Mark A. Malesker and Lee E. Morrow
LEARNING OBJECTIVES
Upon completion of the chapter, the reader will be able to:
1. Estimate the volumes of various body fluid compartments.
2. Calculate the daily maintenance fluid requirement for patients given their weight, and gender.
3. Differentiate among currently available fluids for volume resuscitation.
4. Identify the electrolytes primarily found in the extracellular and intracellular fluid compartments.
5. Describe the unique relationship between serum sodium concentration and total body water (TBW).
6. Review the etiology, clinical presentation, and management for disorders of sodium, potassium, calcium, phosphorus, and magnesium.
KEY CONCEPTS
Total body water (TBW) is approximately 50% of lean body weight in normal females and 60% of lean body weight in males. TBW is comprised of the intracellular fluid (two-thirds of TBW) and the extracellular fluid (one-third of TBW). The extracellular fluid is made up of two major fluid subcompartments: the interstitial fluid and the intravascular fluid.
Therapeutic fluids include crystalloid and colloid solutions. The most commonly used crystalloids include normal saline, hypertonic saline, and lactated Ringer’s solution. Examples of colloids include albumin, the dextrans, hetastarch, and fresh-frozen plasma.
The calculated serum osmolality helps determine deviations in TBW content.
Concentrated electrolytes (potassium chloride [KCl], potassium phosphate, and sodium chloride [NaCl] greater than 0.9%) should not be stored in patient care areas as a patient safety measure.
Hyponatremia is a very common finding in hospitalized patients and is defined as a serum sodium concentration below 136 mEq/L (136 mmol/L).
IV potassium infusions running at rates of greater than 10 mEq/h require cardiac monitoring.
Calcium gluconate is the preferred peripherally infused calcium supplement because it is less irritating to the veins. Calcium chloride (CaCl) must be infused via a central line.
Severe hypophosphatemia can result in impaired diaphragmatic contractility and acute respiratory failure.
Serum magnesium concentrations do not correlate well with total body magnesium stores. For this reason, magnesium supplementation is often given empirically to critically ill patients.
BODY FLUID COMPARTMENTS
A thorough understanding of the fundamentals of fluid and electrolyte homeostasis is essential given the frequency with which clinical disturbances are seen and the profound effects these disturbances can have on various aspects of patient care. However, the interplay of body fluids, serum electrolytes, and clinical monitoring is complex, and a thorough command of these issues is a challenging task even for advanced practitioners.1 Practitioners must be familiar with the key concepts of body compartment volumes, calculation of daily fluid requirements, and the various types of fluid available for replacement. The management of disorders of sodium, potassium, calcium, phosphorus, and magnesium integrates these concepts with issues of dose recognition and patient safety.
The most fundamental concept to grasp is an assessment of total body water (TBW), which is directly related to body weight. TBW constitutes approximately 50% of lean body weight in healthy females and 60% of lean body weight in males. The percentage of TBW decreases as body fat increases and/or with age (75–85% of body weight is water for newborns). Unless the patient is obese (body weight greater than 120% of ideal body weight [IBW]), clinicians typically use a patient’s actual body weight when calculating TBW.2 In obese patients, it is customary to estimate TBW using lean body weight or IBW as calculated by the Devine-Devine method: males’ lean body weight = 50 kg + (2.3 kg/in. × [height in inches − 60]) and females’ lean body weight = 45.5 kg + (2.3 kg/in. × [height in inches − 60]).3–5Note that 1 kg is equivalent to 2.2 lb, 1 in. is equivalent to 2.54 cm, and 1 L of water weighs 1 kg (2.2 lb).
The intracellular fluid (ICF) represents the water contained within cells and is rich in electrolytes such as potassium, magnesium, phosphates, and proteins. The ICF is approximately two-thirds of TBW regardless of gender. For a 70-kg man, this would mean that the TBW is 42 L and the ICF is approximately 28 L. For a 70-kg woman, these values would be 35 L and 24 L, respectively. Note that ICF represents approximately 40% of total body weight in men and approximately 33% of total body weight in women.
The extracellular fluid (ECF) is the fluid outside the cell and is rich in sodium, chloride, and bicarbonate. The ECF is approximately one-third of TBW (14 L in a 70-kg man or 12 L in a 70-kg woman) and is subdivided into two compartments: the interstitial fluid and the intravascular fluid. The interstitial fluid represents the fluid occupying the spaces between cells, and is about 25% of TBW (10.5 L in a 70-kg man or 8.8 L in a 70-kg woman). The intravascular fluid (also known as plasma) represents the fluid within the blood vessels and is about 8% of TBW (3.4 L in a 70-kg man or 2.8 L in a 70-kg woman). Because the exact percentages are cumbersome to recall, many clinicians accept that the ECF represents roughly 20% of body weight (regardless of gender) with 15% in the interstitial space and 5% in the intravascular space.6 Note that serum electrolytes are routinely measured from the ECF.
The transcellular fluid includes the viscous components of the peritoneum, pleural space, and pericardium, as well as the cerebrospinal fluid, joint space fluid, and the GI digestive juices. Although the transcellular fluid normally accounts for about 1% of TBW, this amount can increase significantly during various illnesses favoring fluid collection in one of these spaces (e.g., pleural effusions or ascites in the peritoneum). The accumulation of fluid in the transcellular space is often referred to as “third spacing.” To review the calculations of the body fluid compartments in a representative patient, see Patient Encounter 1.
Fluid balance is assessed by several means each of which has its limitations. Blood pressure (BP) measurements estimate fluid status relative to the amount of blood volume pumped by the heart but are affected by cardiac function and vascular pliability. Patients with significant volume deficiency may appear hypotensive, but this is a late finding that may require greater than 20% of TBW to be lost. Patients with significant volume excess may appear edematous; however, third spacing may hide this finding until late in the course as well. The physical exam can indicate the presence of fluid deficits (dry mucous membranes) and fluid excess (peripheral edema, coarse breath sounds). More invasive assessments would include the use of an arterial catheter, a pulmonary artery catheter to measure left ventricular function and fluid status, and a central venous catheter, which measures fluid status and right ventricular function. However, the correlation between these measured pressures and their associated volume is an area of debate.
Patient Encounter 1: Body Fluid Compartments
Calculate the total body water, ICF, and extracellular fluid in a 70-kg male.
To maintain fluid balance, the total amount of fluid gained throughout the day (input, or “ins”) must equal the total amount of fluid lost (output, or “outs”). Although most forms of the body’s input and output can be measured, several cannot. For a normal adult on an average diet, ingested fluids are easily measured and average 1,400 mL/day. Other fluid inputs, such as those from ingested foods and the water by-product of oxidation, are not directly measurable. Fluid outputs such as urinary and stool losses are also easily measured and are referred to as sensible losses. Other sources of fluid loss, such as evaporation of fluid through the skin and/or lungs, are not readily measured and are called insensible losses. Table 27–1 shows the estimated ins and outs (I&Os) for a healthy 68-kg (150-lb) man.6 The measurable I&Os are routinely measured in hospitalized patients and are used to estimate total fluid balance for each 24-hour period. It is important to realize that in hospitalized patients, multiple other forms of fluid loss must be considered. These include losses from enteric suctioning (most commonly, nasogastric [NG] tubes), from surgical drains (e.g., chest tubes, nephrostomy tubes, and pancreatic drains), via fistulous tracts, and enhanced evaporative losses (burns and fever).
TBW depletion (often referred to as “dehydration”) is typically a gradual, chronic problem. Because TBW depletion represents a loss of hypotonic fluid (proportionally more water is lost than sodium) from all body compartments, a primary disturbance of osmolality is usually seen. The signs and symptoms of TBW depletion include CNS disturbances (mental status changes, seizures, and coma), excessive thirst, dry mucous membranes, decreased skin turgor, elevated serum sodium, increased plasma osmolality, concentrated urine, and acute weight loss. Common causes of TBW depletion include insufficient oral intake, excessive insensible losses, diabetes insipidus, excessive osmotic diuresis, and impaired renal concentrating mechanisms. Long-term care residents are frequently admitted to the acute care hospital with TBW depletion secondary to lack of adequate oral intake, often with concurrent excessive insensible losses.
Table 27–1 Approximate I&Os for a Healthy 68-kg (150-lb) Man
The volume of fluid required to correct TBW depletion equals the basal fluid requirement plus ongoing exceptional losses plus the fluid deficit. Basal daily fluid requirements are calculated using the formulas in Table 27–2. For an adult, this represents 1,500 mL/day for the first 20 kg of body weight plus 20 mL/day for each additional kilogram. The volume of replacement fluids required for a given patient (the fluid deficit) can be estimated by the acute weight change in the patient (1 kg = 1 L of fluid). Because the precise weight change is not typically known, it is often calculated as follows: fluid deficit = normal TBW - present TBW. Normal TBW is estimated based on the patient’s height using the formulas in Table 27–2, and the present TBW is estimated based on the patient’s current body weight. The choice of fluids used for replacement is guided by the presence of concurrent electrolyte abnormalities. The adequacy of replacement is guided by each patient’s objective response to fluid replacement (improved skin turgor, adequate urine output, normalization of heart rate, BP, etc.).
Once TBW has been restored, the volume of “maintenance” fluid equals the basal fluid requirement plus ongoing exceptional losses. If the pathophysiologic process leading to TBW depletion has not been identified and corrected (or accounted for in the calculation of maintenance fluid requirements), TBW depletion will quickly recur. To review the concepts involved in the calculation of replacement fluids for a representative patient see Patient Encounter 2.
Compared to TBW depletion, ECF depletion tends to occur acutely. In this setting, rapid and aggressive fluid replacement is required to maintain adequate organ perfusion. Because ECF depletion is generally due to the loss of isotonic fluid (proportional losses of sodium and water), major disturbances of plasma osmolality are not common. ECF depletion manifests clinically as signs and symptoms associated with decreased tissue perfusion: dizziness, orthostasis, tachycardia, decreased urine output, increased hematocrit, decreased central venous pressure, and/or hypovolemic shock. Common causes of ECF depletion include external fluid losses (burns, hemorrhage, diuresis, GI losses, and adrenal insufficiency) and third spacing of fluids (septic shock, anaphylactic shock, or abdominal ascites).
Table 27–2 Useful Calculations for the Estimation of Patient Maintenance Fluid Requirements
|
Neonate (1−10 kg) = 100 mL/kg |
|
Child (10−20 kg) = 1,000 mL + 50 mL for each kilogram greater than 10 |
|
Adult (greater than 20 kg) = 1,500 mL + 20 mL for each kilogram greater than 20 |
Patient Encounter 2: Fluid Requirements
Calculate the daily fluid requirement for a 70-kg adult male.
In clinical practice, the most commonly encountered problem is depletion of TBW and ECF. Accordingly, the fluid resuscitation strategy should address both of these compartments. As these compartments are repleted, serum electrolytes must be monitored closely as discussed in subsequent sections of this chapter.
THERAPEUTIC FLUIDS
Crystalloids
Therapeutic IV fluids include crystalloid solutions, colloidal solutions, and oxygen-carrying resuscitation solutions. Crystalloids are composed of water and electrolytes, all of which pass freely through semipermeable membranes and remain in the intravascular space for shorter periods of time. As such, these solutions are very useful for correcting electrolyte imbalances, but result in smaller hemodynamic changes for a given unit of volume.
Crystalloids can be classified further according to their tonicity. Isotonic solutions (i.e., normal saline or 0.9% sodium chloride [NaCl]) have a tonicity equal to that of the ICF (approximately 310 mEq/L or 310 mmol/L) and do not shift the distribution of water between the ECF and the ICF. Because hypertonic solutions (i.e., hypertonic saline or 3% NaCl) have greater tonicity than the ICF (greater than 376 mEq/L or 376 mmol/L), they draw water from the ICF into the ECF. In contrast, hypotonic solutions (i.e., 0.45% NaCl) have less tonicity than the ICF (less than 250 mEq/L or 250 mmol/L) leading to osmotic pressure gradient that favors shifts of water from the ECF into the ICF. The tonicity, electrolyte content, and glucose content of selected fluids are shown in Table 27–3.
The tonicity of crystalloid solutions is directly related to their sodium concentration. The most commonly used crystalloids include normal saline, hypertonic saline, and lactated Ringer’s solution. Excessive administration of any fluid replacement therapy, regardless of tonicity, can lead to fluid overload, particularly in patients with cardiac or renal insufficiency. Glucose is often added to hypotonic crystalloids in amounts than result in isotonic fluids (D5W, D5½NS, and D5¼NS). These solutions are often used as maintenance fluids to provide basal amounts of calories and water.
Normal Saline (0.9% NaCl or NS)
Normal saline is an isotonic fluid composed of water, sodium, and chloride. It provides primarily ECF replacement and can be used for virtually any cause of TBW depletion. Common uses of normal saline include perioperative fluid administration; volume resuscitation of shock, hemorrhage, or burn patients; fluid challenges in hypotensive or oliguric patients; and hyponatremia. Normal saline can also be used to treat metabolic alkalosis (also known as contraction alkalosis).
Table 27–3 Electrolyte and Dextrose Content of Selected Crystalloid Fluids
Half-Normal Saline (0.45% NaCl or ½ NS)
Half-normal saline is a hypotonic fluid that provides free water in relative excess when compared to the sodium concentration. This crystalloid is typically used to treat patients who are hypertonic due to primary depletion of the ECF. Because half-normal saline is hypotonic, serum sodium must be closely monitored during administration.
Hypertonic Saline (3% NaCl)
Hypertonic saline is obviously hypertonic and provides a significant sodium load to the intravascular space. This solution is used very infrequently given the potential to cause significant shifts in the water balance between the ECF and the ICF. It is typically used to treat patients with severe hyponatremia who have symptoms attributable to low serum sodium. Hypertonic saline in concentrations of 7.5% to 23.4% has been used to acutely lower intracranial pressure in the setting of traumatic brain injury and stroke. The literature is inconsistent for the appropriate hypertonic concentration, dosing, timing of replacement, and goals for use in this population. Serum sodium and neurologic status must be very closely monitored whenever given.
Ringer’s Lactate
This isotonic volume expander contains sodium, potassium, chloride, and lactate in concentrations that approximate the fluid and electrolyte composition of the blood. Ringer’s lactate (also known as “lactated Ringer” or LR) provides ECF replacement and is most often used in the perioperative setting, and for patients with lower GI fluid losses, burns, or dehydration. The lactate component of LR works as a buffer to increase the pH. Accordingly, large volumes of LR may cause iatrogenic metabolic alkalosis. Because patients with significant liver disease are unable to metabolize lactate sufficiently, LR administration in this population may lead to accumulation of lactate with iatrogenic lactic acidosis.
5% Dextrose in Water (D5W)
D5W is a solution of free water and dextrose that provides a modest amount of calories but no electrolytes. Although it is technically isotonic, it acts as a hypotonic solution in the body. It is commonly used to treat severe hypernatremia. D5 W is also used in small volumes (100 mL) to dilute many IV medications or at a low infusion rate (10–15 mL/h) to “keep the vein open” (KVO) for IV medications.
Colloids
In contrast to crystalloids, colloids do not dissolve into a true solution, and therefore do not pass readily across semipermeable membranes. As such, colloids effectively remain in the intravascular space and increase the oncotic pressure of the plasma. This effectively shifts fluid from the interstitial compartment to the intravascular compartment. In clinical practice, these theoretical benefits are generally short-lived (given metabolism of colloidal proteins/sugars) and for most patients there is little therapeutic advantage of colloids over crystalloids or vice versa. Examples of colloids include 5% albumin, 25% albumin, the dextrans, hetastarch, and fresh-frozen plasma (FFP). Because each of these agents contains a substance (proteins and complex sugars) that will ultimately be metabolized, the oncotic agent will be ultimately lost and only the remaining hypotonic fluid delivery agent will remain. As such, use of large volumes of colloidal agents is more likely to induce fluid overload compared to crystalloids. Although smaller volumes of colloids have equal efficacy as larger volumes of crystalloids, they generally must be infused more slowly. Often the net result is that the time to clinical benefit is the same regardless of which class of fluid is utilized. For example, 500 mL of normal saline is required to increase the systolic BP to the same degree as seen with approximately 250 mL of 5% albumin; however, the normal saline can be administered twice as fast.
Albumin
Albumin is a protein derived from fractionating human plasma. Because albumin infusion is expensive and may be associated with adverse events, it should be used for acute volume expansion and not as a supplemental source of protein calories. Historically, albumin was used indiscriminately in the intensive care unit until anecdotal publications suggested that albumin may cause immunosuppression. However, the recently completed Saline Versus Albumin Fluid Evaluation (SAFE) trial randomized nearly 7,000 hypovolemic patients to either albumin or normal saline therapy and found that the mortality for those who received albumin was the same as for those who received normal saline.7 A subsequent post hoc analysis reported that patients with traumatic brain injury had higher mortality rates when given albumin for fluid resuscitation. These conflicting findings highlight the controversy and confusion surrounding the use of human albumin versus normal saline therapy for resuscitation of critically ill patients.8–10Albumin combined with furosemide has been demonstrated to improve fluid balance, oxygenation, and hemodynamics in the subset of patients with acute lung injury who have low serum protein.11
Recent events have resulted in an albumin shortage in the United States with ongoing allocation of all albumin products. In brief, albumin is obtained as a by-product of routine intravenous immunoglobulin (IVIG) processing. As a result, the albumin supply is driven by the amount of plasma fractioning for IVIG. Increased efficiency of the IVIG collection techniques and decreased IVIG consumption has led to an unintended shortage of albumin available for use. Based upon this limited availability, health systems and hospitals have had to define the appropriate albumin indications for their patients and ration albumin accordingly. Evidence-based indications for albumin include plasmaphoresis/apharesis, large volume paracentesis (greater than 4 liters removed), hypotension in hemodialysis, and the need for aggressive diuresis in hypoalbuminemic hypotensive patients. Inappropriate uses of albumin include nutritional supplementation, impending hepatorenal syndrome, pancreatitis, alteration of drug pharmacokinetics, or acute normovolemic hemodilution in surgery. Practitioners can keep up with medication shortages by checking the American Society of Health-System Pharmacists (ASHP) website (www.ashp.org).
Hetastarch and Dextran
While albumin is the most commonly used colloid, the other available products are not without their own risks and benefits. Hetastarch (various manufacturers) and Voluven contain 6% starch and 0.9% NaCl. This product has no oxygen-carrying capacity and is administered intravenously as a plasma expander. Limitations of this product include acquisition cost, hypersensitivity reactions, and bleeding. Dosing should be reduced in the presence of renal dysfunction. Hextend is a comparable plasma expander that contains 6% hetastarch in lactated electrolyte solution. Low-molecular-weight dextran (various manufacturers) and high-molecular-weight dextran (various manufacturers) are polysaccharide plasma expanders. Anaphylactic reactions and prolonged bleeding times have limited the use of these products. Potential mechanisms of colloid solution-induced bleeding include platelet inhibition or possible dilution of clotting factors via infusion of a large volume colloid solution. Although FFP has been used as a volume expander in cases of excessive blood loss (surgery or trauma) and to prevent bleeding in the presence of abnormal coagulation studies, it is now rarely used for volume expansion given risks of anaphylaxis, potential for viral transmission, and increased nosocomial infection rates.
Fluid Management Strategies
Classic indications for IV fluid include maintenance of BP, restoring the ICF volume, replacing ongoing renal or insensible losses when oral intake is inadequate, and the need for glucose as a fuel for the brain.12 Although large volumes of fluid are given during the resuscitation of most trauma patients, a recent analysis reported uncertainty about the use of early large volume fluid replacement in patients with active bleeding, calling into question our understanding of the need for fluids in various patient populations.13
When determining the appropriate fluid to be utilized, it is important to first determine the type of fluid problem (TBW versus ECF depletion), and start therapy accordingly. For patients demonstrating signs of impaired tissue perfusion, the immediate therapeutic goal is to increase the intravascular volume and restore tissue perfusion. The standard therapy is normal saline given at 150 to 500 mL/h (for adult patients) until perfusion is optimized. Although LR is a therapeutic alternative, lactic acidosis may arise with massive or prolonged infusions. In severe cases, a colloid or blood transfusion may be indicated to increase oncotic pressure within the vascular space. Once isovolemia is achieved, patients may be switched to a more hypotonic maintenance solution (0.45% NaCl) at a rate that delivers estimated daily needs.
The clinical scenario and the severity of the volume abnormality dictate monitoring parameters during fluid replacement therapy. These may include the subjective sense of thirst, mental status, skin turgor, orthostatic vital signs, pulse rate, weight changes, blood chemistries, fluid input and output, central venous pressure, pulmonary capillary wedge pressure, and cardiac output. Fluid replacement requires particular caution in patient populations at risk of fluid overload, such as those with renal failure, cardiac failure, hepatic failure, or the elderly. Other complications of parenteral fluid therapy include IV site infiltration, infection, phlebitis, thrombophlebitis, and extravasation.
In summary, common settings for fluid resuscitation include hypovolemic patients (e.g., sepsis or pneumonia), hypervolemic patients (e.g., congestive heart failure [CHF], cirrhosis, or renal failure), euvolemic patients who are unable to take oral fluids in proportion to insensible losses (e.g., the perioperative period), and patients with electrolyte abnormalities (see below).
ELECTROLYTES
Normally, the number of anions (negatively charged ions) and cations (positively charged ions) in each fluid compartment are equal. Cell membranes play the critical role of maintaining distinct ICF and ECF spaces, which are biochemically distinct. Serum electrolyte measurements reflect the stores of ECF electrolytes rather than that of ICF electrolytes. Table 27–4 lists the chief cations and anions along with their normal concentrations in the ECF and ICF. The principal cations are sodium, potassium, calcium, and magnesium, while the key anions are chloride, bicarbonate, and phosphate. In the ECF, sodium is the most common cation and chloride is the most abundant anion, while in the ICF, potassium is the primary cation and phosphate is the main anion. Normal serum electrolyte values are listed in Table 27–5.
Osmolality is a measure of the number of osmotically active particles per unit of solution, independent of the weight or nature of the particle. Equimolar concentrations of all substances in the undissociated state exert the same osmotic pressure. Although the normal serum osmolality is 280 to 300 mOsm/kg (280–300 mmol/kg), multiple scenarios exist where this value becomes markedly abnormal. The calculated serum osmolality helps determine deviations in TBW content. As such, it is often useful to calculate the serum osmolality as follows:
Table 27–4 Normal Cation and Anion Concentrations in the ECF and ICF
Table 27–5 Normal Ranges for Serum Electrolyte Concentrations
Serum osmolality (mOsm/L) = 2 (Na mEq/L) + (glucose [mg/dL])/18 + (BUN [mg/dL])/2.8.
Note: For glucose, multiply by a factor of 0.055 to convert conventional glucose units (mg/dL) to SI glucose units (mmol/L). To convert SI units of glucose (mmol/L) to conventional glucose units (mg/dL), multiply SI units by a factor of 18.18. For blood urea nitrogen (BUN), multiply by a factor of 0.357 to convert conventional BUN units (mg/dL) to SI BUN units (mmol/L). To convert SI units of BUN (mmol/L) to conventional BUN units (mg/dL), multiply SI units by a factor of 2.8.
Because the body regulates water to maintain osmolality, deviations in serum osmolality are used to estimate TBW stores. Water moves freely across all cell membranes, making serum osmolality an accurate reflection of the osmolality within all body compartments. An increase in osmolality is equated with a loss of water greater than the loss of solute (TBW depletion). A decrease in serum osmolality is seen when water is retained in excess of solute (CHF or hepatic cirrhosis). The difference between the measured serum osmolality and the calculated serum osmolality, using the equation above, is referred to as the osmolar gap. Under normal circumstances the osmolar gapshould be 10 mOsm/L or less. An increased osmolar gap suggests the presence of a small, osmotically active agent and is most commonly seen with the ingestion of alcohols (ethanol, methanol, ethylene glycol, or isopropyl alcohol) or medications such as mannitol or lorazepam. Patient Encounter 3 illustrates the utility of serum osmolality in a clinical setting.
Patient Encounter 3: Calculate the Plasma Osmolality
A 50-year-old homeless man is brought to the emergency department staggering and smelling like beer. Rapid respiration, tachycardia, and a BP of 90/60 mm Hg were noted. The sodium is 142 mEq/L (142 mmol/L), potassium 3.6 mEq/L (3.6 mmol/L), chloride 100 mEq/L (100 mmol/L), bicarbonate 12 mEq/L (12 mmol/L), glucose 180 mg/dL (9.99 mmol/L), and BUN 28 mg/dL (9.99 mol/L). The measured osmolarity is 360 mOsm/L.
Calculate the osmolality.
Calculate the osmolar gap.
What is the likely cause of an increased gap in this patient?
Many of the electrolyte disturbances discussed in the remainder of this chapter represent medical emergencies that call for aggressive interventions including the use of concentrated electrolytes. However, these solutions are a frequent source of medical errors with significant potential for patient harm. As such, the 2005 National Patient Safety Goals published by the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) recommends that concentrated electrolyte solutions (KCl, potassium phosphate, and NaCl greater than 0.9%) be removed from patient care areas. In addition, JCAHO recommends standardizing and limiting the number of drug concentrations available in each institution so as to further reduce the risk of medication errors and improve outcomes.14
Sodium
The body’s normal daily sodium requirement is 1.0 to 1.5 mEq/kg (80–130 mEq, which is 80–130 mmol) to maintain a normal serum sodium concentration of 136 to 145 mEq/L (136–145 mmol/L).15 Sodium is the predominant cation of the ECF and largely determines ECF volume. Sodium is also the primary factor in establishing the osmotic pressure relationship between the ICF and ECF. All body fluids are in osmotic equilibrium and changes in serum sodium concentration are associated with shifts of water into and out of body fluid compartments. When sodium is added to the intravascular fluid compartment, fluid is pulled intravascularly from the interstitial fluid and the ICF until osmotic balance is restored. As such, a patient’s measured sodium concentration should not be viewed as an index of sodium need because this parameter reflects the balance between total body sodium content and TBW. Disturbances in the sodium concentration most often represent disturbances of TBW. Sodium imbalances cannot be properly assessed without first assessing the body fluid status.
Hyponatremia is very common in hospitalized patients and is defined as a serum sodium concentration below 136 mEq/L (136 mmol/L). Clinical signs and symptoms appear at concentrations below 120 mEq/L (120 mmol/L) and typically consist of agitation, fatigue, headache, muscle cramps, and nausea. With profound hyponatremia (less than 110 mEq/L [110 mmol/L]), confusion, seizures, and coma may be seen. Because therapy is also influenced by volume status, hypo-natremia is further defined as: (a) hypertonic hyponatremia; (b) hypotonic hyponatremia with an increased ECF volume; (c) hypotonic hyponatremia with a normal ECF volume; and (d) hypotonic hyponatremia with a decreased ECF volume.16
Hypertonic hyponatremia is usually associated with significant hyperglycemia. Glucose is an osmotically active agent that leads to an increase in TBW with little change in total body sodium. For every 60 mg/dL (3.33 mmol/L) increase in serum glucose above 200 mg/dL (11.1 mmol/L), the sodium concentration is expected to decrease by approximately 1 mEq/L (1 mmol/L). Appropriate treatment of the hyperglycemia will return the serum sodium concentration to normal.15
Hypotonic hyponatremia with an increase in ECF (hypervolemic hyponatremia) is also known as dilutional hyponatremia. In this scenario, patients have an excess of total body sodium and TBW; however, the excess in TBW is greater than the excess in total body sodium. Common causes include CHF, hepatic cirrhosis, and nephrotic syndrome. Treatment includes sodium and fluid restriction in conjunction with treatment of the underlying disorder—for example, salt and water restrictions are used in the setting of CHF along with loop diuretics, angiotensin-converting enzyme inhibitors, and spironolactone.15
In hypotonic hyponatremia with a normal ECF volume (euvolemic hyponatremia), patients have an excess of TBW with relatively normal sodium content. In essence, there is a presence of excess free water. This is most frequently seen in patients with the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Common causes of SIADH include carcinomas (e.g., lung or pancreas), pulmonary disorders (e.g., pneumonias or tuberculosis), CNS disorders (e.g., meningitis, stroke, tumor, or trauma), and medications (e.g., sulfonylureas, antineoplastic agents, barbiturates, morphine, antipsychotics, tricyclics, nonsteroidal anti-inflammatory agents, selective serotonin reuptake inhibitors, dopamine agonists, and general anesthetics). These medications stimulate the release of antidiuretic hormone (ADH) from the pituitary gland resulting in water retention and dilution of the body’s sodium stores. Treatment generally consists of fluid restriction alone. Hypertonic saline is used only when the sodium concentration is less than 110 mEq/L (110 mmol/L) and/or severe symptoms (e.g., seizures) are present. Refractory SIADH may respond to demeclocycline (Declomycin, ESP Pharma) dosed at 900 to 1,200 mg/day, lithium (various generics), furosemide (various generics), or urea. Given the limitations associated with these treatment strategies (unpredictable therapeutic effects and side effects), the arginine vasopressin antagonist conivaptan (Vaprisol, Astellas) was developed for short-term treatment of euvolemic hyponatremia. While conivaptan can also be used to manage hypervolemic hyponatremia in hospitalized patients, it should not be used for hypovolemic hyponatremia. Conivaptan is dosed 20 mg IV over 30 minutes, followed by a 20 mg continuous infusion over 24 hours for up to 4 days.
In hypotonic hyponatremia with a decreased ECF volume (hypovolemic hyponatremia), patients usually have a deficit of both total body sodium and TBW, but the sodium deficit exceeds the TBW deficit. Common causes include diuretic use, profuse sweating, wound drainage, burns, GI losses (vomiting or diarrhea), hypoadrenalism (low cortisol and low aldosterone), and renal tubular acidosis. Treatment includes the administration of sodium to correct the sodium deficit and water to correct the TBW deficit. The sodium deficit can be calculated with the following equation2:
Sodium deficit (mEq) = (TBW [in liters]) (desired Na+ concentration [mEq/L or mmol/L] - current Na+ concentration).
Although both water and sodium are required in this instance, sodium needs to be provided in excess of water to fully correct this abnormality. As such, hypertonic saline (3% NaCl) is often used. One can estimate the change in serum sodium concentration after 1 L of 3% NaCl infusion using the following equation16:
Change in serum Na+ (mEq/L or mmol/L) = (infusate Na+ - serum Na+)/(TBW + 1).
In this formula, TBW is increased by 1 to account for the addition of the liter of 3% NaCl. Patient Encounters 4 and 5 illustrate the concepts of calculating and correcting the sodium deficit.
Depending on the severity of the hyponatremia and acuity of onset, 0.9%, 3%, or 5% NaCl can be utilized. Most patients can be adequately managed with normal saline rehydration, which is generally the safest agent. Hypertonic saline (3% or 5% NaCl) is generally reserved for patients with severe hyponatremia (less than 120 mEq/L [120 mmol/L]) accompanied by coma, seizures, or high urinary sodium losses. Roughly one-third of the sodium deficit can be replaced over the first 12 hours as long as the replacement rate is less than 0.5 mEq/h (0.5 mmol/L). The remaining two-thirds of the deficit can be administered over the ensuing days. Overly aggressive correction of symptomatic hyponatremia (greater than 12 mEq/L [12 mmol/L] per day) can result in central pontine myelinolysis.17 Given the potential for irreversible neurologic damage if untreated or if improperly treated, acute hyponatremia is an urgent condition that should be promptly treated with careful attention to monitoring serial sodium values and adjusting therapeutic infusions accordingly.18
Patient Encounter 4: Calculation of Sodium Deficit
Calculate the sodium deficit for a 75-kg male with a serum sodium of 123 mEq/L (123 mmol/L).
Patient Encounter 5: Estimate the Anticipated Change in Serum Sodium
Estimate the anticipated change in serum sodium concentration after the infusion of 1 L of 3% NaCl in a 75-kg male with a serum sodium of 123 mEq/L (123 mmol/L).
Hypernatremia is a serum sodium concentration greater than 145 mEq/L (145 mmol/L) and can occur in the absence of a sodium deficit (pure water loss) or in its presence (hypotonic fluid loss).19 The signs and symptoms of hypernatremia manifest with a serum sodium concentration of greater than 160 mEq/L (160 mmol/L) and are usually the same as those found in TBW depletion: thirst, mental slowing, and dry mucous membranes. Signs and symptoms become more profound as hypernatremia worsens, with the patient eventually demonstrating confusion, hallucinations, acute weight loss, decreased skin turgor, intracranial bleeding, and/or coma. Many coexisting disorders and medications may complicate the diagnosis.
The classic causes of hypernatremia are associated with TBW depletion. These include dehydration from loss of hypotonic fluid from the respiratory tract or skin, decreased water intake, osmotic diuresis (e.g., mannitol, available as generic), and diabetes insipidus (e.g., decreased ADH; phenytoin, available as generic; lithium, available as generic). Hypernatremia in hospitalized patients occurs secondary to inappropriate fluid management in patients at risk for increased free water losses and impaired thirst or restricted water intake.20 Iatrogenic hypernatremia is occasionally caused by the administration of excessive hypertonic saline. Treatment of hypernatremia includes calculation of the TBW deficit followed by the administration of hypotonic fluids as previously described. The fluid volume should be replaced over 48 to 72 hours depending on the severity of symptoms and the degree of hypertonicity.21 For asymptomatic patients, the rate of correction should not exceed 0.5 mEq/L/h (0.5 mmol/L/h). One rule of thumb is to replace half the calculated TBW deficit over 12 to 24 hours and the other half of the deficit over the next 24 to 48 hours.2,19 Excessively rapid correction of hypernatremia may lead to cerebral edema and death. Patient Encounters 6 and 7 reinforce the concepts of calculating TBW deficit and expected changes in serum sodium concentration with therapy.
Patient Encounter 6: Calculate Water Deficit
Calculate the water deficit in a 75-kg male with a serum sodium of 154 mEq/L (154 mmol/L).
Patient Encounter 7: Calculate the Anticipated Change in Serum Sodium
Calculate the anticipated change in serum sodium concentration after IV infusion of 1 L of 5% dextrose in a 75-kg male with a serum sodium of 156 mEq/L (156 mmol/L).
Potassium
The body’s normal daily potassium requirement is 0.5 to 1 mEq/kg (0.5–1 mmol/kg) or 40 to 80 mEq (40–80 mmol) to maintain a serum potassium concentration of 3.5 to 5 mEq/L (3.5–5 mmol/L). Potassium is the most abundant cation in the ICF, balancing the sodium contained in the ECF and maintaining electroneutrality of bodily fluids. Because the majority of potassium is intracellular, serum potassium concentration is not a good measure of total body potassium; however, clinical manifestations of potassium disorders correlate well with serum potassium. The acid–base balance of the body affects serum potassium concentrations: hyperkalemia is routinely seen in patients with decreased pH (acidosis). Potassium regulation is primarily under the control of the kidneys with excess dietary potassium being excreted in the urine. Although mild abnormalities of serum potassium are considered a nuisance, severe hyperkalemia or hypokalemia can be life-threatening.22,23,32
Hypokalemia (serum potassium less than 3.5 mEq/L [3.5 mmol/L]) is a common clinical problem. While generally asymptomatic, signs and symptoms of hypokalemia include cramps, muscle weakness, polyuria, electrocardiogram (ECG) changes (flattened T-waves and presence of U-waves), and cardiac arrhythmias (bradycardia, heart block, atrial flutter, premature ventricular contractions, and ventricular fibrillation). Causes of hypokalemia include GI losses (vomiting, diarrhea, or NG tube suction), renal losses (high aldosterone and low magnesium), inadequate potassium intake (in IV fluids or oral), or alkalosis. Many medications can precipitate hypokalemia. β2-agonists (e.g., albuterol, available as generic) and insulin (multiple product formulations) lower potassium via cellular redistribution. The use of loop diuretics (furosemide [Lasix], also available as generic), thiazide diuretics (hydrochlorothiazide, available as generic), high-dose antibiotics (penicillin, available as generic), and corticosteroids (prednisone, available as generic) cause renal potassium wasting. In addition, amphotericin B (available as generic), cisplatin (available as generic), and foscarnet (Foscavir, AstraZeneca) can also produce hypokalemia secondary to depletion of magnesium. Hypomagnesemia diminishes intracellular potassium concentration and produces potassium wasting. Given the potential for significant morbidity and mortality, serum potassium concentrations should be monitored closely for patients with known (or suspected) hypokalemia.2,24,32 Hypokalemia is a risk factor for digitalis toxicity.
Each 1 mEq/L (1 mmol/L) fall in serum potassium (i.e., from 4 to 3 mEq/L [4 to 3 mmol/L]) represents a loss of approximately 200 mEq (200 mmol) of potassium in the adult. However, when the serum potassium is below 3 mEq/L (3 mmol/L), each 1 mEq/L fall in serum potassium represents a 200 to 400 mEq (200–400 mmol) reduction in serum concentration in the adult patient. Potassium repletion should be guided by close monitoring of serial serum concentrations instead of using empirically chosen amounts. Of the five potassium salts available, potassium acetate (10.2 mEq/K+/g or 10.2 mmol/K+/g) and KCl (13.4 mEq/K+/g or 13.4 mmol/K+/g) are the most commonly used forms. When hypokalemia occurs in the setting of alkalosis, KCl is the preferred agent; in acidosis, potassium should be provided in the form of acetate, citrate, bicarbonate, or gluconate salt. Table 27–6 outlines the potassium content of each potassium salt preparation, and Table 27–7 lists each of the oral potassium replacement products. Potassium acetate and chloride are available for IV infusions as premixed solutions. The usual dose of these agents is 10 to 20 mEq (10–20 mmol) diluted in 1,000 mL of normal saline.2,24,25
Moderate hypokalemia is defined as a serum potassium of 2.5 to 3.5 mEq/L (2.5–3.5 mmol/L) without ECG changes. In this setting, potassium replacement can usually be given orally at a dose of 40 to 120 mEq/day (40–120 mmol/day). Anecdotally, oral potassium supplementation (see Table 27–7) is often more effective in repleting moderate hypokalemia. For patients with an ongoing source of potassium loss, chronic replacement therapy should be considered. The potassium deficit is a rough approximation of the amount of potassium needed to be replaced and can be estimated as follows:
Table 27–6 Potassium Content in Various Potassium Salt Preparations
Potassium deficit (mEq) = (4.0 − current serum potassium) × 100
Severe hypokalemia is defined as a serum potassium less than 2.5 mEq/L (2.5 mmol/L) or hypokalemia of any magnitude that is associated with ECG changes (e.g., flattening of T-wave or elevation of U-wave) and cardiac arrhythmias. In these situations, IV replacement should be initiated urgently. Potassium infusion at rates exceeding 10 mEq/h requires cardiac monitoring given the potential for cardiac arrhythmias. Although the maximally concentrated solution for potassium replacement is 80 mEq/L (80 mmol/L), the maximum infusion rate is 40 mEq/h (40 mmol/h), and must be administered via a central line. Table 27–8 outlines current IV potassium replacement guidelines.
Caution must be exercised when repleting potassium with IV agents given possible vein irritation and/or thrombophlebitis. The risk of these complications is minimized by using less concentrated solutions and by giving infusions via central access if possible. Administration of potassium in vehicles containing glucose is discouraged, as glucose facilitates the intracellular movement of potassium. Post-therapy improvements in serum potassium may be transient and continuous monitoring is required. Patients with a low serum magnesium will have exaggerated potassium losses from the kidneys and GI tract leading to refractory hypokalemia. In this situation, the magnesium deficit must be corrected in order to successfully treat the concurrent potassium deficiency. In the hypokalemic patient with concurrent acidosis, potassium is often given as the acetate salt, given that acetate is metabolized to bicarbonate. In the patient with depleted phosphorus and potassium, therapy with potassium phosphate is the natural choice.22,26,27
Table 27–7 Oral Potassium Replacement Products
Hyperkalemia is defined as a serum potassium concentration greater than 5 mEq/L (5 mmol/L). Manifestations of hyperkalemia include muscle weakness, paresthesias, hypotension, ECG changes (e.g., peaked T-waves, shortened QT intervals, and wide QRS complexes), cardiac arrhythmias, and a decreased pH. Causes of hyperkalemia fall into three broad categories: (a) increased potassium intake, (b) decreased potassium excretion, and (c) potassium release from the intra-cellular space.
Increased potassium intake results from excessive dietary potassium (salt substitutes), excess potassium in IV fluids, and other select medications (potassium-sparing diuretics, cyclosporine [available as generic], angiotensin-converting enzyme inhibitors, nonsteroidal anti-inflammatory agents, pentamidine [available as generic], unfractionated heparin, and low-molecular-weight heparins). Decreased potassium excretion results from acute renal failure, chronic renal failure, or Addison’s disease. Excess potassium release from cells results from tissue breakdown (surgery, trauma, hemolysis, or rhabdomyolysis), blood transfusions, and metabolic acidosis.
In addition to discontinuing all potassium supplements, potassium-sparing medications, and potassium-rich salt substitutes, management of hyperkalemia addresses three concurrent strategies: (a) agents to antagonize the proarrhythmic effects of hyperkalemia; (b) agents to drive potassium into the intracellular space and acutely lower the serum potassium; and (c) agents that will definitively (but more gradually) lower the total body potassium content.28 If the serum potassium concentration is greater than 7 mEq/L (7 mmol/L) and/or ECG changes are present, IV calcium is provided to stabilize the myocardium. Depending on the acuity of the situation, 1 g of calcium chloride (13.5 mEq or 6.75 mmol) is administered by direct injection or diluted in 50 mL of D5W and delivered IV over 15 minutes. Clinical effects are seen within 1 to 2 minutes of infusion and persist for 10 to 30 minutes. Repeat doses may be administered as necessary. Because most patients with clinically significant hyperkalemia receive multiple boluses of calcium directed by ECG findings, iatrogenic hypercalcemia is a potential complication of hyperkalemia treatment. As such, total calcium concentration is commonly checked with each potassium concentration measurement. Ionized calcium measurements should be obtained in patients who have comorbid conditions that would lead to inconsistency between total serum calcium and free calcium (abnormal albumin, protein, or immunoglobulin concentrations).
Table 27–8 Recommended Potassium Dosage/Infusion Rate
Dextrose and insulin (with or without sodium bicarbonate) are typically given at the time of calcium therapy in order to redistribute potassium into the intracellular space. Dextrose 50% (25 g in 50 mL) can be given by slow IV push over 5 minutes or dextrose 10% with 20 units of regular insulin can be given by continuous IV infusion over 1 to 2 hours. The onset of action for this combination is 30 minutes and the duration of clinical effects is 2 to 6 hours. High-dose inhaled β2-agonists (e.g., albuterol, available as generic) may also be used to acutely drive potassium into the intracellular space.
It is critically important to recognize that the treatments of hyperkalemia discussed thus far are transient, temporizing measures. They are intended to provide time to institute definitive therapy aimed at removing excess potassium from the body. Agents that increase potassium excretion from the body include sodium polystyrene sulfonate, loop diuretics, and hemodialysis or hemofiltration (used only in patients with renal failure). Sodium polystyrene sulfonate (Kayexalate, various manufacturers) can be given orally, via NG tube, or as a rectal retention enema and is dosed at 15 to 60 g in four divided doses per day.
Calcium
More than 99% of total body calcium is found in bone; the remaining less than 1% is in the ECF and ICF. calcium plays a critical role in the transmission of nerve impulses, skeletal muscle contraction, myocardial contractions, maintenance of normal cellular permeability, and the formation of bones and teeth. There is a reciprocal relationship between the serum calcium concentration (normally 8.6−10.2 mg/dL [2.15−2.55 mmol/L]) and the serum phosphate concentration that is regulated by a complex interaction between parathyroid hormone, vitamin D, and calcitonin. About one-half of the serum calcium is bound to plasma proteins; the other half is free ionized calcium. Given that the serum calcium has significant protein binding, the serum calcium measurement must be corrected in patients who have low albumin concentrations (the major serum protein). The most commonly used formula adds 0.8 mg/dL (0.2 mmol/L) of calcium for each gram of albumin deficiency as follows:
Corrected [Ca] = Measured [Ca mg/dL] + [0.8 × (4 − measured albumin g/dL)]29–31
Note: To convert conventional units (mg/dL) to SI calcium units multiply by a factor of 0.25. To convert SI calcium units to conventional calcium units multiply by a factor of 4. To convert conventional albumin units (g/dL) to SI albumin units (g/dL) multiple by a factor of 10. To convert SI albumin units (g/dL) to conventional albumin units (g/dL) divide by a factor of 2.
Hypocalcemia is caused by inadequate intake (vitamin deficiency, poor dietary calcium sources, alcoholism) or excessive losses (hypoparathyroidism, renal failure, alkalosis, pancreatitis). Clinical manifestations of hypocalcemia are seen with total serum concentrations less than 6.5 mg/dL (1.63 mmol/L) or an ionized calcium of less than 1.12 mmol/L and include tetany, circumoral tingling, muscle spasms, hypoactive reflexes, anxiety, hallucinations, hypotension, myocardial infarction, seizures, lethargy, stupor, and Trousseau’s sign or Chvostek’s sign.32,37 Trousseau’s sign is elicited by inflating a BP cuff on the patient’s upper arm, whereby hypocalcemic patients will experience tetany of the wrist and hand as evidenced by thumb adduction, wrist flexion, and metacarpophalangeal joint flexion. Chvostek’s sign is elicited by tapping on the proximal distribution of the facial nerve (adjacent to the ear). This will produce a brief spasm of the upper lip, eye, nose, or face in hypocalcemic patients. Ionized calcium concentrations are typically used to assess calcium status in the critically ill patient.
Causes of hypocalcemia include hypoparathyroidism, hypomagnesemia, alcoholism, hyperphosphatemia, blood product infusion (due to chelation by the citrate buffers), chronic renal failure, vitamin D deficiency, acute pancreatitis, alkalosis, and hypoalbuminemia. In the setting of hypo-calcemia, magnesium concentration should be checked and corrected if low. Given that hypocalcemia may be caused by hypomagnesemia, clinicians should be aware that the serum calcium concentrations may not normalize until serum magnesium is replaced. Medications that cause hypocalcemia include phosphate replacement products, loop diuretics, phenytoin (Dilantin, available as generic), phenobarbital (available as generic), corticosteroids, aminoglycoside antibiotics, and acetazolamide (available as generic).34,39,42
Oral calcium replacement products include calcium carbonate (OsCal, GlaxoSmithKline and various generics; Tums, GlaxoSmithKline and various generics) and calcium citrate (Citrical, Mission Pharmacal, and various generics). IV calcium replacement products include calcium gluconate and calcium chloride (both products available as generic). Calcium gluconate is preferred for peripheral use because it is less irritating to the veins; it may also be given intramuscularly. Each 10 mL of a 10% calcium gluconate solution provides 90 mg (4.5 mEq or 2.25 mmol) of elemental calcium. Calcium chloride is associated with more venous irritation and extravasation and is generally reserved for administration via central line. Each 10 mL of a 10% calcium chloride solution contains 270 mg (13.5 mEq or 6.75 mmol) of elemental calcium. IV calcium products are given as a slow push or added to 500 to 1,000 mL of 0.9% normal saline for slow infusion.37,42 In addition to hypocalcemia, IV calcium may also be used for massive blood transfusions, calcium channel blocker overdose, and emergent hyperkalemia and hypermagnesemia.
For acute symptomatic hypocalcemia, 200 to 300 mg of elemental calcium is administered IV and repeated until symptoms are fully controlled. This is achieved by infusing 1 g of calcium chloride or 2 to 3 g of calcium gluconate at a rate no faster than 30 to 60 mg of elemental calcium per minute. More rapid administration is associated with hypotension, bradycardia, or cardiac asystole. Total calcium concentration is commonly monitored in critically ill patients. Under normal circumstances, about half of calcium is loosely bound to serum proteins while the other half is free. Total calcium concentration measures bound and free calcium. Ionized calcium measures free calcium only. Under usual circumstances, a normal calcium concentration implies a normal free ionized calcium concentration. Ionized calcium should be obtained in patients with comorbid conditions that would lead to inconsistency between total calcium and free serum calcium (abnormal albumin, protein, or immunoglobulin concentrations). For chronic asymptomatic hypocalcemia, oral calcium supplements are given at doses of 2 to 4 g/day of elemental calcium. Many patients with calcium deficiency have concurrent vitamin D deficiency that must also be corrected in order to restore calcium homeostasis.2,37,38
Hypercalcemia is defined as a calcium concentration greater than 10.2 mg/dL (2.55 mmol/L). It may be categorized as mild if total serum calcium is 10.3 to 12 mg/dL (2.575–3 mmol/L), moderate if total serum calcium is 12.1 to 13 mg/dL (3.025–3.25 mmol/L), or severe when serum concentration is greater than 13 mg/dL (3.25 mmol/L). Causes of hyper-calcemia include hyperparathyroidism, malignancy, Paget’s disease, Addison’s disease, granulomatous diseases (e.g., tuberculosis, sarcoidosis, or histoplasmosis), hyperthyroidism, immobilization, multiple bony fractures, acidosis, and milk-alkali syndrome. Multiple medications cause hypercalcemia and include thiazide diuretics, estrogens, lithium (available as generic), tamoxifen (Nolvadex, available as generic), vitamin A, vitamin D, and calcium supplements.2,33,37,42
Because the severity of symptoms and the absolute serum concentration are poorly correlated in some patients, institution of therapy should be dictated by the clinical scenario. All patients with hypercalcemia should be treated with aggressive rehydration: normal saline at 200 to 300 mL/h is a routine initial fluid prescription. For patients with mild hypercalcemia, hydration alone may provide adequate therapy. The moderate and severe forms of hypercalcemia are more likely to have significant manifestations and require prompt initiation of additional therapy. These patients may present with anorexia, confusion, and/or cardiac manifestations (bradycardia and arrhythmias with ECG changes). Total calcium concentrations greater than 13 mg/dL (3.25 mmol/L) are particularly worrisome, as these concentrations can unexpectedly precipitate acute renal failure, ventricular arrhythmias, and sudden death.
Once fluid administration has repleted the ECF, forced diuresis (with associated calcium loss) can be initiated with a loop diuretic. For this approach to be successful, normal kidney function is required. In renal failure patients, the alternative therapy is emergent hemodialysis. Other treatment options include bisphosphonates (zoledronic acid [Zometa, Novartis], pamidronate [Aredia, available as generic]), hydrocortisone (available as generic), mithramycin (Mithracin), calcitonin, and gallium. Given their efficacy and favorable side-effect profile, bisphosphonates are typically the agents of choice. Table 27–9outlines the treatment options for hypercalcemia including time to onset of effect, duration of effect, and efficacy.2,34,37,38
Phosphorus
Phosphorus is primarily found in the bone (80%–85%) and ICF (15%–20%): the remaining less than 1% is found in the ECF. Note that phosphorus is the major anion within the cells. Given this distribution, serum phosphate concentration does not accurately reflect total body phosphorus stores. Phosphorus is expressed in milligrams (mg) or millimoles (mmol), not as milliequivalents (mEq). Because phosphorus is the source of phosphate for adenosine triphosphate (ATP) and phospholipid synthesis, manifestations of phosphorus imbalance are variable.
Dietary intake, parathyroid hormone levels, and renal function are the major determinants of the serum phosphorus concentration, which is normally 2.7 to 4.5 mg/dL (0.87–1.45 mmol/L).2,35–37Hypophosphatemia is defined by a serum phosphorus concentration less than 2.5 mg/dL (0.81 mmol/L); severe hypophosphatemia occurs when the phosphorus concentration is less than 1 mg/dL (0.323 mmol/L). Hypophosphatemia can be caused by increased distribution to the ICF (hyperglycemia, insulin therapy, or malnourishment), decreased absor ption (star vat ion, excessive use of phosphorus-binding antacids, vitamin D deficiency, diarrhea, or laxative abuse) or increased renal loss (diuretic use, diabetic ketoacidosis, alcohol abuse, hyperparathyroidism, or burns).38,39 Severe hypophosphatemia can result in impaired diaphragmatic contractility and acute respiratory failure. Medications that cause hypophosphatemia include diuretics (acetazolamide [Diamox, available as generic], furosemide [Lasix, available as generic], hydrochlorothiazide [Hydrodiuril, available as generic]), sucralfate (Carafate, available as generic), corticosteroids, cisplatin (available as generic), antacids (aluminum carbonate, calcium carbonate, and magnesium oxide [antacids all available as generic]), foscarnet (Foscavir, Astra Zeneca), phenytoin (Dilantin, available as generic), phenobarbital (available as generic), and phosphate binders (sevelamer [Renvela, Genzyme Corp.], and calcium acetate [PhosLo, Nabi]).
Table 27–9 Selected Treatment Options for the Management of Hypercalcemia
Signs and symptoms of hypophosphatemia include par-esthesias, muscle weakness, myalgias, bone pain, anorexia, nausea, vomiting, red blood cell breakdown (hemo-lysis), acute respiratory failure, seizures, and coma.38,40 For mild hypophosphatemia, patients should be encouraged to eat a high-phosphorus diet including eggs, nuts, whole grains, meat, fish, poultry, and milk products. For moderate hypophosphatemia (1–2.5 mg/dL, 0.323–0.808 mmol/L), oral supplementation of 1.5 to 2 g/day (30–60 mmol/day) is usually adequate. Diarrhea may be a dose-limiting side effect with oral phosphate replacement products. Injectable phosphate products are reserved for patients with severe hypophos-phatemia or those in the intensive care unit.41 The available agents are provided as sodium or potassium salts; however, unless concurrent hypokalemia is present, sodium phosphate is usually used. Empirically, if the serum phosphorus is 2.3 to 2.7 mg/dL (0.74–0.87 mmol/L), the corresponding IV phosphorus dose is 0.08 to 0.16 mmol/kg; for a serum phosphorus of 1.5 to 2.2 mg/dL (0.48–0.71 mmol/L), the replacement dose is 0.16 to 0.32 mmol/kg; and the dose is 0.32 to 0.64 mmol/kg when the serum phosphorus is less than 1.5 mg/dL (0.48 mmol/L).2 IV phosphorus preparations are usually infused over 4 to 12 hours. Table 27–10 compares the available phosphate replacement products.
Hyperphosphatemia is defined by a serum phosphorus concentration greater than 4.5 mg/dL (1.45 mmol/L). The manifestations of hyperphosphatemia are similar to findings of hypocalcemia (see above), and include paresthesias, ECG changes (prolonged QT interval and prolonged ST segment), and metastatic calcifications. Causes of hyperphosphatemia include impaired phosphorus excretion (hypoparathyroidism or renal failure), redistribution of phosphorus to the ECF (acid–base imbalance, rhabdomyolysis, muscle necrosis, or tumor lysis during chemotherapy), and increased phosphorus intake (various medications).38 Medications that can cause hyperphosphatemia include enemas containing phosphorus (e.g., Fleet, Fleet), laxatives containing phosphate or phosphorus, oral or parenteral phosphorus supplements (e.g., Neutra-Phos, Ortho McNeil), vitamin D supplements, and the bisphosphonates (e.g., pamidronate, various manufacturers).42
Hyperphosphatemia is generally benign and rarely needs aggressive therapy. Dietary restriction of phosphate and protein is effective for most minor elevations. Phosphate binders such as aluminum-based antacids, calcium carbonate, calcium acetate (PhosLo, Nabi), sevelamer (Renvela, Genzyme), and lanthanum carbonate (Fosrenol, Shire) may be necessary for some patients (typically those with chronic renal failure).43 If patients exhibit findings of hypocalcemia (tetany), IV calcium should be administered empirically.
Magnesium
The body’s normal daily magnesium requirement is 300 to 350 mg/day to maintain a serum magnesium concentration of 1.5 to 2.4 mg/dL (0.75–1.2 mmol/L). Because magnesium is the second most abundant ICF cation, serum concentrations are a relatively poor measure of total body stores. Magnesium catalyzes and/or activates more than 300 enzymes, provides neuromuscular stability, and is involved in myocardial contraction. Magnesium is generally not part of standard chemistry panels, and therefore must be ordered separately.2,37,42,44,45
Hypomagnesemia is defined as a serum magnesium less than 1.5 mg/dL (0.75 mmol/L), and is most frequently seen in the intensive care and postoperative settings. Hypomagnesemia results from inadequate intake (alcoholism, dietary restriction, or inadequate magnesium in total parenteral nutrition [TPN]), inadequate absorption (steatorrhea, cancer, malab-sorption syndromes, or excess calcium or phosphorus in the GI tract), excessive GI loss of magnesium (diarrhea, laxative abuse, NG tube suctioning, or acute pancreatitis), or excessive urinary loss of magnesium (primary hyperaldosteronism, certain medications, diabetic ketoacidosis, and renal disorders). Hypomagnesemia often occurs in the setting of hypokalemia and hypocalcemia. Clinicians should evaluate the magnesium concentration in these patients and correct if low. In order for calcium and potassium concentrations to normalize, magnesium supplementation is often required. Medications that potentially can cause hypomagnesemia include aminoglycoside antibiotics, amphotericin B (available as generic), cisplatin (available as generic), insulin, cyclosporine (available as generic), loop diuretics, and thiazide diuretics. There is also a strong correlation between hypokalemia and hypomagnesemia.38,42,46
Table 27–10 Phosphate Replacement Products
The findings of hypomagnesemia include muscle weakness, cramps, agitation, confusion, tremor, seizures, ECG changes (increased PR interval, prolonged QRS complex, and increased QT interval), findings of hypocalcemia (see above), refractory hypokalemia (see above), metabolic alkalosis, and digoxin toxicity.42,47,48
Asymptomatic mild magnesium deficiencies (1.0–1.5 mg/dL) (0.5–0.75 mmol/L) can be managed with increased oral intake of magnesium-containing foods or with oral supplementation. Magnesium oxide (MagOx, Blaine Pharmaceuticals and various manufacturers) 400 mg tablets contain 241 mg (20 mEq or 10 mmol) of magnesium. Diarrhea is often a dose-limiting side effect of oral supplementation. Severely deficient patients (less than 1.0 mg/dL) (0.5 mmol/L) and all deficient critically ill patients should be managed with IV magnesium sulfate. Ten milliliters of a 10% magnesium sulfate solution contains 1 g of magnesium, which is equivalent to 98 mg (8.12 mEq or 4.06 mmol) of elemental magnesium. IV magnesium supplementation may also be used in the setting of status asthmaticus, premature labor, and torsades de pointes. Magnesium concentrations need to be monitored closely in these patients. Because magnesium concentration does not correlate well with total body magnesium stores, magnesium is often administered empirically to critically ill patients.2,37
The most common causes of hypermagnesemia are renal failure, often in conjunction with magnesium-containing medications (cathartics, antacids, or magnesium supplements), and lithium therapy (available as generic). Hypermagnesemia is defined as a serum magnesium concentration greater than 2.4 mg/dL (1.2 mmol/L). Mild hypermagnesemia is present if the serum magnesium concentration is between 2.5 and 4 mg/dL (1.25–2 mmol/L) and manifests as nausea, vomiting, cutaneous vasodilation, and bradycardia. Moderate hypermagnesemia is present if the serum magnesium concentration is between 4 and 12 mg/dL (2–6 mmol/L) and may manifest with hyporeflexia, weakness, somnolence, hypotension, and ECG changes (increased QRS interval). Severe hypermagnesemia is present if the serum magnesium concentration is greater than 13 mg/dL (6.5 mmol/L) and can manifest as muscle paralysis, complete heart block, asystole, respiratory failure, refractory hypotension, and death.2,49
All patients with hypermagnesemia should have all magnesium supplements or magnesium-containing medications discontinued.2,37 Iatrogenic hypermagnesemia has been observed after IV magnesium therapy for refractory asthma or pre-eclampsia. Mild hypermagnesemia and moderate hypermagnesemia without cardiac findings can be treated with normal saline infusion and furosemide therapy (assuming the patient has normal renal function). Moderate hypermagnesemia with cardiac irritability and severe hypermagnesemia require concurrent IV calcium gluconate to reverse the neuromuscular and cardiovascular effects. Calcium gluconate given at typical doses of 1 to 2 g IV will have transient effects and can be repeated as clinically indicated. Hemodialysis may be necessary for those with severely compromised renal function.
CONCLUSION
Because disturbances in fluid balance are routinely encountered in clinical medicine, it is essential to have a thorough understanding of body fluid compartments and the therapeutic use of fluids. Similarly, disturbances in serum sodium, potassium, calcium, phosphorus, and magnesium are ubiquitous and must be mastered by all clinicians. Dysregulation of fluid and/or electrolyte status has serious implications regarding the concepts of drug absorption, volumes of distribution, and toxicity. Similarly, many medications can disrupt fluid and/or electrolyte balance as an unintended consequence.
Patient Encounter 8: Putting It All Together
TO, a 77-year-old male nursing home resident is admitted to the hospital with a 3-day history of altered mental status. The patient was unable to give a history or review of systems. On physical examination, the vital signs revealed a BP of 100/60 mm Hg, pulse 110 beats per minute, respirations 14 per minute, and a temperature of 38.3°C (101°F). Rales and dullness to percussion were noted at the posterior right base. The cardiac exam was significant for tachycardia. No edema was present. Laboratory studies included sodium 160 mEq/L (160 mmol/L), potassium 4.6 mEq/L (4.6 mmol/L), chloride 120 mEq/L (120 mmol/L), bicarbonate 30 mEq/L (30 mmol/L), glucose 104 mg/dL (5.77 mmol/L), BUN 34 mg/dL (12.14 mmol/L), and creatinine 2.2 mg/dL (194.5 μmol/L). The CBC was within normal limits. Chest x-ray indicated a right lower lobe pneumonia.
The patient is 5 ft 10 in. (152.4 cm) tall and currently weighs 72.6 kg (160 lb). His normal weight is 77.1 kg (170 lb).
What are the likely causes for the increased sodium concentration in this patient?
Calculate the TBW, ICF, and ECF for this patient.
Calculate TO’s fluid deficit if one is present.
In the next 24 hours, the medical team wants to replace 50% of the fluid deficit plus an extra 240 mL to account for increased insensible losses in addition to the patient’s maintenance needs. Using the equation (1,500 mL + 20 mL for each kilogram greater than 20 kg), calculate the rate of fluid administration for the total fluids needed in this 24-hour period and over the next 48 hours.
Calculate TO’s daily maintenance fluids.
Calculate TO’s fluid administration rate for the first 24 hours (Hospital day 1).
Calculate TO’s fluids for the subsequent 48 hours (hospital days 2 and 3) if the goal is to replete the remaining fluid deficit during that time.
What type of fluid should be used to treat TO’s fluid disorder?
Abbreviations Introduced in This Chapter
Self-assessment questions and answers are available at http://www.mhpharmacotherapy.com/pp.html.
REFERENCES
1. Faber MD, Kupin WL, Heilig CW, Narins RG. Common fluid–electrolyte and acid–base problems in the intensive care unit: Selected issues. Semin Nephrol 1994;14:8–22.
2. Kraft MD, Btaiche IF, Sacks GS, Kudsk KA. Treatment of electrolyte disorders in adult patients in the intensive care unit. Am J Health Syst Pharm 2005;62:1663–1682.
3. Faubel S, Topf J. The Fluid Electrolyte and Acid–Base Companion. San Diego, CA: Alert and Oriented publishing, 1999.
4. Chenevey B. Overview of fluids and electrolytes. Nurs Clin North Am 1987;22:749–759.
5. Devine BJ. Gentamicin therapy. Drug Intell Clin Pharm 1974;7:650–655.
6. Rose BD, Post TW. Clinical Physiology of Acid–Base and Electrolyte Disorders. New York: McGraw Hill, 2001.
7. The SAFE Study Investigators. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med 2004;350:2247–2256.
8. The Albumin Reviewers (Alderson P, Bunn F, Lefebvre C, Li Wan Po A, Li L, Roberts I, Schlerhout G). Human albumin solution for resuscitation and volume expansion in critically ill patients. The Cochrane Database of Systematic Reviews 2004, Issue 4. Art. No.: CD001208.pub2. DOI: 10.1002/14651858.CD001208.pub2.
9. Vincent JL, Gerlach H. Fluid resuscitation in severe sepsis and septic shock: An evidence based review. Crit Care Med 2004;32(Suppl):S451–S454.
10. Weil MH, Tang W. Albumin versus crystalloid solutions for the critically ill and injured. Crit Care Med 2004;32:2154–2155.
11. Martiin GS, Mangialardi RJ, Wheeler AP, et al. Albumin and furosemide therapy in hypoproteinemic patients with acute lung injury. Crit Care Med 2002;30:2175–2182.
12. Shafiee MAS, Bohn D, Hoorn EJ, Halperin ML. How to select optimal maintenance intravenous therapy. QJ Med 2003;96:601–610.
13. Kwan I, Bunn F, Roberts I, on behalf of the WHO Pre-Hospital Trauma Care Steering Committee. Timing and volume of fluid administration for patients with bleeding. The Cochrane Database of Systematic Reviews 2003, Issue 3, Art. No.:CD002245. DOI: 10.1002/145651858.CD002245.
14. Joint Commission for the Accreditation of Healthcare Organizations. http:www.jointcommission.org/GeneralPublic/NPSG/05_gp_npsg.htm
15. Kumar S, Berl T. Sodium. Lancet 1998;352:220–228.
16. Adrigoue H, Madias NE. Hyponatremia. N Engl J Med 2000;342:1581–1589.
17. Sterns RH. The treatment of hyponatremia: First, do no harm. Am J Med 1990;88:557–560.
18. Cluitmans FHM, Meinders AE. Management of severe hyponatremia: Rapid or slow correction? Am J Med 1990;88:161–166.
19. Adrogue HJ, Madias NE. Hypernatremia. N Engl J Med 2000;342:1493–1499.
20. Palevsky PM, Bhagrath R, Greenberg A. Hypernatremia in hospitalized patients. Ann Intern Med 1996;124:197–203.
21. Kang SK, Kim W, Oh MS. Pathogenesis and treatment of hypernatremia. Nephron 2002;92(Suppl 1):14–17.
22. Mandal AK. Hypokalemia and hyperkalemia. Med Clin North Am 1997;81:611–639.
23. Halperin ML. Potassium. Lancet 1998;352:135–140.
24. Gennari FJ. Hypokalemia. N Engl J Med 1998;339:451–458.
25. Hamil RJ, Robinson LM, Wexler HR, Moote C. Efficacy and safety of potassium infusion therapy in hypokalemic critically ill patients. Crit Care Med 1991;19:694–699.
26. Kruge JA, Carlson RW. Rapid correction of hypokalemia using concentrated intravenous potassium chloride infusions. Arch Intern Med 1990;150:613–617.
27. Cohn JN, Kowey PR, Whelton PK, Prisant M. New guidelines for potassium replacement in clinical practice. Arch Intern Med 2000;160:2429–2436.
28. Williams ME. Hyperkalemia. Crit Care Clin 1991;7:155–174.
29. Carroll MF, Schade DS. A practical approach to hypercalcemia. Am Fam Physician 2003;67:1959–1966.
30. Bushinsky DA, Monk RD. Calcium. Lancet 1998;352:305–311.
31. Zaloga GP. Hypocalcemia in critically ill patients. Crit Care Med 1992;20:251–262.
32. Body JJ, Bouillon R. Emergencies of calcium homeostasis. Rev Endocr Metab Disord 2003;4:167–175.
33. Bilezikian JP. Clinical review 51. Management of hypercalcemia. J Clin Endocrinol Metab 1993;77:1445–1449.
34. Davidson TG. Conventional treatment of hypercalcemia of malignancy. Am J Health-Syst Pharm 2001;58(Suppl 3):S8–S15.
35. Knochel JP. The pathophysiology and clinical characteristics of severe hypophosphatemia. Arch Intern Med 1977;137:203–220.
36. Stoff JS. Phosphate homeostasis and hypophosphatemia. Am J Med 1982;72:489–495.
37. Metheny NM. Fluid and Electrolyte Balance: Nursing Considerations. 4th ed. Lippincott, NY; 2000.
38. Just the Facts: Fluids and Electrolytes. Philadelphia: Lippincott Williams & Wilkins, 2005.
39. Weisinger JR, Bellorin-Font E. Magnesium and phosphorous. Lancet 1998;352:391–396.
40. Aubier M, Murciano D, Lecocguic Y, et al. Effect of hypophosphatemia on diaphragmatic contractility in patients with acute respiratory failure. N Engl J Med 1985;313:420–424.
41. Perreault MM, Ostron NI, Tiemey MG. Efficacy and safety of intravenous phosphate replacement in critically ill patients. Ann Pharmacother 1997;31:683–688.
42. Kee JL, Paulanka BJ, Purnell LD. Fluids and Electrolytes with Clinical Applications. A Programmed Approach. 7th ed. Clifton Park, NY: Delmar Learning, 2000.
43. Schucker JJ, Ward KE. Hyperphosphatemia and phosphate buffers. Am J Health-Syst Pharm 2005;62:2355–2361.
44. Oster JR, Epstein M. Management of magnesium depletion. Am J Nephrol 1988;8:349–354.
45. Al-Ghamdi SMG, Cameron EC, Sutton AL. Magnesium deficiency: Pathophysiologic and clinical overview. Am J Kidney Dis 1994;24:737–752.
46. Salem M, Munoz R, Chernow B. Hypomagnesemia in critical illness: A common and clinically important problem. Crit Care Clin 1991;7:225–252.
47. Zalman SA. Hypomagnesemia. J Am Soc Nephrol 1999;10:1616–1622.
48. Dube L, Granry JC. Thet herapeutic use of magnesium in anest hesiology, intensive care and emergency medicine: A review. Can J Anesth 2003;50:732–746.
49. Van Hook JW. Hypermagnesemia. Crit Care Clin 1991;7:215–223.