate enteral or parenteral nutrition, and chronic absorption of potassium from degenerated RBCs from a retroperitoneal hematoma or GI bleed.

Clinical Manifestations and Management

The clinical signs and symptoms of hyperkalemia are predominantly neuromuscular (muscle weakness, paralysis) and cardiac (electrocardiographic [EKG] changes—peaked T waves, prolonged PR interval, widened QRS, arrhythmias, and asystole).

The patient with hyperkalemia is best approached with following principles in mind: (1) identify and discontinue all medications that may be deranging normal potassium homeostasis; (2) discontinue all potassium containing IV fluids; (3) shift potassium into the IC space; and (4) increase potassium elimination through the kidneys and the GI tract.

For patients who have EKG changes associated with hyperkalemia, IV calcium (10% calcium chloride or calcium gluconate 500-1000 mg over 2-5 minutes) is needed to stabilize the cardiac cells and lower the risk of fatal arrhythmias. Patients with muscle weakness or paralysis and those who have acute renal failure may require urgent dialysis. An early renal consultation is recommended for these patients.

The most rapid way to lower serum potassium is with the use of inhaled beta agonists (nebulized albuterol 10-20 mg over 15 minutes) and insulin (50 mL of D50W + 10U regular insulin over 15-30 minutes). These agents will acutely shift potassium into the IC space. In the hyperglycemic patient, insulin therapy will dissipate the gradient for solvent drag across the cell membrane in addition to pushing potassium back into the IC space. If a patient is acidemic, neutralizing the serum pH with IV sodium bicarbonate (50 mEq intravenous push (IVP)) will facilitate potassium entry back into cells. While beta agonists and insulin acutely shift potassium into cells, these measures are short lived and rebound hyperkalemia can occur if additional steps are not taken at the same time to permanently remove potassium from the body. Infusion with 0.9% NS will promote a kaliuresis by increasing delivery of sodium to the distal tubule. If clinically appropriate, a loop diuretic can be used alone or in combination with IV 0.9% NS to promote renal potassium elimination. Potassium losses can also be affected via the GI tract. Sodium polystyrene (15-30 g) will exchange potassium for sodium across the colonic mucosa. However, it may take several days to appreciably lower the serum potassium since delivery to the colon is dependent on GI transit time. Sodium polystyrene can be given as a rectal suppository or orally in combination with sorbitol for faster delivery to its site of action at the colonic mucosa. Care should be taken when prescribing this medication to patients in the postoperative period following abdominal surgery and in patients who are hypotensive or have decreased GI motility. These patients may be at increased risk of bowel necrosis with this therapy.¹⁷ Sodium polystyrene and sodium bicarbonate can both worsen fluid retention in patients with volume overload and should be used with caution in this setting.

Hypokalemia

The frequency of hypokalemia in the adult ICU population has not been well documented, but it is encountered fairly commonly. In the pediatric ICU population, the reported frequency is 40%.¹⁸ The same principles apply when approaching hypokalemia as is the case with hyperkalemia. That is to say, it is necessary to systematically identify factors that will (1) shift potassium into the IC space (beta agonists, epinephrine, insulin, dobutamine, respiratory alkalosis, and refeeding); (2) increase GI losses of potassium (nasogastric tube (NGT) suction; vomiting, diarrhea, and sodium polystyrene sulfonate); (3) increase renal potassium losses (diuretics, hypomagnesemia, aminoglycosides, amphotericin, cisplatin, ifosfamide, fludrocortisone, postobstructive diuresis, and post-acute tubular necrosis (ATN) diuresis); and (4) diminish oral potassium intake. In the setting of a post-ATN and a postobstructive diuresis, renal tubular resorptive function is impaired so patients can excrete large amounts of isosthenuric urine containing significant amounts of electrolytes. In the refeeding syndrome, the introduction of carbohydrates and subsequent increase in insulin release will shift potassium to the IC compartment.

Clinical Manifestations and Treatment

The clinical manifestations of hypokalemia are predominantly cardiac (arrhythmias, EKG changes [flattening of the T wave, U wave]) and neuromuscular (muscle weakness, cramping and ileus, and constipation). Fairly small decrements in serum potassium values can actually represent significant potassium deficits since most of the potassium stores are in the IC space. For example, mild hypokalemia with a serum K of 3.0 mEq/L can actually reflect up to a 300 mEq total body deficit.¹⁹ There is no reliable way to measure the total body potassium deficit.

In general, ICU patients receive potassium replacement intravenously, but oral administration of potassium is preferable if possible. Potassium infusions can be caustic to peripheral veins, so for doses exceeding 10 mEq/h, a central line should be used. Continuous EKG monitoring is appropriate in those patients with an abnormal EKG for whom it may be necessary to infuse potassium at rates exceeding 20 mEq/h. In all patients, especially those with renal impairment, serum potassium levels should be repeated after electrolyte replacement to ensure adequate correction and to avoid over correction. In patients with concomitant hypomagnesemia, the hypomagnesemia needs to corrected first because hypomagnesemia will cause efflux of potassium from the renal tubules and can result in resistance to potassium supplementation. For ICU patients with diuretic-induced hypokalemia who require further diuretic therapy, in addition to correcting the hypokalemia, consideration should be given to adding to or replacing the loop diuretic with a potassium sparing diuretic such as spironolactone, triamterene, or amiloride.

Serum calcium reflects less than 1% of total body calcium, as 99% of total body calcium resides in the bones. Of the remaining 1% of serum calcium, 50% is bound to albumin and 50% is unbound or biologically active calcium. Common conditions in ICU patients can affect the amount of unbound (free) calcium. For example, in the setting of metabolic alkalosis, there is increased calcium binding to albumin and in the setting of metabolic acidosis, decreased calcium binding to albumin. Because ICU patients are often hypoalbuminemic and have derangements in their acid base status, measuring ionized serum calcium levels is the best method for determining an individual's true serum calcium status.²⁰

The chief regulators of serum calcium levels are parathyroid hormone (PTH), vitamin D levels, and calcitonin. Calcium acts as a key IC regulator and messenger. As a result, some clinically important manifestations of disordered calcium homeostasis in the ICU patient include neuromuscular and cardiac dysfunction. Symptoms of severe hypocalcemia include tetany, seizures, a prolonged QT interval, and ventricular arrhythmias.

Hypocalcemia

Hypocalcemia is ubiquitous in the ICU, affecting 80% to 90% of all patients,¹⁶ and when present, is associated with longer ICU stays, increased mortality and higher rates of bacteremia.²¹ It can be the result of low vitamin D levels and abnormalities in the release or effect of PTH. Hypoparathyroidism and hypomagnesemia can both decrease PTH secretion and hypomagnesemia additionally diminishes the effect of PTH on skeletal tissue and so will decrease calcium release from bone.

The patients who come to the ICU following a parathyroidectomy can have severe and abrupt hypocalcemia. Following resection of the parathyroid gland for secondary or tertiary hypoparathyroidism, the tonic release of high levels of PTH suddenly dramatically decreases. Serum calcium rushes into the skeletal compartment and can result in severe symptomatic hypocalcemia. This is referred to as the “hungry bone syndrome.”

In cancer patients, tumor lysis syndrome can occur spontaneously or following chemotherapy. As the tumor cells release their IC contents, the resultant acute hyperphosphatemia becomes the source for calcium phosphate precipitates and this will abruptly lower the serum calcium. A similar scenario of acute calcium phosphorus precipitate formation occurs in the setting of rhabdomyolysis and following exposure to phosphorus containing laxatives and enemas which are commonly used prior to colonoscopies. Hyperphosphatemia will further lower serum calcium levels by causing decreased levels of 1,25(OH)₂ vitamin D.

In patients who transfused with large amounts of blood products, and in those patients receiving citrate anticoagulation during plasmapheresis or continuous renal replacement therapy (CRRT), hypocalcemia can result from citrate acting as a chelator of ionized calcium. Gadolinium contrast interferes with calcium assays and can cause spurious hypocalcemia. However, the ionized serum calcium measurements are not affected.²²

Clinical Manifestations and Treatment

For acute correction of symptomatic hypocalcemia, IV calcium gluconate or calcium chloride (10 mL of a 10% solution) can be administered over 10 minutes. For patients with hungry bone syndrome, in addition to IV pushes of calcium chloride or calcium gluconate, a continuous IV calcium infusion, with frequent monitoring of serum calcium, may be necessary to maintain normal serum calcium levels. When hypocalcemia is accompanied by hypomagnesemia, the hypomagnesemia will need to be corrected first or the hypocalcemia can become resistant to calcium supplementation due to the effect of hypomagnesemia on PTH release and action on its end organs. When hypocalcemia is accompanied by metabolic acidosis, the hypocalcemia should be corrected before the acidosis because correcting the acidosis first will further lower the serum calcium and possibly precipitate symptomatic hypocalcemia. In patients with hypocalcemia due to formation of calcium phosphorus complexes (pancreatitis, tumor lysis syndrome), hypocalcemia should only be corrected if patients become symptomatic. If the calcium phosphorus product exceeds 60, then dialysis should be considered to lower the calcium phosphorus product prior to calcium repletion.

Hypercalcemia

Hypercalcemia occurs less often than hypocalcemia in the ICU. When present, the level of hypercalcemia can be an important clue to its pathogenesis. Serum calcium values above 13 mg/dL should raise suspicion for hypercalcemia of malignancy in the appropriate clinical setting. Hypercalcemia of malignancy is most often attributable to PTH related protein and, less frequently, to osteolytic cytokines and exogenous calcitriol production. Less severe levels of hypercalcemia can be seen in association diseases that increase bone resorption (immobility, thyrotoxicosis, and Paget's and hypervitaminosis A); diseases that increase intestinal absorption of calcium (milk alkali syndrome and hypervitaminosis D); any cause of increased PTH levels (primary, secondary, or tertiary hyperparathyroidism); elevated Vitamin D levels (from oral supplements, or granulomatous diseases, such as tuberculosis or sarcoidosis); and medications (thiazide diuretics, lithium, theophylline, and teriparatide). Adrenal insufficiency causes hypercalcemia via several mechanisms (volume contraction, increased bone resorption, and increased tubular absorption of calcium).

Clinical Manifestations and Treatment

Some neurologic manifestations of hypercalcemia include anorexia, confusion, and obtundation. Cardiac manifestations include arrhythmias and EKG changes (shortened QT). Importantly, hypercalcemia can cause a NDI. Free water losses in the urine from the NDI, in addition to diminished oral intake due to decrease mental acuity and anorexia in these patients, results in significant volume depletion in hypercalcemic patients. Therefore, aggressive volume resuscitation is a cornerstones of therapy for hypercalcemia.

The primary goals in the management of hypercalcemia are to (1) increase urinary excretion of calcium and (2) inhibit bone resorption. To this end, in the absence of edema, aggressive volume expansion with 0.9% NS at rates needed to promote a urine output of 100 o 150 cc/h is recommended. These patients often may require a 1 to 2 L bolus of 0.9% NS to replace the fluid deficit and then require an infusion rate of 150 to 200 mL/h. Once the patient is adequately volume replete, furosemide can be used to promote a calciuresis. It is recommended that furosemide not be given prior to adequate volume resuscitation since the diuretic can further compromise the hemodynamic status of these dehydrated patients. Calcitonin (4 units/kg every SQ every 12 hours for 4-6 doses) will begin to lower serum calcium within 4 to 6 hours of administration, with a maximum effect of 1 to 2 mg/dL (0.3-0.5 mmol/L). It does so by inhibiting bone resorption and by increasing urinary calcium excretion. Unfortunately, tachyphylaxis due to downregulation of it receptors occurs after repeated dosing so the medication loses efficacy after 48 hours. In patients who are volume overloaded or anuric, dialysis with a low calcium dialysate (2.5 mEq/L) may be necessary to treat hypercalcemia.

Bisphosphonates (BPs) have become another cornerstone for management of hypercalcemia. Pamidronate and zoledronate currently have Food and Drug Administration (FDA) approval for the management of hypercalcemia, but pamidronate should be preferentially used in patients with renal insufficiency and a creatine clearance less than 30 mL/min. Please consult dosing guidelines for zoledronic acid for patients with mildly impaired renal function. Since the onset of action of BPs is 2 to 4 days, it is recommended that they be administered at the time that hypercalcemia is first diagnosed.

Phosphorus is another anion which is primarily contained in the bones and soft tissue, with only 1% circulating in the EC space. Phosphorus is the building block for adenosine triphosphate, which is required for all energy requiring physiologic and metabolic functions. Therefore, IC phosphate depletion can produce multiorgan dysfunction due to decrease oxygen release to the cardiac (decreased myocardial contractility), pulmonary (respiratory failure due to diaphragmatic paralysis), GI (dysphagia and ileus), neurologic (parasthesias and seizures) and skeletal systems (rhabdomyolysis and myopathy).

Hypophosphatemia

In the general hospital wards, about 5% of patients have serum phosphorus levels less than 2.5 mg/dL, while the prevalence of hypophosphatemia in patients with severe sepsis and trauma is reported to be 30% to 50%.²³ Patients in the ICU have conditions which predispose them to developing hypophosphatemia via the three major mechanisms: (1) redistribution of phosphorus to the IC space (due to respiratory alkalosis, glucose, and insulin release during carbohydrate refeeding in malnourished patients); (2) redistribution of phosphorus into the bone (hungry bone syndrome [see section on hypocalcemia] and bisphosphonate therapy); (3) decreased intestinal absorption of phosphorus (steatorrhea, chronic diarrhea, or prolonged starvation, phosphate binding in the gut by aluminum or magnesium containing antacids); and (4) increased phosphaturia (any cause of increased PTH, vitamin D deficiency, acetazolamide, thiazide diuretics, or Fanconi syndrome [multiple myeloma and ifosfamide]). Patients on continuous CRRT will also lose phosphorus to the dialysate.

Treatment

Phosphorus replacement is available as potassium phosphate and sodium phosphate. Keep in mind that each mmol of potassium phosphate contains 1.47 mEq of potassium. Therefore, 15 mmol of potassium phosphate will deliver 22.5 mEq of potassium to the patient. For patients with symptomatic hypophosphatemia, phosphorus can be given at a rate of up to 7 mmol/h.²⁴ Serum phosphorus levels should be checked 2 to 4 hours after IV repletion since phosphorus can quickly shift into the IC space. Whenever possible, oral phosphorus is preferred for the correction of asymptomatic hypophosphatemia and when the serum phosphorus level is more than 2 mg/dL.

Hyperphosphatemia

Since the kidneys are very efficient at maintaining normal phosphorus balance, there has to be some element of renal dysfunction present for hyperphosphatemia to develop. Most of the total body phosphorus is contained within cells and the skeletal tissue. Therefore, release massive amounts of IC phosphorus from cell lysis (tumor lysis syndrome and massive blood transfusions), muscle injury (rhabdomyolysis), and acute EC shifts of phosphorus (lactic and diabetic ketoacidosis) will acutely increase serum phosphorus. Acute elevations in the levels of serum phosphorus have been also been reported following ingestion of large amounts of phosphorus containing laxatives used for colonoscopy bowel preparation. Hypoparathyroidism and vitamin D toxicity are also causes of hyperphosphatemia.

When there is an acute increase in serum phosphorus levels, phosphorus will complex with calcium to form calcium phosphate crystals, which in turn can cause obstructive uropathy and acute kidney injury. The acute kidney injury will in turn further compromise renal clearance of phosphorus.

Treatment

In addition to identifying and correcting underlying causes of hyperphosphatemia and infusion of NS to promote phosphaturia is central in the management of this disorder. In those patients with oral intake, oral phosphate binders can be used to bind phosphorus in the gut. However, oral phosphate binders have no benefit to those patients who are not being fed orally. HD may be required to lower the serum phosphorus in patients who are anuric or oliguria AND for those with a calcium phosphorus product more than 55-60; and in the patient with symptomatic hypocalcemia. Continuous dialysis (CRRT) will lower the phosphorus more continuously that intermittent HD and there may be rebound hyperphosphatemia in between treatments when intermittent HD is used.

Magnesium is principally an IC cation, with only 1% of the total body content contained in the EC space. Magnesium homeostasis is predominantly handled by the kidneys with important contributions from the GI tract and parathyroid hormone. Importantly, the cation serves as a cofactor for reactions involving adenosine triphosphate. Hypomagnesemia can result from renal losses (aminoglycosides, thiazide and loop diuretics, amphotericin, cisplatin, epithelial growth factor inhibitors [cetuximab] alcoholism, and cyclosporine), GI losses (proton pump inhibitors, short bowel syndrome, malabsorption, and steatorrhea), and diminished intake (malnutrition). Magnesium can also be chelated in circulation by citrate (massive blood transfusions) and foscarnet. Hypokalemia and hypocalcemia frequently coexist with hypomagnesemia. The hypokalemia may be due to impaired function of the sodium potassium pump and the hypocalcemia is due to impaired PTH secretion and activity. Hypermagnesemia is often the result of iatrogenesis and oftentimes occurs in the setting of impaired renal function.

Hypomagnesemia

Hypomagnesemia is frequently found in critically ill patients, with a reported prevalence of 60% to 65%.²⁵ When it is present, it is associated with greater morbidity and mortality.²⁶ Clinically important manifestations of hypomagnesemia include EKG changes (arrhythmias and torsades de pointes), neuromuscular problems (tetany and seizures), electrolyte disorders (hypokalemia and hypocalcemia), and impaired PTH release and action.

Treatment

In patients with cardiac and neuromuscular manifestations of hypomagnesemia, 1 to 2 g of magnesium sulfate can be given as a IV bolus or over 60 minutes, followed by an IV infusion to keep the serum magnesium more than 1.5 mEq/L.²⁷ When repleting magnesium, it is important to keep in mind that magnesium distributes into the tissue space very slowly, and that acute increases in serum magnesium inhibits magnesium reabsorption in the renal tubules. Therefore, when magnesium is given rapidly, up to 50% of the IV dose is lost in the urine. Therefore, the best way to supplement magnesium intravenously is to do so very slowly, at a rate not exceeding 1 g/h. It is best to allow several hours to elapse before checking the postrepletion serum magnesium levels since levels drawn immediately after supplementation may be spuriously elevated. In ICU patients with asymptomatic hypomagnesemia who are able to tolerate oral magnesium, the oral route for magnesium repletion is preferable. Unfortunately, oral magnesium supplements can cause diarrhea.

Hypermagnesemia

Since the kidneys are rapidly able to excrete magnesium when serum magnesium increases acutely, hypermagnesemia most frequently occurs when patients with underlying renal insufficiency are given a large dose of magnesium. For example, when ICU patients are given magnesium containing laxatives or antacids.

Clinical manifestations of hyperkalemia include neurologic (loss of deep tendon reflexes), cardiac (bradycardia, hypotension, heart block, and cardiac arrest), neuromuscular disturbances (respiratory paralysis), and death.

Treatment

In all cases of hypermagnesemia, the exogenous magnesium needs to be discontinued. In patients with asymptomatic hypomagnesemia, loop diuretics can be used in nonoliguric patients and dialysis may be required in oliguric and anuric patients. When the patient is symptomatic, IV calcium chloride 500 to 1000 mg (via a central line), or IV calcium gluconate 1 to 3 g (if a central line is not available) can be rapidly infused until the neuromuscular and cardiac disturbances are reversed. HD may be required as well.