CLINICAL REVIEW Electrolyte disorders

CLINICAL REVIEW

Treatment of electrolyte disorders in adult patients in the intensive care unit

MICHAEL D. KRAFT, IMAD F. BTAICHE, GORDON S. SACKS, AND KENNETH A. KUDSK

lectrolytes are involved in many metabolic and homeostatic Purpose. The treatment of electrolyte dis- mining the proper dosages for adult pa- functions, including enzymatic orders in adult patients in the intensive tients in the ICU are provided. Treatment E care unit (ICU), including guidelines for cor- is often empirical, based on published lit- and biochemical reactions, the recting specific electrolyte disorders, is erature, expert recommendations, and the maintenance of cell membrane struc- reviewed. patient’s response to the initial treatment. ture and function, neurotransmis- Summary. Electrolytes are involved in Actual electrolyte correction requires indi- sion, nerve signal conduction, hor- many metabolic and homeostatic func- vidual adjustment based on the patient’s mone function, muscle contraction, tions. Electrolyte disorders are common in clinical condition and response to therapy. cardiovascular function, bone com- adult patients in the ICU and have been Clinicians should be knowledgeable about position, and fluid and acid–base associated with increased morbidity and electrolyte and the underlying mortality, as has the improper treatment pathophysiology of electrolyte disorders regulation. In addition to serum elec- of electrolyte disorders. A limited number in order to provide the optimal therapy to trolyte concentrations, signs and of prospective, randomized, controlled patients. symptoms of specific electrolyte dis- studies have been conducted evaluating Conclusion. Treatment of electrolyte disor- orders should be monitored in pa- the optimal treatment of electrolyte disor- ders is often empirical, based on published tients with electrolyte abnormalities. ders. Recommendations for treatment of literature, expert opinion and recommen- The severity of symptoms related to electrolyte disorders in adult patients in dations, and patient’s response to the initial electrolyte disorders generally corre- the ICU are provided based on these stud- treatment. Clinicians should be knowl- ies, as well as case reports, expert opinion, edgeable about electrolyte homeostasis lates with the severity of the disorder and clinical experience. The etiologies of and the underlying pathophysiology of and the rate at which the disorder and treatments for hypo- electrolyte disorders to provide optimal developed. Multiple mechanisms tonic and (hypovolemic, therapy for patients. may be involved in electrolyte abnor- isovolemic, and hypervolemic), hy- malities in adult patients in the in- pokalemia and , hypophos- Index terms: Calculations; Critical illness; tensive care unit (ICU), including al- phatemia and , Dosage; Electrolytes; Equations; Methodol- tered absorption and distribution; and hypercalcemia, and hy- ogy; Mortality; Protocols; Water-electrolyte pomagnesemia and imbalance excessive or inadequate administra- are discussed, and equations for deter- Am J Health-Syst Pharm. 2005; 62:1663-82 tion; alterations in hormonal, neuro-

MICHAEL D. KRAFT, PHARM.D., is Clinical Assistant Professor, De- Surgery, University of Wisconsin—Madison. partment of Clinical Sciences, College of Pharmacy, University of Address correspondence to Dr. Kraft at the Department of Phar- Michigan (UM), Ann Arbor, and Clinical Pharmacist, Department of macy Services, University of Michigan Health System, UH/B2 D301, Pharmacy Services, University of Michigan Health System (UMHS), Box 0008, 1500 East Medical Center Drive, Ann Arbor, MI 48109- Ann Arbor. IMAD F. BTAICHE, PHARM.D., BCNSP, is Clinical Associ- 0008 ([email protected]). ate Professor, Department of Clinical Sciences, College of Pharmacy, UM, and Clinical Pharmacist, Department of Pharmacy Services, Copyright © 2005, American Society of Health-System Pharma- UMHS. GORDON S. SACKS, PHARM.D., BCNSP, is Clinical Associate cists, Inc. All rights reserved. 1079-2082/05/0802-1663$06.00. Professor, Pharmacy Practice Division, School of Pharmacy; and DOI 10.2146/ajhp040300 KENNETH A. KUDSK, M.D., is Professor of Surgery, Department of

Am J Health-Syst Pharm—Vol 62 Aug 15, 2005 1663 CLINICAL REVIEW Electrolyte disorders logic, and homeostatic mechanisms; adult patients in the ICU. In addi- measured directly or calculated using or altered excretion via gastrointesti- tion, there are no definitive recom- the following equation: nal (GI) and renal losses, as well as mendations for the optimal dosing changes in fluid status and fluid weight for adult patients, particularly Serum osmolality (mosmole/kg in shifts. Excessive losses should be cor- the obese. Clinicians frequently “ad- water) = (2 × serum sodium conc. rected by administering the appro- just” body weight (e.g., using body in meq/L) + (serum urea conc. in priate replacement fluid (i.e., com- mass index [BMI] or percent above mg/dL/2.8) + (serum glucose position of the replacement fluid ideal body weight [IBW]) in patients conc. in mg/dL/18) should match that of the fluid lost) who are obese; however, there are no in adequate amounts (e.g., 0.5–1 mL data identifying the optimal way to Changes in serum sodium con- per 1 mL of output) and giving estimate this adjusted weight. Fur- centration usually reflect changes in maintenance fluids. Clinicians thermore, there is considerable de- water balance; however, total body should always consider the possibili- bate as to what degree of obesity the sodium concentration may be in- ty of laboratory error, sampling er- clinician should consider to use an creased, decreased, or normal. ror, or blood-sample hemolysis be- adjusted body weight or how to ap- Therefore, volume status must also fore initiating therapy, especially propriately adjust body weight to op- be assessed in patients with hy- when the patient is asymptomatic timize dosing and minimize the risk ponatremia or hypernatremia be- and electrolytes were previously nor- for overdose and associated adverse fore initiating treatment. Rose and mal with little or no change in thera- effects. Total body water in men is Post1 have written an excellent re- pies or clinical condition. If an error slightly higher than that in women, view and discussion of the concepts is suspected, a repeat analysis should and it is estimated that adipose tissue of sodium and water balance and be obtained before treatment. Since is composed of approximately 10– . the is the major organ in- 30% water.48-52 Therefore, we suggest Sodium imbalances are common volved in fluid and electrolyte ho- using an adjusted body weight in ICU patients, yet often poorly un- meostasis, very close attention must (AdjBW) in obese adult patients48-52 derstood. Caution must be exercised be given to renal function in all pa- (i.e., actual weight > 130% of IBW or to avoid inappropriate correction of tients before correcting any electro- BMI ≥ 30 kg/m2) when weight-based the sodium imbalance, which could lyte disorder. dosing is required using the follow- result in further complications, mor- The pathophysiology, etiology, ing calculations: bidity, and death.1,2,53-66 and clinical manifestations of specif- Hyponatremia. Hyponatremia ic electrolyte disorders have been AdjBW (men) = ([weight in kg – IBW (serum sodium concentration of thoroughly reviewed.1-47 This review in kg] × 0.3) + IBW <135 meq/L) may reflect increased, focuses on the treatment of such dis- AdjBW (women) = ([weight in kg – decreased, or normal total body sodi- orders in adult patients in the ICU IBW in kg] × 0.25) + IBW um concentrations and necessitates and is intended to provide clinicians assessment of serum osmolality. As with guidelines for correcting specif- Sodium hypoosmolar (hypotonic) hypo- ic electrolyte disorders in these pa- Sodium is the most abundant ex- natremia can develop in the presence tients by applying estimations based tracellular cation and has a normal of hypovolemia, isovolemia, or hy- on evidence in the literature and serum concentration of 135–145 pervolemia, the patient’s fluid vol- clinical experience. Actual electrolyte meq/L. Normal homeostatic mecha- ume must also be assessed. The po- correction requires individual ad- nisms keep the serum sodium con- tential etiologies of hyponatremia are justment by evaluating the patient’s centration and serum osmolality numerous, depending on the pa- clinical condition and response to (275–290 mosmole/kg water) within tient’s serum osmolality and fluid therapy. The equations and recom- narrow therapeutic ranges. Osmotic volume (Figure 1).1,3,6,8,9 mendations provided are not meant pressure and osmolality determine The signs and symptoms of hy- to replace sound clinical judgment the distribution of water between ponatremia are often nonspecific, and knowledge of electrolyte homeo- various body compartments, with and most are related to the change in stasis and the underlying pathophys- sodium being the major osmotically serum osmolality and consequent iology of electrolyte disorders. active substance in the extracellular fluid shifts in the central nervous sys- fluid. Water will flow from the com- tem (CNS). These signs and symp- Dosing guidelines partment with lower osmolality to toms can include headache, lethargy, There are limited data and con- the compartment of higher osmolali- disorientation, restlessness, nausea, flicting opinions and recommenda- ty until osmotic equilibrium is , muscle cramps or weak- tions on the dosing of electrolytes in achieved. Serum osmolality can be ness, depressed reflexes, seizures,

1664 Am J Health-Syst Pharm—Vol 62 Aug 15, 2005 CLINICAL REVIEW Electrolyte disorders

Figure 1. Classification and common etiologies of hyponatremia.1,3,6,8,9 NSAIDs = nonsteroidal antiinflammatory drugs.

HYPONATREMIA

Assess serum osmolality/tonicity

Normal serum Low serum Elevated serum osmolality osmolality osmolality

Isotonic Hyponatremia Hypertonic Hyponatremia Pseudohyponatremia Hyperglycemia Hypertonic sodium-free Hyperproteinemia solutions (e.g., mannitol)

Hypotonic Hyponatremia

Assess volume status

Hypovolemic Isovolemic Hypervolemic

Hypovolemic Hypotonic Isovolemic Hypervolemic Hypotonic Hyponatremia Syndrome of inappropriate antidiuretic Hyponatremia Renal losses hormone / Acute psychosis Congestive mineralocorticoid deficiency Central nervous system disorders Excessive diuresis Malignancy (e.g., pulmonary tumors) Renal failure (e.g., Medications ) Antineoplastic agents (e.g., Osmotic diuretics (e.g., cyclophosphamide, vincristine) glucose, mannitol, urea) Antipsychotics (e.g., haloperidol, Salt-wasting nephropathy thioridazine, thiothixene) Cerebral salt wasting Carbamazepine Desmopressin Nonrenal losses NSAIDs (e.g., ibuprofen) Blood loss/hemorrhage Opiates (e.g., morphine, meperidine) Gastrointestinal losses Oxytocin Vomiting Selective serotonin reuptake inhibitors Nasogastric suction (e.g., fluoxetine, sertraline) Diarrhea Tricyclic antidepressants (e.g., Obstruction, ileus amitriptyline, imipramine) Skin losses Pulmonary infections (e.g., pneumonia, Burns/open wounds tuberculosis) Excessive sweat losses Severe pain (e.g., marathon runners) Stroke Trauma Adrenal insufficiency Hypothyroidism

coma, and death.7-9 In addition, evi- with acute reductions in serum sodi- Morbidity and mortality may be due dence of hypovolemia or hyper- um concentrations over 12 hours or to hyponatremia itself, the underly- volemia may be present, depending less.9,67 Documented hyponatremia ing disease state, or the inappropriate on the etiology of the hyponatremia (serum sodium concentration of treatment of hyponatremia. Proper and the patient’s volume status. The <130 meq/L) is associated with up to treatment depends on prompt and severity of symptoms is related to the a 60-fold increase in mortality, and appropriate identification, diagnosis, rate of development and severity of mortality rates are significantly higher and classification and is based on the hyponatremia, with more severe in patients whose serum sodium con- patient’s serum osmolality and fluid symptoms developing in patients centration drops below 120 meq/L.68 volume.3,6-11,13,69-93

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Symptomatic hyponatremia. Se- The maximum recommended in- 50 mL/hr may be an appropriate vere symptomatic hyponatremia crease in serum sodium concentra- starting point (depending on the se- (e.g., altered mental status, seizures) tion is 8–12 meq/L per 24 verity of hyponatremia). Adjust- requires prompt correction with hours,9,54,55,59,61-65 with complete cor- ments should be based on the pa- free-water restriction and i.v. admin- rection over 48–96 hours. Fifty per- tient’s response and calculated with istration of hypertonic saline (e.g., cent of the estimated sodium deficit the above equations. 3% sodium chloride injection = 512 is usually administered over the first Hypovolemic hypotonic hyponatre- meq sodium/L) at a rate of 15–80 24 hours and the remainder over the mia. In patients with hypovolemic mL/hr9,11,69 or up to 1–2 mL/kg/hr for next 24–72 hours. A reasonable hypotonic hyponatremia, the ap- two to three hours,6,8,11 with the pos- short-term treatment goal is to cor- proximate sodium deficit should be sible addition of a loop (e.g., rect the serum sodium to 120–130 calculated to estimate replacement ) in nonhypovolemic pa- meq/L55,56,59,61,63,65,72,73 or lower in pa- needs and corrected with 0.9% sodi- tients.11,70 Reversible causes of hy- tients whose serum sodium concen- um chloride injection or lactated ponatremia (e.g., excessive i.v. admin- tration is ≤105 meq/L.55,63,65,72,73 Se- Ringer’s solution according to guide- istration of hypotonic fluids, such as rum sodium concentration should lines for rate of correction and moni- 5% dextrose injection) should first be not be corrected initially to more toring discussed previously. identified and corrected with the re- than 135 meq/L56 and should not ex- Isovolemic hypotonic hyponatre- striction of hypotonic fluids. ceed the upper limit of normal (145 mia. Isovolemic hypotonic hy- The approximate sodium deficit meq/L) at any time during treat- ponatremia is treated with water re- should be calculated to estimate re- ment. Serum sodium levels should be striction. Mild diuresis with a loop placement needs using the following monitored frequently (e.g., every 2–4 diuretic (e.g., i.v. furosemide 20–40 equation: hours) until the patient is asymp- mg every 6–12 hours) may also be tomatic, then every 4–8 hours until helpful. Syndrome of inappropriate Sodium deficit (meq) = TBW × the serum sodium is within the nor- antidiuretic hormone (SIADH) is the (140 – measured serum sodium mal range. Overly rapid correction of most common cause of isovolemic conc.), serum sodium levels can induce neu- hypotonic hyponatremia. SIADH is rologic complications, including characterized by an inappropriate re- where central pontine myelinolysis,53-59,61-64 sponse of antidiuretic hormone which manifests clinically as a gradu- (ADH) to any volume or osmotic TBW (men) = 0.6 L/kg × weight in kg al onset of neurologic alterations oc- stimuli that normally affect ADH se- and TBW (women) = 0.5 L/kg × curring within one to six days of rap- cretion. There may be increased weight in kg id correction. Findings may include ADH release or increased kidney re- pseudobulbar palsy, quadriparesis, sponse to ADH. Patients are hy- The estimated percentage of body seizures, and movement disorders. ponatremic in the setting of serum water for normal men is 60% (0.6) Alternatively, one can estimate the hypotonicity (<270 mosmole/L) and and the estimated percent body wa- anticipated change in serum sodium do not have evidence of edema or ter for normal women is 50% (0.5). levels after i.v. infusion of 1 L of 3% pituitary, thyroid, adrenal, cardiac, These percentages are often higher in sodium chloride injection using the renal, or hepatic dysfunction.3,6,8 Pa- ICU patients. We suggest using the following equation69: tients have impaired free-water ex- AdjBW to calculate the sodium deficit cretion, with normal excretion of so- of patients who are significantly obese. Change in serum sodium conc. = dium. The urine is inappropriately Serum sodium concentrations (512 meq/L – serum sodium concentrated (>100 mosmole/kg) should be corrected at a rate of 1–2 conc.)/TBW + 1 with an increase in urine sodium meq/L/hr for patients with symp- concentration of greater than 20–30 tomatic hyponatremia or severe and after i.v. infusion of 1 L of 0.9% meq/L.3,6,8 The continued intake of acute hyponatremia (e.g., change in sodium chloride injection with the water (or hypotonic fluids) will ulti- serum sodium concentration of >0.5 following equation69: mately lead to the development of meq/L/hr or onset in less than 48 hyponatremia. Numerous condi- hours)6,10,55,56,58-60,71 and no faster than Change in serum sodium conc. = tions and medications may induce 0.5 meq/L/hr when hyponatremia (154 meq/L – serum sodium SIADH (Figure 1). In the case of is chronic (i.e., develops over more conc.)/TBW + 1 drug-induced SIADH, the suspected than two or three days) or when agent should be discontinued, if pos- the time over which the hyponatrem- With this calculation, initiation of sible. The primary acute therapy for ia developed is unknown.54,55,58,61,63 3% sodium chloride injection at 15– SIADH is correction of the underly-

1666 Am J Health-Syst Pharm—Vol 62 Aug 15, 2005 CLINICAL REVIEW Electrolyte disorders ing disorder and water restriction in patients with renal failure is usual- by avoiding excessive carbohydrate (<1000 to 1500 mL daily).3,6,74 Pa- ly classified as hypotonic because the loads. Serum sodium levels should be tients with severe symptomatic effective serum osmolality is generally monitored as previously described. SIADH may require more aggressive reduced. Pseudohyponatremia. Pseudohy- therapy with i.v. furosemide 1 mg/kg Treatment includes optimizing ponatremia occurs when there is an as needed to maintain desired nega- treatment of the underlying cause, in increase in the nonaqueous portion tive fluid balance and replacement of addition to sodium and fluid restric- of the serum, such as with hyperlipi- urinary sodium losses with hyper- tion (e.g., 1000–1500 mL daily) and demia and hyperproteinemia. This is tonic saline (3% sodium chloride in- diuresis with a loop diuretic (e.g., not a true hyponatremia, since the jection).3,6,70 Other drug therapies for furosemide). sodium concentration in the aque- SIADH include oral or i.v. furose- and hyper- ous portion of the serum remains mide (30–80 mg daily) with oral so- tonic hyponatremia. Therapy for iso- normal. Pseudohyponatremia has dium chloride supplementation75-78 tonic hyponatremia and hypertonic been historically related to the older and oral urea crystals (30–60 g dai- hyponatremia should be aimed at method for measuring serum sodi- ly).79-81 However, the use of oral urea identifying and correcting the under- um levels using flame-emission spec- has been limited in clinical prac- lying cause. Hypertonic hyponatre- trophotometry. This method has tice.74,78 hydrochlo- mia may result from hyperglycemia largely been replaced with a more ride 600–1200 mg orally daily can be or administration of hypertonic so- specific technique that uses sodium- used to treat chronic SIADH,82-85 but dium-free solutions. Hyperglycemia selective electrodes to measure serum it is not as effective for treating acute causes a shift of water out of cells into sodium. However, this new tech- SIADH because of its delayed onset the extracellular space, resulting in nique may not completely eliminate of action.78,84 Demeclocycline should dilution of serum sodium. For every the problem, and serum osmolality be used with caution because it may 100-mg/dL increase in serum glucose should be measured in patients with have potentially negative effects on concentration above 100 mg/dL, the hyponatremia. renal function,83,84,86 especially in pa- serum sodium concentration would Hypernatremia. Hypernatremia tients with underlying hepatic dys- be expected to decrease by approxi- (serum sodium concentration of function87,88 or congestive heart fail- mately 1.6 meq/L.93 Therefore, the >145 meq/L) reflects a water deficit ure.89,90 Phenytoin sodium 200–300 corrected serum sodium concentra- relative to total body sodium levels mg orally daily may be an alternative tion should be calculated using the and is associated with serum hyper- therapy for chronic SIADH, but not following equation before attempt- tonicity. Total body sodium may be for acute management.91 Lithium ing the correction: increased, decreased, or normal, and carbonate 600–1200 mg orally daily assessment of the patient’s volume has been used as a last line of therapy Corrected serum sodium conc. = status is required. There are several for SIADH74,78,92; however, its use serum sodium conc. + 1.6([serum potential etiologies of hypernatrem- may be limited by its toxicity74,78,84 glucose conc. – 100]/100) ia, depending on the alteration in the and lack of efficacy.84 patient’s volume status (Table Hypervolemic hypotonic hy- Infusion of any sodium-free iso- 1).3,6,8,14 Generally, hypernatremia de- ponatremia. Hypervolemic hypoton- tonic or hypertonic solutions (e.g., velops when the thirst mechanism is ic hyponatremia often occurs in criti- mannitol) should be stopped if clini- not functioning normally or if access cally ill patients, especially those with cally appropriate. Hyperglycemia to free water is limited or con- cardiac, renal, or hepatic insufficien- should be controlled with insulin trolled.3,70 The latter occurs in acutely cy. It also occurs in postoperative pa- therapy (e.g., sliding-scale regular in- ill ICU patients when fluid intake is tients due to the i.v. administration sulin or continuous i.v. infusion) and controlled or restricted. of large volumes of resuscitation flu- ids. Patients with renal failure who develop hyponatremia will usually Table 1. have a decreased effective serum os- Classification and Common Etiologies of Hypernatremia3,6,8,14 molality, but the measured serum Classification Etiology osmolality may be elevated due to Hypovolemic Loss of hypotonic fluids (vomiting, diarrhea, nasogastric uremia. However, because urea dis- suctioning, osmotic diuresis, burns and open wounds, sweat, tributes freely across membranes and lungs) Isovolemic Diabetes insipidus (central diabetes, nephrogenic diabetes is considered an ineffective osmole, it insipidus) does not contribute to the effective Hypervolemic Hypertonic saline solutions, sodium bicarbonate solutions, osmolality. Therefore, hyponatremia mineralocorticoid excess (hyperaldosteronism)

Am J Health-Syst Pharm—Vol 62 Aug 15, 2005 1667 CLINICAL REVIEW Electrolyte disorders

Similar to hyponatremia, the signs brain cells have not yet fully adapted mia can be estimated using the fol- and symptoms of hypernatremia to the imbalance.2 However, the lowing equation: can be nonspecific, and most are re- mortality rate increases with more lated to changes in serum osmolality rapid correction of hypernatremia.94 Water deficit (in liters) = TBW × in the CNS. Clinical manifestations Therefore, in the case of acute hyper- ([serum sodium conc./140] – 1) of hypernatremia in adult patients natremia, the serum sodium concen- can include lethargy, irritability, rest- tration should be corrected no faster Half of the water deficit should be lessness, thirst, muscle irritability than 1–2 meq/L/hr to avoid cerebral replaced over the first 24 hours, and and spasticity, hyperreflexia, sei- edema.8,14,97 Extreme caution is war- the remainder replaced over the fol- zures, coma, and death.7,8,14 Evidence ranted in the case of chronic hyper- lowing 24–72 hours, with the total of hypovolemia or hypervolemia natremia or if hypernatremia devel- correction taking place over 48–96 may be present. Severity of symp- oped over an unknown length of hours.8,14,95,97 Serum sodium concen- toms may also correlate with severity time, because rapid correction can tration should be decreased by a and the rate of development of result in brain edema, swelling, her- maximum of 10–12 meq/L per 24 hypernatremia.7,14 niation, and death.2 In these cases, hours.14,98 When the patient is hypov- Hypernatremia is associated with the serum sodium concentration olemic or hypotensive, isotonic 0.9% increased morbidity and mortali- should be corrected at a maximum sodium chloride injection or lactated ty.6,94-96 The overall mortality rate in rate of 0.5 meq/L/hr.14,98 Ringer’s solution should be used to adult patients with hypernatremia is The anticipated change in serum help correct the hemodynamic insta- approximately 40–70%,94-96 although sodium levels after i.v. infusion of bility. Otherwise, 5% dextrose injec- the mortality rate directly attributed 1 L of 5% dextrose injection can tion or a hypotonic saline solution to hypernatremia itself is likely low- be estimated using the following (0.225% or 0.45% sodium chloride er.95 Adults with a serum sodium equation69: injection) can be used. concentration of >160 meq/L have a Patients with symptomatic hyper- mortality rate of >75%.6,94 Mortality Change in serum sodium conc. = (0 natremia (e.g., altered mental status, associated with chronic hypernatrem- meq/L – serum sodium conc.)/ seizures, coma) should have their sodi- ia is lower than with acute hypernatre- (TBW + 1) um levels monitored every 2–4 hours. mia.6,94,96 Morbidity and mortality as- Once symptoms resolve, serum sodi- sociated with hypernatremia are often and after i.v. infusion of 1 L of um should be monitored frequently due to the underlying disease process 0.225% sodium chloride injection (i.e., every 4–8 hours) until normal. A or inappropriate treatment of the dis- with the following equation69: goal serum sodium concentration of order.94,95 Therefore, prompt assess- 145 meq/L has been suggested.14 ment, diagnosis, and proper therapy of Change in serum sodium conc. = Hypovolemic hypernatremia. The hypernatremia are essential. (38.5 meq/L – serum sodium water deficit associated with this Proper treatment depends on the conc.)/(TBW + 1) condition should be calculated. After characterization of hypernatremia correcting the initial hypovolemia (hypovolemic, isovolemic, or hyper- and after i.v. infusion with 1 L of with 0.9% sodium chloride injection volemic) and its magnitude, length 0.45% sodium chloride injection or lactated Ringer’s solution in he- of time over which it developed, and with the following equation: modynamically unstable patients, the severity of symptoms. All revers- the water deficit should be corrected ible causes should be identified and Change in serum sodium conc. = (77 with a hypotonic solution. The ap- corrected. Administration of sodium meq/L – serum sodium conc.)/ propriate type and amount of main- (e.g., hypertonic saline or sodium bi- (TBW + 1) tenance fluid should be provided, carbonate) should be discontinued along with treatment of the deficit to or reduced if clinically appropriate, and after i.v. infusion with 1 L prevent further dehydration. the sodium concentration of i.v. flu- of 0.9% sodium chloride injection Isovolemic hypernatremia. Iso- ids should be lowered (e.g., 0.225% with the following equation69: volemic hypernatremia can result sodium chloride injection or 5% from a relative water deficit (i.e., dextrose injection), and medication Change in serum sodium conc. = free-water or hypotonic sodium loss- solvents should be changed to 5% (154 meq/L – serum sodium es) or relative sodium excess (e.g., dextrose injection, if compatible. If conc.)/(TBW + 1) isotonic sodium administration hypernatremia developed rapidly [0.9% sodium chloride injection] for (i.e., over a period of hours), correc- Alternatively, the relative water hypotonic losses, such as those tion is usually well tolerated because deficit associated with hypernatre- through the skin). The relative water

1668 Am J Health-Syst Pharm—Vol 62 Aug 15, 2005 CLINICAL REVIEW Electrolyte disorders deficit should be calculated to guide bicarbonate solutions, or large vol- . Hypokalemia is treatment, and sodium restriction is umes of isotonic saline (0.9% sodi- defined as a serum con- also warranted. Isovolemic hyper- um chloride) in the ICU to maintain centration below 3.5 meq/L and con- natremia is typically seen in patients circulation and blood pressure. Pa- sidered severe if below 2.5 meq/L or with diabetes insipidus (DI). DI re- tients may also have ongoing losses if a patient is symptomatic. Because sults in excretion of a large volume of of hypotonic body fluids (e.g., GI hypokalemia results in membrane hypotonic urine (e.g., 3–15 L daily) losses). It is best treated with the re- hyperpolarization and impaired and polydipsia.3,15 The differentia- moval of sodium products, sodium muscular contraction, its signs and tion should be made between central restriction, and the use of diuretics symptoms generally involve changes DI (CDI) and nephrogenic DI (loop or thiazide) to restore nor- in muscle and cardiovascular func- (NDI). CDI is a result of impaired monatremia and euvolemia. Hypo- tion. Patients with mild hypokalemia synthesis or the release of ADH, and tonic saline (e.g., 0.225% sodium (e.g., serum potassium approximately NDI results from a lack of kidney re- chloride) or 5% dextrose injection 3–3.4 meq/L) may be asymptomatic. sponsiveness to ADH. Urinary re- can also be administered with diuret- Signs and symptoms of hypokalemia sponse (volume and osmolality) to ics during correction of hypernatre- include nausea, vomiting, weakness, administration of exogenous ADH mia to decrease total body sodium constipation, paralysis, respiratory (e.g., desmopressin acetate 1 μg s.c.) and volume while providing mainte- compromise, and rhabdomyolysis.18-22 can differentiate between CDI and nance fluid and preventing further The most severe and concerning ad- NDI.15 Common etiologies of CDI abnormalities. verse effects related to hypokalemia include trauma, neurosurgery, tu- are electrocardiogram (ECG) chang- mors, head trauma, infection, or Potassium es, cardiac arrhythmias, and sudden cerebrovascular diseases (e.g., Potassium is the second most death, especially in patients with hy- thrombosis, aneurysm).6,8,15 NDI can abundant cation in the body. Ap- pertension, myocardial ischemia, or be acquired or, more rarely, congeni- proximately 98% of total body potas- heart failure. ECG changes can include tal. Common causes of acquired NDI sium is found in the intracellular ST-segment depression, T-wave flat- include hypokalemia, hypercalcemia, space, with approximately 2% in the tening, T-wave inversion, and the polycystic kidney disease, advanced extracellular space.17,23 The normal presence of U waves.18-22 renal diseases, and medications, such serum potassium concentration is Hypokalemia can develop in ICU as lithium (most commonly),15,99 de- 3.5–5.0 meq/L. Potassium has many patients as a result of intracellular meclocycline, foscarnet, antipsychot- physiological functions, including shifts of potassium, increased losses ics (e.g., clozapine), gentamicin, am- cellular metabolism, glycogen and of potassium, or, less commonly, de- photericin B, and cimetidine.6,8,15,16,100 protein synthesis, and regulation of creased ingestion or administration I.V. 5% dextrose injection should the electrical action potential across of potassium. Serum potassium lev- be administered to balance urine cell membranes, especially in the els do not correlate well with intra- losses. Treatment of CDI may in- myocardium.18,20 cellular potassium levels104 and may clude the administration of an ADH The rate-limiting step for potassi- not correlate with total body potassi- analog (e.g., desmopressin acetate um entry into the cells is the sodium– um. Therefore, hypokalemia may not 10–20 μg intranasally twice daily or potassium-adenosine triphosphatase imply a depletion of body potassium 1–2 μg subcutaneously twice daily).15 pump that maintains a higher intra- stores. Potassium supplementation Treatment of NDI includes removing cellular potassium level. Several fac- and dosing are largely empirical and the causative agent. A thiazide di- tors affect the activity of this pump, guided by serum potassium levels. It uretic or indomethacin may be bene- including insulin, glucagon, cathe- has been estimated that for every 0.3- ficial but should be used cautiously cholamines, aldosterone, acid-base meq/L decrease in serum potassium because of potentially negative renal status, plasma osmolality, and intra- concentration, the total body potas- effects.16 Lithium-induced NDI may cellular potassium levels. Critically ill sium deficit is approximately 100 be treated successfully with oral hy- patients in the ICU often have ab- meq.21 Critically ill patients may have drochlorothiazide 50 mg twice dai- normalities in one or more of these underlying conditions or receive ly,101 oral indomethacin 50 mg three mediators or conditions. Under nor- medications that can cause hy- times daily,102 or oral amiloride hy- mal physiological conditions, 80% of pokalemia. Metabolic alkalosis caus- drochloride 5–10 mg twice daily.103 potassium is excreted through the es an intracellular shift of potassium; Hypervolemic hypernatremia. Hy- kidneys, with at least 90% actively re- however, the total body potassium pervolemic hypernatremia is usually absorbed along the kidney tubule.20 level will not change. Correction of a result of the administration of About 15% of potassium is excreted the underlying metabolic alkalosis hypertonic saline solutions, sodium in feces and 5% in sweat.19,20 should result in redistribution of po-

Am J Health-Syst Pharm—Vol 62 Aug 15, 2005 1669 CLINICAL REVIEW Electrolyte disorders tassium into the extracellular space rect coexisting hypokalemia and potassium supplementation should and correction of hypokalemia. Oth- . not exceed 240–400 meq/day. er common causes of hypokalemia We recommend an initial i.v. po- Potassium concentration in solu- due to intracellular shifts of potassi- tassium dose of 20–40 meq for an tions for continuous infusion via a um include β-adrenergic agonists ICU patient with mild to moderate peripheral vein should be limited to (e.g., albuterol), insulin, theophyl- hypokalemia (serum potassium con- 80 meq/L. Potassium concentrations line, and caffeine.21,22 Common caus- centration = 2.5–3.4 meq/L) (Table of up to 120 meq/L can be used for es of hypokalemia due to potassium 2).105-107 Patients with symptomatic central-vein infusion. I.V. potassium losses include potassium-wasting di- or severe hypokalemia (serum potas- should be diluted in an appropriate uretics (loop and thiazide), sodium sium concentration of <2.5 meq/L) diluent before infusion, preferably sa- polystyrene sulfonate, corticoster- require more aggressive therapy with line solutions. Dextrose-containing oids (especially mineralocorticoids initial i.v. potassium doses of up to vehicles should be avoided, as they such as fludrocortisone), aminogly- 40–80 meq. Patients with impaired may worsen the hypokalemia by cosides, amphotericin B, magnesium renal function should receive no stimulating insulin release that will depletion, renal replacement thera- more than 50% of the recommended cause intracellular shifting of potassi- pies (e.g., hemodialysis, continuous initial potassium dose. Multiple dos- um.108 Potassium infusion via a pe- renal replacement therapy [CRRT]), es of potassium can be repeated to ripheral vein may cause burning pain and GI losses (e.g., diarrhea, nasogas- normalize serum potassium concen- and phlebitis at the infusion site. tric suctioning).21,22 trations if necessary; however, serum Adding 1 mL of 1% lidocaine to a Goals of therapy for hypokalemia potassium levels should be checked potassium solution of 10–20 meq/ include avoidance or resolution of after a total dose of 60–80 meq before 100 mL may minimize the pain at the symptoms, returning the serum po- further potassium is administered infusion site. However, this could tassium concentration to the normal (within one to four hours after dose mask a sign of underlying venous range (i.e., 3.5–5 meq/L), and avoid- administration). Potassium should damage. ing hyperkalemia. Hypokalemia is never be administered as a rapid in- Oral potassium chloride supple- treated by administering oral or i.v. fusion because of the risk of serious ments are available in capsule, tablet, potassium supplements. I.V. potassi- or fatal consequences. Intermittent or liquid (liquid, powder for solu- um supplementation (as chloride, potassium dosing can be safely tion) formulations, but liquid for- acetate, or phosphate salts) is re- achieved at potassium infusion rates mulations have an unpleasant taste. served for the treatment of severe hy- of 10–20 meq/hr. If an infusion Liquid formulations may be appro- pokalemia, symptomatic hypokale- rate exceeding 10 meq/hr is needed, priate (and preferred) for critically ill mia, or when the GI tract cannot be continuous cardiac monitoring is patients with a functional GI tract used, and ICU patients may often recommended to detect any signs if a nasoenteric tube is in place. have one or more of these condi- of hyperkalemia, and infusion via Extended-release oral formulations tions. Oral potassium supplements a central venous catheter is recom- are also available. The controlled- are available as chloride, bicarbonate, mended to minimize infusion- release microencapsulated tablet ap- citrate, gluconate, and phosphate related burning and phlebitis. Potas- pears to be better tolerated and salts. The most commonly used sium infusion rates exceeding 20 causes less GI erosion than the oral or i.v. supplement is potassium meq/hr are rarely needed. In critical extended-release wax-matrix tab- chloride. Potassium acetate and bi- situations, infusion rates as high as let.109-111 However, if the patient can- carbonate can be used when the cor- 40 meq/hr have been used but should not swallow or receive oral medica- rection of acidemia is also desired. be reserved for emergent cases or tions, this may not be a therapeutic Potassium phosphate is used to cor- symptomatic patients.107 Total daily option. Oral potassium dosages of 40–100 meq daily are usually suffi- cient to correct hypokalemia. The Table 2. total daily dosage should be divided Empirical Treatment of Hypokalemia105-107 into two to four doses to avoid ad- Serum Potassium I.V. Potassium verse GI effects. An oral potassium Severity a Concentration (meq/L) Replacement Dose (meq) dosage of 20 meq daily has been sug- Mild to moderate 2.5–3.4 20–40 Severe <2.5 40–80 gested to prevent hypokalemia in pa- aIn patients with normal renal function; patients with renal insufficiency should receive ≤50% of the initial tients receiving chronic diuretic empirical dose. Rate of infusion = 10–20 meq potassium per hour; maximum infusion rate = 40 meq potassium therapy.112 Patients in the ICU who per hour. Continuous cardiac monitoring and infusion via a central venous catheter are recommended for infusion rates >10 meq potassium per hour. Maximum potassium = 80 meq/L via a peripheral vein; up to 120 receive higher or more frequent dos- meq/L via a central vein (admixed in 0.9% or 0.45% sodium chloride injection). es of potassium-wasting diuretics

1670 Am J Health-Syst Pharm—Vol 62 Aug 15, 2005 CLINICAL REVIEW Electrolyte disorders may require i.v. therapy with higher the serum potassium concentration and other medications that can cause doses. An alternative therapy to po- exceeds 5.5 meq/L. Signs and symp- hyperkalemia should be stopped, or tassium supplementation in correct- toms of hyperkalemia include mus- the dosages decreased, if feasible. Ta- ing or preventing hypokalemia is the cle twitching, cramping, weakness, ble 3 lists therapies for the treatment use of potassium-sparing diuretics ascending paralysis, ECG changes of hyperkalemia.19,20,23 I.V. calcium (e.g., spironolactone, triamterene, (e.g., tall peaked T-waves, prolonged (e.g., calcium gluconate) should be amiloride), which are especially use- PR-interval, widened QRS complex, given to symptomatic patients or ful in patients receiving drugs known shortened QT-interval) and arrhyth- those with ECG changes, with the to deplete potassium.20 However, in mias (e.g., bradyarrhythmias, ven- calcium dose repeated as needed the acute setting, these agents may tricular fibrillation, asystole).18-20,23 based on the ECG changes. However, not be as effective as other agents Similar to hypokalemia, true hy- this is a temporary treatment to an- (e.g., furosemide) in adult ICU pa- perkalemia can develop due to extra- tagonize the effects of potassium and tients when large volumes of excess cellular shifts of potassium, increased will not remove potassium from the fluid must be removed and excreted. potassium ingestion, or impaired po- body. In addition, the longer time to onset tassium elimination. Pseudohyper- In patients without symptoms, of these medications may be a limita- kalemia can be an artifact of hemoly- rapid correction of hyperkalemia can tion in treating acute hypokalemia. sis from a traumatic blood draw or be achieved by promoting intracellu- Magnesium is important in the when the blood sample is contami- lar distribution with insulin and dex- regulation of intracellular potassi- nated with infused potassium. As trose, sodium bicarbonate, or al- um.104 Hypomagnesemia may result such, when a serum potassium level buterol. Sodium bicarbonate should in refractory hypokalemia, likely due is inappropriately elevated for the be used with caution in patients with to accelerated renal potassium loss or clinical situation, the blood test must heart failure or renal failure due to its impairment of sodium–potassium be repeated to confirm the diagnosis sodium content, which could exacer- pump activity.113 When hypokalemia and avoid unnecessary or inappro- bate fluid retention in these patients. and hypomagnesemia coexist, mag- priate treatment of hyperkalemia. These therapies can have a rapid ef- nesium deficiency should be correct- Hyperkalemia is most common- fect; however, they only cause a tem- ed to facilitate the correction of ly seen in the setting of renal porary redistribution of potassium to hypokalemia.114 insufficiency, and acute renal fail- the intracellular space and do not Serum potassium levels should be ure is frequently seen in ICU pa- change total body potassium levels. monitored frequently (every 1–6 tients. Potassium-sparing diuretics, Further therapies aimed at in- hours) in patients with severe hy- angiotensin-converting-enzyme in- creasing potassium elimination from pokalemia if symptoms are present hibitors, nonsteroidal antiinflamma- the body include potassium-wasting or if aggressive i.v. treatment is ongo- tory drugs, and hypoaldosteronism diuretics, sodium polystyrene sul- ing. Monitoring of serum potassium can impair potassium excretion and fonate, and renal replacement thera- after i.v. repletion in ICU patients cause hyperkalemia.23 Metabolic aci- py. Administration of a loop diuretic with mild to moderate hypokalemia dosis results in an extracellular shift enhances renal potassium elimina- (within 2–8 hours) may be appropri- of potassium, without changes in to- tion. Sodium polystyrene sulfonate, a ate, in addition to routine monitor- tal body potassium. Correction of cation-exchange resin, binds potassi- ing (e.g., every 24–48 hours). The the underlying metabolic acidosis re- um in the GI tract and eliminates it response to oral potassium repletion distributes potassium into the intra- from the body. Caution should be is generally delayed compared to cellular space and corrects the hyper- used when giving sodium polysty- i.v. repletion, and routine monitor- kalemia. Other causes of extracellular rene sulfonate to patients with heart ing may be appropriate if hypokale- shifts of potassium include succinyl- failure or severe hepatic disease be- mia is not severe and the patient is choline, β-adrenergic blockers, dig- cause of the drug’s sodium content. asymptomatic. oxin overdose, and muscular injury Necrosis of the GI tract has been re- Hyperkalemia. Hyperkalemia (e.g., trauma, rhabdomyolysis).23 ported in patients who received sodi- (serum potassium concentration of The goals of the hyperkalemia um polystyrene sulfonate in sorbi- >5.0 meq/L) can become life threat- therapy are to antagonize the cardiac tol.115-120 Sorbitol, used as a diluent to ening when the serum potassium effects of potassium, reverse symp- counteract constipation with sodium concentration exceeds 6.5 meq/L. toms (if present), and return serum polystyrene sulfonate, is believed to Clinical manifestations of hyperkale- potassium to normal while avoiding be an important factor in inducing mia are related to changes in neuro- overcorrection. All sources of exoge- necrosis.115,116 As such, sodium poly- muscular and cardiac function. Pa- nous potassium should be discontin- styrene sulfonate in sorbitol should tients are often asymptomatic until ued, and potassium-sparing diuretics be used with extreme caution, or

Am J Health-Syst Pharm—Vol 62 Aug 15, 2005 1671 CLINICAL REVIEW Electrolyte disorders

Table 3. Treatments for Hyperkalemia19,20,23 Time Duration TreatmentDose Route to Onset of Effect Mechanism of Action and Effects Calcium gluconatea,b 1–2 g (4.56–9.12 I.V. over 5–10 min 1–2 min 10–30 min Antagonizes cardiac conduction meq cacium) abnormalities Sodium bicarbonatea 50–100 meq I.V. over 2–5 min 30 min 2–6 hr Increases serum pH; redistributes potassium into cells Insulin (regular)a (with 5–10 units I.V. with 50 mL of 15–45 min 2–6 hr Redistributes potassium into cells dextrose) 50% dextrose injection 50% dextrose 50 mL (25 g) I.V. over 5 min 30 min 2–6 hr Increases insulin release; redistributes potassium into cells; prevents hypoglycemia when insulin is given 10% dextrose 1000 mL (100 g) I.V. over 1–2 hr 30 min 2–6 hr Increases insulin release; redistributes potassium into cells; prevents hypoglycemia when given with insulin Furosemide 20–40 mg I.V. 5–15 min 4–6 hr Increases renal potassium loss Sodium polystyrene 15–60 g Oral or rectal 1 hr 4–6 hr Resin exchanges sodium for sulfonatec potassium; increases fecal potassium elimination Albuterol 10–20 mg Nebulized over 10 30 min 1–2 hr Stimulates sodium–potassium pump; min redistributes potassium into cells Hemodialysis 2–4 hr NAd Immediate Variable Removes potassium from plasma aFirst-line therapies in hyperkalemic emergencies. bRepeat dose in five minutes if abnormal electrocardiogram persists. Calcium chloride may also be used, but calcium gluconate is preferred over calcium chloride for peripheral venous administration because it causes less venous irritation. Calcium chloride (1000 mg = 13.6 meq calcium) provides three times more calcium than calcium gluconate (1 g = 4.56 meq calcium). cCan be used to treat acute hyperkalemia, but the effects may not be seen for several hours. Removes 0.5–1 meq of potassium per 1 g of sodium polystyrene sulfonate. dNA = not applicable. avoided, especially in uremic patients mia will only redistribute potassium cluding bone composition, cell under stress or with critical ill- and not remove it from the body. membrane composition, nerve con- ness,115,116,118 patients with hypoten- Continued monitoring of serum po- duction, and muscle function.24,25,27,28 sion or decreased GI perfusion,116,120 tassium levels in patients with hyper- It provides energy-rich bonds in the and patients with GI obstruction or kalemia after resolution of symptoms form of adenosine triphosphate decreased GI motility.119 Renal re- is recommended after therapeutic in- (ATP) and is required in all physio- placement therapy is indicated if hy- terventions every 4–12 hours until logical, homeostatic, and metabolic perkalemia is associated with renal serum potassium levels return to functions that require energy. This is failure or if potassium-wasting di- normal. Routine monitoring of se- especially important in critically ill uretics or sodium polystyrene sul- rum potassium levels (every 24–48 patients in the ICU, who often expe- fonate fails.18 Renal replacement hours) is also recommended in adult rience hypermetabolism and may therapy can be used as part of the patients in the ICU. have higher phosphorus require- initial treatment regimen for acute ments. Adequate total body phos- hyperkalemia and will permanently Phosphorus phorus and phosphate are necessary remove potassium from the body, Phosphorus is the main intracel- for glucose utilization, glycolysis, but the effects of potassium removal lular anion. The normal serum con- ATP synthesis, numerous biochemi- and lowered serum potassium levels centration of phosphorus is 2.7–4.5 cal reactions, 2,3-diphosphoglycerate may not be seen for several hours. mg/dL; however, the majority of synthesis and function (which are In addition, renal replacement thera- phosphorus in the body exists in the necessary for oxygen release from he- py is more invasive and technically bones and soft tissues, with approxi- moglobin and delivery to tissues), difficult. mately 1% of total body phosphorus neurologic function, and muscular Serum potassium should be in the extracellular fluid.24,25,27,28 function (especially the myocardium monitored frequently throughout Therefore, serum phosphorus levels and diaphragm).24,25,27,28,121-124 treatment (every 1–6 hours) in may not reflect total body phospho- Hypophosphatemia. Hypophos- symptomatic patients with severe hy- rus levels. Phosphorus exists prima- phatemia (serum phosphorus con- perkalemia, keeping in mind that rily as phosphate in the serum and centration of <2.7 mg/dL) can lead to many therapies for acute hyperkale- has many important functions, in- severe clinical sequelae, including

1672 Am J Health-Syst Pharm—Vol 62 Aug 15, 2005 CLINICAL REVIEW Electrolyte disorders impaired diaphragmatic contractility cause serum concentrations may not bophlebitis from potassium phos- and acute respiratory failure, tissue correlate with total body stores. Ta- phate) and to reduce the risk of hypoxia, decreased myocardial con- ble 4 provides suggested dosages of calcium–phosphate precipitation. tractility, paralysis, weakness, pares- i.v. phosphate for hypophospha- However, doses can be infused up to thesias, neurologic dysfunction, temia in patients with normal renal a rate of 7 mmol of phosphate per seizures, and death.24,25,27,28,121-128 Crit- function.129-135 In patients with im- hour.134,135 Phosphorus can quickly ically ill adult patients in the ICU of- paired renal function who are not shift between compartments within ten have underlying conditions that being treated with CRRT, we recom- the body and serum concentrations predispose them to developing hypo- mend administering ≤50% of the ini- can fluctuate24,28,129; therefore, a re- phosphatemia (malnutrition, inade- tial empirical phosphate dosage. Pa- peat serum phosphorus level should quate body phosphorus stores or in- tients being treated with CRRT may be checked two to four hours after adequate phosphate administration, require higher initial dosages (i.e., administering a dose. Additional alkalosis [respiratory and metabolic], closer to empirical doses used for pa- phosphate supplements should be diabetic ketoacidosis, alcoholism, tients with normal renal function), given until the patient is asymptom- vomiting or gastric losses) or receive depending on the severity of hypo- atic and the serum phosphorus con- therapies or medications that can phosphatemia, the amount of phos- centration is at least >2.0 mg/dL, cause hypophosphatemia (CRRT, in- phorus being removed with CRRT, with a final goal of returning the se- sulin, diuretics, antacids, sucralfate, and whether or not phosphorus is rum phosphorus levels to within and administration of carbohydrate used in the dialysate or replacement normal range. loads).25,27,28 Administration of car- fluid. We recommend using AdjBW Increasing total caloric load has bohydrate loads or parenteral nutri- in significantly obese patients to been associated with reduced serum tion is likely to cause hypophos- minimize the risk of overdosing and phosphorus levels in patients receiv- phatemia if an adequate amount of subsequent hyperphosphatemia. ing parenteral nutrition.121 It is nec- phosphate is not supplied, especially Further supplementation in all cases essary to provide approximately 10– in malnourished patients who should be guided by clinical response 15 mmol of phosphate per 1000 kcal are at risk for developing severe to the initial dosage. to maintain normal serum phospho- hypophosphatemia and refeeding The i.v. phosphate preparations rus levels.121 Severely malnourished syndrome.30,121,122,125-128 used are available as the potassium or patients will likely have higher daily Given the potential adverse effects sodium salts. Potassium phosphate phosphate requirements and should of hypophosphatemia, serum phos- can be used in patients with simulta- be supplemented accordingly. Criti- phorus concentrations in critically ill neous hypokalemia; otherwise, sodi- cally ill patients may also require patients should be maintained within um phosphate is recommended. Cli- additional supplementation or ad- the normal range. Treatment of hy- nicians must also be aware of the justment of parenteral nutrition for- pophosphatemia depends on the potassium and sodium content of mulations to meet daily phosphorus magnitude of hypophosphatemia these preparations. One millimole of requirements. and whether or not the patient is potassium phosphate contains 1.47 Patients with refractory hypo- symptomatic. Asymptomatic mild meq of potassium, and 1 mmol of phosphatemia may require a daily hypophosphatemia may be treated sodium phosphate contains 1.33 phosphate supplementation of phos- with oral phosphate supplementa- meq of sodium. Total phosphate phate (1) as an oral powder for solu- tion if the GI tract is functional. doses are usually infused over four tion three or four times daily after However, oral phosphate supple- to six hours to minimize infusion- meals and at bedtime, (2) as an i.v. ments may cause diarrhea, and oral related adverse effects (e.g., throm- supplement, or (3) by increasing the absorption may be unreliable. Pa- tients with symptomatic, moderate, Table 4. or severe hypophosphatemia, along 129-135 with patients who cannot tolerate Empirical Treatment of Hypophosphatemia oral supplements or receive oral Serum Phosphorus I.V. Phosphate a,b medications, should receive i.v. Concentration (mg/dL) Replacement Dose (mmol/kg) phosphate supplementation to cor- 2.3–2.7 0.08–0.16 1.5–2.2 0.16–0.32 rect serum phosphorus levels. These <1.5 0.32–0.64 conditions can be seen frequently in aIn patients with normal renal function; patients with renal insufficiency should receive ≤50% of the initial critically ill patients in the ICU. Esti- empirical dose. Maximum infusion rate = 7 mmol phosphate per hour. bThe authors suggest using adjusted body weight (AdjBW) in patients who are significantly obese (weight of mating the appropriate dosage of >130% of ideal body weight [IBW] or have a body mass index of ≥30 kg/m2): AdjBW (men) = ([wt (kg) – IBW (kg)] phosphate is largely empirical be- × 0.3) + IBW; AdjBW (women) = ([wt (kg) – IBW (kg)] × 0.25) + IBW.

Am J Health-Syst Pharm—Vol 62 Aug 15, 2005 1673 CLINICAL REVIEW Electrolyte disorders maintenance amount in parenteral laxatives in patients with compro- of the variation in the amount of nutrition. mised renal function.136,138 Other eti- phosphorus removed during these Well-nourished patients receiving ologies of hyperphosphatemia in- therapies. Oral phosphate binders, nutrition support should have their clude acidosis (respiratory and available as calcium, aluminum, serum phosphorus levels monitored metabolic), hemolysis, rhabdomyol- and magnesium salts or as the non- daily or every other day. Malnour- ysis, hypoparathyroidism, and vita- ionic phosphate binder sevelamer, ished patients receiving nutrition min D toxicity.25,26 can be effective in lowering serum support should have their levels The most common clinical mani- phosphorus levels. Table 5 lists sug- monitored more closely initially festation of hyperphosphatemia is hy- gested pharmacologic treatments of (e.g., every 6–12 hours) as they pocalcemia due to calcium–phosphate hyperphosphatemia.142-144 have a higher risk of developing precipitation, which can lead to teta- Phosphate binders, especially hypophosphatemia, refeeding syn- ny and other clinical manifestations of those containing magnesium and drome, and subsequent complica- hypocalcemia.25,26 The risk of calcium– aluminum, should be used cautious- tions.30,122,125-128 Patients with renal phosphate precipitation appears to ly. Magnesium may cause diarrhea insufficiency should have their increase when the serum calcium and aluminum may cause constipa- serum phosphorus levels closely level multiplied by the serum phos- tion. Both magnesium and alumi- monitored because of the risk of phorus concentration exceeds 55–60 num may accumulate in patients hyperphosphatemia. mg2/dL2.98,139,140 Calcium–phosphate with renal insufficiency and lead to Hyperphosphatemia. Hyper- crystals can also deposit into soft toxicity. Therefore, calcium salts are phosphatemia is defined as a serum tissues and cause further organ preferred in patients with chronic re- phosphorus concentration of >4.5 damage.25,26,140,141 nal insufficiency or when long-term mg/dL. Serum phosphorus values Treatment of hyperphosphatemia therapy is required. Because it is should be interpreted cautiously requires identification and correc- significantly more expensive than since they may not correlate with to- tion of the underlying cause. The other treatments, sevelamer should tal body stores of phosphorus. The goals of therapy include returning be reserved for use in hyperphos- most common cause of hyperphos- the serum phosphorus concentration phatemia with hypercalcemia in phatemia in critically ill patients is to normal (2.7–4.5 mg/dL), avoiding chronic renal failure or hyperphos- renal insufficiency.25,26 Excessive i.v. or resolving symptoms of hyper- phatemia refractory to other treat- or oral administration of phosphate, phosphatemia, and maintaining ments. Prolonged use of phosphate such as in ICU patients receiving spe- the serum (calcium × phosphorus) binders may paradoxically result in cialized parenteral or enteral nutri- at <55–60 mg2/dL2.140,141 Daily phos- hypophosphatemia. tion, can also cause hyperphos- phate intake (e.g., in parenteral Because of the delayed onset of phatemia, especially in those with or enteral nutrition formulas) must therapies for hyperphosphatemia, fre- renal insufficiency.25,26,136-138 Severe be adjusted for patients with renal quent monitoring of serum phospho- hyperphosphatemia has been report- insufficiency. Requirements may rus levels is not usually needed. Rou- ed following treatment of constipa- differ in patients receiving CRRT tine monitoring of serum phosphorus tion with phosphorus-containing or intermittent hemodialysis because levels (every 24–48 hours) is probably

Table 5. Pharmacologic Treatment of Hyperphosphatemia142-144 Dosage Initial Maximum Medication Forms Recommended Dosagea Recommended Dosagea Calcium acetate Tablet: 667 mg 2 tablets or gelcaps three times 4 tablets or gelcaps with each meal Gelcap: 667 mg daily with meals daily; avoid hypercalcemia Calcium carbonate Tablet, capsule, liquid, and 1–2 g three times daily with meals 7 g/day; avoid hypercalcemia powder; various strengths Aluminum hydroxide Tablets: 300 and 600 mg 1–2 tablets or 15–30 mL three or 1800 mg (3–6 tablets) or 30 mL every Suspension: 320 mg/5 mL four times daily with meals and at 4 hr bedtime Magnesium hydroxide Tablets: 300 and 600 mg 1–2 tablets or 5–15 mL three times 2–4 tablets four times daily with meals Liquids: 400 and 800 mg/ daily with meals or 15 mL four times daily with meals 5 mL and at bedtime Sevelamer Tablets: 400 and 800 mg 800–1600 mg three times daily 4000 mg three times daily with meals Capsule: 403 mg with meals aMay require higher doses in rare situations or in some patients with chronic renal insufficiency and severe hyperphosphatemia. The dosage should be adjusted to achieve the goal serum phosphorus level in these situations.

1674 Am J Health-Syst Pharm—Vol 62 Aug 15, 2005 CLINICAL REVIEW Electrolyte disorders appropriate for most patients; patients tients with hypoalbuminemia or ride should be restricted to use in ur- with severe symptoms or those receiv- acid–base imbalance,145 direct mea- gent and emergent situations. One ing renal replacement therapy may re- surement of ionized calcium concen- method to reduce the risk for errors quire more frequent monitoring. tration in critically ill ICU patients is associated with ordering and dosing of recommended.32-35 The normal range calcium is to order calcium gluconate Calcium for ionized serum calcium concen- in milliequivalents of calcium or in Calcium functions in bone metab- tration is 1.12–1.30 mmol/L. Meta- grams of calcium gluconate and to or- olism, blood coagulation, platelet bolic alkalosis increases calcium der calcium chloride in milliequiva- adhesion, neuromuscular activity, binding to plasma proteins, reducing lents of calcium or in milligrams of endocrine and exocrine secretory the serum level of ionized calcium. calcium chloride. Regardless of the functions, and electrophysiology of Conversely, metabolic acidosis de- method used to order calcium salts, the heart and smooth muscles. Se- creases calcium binding to plasma the terms “ampule,” “amp,” and rum calcium concentration is regu- proteins, increasing the serum con- “mL” should not be used to order the lated by parathyroid hormone, vita- centration of ionized calcium. dosage of calcium, and the calcium min D, and calcitonin.32 The normal Hypocalcemia. Hypocalcemia salt should always be specified.150 range for total serum calcium con- (total serum calcium concentration Calcium gluconate is also the pre- centration is 8.6–10.2 mg/dL. of <8.6 mg/dL or ionized calcium ferred salt for peripheral venous ad- About 99% of total body calcium concentration of <1.1 mmol/L) is ministration since calcium chloride is found in bones, with less than 1% primarily due to hypoalbuminemia. infusion may cause tissue necrosis if in the serum.33 Approximately 40– Other causes include hypo- extravasation occurs.153,154 Calcium 50% of calcium in the blood is bound magnesemia, hyperphosphatemia, should not be infused in the same i.v. to plasma proteins, primarily albu- sepsis, pancreatitis, renal insufficien- catheter as solutions containing phos- min.33,35 Hypoalbuminemia, which is cy, hypoparathyroidism, and admin- phate because of the risk of calcium– frequently seen in critically ill pa- istration of blood preserved with phosphate precipitation. tients, can therefore cause a decrease citrate.33,35 The hallmark sign of se- Asymptomatic hypocalcemia due in total serum calcium levels. For vere acute hypocalcemia is tetany. to hypoalbuminemia requires no each 1-g/dL decrease in serum albu- Other neuromuscular, CNS, and car- therapy. Severe hypocalcemia (total min concentration (below 4 g/dL), diovascular symptoms may be serum calcium concentration of <7.5 total serum calcium concentration de- present, even with mild to moderate mg/dL or ionized calcium concentra- creases by approximately 0.8 mg/dL.34 hypocalcemia. Signs and symptoms tion of <0.9 mmol/L) or acute symp- Therefore, in patients with hypoal- of chronic hypocalcemia include skin tomatic hypocalcemia requires buminemia the serum calcium con- manifestations, such as brittle and prompt correction with i.v. calcium centration should be corrected for grooved nails, hair loss, dermatitis, administration.5,32,142 Initially, 1000 this. The corrected serum calcium and eczema.32 mg of calcium chloride (13.6 meq of concentration in patients with I.V. calcium gluconate and calcium calcium) or 3 g of calcium gluconate hypoalbuminemia can be estimated chloride are used to treat hypocalce- (13.7 meq of calcium) may be given using the following equation: mia when rapid correction of serum over 10 minutes to control symp- calcium levels is required. Calcium toms (Table 6). Since an i.v. bolus Corrected serum calcium conc. = chloride provides three times more dose of calcium may only be effective serum calcium conc. + (0.8 × [4 – elemental calcium than an equivalent for about two hours or less,35,155,156 serum albumin conc.]) amount of calcium gluconate. Recent severe acute hypocalcemia may not reports have described errors in cal- be corrected with intermittent i.v. Ionized or unbound calcium is the cium dosing and administration due bolus doses. Instead, a continuous biologically active form of calcium to confusion over the calcium salt, infusion of i.v. calcium may be re- and accounts for about 50% of calci- dosage, and manner in which calci- quired, with close monitoring of se- um in the blood under normal con- um was ordered, as well as potential- rum calcium levels at least every six ditions.33 Ionized serum calcium is ly confusing product labels.146-149 We hours during the infusion.5,32 The in- closely regulated by the endocrine recommend that institutions estab- fusion rate should not exceed 0.8–1.5 system and is a better indicator of the lish a standardized method for or- meq/min because of the potential functional status of calcium metabo- dering calcium to minimize the risk risk for cardiac arrhythmias associat- lism than total calcium levels. Be- of dosing errors.150-152 Calcium glu- ed with rapid calcium infusion.5 cause of the poor correlation be- conate should be used as the preferred Typically, a calcium gluconate tween ionized calcium and total salt for routine calcium maintenance dose of 1–2 g (4.56–9.12 meq of cal- calcium levels, especially in ICU pa- and supplementation; calcium chlo- cium) is mixed in 100 mL of 5% dex-

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Table 6. Empirical Dosages of I.V. Calcium5,32,142 Preferred Intermittent Degree of Hypocalcemia Calcium Salta Bolus Dosage Continuous Infusion Dosageb Mild to moderate, Gluconate 1–2 g calcium gluconate over 4.56–9.12 meq calcium over 30– asymptomatic 30–60 minutes; may repeat 60 minutes; may repeat every 6 every 6 hours as needed hours as needed Severe, symptomatic Chloride or gluconate 1000 mg calcium chloride or 3 13.6 meq calcium over 10 g calcium gluconate over 10 minutes; may repeat as needed minutes; may repeat as needed Severe, symptomatic; Chloride or gluconate Not applicable 0.8–1.5 meq calcium per minute; refractory to intermittent monitor serum calcium every 6 bolus doses hours or more frequently aCalcium chloride should be administered via a central venous catheter to avoid extravasation and tissue necrosis; 1000 mg calcium chloride = 13.6 meq calcium; 1 g calcium gluconate = 4.56 meq calcium. bMaximum rate of intravenous infusion = 1.5 meq calcium per minute.

trose injection or 0.9% sodium chlo- (total serum calcium concentration the intravascular volume contraction ride injection and infused over 30–60 of 10.3–12.9 mg/dL) or severe (total caused by hypercalcemia. After ade- minutes. The dose can be repeated serum calcium concentration of ≥13 quate hydration is achieved, furo- every 6 hours as needed until serum mg/dL). semide 40–100 mg i.v. every one to calcium levels have normalized. Hy- The primary causes of hypercalce- four hours can be used to enhance pocalcemia due to citrated blood mia are malignancy (e.g., breast can- renal calcium elimination and avoid transfusion can be treated by admin- cer, lung cancer, multiple myeloma, fluid overload from the saline hydra- istering 1.35 meq of calcium for each non-Hodgkin’s lymphoma) and tion, but caution should be taken to 100 mL of blood transfused.142 In ad- primary hyperparathyroidism.33,36 avoid further intravascular volume dition to the monitoring described Certain medications (e.g., thiazide depletion. Saline hydration and furo- above, routine monitoring of serum diuretics, lithium), vitamin A toxici- semide can reduce serum calcium calcium levels (total or ionized) in ty, vitamin D toxicity, milk-alkali levels by about 2–3 mg/dL within the adult patients in the ICU is recom- syndrome, adrenal insufficiency, im- first 48 hours of treatment.159 Hemo- mended (every 24–48 hours). mobilization, Paget’s disease, rhab- dialysis may be necessary in life- If concomitant hypomagnesemia is domyolysis, and tuberculosis can threatening hypercalcemia or in pa- present, magnesium supplements also cause hypercalcemia.5,33,36,37 tients with impaired renal function.38 should be given to help correct the hy- Chronic hypercalcemia may cause Bisphosphonates (e.g., etidronate, pocalcemia. The exact mechanism of nephrolithiasis, metastatic calcifica- pamidronate, zoledronic acid) are this interaction is unknown; however, tion, and renal failure.37 potent inhibitors of bone resorption it is hypothesized that magnesium de- Mild hypercalcemia usually re- via action on osteoblast and osteo- ficiency may impair the release or ac- sponds well to hydration and am- clast precursors and are frequently tivity of parathyroid hormone.26,157,158 bulation. Patients with severe hy- used for the treatment of hypercalce- Oral calcium supplements may be percalcemia frequently suffer from mia of malignancy. Etidronate diso- used once serum calcium levels are anorexia, fatigue, or confusion. Se- dium is effective when given intrave- corrected by administration of i.v. vere hypercalcemia may have cardiac nously at a dosage of 7.5 mg/kg/day calcium. Chronic or asymptomatic manifestations, such as bradycardia over 2 hours for three to seven days. hypocalcemia can be treated with or arrhythmias with ECG changes.31 Pamidronate disodium is given as a oral calcium supplements and vita- Severe hypercalcemia or hypercalcem- single i.v. dose of 60–90 mg infused min D. Table 7 describes the calcium ic crisis with a total serum calcium over 2–24 hours. The usual dose of supplements available, their elemen- concentration of >13 mg/dL requires zoledronic acid is a single i.v. dose of tal calcium content, and the forms emergency treatment because it can 4–8 mg infused over 15 minutes. Be- available for specific administration lead to acute renal failure, obtunda- cause of their prolonged time until routes. tion, ventricular arrhythmias, coma, onset of action, bisphosphonates Hypercalcemia. Hypercalcemia is and death.33,36 Treatment should be- have a limited role in the acute treat- defined as a total serum calcium con- gin promptly, starting with i.v. hy- ment of hypercalcemia; serum calci- centration of >10.2 mg/dL and can dration using 0.9% sodium chloride um levels usually begins to decline be characterized as mild to moderate infusion at 200–300 mL/hr to reverse within two days of the first bisphos-

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Table 7. may not correlate with intracellular Calcium Supplements concentrations or total body magne- 44,104,166 Calcium Elemental Elemental Administration sium levels. Therefore, treat- Salt Calcium (meq/g) Calcium (%) Routea ment of hypomagnesemia is largely Calcium chloride 13.6 27 I.V. empirical. Monitoring serum mag- Calcium gluconate 4.56 9 I.V. or oral nesium levels and monitoring the pa- Calcium acetate 12.7 25 I.V. or oral Calcium carbonate 20 40 Oral tient for resolution of signs and Calcium citrate 10.5 21 Oral symptoms of hypomagnesemia are aMaximum rate of i.v. infusion = 1.5 meq/min. the most readily available method for assessing the effectiveness of magne- sium supplementation. Because hy- phonate dose. A major advantage of the patient’s clinical condition, med- pomagnesemia is observed frequently pamidronate and zoledronic acid is ications (e.g., loop diuretics, ampho- in critically ill patients42,161-163 and has their effectiveness in a single-dose regi- tericin B), and alcohol use. been associated with increased mor- men.160 Zoledronic acid also has the Hypomagnesemia. Hypomag- tality,163,164 the serum magnesium advantage of a short infusion time. nesemia (serum magnesium concen- concentrations in critically ill pa- Bisphosphonates remain the tration of <1.5 mg/dL) is frequently tients in the ICU should be kept at drugs of choice for the treatment of observed in critically ill patients42,161-163 1.5 mg/dL or higher. Patients who hypercalcemia outside of the acute and has been associated with in- have recently had an acute myocar- setting. However, other medications, creased mortality.163,164 Severe hypo- dial infarction may require higher including glucocorticoids, calcito- magnesemia (serum magnesium concentrations (≥1.7 mg/dL) to pre- nin, plicamycin, and gallium nitrate, concentration of <1.0 mg/dL) can vent cardiac arrhythmias.167,168 have also been used.33,36,38,159 I.V. result in ECG changes, arrhyth- The goals of therapy should be to phosphates should not be used to mias (including torsades de avoid or resolve symptoms, return correct hypercalcemia because of the pointes), seizures, coma, and even the serum magnesium concentration potential for calcium–phosphate death.43,44 Hypomagnesemia may to 1.5–2.4 mg/dL, and avoid hyper- precipitation, which could result in cause concomitant refractory hy- magnesemia. Oral magnesium sup- further morbidity, including meta- pokalemia and hypocalcemia. Al- plements are available; however, static , hypotension, and though the exact mechanisms of problems with administration, slow renal failure. these observations are unknown, hy- onset of action, and GI intolerance pokalemia is likely a result of may limit their utility. The i.v. route Magnesium impaired activity of the sodium– of administration is preferred, espe- Magnesium is the second most potassium pump,113 and hypocal- cially in critically ill patients with se- abundant intracellular cation. It is cemia is likely due to impaired par- vere symptomatic hypomagnesemia. found primarily in bone, muscle, and athyroid release or activity.26,157,158 Few i.v. dosing regimens for the soft tissue, with about 1% of the total Causes of hypomagnesemia include treatment and repletion of hypo- body content in the extracellular flu- excessive GI losses, renal losses, sur- magnesemia have been suggest- id.26,44 The normal serum magnesium gery, trauma, infection or sepsis, ed.46,166-172 has concentration ranges from 1.5 to 2.4 burns, transfusion of blood pre- been associated with a total body mg/dL. Magnesium serves as an im- served with citrate, starvation, mal- magnesium deficiency of 1.0–2.0 portant cofactor for numerous en- nutrition, alcoholism, and certain meq/kg.169 Magnesium distributes zymes and in many biochemical re- medications (e.g., thiazide and loop into tissues slowly, but renal elimina- actions and is a required cofactor for diuretics, aminoglycosides, ampho- tion is rapid, with up to 50% of an reactions involving ATP.39,40 Magne- tericin B, cisplatin, cyclospor- i.v. dose of magnesium excreted in sium is absorbed throughout the ine).43,44,46,165,166 Use of cardiac glyco- the urine.42-45,169,170,173 Therefore, infu- small intestine, with the majority of sides (e.g., digoxin) has also been sion time is critical, and additional absorption occurring in the ileum associated with hypomagnesemia, supplementation may be required af- and jejunum.41 Magnesium homeo- possibly by enhancing magnesium ter the initial dose, with total reple- stasis is primarily handled by the kid- excretion, and hypomagnesemia may tion taking several days. For patients neys,42 but GI function, parathyroid potentiate digoxin toxicity (e.g., with mild to moderate hypo- hormone, and plasma magnesium dysrhythmias).43,44,46,165,166 magnesemia, 8–32 meq of magnesium concentrations also play a major Only about 1% of magnesium should be given (up to 1.0 meq/kg). role.41 Several other factors can affect stores are found in the extracellular Severe hypomagnesemia should be magnesium homeostasis, including space, and serum magnesium levels treated with 32–64 meq of magne-

Am J Health-Syst Pharm—Vol 62 Aug 15, 2005 1677 CLINICAL REVIEW Electrolyte disorders sium (up to 1.5 meq/kg) (Table 8). tion and increasing the risk of ad- causes of hypermagnesemia are renal Doses of <6 g of magnesium sulfate verse effects. Therefore, a lower rate insufficiency and iatrogenic causes.39,44 should be infused over 8–12 hours, of magnesium infusion may increase The primary therapy for hyper- with higher doses infused over 24 the fraction of the magnesium dose magnesemia is to discontinue exoge- hours. Because of the slow equilibra- that is retained and decrease the risk- nous magnesium administration. tion of magnesium between serum of inducing hypermagnesemia.169,170,174 I.V. calcium should be administered and intracellular spaces and tissues Severe symptomatic hypomagnesemia to patients with severe symptomatic (e.g., bone, red blood cells, mus- or conditions such as preeclampsia hypermagnesemia to reverse the car- cle),44,174 the serum magnesium levels and eclampsia may require more ag- diovascular and neuromuscular ef- could appear artificially high if mea- gressive magnesium therapy, with fects.44,47 I.V. calcium chloride doses sured too soon after a dose is given.174 doses up to 4 g magnesium sulfate of 500–1000 mg (7.8–13.6 meq of We recommend administering (32 meq of magnesium) over four to calcium) should be administered via 50% or less of the suggested empiri- five minutes, with close monitor- a central venous catheter over 5–10 cal magnesium dose in patients with ing.169,170 Serum magnesium levels minutes and repeated until symp- renal insufficiency to decrease the should be monitored at least once toms resolve. If the patient does not risk of hypermagnesemia. For i.v. ad- daily during magnesium repletion, in have a central venous catheter, 1–3 g ministration, the magnesium sulfate addition to routine monitoring (ev- of i.v. calcium gluconate (4.56–13.7 concentration should be diluted to ery 24–48 hours). meq of calcium) should be infused 20% (20 g/100 mL) or less before ad- Hypermagnesemia. Hypermag- over 3–10 minutes. Patients with ministration, but the undiluted 50% nesemia is defined as a serum magne- asymptomatic hypermagnesemia solution may be administered intra- sium concentration of >2.4 mg/dL. may be treated with magnesium re- muscularly to adults.175 Because a re- Generally, patients tolerate mild hy- striction, loop diuretics, or hemodi- nal threshold for magnesium exists, permagnesemia (serum magnesium alysis.44,47 Magnesium-containing with up to 50% of an i.v. dose being concentration of 2.5–4 mg/dL) and antacids and other medications con- eliminated in the urine,42-45,169,170,173 are usually asymptomatic.44,47 Pa- taining magnesium should be avoid- i.v. magnesium sulfate should be tients with moderate hyperma- ed in patients with renal insufficien- administered at a maximum rate of gnesemia (4–12.5 mg/dL) may ex- cy. Serum magnesium levels should 1 g/hr (8 meq of magnesium per hibit signs and symptoms, including be monitored at least once daily dur- hour) in asymptomatic patients with nausea, vomiting, loss of deep ing treatment. More frequent moni- hypomagnesemia, and the total dose tendon reflexes, hypotension, brady- toring may be required in symptom- should not exceed 12 g (100 meq of cardia, and ECG changes (e.g., in- atic patients when more aggressive magnesium) over 12 hours.169 Care- creased PR interval, increased QRS therapy is used (e.g., loop diuretics, ful monitoring is also prudent, espe- interval duration).39,43,44,47 Severe hy- hemodialysis). Serum magnesium cially when doses approach the maxi- permagnesemia (>12.5–32 mg/dL) concentration should be maintained mum recommendations.169 Rapid can result in respiratory paralysis, re- in the normal range (1.5–2.4 mg/dL) rates of magnesium infusion may ex- fractory hypotension, atrioventricular and hypomagnesemia avoided dur- ceed the renal threshold, resulting in block, cardiac arrest, and ing treatment. increased urinary magnesium excre- death.39,44,47,176 The most common Conclusion Table 8. Treatment of electrolyte disorders Empirical Treatment of Hypomagnesemia42,45,166-173 is often empirical, based on pub- lished literature, expert opinion and Serum Magnesium I.V. Magnesium Severity Concentration (mg/dL) Replacement Dosea,b recommendations, and the patient’s Mild to moderate 1.0–1.5 8–32 meq magnesium (1–4 g response to the initial treatment. Cli- magnesium sulfate), up to nicians should be knowledgeable 1.0 meq/kg about electrolyte homeostasis and Severe <1.0 32–64 meq magnesium (4–8 g magnesium sulfate), up the underlying pathophysiology of to 1.5 meq/kg electrolyte disorders to provide opti- aIn patients with normal renal function; patients with renal insufficiency should receive ≤50% of the initial mal therapy for patients. empirical dose. Maximum rate of infusion = 8 meq magnesium per hour (1 g magnesium sulfate per hour), up to 100 meq magnesium (approximately 12 g magnesium sulfate) over 12 hours if asymptomatic; up to 32 meq References magnesium (4 g magnesium sulfate) over 4–5 minutes in severe symptomatic hypomagnesemia. 1 g magnesium sulfate = 8.1 meq magnesium. 1. Rose BD, Post TW. Clinical physiology bThe authors suggest using adjusted body weight (AdjBW) in patients who are significantly obese (weight of of acid-base and electrolyte disorders. >130% of ideal body weight [IBW] or have a body mass index of ≥30 kg/m2): AdjBW (men) = ([wt (kg) – IBW (kg)] 5th ed. New York: McGraw-Hill; × 0.3) + IBW; AdjBW (women) = ([wt (kg) – IBW (kg)] × 0.25) + IBW. 2001:241-98,682-821.

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