Donald S. Prough
J. Sean Funston
Christer H. Svensén
Scott W. Wolf
1. The Henderson-Hasselbalch equation describes the relationship between pH, Paco2, and serum bicarbonate. The Henderson equation defines the previous relationship but substitutes hydrogen concentration for pH.
2. The pathophysiology of metabolic alkalosis is divided into generating and maintenance factors. A particularly important maintenance factor is renal hypoperfusion, often due to hypovolemia.
3. The addition of iatrogenic respiratory alkalosis to metabolic alkalosis can produce severe alkalemia.
4. Metabolic acidosis occurs as a consequence of the use of bicarbonate to buffer endogenous organic acids or as a consequence of external bicarbonate loss. The former causes an increase in the anion gap (Na+ - [Cl- + [HCO3-]]).
5. When substituting mechanical ventilation for spontaneous ventilation in a patient with severe metabolic acidosis, it is important to maintain an appropriate level of ventilatory compensation, pending effective treatment of the primary cause for the metabolic acidosis.
6. Sodium bicarbonate, never proved to alter outcome in patients with lactic acidosis, should be reserved for those patients with severe acidemia.
7. Tight control of blood glucose in critically ill surgical patients has been associated with substantial improvements in mortality.
8. In patients undergoing moderate surgical procedures, generous administration of fluids is associated with fewer minor complications, such as nausea, vomiting, and drowsiness.
9. In patients undergoing colon surgery, careful perioperative fluid restriction has been associated with lower mortality and better wound healing.
10. Homeostatic mechanisms are usually adequate for the maintenance of electrolyte balance. However, critical illnesses and their treatment strategies can cause significant perturbations in electrolyte status, possibly leading to worsened patient outcome.
11. Disorders of the concentration of sodium, the principal extracellular cation, depend on the total body water concentration and can lead to neurologic dysfunction. Disorders of potassium, the principal intracellular cation, are influenced primarily by insults that result in increased total body losses of potassium or changes in distribution.
12. Calcium, phosphorus, and magnesium are all essential for maintenance and function of the cardiovascular system. In addition, they also provide the milieu that ensures neuromuscular transmission. Disorders affecting any one of these electrolytes may lead to significant dysfunction and possibly result in cardiopulmonary arrest.
As a consequence of underlying diseases and of therapeutic manipulations, surgical patients develop potentially harmful disorders of acid-base equilibrium, intravascular and extravascular volume, and serum electrolytes. Precise perioperative management of acid-base status, fluids, and electrolytes may limit perioperative morbidity and mortality. Recent data provide provocative insights regarding appropriate perioperative fluid management in patients undergoing both ambulatory and major inpatient surgery or the possibility of chronic hypercapnia.
Acid-Base Interpretation and Treatment
Management of perioperative acid-base disturbances requires an understanding of the four simple acid-base disorders—metabolic alkalosis, metabolic acidosis, respiratory alkalosis, and respiratory acidosis—as well as more complex combinations of disturbances. This section will review the pathogenesis, major
complications, physiologic compensatory mechanisms, and treatment of common perioperative acid-base abnormalities.
Overview of Acid-Base Equilibrium
Conventionally, acid-base equilibrium is described using the Henderson-Hasselbalch equation:
where 6.1 = the pKa of carbonic acid and 0.03 is the solubility coefficient in blood of carbon dioxide (CO2). Within this context, pH is the dependent variable while the bicarbonate concentration [HCO3-] and Paco2 are independent variables; therefore, metabolic alkalosis and acidosis are defined as disturbances in which [HCO3-] is primarily increased or decreased and respiratory alkalosis and acidosis are defined as disturbances in which Paco2 is primarily decreased or increased. pH, the negative logarithm of the hydrogen ion concentration ([H+]), defines the acidity or alkalinity of solutions or blood. The simpler Henderson equation, after conversion of pH to [H+], also describes the relationship between the three major variables measured or calculated in blood gas samples:
To approximate the logarithmic relationship of pH to [H+], assume that [H+] is 40 mmol/L at a pH of 7.4; that an increase in pH of 0.10 pH units reduces [H+] to 0.8 × the starting [H+] concentration; that a decrease in pH of 0.10 pH units increases the [H+] by a factor of 1.25; and that small changes (i.e., <0.05 pH units) produce reciprocal increases or decreases of approximately 1.0 mmol/L in [H+] for each 0.01 decrease or increase pH units.
The alternative “Stewart” approach to acid-base interpretation distinguishes between the independent variables and dependent variables that determine pH.1,2 The independent variables are Paco2, the strong (i.e., highly dissociated) ion difference, and the concentration of proteins, which usually are not strong ions. The strong ions include sodium (Na+), potassium (K+), chloride (Cl-), and lactate. The strong ion difference, calculated as (Na+ + K+ - Cl-), under normal circumstances is approximately 42 mEq/L. In general, the Stewart approach provides more insight into the mechanisms underlying acid-base disturbances, in contrast to the more descriptive Henderson-Hasselbalch approach. However, the clinical interpretation or treatment of common acid-base disturbances is rarely handicapped by the simpler constructs of the conventional Henderson-Hasselbalch or Henderson equations.
Metabolic alkalosis, characterized by hyperbicarbonatemia (>27.0 mEq/L) and usually by an alkalemic pH (>7.45), occurs frequently in postoperative patients and critically ill patients. Factors that generate metabolic alkalosis include vomiting and diuretic administration (Table 14-1).3 Maintenance of metabolic alkalosis depends on a continued stimulus, such as renal hypoperfusion, hypokalemia, hypochloremia or hypovolemia, for distal tubular reabsorption of [HCO3-] (Table 14-2).3
Metabolic alkalosis is associated with hypokalemia, ionized hypocalcemia, secondary ventricular arrhythmias, increased digoxin toxicity, and compensatory hypoventilation (hypercarbia), although compensation rarely results in Paco2 >55 mm Hg (Table 14-3). Alkalemia may reduce tissue oxygen availability by shifting the oxyhemoglobin dissociation curve to the left and by decreasing cardiac output. During anesthetic management, inadvertent addition of iatrogenic respiratory alkalosis to pre-existing metabolic alkalosis may produce severe alkalemia and precipitate cardiovascular depression, dysrhythmias, hypokalemia, and the complications.
In patients in whom arterial blood gases have not yet been obtained, serum electrolytes and a history of major risk factors, such as vomiting, nasogastric suction, or chronic diuretic use, can suggest metabolic alkalosis. Total CO2 (usually abbreviated on electrolyte reports as CO2) should be about 1.0 mEq/L greater than [HCO3-] on simultaneously obtained arterial blood gases. If either calculated [HCO3-] on the arterial blood gases or “CO2” on the serum electrolytes exceeds normal (24 and 25 mEq/L, respectively) by >4.0 mEq/L, either the patient has a primary metabolic alkalosis or has conserved bicarbonate in response to chronic hypercarbia. Recognition
of hyperbicarbonatemia on the preoperative serum electrolytes justifies arterial blood gas analysis and should alert the anesthesiologist to the likelihood of factors that generate or maintain metabolic alkalosis (see Tables 14-1 and 14-2).
Table 14-1 Generation of Metabolic Alkalosis
Table 14-2 Factors that Maintain Metabolic Alkalosis
Treatment of metabolic alkalosis consists of etiologic and nonetiologic therapy. Etiologic therapy consists of measures such as expansion of intravascular volume or the administration of potassium. Infusion of 0.9% saline will dose-dependently increase serum [Cl-] and decrease serum [HCO3-].4 Nonetiologic therapy includes administration of acetazol-amide (a carbonic anhydrase inhibitor that causes renal bicarbonate wasting), infusion of [H+] in the form of ammonium chloride, arginine hydrochloride, or 0.1 N hydrochloric acid (100 mmol/L), or dialysis against a high-chloride/low bicarbonate dialysate.3 Of the previously mentioned factors, 0.1 N hydrochloric acid most rapidly corrects life-threatening metabolic alkalosis but must be infused into a central vein; peripheral infusion will cause severe tissue damage.
Metabolic acidosis, characterized by hypobicarbonatemia (<21 mEq/L) and usually by an acidemic pH (<7.35), can be innocuous or reflect a life-threatening emergency. Metabolic acidosis occurs as a consequence of buffering by bicarbonate of endogenous or exogenous acid loads or as a consequence of abnormal external loss of bicarbonate.5,6,7 Approximately 70 mmol of acid metabolites are produced, buffered, and excreted daily; these include about 25 mmol of sulfuric acid from amino acid metabolism, 40 mmol of organic acids, and phosphoric and other acids. Extracellular volume in a 70-kg adult contains 336 mmol of bicarbonate buffer (24 mEq/L × 14 L of extracellular volume). Glomerular filtration of plasma volume necessitates reabsorption of 4,500 mmol of bicarbonate daily, of which 85% is reabsorbed in the proximal tubule, 10% in the thick ascending limb, and the remainder is titrated by proton secretion in the collecting duct.
Table 14-3 Respiratory Compensation in Response to Metabolic Alkalosis and Metabolic Acidosis
Calculation of the anion gap [(Na+ - ([Cl-] + [HCO3-])] distinguishes between two types of metabolic acidosis (Table 14-4).8 The anion gap is normal (<13 mEq/L) in situations such as diarrhea, biliary drainage, and renal tubular acidosis
in which bicarbonate is lost externally. The anion gap also is normal or reduced in hyperchloremic acidosis associated with perioperative infusion of substantial quantities of 0.9% saline.4,9 Metabolic acidosis associated with a high anion gap (>13 mEq/L) occurs because of excess production or decreased excretion of organic acids or ingestion of one of several toxic compounds (Table 14-4). In metabolic acidosis associated with a high anion gap, bicarbonate ions are consumed in buffering hydrogen ions, while the associated anion replaces bicarbonate in serum. Because three quarters of the normal anion gap consists of albumin, the calculated anion gap should be corrected for hypoalbuminemia by adding to the calculated anion gap the difference between measured serum albumin and a normal albumin concentration of 4.0 g/dL multiplied by 2.0 to 2.5.10 In general, an increase in the albumin-corrected anion gap (ΔAG) should be approximately matched by a decrease in the serum [HCO3-] (ΔHCO3-).11 A ratio of ΔAG: ΔHCO3- that is <0.8 or >1.2 should prompt consideration of a mixed acid-base disturbance.
Table 14-4 Differential Diagnosis of Metabolic Acidosis
Sufficient reductions in pH may reduce myocardial contractility, increase pulmonary vascular resistance, and decrease systemic vascular resistance. It is particularly important to note that failure of a patient to appropriately hyperventilate in response to metabolic acidosis is physiologically equivalent to respiratory acidosis and suggests clinical deterioration. If a patient with metabolic acidosis requires mechanical ventilation, for example, during general anesthesia, every attempt should be made to maintain an appropriate level of ventilatory compensation (see Table 14-3) until the primary process can be corrected. Table 14-5 illustrates failure to maintain compensatory hyperventilation.
The anesthetic implications of metabolic acidosis are proportional to the severity of the underlying process. Although a patient with hyperchloremic metabolic acidosis may be relatively healthy, those with lactic acidosis, ketoacidosis, uremia, or toxic ingestions will be chronically or acutely ill. Preoperative assessment should emphasize volume status and renal function. If shock has caused metabolic acidosis, direct arterial pressure monitoring and preload may require assessment via echocardiography or pulmonary arterial catheterization. Intraoperatively, one should be concerned about the possibility of exaggerated hypotensive responses to drugs and positive pressure ventilation. In planning intravenous fluid therapy, consider that balanced salt solutions tend to increase [HCO3-] (e.g., by metabolism of lactate to bicarbonate) and pH and 0.9% saline tends to decrease [HCO3-] and pH.
The treatment of metabolic acidosis consists of the treatment of the primary pathophysiologic process, that is, hypo-perfusion, hypoxia, and if pH is severely decreased, administration of NaHCO3-. Hyperventilation, although an important compensatory response to metabolic acidosis, is not definitive therapy for metabolic acidosis. The initial dose of NaHCO3 can be calculated as:
where 0.3 = the assumed distribution space for bicarbonate and 24 mEq/L is the normal value for [HCO3-] on arterial blood gas determination. The calculation markedly underestimates dosage in severe metabolic acidosis. In infants and children, a customary initial dose is 1.0 to 2.0 mEq/kg of body weight.
Both evidence and opinion suggest that NaHCO3 should rarely be used to treat acidemia induced by metabolic acidosis.5,6,12 In critically ill patients with lactic acidosis, there were no important differences between the physiologic effects (other than changes in pH) of 0.9 M NaHCO3 and 0.9 M sodium chloride.13 Importantly, NaHCO3 did not improve the cardiovascular response to catecholamines and actually reduced plasma ionized calcium.13 Although many clinicians continue to administer NaHCO3 to patients with persistent lactic acidosis and ongoing deterioration, neither NaHCO3 nor dichloroacetate14 has improved outcome. The buffer THAM (tris-hydroxymethyl aminomethane) effectively reduces [H+], does not increase plasma [Na+], does not generate CO2 as a byproduct of buffering, and does not decrease plasma [K+]15; however, there is no generally accepted indication for THAM.
Respiratory alkalosis, always characterized by hypocarbia (Paco2 ≤35 mm Hg) and usually characterized by an alkalemic pH (>7.45), results from an increase in minute ventilation that is greater than that required to excrete metabolic CO2 production. Because respiratory alkalosis may be a sign of pain, anxiety, hypoxemia, central nervous system disease, or systemic sepsis, the development of spontaneous respiratory alkalosis in a previously normocarbic patient requires prompt evaluation. The hyperventilation syndrome, a diagnosis of exclusion, is most often encountered in the emergency department.16
Respiratory alkalosis, like metabolic alkalosis, may produce hypokalemia, hypocalcemia, cardiac dysrhythmias, bronchoconstriction, and hypotension, and may potentiate the toxicity of digoxin. In addition, both brain pH and cerebral blood flow are tightly regulated and respond rapidly to changes in systemic pH.17 Doubling minute ventilation reduces Paco2 to 20 mm Hg and halves cerebral blood flow; conversely, halving minute ventilation doubles Paco2 and doubles cerebral blood
flow. Therefore, acute hyperventilation may be useful in neurosurgical procedures to reduce brain bulk and to control intracranial pressure (ICP) during emergent surgery for noncranial injuries associated with acute closed head trauma. In those situations, intraoperative monitoring of arterial blood gases, correlated with capnography, will document adequate reduction of Paco2. Acute profound hypocapnia (<20 mm Hg) may produce electroencephalographic evidence of cerebral ischemia. If Paco2 is maintained at abnormally high or low levels for 8 to 24 hours, cerebral blood flow will return toward previous levels, associated with a return of cerebrospinal fluid [HCO3-] toward normal.
Table 14-5 Failure to Maintain Appropriate Ventilatory Compensation for Metabolic Acidosisa
Treatment of respiratory alkalosis per se is often not required. The most important steps are recognition and treatment of the underlying cause.16 For instance, correction of hypoxemia or hypoperfusion-induced lactic acidosis should result in resolution of the associated increases in respiratory drive. Preoperative recognition of chronic hyperventilation necessitates intraoperative maintenance of a similar Paco2.
Respiratory acidosis, always characterized by hypercarbia (Paco2 ≤45 mm Hg) and usually characterized by a low pH (<7.35), occurs because of a decrease in minute alveolar ventilation (VA), an increase in production of carbon dioxide (VCO2) or both, from the equation:
where K = constant (rebreathing of exhaled, carbon dioxide-containing gas may also increase Paco2). Respiratory acidosis may be either acute, without compensation by renal [HCO3-] retention, or chronic, with [HCO3-] retention offsetting the decrease in pH (Table 14-6). A reduction in VA may be due to an overall decrease in minute ventilation (VE) or to an increase in the amount of wasted ventilation (VD), according to the equation:
Table 14-6 Changes of [HCO3-] and pH in Response to Acute and Chronic Changes in Paco2
Decreases in VE may occur because of central ventilatory depression by drugs or central nervous system injury because of increased work of breathing, or because of airway obstruction or neuromuscular dysfunction. Increases in VD occur with chronic obstructive pulmonary disease, pulmonary embolism, and most acute forms of respiratory failure. VCO2may be increased by sepsis, high-glucose parenteral feeding, or fever.
Patients with chronic hypercarbia due to intrinsic pulmonary disease require careful preoperative evaluation. The ventilatory restriction imposed by upper abdominal or thoracic surgery may aggravate ventilatory insufficiency after surgery. Administration of narcotics and sedatives, even in small doses, may cause hazardous ventilatory depression. Preoperative evaluation should consider direct arterial pressure monitoring and frequent intraoperative blood gas determinations, as well as strategies to manage postoperative pain with minimal doses of systemic opioids. Intraoperatively, a patient with chronically compensated hypercapnia should be ventilated to maintain a normal pH. Inadvertent restoration of normal VA may result in profound alkalemia. Postoperatively, prophylactic ventilatory support may be required for selected patients with chronic hypercarbia. Epidural narcotic administration represents one potential alternative that may provide adequate postoperative analgesia while limiting depression of ventilatory drive.
The treatment of respiratory acidosis depends on whether the process is acute or chronic. Acute respiratory acidosis may require mechanical ventilation unless a simple etiologic factor (i.e., narcotic overdosage or residual muscular blockade) can be treated quickly. Bicarbonate administration rarely is indicated unless severe metabolic acidosis is also present or unless mechanical ventilation is ineffective in reducing acute hypercarbia. In contrast, chronic respiratory acidosis is rarely managed with ventilation but rather with efforts to improve pulmonary function. In patients requiring mechanical ventilation for acute respiratory failure, ventilation with a lung-protective strategy may result in hypercapnia, which occasionally may require administration of buffers to avoid excessive acidemia.18
Practical Approach to Acid-Base Interpretation
Rapid interpretation of a patient's acid-base status involves the integration of three sets of data: arterial blood gases, electrolytes, and history. A systematic, sequential approach facilitates interpretation (Table 14-7). Acid-base assessment usually can be completed before initiating therapy; however, inspection of arterial blood gas data may disclose disturbances (e.g., respiratory acidosis or metabolic acidosis with pH <7.1) that require immediate attention.
The second step is to determine whether a patient is acidemic (pH <7.35) or alkalemic (pH >7.45). The pH status will usually indicate the predominant primary process, that is, acidosis produces acidemia; and alkalosis produces alkalemia. Note that the suffix “-osis” indicates a primary process that, if unopposed, will produce the corresponding pH change. The suffix “-emia” refers to the pH. A compensatory process is not considered an “-osis.” Of course, a patient may have mixed “-oses,” that is, more than one primary process.
The third step is to determine whether the entire arterial blood gas picture is consistent with a simple acute respiratory alkalosis or acidosis (see Table 14-6). For example, a patient with acute hypocapnia (Paco2 30 mm Hg) would have a pH increase of 0.10 units to a pH of 7.50 and a decrease of calculated [HCO3-] to 22 mEq/L.
As the fourth step, if changes in Paco2, pH, and [HCO3-] are not consistent with a simple acute respiratory disturbance, chronic respiratory acidosis (≥24 hours)
or metabolic acidosis or alkalosis should be considered. In chronic respiratory acidosis, pH returns to nearly normal as bicarbonate is retained by the kidneys (Table 14-6), usually at a ratio of 4 to 5 mEq/L per 10 mm Hg chronic increase in Paco2.19 For example, chronic hypoventilation at a Paco2 of 60 mm Hg would be associated with an increase in [HCO3-] of 8 to 10 mEq/L so that [HCO3-] would be expected to range from 32 to 34 mEq/L and pH would be expected to be within the low normal range (7.35 to 7.38). If neither an acute nor chronic respiratory change appears to explain the arterial blood gas data, then a metabolic disturbance must also be present.
Table 14-7 Sequential Approach to Acid-Base Interpretation
The fifth question addresses respiratory compensation for metabolic disturbances. Respiratory compensation for metabolic disturbances occurs more rapidly than renal compensation for respiratory disturbances (Table 14-3). Several general rules describe compensation. First, overcompensation is rare. Second, inadequate or excessive compensation suggests an additional primary disturbance. Third, hypobicarbonatemia associated with an increased anion gap is never compensatory.
The sixth question, whether an anion gap is present, should be assessed even if the arterial blood gases appear straightforward. The simultaneous occurrence of metabolic alkalosis and metabolic acidosis may result in an unremarkable pH and [HCO3-]; therefore, the combined abnormality may only be appreciated by examining the anion gap (if the cause of the metabolic acidosis is associated with a high anion gap). As noted previously, correct assessment of the anion gap requires correction for hypoalbuminemia.10 Metabolic acidoses associated with increased anion gaps require specific treatments, thus necessitating a correct diagnosis and differentiation from hyperchloremic metabolic acidosis. For instance, if metabolic acidosis results from administration of large volumes of 0.9% saline, no specific treatment of metabolic acidosis would usually be necessary.
The seventh and final question is whether the clinical data are consistent with the proposed acid-base interpretation. Failure to integrate clinical findings with arterial blood gas and plasma electrolyte data may lead to serious errors in interpretation and management.
The following two hypothetical cases illustrate the use of the algorithm and rules of thumb previously discussed.
Example Number 1
A 65-year-old woman has undergone 12 hours of an expected 16-hour radical neck dissection and flap construction. Estimated blood loss is 1,000 mL. She has received three units of packed red blood cells and six L of 0.9 % saline. Her blood pressure and heart rate have remained stable while anesthetized with 0.5% to 1.0% isoflurane in 70:30 nitrous oxide and oxygen. Urinary output is adequate. Arterial blood gas levels are shown in Table 14-8.
Table 14-8 Hyperchloremic Metabolic Acidosis During Prolonged Surgery
The step-by-step interpretation is as follows:
1. The pH requires no immediate treatment.
2. The pH is normal.
3. The arterial blood gases cannot be adequately explained by acute hypocarbia. The predicted pH would be 7.48 and the predicted [HCO3-] would be 22 mEq/L (see Table 14-6).
4. A metabolic acidosis appears to be present.
5. Patients under general anesthesia with controlled mechanical ventilation cannot compensate for metabolic acidosis. However, spontaneous hypocapnia of this magnitude would represent slight overcompensation for metabolic acidosis (see Table 14-3) and would suggest the presence of a primary respiratory alkalosis.
6. Metabolic acidosis occurring during prolonged anesthesia and surgery could suggest lactic acidosis and prompt additional fluid therapy or other attempts to improve perfusion. However, serum electrolytes reveal an anion gap that is slightly less than normal (Table 14-8), indicating that the metabolic acidosis is probably the result of dilution of the extracellular volume with a high-chloride fluid. Correction of the anion gap for the serum albumin of 3.0 g/dL only increases the anion gap to 10 to 11 mEq/L, again consistent with hyperchloremic metabolic acidosis. After differentiation from high anion-gap metabolic acidoses, hyperchloremic acidosis secondary to infusion of high-chloride fluid usually requires no treatment. The arterial blood gases and serum electrolytes are compatible with the clinical picture.
Example Number 2
A 35-year-old man, 3 days after appendectomy, develops nausea with recurrent emesis persisting for 48 hours. An arterial blood gas reveals the results shown in the middle column ofTable 14-9.
1. The pH of 7.50 requires no immediate intervention.
2. The pH is alkalemic, suggesting a primary alkalosis.
3. An acute Paco2 of 46 mm Hg would yield a pH of approximately 7.37; therefore, this is not simply an acute ventilatory disturbance.
4. The patient has a primary metabolic alkalosis as suggested by the [HCO3-] of 35 mEq/L.
5. The limits of respiratory compensation for metabolic alkalosis are wide and difficult to predict for individual patients. The rules of thumb, summarized in Table 14-3, suggest that [HCO3-] + 15 should equal the last two digits of the pH and that the Paco2 should increase 5 to 6 mm Hg
for every 10 mEq/L change in serum [HCO3-], that is, a pH of 7.50 and a Paco2 of 46 mm Hg are within the expected range.
6. The anion gap is 10 mEq/L.
7. The diagnosis of a primary metabolic alkalosis with compensatory hypoventilation is consistent with the history of recurrent vomiting. Consider how the arterial blood gases could change if vomiting were sufficiently severe to produce hypovolemic shock and lactic acidosis (third column, Table 14-9).
Table 14-9 Metabolic Alkalosis Secondary to Nausea and Vomiting with Subsequent Lactic Acidosis Secondary to Hypovolemia
This sequence illustrates the important concept that the final pH, Paco2 and [HCO3-] represent the result of all of the vectors operating on acid-base status. Complex or “triple disturbances” can only be interpreted using a thorough, stepwise approach.
Body Fluid Compartments
Accurate replacement of fluid deficits necessitates an understanding of the expected distribution spaces of water, sodium, and colloid. The sum of intracellular volume (ICV), which constitutes 40% of total body weight, and extracellular volume (ECV), which constitutes 20% of body weight, comprises total body water (TBW), which therefore approximates 60% of total body weight. Plasma volume (PV), equals about one fifth of ECV, the remainder of which is interstitial fluid volume (IFV). Red cell volume, approximately 2 L, is part of ICV.
The distribution volume of sodium-free water is TBW. The distribution volume of infused sodium is ECV, which contains equal sodium concentrations ([Na+]) in the PV and IF. Plasma [Na+] is approximately 140 mEq/L. The predominant intracellular cation, potassium, has an intracellular concentration ([K+]) approximating 150 mEq/L. Albumin, the most important oncotically active constituent of ECV, is unequally distributed in PV (~4 g/dL) and IFV (~1 g/dL). The IFV concentration of albumin varies greatly among tissues; however, ECV is the distribution volume for colloid solutions.
Distribution of Infused Fluids
Conventionally, clinical prediction of plasma volume expansion after fluid infusion assumes that body fluid spaces are static. Kinetic analysis of plasma volume expansion replaces the static assumption with a dynamic description. As an example of the static approach, assume that a 70-kg patient has suffered an acute blood loss of 2,000 mL, approximately 40% of the predicted 5-L blood volume. The formula describing the effects of replacement with 5% dextrose in water (D5W), lactated Ringer solution, or 5% or 25% human serum albumin is as follows:
Rearranging the equation yields the following:
To restore blood volume using D5W, assuming a distribution volume for sodium-free water of TBW, requires 28 L:
where 2 L is the desired PV increment, 42 L = TBW in a 70-kg person, and 3 L is the normal estimated PV.
To restore blood volume using lactated Ringer solution requires 9.1 L:
where 14 L = ECV in a 70-kg person.
If 5% albumin, which exerts colloid osmotic pressure similar to plasma, were infused, the infused volume initially would remain in the PV, perhaps attracting additional interstitial fluid intravascularly. Twenty-five percent human serum albumin, a concentrated colloid, expands PV by approximately 400 mL for each 100 mL infused.
However, these static analyses are simplistic. Infused fluid does not simply equilibrate throughout an assumed distribution volume but is added to a highly regulated system that attempts to maintain intravascular, interstitial, and intracellular volume. A more comprehensive kinetic model was proposed by Svensen and Hahn.20 Kinetic models of intravenous fluid therapy allow clinicians to predict more accurately the time course of volume changes produced by infusions of fluids of various compositions. Kinetic analysis permits estimation of peak volume expansion and rates of clearance of infused fluid and complements analysis of “pharmacodynamic” effects, such as changes in cardiac output or cardiac filling pressures.
Using a kinetic approach to fluid therapy permits analysis of the effects of common physiologic and pharmacologic influences on fluid distribution in experimental animals or humans. For example, in chronically instrumented sheep, isoflurane anesthesia and the conscious state were associated with similar kinetics of PV expansion after fluid infusion, but reduced urinary output in anesthetized sheep demonstrated
that expansion of extravascular volume was relatively greater during anesthesia21; subsequent experiments demonstrated that this effect was attributable to isoflurane and not to mechanical ventilation during anesthesia.22 Also in chronically instrumented sheep, administration of catecholamine infusions before and during fluid infusions profoundly altered intravascular fluid retention, with phenylephrine diminishing and isoproterenol enhancing intravascular fluid retention (Fig. 14-1).23
Figure 14-1. A. Blood hemoglobin (mean ± SEM) sampled at three baseline periods during a 30-minute catecholamine infusion and for 3 hours after starting a 20-minute 0.9% NaCl bolus of 24 mL/kg. Catecholamine protocols are dopamine (Dopa, open diamonds), isoproterenol (Iso, closed circles), phenylephrine (Phen, open triangles), and no-drug control (Control, closed squares). The 0.9% NaCl bolus decreased hemoglobin in all protocols at the end of the 20-minute 0.9% NaCL infusion and in all protocols except the Phen protocol thereafter. Postinfusion protocol differences were Phen > Dopa = Control > Iso. B. Calculated blood volume (mean ± SEM) at three baseline periods during a catecholamine infusion and for 3 hours after starting a 20-minute 0.9% NaCl bolus of 24 mL/kg. The 0.9% NaCl bolus increased blood volume in all protocols at T20 and in all protocols except the Phen protocol thereafter. Postinfusion protocol differences were Iso > Dopa = Control > Phen. NS, normal saline bolus. (From Vane LA, Prough DS, Kinsky MA, Williams CA, Grady JJ, Kramer GC: Effects of different catecholamines on the dynamics of volume expansion of crystalloid infusion. Anesthesiology 2004; 101: 1136–1144, with permission).
Regulation of Extracellular Fluid Volume
Total body water content is regulated by the intake and output of water. Water intake includes ingested liquids plus an average of 750 mL ingested in solid food and 350 mL that is generated metabolically. Insensible losses are normally 1 L/day and gastrointestinal losses are 100 to 150 mL/day. Thirst, the primary mechanism of controlling water intake, is triggered by an increase in body fluid tonicity or by a decrease in extracellular volume.
Reabsorption of filtered water and sodium is enhanced by changes mediated by the hormonal factors antidiuretic hormone (ADH), atrial natriuretic peptide (ANP), and aldosterone. Renal water handling has three important components: (1) delivery of tubular fluid to the diluting segments of the nephron, (2) separation of solute and water in the diluting segment, and (3) variable reabsorption of water in the collecting ducts. In the descending loop of Henle, water is reabsorbed while solute is retained to achieve a final osmolality of tubular fluid of approximately 1,200 mOsm/kg (Fig. 14-2). This concentrated fluid is then diluted by the active reabsorption of electrolytes in the ascending limb of the loop of Henle and in the distal tubule, both of which are relatively impermeable to water. As fluid exits the distal tubule and enters the collecting duct, osmolality is approximately 50 mOsm/kg. Within the collecting duct, water reabsorption is modulated by ADH (also called vasopressin). Vasopressin binds to V2 receptors along the basolateral membrane of the collecting duct cells, then stimulates the synthesis and insertion of the aquaporin-2 water channel into the luminal membrane of collecting duct cells.24
Plasma hypotonicity suppresses ADH release, resulting in excretion of dilute urine. Hypertonicity stimulates ADH secretion, which increases the permeability of the collecting duct to water and enhances water reabsorption. In response to changing plasma [Na+], changing secretion of ADH can vary urinary osmolality from 50 to 1,200 mOsm/kg and urinary volume from 0.4 to 20 L/day (Fig. 14-3).25 Other factors that stimulate ADH secretion, although none as powerfully as plasma tonicity, include hypotension, hypovolemia, and nonosmotic stimuli such as nausea, pain, and medications, including opiates.
Two powerful hormonal systems regulate total body sodium. The natriuretic peptides, ANP, brain natriuretic peptide, and C-type natriuretic peptide, defend against sodium overload26,27,28 and the renin-angiotensin-aldosterone axis defends against sodium depletion and hypovolemia. ANP, released from the cardiac atria in response to increased atrial stretch, exerts vasodilatory effects and increases the renal excretion of sodium and water. ANP secretion is decreased during hypovolemia. Even in patients with chronic (nonoliguric) renal insufficiency, infusion of ANP in low, nonhypotensive doses increased sodium excretion and augmented urinary losses of retained solutes.29
Aldosterone is the final common pathway in a complex response to decreased effective arterial volume, whether decreased effective arterial volume is true or relative, as in edematous states or hypoalbuminemia. In this pathway, decreased stretch in the baroreceptors of the aortic arch and carotid body and stretch receptors in the great veins, pulmonary vasculature, and atria result in increased sympathetic tone. Increased sympathetic tone, in combination with decreased renal perfusion, leads to renin release and formation of angiotensin I from angiotensinogen. Angiotensin-converting enzyme (ACE) converts angiotensin I to angiotensin II, which stimulates the adrenal cortex to synthesize and release aldosterone.30 Acting primarily in the distal tubules, high concentrations of aldosterone cause sodium reabsorption and may reduce urinary excretion of sodium nearly to zero. Intrarenal physical factors are also important in regulating sodium balance. Sodium loading decreases colloid osmotic pressure, thereby increasing the glomerular filtration rate (GFR), decreasing net sodium reabsorption and increasing distal sodium delivery, which, in turn, suppresses renin secretion.
Figure 14-2. Renal filtration, reabsorption, and excretion of water. Open arrows represent water and solid arrows represent electrolytes. Water and electrolytes are filtered by the glomerulus. In the proximal tubule (1), water and electrolytes are absorbed isotonically. In the descending loop of Henle (2), water is absorbed to achieve osmotic equilibrium with the interstitium while electrolytes are retained. The numbers (300, 600, 900, and 1200) between the descending and ascending limbs represent the osmolality of the interstitium in milliosmoles per kilogram. The delivery of solute and fluid to the distal nephron is a function of proximal tubular reabsorption; as proximal tubular reabsorption increases, delivery of solute to the medullary (3a) and cortical (3b) diluting sites decreases. In the diluting sites, electrolyte-free water is generated through selective reabsorption of electrolytes while water is retained in the tubular lumen, generating a dilute tubular fluid. In the absence of vasopressin, the collecting duct (4a) remains relatively impermeable to water and a diluted urine is excreted. When vasopressin acts on the collecting ducts (4b), water is reabsorbed from these vasopressin-responsive nephron segments, allowing the excretion of a concentrated urine. (From Fried LF, Palevsky PM: Hyponatremia and hypernatremia, The Medical Clinics of North America. Renal Disease. Edited by Saklayen MG. Philadelphia, WB Saunders Company, 1997, pp 585–609, with permission.)
Figure 14-3. Left. The sigmoid relationship between plasma vasopressin (VP) and urinary osmolality. Data were obtained during water loading and fluid restriction in a group of healthy adults. Maximum urinary concentration is achieved by plasma VP values of 3 to 4 pmol/L. Right. The linear relationship between plasma osmolality and plasma VP. Increases in VP in response to hypertonicity induced by infusion of 855 mmol/L saline in a group of healthy adults. The shaded area represents the reference range response. LD represents the limit of detection of the VP assay, 0.3 pmol/L. (From Ball SG: Vasopressin and disorders of water balance: the physiology and pathophysiology of vasopressin. Ann Clin Biochem 2007; 44: 417–431, with permission.)
Fluid Replacement Therapy
Maintenance Requirements for Water, Sodium, and Potassium
Calculation of maintenance fluid requirements is of limited value in determining intraoperative fluid requirements. However, calculation of maintenance fluid requirements (Table 14-10) is useful for estimating water and electrolyte deficits that result from preoperative restriction of oral food and fluids and for estimating the ongoing requirements for patients with prolonged postoperative bowel dysfunction. In healthy adults, sufficient water is required to balance gastrointestinal losses of 100 to 200 mL/day, insensible losses of 500 to 1,000 mL/day (half of which is respiratory and half is cutaneous), and urinary losses of 1,000 mL/day. Urinary losses exceeding 1,000 mL/day may represent an appropriate physiologic response to ECV expansion or pathophysiologic inability to conserve salt or water.
Daily adult requirements for sodium and potassium are approximately 75 and 40 mEq/kg, respectively, although wider ranges of sodium intake than potassium intake are physiologically tolerated because renal sodium conservation and excretion are more efficient than potassium conservation and excretion. Therefore, healthy, 70-kg adults require 2,500 mL/day of water containing a [Na+] of 30 mEq/L and a [K+] of 15 to 20 mEq/L. Intraoperatively, fluids containing sodium-free water (i.e., [Na+] < 130 mEq/L) are rarely used in adults because of the necessity for replacing isotonic losses and the risk of postoperative hyponatremia.
Traditionally, glucose-containing intravenous fluids have been given in an effort to prevent hypoglycemia and limit protein catabolism. However, because of the hyperglycemic response associated with surgical stress, only infants and patients receiving insulin or drugs that interfere with glucose synthesis are at risk for hypoglycemia. Iatrogenic hyperglycemia can limit the effectiveness of fluid resuscitation by inducing an osmotic diuresis and, in animals, may aggravate ischemic neurologic injury.31 Although associated with worsened outcome after subarachnoid hemorrhage32 and traumatic brain injury33 in humans, hyperglycemia may also constitute a hormonally mediated response to more severe injury. In critically ill patients, some evidence suggests that tight control of plasma glucose (maintenance of plasma glucose between 80 and 110 mg/dL) is associated with reduced mortality and morbidity, but other evidence does not.34,35,36,37 Evidence also suggests that tight glucose control improves outcome in surgical patients.38
Surgical Fluid Requirements
Water and Electrolyte Composition of Fluid Losses
Surgical patients require replacement of PV and ECV losses secondary to wound or burn edema, ascites, and gastrointestinal secretions. Wound and burn edema and ascitic fluid are protein-rich and contain electrolytes in concentrations similar to plasma. Although gastrointestinal secretions vary greatly in composition, the composition of replacement fluid need not be closely matched if ECV is adequate and renal and cardiovascular functions are normal. Substantial loss of gastrointestinal fluids requires more accurate replacement of electrolytes (i.e., potassium, magnesium, phosphate). Chronic gastric losses may produce hypochloremic metabolic alkalosis that can be corrected with 0.9% saline; chronic diarrhea may produce hyperchloremic metabolic acidosis that may be prevented or corrected by infusion of fluid containing bicarbonate or bicarbonate substrate (e.g., lactate). If cardiovascular or renal function is impaired, more precise replacement may require frequent assessment of serum electrolytes.
Table 14-10 Hourly and Daily Maintenance Water Requirements
Influence of Perioperative Fluid Infusion Rates on Clinical Outcomes
Conventionally, intraoperative fluid management has included replacement of fluid that is assumed to accumulate extravascularly in surgically manipulated tissue. Until recently, perioperative clinical practice included, in addition to maintenance fluids and replacement of estimated blood loss, 4 to 6 mL/kg/hr for procedures involving minimal tissue trauma, 6 to 8 mL/kg/hr for those involving moderate trauma, and 8 to 12 mL/kg/hr for those involving extreme trauma.
However, recent clinical trials strongly link perioperative fluid management to potentially important alterations of both minor and major morbidity. Moreover, the influence of fluid volume may be specific to the type of surgery and to the types of fluid used. Maharaj et al.39 randomized 80 ASA I-II patients scheduled for gynecologic laparoscopy either to large volume, defined as 2.0 mL/kg/hr of fasting over 20 minutes preoperatively (e.g., 1,440 mL/60 kg in a patient who had been fasting for 12 hours) or small volume, defined as total fluid of 3.0 mL/kg over 20 minutes preoperatively. In patients receiving the higher dose, postoperative nausea and vomiting and pain were significantly reduced (Fig. 14-4).39 Holte et al.40 randomized 48 ASA I-II patients undergoing laparoscopic cholecystectomy to receive either 15 or 40 mL/kg of lactated Ringer solution intraoperatively; the higher dose of fluid was associated with improved postoperative pulmonary function and exercise capacity, reduced neurohumoral stress response, and improvements in nausea, general sense of well-being, thirst, dizziness, drowsiness, fatigue, and balance function. Holte et al.41 randomized 48 ASA I-III patients undergoing fast-track elective knee arthroplasty under intraoperative epidural/spinal anesthesia and postoperative epidural analgesia to either liberal or restricted fluids. Median intravenous fluid administered intraoperatively and in the postanesthesia care unit in the restrictive group was 1,740 mL (range, 1,100 to 2,165 mL) of lactated Ringer solution and in the liberal group was 3,275 mL (range, 2,400 to 4,000 mL). Restrictive fluid administration was associated with a higher incidence of vomiting but less hypercoagulability and no difference in short-term postoperative mobility or ileus. Therefore, fluid restriction appears to be less well tolerated than more liberal fluid therapy in patients undergoing surgery of limited scope, but perhaps at the expense of hypercoagulability.
In patients undergoing major intra-abdominal surgery, recent randomized controlled trials also suggest that restrictive fluid administration is associated with a combination of positive and negative effects. Brandstrup et al.42 randomized 172 elective colon surgery patients to either restrictive perioperative fluid management or standard perioperative fluid management, with the primary goal of maintaining preoperative body weight in the fluid-restricted group. By design, the fluid-restricted group received less perioperative fluid and
acutely gained <1 kg in contrast to >3 kg in the standard therapy group. More importantly, cardiopulmonary complications, tissue-healing complications, and total postoperative complications were significantly fewer in the fluid-restricted group. In 152 patients undergoing intra-abdominal surgery, including colon surgery, Nisanevich et al.43 reported less prompt return of gastrointestinal function and longer hospital stays in patients receiving conventional fluid therapy (10 mL/kg/hr of lactated Ringer solution) than in patients receiving restricted fluid therapy (4.0 mL/kg/hr). In a small clinical trial comparing gastric emptying in patients randomized to receive postoperative fluids at a restricted (≤2.0 L/day of water; ≤77 mEq/day) or liberal regimen (≥3.0 L/day of water; ≥154 mEq/day), gastric emptying time for both liquids and solids was significantly reduced in patients receiving restricted fluids (Fig. 14-5).44 Khoo et al.45 randomized 70 ASA I-III patients undergoing elective colorectal surgery to conventional perioperative management, including intraoperative fluid management at the discretion of the anesthesiologist, or to multimodal perioperative management, including intraoperative fluid restriction, unrestricted postoperative oral intake, prokinetic agents, early ambulation, and postoperative epidural analgesia. Multimodal perioperative multimodal management was associated with a reduced median stay (5 vs. 7 days) and fewer cardiorespiratory and anastomotic complications, but more hospital readmissions. Holte et al.46 randomized 32 ASA I-III patients undergoing “fast-track” colon resection under combined epidural/general anesthesia to intraoperative fluid administration using either a restrictive (median, 1,640 mL; range, 935 to 2,250 mL) or liberal (median, 5,050 mL; range, 3,563 to 8,050 mL) regimen. Fluid-restricted patients had significantly improved postoperative forced vital capacity and fewer, less severe episodes of oxygen saturation but at the expense of increased stress responses (aldosterone, antidiuretic hormone and angiotensin II measurements) and a statistically insignificantly increased number of complications.
Figure 14-4. Top. Mean postoperative verbal analog scale (VAS) nausea scores in each group over the first 72 postoperative hours. Mean VAS nausea scores were significantly lower in the group that received the large-volume intravenous fluid infusion compared with the control group at 1, 4, 24, and 72 hours postoperatively. Bottom. Mean postoperative VAS pain scores in each group over the first 72 postoperative hours. Mean VAS pain scores were significantly lower in the group that received the large-volume intravenous fluid infusion compared with the control group at 0, 1, 24, and 72 hours postoperatively. *Significantly higher (p < 0.05, t-test postanalysis of variance) VAS score compared with the large volume group. PACU, postanesthesia care unit. (From Maharaj CH, Kallam SR, Malik A, Hassett P, Grady D, Laffey JG: Preoperative intravenous fluid therapy decreases postoperative nausea and pain in high risk patients. Anesth Analg 2005; 100: 675–682, with permission.)
Critically ill patients with acute lung injury represent an important group that may benefit from careful regulation of fluid intake. The ARDS Clinical Trials Network47 randomized
1,000 patients with acute lung injury to a 7-day trial comparing a conservative fluid strategy with a liberal fluid strategy. Over the course of the trial the conservative strategy group had a cumulative net fluid balance that was slightly negative in comparison to a mean net cumulative fluid balance in the liberal group of nearly 7.0 L. Although overall mortality was no different in the two groups, the conservative fluid group had improved oxygenation and required fewer days of mechanical ventilation and intensive care. Despite achieving a negative fluid balance, the conservative strategy group had no greater incidence of acute renal failure.
Figure 14-5. Solid and liquid phase gastric emptying times (T50) after 4 days of standard or restricted intravenous postoperative fluid therapy. Solid lines are medians, shaded areas interquartile ranges, and whiskers represent extreme values. Differences between medians for solid and liquid phase T50 were 56 minutes (95% confidence interval: 12 to 132 minutes) and 52 minutes (9 to 95 mn), respectively. (Reprinted with permission from Lobo DN, Bostock KA, Neal KR, Perkins AC, Rowlands BJ, Allison SP: Effect of salt and water balance on recovery of gastrointestinal function after elective colonic resection: a randomised controlled trial. Lancet 2002; 359: 1812).
Colloids, Crystalloids, and Hypertonic Solutions
Physiology and Pharmacology
Osmotically active particles attract water across semipermeable membranes until equilibrium is attained. The osmolarity of a solution refers to the number of osmotically active particles per liter of solvent; osmolality, a measurement of the number of osmotically active particles per kilogram, can be estimated as follows:
where osmolality is expressed in mmol/kg, [Na+] is expressed in mEq/L, serum glucose is expressed in mg/dL, and BUN is blood urea nitrogen expressed in mg/dL. Sugars, alcohols, and radiographic dyes increase measured osmolality, generating an increased “osmolal gap” between the measured and calculated values.
A hyperosmolar state occurs whenever the concentration of osmotically active particles is high. Both uremia (increased BUN) and hypernatremia (increased serum sodium) increase serum osmolality. However, because urea distributes throughout TBW, an increase in BUN does not cause hypertonicity. Sodium, largely restricted to the ECV, causes hypertonicity, that is, osmotically mediated redistribution of water from ICV to ECV. The term tonicity is also used colloquially to compare the osmotic pressure of a parenteral solution to that of plasma.
Although only a small proportion of the osmotically active particles in blood consist of plasma proteins, those particles are essential in determining the equilibrium of fluid between the interstitial and plasma compartments of ECV. The reflection coefficient (σ) describes the permeability of capillary membranes to individual solutes, with 0 representing free permeability and 1.0 representing complete impermeability. The reflection coefficient for albumin ranges from 0.6 to 0.9 in various capillary beds. Because capillary protein concentrations exceed interstitial concentrations, the osmotic pressure exerted by plasma proteins (termed colloid osmotic pressure or oncotic pressure) is higher than interstitial oncotic pressure and tends to preserve PV. The filtration rate of fluid from the capillaries into the interstitial space is the net result of a combination of forces, including the gradient from intravascular to interstitial colloid osmotic pressures and the hydrostatic gradient between intravascular and interstitial pressures. The net fluid filtration at any point within a systemic or pulmonary capillary is represented by Starling's law of capillary filtration, as expressed in the equation:
where Q = fluid filtration, k = capillary filtration coefficient (conductivity of water), A = the area of the capillary membrane, Pc = capillary hydrostatic pressure, Pi = interstitial hydrostatic pressure, σ = reflection coefficient for albumin, πi = interstitial colloid osmotic pressure, and πc = capillary colloid osmotic pressure.
The IFV is determined by the relative rates of capillary filtration and lymphatic drainage. Pc, the most powerful factor promoting fluid filtration, is determined by capillary flow, arterial resistance, venous resistance, and venous pressure. If capillary filtration increases, the rates of water and sodium filtration usually exceed protein filtration, resulting in preservation of πc, dilution of πi, and preservation of the oncotic pressure gradient, the most powerful factor opposing fluid filtration. When coupled with increased lymphatic drainage, preservation of the oncotic pressure gradient limits the
accumulation of IF. If Pc increases at a time when lymphatic drainage is maximal, then IFV accumulates, forming edema.
Clinical Implications of Choices Between Alternative Fluids
If membrane permeability is intact, colloids such as albumin or hydroxyethyl starch preferentially expand PV rather than IFV. Concentrated colloid-containing solutions (e.g., 25% albumin) exert sufficient oncotic pressure to translocate substantial volumes of IFV into the PV, thereby increasing PV by a volume that exceeds the original infused volume. PV expansion unaccompanied by IFV expansion offers apparent advantages: lower fluid requirements, less peripheral and pulmonary edema accumulation, and reduced concern about the cardiopulmonary consequences of later fluid mobilization (Table 14-11).
However, exhaustive research has failed to establish the superiority of either colloid-containing or crystalloid-containing fluids for either intraoperative or postoperative use. Moretti et al.48 reported that patients who were randomized to receive 6% hetastarch had less postoperative nausea and vomiting than those who received lactated Ringer solution without colloid. In addition, colloid administration appears to have been an essential component of perioperative management strategies that demonstrated improved morbidity after colon surgery42 and after major surgery in conjunction with goal-directed fluid challenges.49,50
In critically ill patients and patients undergoing more extensive surgery, systematic reviews of available comparisons of colloid versus crystalloid51 and albumin versus crystalloid52suggested that the choice of fluid did not influence mortality. A recent randomized controlled trial comparing 4% albumin with 0.9% saline for fluid maintenance in 6,997 critically ill patients supports the conclusion that choice of colloid or crystalloid does not influence mortality.53 Baseline serum albumin concentration did not alter the lack of effect of albumin management on outcome.54 However, subgroup analyses suggested that crystalloid treatment could be superior in patients after trauma and that colloid could be superior in patients with severe sepsis.53 Subsequent 2-year follow-up of a subset of 460 patients with traumatic brain injury (Glasgow Coma Scale score ≤13) demonstrated a nearly twofold increased risk of death in patients receiving colloid fluid management.55
Although hydroxyethyl starch, the most commonly used synthetic colloid, is less expensive than albumin, large doses (exceeding 20 mL/kg/day) produce laboratory evidence of coagulopathy.56 Recently, a new hydroxyethyl starch formulation has been introduced that contains a different mix of molecular sizes and is dissolved in a base consisting of a balanced salt solution rather than 0.9% saline. Proposed advantages of the new formulation include less risk of inducing coagulopathy and of hyperchloremic metabolic acidosis.57However, lower molecular-weight hetastarch formulations appear to influence coagulation less. 56 Further refinement is likely to occur in the distinctions among various clinically available colloids.58
Implications of Crystalloid and Colloid Infusions on Intracranial Pressure
Because the cerebral capillary membrane, the blood–brain barrier, is highly impermeable to sodium, abrupt changes in serum osmolality produced by changes in serum sodium, produce reciprocal changes in brain water. In anesthetized rabbits, reducing plasma osmolality from 295 to 282 mOsm/kg (which decreases plasma osmotic pressure by ~250 mm Hg) increased cortical water content and ICP; in contrast reducing colloid osmotic pressure from 20 to 7 mm Hg produced no significant change in either variable.59 Similar independence of brain water and ICP from colloid osmotic pressure has been demonstrated with prolonged hypoalbuminemia60 and in animals after forebrain ischemia61 and focal cryogenic injury.62Although rats had reduced brain water after fluid percussion traumatic brain injury if colloid oncotic pressure was increased with hetastarch,63 these observations must be balanced against the apparent increase in mortality in traumatic brain injury patients managed with albumin rather than 0.9% saline during intensive care.55
Clinical Implications of Hypertonic Fluid Administration
An ideal alternative to conventional crystalloid and colloid fluids would be inexpensive, would produce minimal peripheral or pulmonary edema, would generate sustained hemodynamic effects, and would be effective even if administered in small volumes. Hypertonic, hypernatremic solutions, with or without added colloid, appear to fulfill some of these criteria (Table 14-12).
Current enthusiasm for hypertonic resuscitation was stimulated by the work of Velasco et al.,64 who successfully used small volumes (6.0 mL/kg) of 7.5% hypertonic saline as the sole resuscitative measure in dogs after severe hemorrhage. Hypertonic solutions exert favorable effects on cerebral hemodynamics, in part because of the reciprocal relationship
between plasma osmolality and brain water.59 ICP increased during resuscitation from hemorrhagic shock with lactated Ringer solution but remained unchanged if 7.5% saline was infused in a sufficient volume to comparably improve systemic hemodynamics.65 However, improvements in ICP gradually are lost. Delayed increases in ICP were reported after hypertonic resuscitation from hypovolemic shock accompanied by an intracranial mass lesion.66 In addition, systemic hemodynamic improvement produced by hypertonic resuscitation is short-lived.65 Strategies to prolong the therapeutic effects beyond 30 to 60 minutes include continued infusion of hypertonic saline, subsequent infusion of blood or conventional fluids, or addition of colloid to hypertonic resuscitation.
Table 14-11 Claimed Advantages and Disadvantages of Colloid Versus Crystalloid Intravenous Fluids
Table 14-12 Hypertonic Resuscitation Fluids: Advantages and Disadvantages
Despite concerns about central nervous system dysfunction due to hypertonicity and hypernatremia associated with hypertonic saline, acute increases in serum sodium to 155 to 160 mEq/L produced no apparent harm in humans resuscitated with hypertonic saline.67 Central pontine myelinolysis, which follows rapid correction of severe, chronic hyponatremia, has not been observed in clinical trials of hypertonic resuscitation. Despite theoretical considerations favoring the use of hypertonic saline in resuscitation of patients with traumatic brain injury, a recent randomized trial failed to demonstrate an improvement in outcome.68
Will clinicians routinely use hypertonic or combination hypertonic/hyperoncotic fluids for resuscitation in the future? Pending further preclinical work, the theoretical advantages of such fluids appear most attractive in the acute resuscitation of hypovolemic patients who have decreased intracranial compliance.69
Fluid Status: Assessment and Monitoring
For most surgical patients, conventional clinical assessment of the adequacy of intravascular volume is appropriate. For high-risk patients, goal-directed hemodynamic management may be superior.
Conventional Clinical Assessment
Clinical quantification of blood volume and ECV begins with recognition of deficit-generating settings such as bowel obstruction, preoperative bowel preparation, chronic diuretic use, sepsis, burns, and trauma. Physical signs that suggest hypovolemia include oliguria, supine hypotension, and a positive tilt test. Oliguria implies hypovolemia, although hypovolemic patients may be nonoliguric and normovolemic patients may be oliguric because of renal failure or stress-induced endocrine responses.70 Supine hypotension implies a blood volume deficit exceeding 30%, although arterial blood pressure within the normal range could represent relative hypotension in an elderly or chronically hypertensive patient.
In the tilt test, a positive response is defined as an increase in heart rate ≥20 beats per minute and a decrease in systolic blood pressure ≥20 mm Hg when the subject assumes the upright position. However, young, healthy subjects can withstand acute loss of 20% of blood volume while exhibiting only postural tachycardia and variable postural hypotension. In contrast, orthostasis may occur in 20 to 30% of elderly patients despite normal blood volume. In volunteers, withdrawal of 500 mL of blood71 was associated with a greater increase in heart rate on standing than before blood withdrawal, but with no significant difference in the response of blood pressure or cardiac index.
Laboratory evidence that suggests hypovolemia or ECV depletion includes azotemia, low urinary sodium, metabolic alkalosis (if hypovolemia is mild), and metabolic acidosis (if hypovolemia is severe). Hematocrit is virtually unchanged by acute hemorrhage until fluids are administered or until fluid shifts from the interstitial to the intravascular space. BUN, normally 8.0 to 20 mg/dL, is increased by hypovolemia, high-protein intake, gastrointestinal bleeding, or accelerated catabolism and decreased by severe hepatic dysfunction. Serum creatinine (SCr), a product of muscle catabolism, may be misleadingly low in elderly adults, females, and debilitated or malnourished patients. In contrast, in muscular or acutely catabolic patients, SCr may exceed the normal range (0.5 to 1.5 mg/dL) because of greater muscle protein metabolism. A ratio of BUN to SCr exceeding the normal range (10 to 20) suggests dehydration. In prerenal oliguria, enhanced sodium reabsorption should reduce urinary [Na+] to ≤20 mEq/L and enhanced water reabsorption should increase urinary concentration (i.e., urinary osmolality >400, urine/plasma creatinine ratio >40:1). However, the sensitivity and specificity of measurements of urinary variables may be misleading. Although hypovolemia does not generate metabolic alkalosis, ECV depletion is a potent stimulus for the maintenance of metabolic alkalosis. Severe hypovolemia may result in systemic hypoperfusion and lactic acidosis.
Intraoperative Clinical Assessment
Visual estimation, the simplest technique for quantifying intraoperative blood loss, assesses the amount of blood absorbed by gauze squares and laparotomy pads and adds an estimate of
blood accumulation on the floor and surgical drapes and in suction containers. Both surgeons and anesthesia providers tend to underestimate losses.
Assessment of the adequacy of intraoperative fluid resuscitation integrates multiple clinical variables, including heart rate, blood pressure, urinary output, arterial oxygenation, and pH. Tachycardia is an insensitive, nonspecific indicator of hypovolemia. In patients receiving potent inhalational agents, maintenance of a satisfactory blood pressure implies adequate intravascular volume. Preservation of blood pressure, accompanied by a CVP of 6 to 12 mm Hg, more strongly suggests adequate replacement. During profound hypovolemia, indirect measurements of blood pressure may significantly underestimate true blood pressure. In patients undergoing extensive procedures, direct arterial pressure measurements are more accurate than indirect techniques and provide convenient access for obtaining arterial blood samples. An additional advantage of direct arterial pressure monitoring may be recognition of increased systolic blood pressure variation accompanying positive pressure ventilation in the presence of hypo-volemia.72,73
Urinary output usually declines precipitously during moderate to severe hypovolemia. Therefore, in the absence of glycosuria or diuretic administration, a urinary output of 0.5 to 1.0 mL/kg hr during anesthesia suggests adequate renal perfusion. Arterial pH may decrease only when tissue hypoperfusion becomes severe. Cardiac output can be normal despite severely reduced regional blood flow. Mixed venous hemoglobin desaturation, a specific indicator of poor systemic perfusion, reflects average perfusion in multiple organs and cannot supplant regional monitors such as urinary output.
A promising technique for assessing the adequacy of cardiac preload during high-risk surgical procedures is the use of esophageal Doppler that measures blood flow in the descending thoracic aorta and that also measures the duration of aortic systole, which, if corrected for heart rate, correlates with left ventricular preload.74,81 In general, a corrected flow time <0.35 second suggests that volume expansion should improve cardiac output, while a corrected flow time >0.40 second suggests that further volume expansion will be ineffective.
Oxygen Delivery as a Goal of Management
No intraoperative monitor is sufficiently sensitive or specific to detect hypoperfusion in all patients. One key variable that has been associated with improved outcome in high-risk surgical patients and critically ill patients is a systemic oxygen delivery (Do2) ≥ 600mL O2/m2 min (equivalent to a cardiac index [CI] of 3.0 L/m2 min, a [Hgb] of 14 g/dL, and 98% oxyhemoglobin saturation). At present, available data are consistent with two inferences. First, there is no apparent benefit for patients other than surgical patients75 and patients undergoing initial resuscitation from septic shock in the emergency department.76 In surgical patients, early initiation of goal-directed resuscitation is associated with better outcome than delayed initiation.77 Second, outcome may be strongly influenced by the choice of methods to increase oxygen delivery, that is, the choice of fluid administration or various inotropic agents. Lobo et al.78 randomized 50 high-risk patients, defined as elderly patients with coexistent pathologies who were undergoing major elective surgery, to goal-directed hemodynamic therapy either with fluids alone or with fluids plus dobutamine. Hemodynamic goals intraoperatively and for the first 24 hours postoperatively consisted of DO2I >600 mL O2/m2 min. Postoperative cardiovascular complications occurred significantly more frequently in the group receiving fluids alone (13/25, 52%, vs. 4/25, 16%; relative risk, 3.25; 95% CI, 1.22–8.60; p < 0.05) and mortality was greater, but not statistically significantly greater in this small series. Increased fluid given as part of goal-oriented resuscitation has been associated with an increased incidence of abdominal compartment syndrome in trauma patients.79 Wilson et al. 80 randomized 138 patients undergoing major elective surgery into three groups. One group received routine perioperative care; one received fluid and dopexamine preoperatively, intraoperatively, and postoperatively to maintain oxygen delivery ≥600 mL O2/m2 min; and the third received fluid plus epinephrine preoperatively, intraoperatively, and postoperatively to achieve the same end points. In the two groups in which oxygen delivery was supported, only 3 of 92 died, compared with 8 of 46 control patients. However, the complication rate was significantly lower in the dopexamine group than in the epinephrine group.
Recently, several studies have reported improved outcome based on adjustment of perioperative fluids through the use of an esophageal Doppler monitor.81 Using the esophageal Doppler to guide administration of colloid boluses, Venn et al.49 and Gan et al.50 have reported shortened length of hospital stay after hip surgery and major surgery, respectively. Of note, Horowitz and Kumar82 speculated that the infusion of colloid rather than the monitor-driven algorithm was responsible for the improved results.
Sodium, the principal extracellular cation and solute, is essential for generation of action potentials in neurologic and cardiac tissue. Disorders (pathologic increases or decreases) oftotal body sodium are associated with corresponding increases or decreases of ECV and PV. Disorders of sodium concentration, that is, hyponatremia and hypernatremia, usually result from relative excesses or deficits, respectively, of water. Regulation of total body sodium and [Na+] is accomplished primarily by the endocrine and renal systems (Table 14-13). Secretion of aldosterone and ANP control total body sodium. ADH, which is secreted in response to increased osmolality or decreased blood pressure, primarily regulates [Na+]. Therefore, primary hyperaldosteronism is associated with hypervolemia and with hypertension, but not with abnormal [Na+].83,84
Hyponatremia, defined as [Na+] < 130 mEq/L, is the most common electrolyte disturbance in hospitalized patients. In the majority of hyponatremic patients, total body sodium is normal or increased. The most common clinical scenarios associated with hyponatremia include the postoperative state, acute intracranial disease, malignant disease, medications, and acute pulmonary disease. Hyponatremia is associated with increased mortality, both as a direct effect of hyponatremia and because of the association between hyponatremia and severe systemic disease.
The signs and symptoms of hyponatremia depend on both the rate and severity of the decrease in plasma [Na+]. Symptoms that can accompany severe hyponatremia ([Na+] < 120 mEq/L) include loss of appetite, nausea, vomiting, cramps, weakness, altered level of consciousness, coma, and seizures.
Acute central nervous system manifestations of hyponatremia result from brain overhydration. Because the blood–brain barrier is poorly permeable to sodium but freely permeable to water, a rapid decrease in plasma [Na+] promptly increases both extracellular and intracellular brain
water. Because the brain rapidly compensates for changes in osmolality, acute hyponatremia produces more severe symptoms than chronic hyponatremia. The symptoms of chronic hyponatremia probably relate to depletion of brain electrolytes. Once brain volume has compensated for hyponatremia, rapid increases in [Na+] may lead to abrupt brain dehydration.
Table 14-13 Regulation of Total Body Electrolyte Mass and Plasma Concentrations
In hyponatremic patients, serum osmolality may be normal, high or low (Fig. 14-6). Hyponatremia with a normal or high serum osmolality results from the presence of a nonsodium solute, such as glucose or mannitol, which holds water within the extracellular space and results in dilutional hyponatremia. The presence of a nonsodium solute may be inferred if measured osmolality exceeds calculated osmolality by >10 mOsm/kg. For example, plasma [Na+] decreases approximately 2.4 mEq/L for each 100 mg/dL rise in glucose concentration with perhaps even greater decreases as glucose concentration >400 mg/dL.85 In anesthesia practice, a common cause of hyponatremia associated with a normal osmolality is the absorption of large volumes of sodium-free irrigating solutions (containing mannitol, glycerine, or sorbitol as the solute) during transurethral resection of the prostate.86 Neurologic symptoms are minimal if mannitol is used because the agent does not cross the blood–brain barrier and is excreted with water in the urine. In contrast, as glycine or sorbitol is metabolized, hyposmolality will gradually develop and cerebral edema may appear as a late complication, that is, hypoosmolality is more important in generating symptoms than hyponatremia per se.86 Hyponatremia with a normal or elevated serum osmolality also may accompany renal insufficiency. BUN, included in the calculation of total osmolality, distributes throughout both ECV and ICV. Calculation of effective osmolality (2[Na+] + glucose/18) excludes the contribution of urea to tonicity and demonstrates true hypotonicity.
Hyponatremia with low serum osmolality may be associated with a high, low, or normal total body sodium and PV. Therefore, hyponatremia with hyposmolality (Fig. 14-6) is evaluated by assessing total body sodium content, BUN, SCr, urinary osmolality, and urinary [Na+]. Hyponatremia with increased total body sodium is characteristic of edematous states, that is, congestive heart failure, cirrhosis, nephrosis, and renal failure. Aquaporin 2, the vasopressin-regulated water channel, is up-regulated in experimental congestive heart failure,87 and cirrhosis88 and decreased by chronic vasopressin stimulation.89 In patients with renal insufficiency, reduced urinary diluting capacity can lead to hyponatremia if excess free water is given. In general, diseases that prompt hospitalization generate numerous stimuli for secretion of arginine vasopressin (AVP), which has prompted some experts to suggest that hyponatremic fluids rarely be given to hospitalized patients.90
The underlying mechanism of hypovolemic hyponatremia is secretion of AVP synonymous with ADH in response to volume contraction in association with ongoing oral or intravenous intake of hypotonic fluid.91 Angiotensin II also decreases renal free water clearance. Thiazide diuretics, unlike loop diuretics, promote hypovolemic hyponatremia by interfering with urinary dilution in the distal tubule.91 Hypo-volemic hyponatremia associated with a urinary [Na+] >20 mmol/L suggests mineralocorticoid deficiency, especially if serum [K+], BUN, and SCr are increased.91
The cerebral salt-wasting syndrome is an often severe, symptomatic salt-losing diathesis that appears to be mediated by brain natriuretic peptide and in which, in contrast to the syndrome of inappropriate antidiuretic hormone secretion (SIADH), secretion of arginine vasopressin is appropriate91; patients at risk for the cerebral salt wasting syndrome include those with cerebral lesions due to trauma, subarachnoid hemorrhage, tumors, and infection. In patients after subarachnoid hemorrhage, administration of hydrocortisone 1,200 mg/day prevented the cerebral salt-wasting syndrome.92
Euvolemic hyponatremia most commonly is associated with nonosmotic vasopressin secretion, for example, glucocorticoid deficiency, hypothyroidism, thiazide-induced hyponatremia, SIADH, and the reset osmostat syndrome. Total body sodium and ECV are relatively normal and edema is rarely evident. SIADH may be idiopathic but also is associated with diseases of the central nervous system and with pulmonary disease (Table 14-14). Euvolemic hyponatremia is usually associated with exogenous AVP administration, pharmacologic potentiation of AVP action, drugs that mimic the action of AVP in the renal tubules, or excessive ectopic AVP secretion. Tissues from some small cell lung cancers, duodenal cancers, and pancreatic cancers increase AVP production in response to osmotic stimulation.91
At least 4.0% of postoperative patients develop plasma [Na+] <130 mEq/L. Although neurologic manifestations usually do not accompany postoperative hyponatremia, signs of hypervolemia are occasionally present. Much less frequently, postoperative hyponatremia is accompanied by mental status changes, seizures and transtentorial herniaton,93attributable in part to intravenous administration of hypotonic fluids, secretion of AVP, and other factors, including drugs and altered renal function, that influence perioperative water balance.
Women appear to be more vulnerable than men and premenopausal women appear to be more vulnerable than postmenopausal women to brain damage secondary to postoperative hyponatremia.94 Postoperative hyponatremia can develop even with infusion of isotonic fluids if AVP is persistently increased. Twenty-four hours after surgery, mean plasma [Na+] in 22 women (mean age, 42 years) undergoing uncomplicated gynecologic surgery had decreased from 140 ± 1 to 136 ± 0.5 mEq/L.95 Although the patients retained sodium perioperatively, they retained proportionately more water (an average of 1.1 L of electrolyte-free water). Careful postoperative attention to fluid and electrolyte balance may minimize the occurrence of symptomatic hyponatremia.
Figure 14-6. Algorithm by which hyponatremia can be evaluated. SIADH, syndrome of inappropriate antidiuretic hormone secretion; R/O, rule out; CHF, congestive heart failure.
If both [Na+] and measured osmolality are below the normal range, hyponatremia is further evaluated by first assessing volume status using physical findings and laboratory data. In hypovolemic patients or edematous patients, the ratio of BUN to SCr should be >20:1. Urinary [Na+] is generally <15 mEq/L in edematous states and volume depletion and >20 mEq/L in hyponatremia secondary to renal salt wasting or renal failure with water retention.
The criteria for the diagnosis of SIADH are listed in Table 14-15. Urinary [Na+] should be >20 mEq/L unless fluids have been restricted. Arieff96 has argued that the diagnosis of SIADH may be inaccurately applied to functionally hypo-volemic postoperative patients, in whom, by definition, AVP secretion would be “appropriate.”
Treatment of hyponatremia associated with a normal or high serum osmolality requires reduction of the elevated concentrations of the responsible solute, for example, urea or mannitol. Uremic patients are treated by free water restriction or dialysis. Treatment of edematous (hypervolemic) patients necessitates restriction of both sodium and water, usually accompanied by efforts to improve cardiac output and renal perfusion and to use diuretics to inhibit sodium reabsorption (Fig. 14-7). In hypovolemic, hyponatremic patients, blood volume must be restored, usually by infusion of 0.9% saline, and excessive sodium losses must be curtailed. Correction of hypovolemia usually results in removal of the stimulus for AVP release, accompanied by a rapid water diuresis.
The cornerstone of SIADH management is free water restriction and elimination of precipitating causes. Water
restriction, sufficient to decrease TBW by 0.5 to 1.0 L per day, decreases ECV even if excessive AVP secretion continues. The resultant reduction in GFR enhances proximal tubular reabsorption of salt and water, thereby decreasing free water generation, and stimulates aldosterone secretion. As long as free water losses (i.e., renal, skin, gastrointestinal) exceed free water intake, plasma [Na+] will increase. During treatment of hyponatremia, increases in plasma [Na+] are determined both by the composition of the infused fluid and by the rate of renal free water excretion.97 Free water excretion can be increased by administering furosemide.
Table 14-14 Common Associations with the Syndrome of Inappropriate Antidiuretic Hormone Secretion
Recently, vasopressin receptor blocking agents have been developed that inhibit the action of AVP on the renal collecting ducts.98,99,100,101 In phase 3 clinical trials, these agents have proven to be safe and efficacious in hyponatremic patients, appearing to have particular value in patients with hypervolemic hyponatremia secondary to congestive heart failure.98Conivaptan, which inhibits both V1α and V2 receptors, has been approved for treatment of normovolemic and hypervolemic hyponatremic patients.100 However, potential decreases in blood pressure associated with V1α receptor blockade necessitate caution in patients with borderline low blood pressure.101 Tolvaptan, a selective V2 receptor antagonist, also has proven effective in clinical trials.102 Within a few years, vaptans will likely become a mainstay of therapy for normovolemic and hyper-volemic hypernatremia.101
Table 14-15 Diagnostic Criteria for Syndrome of Inappropriate Antidiuretic Hormone Secretion
Neurologic symptoms or profound hyponatremia ([Na+] <115 to 120 mEq/L) requires more aggressive therapy. Hypertonic (3%) saline is most clearly indicated in patients who have seizures or patients who acutely develop symptoms of water intoxication secondary to intravenous fluid administration. In such cases, 3% saline may be administered at a rate of 1 to 2 mL/kg/hr, to increase plasma [Na+] by 1 to 2 mEq/L/hr; however, this treatment should not continue for more than a few hours. Three percent saline may only transiently increase plasma [Na+] because ECV expansion results in increased urinary sodium excretion. Intravenous furosemide, combined with quantitative replacement of urinary sodium losses with 0.9% or 3.0% saline, can rapidly increase plasma [Na+], in part by increasing free water clearance.
The rate of treatment of hyponatremia continues to generate controversy, extending from “too fast, too soon” to “too slow, too late.” Although delayed correction may result in neurologic injury, inappropriately rapid correction may result in abrupt brain dehydration (Fig. 14-8) or permanent neurologic sequelae (i.e., osmotic demyelination syndrome),103cerebral hemorrhage, or congestive heart failure. The symptoms of the osmotic demyelination syndrome vary from mild (transient behavioral disturbances or seizures) to severe (including pseudobulbar palsy and quadriparesis).
The principal determinants of neurologic injury appear to be the magnitude and chronicity of hyponatremia and the rate of correction. The osmotic demyelination syndrome is more likely when hyponatremia has persisted >48 hours. Most patients in whom the osmotic demyelination syndrome is fatal have undergone correction of plasma [Na+] of more than 20 mEq/L/day. Other risk factors for the development of the osmotic demyelination syndrome include alcoholism, poor nutritional status, liver disease, burns, and hypokalemia.
Figure 14-7. Hyponatremia is treated according to the etiology of the disturbance, the level of serum osmolality, and a clinical estimation of total body sodium.
Figure 14-8. Brain water and solute in concentrations in hyponatremia. If normal plasma sodium (Na; A) suddenly decreased, the increase in brain water theoretically would be proportional to the decrease in plasma Na (B). However, because of adaptive loss of cerebral intracellular solute, cerebral edema is minimized in chronic hyponatremia (C). Once adaptation has occurred, a rapid return of plasma Na concentration toward a normal level results in brain dehydration (D). (From Sterns RH: Vignettes in clinical pathophysiology. Neurological deterioration following treatment for hyponatremia. Am J Kidney Dis 1989; XIII: 434–437, with permission.)
The clinician faces formidable difficulties in predicting the rate at which plasma [Na+] will increase because increases in plasma [Na+] are determined both by the composition of the infused fluid and by the rate of renal free water excretion. The expected change in plasma [Na+] resulting from 1 L of selected infusate can be estimated using the following equation104:
where Δ[Na+]s = the change in the patient's serum [Na+], [Na+]inf = [Na+] of the infusate, [Na+]s = the patient's serum [Na+], TBW = the patient's estimated total body water in liters, and 1 = a factor added to take into account the volume of infusate.
Treatment should be interrupted or slowed when symptoms improve. Frequent determinations of [Na+] are important to prevent correction at a rate >1 to 2 mEq/L in any 1 hour and >8 mEq/L in 24 hours.105 Initially, plasma [Na+] may be increased by 1 to 2 mEq/L/hr; however, the rate of correction should then be slowed to avoid excessively rapid correction. Hypernatremia should be avoided. Once plasma [Na+] exceeds 120 to 125 mEq/L, water restriction alone is usually sufficient to normalize [Na+]. As acute hyponatremia is corrected, central nervous system signs and symptoms usually improve within 24 hours, although 96 hours may be necessary for maximal recovery.
For patients who require long-term pharmacologic therapy of hyponatremia, demeclocycline is currently the drug of choice.106 Although better tolerated than lithium, demeclocycline may induce nephrotoxicity, a particular concern in patients with hepatic dysfunction. Hemodialysis is occasionally necessary in severely hyponatremic patients who cannot be adequately managed with drugs or hypertonic saline. Once hyponatremia has improved, careful fluid restriction is necessary to avoid recurrence of hyponatremia. In the future, oral receptor antagonists may be used to treat chronic hyponatremia.
Figure 14-9. Severe hypernatremia is evaluated by first separating patients into hypovolemic, euvolemic, and hypervolemic groups based on assessment of extracellular volume (ECV). Next, potential etiologic factors are diagnostically assessed. [Na+], serum sodium concentration; UNa, urinary sodium concentration; UOSm, urinary osmolality.
Hypernatremia ([Na+] >150 mEq/L) indicates an absolute or relative water deficit. Normally, slight increases in tonicity or [Na+] stimulate thirst and AVP secretion. Therefore, severe, persistent hypernatremia occurs only in patients who cannot respond to thirst by voluntary ingestion of fluid, that is, obtunded patients, anesthetized patients, and infants.
Hypernatremia produces neurologic symptoms (including stupor, coma, and seizures), hypovolemia, renal insufficiency (occasionally progressing to renal failure), and decreased urinary concentrating ability. Because hypernatremia frequently results from diabetes insipidus (DI) or osmotically induced losses of sodium and water, many patients are hypovolemic or bear the stigmata of renal disease. Postoperative neurosurgical patients who have undergone pituitary surgery are at particular risk of developing transient or prolonged DI. Polyuria may be present for only a few days within the first week of surgery, may be permanent, or may demonstrate a triphasic sequence: early DI, return of urinary concentrating ability, then recurrent DI.107
The clinical consequences of hypernatremia are most serious at the extremes of age and when hypernatremia develops abruptly. Geriatric patients are at increased risk of hypernatremia because of decreased renal concentrating ability and decreased thirst. Brain shrinkage secondary to rapidly developing hypernatremia may damage delicate cerebral vessels, leading to subdural hematoma, subcortical parenchymal hemorrhage, subarachnoid hemorrhage, and venous thrombosis. Polyuria may cause bladder distention, hydronephrosis, and permanent renal damage. Although the mortality of hypernatremia is 40 to 55%, it is unclear whether hypernatremia contributes to mortality or is simply a marker of severe associated disease.
Surprisingly, if plasma [Na+] is initially normal, moderate acute increases in plasma [Na+] do not appear to precipitate central pontine myelinolysis. However, larger accidental increases in plasma [Na+] have produced severe consequences in children. In experimental animals, acute severe hypernatremia (acute increase from 146 to 170 mEq/L) caused neuronal damage at 24 hours, suggestive of early central pontine myelinolysis.108
By definition, hypernatremia indicates an absolute or relative water deficit and is always associated with hypertonicity. Hypernatremia can be generated by hypotonic fluid loss, as in burns, gastrointestinal losses, diuretic therapy, osmotic diuresis, renal disease, mineralocorticoid excess or deficiency, and iatrogenic causes or can be generated by isolated water loss, as in central or nephrogenic DI. The acquired form of
nephrogenic DI is more common and usually less severe than the congenital form. As chronic renal failure advances, most patients have defective concentrating ability, resulting in resistance to AVP associated with hypotonic urine. Because hypo-volemia accompanies most pathologic water loss, signs of hypoperfusion also may be present. In many patients, before the development of hypernatremia, an increased volume of hypotonic urine suggests an abnormality in water balance. Although uncommon as a cause of hypernatremia, isolated sodium gain occasionally occurs in patients who receive large quantities of sodium, such as treatment of metabolic acidosis with 8.4% sodium bicarbonate, in which [Na+] is approximately 1,000 mEq/L, or perioperative or prehospital treatment with hypertonic saline resuscitation solutions.
Hypernatremic patients can be separated into three groups, based on clinical assessment of ECV (Fig. 14-9). Note that plasma [Na+] does not reflect total body sodium, which must be estimated separately based on signs of the adequacy of ECV. Polyuric, hypernatremic patients may be undergoing solute diuresis or may have DI. Measurement of urinary sodium and osmolality can help to differentiate the various causes. A urinary osmolality <150 mOsm/kg in the setting of hypertonicity and polyuria is diagnostic of DI.
Treatment of hypernatremia produced by water loss requires repletion of water as well of associated deficits in total body sodium and other electrolytes (Table 14-16). Common errors in treating hypernatremia include excessively rapid correction as well as failing to appreciate the magnitude of the water deficit and failing to account for ongoing maintenance requirements and continued fluid losses in planning therapy.
The first step in treating hypernatremia is to estimate the TBW deficit, which can be accomplished by inserting the measured plasma [Na+] into the equation:
where 140 is the middle of the normal range for [Na+]. Adrogue and Madias109 proposed an equation (see Eq. 14-12) that can be used in hypernatremic patients as it can be in hyponatremic patients to predict the expected decrease in serum [Na+] produced by infusion of 1 L of infusate.104 The accuracy of this equation has recently been validated in a large clinical series of hypernatremic and hyponatremic patients.110
Table 14-16 Hypernatremia: Acute Treatment
Figure 14-10. A. The concentration of sodium is reflected in the intensity of the stippling: the upper figure, representing extracellular volume (smaller circle) and intracellular volume (larger circle), is more heavily stippled, that is, serum sodium is higher. B. In response to an acute increase in serum sodium resulting from water loss, both intracellular and extracellular volume substantially decrease. The brain (schematically illustrated) shrinks in proportion to the reduction in intracellular volume in other tissues. C. However, owing to the production of idiogenic osmoles, the brain rapidly restores its intracellular volume, despite the persistent reduction in intracellular volume in other tissues and in extracellular volume. D. With excessively rapid correction of hypernatremia (the reduction in serum sodium is reflected in the decrease in the intensity of stippling), the brain expands to greater than its original size. The resulting increase in cerebral edema and intracranial pressure can cause severe neurologic damage. (Modified from Feig PU: Hypernatremia and hypertonic syndromes. Med Clin North Am 1981; 65: 271–290, with permission.)
Hypernatremia must be corrected slowly because of the risk of neurologic sequelae such as seizures or cerebral edema (Fig. 14-10). At the cellular level, restoration of cell volume occurs remarkably quickly after tonicity is altered; as a consequence, acute treatment of hypertonicity may result in overshooting the original, normotonic cell volume. The water deficit should be replaced over 24 to 48 hours, and the plasma [Na+] should not be reduced by more than 1 to 2 mEq/L/hr. Reversible underlying causes should be treated. Hypovolemia should be corrected promptly with 0.9% saline. Although the
[Na+] of 0.9% saline is 154 mEq/L, the solution is effective in treating volume deficits and will reduce [Na+] that exceeds 154 mEq/L in hypovolemic hypernatremic patients. Once hypovolemia is corrected, water can be replaced orally or with intravenous hypotonic fluids, depending on the ability of the patient to tolerate oral hydration. In the occasional sodium-overloaded patient, sodium excretion can be accelerated using loop diuretics or dialysis.
The management of hypernatremia secondary to DI varies according to whether the cause is central or nephrogenic (see Table 14-16). The two most suitable agents for correcting central DI (an AVP deficiency syndrome) are desmopressin (DDAVP) and aqueous vasopressin. DDAVP, given subcutaneously in a dose of 1 to 4 µg or intranasally in a dose of 5 to 20 µg every 12 to 24 hours, is effective in most patients. DDAVP is preferred because it has a longer duration of action than AVP and lacks vasoconstrictor effects.111 Incomplete AVP deficits (partial DI) often are effectively managed with pharmacologic agents that stimulate AVP release or enhance the renal response to AVP. Chlorpropamide, which potentiates the renal effects of vasopressin, and carbamazepine, which enhances vasopressin secretion, have been used to treat partial central DI, but are associated with clinically important side effects. In nephrogenic DI, salt and water restriction or thiazide diuretics induce contraction of ECV, thereby enhancing fluid reabsorption in the proximal tubules. If less filtrate passes through into the collecting ducts, less water will be excreted.
Potassium plays an important role in cell membrane physiology, especially in maintaining resting membrane potentials and in generating action potentials in the central nervous system and heart. Potassium is actively transported into cells by a Na/K adenosine triphosphatase (ATPase) pump, which maintains an intracellular [K+] that is at least 30-fold greater than extracellular [K+]. Intracellular potassium concentration ([K+]) is normally 150 mEq/L while the extracellular concentration is only 3.5 to 5.0 mEq/L. Serum [K+] measures about 0.5 mEq/L higher than plasma [K+] because of cell lysis during clotting. Total body potassium in a 70-kg adult is approximately 4,256 mEq, of which 4,200 mEq is intracellular; of the 56 mEq in the ECV, only 12 mEq is located in the PV. The ratio of intracellular to extracellular potassium contributes to the resting potential difference across cell membranes and therefore to the integrity of cardiac and neuromuscular transmission. The primary mechanism that maintains potassium inside cells is the negative voltage created by the transport of three sodium ions out of the cell for every two potassium ions transported in. Both insulin and β agonists promote potassium entry into cells.112,113 Metabolic and respiratory acidosis tends to shift potassium out of cells, while metabolic and respiratory alkalosis favors movement into cells.
Usual potassium intake varies between 50 and 150 mEq/day. Freely filtered at the glomerulus, most potassium excretion is urinary, with some fecal elimination. Most filtered potassium is reabsorbed; usually, excretion is approximately equal to daily intake. As long as GFR is >8 mL/min, dietary potassium intake, unless greater than normal, can be excreted. Assuming a plasma [K+] of 4.0 mEq/L and a normal GFR of 180 L/day, 720 mEq of potassium is filtered daily, of which 85 to 90% is reabsorbed in the proximal convoluted tubule and loop of Henle. The remaining 10 to 15% reaches the distal convoluted tubule, which is the major site at which potassium excretion is regulated. Excretion of potassium ions is a function of open potassium channels and the electrical driving force in the cortical collecting duct.
The two most important regulators of potassium excretion are plasma [K+] and aldosterone. Potassium secretion into the distal convoluted tubules and cortical collecting ducts is increased by hyperkalemia, aldosterone, alkalemia, increased delivery of Na+ to the distal tubule and collecting duct, high urinary flow rates, and the presence in luminal fluid of nonreabsorbable anions such as carbenicillin, phosphates, and sulfates. As sodium reabsorption increases, the electrical driving force opposing reabsorption of potassium is increased. Aldosterone increases sodium reabsorption by inducing a more open configuration of the epithelial sodium channel; potassium-sparing diuretics (amiloride and triamterene) and trimethoprim block the epithelial sodium channel, thereby increasing potassium reabsorption. Magnesium depletion contributes to renal potassium wasting.
Uncommon among healthy persons, hypokalemia ([K+] <3.5 mEq/L) is a frequent complication of treatment with diuretic drugs and occasionally complicates other diseases and treatment regimens (Table 14-17). Plasma [K+] poorly reflects
total body potassium; hypokalemia may occur with normal, low, or high total body potassium. However, as a general rule, a chronic decrement of 1.0 mEq/L in the plasma [K+] corresponds to a total body deficit of approximately 200 to 300 mEq. In uncomplicated hypokalemia, the total body potassium deficit exceeds 300 mEq if plasma [K+] is <3.0 mEq/L and 700 mEq if plasma [K+] is <2.0 mEq/L.
Table 14-17 Causes of Renal Potassium Loss
The symptoms and signs of hypokalemia primarily relate to neuromuscular and cardiovascular function. Hypokalemia causes muscle weakness and, when severe, may even cause paralysis. With chronic potassium loss, the ratio of intracellular to extracellular [K+] remains relatively stable; in contrast, acute redistribution of potassium from the extracellular to the intracellular space substantially changes resting membrane potentials. Cardiac rhythm disturbances are among the most dangerous complications of potassium deficiency. Acute hypokalemia causes hyperpolarization of the cardiac cell and may lead to ventricular escape activity, re-entrant phenomena, ectopic tachycardias, and delayed conduction. In patients treated with digoxin, hypokalemia increases toxicity by increasing myocardial digoxin binding and pharmacologic effectiveness. Hypokalemia contributes to systemic hypertension, especially when combined with a high-sodium diet. In diabetic patients, hypokalemia impairs insulin secretion and end-organ sensitivity to insulin. Although no clear threshold has been defined for a level of hypokalemia below which safe conduct of anesthesia is compromised, [K+] <3.5 mEq/L in cardiac surgical patients has been associated with an increased incidence of perioperative dysrhythmias, especially atrial fibrillation/flutter.114
Potassium depletion also induces defects in renal concentrating ability, resulting in polyuria and a reduction in GFR. Potassium replacement improves GFR, although the concentrating deficit may not improve for several months after treatment. If hypokalemia is sufficiently prolonged, chronic renal interstitial damage may occur. In experimental animals, hypokalemia was associated with intrarenal vasoconstriction and a pattern of renal injury similar to that produced by ischemia.115
Figure 14-11. A diagnostic flow chart for hypokalemia with a high rate of K+ excretion. ECF, extracellular fluid. (From Lin SH, Halperin ML: Hypokalemia: a practical approach to diagnosis and its genetic basis. Curr Med Chem 2007; 14: 1551–1565, with permission.)
Hypokalemia may result from chronic depletion of total body potassium or from acute redistribution of potassium from the ECV to the ICV. Redistribution of potassium into cells occurs when the activity of the sodium-potassium ATPase pump is acutely increased by extracellular hyperkalemia or increased intracellular concentrations of sodium, as well as by insulin, carbohydrate loading (which stimulates release of endogenous insulin), β2 agonists, and aldosterone. Both metabolic and respiratory alkalosis lead to decreases in plasma [K+].
Causes of chronic hypokalemia include those etiologies associated with renal potassium conservation (extrarenal potassium losses; low urinary [K+]) and those with renal potassium wasting (Fig. 14-11).116 A low urinary [K+] suggests inadequate dietary intake or extrarenal depletion (in the absence of recent diuretic use). Diuretic-induced urinary potassium losses are frequently associated with hypokalemia, secondary to increased aldosterone secretion, alkalemia, and increased renal tubular flow. Aldosterone does not cause renal potassium wasting unless sodium ions are present; that is, aldosterone primarily controls sodium reabsorption, not potassium excretion. Renal tubular damage due to nephrotoxins such as aminoglycosides or amphotericin B may also cause renal potassium wasting.
Initial evaluation of hypokalemia includes a medical history (e.g., diarrhea, vomiting, diuretic or laxative use), physical
examination (e.g., hypertension, cushingoid features, edema), measurement of serum electrolytes (e.g., magnesium), arterial pH assessment, and evaluation of the electrocardiogram (ECG). Measurement of 24-hour urinary excretion of sodium and potassium may distinguish extrarenal from renal causes. Magnesium deficiency, associated with aminoglycoside and cisplatin therapy, can generate hypokalemia that is resistant to replacement therapy. Plasma renin and aldosterone levels may be helpful in the differential diagnosis of hypokalemia of unclear origin, especially if primary hyperaldosteronism is suspected.117 Characteristic electrocardiographic changes associated with hypokalemia include flat or inverted T waves, prominent U waves, and ST segment depression.
Table 14-18 Hypokalemia: Treatment
The treatment of hypokalemia consists of potassium repletion, correction of alkalemia, and removal of offending drugs (Table 14-18). Hypokalemia secondary only to acute redistribution (e.g., secondary to acute alkalemia) may not require treatment. There is no urgent need for potassium replacement therapy in mild-to-moderate hypokalemia (3 to 3.5 m Eq/L) in patients who have no symptoms. If total body potassium is decreased, oral potassium supplementation is preferable to intravenous replacement. Potassium is usually replaced as the chloride salt because coexisting chloride deficiency may limit the ability of the kidney to conserve potassium.
Intravenous potassium repletion, when necessary, must be performed cautiously (i.e., usually at a rate ≤10 to 20 mEq/hr) because the magnitude of potassium deficits is unpredictable. The plasma [K+] and the ECG must be monitored during rapid repletion (10 to 20 mEq/hr) to avoid hyperkalemic complications. The plasma [K+] and ECG should be monitored to detect inadvertent hyperkalemia. Particular care should be taken in patients who have concurrent acidemia, type IV renal tubular acidosis, diabetes mellitus, or in those patients receiving nonsteroidal anti-inflammatory agents, ACE inhibitors, or β2 blockers, all of which delay movement of extracellular potassium into cells. Beta1-blockers do not delay movement of extracellular potassium into cells or predispose patients to hyperkalemia.118
However, in patients with life-threatening dysrhythmias secondary to hypokalemia, serum [K+] must be rapidly increased. Assuming that PV in a 70-kg adult is 3.0 L, administration of 6.0 mEq/L of potassium in 1.0 minute will acutely increase serum [K+] by no more than 2.0 mEq/L because redistribution into interstitial fluid and intracellular volume will decrease the quantity remaining in the plasma volume.
Hypokalemia associated with hyperaldosteronemia (e.g., primary aldosteronism, Cushing syndrome) usually responds favorably to reduced sodium intake and increased potassium intake. Hypomagnesemia, if present, aggravates the effects of hypokalemia, impairs potassium conservation, and should be treated. Potassium supplements or potassium-sparing diuretics should be given cautiously to patients who have diabetes mellitus or renal insufficiency, which limit compensation for acute hyperkalemia. In patients such as those who have diabetic ketoacidosis, who are both hypokalemic and acidemic, potassium administration should precede correction of acidosis to avoid a precipitous decrease in plasma [K+] as pH increases.
In patients with normal serum potassium accompanied by symptoms of potassium depletion (e.g., muscle fatigue), history of potassium loss or insufficient intake, or in patients in whom potassium depletion may be of special threat (e.g., patients on diuretics, digitalis, or β2 agonists), muscle biopsy with measurement of muscle potassium concentration may be a useful procedure to detect and quantify potassium depletion.
The most lethal manifestations of hyperkalemia ([K+] >5.0 mEq/L) involve the cardiac conducting system and include dysrhythmias, conduction abnormalities, and cardiac arrest. In anesthesia practice, the classic example of hyperkalemic cardiac toxicity is associated with the administration of succinylcholine to paraplegic, quadriplegic or severely burned119patients. If plasma [K+] is <6.0 mEq/L, cardiac effects are negligible. As the concentration increases further, the electrocardiogram shows tall, peaked T waves, especially in the precordial leads. With further increases, the PR interval becomes prolonged, followed by a decrease in the amplitude of the P wave. Finally, the QRS complex widens into a pattern resembling a sine wave, as a prelude to cardiac standstill (Fig. 14-12).112 Hyperkalemic cardiotoxicity is enhanced by hyponatremia, hypocalcemia, or acidosis. Because progression to fatal cardiotoxicity is unpredictable and often swift, the presence of hyperkalemic ECG changes mandates immediate therapy. The life-threatening cardiac effects usually require more urgent treatment than other manifestations of hyperkalemia. However, ascending muscle weakness appears when plasma [K+] approaches 7.0 mEq/L, and may progress to flaccid paralysis, inability to phonate, and respiratory arrest.
The most important diagnostic issues are medical history, emphasizing recent drug therapy, and assessment of renal function. Although the ECG may provide the first suggestion of hyperkalemia in some patients, and despite the well-described effects of hyperkalemia on cardiac conduction and rhythm, the ECG is an insensitive and nonspecific method of detecting hyperkalemia. If hyponatremia is also present, adrenal function should be evaluated.
Hyperkalemia may occur with normal, high, or low total body potassium stores. A deficiency of aldosterone, a major regulator of potassium excretion, leads to hyperkalemia in adrenal insufficiency and hyporeninemic hypoaldosteronism, a state associated with diabetes mellitus, renal insufficiency, and advanced age. Because the kidneys excrete potassium, severe renal insufficiency commonly causes hyperkalemia. Patients with chronic renal insufficiency can maintain normal plasma [K+] despite markedly decreased GFR because urinary potassium excretion depends on tubular secretion rather than glomerular filtration if GFR exceeds 8 mL/min.
Drugs are now the most common cause of hyperkalemia, especially in elderly patients. Drugs that may limit potassium excretion include nonsteroidal anti-inflammatory drugs, ACE inhibitors, cyclosporin, and potassium-sparing diuretics such as triamterene. Drug-induced hyperkalemia most commonly occurs in patients with other predisposing factors, such as diabetes mellitus, renal insufficiency, advanced age, or hyporeninemic hypoaldosteronism. ACE inhibitors are
particularly likely to produce hyperkalemia in patients who have congestive heart failure.120
Figure 14-12. Electrocardiographic (ECG) manifestations of hyperkalemia. (From Sood MM, Sood AR, Richardson R: Emergency management and commonly encountered outpatient scenarios in patients with hyperkalemia. Mayo Clin Proc 2007; 82: 1553–1561, with permission.)
In patients who have normal total body potassium, hyperkalemia may accompany a sudden shift of potassium from the ICV to the ECV because of acidemia, increased catabolism, or rhabdomyolysis. Metabolic acidosis and respiratory acidosis tend to cause an increase in plasma [K+]. However, organic acidoses (i.e., lactic acidosis, ketoacidosis) have little effect on [K+], whereas mineral acids cause significant cellular shifts. In response to increased hydrogen ion activity because of addition of acids, potassium will increase if the anion remains in the extracellular volume. Neither lactate nor ketoacids remain in the extracellular fluid. Therefore, hyperkalemia in these circumstances reflects tissue injury or lack of insulin. Pseudohyperkalemia, which occurs when potassium is released from cells in blood collection tubes, can be diagnosed by comparing serum and plasma K+ levels from the same blood sample. Hyperkalemia usually accompanies malignant hyperthermia.
The treatment of hyperkalemia is aimed at eliminating the cause, reversing membrane hyperexcitability, and removing potassium from the body (Fig. 14-13).112,113,120,121Mineralocorticoid deficiency can be treated with 9-α-fludrocortisone (0.025 to 0.10 mg/day). Hyperkalemia secondary to digitalis intoxication may be resistant to therapy because attempts to shift potassium from the ECV to the ICV are often ineffective. In this situation, use of digoxin-specific antibodies has been successful.
Emergent management of severe hyperkalemia is described in detail in Table 14-19. Membrane hyperexcitability can be antagonized by translocating potassium from the ECV to the ICV, removing excess potassium, or (transiently) by infusing calcium chloride to depress the membrane threshold potential. Pending definitive treatment, rapid infusion of calcium chloride (1 g of CaCl2 over 3 minutes, or two to three ampules of 10% calcium gluconate over 5 minutes) may stabilize cardiac rhythm (Table 14-19). Calcium should be given cautiously if digitalis intoxication is likely. Insulin, in a dose-dependent fashion, causes cellular uptake of potassium by increasing the activity of the sodium/potassium ATPase pump. Insulin increases cellular uptake of potassium best when high insulin levels are achieved by intravenous injection of 5 to 10 units of regular insulin, accompanied by 50 mL of 50% glucose.112,120 β2-Adrenergic drugs such as salbutamol and albuterol also increase potassium uptake by skeletal muscle and reduce plasma [K+], an action that may explain hypokalemia with severe, acute illness. Salbutamol, a selective β2 agonist, decreases serum potassium acutely by 1 mEq/L or more when given by inhalation or intravenously, although cardiac dysrhythmias may occasionally complicate treatment with selective β2 agonists.112 Although administration of sodium bicarbonate has long been considered a part of the treatment of hyperkalemia, bicarbonate, when used alone, is relatively ineffective and is no longer favored.120
Potassium may be removed from the body by the renal or gastrointestinal routes. Furosemide promotes kaliuresis in a dose-dependent fashion. Sodium polystyrene sulfonate resin (Kayexalate), which exchanges sodium for potassium, can be given orally (30 g) or as a retention enema (50 g in 200 mL of 20% sorbitol). However, sodium overload and hypervolemia are potential risks. Rarely, when temporizing measures are insufficient, emergency hemodialysis may remove 25 to 50 mEq/hr. Peritoneal dialysis is less efficient.
Calcium is a divalent cation found primarily in the extracellular fluid. The free calcium concentration [Ca2+] in ECV is approximately 1 mM, whereas the free [Ca2+] in the ICV approximates 100 mM, a gradient of 10,000 to 1. Circulating calcium consists of a protein-bound fraction (40 to 50%), a fraction bound to inorganic anions (10 to 15%), and an ionized fraction (45 to 50%), which is the physiologically active and homeostatically regulated component. Acute acidemia increases and acute alkalemia decreases ionized calcium.122
Because mathematical formulae that “correct” total calcium measurements for albumin concentration are inaccurate in critically ill patients,123 ionized calcium should be directly measured.
Figure 14-13. Algorithmic management of hyperkalemia. ECG, electrocardiographic; IV, intravenous; K, potassium; ECF, extracellular fluid; ICF, intracellular fluid; MDI, metered-dose inhaler; NaCl, sodium chloride. (From Sood MM, Sood AR, Richardson R: Emergency management and commonly encountered outpatient scenarios in patients with hyperkalemia. Mayo Clin Proc 2007; 82: 1553–1561, with permission.)
In general, calcium is essential for all movement that occurs in mammalian systems. Essential for normal excitation-contraction coupling, calcium is also necessary for proper function of muscle tissue, ciliary movement, mitosis, neurotransmitter release, enzyme secretion, and hormonal secretion. Cyclic adenosine monophosphate (cAMP) and phosphoinositides, which are major second messengers regulating cellular metabolism, function primarily through the regulation of calcium movement. Activation of numerous intracellular enzyme systems requires calcium. Calcium is important both for generation
of the cardiac pacemaker activity and for generation of the cardiac action potential and therefore is the primary ion responsible for the plateau phase of the action potential. Calcium also plays vital functions in membrane and bone structure.
Table 14-19 Severe Hyperkalemiaa Treatment
Serum [Ca2+] is regulated by multiple factors (Fig. 14-14),124 including a calcium receptor124,125 and several hormones. Parathyroid hormone (PTH) and calcitriol, the most important neurohumoral mediators of serum [Ca2+],126 mobilize calcium from bone, increase renal tubular reabsorption of calcium, and enhance intestinal absorption of calcium. Vitamin D, after ingestion or cutaneous manufacture under the stimulus of ultraviolet light, is 25-hydroxylated to calcidiol in the liver and then is 1-hydroxylated to calcitriol, the active metabolite, in the kidney. Even in the absence of dietary calcium intake, PTH and vitamin D can maintain a normal circulating [Ca2+] by mobilizing calcium from bone. In addition to the key roles played by PTH and calcitriol in regulating serum [Ca2+], other recently described pathways play key molecular roles in bone resorption. The receptor activator of nuclear factor κB (RANK), RANK ligand (RANKL), and osteoprotegenerin play key molecular roles; binding of RANKL to RANK stimulates osteoclast activity, whereas binding of RANKL to osteoprogenerin, a soluble decoy receptor, disrupts binding to RANK.127
Figure 14-14. Schematic representation of the regulatory system maintaining Ca2+ homeostasis. The solid arrows and lines delineate effects of parathyroid hormone (PTH) and 1,25 (OH)2D3 (dihydroxyvitamin D) on their target tissues; dashed arrows and lines show examples of how extracellular Ca2+ or phosphate ions act directly on tissues regulating mineral ion metabolism. Ca, calcium; PO4, phosphate; ECF, extracellular fluid; cAMP, cyclic adenosine monophosphate; 25(OH)D = 25-hydroxyvitamin D; negative signs indicate inhibitory actions and plus signs indicate stimulatory effects. (Reprinted with permission from Brown EM, Pollak M, Hebert SC: The extracellular calcium-sensing receptor: its role in health and disease. Ann Rev Med 1998; 49: 15–29).
Hypocalcemia (ionized [Ca2+] <4.0 mg/dL or <1.0 mmol/L) occurs as a result of failure of PTH or calcitriol action or because of calcium chelation or precipitation, not because of calcium deficiency alone. PTH deficiency can result from surgical damage or removal of the parathyroid glands or from suppression of the parathyroid glands by severe hypo- or hypermagnesemia. Burns, sepsis, and pancreatitis may suppress parathyroid function and interfere with vitamin D action. Vitamin D deficiency may result from lack of dietary vitamin D or vitamin D malabsorption in patients who lack sunlight exposure. Hyperphosphatemia-induced hypocalcemia
may occur as a consequence of overzealous phosphate therapy, from cell lysis secondary to chemotherapy, or as a result of cellular destruction from rhabdomyolysis. Precipitation of CaHPO4 complexes occurs with hyperphosphatemia. However, ionized [Ca2+] only decreases approximately 0.019 mM for each 1.0 mM increase in phosphate concentration. In massive transfusion, citrate may produce hypocalcemia by chelating calcium; however, decreases are usually transient and produce negligible cardiovascular effects, unless citrate clearance is decreased (e.g., by hepatic or renal disease or hypothermia) or blood transfusion exceeds 5 units of packed red blood cells.128 Alkalemia resulting from hyperventilation or sodium bicarbonate injection can acutely decrease [Ca2+].
Table 14-20 Hypocalcemia: Clinical Manifestations
The hallmark of hypocalcemia is increased neuronal membrane irritability and tetany (Table 14-20). Early symptoms include sensations of numbness and tingling involving fingers, toes, and the circumoral region. In frank tetany, tonic contraction of respiratory muscles may lead to laryngospasm, bronchospasm, or respiratory arrest. Smooth muscle spasm can result in abdominal cramping and urinary frequency. Mental status alterations include irritability, depression, psychosis, and dementia. Hypocalcemia may impair cardiovascular function and has been associated with heart failure, hypotension, dysrhythmias, insensitivity to digitalis, and impaired β-adrenergic action.
Reduced ionized serum calcium occurs in as many as 88% of critically ill patients, 66% of less severely ill intensive care unit patients and 26% of hospitalized non–intensive care unit patients.129 Patients at particular risk include patients after multiple trauma and cardiopulmonary bypass. In most such patients, ionized hypocalcemia is clinically mild ([Ca2+] 0.8 to 1.0 mmol/L).
Initial diagnostic evaluation should concentrate on history and physical examination, laboratory evaluation of renal function, and measurement of serum phosphate concentration. Latent hypocalcemia can be diagnosed by tapping on the facial nerve to elicit Chvostek sign or by inflating a sphygmomanometer to 20 mm Hg above systolic pressure, which produces radial and ulnar nerve ischemia and causes carpal spasm known as Trousseau sign. The differential diagnosis of hypocalcemia can be approached by addressing four issues: age of the patient, serum phosphate concentration, general clinical status, and duration of hypocalcemia.130 Low or normal phosphate concentrations imply vitamin D or magnesium deficiency. An otherwise healthy patient with chronic hypocalcemia probably is hypoparathyroid. High phosphate concentrations suggest renal failure or hypoparathyroidism. In renal insufficiency, reduced phosphorus excretion results in hyperphosphatemia, which down-regulates the 1α-hydroxylase responsible for the renal conversion of calcidiol to calcitriol. This, in combination with decreased production of calcitriol secondary to reduced renal mass, causes reduced intestinal absorption of calcium and hypocalcemia.126 Chronically ill adults with hypocalcemia often have disorders such as malabsorption, osteomalacia, or osteoblastic metastases.
Table 14-21 Hypocalcemia: Acute Treatment
The definitive treatment of hypocalcemia necessitates identification and treatment of the underlying cause (Table 14-21). Symptomatic hypocalcemia usually occurs when serum ionized [Ca2+] is <0.7 mM.
Unnecessary offending drugs should be discontinued. Hypocalcemia resulting from hypomagnesemia or hyperphosphatemia is treated by repletion of magnesium or removal of phosphate. Treatment of a patient who has tetany and hyperphosphatemia requires coordination of therapy to avoid the consequences of metastatic soft-tissue calcification.131Potassium and other electrolytes should be measured and abnormalities should be corrected. Hyperkalemia and hypomagnesemia potentiate hypocalcemia-induced cardiac and neuromuscular irritability. In contrast, hypokalemia protects against hypocalcemic tetany; therefore, correction of hypokalemia without correction of hypocalcemia may provoke tetany.
Mild, ionized hypocalcemia should not be overtreated. For instance, in most patients after cardiac surgery, administration of calcium only increases blood pressure and actually attenuates the β-adrenergic effects of epinephrine. In normocalcemic dogs, calcium chloride primarily acts as a peripheral vasoconstrictor, with transient reduction of myocardial contractility; in hypocalcemic dogs, calcium infusion significantly improves contractile performance and blood pressure.132 Therefore, calcium infusions should be of limited value in surgical patients unless there is demonstrable evidence of ionized hypocalcemia. Calcium salts appear to confer no benefit to patients already receiving inotropic or vasoactive agents.
The cornerstone of therapy for confirmed, symptomatic, ionized hypocalcemia ([Ca2+] <0.7 mM) is calcium administration. In patients who have severe hypocalcemia or hypocalcemic symptoms, calcium should be administered intravenously. In emergency situations, in an averaged-sized adult, the “rule of 10s” advises infusion of 10 mL of 10% calcium gluconate (93 mg elemental calcium) over 10 minutes, followed by a continuous infusion of elemental calcium, 0.3 to 2 mg/kg/hr (i.e., 3 to 16 mL/hr of 10% calcium gluconate for a 70-kg adult). Calcium salts should be diluted in 50 to 100 mL D5W (to limit venous irritation and thrombosis), should not be mixed with bicarbonate (to prevent precipitation), and must be given cautiously to digitalized patients because calcium increases the toxicity of
digoxin. Continuous ECG monitoring during initial therapy will detect cardiotoxicity (e.g., heart block, ventricular fibrillation). During calcium replacement, the clinician should monitor serum calcium, magnesium, phosphate, potassium, and creatinine. Once the ionized [Ca2+] is stable in the range of 4 to 5 mg/dL (1.0 to 1.25 mM), oral calcium supplements can substitute for parenteral therapy. Urinary calcium should be monitored in an attempt to avoid hypercalciuria (>5 mg/kg per 24 hours) and urinary tract stone formation.
When supplementation fails to maintain serum calcium within the normal range, or if hypercalciuria develops, vitamin D or vitamin D analogs may be added. Although the principal effect of vitamin D is to increase enteric calcium absorption, osseous calcium resorption is also enhanced. When rapid changes in dosage are anticipated or an immediate effect is required (e.g., postoperative hypoparathyroidism), shorter-acting calciferols such as dihydrotachysterol may be preferable. Because the effect of vitamin D is not regulated, the dosages of calcium and vitamin D should be adjusted to raise the serum calcium into the low normal range.
Adverse reactions to calcium and vitamin D include hypercalcemia and hypercalciuria. If hypercalcemia develops, calcium and vitamin D should be discontinued and appropriate therapy given. The toxic effects of vitamin D metabolites persist in proportion to their biologic half-lives (ergocalciferol, 20 to 60 days; dihydrotachysterol, 5 to 15 days; calcitriol, 2 to 10 days). Glucocorticoids antagonize the toxic effects of vitamin D metabolites.
Although ionized [Ca2+] most accurately defines hypercalcemia (ionized [Ca2+] >1.5 mmol/L or total serum calcium >10.5 mg/dL), hypercalcemia customarily is discussed in terms of total serum calcium. In hypoalbuminemic patients, total serum calcium can be estimated (albeit inaccurately) by assuming an increase of 0.8 mg/dL for every 1 g/dL of albumin concentration below 4.0 g/dL. Patients in whom total serum calcium is <11.5 mg/dL are usually asymptomatic. Patients with moderate hypercalcemia (total serum calcium 11.5 to 13 mg/dL) may show symptoms of lethargy, anorexia, nausea, and polyuria. Severe hypercalcemia (total serum calcium >13 mg/dL) is associated with more severe neuromyopathic symptoms, including muscle weakness, depression, impaired memory, emotional lability, lethargy, stupor, and coma. The cardiovascular effects of hypercalcemia include hypertension, arrhythmias, heart block, cardiac arrest, and digitalis sensitivity. Skeletal disease may occur secondary to direct osteolysis or humoral bone resorption.
Hypercalcemia impairs urinary concentrating ability and renal excretory capacity for calcium by irreversibly precipitating calcium salts within the renal parenchyma and by reducing renal blood flow and GFR. In response to hypovolemia, renal tubular reabsorption of sodium enhances renal calcium reabsorption. Effective treatment of severe hypercalcemia is necessary to prevent progressive dehydration and renal failure leading to further increases in total serum calcium, because volume depletion exacerbates hypercalcemia.133Hypercalcemia occurs when calcium enters the ECV more rapidly than the kidneys can excrete the excess. Clinically, hypercalcemia most commonly results from an excess of bone resorption over bone formation, usually secondary to malignant disease, hyperparathyroidism, hypocalciuric hypercalcemia, thyrotoxicosis, immobilization, and granulomatous diseases. Granulomatous diseases produce hypercalciuria and hypercalcemia because of conversion by granulomatous tissue of calcidiol to calcitriol.126
Malignancy may produce hypercalcemia either through bone destruction or secretion by malignant tissue of hormones that promote hypercalcemia. Examples of malignancy-associated hormonal effects include secretion by solid tumors of parathormonelike peptides and derangement of the RANKL/osteoprogenerin system in multiple myeloma.134 Primary hyperparathyroidism is associated with weakness, weight loss, and anemia, symptoms that suggest malignancy but may result simply from hyperparathyroidism. Hypercalcemia associated with granulomatous diseases (e.g., sarcoidosis) results from the production of calcitriol by granulomatous tissue. To compensate for increased gut absorption or bone resorption of calcium, renal excretion can readily increase from 100 to more than 400 mg/day. Factors that promote hypercalcemia may be offset by coexisting disorders, such as pancreatitis, sepsis, or hyperphosphatemia, that cause hypocalcemia.
Although definitive treatment of hypercalcemia requires correction of underlying causes, temporizing therapy may be necessary to avoid complications and to relieve symptoms. Total serum calcium exceeding 14 mg/dL represents a medical emergency. General supportive treatment includes hydration, correction of associated electrolyte abnormalities, removal of offending drugs, dietary calcium restriction, and increased physical activity. Because anorexia and antagonism by calcium of ADH action invariably lead to sodium and water depletion, infusion of 0.9% saline will dilute serum calcium, promote renal excretion, and can reduce total serum calcium by 1.5 to 3 mg/dL. Urinary output should be maintained at 200 to 300 mL/hr. As GFR increases, sodium ions increase calcium excretion by competing with calcium ions for reabsorption in the proximal renal tubules and loop of Henle.
Furosemide further enhances calcium excretion by increasing tubular sodium. Patients who have renal impairment may require higher doses of furosemide. During saline infusion and forced diuresis, careful monitoring of cardiopulmonary status and electrolytes, especially magnesium and potassium, is required. Intensive diuresis and saline administration can achieve net calcium excretion rates of 2,000 to 4,000 mg per 24 hours, a rate 8 times greater than saline alone, but still somewhat less than the 6,000 mg every 8 hours that can be removed by hemodialysis. Patients treated with phosphates for hypercalcemia should be well hydrated.
Bone resorption, the primary cause of hypercalcemia, can be minimized by increasing physical activity and initiating drug therapy with biphosphonates, calcitonin, glucocorticoids, or calcimetrics.135 Bisphosphonates, currently the first-line therapy for acute hypercalcemia, inhibit osteoclast function and viability. Bisphosphonates are the principal drugs for the management of hypercalcemia mediated by osteoclastic bone resorption.134 Pamidronate, unlike earlier biphosphonates, does not appear to worsen renal insufficiency. More recently released biphosphonates include alendronate, risedronate. and zoledronate. Risedronate has been associated with less gastrointestinal morbidity than alendronate.136,137 Zoledronate has the most rapid onset of action among the biphosphonates and prolongs the duration before relapse of hypercalcemia; however, zoledronate has been associated with compromised renal function.135 Biphosphonates also are used to control osteoporosis in both men and women.138,139
Calcitonin, usually reserved as a secondary treatment for life-threatening hypercalcemia, lowers serum calcium within 24 to 48 hours and is more effective when combined with glucocorticoids.134,135 Usually calcitonin reduces total serum calcium by only 1 to 2 mg/dL. Although calcitonin is relatively nontoxic, more than 25% of patients may not respond. Thus, calcitonin is unsuitable as a first-line drug during life-threatening hypercalcemia. Hydrocortisone is effective in treating hypercalcemic patients with lymphatic malignancies, vitamin D or A intoxication, and diseases associated with production by tumor or granulomas of 1,25(OH)2D or osteoclast-activating factor. Glucocorticoids rarely improve hypercalcemia secondary to malignancy or hyperparathyroidism.
In the near future, calcimetics may become the treatment of choice for suppressing primary, secondary, and tertiary hyperparathyroidism. With the first agent, cinacalcet, recently released for clinical use in the United States and others undergoing clinical trials, calcimetic agents also reduce inorganic phosphate concentration (Pi) and the calcium × phosphate product.140,141,142 Although hyperparathyroidectomy remains the treatment of choice for primary hyperparathyroidism, calcimetics represent an alternative for patients who are not acceptable candidates for surgery.142 In hyperparathyroidism secondary to chronic renal failure, conventional treatment with calcium supplements, phosphate binders, and vitamin D analogs reduces the associated secondary hyperparathyroidism but also generate undesirable side effects, including hypercalcemia.140 In effect, such patients develop a variation of the milk-alkali syndrome.143 In chronic renal failure patients, calcimetics reduce serum calcium, Pi and the calcium × phosphate product by sensitizing the parathyroid calcium receptor to calcium.141 In addition, calcimetics appear to be effective in tertiary hyperparathyroidism, which develops after renal transplantation in 25 to 50% of renal allograft recipients.142
Phosphates lower serum calcium by causing deposition of calcium in bone and soft tissue. Because the risk of extraskeletal calcification of organs such as the kidneys and myocardium is less if phosphates are given orally, the intravenous route should be reserved for patients with life-threatening hypercalcemia and those in whom other measures have failed.
Phosphorus, in the form of inorganic phosphate (Pi), is distributed in similar concentrations throughout intracellular and extracellular fluid. Of total body phosphorus, 90% exists in bone, 10% is intracellular, and the remainder, <1%, is found in the extracellular fluid. Phosphate circulates as the free ion (55%), complexed ion (33%), and in a protein-bound form (12%). Blood levels vary widely: the normal total Pi ranges from 2.7 to 4.5 mg/dL in adults.
Control of Pi is achieved by altered renal excretion and redistribution within the body compartments. Absorption occurs in the duodenum and jejunum and is largely unregulated. Phosphate reabsorption in the kidney is primarily regulated by PTH, dietary intake, and insulinlike growth factor. Phosphate is freely filtered at the glomerulus and its concentration in the glomerular ultrafiltrate is similar to that of plasma. The filtered phosphate is then reabsorbed in the proximal tubule where it is cotransported with sodium. Proximal tubular reabsorption of phosphorus occurs by passive cotransport with sodium. Cotransport is regulated by phosphorus intake and PTH. Phosphate excretion is increased by volume expansion and decreased by respiratory alkalosis.
Phosphates provide the primary energy bond in ATP and creatine phosphate. Therefore, severe phosphate depletion results in cellular energy depletion. Phosphorus is an essential element of second-messenger systems, including cAMP and phosphoinositides, and a major component of nucleic acids, phospholipids, and cell membranes. As part of 2,3-diphosphoglycerate, phosphate promotes release of oxygen from the hemoglobin molecule. Phosphorus also functions in protein phosphorylation and acts as a urinary buffer.
Hypophosphatemia is characterized by low levels of phosphate-containing cellular components, including ATP, 2,3-diphosphoglycerate, and membrane phospholipids. Serious life-threatening organ dysfunction may occur when the serum Pi falls below 1 mg/dL. Neurologic manifestations of hypophosphatemia include paresthesias, myopathy, encephalopathy, delirium, seizures, and coma.144 Hematologic abnormalities include dysfunction of erythrocytes, platelets, and leukocytes. Because hypophosphatemia limits the chemotactic, phagocytic, and bactericidal activity of granulocytes, associated immune dysfunction may contribute to the susceptibility of hypophosphatemic patients to sepsis.145 Muscle weakness and malaise are common. Respiratory muscle failure and myocardial dysfunction are potential problems of particular concern to anesthesiologists. Rhabdomyolysis is a complication of severe hypophosphatemia.
Common in postoperative and traumatized patients, hypophosphatemia (Pi <2.5 mg/dL) is caused by three primary abnormalities in Pi homeostasis: an intracellular shift of Pi, an increase in renal Pi loss, and a decrease in gastrointestinal Pi absorption. Carbohydrate-induced hypophosphatemia (the “refeeding syndrome”),146 mediated by insulin-induced cellular Pi uptake, is the type most commonly encountered in hospitalized patients. Hypophosphatemia may also occur as catabolic patients become anabolic and during medical management of diabetic ketoacidosis. Acute alkalemia, which may reduce serum Pi to 1 to 2 mg/dL, increases intracellular consumption of Pi by increasing the rate of glycolysis. Hyperventilation significantly reduces Pi and, importantly, the effect is progressive after cessation of hyperventilation.147 Acute correction of respiratory acidemia may also result in severe hypophosphatemia. Respiratory alkalosis probably explains the hypophosphatemia associated with Gram-negative bacteremia and salicylate poisoning. Excessive renal loss of Pi explains the hypophosphatemia associated with hyperparathyroidism, hypomagnesemia, hypothermia, diuretic therapy, and renal tubular defects in Pi absorption. Excess gastrointestinal loss of Pi is most commonly secondary to the use of Pi-binding antacids or to malabsorption syndromes.
Measurement of urinary Pi aids in differentiation of hypophosphatemia due to renal losses from that are due to excessive gastrointestinal losses or redistribution of Pi into cells. Extrarenal causes of hypophosphatemia cause avid renal tubular Pi reabsorption, reducing urinary excretion to <100 mg/day.
Patients who have severe (<1 mg/dL) or symptomatic hypophosphatemia require intravenous phosphate administration (Table 14-22).144,147 In chronically hypophosphatemic patients, 0.2 to 0.68 mmol/kg (5 to 16 mg/kg elemental phosphorus) should be infused over 12 hours. For moderately hypophosphatemic adult patients suffering from critical illness, the use of 15 mmol boluses (465 mg) mixed with 100 mL of 0.9% sodium chloride and given over a 2-hour period safely repletes phosphate.148 The dosage is then adjusted as indicated by the serum Pi level because the cumulative deficit cannot be predicted accurately. Oral therapy can be substituted for parenteral Pi once the serum Pi level exceeds 2.0 mg/dL. Continued therapy with Pi supplements is required for 5 to 10 days in order to replenish body stores.
Table 14-22 Hypophosphatemia: Acute Treatment
Phosphate should be administered cautiously to hypocalcemic patients because of the risk of precipitating more severe hypocalcemia. In hypercalcemic patients, Pi may cause soft-tissue calcification. Phosphorus must be given cautiously to patients with renal insufficiency because of impaired excretory ability. During treatment, close monitoring of serum Pi, calcium, magnesium, and potassium is essential to avoid complications.
The clinical features of hyperphosphatemia (Pi >5.0 mg/dL) relate primarily to the development of hypocalcemia and ectopic calcification. Hyperphosphatemia is caused by three basic mechanisms: inadequate renal excretion, increased movement of Pi out of cells, and increased Pi or vitamin D intake. Rapid cell lysis from chemotherapy, rhabdomyolysis, and sepsis can cause hyperphosphatemia, especially when renal function is impaired. Renal failure is the most common cause of hyperphosphatemia.
Renal excretion of Pi remains adequate until the GFR falls below 20 to 25 mL/min. Accumulation of Pi in patients with chronic renal failure merits the inclusion of Pi as a uremic toxin.149
Measurements of BUN, creatinine, GFR, and urinary Pi are helpful in the differential diagnosis of hyperphosphatemia. Normal renal function accompanied by high Pi excretion (>1,500 mg/day) indicates an oversupply of Pi. An elevated BUN, elevated creatinine, and low GFR suggest impaired renal excretion of Pi. Normal renal function and Pi excretion <1,500 mg/day suggest increased Pi reabsorption (i.e., hypoparathyroidism).
Hyperphosphatemia is corrected by eliminating the cause of the Pi elevation and correcting the associated hypocalcemia. Calcium supplementation of hypocalcemic patients should be delayed until serum phosphate has fallen below 2.0 mmol/L (6.0 mg/dL).126 The serum concentration of Pi is reduced by restricting intake, increasing urinary excretion with saline and acetazolamide (500 mg every 6 hours), and increasing gastrointestinal losses by enteric administration of aluminum hydroxide (30 to 45 mL every 6 hours).
Although calcimetics may replace Pi-binders for managing hyperphosphatemia in patients with chronic renal failure, several remain in common use. Calcium-based binders may contribute to hypercalcemia, sevelamer hydrochloride binds bile acids, and lanthanum carbonate offers the advantage of requiring patients to ingest fewer pills.150 Hemodialysis and peritoneal dialysis are effective in removing Pi in patients who have renal failure.
Magnesium is an important, multifunctional, divalent cation located primarily in the intracellular space. Approximately 50% of the typical adult's 24 g of magnesium is located in bone, 12 g is located intracellularly (approximately one-half or 6 g in muscle), and <1% (<240 mg) of total body magnesium circulates in the serum.151 Of the normal circulating total magnesium concentration (1.5 to 1.9 mEq/L or 0.75 to 0.95 mmol/L or 1.5 to 1.9 mg/dL), there are three components: protein-bound (30%), anion-bound (15%), and ionized (55%), of which only ionized magnesium is active.
Magnesium is necessary for enzymatic reactions involving DNA and protein synthesis, energy metabolism, glucose utilization, and fatty acid synthesis and breakdown.152 As a primary regulator or cofactor in many enzyme systems, magnesium is important for the regulation of the sodium-potassium pump, Ca-ATPase enzymes, adenyl cyclase, proton pumps, and slow calcium channels. Magnesium has been called an endogenous calcium antagonist because regulation of slow calcium channels contributes to maintenance of normal vascular tone, prevention of vasospasm, and perhaps the prevention of calcium overload in many tissues. Because magnesium partially regulates PTH secretion and is important for the maintenance of end-organ sensitivity to both PTH and vitamin D, abnormalities in ionized magnesium concentration ([Mg2+]) may result in abnormal calcium metabolism. Magnesium functions in potassium metabolism primarily through regulating sodium-potassium ATPase, an enzyme that controls potassium entry into cells, especially in potassium-depleted states, and controls reabsorption of potassium by the renal tubules. In addition, magnesium functions as a regulator of membrane excitability and serves as a structural component in both cell membranes and the skeleton.
Because magnesium stabilizes axonal membranes, hypomagnesemia decreases the threshold of axonal stimulation and increases nerve conduction velocity. Magnesium also influences the release of neurotransmitters at the neuromuscular junction by competitively inhibiting the entry of calcium into the presynaptic nerve terminals. The concentration of calcium required to trigger calcium release and the rate at which calcium is released from the sarcoplasmic reticulum are inversely related to the ambient magnesium concentration. Thus, the net effect of hypomagnesemia is muscle that contracts more in response to stimuli and is tetany-prone.
Magnesium is widely available in foods and is absorbed through the gastrointestinal tract, although dietary consumption appears to have decreased over several decades.152 Seventy percent of plasma magnesium is filtered through the glomerular membrane; of the filtered magnesium, 30% is absorbed in the proximal tubule, 60% in the thick ascending loop of Henle, and 10 to 15 % in the distal tubule.151 While both magnesium and Pi are primarily regulated by intrinsic renal mechanisms, PTH exerts a greater effect on renal loss of Pi.
Magnesium has been used to help manage an impressive array of clinical problems in patients who are not hypomagnesemic. Therapeutic hypermagnesemia is used to treat patients with premature labor, pre-eclampsia, and eclampsia. Because magnesium blocks the release of catecholamines from adrenergic nerve terminals and the adrenal glands, magnesium has been used reduce the effects of catecholamine excess in patients with tetanus and pheochromocytoma.153 In patients awaiting liver transplantation, one study showed that administration of magnesium significantly reversed hypocoagulability.154 Although clinical data are inconsistent, magnesium also may exert an analgesic effect on postoperative pain,153,155 perhaps in part due to magnesium's antagonism of the N-methyl-D-aspartate glutamate receptor.153 Magnesium has been proposed as part of an antivasospasm regimen after subarachnoid hemorrhage, but its efficacy may be limited by induction of increasing magnesium levels of hypocalcemia, which in turn could aggravate cerebral vasospasm.156Surprisingly, redistribution of magnesium after subarachnoid hemorrhage has been correlated with ECG changes.157
Magnesium administration may influence dysrhythmias by direct effects on myocardial membranes, by altering cellular potassium and sodium concentrations, by inhibiting cellular calcium entry, by improving myocardial oxygen supply and demand, by prolonging the effective refractory period, by depressing conduction, by antagonizing catecholamine action on the conducting system, and by preventing vasospasm. Administration of magnesium reduces the incidence of dysrhythmias after myocardial infarction and in patients with congestive heart failure.158 In humans with ischemic myocardium, magnesium prevented ischemic increases in action potential duration and membrane repolarization.159
After acute myocardial infarction, intravenous magnesium administration decreased short-term mortality.160 In addition, magnesium may be useful as treatment for torsades de pointes, even in normomagnesemic patients.161 Treatment of hypomagnesemia during cardiopulmonary bypass decreased the incidence of postoperative ventricular tachycardia from 30 to 7% and increased the frequency of continuous sinus rhythm from 5 to 34%.162
The clinical features of hypomagnesemia ([Mg2+] <1.8 mg/dL), like those of hypocalcemia, are characterized by increased neuronal irritability and tetany (Table 14-23).151 Symptoms are rare when the serum [Mg2+] is 1.5 to 1.7 mg/dL; in most symptomatic patients serum [Mg2+] is <1.2 mg/dL. Patients frequently complain of weakness, lethargy, muscle spasms, paresthesias, and depression. When severe, hypomagnesemia may induce seizures, confusion, and coma. Cardiovascular abnormalities include coronary artery spasm, cardiac failure, dysrhythmias, and hypotension. Severe hypomagnesemia may reduce the response of adenylate cyclase to stimulation of the PTH receptor.163 Hypomagnesemia can aggravate digoxin toxicity and congestive heart failure.
Rarely resulting from inadequate dietary intake, hypomagnesemia most commonly is caused by inadequate gastrointestinal absorption, excessive magnesium losses, or failure of renal magnesium conservation. Hypomagnesemia is particularly frequent in alcoholic patients.151 Of alcoholic patients admitted to the hospital, 30% are hypomagnesemic.164 Excessive loss of magnesium is associated with prolonged nasogastric suctioning, gastrointestinal or biliary fistulas, and intestinal drains. Inability of the renal tubules to conserve magnesium complicates a variety of systemic and renal diseases, although advanced renal disease with a decreased GFR may lead to magnesium retention. Polyuria, whether secondary to ECV expansion or to pharmacologic or pathologic diuresis, may result in excessive urinary magnesium excretion. Various drugs, including aminoglycosides, cis-platinum, cardiac glycosides, and diuretics, enhance urinary magnesium excretion. Intracellular shifts of magnesium as a result of thyroid hormone or insulin administration may also decrease serum [Mg2+].
Because the sodium-potassium pump is magnesium-dependent, hypomagnesemia increases myocardial sensitivity to digitalis preparations and may cause hypokalemia as a result of renal potassium wasting. Attempts to correct potassium deficits with potassium-replacement therapy alone may not be successful without simultaneous magnesium therapy. Magnesium is important in the regulation of potassium channels. The interrelationships of magnesium and potassium in cardiac tissue have probably the greatest clinical relevance in terms of dysrhythmias, digoxin toxicity, and myocardial infarction. Both severe hypomagnesemia and hypermagnesemia suppress PTH secretion and can cause hypocalcemia. Severe hypomagnesemia may also impair end-organ response to PTH.
Hypomagnesemia is associated with hypokalemia, hyponatremia, hypophosphatemia, and hypocalcemia. The reported prevalence of hypomagnesemia in hospitalized and critically ill patients varies from 11 to 61%, with the variability attributable to differences in measurement technique.165 Recent development of a specific electrode to measure ionized [Mg2+] has demonstrated an association between hypomagnesemia, use of
diuretics, and development of sepsis.165 Patients who develop hypomagnesemia while in intensive care have an increased mortality.165 Serum [Mg2+] may not reflect intracellular magnesium content. Peripheral lymphocyte magnesium concentration correlates well with skeletal and cardiac magnesium content.
Table 14-23 Manifestations of Altered Serum Magnesium Concentrations
Table 14-24 Hypomagnesemia: Acute Treatment
Measurement of 24-hour urinary magnesium excretion is useful in separating renal from nonrenal causes of hypomagnesemia. Normal kidneys can reduce magnesium excretion to <1 to 2 mEq/day in response to magnesium depletion. Hypomagnesemia accompanied by high urinary excretion of magnesium (>3 to 4 mEq/day) suggests a renal etiology. In the magnesium-loading test, urinary [Mg2+] excretion is measured for 24 hours after an intravenous magnesium load.166
Magnesium deficiency is treated by the administration of magnesium supplements (Table 14-24). One gram of magnesium sulfate provides approximately 4 mmol (8 mEq, or 98 mg) of elemental magnesium. Mild deficiencies can be treated with diet alone. Replacement must be added to daily magnesium requirements (0.3 to 0.4 mEq/kg/day). Symptomatic or severe hypomagnesemia ([Mg2+] <1.0 mg/dL) should be treated with parenteral magnesium: 1 to 2 g (8 to 16 mEq) of magnesium sulfate as an intravenous bolus over the first hour, followed by a continuous infusion of 2 to 4 mEq/hr. Therapy should be guided subsequently by the serum magnesium level. The rate of infusion should not exceed 1 mEq/min, even in emergency situations, and the patient should receive continuous cardiac monitoring to detect cardiotoxicity. Because magnesium antagonizes calcium, blood pressure and cardiac function should be monitored, although blood pressure and cardiac output usually change little during magnesium infusion.
During repletion, patellar reflexes should be monitored frequently and magnesium withheld if they become suppressed. Patients who have renal insufficiency have a diminished ability to excrete magnesium and require careful monitoring during therapy. Repletion of systemic magnesium stores usually requires 5 to 7 days of therapy, after which daily maintenance doses of magnesium should be provided. Magnesium can be given orally, usually in a dose of 60 to 90 mEq/day of magnesium oxide. Hypocalcemic, hypomagnesemic patients should receive magnesium as the chloride salt because the sulfate ion can chelate calcium and further reduce the serum [Ca2+].
Most cases of hypermagnesemia ([Mg2+] >2.5 mg/dL) are iatrogenic, resulting from the administration of magnesium in antacids, enemas, or parenteral nutrition, especially to patients with impaired renal function. Other rarer causes of mild hypermagnesemia are hypothyroidism, Addison disease, lithium intoxication, and familial hypocalciuric hypercalcemia. Hypermagnesemia is rarely detected in routine electrolyte determinations.151 Hypermagnesemia antagonizes the release and effect of acetylcholine at the neuromuscular junction. The result is depressed skeletal muscle function and neuromuscular blockade. Magnesium potentiates the action of nondepolarizing muscle relaxants and decreases potassium release in response to succinylcholine. The clinical features of progressive hypermagnesemia are listed in Table 14-23.151
The neuromuscular and cardiac toxicity of hypermagnesemia can be acutely, but transiently, antagonized by giving intravenous calcium (5 to 10 mEq) to buy time while more definitive therapy is instituted.151 All magnesium-containing preparations must be stopped. Urinary excretion of magnesium can be increased by expanding ECV and inducing diuresis with a combination of saline and furosemide. In emergency situations and in patients with renal failure, magnesium may be removed by dialysis.
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Editors: Barash, Paul G.; Cullen, Bruce F.; Stoelting, Robert K.; Cahalan, Michael K.; Stock, M. Christine