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Fluids and Electrolytes Evaluation Total body water is usually estimated as 60% and 50% of lean The most common cause of hypernatremia is loss of hypo- body weight in young men and women, respectively, and approx- tonic body fluids with inadequate water replacement due to imately 50% and 45% in older men and women, respectively. lack of access or absence of thirst. Hypotonic losses may If possible, water should be administered orally or by result from diarrhea, the respiratory tract, excessive sweat- means of a nasogastric tube. Because dextrose-containing ing, or renal losses from osmotic diuresis (such as with glu- solutions may cause glycosuria and increased free water losses, cosuria). If the losses are nonrenal, urine osmolality will be it is important to monitor serum glucose and maintain it elevated to >600 mOsm/kg H,O. In osmotic diuresis, urine below 180 mg/dL (10 mmol/L). In the presence of hemody- osmolality is usually between 300 and 600 mOsm/kg H,O. namic compromise due to intravascular volume depletion, Hypotonic losses with inadequate replacement result in replacement fluid should be isotonic saline; otherwise, a intravascular volume depletion with orthostasis or frank hypotonic solution (half [0.45%] normal saline) can be used. hypotension. In patients with diabetes insipidus, the first step is deter- Hypertonic hypernatremia can also occur with adminis- mining whether the defect is secondary to a defect in ADH tration of excessive quantities of hypertonic saline or sodium secretion or an ADH action. Central diabetes insipidus can be bicarbonate, or with salt ingestion. The acute increase in treated with intranasal or oral desmopressin, a synthetic ana- sodium causes water to move out of brain cells, causing logue of vasopressin. Nephrogenic diabetes insipidus is more shrinkage and neurologic findings. Symptoms can range from difficult to treat. Therapy is aimed at limited solute intake to lethargy to seizures and coma. Physical examination fre- decrease the amount of free water that the kidney can excrete

sodium causes water to move out of brain cells, causing logue of vasopressin. Nephrogenic diabetes insipidus is more shrinkage and neurologic findings. Symptoms can range from difficult to treat. Therapy is aimed at limited solute intake to lethargy to seizures and coma. Physical examination fre- decrease the amount of free water that the kidney can excrete quently reveals intravascular volume overload. and induction of mild volume depletion using a thiazide diu- Less commonly, hypernatremia may be secondary to retic to increase salt and water reabsorption proximal to the either an inadequate release (central diabetes insipidus) or collecting duct. The polyuria associated with lithium-induced action of ADH (nephrogenic diabetes insipidus). Central dia- nephrogenic diabetes insipidus can be ameliorated with the betes insipidus can result from tumors that invade the hypo- addition of amiloride, which reduces lithium uptake by the thalamus, infiltrating diseases such as sarcoidosis, or surgical principal cell of the cortical collecting tubule. destruction. Nephrogenic diabetes insipidus is often caused by drugs such as lithium. Common symptoms are polydipsia and e The most common cause of hypernatremia is loss of polyuria. Urine osmolality <300 mOsm/kg H,O in a hyperna- hypotonic body fluids with inadequate water replace- tremic patient confirms the diagnosis. An increase in urine ment due to lack of access or thirst. osmolality after a dose of desmopressin (ADH analogue) dis- tinguishes between central and nephrogenic diabetes insipi- e If hypernatremia has occurred over >24 hours, correc-

quently reveals intravascular volume overload. and induction of mild volume depletion using a thiazide diu- Less commonly, hypernatremia may be secondary to retic to increase salt and water reabsorption proximal to the either an inadequate release (central diabetes insipidus) or collecting duct. The polyuria associated with lithium-induced action of ADH (nephrogenic diabetes insipidus). Central dia- nephrogenic diabetes insipidus can be ameliorated with the betes insipidus can result from tumors that invade the hypo- addition of amiloride, which reduces lithium uptake by the thalamus, infiltrating diseases such as sarcoidosis, or surgical principal cell of the cortical collecting tubule. destruction. Nephrogenic diabetes insipidus is often caused by drugs such as lithium. Common symptoms are polydipsia and e The most common cause of hypernatremia is loss of polyuria. Urine osmolality <300 mOsm/kg H,O in a hyperna- hypotonic body fluids with inadequate water replace- tremic patient confirms the diagnosis. An increase in urine ment due to lack of access or thirst. osmolality after a dose of desmopressin (ADH analogue) dis- tinguishes between central and nephrogenic diabetes insipi- e If hypernatremia has occurred over >24 hours, correc- dus. Because solute loss is not excessive, hypernatremia from tion should be <0.5 mEq/h (0.5 mmol/h) to prevent water loss is usually associated with minimal symptoms unless cerebral edema. the sodium increases acutely. e In the presence of hypernatremia due to intravascular volume depletion, replacement fluid should be isotonic Management saline; otherwise, a hypotonic solution (half [0.45%] Management of hypernatremia is determined by the underly- normal saline) can be used. ing pathogenesis. When secondary to acute hypertonic gains, treatment needs to rapidly restore normal sodium concentra- tion. Water can be administered as 5% dextrose. The goal is to Disorders of Serum Potassium replace the entire water deficit within 24 hours. Hypokalemia If hypernatremia has occurred over >24 hours, the brain adapts by uptake of electrolytes and other osmotically active Hypokalemia is defined as a serum potassium level <3.5 mEq/L

dus. Because solute loss is not excessive, hypernatremia from tion should be <0.5 mEq/h (0.5 mmol/h) to prevent water loss is usually associated with minimal symptoms unless cerebral edema. the sodium increases acutely. e In the presence of hypernatremia due to intravascular volume depletion, replacement fluid should be isotonic Management saline; otherwise, a hypotonic solution (half [0.45%] Management of hypernatremia is determined by the underly- normal saline) can be used. ing pathogenesis. When secondary to acute hypertonic gains, treatment needs to rapidly restore normal sodium concentra- tion. Water can be administered as 5% dextrose. The goal is to Disorders of Serum Potassium replace the entire water deficit within 24 hours. Hypokalemia If hypernatremia has occurred over >24 hours, the brain adapts by uptake of electrolytes and other osmotically active Hypokalemia is defined as a serum potassium level <3.5 mEq/L solutes. Although rapid correction of sodium could theoreti- (3.5 mmol/L). It can be divided into disorders of internal cally cause cerebral edema, this does not seem to occur in balance (movement of potassium between the intracellular adults, and decreases as much as 1 mEq/h (1 mmol/h) appear and extracellular compartments) and disorders of external to be well tolerated. Nevertheless, most authorities would cor- balance (potassium intake and output) (Figure 7). Serum rect at a rate <O.5 mEq/h (0.5 mmol/h), with a goal correction potassium >3.0 mEq/L (3.0 mmol/L) is usually asympto- of 10 to 12 mEq/L/d (10-12 mmol/L/d). Water deficit or volume matic. Because the ratio of intracellular to extracellular

to be well tolerated. Nevertheless, most authorities would cor- balance (potassium intake and output) (Figure 7). Serum rect at a rate <O.5 mEq/h (0.5 mmol/h), with a goal correction potassium >3.0 mEq/L (3.0 mmol/L) is usually asympto- of 10 to 12 mEq/L/d (10-12 mmol/L/d). Water deficit or volume matic. Because the ratio of intracellular to extracellular of replacement water required is estimated using the formula: potassium is the major determinant of the membrane poten- tial of electrically active tissue, symptoms of hypokalemia (Total Body Water) x [(Current Sodium - Ideal Sodium)/ include weakness or paralysis, decreased gastrointestinal Ideal Sodium] motility or ileus, and cardiac arrhythmias. ECG manifesta- The change in the serum sodium for each liter of infusate tions include ST-segment depression, decreased T-wave can be calculated using the formula: amplitude, and increased U-wave amplitude (Figure 8). (Infusate Sodium) — (Serum Sodium) + (Total Body Water + 1) Severe hypokalemia can cause rhabdomyolysis. 14

Fluids and Electrolytes Hypokalemia (serum potassium <3.5 mEq/L [3.5 mmol/L]) | \ | \ Disorders of internal balance Disorders of external balance Pseudohypokalemia 1 Y. Y Yi \ i 4 | Insulin | B-Agonists | Periodic Barium toxicity; Cellular | Decreased intake Increased excretion paralysis cesium toxicity uptake (B,,/folate)? J Renal | | Gl (diarrhea) | Metabolic alkalosis present? | No de Yes

Renal | | Gl (diarrhea) | Metabolic alkalosis present? | No de Yes ‘ } Y ‘ i 4 ' ‘ Non-reabsorbable 4 Magnesium Medications RTA | Vomiting; Tubular defects Hyperaldo- Apparent anions (diuretics; (proximal; distal) nasogastric (Liddle; Bartter; steronism aldosterone (bicarbonate; aminoglycosides; suction Gitelman) excess hippurate; cisplatinum; ketoacids) amphotericin) FIGURE 7. Causes of hypokalemia. Gl = gastrointestinal; RTA=renal tubular acidosis. ‘Treatment of megaloblastic anemia (B,,/folate deficiency). FIGURE 8. Hypokalemia is responsible for the changes on the ECG. The characteristic ECG finding in hypokalemia is the appearance of a U wave after the T wave, eventually replacing the T wave. Initially, T waves decrease in amplitude, and the ST segment flattens. Then U waves appear after the T waves, as seen in this image. The U waves ultimately replace the T waves completely; this may give the impression of QT prolongation, but it is a QU interval. 15

Fluids and Electrolytes Evaluation caused by mutations in transporters that mimic the effects of The cause of hypokalemia can usually be determined from the diuretics on the tubule (e.g., mimicking loop diuretics in history and simple laboratory evaluation. Rarely, hypokalemia Bartter syndrome and thiazides in Gitelman syndrome). In is spurious, as can occur in leukemia when delayed sample Bartter syndrome, urinary calcium excretion is normal or processing allows large numbers of metabolically active leuko- increased, whereas in Gitelman syndrome, hypocalciuria cytes to take up potassium. In addition to leukocytosis, a clue occurs. Finally, proximal and distal renal tubular acidosis is to pseudohypokalemia is the lack of signs and symptoms asso- associated with potassium wasting. ciated with hypokalemia. Hypokalemia can occur secondary to disordered internal Management balance. Insulin or B.-agonists shift potassium into cells, caus- The total body potassium deficit is difficult to predict and can ing an acute, transient, and modest hypokalemia that is usually be up to 200 mEq (200 mmol) for each mEq/L (mmol/L) asymptomatic. Ingestion of soluble barium or cesium salts, decrease in plasma potassium. In patients with neuromuscu- which block potassium exit from cells, can produce severely lar or cardiac symptoms, it is important to increase the potas- symptomatic hypokalemia with levels below 2.0 mEq/L sium promptly. Intravenous potassium can be safely infused at (2.0 mmol/L). Increased cell production after repletion of vita- 20 mEq/h (20 mmol/h). Infusion through a central vein can be min B,, or folate in deficient individuals can also cause increased to 40 mEq/h (40 mmol/h) with close monitoring. hypokalemia. Hypokalemic periodic paralysis, either an For mild hypokalemia (2.5-3.5 mEq/L [2.5-3.5 mmol/L]), oral inherited autosomal dominant disorder or an acquired disor- supplementation using potassium chloride or potassium der seen in patients with hyperthyroidism usually of Japanese bicarbonate is usually adequate. Concurrent hypomagnesemia descent, may present with severe muscle weakness and must be corrected to prevent ongoing potassium losses. In

min B,, or folate in deficient individuals can also cause increased to 40 mEq/h (40 mmol/h) with close monitoring. hypokalemia. Hypokalemic periodic paralysis, either an For mild hypokalemia (2.5-3.5 mEq/L [2.5-3.5 mmol/L]), oral inherited autosomal dominant disorder or an acquired disor- supplementation using potassium chloride or potassium der seen in patients with hyperthyroidism usually of Japanese bicarbonate is usually adequate. Concurrent hypomagnesemia descent, may present with severe muscle weakness and must be corrected to prevent ongoing potassium losses. In paralysis. patients with potassium wasting, potassium-sparing diuretics Most cases of hypokalemia are due to disordered external can be helpful. When significant hypokalemia is secondary to balance with total body potassium depletion, usually from acute transcellular shifts, total body potassium is normal and increased potassium excretion. Because the kidney can almost excessive potassium replacement may cause rebound cease potassium excretion, only a severely compromised diet hyperkalemia.

balance with total body potassium depletion, usually from acute transcellular shifts, total body potassium is normal and increased potassium excretion. Because the kidney can almost excessive potassium replacement may cause rebound cease potassium excretion, only a severely compromised diet hyperkalemia. can cause hypokalemia. The major determinants of renal potassium secretion are distal tubular flow rate and aldoster- e ECG manifestations of hypokalemia include ST-segment one, both of which increase sodium reabsorption, increasing depression, decreased T-wave amplitude, and increased the electronegativity of the tubule lumen and promoting U-wave amplitude. potassium secretion. Under normal conditions, distal flow and e In patients with hypokalemia and neuromuscular or aldosterone levels are inversely related, thus preventing dis- cardiac symptoms, intravenous potassium (20 mEq/h ruptions in potassium homeostasis by changes in intravascu- [20 mmol/h]) can be used to increase the potassium lar volume. promptly. The gold standard to distinguish between renal and extra- renal causes of total body potassium depletion is a 24-hour urine potassium <30 mEq/24 h (30 mmol/d); however, this Hyperkalemia test is often impractical. The preferred alternative is a spot Hyperkalemia is defined by a serum potassium level >5.0 mEq/L urine potassium-creatinine ratio. A value <13 mEq/g identifies (5.0 mmol/L). Levels >6.0 mEq/L (6.0 mmol/L) can cause fatal hypokalemia secondary to lack of intake, transcellular shifts, arrhythmias. Slow increases in potassium are better tolerated or gastrointestinal losses. than abrupt increases. Signs and symptoms of hyperkalemia Gastrointestinal losses are usually caused by diarrhea or are manifested in electrically active tissue and include muscle laxative abuse. Frequently, a concomitant metabolic acidosis is weakness and ECG abnormalities. present. Renal potassium wasting may be caused by numerous disorders, including medications (most commonly diuretics), Evaluation delivery of non-reabsorbable anions (such as bicarbonate) to Initial evaluation of hyperkalemia requires a history and phys- the distal tubule, aldosterone excess, hypomagnesemia, and ical examination, review of all medications, assessment of tubular defects (see Figure 8). kidney function, and an ECG. Initial ECG manifestations Hyperaldosteronism is associated with hypertension and include peaked precordial T waves and a shortened QT inter- a metabolic alkalosis. Hypomagnesemia can cause potassium val. With progression of hyperkalemia, lengthening of the PR wasting, and renal potassium wasting also occurs in inherited interval, loss of the P wave, widening of the QRS complex, a tubular defects, including Liddle, Bartter, and Gitelman syn- sine wave pattern, and asystole may occur (Figure 9). However, dromes. In Liddle syndrome, increased sodium reabsorption ECG findings do not always correlate with the serum potas- in the distal nephron causes hypertension, metabolic alkalosis, sium level and do not necessarily progress in an orderly and potassium wasting. Bartter and Gitelman syndromes are fashion.

can cause hypokalemia. The major determinants of renal potassium secretion are distal tubular flow rate and aldoster- e ECG manifestations of hypokalemia include ST-segment one, both of which increase sodium reabsorption, increasing depression, decreased T-wave amplitude, and increased the electronegativity of the tubule lumen and promoting U-wave amplitude. potassium secretion. Under normal conditions, distal flow and e In patients with hypokalemia and neuromuscular or aldosterone levels are inversely related, thus preventing dis- cardiac symptoms, intravenous potassium (20 mEq/h ruptions in potassium homeostasis by changes in intravascu- [20 mmol/h]) can be used to increase the potassium lar volume. promptly. The gold standard to distinguish between renal and extra- renal causes of total body potassium depletion is a 24-hour urine potassium <30 mEq/24 h (30 mmol/d); however, this Hyperkalemia test is often impractical. The preferred alternative is a spot Hyperkalemia is defined by a serum potassium level >5.0 mEq/L urine potassium-creatinine ratio. A value <13 mEq/g identifies (5.0 mmol/L). Levels >6.0 mEq/L (6.0 mmol/L) can cause fatal hypokalemia secondary to lack of intake, transcellular shifts, arrhythmias. Slow increases in potassium are better tolerated or gastrointestinal losses. than abrupt increases. Signs and symptoms of hyperkalemia Gastrointestinal losses are usually caused by diarrhea or are manifested in electrically active tissue and include muscle laxative abuse. Frequently, a concomitant metabolic acidosis is weakness and ECG abnormalities. present. Renal potassium wasting may be caused by numerous disorders, including medications (most commonly diuretics), Evaluation delivery of non-reabsorbable anions (such as bicarbonate) to Initial evaluation of hyperkalemia requires a history and phys- the distal tubule, aldosterone excess, hypomagnesemia, and ical examination, review of all medications, assessment of tubular defects (see Figure 8). kidney function, and an ECG. Initial ECG manifestations Hyperaldosteronism is associated with hypertension and include peaked precordial T waves and a shortened QT inter- a metabolic alkalosis. Hypomagnesemia can cause potassium val. With progression of hyperkalemia, lengthening of the PR wasting, and renal potassium wasting also occurs in inherited interval, loss of the P wave, widening of the QRS complex, a tubular defects, including Liddle, Bartter, and Gitelman syn- sine wave pattern, and asystole may occur (Figure 9). However, dromes. In Liddle syndrome, increased sodium reabsorption ECG findings do not always correlate with the serum potas- in the distal nephron causes hypertension, metabolic alkalosis, sium level and do not necessarily progress in an orderly and potassium wasting. Bartter and Gitelman syndromes are fashion. 16

Fluids and Electrolytes short and therefore is never definitive therapy. Intravenous administration of insulin alone if serum glucose is >250 mg/dL (13.9 mmol/L) or with 10% dextrose will drive potassium into seiaaasat inte cells, and is effective for up to 6 hours. Potassium can also be | 4 roo shifted into cells using high-dose nebulized albuterol. Sodium bicarbonate therapy has fallen out of favor because it does not promote redistribution of potassium.

| 4 roo shifted into cells using high-dose nebulized albuterol. Sodium bicarbonate therapy has fallen out of favor because it does not promote redistribution of potassium. fee Eee uid 1 | ovF | ; 8 MS Definitive treatment of severe hyperkalemia, unrelated to reversible transcellular shift, must include removal of Bas |) CPLR 5 MRS fT pA Bo potassium from the body. In patients without severe kidney disease, loop diuretics can be effective. Use of the potassium exchange resin sodium polystyrene sulfonate is controversial; its effectiveness is limited, and it produces adverse gastroin- testinal effects, including volume overload and, rarely, bowel necrosis. Patiromer and sodium zirconium cyclosilicate bind FIGURE 9. This ECG demonstrates tall, peaked T waves and decreased P waves, potassium in the gastrointestinal tract and effectively lower which are characteristic of hyperkalemia. In experimental models of increasing potassium, there are progressive changes in the ECG beginning with peakedT potassium. Hemodialysis is the treatment of choice in waves, PR prolongation, loss of P waves, widening of ORS, and finally sinusoidal patients with severe hyperkalemia and oliguric kidney waveform. This, however, is not necessarily true in clinical situations. disease. Chronic hyperkalemia is often overtreated and, in the During the clotting process, cells are disrupted with the absence of signs of cardiac toxicity, does not warrant the emer- release of intracellular potassium, and pseudohyperkalemia gent interventions. Limiting potassium intake may be benefi- may occur in serum specimens when there are extreme eleva- cial, and increased sodium intake along with a thiazide or loop tions of leukocytes or platelets. In these cases, a repeat plasma diuretic will increase potassium excretion. In hypoaldosteron- specimen will be normal. A tight tourniquet or excessively ism, fludrocortisone will normalize the potassium; however, it clenched fist during blood draw can also cause local potassium may cause elevated blood pressure and edema, and long-term release. effects of fludrocortisone are unknown. All potentially causa- Hyperkalemia may be caused by transcellular shifts, as tive medications should be discontinued if possible. If neces- occur in states of insulin deficiency or hypertonicity, or with sary, potassium binders may allow continuation of essential the use of B,-adrenergic blockers. Rapid breakdown of cells medications. such as that seen in rhabdomyolysis or tumor lysis syndrome can acutely raise serum potassium levels. Hyperkalemia usually results from increased intake with ¢ Intravenous administration of calcium gluconate quickly

fee Eee uid 1 | ovF | ; 8 MS Definitive treatment of severe hyperkalemia, unrelated to reversible transcellular shift, must include removal of Bas |) CPLR 5 MRS fT pA Bo potassium from the body. In patients without severe kidney disease, loop diuretics can be effective. Use of the potassium exchange resin sodium polystyrene sulfonate is controversial; its effectiveness is limited, and it produces adverse gastroin- testinal effects, including volume overload and, rarely, bowel necrosis. Patiromer and sodium zirconium cyclosilicate bind FIGURE 9. This ECG demonstrates tall, peaked T waves and decreased P waves, potassium in the gastrointestinal tract and effectively lower which are characteristic of hyperkalemia. In experimental models of increasing potassium, there are progressive changes in the ECG beginning with peakedT potassium. Hemodialysis is the treatment of choice in waves, PR prolongation, loss of P waves, widening of ORS, and finally sinusoidal patients with severe hyperkalemia and oliguric kidney waveform. This, however, is not necessarily true in clinical situations. disease. Chronic hyperkalemia is often overtreated and, in the During the clotting process, cells are disrupted with the absence of signs of cardiac toxicity, does not warrant the emer- release of intracellular potassium, and pseudohyperkalemia gent interventions. Limiting potassium intake may be benefi- may occur in serum specimens when there are extreme eleva- cial, and increased sodium intake along with a thiazide or loop tions of leukocytes or platelets. In these cases, a repeat plasma diuretic will increase potassium excretion. In hypoaldosteron- specimen will be normal. A tight tourniquet or excessively ism, fludrocortisone will normalize the potassium; however, it clenched fist during blood draw can also cause local potassium may cause elevated blood pressure and edema, and long-term release. effects of fludrocortisone are unknown. All potentially causa- Hyperkalemia may be caused by transcellular shifts, as tive medications should be discontinued if possible. If neces- occur in states of insulin deficiency or hypertonicity, or with sary, potassium binders may allow continuation of essential the use of B,-adrenergic blockers. Rapid breakdown of cells medications. such as that seen in rhabdomyolysis or tumor lysis syndrome can acutely raise serum potassium levels. Hyperkalemia usually results from increased intake with ¢ Intravenous administration of calcium gluconate quickly decreased renal excretion. Hyperkalemia frequently occurs antagonizes the effects of hyperkalemia on the cardiac

fee Eee uid 1 | ovF | ; 8 MS Definitive treatment of severe hyperkalemia, unrelated to reversible transcellular shift, must include removal of Bas |) CPLR 5 MRS fT pA Bo potassium from the body. In patients without severe kidney disease, loop diuretics can be effective. Use of the potassium exchange resin sodium polystyrene sulfonate is controversial; its effectiveness is limited, and it produces adverse gastroin- testinal effects, including volume overload and, rarely, bowel necrosis. Patiromer and sodium zirconium cyclosilicate bind FIGURE 9. This ECG demonstrates tall, peaked T waves and decreased P waves, potassium in the gastrointestinal tract and effectively lower which are characteristic of hyperkalemia. In experimental models of increasing potassium, there are progressive changes in the ECG beginning with peakedT potassium. Hemodialysis is the treatment of choice in waves, PR prolongation, loss of P waves, widening of ORS, and finally sinusoidal patients with severe hyperkalemia and oliguric kidney waveform. This, however, is not necessarily true in clinical situations. disease. Chronic hyperkalemia is often overtreated and, in the During the clotting process, cells are disrupted with the absence of signs of cardiac toxicity, does not warrant the emer- release of intracellular potassium, and pseudohyperkalemia gent interventions. Limiting potassium intake may be benefi- may occur in serum specimens when there are extreme eleva- cial, and increased sodium intake along with a thiazide or loop tions of leukocytes or platelets. In these cases, a repeat plasma diuretic will increase potassium excretion. In hypoaldosteron- specimen will be normal. A tight tourniquet or excessively ism, fludrocortisone will normalize the potassium; however, it clenched fist during blood draw can also cause local potassium may cause elevated blood pressure and edema, and long-term release. effects of fludrocortisone are unknown. All potentially causa- Hyperkalemia may be caused by transcellular shifts, as tive medications should be discontinued if possible. If neces- occur in states of insulin deficiency or hypertonicity, or with sary, potassium binders may allow continuation of essential the use of B,-adrenergic blockers. Rapid breakdown of cells medications. such as that seen in rhabdomyolysis or tumor lysis syndrome can acutely raise serum potassium levels. Hyperkalemia usually results from increased intake with ¢ Intravenous administration of calcium gluconate quickly decreased renal excretion. Hyperkalemia frequently occurs antagonizes the effects of hyperkalemia on the cardiac with oliguric acute or chronic kidney disease with a glomeru- membrane.

fee Eee uid 1 | ovF | ; 8 MS Definitive treatment of severe hyperkalemia, unrelated to reversible transcellular shift, must include removal of Bas |) CPLR 5 MRS fT pA Bo potassium from the body. In patients without severe kidney disease, loop diuretics can be effective. Use of the potassium exchange resin sodium polystyrene sulfonate is controversial; its effectiveness is limited, and it produces adverse gastroin- testinal effects, including volume overload and, rarely, bowel necrosis. Patiromer and sodium zirconium cyclosilicate bind FIGURE 9. This ECG demonstrates tall, peaked T waves and decreased P waves, potassium in the gastrointestinal tract and effectively lower which are characteristic of hyperkalemia. In experimental models of increasing potassium, there are progressive changes in the ECG beginning with peakedT potassium. Hemodialysis is the treatment of choice in waves, PR prolongation, loss of P waves, widening of ORS, and finally sinusoidal patients with severe hyperkalemia and oliguric kidney waveform. This, however, is not necessarily true in clinical situations. disease. Chronic hyperkalemia is often overtreated and, in the During the clotting process, cells are disrupted with the absence of signs of cardiac toxicity, does not warrant the emer- release of intracellular potassium, and pseudohyperkalemia gent interventions. Limiting potassium intake may be benefi- may occur in serum specimens when there are extreme eleva- cial, and increased sodium intake along with a thiazide or loop tions of leukocytes or platelets. In these cases, a repeat plasma diuretic will increase potassium excretion. In hypoaldosteron- specimen will be normal. A tight tourniquet or excessively ism, fludrocortisone will normalize the potassium; however, it clenched fist during blood draw can also cause local potassium may cause elevated blood pressure and edema, and long-term release. effects of fludrocortisone are unknown. All potentially causa- Hyperkalemia may be caused by transcellular shifts, as tive medications should be discontinued if possible. If neces- occur in states of insulin deficiency or hypertonicity, or with sary, potassium binders may allow continuation of essential the use of B,-adrenergic blockers. Rapid breakdown of cells medications. such as that seen in rhabdomyolysis or tumor lysis syndrome can acutely raise serum potassium levels. Hyperkalemia usually results from increased intake with ¢ Intravenous administration of calcium gluconate quickly decreased renal excretion. Hyperkalemia frequently occurs antagonizes the effects of hyperkalemia on the cardiac with oliguric acute or chronic kidney disease with a glomeru- membrane. lar filtration rate (GFR) <20 mL/min/1.73 m?. Potassium- ¢ Definitive treatment of severe hyperkalemia must sparing diuretics (amiloride, triamterene, spironolactone) also include removal of potassium from the body; patiromer commonly cause hyperkalemia through decreased excretion. and sodium zirconium cyclosilicate can increase gastro- Other medications that decrease potassium excretion include intestinal excretion, loop diuretics can be effective in trimethoprim and pentamidine (by blocking the epithelial patients without severe kidney disease, and hemodialy- sodium channel) and NSAIDs (by decreasing renin). sis is the treatment of choice in patients with severe Hypoaldosteronism caused by ACE inhibitors, angiotensin hyperkalemia and oliguric kidney disease. receptor blockers, heparin, type 4 renal tubular acidosis (often seen in diabetic kidney disease), or primary adrenal insuffi- ciency also causes hyperkalemia, especially in the presence of Disorders of Serum Phosphate excess potassium intake or volume depletion. Hypophosphatemia Hypophosphatemia is defined as a serum phosphate level Management <2.7 mg/dL (0.87 mmol/L). Phosphate (PO,) is found primarily Elevation in the serum potassium level >6.5 mEq/L (6.5 mmol/L), within bone and the intracellular space. Phosphate is required or >6.0 mEq/L (6.0 mmol/L) with ECG changes, should be for metabolic pathways involved in energy production, cellular promptly treated. Treatment is directed at stabilizing the car- repair, and enzymatic activity. Levels <2.0 mg/dL (0.65 mmol/L) diac membrane, shifting potassium into cells, and removing are associated with muscle weakness. Severe hypophosphatemia potassium from the body. Intravenous administration of cal- (<1.0 mg/dL [0.32 mmol/L]) is associated with life-threatening cium gluconate quickly antagonizes the effects of hyperkalemia symptoms, including delirium, seizures, coma, heart failure, on the cardiac membrane. Its duration of action is relatively respiratory failure, rhabdomyolysis, and hemolysis.

lar filtration rate (GFR) <20 mL/min/1.73 m?. Potassium- ¢ Definitive treatment of severe hyperkalemia must sparing diuretics (amiloride, triamterene, spironolactone) also include removal of potassium from the body; patiromer commonly cause hyperkalemia through decreased excretion. and sodium zirconium cyclosilicate can increase gastro- Other medications that decrease potassium excretion include intestinal excretion, loop diuretics can be effective in trimethoprim and pentamidine (by blocking the epithelial patients without severe kidney disease, and hemodialy- sodium channel) and NSAIDs (by decreasing renin). sis is the treatment of choice in patients with severe Hypoaldosteronism caused by ACE inhibitors, angiotensin hyperkalemia and oliguric kidney disease. receptor blockers, heparin, type 4 renal tubular acidosis (often seen in diabetic kidney disease), or primary adrenal insuffi- ciency also causes hyperkalemia, especially in the presence of Disorders of Serum Phosphate excess potassium intake or volume depletion. Hypophosphatemia Hypophosphatemia is defined as a serum phosphate level Management <2.7 mg/dL (0.87 mmol/L). Phosphate (PO,) is found primarily Elevation in the serum potassium level >6.5 mEq/L (6.5 mmol/L), within bone and the intracellular space. Phosphate is required or >6.0 mEq/L (6.0 mmol/L) with ECG changes, should be for metabolic pathways involved in energy production, cellular promptly treated. Treatment is directed at stabilizing the car- repair, and enzymatic activity. Levels <2.0 mg/dL (0.65 mmol/L) diac membrane, shifting potassium into cells, and removing are associated with muscle weakness. Severe hypophosphatemia potassium from the body. Intravenous administration of cal- (<1.0 mg/dL [0.32 mmol/L]) is associated with life-threatening cium gluconate quickly antagonizes the effects of hyperkalemia symptoms, including delirium, seizures, coma, heart failure, on the cardiac membrane. Its duration of action is relatively respiratory failure, rhabdomyolysis, and hemolysis. 17

Fluids and Electrolytes Evaluation tumor lysis syndrome increases serum phosphate, especially if Hypophosphatemia results from transcellular shifts, decreased the GFR is decreased. Hyperphosphatemia can also be associ- intake, or increased excretion. Movement of phosphorous into ated with diabetic ketoacidosis and, less commonly, lactic acido- cells occurs with respiratory alkalosis, insulin treatment, sis. Excessive phosphate intake rarely causes hyperphosphatemia refeeding of starved individuals, or, less commonly, as part of because the kidney rapidly excretes phosphate. However, the hungry bone syndrome following parathyroidectomy or phosphate-containing cathartics can cause acute elevations in with prolonged exposure to continuous renal replacement serum phosphate, especially in patients with reduced GFR. therapy. Ferric carboxymaltose, an intravenous iron prepara- tion, has been associated with hypophosphatemia by causing Management renal phosphate wasting. Medications that bind phosphate in If kidney function is adequate, serum phosphate levels should the gut (calcium, antacids) can decrease effective intake. normalize in 12 to 24 hours. If necessary, phosphate excretion Because the kidney can decrease phosphate excretion to very can be increased with intravenous saline. In patients with low levels, low dietary phosphate rarely causes hypophos- impaired kidney function, dialysis may be necessary. Because phatemia without coexisting malnutrition. Increased excre- many foods contain phosphate, dietary phosphate restriction tion may be caused by diarrhea or renal wasting. Excretion of is difficult. Therefore, patients with chronic hyperphos- >100 mg of phosphate in a 24-hour urine collection or a frac- phatemia must often use agents that bind phosphate in the tional excretion of phosphate (FEPo,) >5% suggests renal wast- gastrointestinal tract to prevent absorption. See Chronic ing. Renal losses of phosphate are seen in hyperparathyroidism Kidney Disease for more information. and in proximal tubular dysfunction.

phatemia without coexisting malnutrition. Increased excre- many foods contain phosphate, dietary phosphate restriction tion may be caused by diarrhea or renal wasting. Excretion of is difficult. Therefore, patients with chronic hyperphos- >100 mg of phosphate in a 24-hour urine collection or a frac- phatemia must often use agents that bind phosphate in the tional excretion of phosphate (FEPo,) >5% suggests renal wast- gastrointestinal tract to prevent absorption. See Chronic ing. Renal losses of phosphate are seen in hyperparathyroidism Kidney Disease for more information. and in proximal tubular dysfunction. e Causes of hyperphosphatemia include cellular lysis with Management release of phosphate, excessive intake, and/or decreased Mild decreases in serum phosphate can be treated with renal excretion from decreased glomerular filtration rate oral sodium or potassium phosphate. Levels <2.0 mg/dL or increased tubular reabsorption (hypoparathyroidism). (0.65 mmol/L) should be treated with intravenous sodium phosphate. Calcitriol is sometimes required to increase intes- e If kidney function is adequate in patients with hyper-

e Causes of hyperphosphatemia include cellular lysis with Management release of phosphate, excessive intake, and/or decreased Mild decreases in serum phosphate can be treated with renal excretion from decreased glomerular filtration rate oral sodium or potassium phosphate. Levels <2.0 mg/dL or increased tubular reabsorption (hypoparathyroidism). (0.65 mmol/L) should be treated with intravenous sodium phosphate. Calcitriol is sometimes required to increase intes- e If kidney function is adequate in patients with hyper- tinal absorption of phosphate. phosphatemia, serum phosphate levels should normalize in 12 to 24 hours; if necessary, phosphate excretion can be increased with intravenous saline, and dialysis can be e Severe hypophosphatemia (<1.0 mg/dL [0.32 mmol/L]) initiated for those with impaired kidney function. is associated with life-threatening symptoms, including delirium, seizures, coma, heart failure, respiratory failure, rhabdomyolysis, and hemolysis. Disorders of Serum Magnesium There are approximately 24 grams of magnesium in the body, e Mild hypophosphatemia can be treated with oral with 99% residing intracellularly and within bone. Magnesium sodium or potassium phosphate; levels <2.0 mg/dL is essential for protein and nucleic acid synthesis, cell adhe- (0.65 mmol/L) should be treated with intravenous sion, enzyme reactions, and modulating channel activity. sodium phosphate.

tinal absorption of phosphate. phosphatemia, serum phosphate levels should normalize in 12 to 24 hours; if necessary, phosphate excretion can be increased with intravenous saline, and dialysis can be e Severe hypophosphatemia (<1.0 mg/dL [0.32 mmol/L]) initiated for those with impaired kidney function. is associated with life-threatening symptoms, including delirium, seizures, coma, heart failure, respiratory failure, rhabdomyolysis, and hemolysis. Disorders of Serum Magnesium There are approximately 24 grams of magnesium in the body, e Mild hypophosphatemia can be treated with oral with 99% residing intracellularly and within bone. Magnesium sodium or potassium phosphate; levels <2.0 mg/dL is essential for protein and nucleic acid synthesis, cell adhe- (0.65 mmol/L) should be treated with intravenous sion, enzyme reactions, and modulating channel activity. sodium phosphate. Hypomagnesemia Hyperphosphatemia Hypomagnesemia is defined by a serum magnesium level Hyperphosphatemia is defined by a serum phosphate level <1.7 mg/dL (0.7 mmol/L). Symptoms usually do not develop until >4.5 mg/dL (1.45 mmol/L). Symptoms are usually related to serum magnesium is <1.2 mg/dL (0.5 mmol/L). Symptoms co-occurring hypocalcemia. Acute elevations in phosphate include tremors, fasciculations, muscle weakness, carpopedal can cause precipitation of calcium phosphate in the kidney, spasm, Chvostek (contraction of the ipsilateral facial muscles by resulting in phosphate nephropathy. tapping the facial nerve) and Trousseau (carpopedal spasm after inflation of blood pressure cuff above systolic blood pressure) Evaluation signs, and seizures. Hypomagnesemia also appears to potentiate Hyperphosphatemia from reduced renal excretion does not cardiac arrhythmogenicity due to hypokalemia, myocardial occur due to reduced GFR unless patients have severe chronic ischemia, and various drugs. In addition, hypomagnesemia causes kidney disease. Hypoparathyroidism decreases excretion hypokalemia due to renal potassium wasting, and it causes hypo- through increased phosphate tubular reabsorption; hypocal- calcemia by impeding parathyroid hormone release and action. cemia is often present. Rare defects in the action of fibroblast growth factor 23 (such as in tumoral calcinosis) also increase Evaluation tubular reabsorption of phosphate. Hypomagnesemia results from decreased gastrointestinal Because phosphate is primarily an intracellular anion, absorption or increased renal secretion. History and physical widespread cellular damage as occurs in rhabdomyolysis and examination often delineate the cause. More than 10 mg of

Hypomagnesemia Hyperphosphatemia Hypomagnesemia is defined by a serum magnesium level Hyperphosphatemia is defined by a serum phosphate level <1.7 mg/dL (0.7 mmol/L). Symptoms usually do not develop until >4.5 mg/dL (1.45 mmol/L). Symptoms are usually related to serum magnesium is <1.2 mg/dL (0.5 mmol/L). Symptoms co-occurring hypocalcemia. Acute elevations in phosphate include tremors, fasciculations, muscle weakness, carpopedal can cause precipitation of calcium phosphate in the kidney, spasm, Chvostek (contraction of the ipsilateral facial muscles by resulting in phosphate nephropathy. tapping the facial nerve) and Trousseau (carpopedal spasm after inflation of blood pressure cuff above systolic blood pressure) Evaluation signs, and seizures. Hypomagnesemia also appears to potentiate Hyperphosphatemia from reduced renal excretion does not cardiac arrhythmogenicity due to hypokalemia, myocardial occur due to reduced GFR unless patients have severe chronic ischemia, and various drugs. In addition, hypomagnesemia causes kidney disease. Hypoparathyroidism decreases excretion hypokalemia due to renal potassium wasting, and it causes hypo- through increased phosphate tubular reabsorption; hypocal- calcemia by impeding parathyroid hormone release and action. cemia is often present. Rare defects in the action of fibroblast growth factor 23 (such as in tumoral calcinosis) also increase Evaluation tubular reabsorption of phosphate. Hypomagnesemia results from decreased gastrointestinal Because phosphate is primarily an intracellular anion, absorption or increased renal secretion. History and physical widespread cellular damage as occurs in rhabdomyolysis and examination often delineate the cause. More than 10 mg of 18

Acid-Base Disorders magnesium in a 24-hour urine collection or a fractional excre- diuresis. For more severe symptoms, intravenous calcium will tion of magnesium (FEy,) >2% suggests renal wasting in the antagonize the effects of magnesium. setting of hypomagnesemia. Causes of decreased magnesium absorption include e Early symptoms of hypermagnesemia include loss of severe malnutrition, diarrhea, and malabsorption. Proton deep tendon reflexes, progressing to flaccid paralysis at pump inhibitors is an important cause of hypomagnesemia, higher levels. with most reported cases occurring after prolonged use, which rapidly reverses upon discontinuation of the drug. e For patients with hypermagnesemia, all magnesium- Hypomagnesemia from renal losses occurs with diuretics, containing medications should be discontinued, and cisplatin, aminoglycosides, or calcineurin inhibitors. Vascular magnesium excretion can be enhanced with saline diu- endothelial growth factor inhibitors used in cancer treatment resis; for more severe symptoms, intravenous calcium can cause significant magnesium wasting. Other causes of will antagonize the effects of magnesium. urine losses include volume expansion, alcohol ingestion, and diabetic ketoacidosis. Management Acid-Base Disorders If significant symptoms are present, 4 grams of magnesium Overview sulfate should be infused over 12 hours and repeated if neces- Hydrogen ions are maintained within narrow limits and deter- sary. Importantly, half of acutely infused intravenous magne- sium is excreted by the kidney; therefore, slow-release oral mine pH (Table 7). Any change in pH results in a predictable magnesium or nasogastric tube delivery may be better to response to limit that change.

Management Acid-Base Disorders If significant symptoms are present, 4 grams of magnesium Overview sulfate should be infused over 12 hours and repeated if neces- Hydrogen ions are maintained within narrow limits and deter- sary. Importantly, half of acutely infused intravenous magne- sium is excreted by the kidney; therefore, slow-release oral mine pH (Table 7). Any change in pH results in a predictable magnesium or nasogastric tube delivery may be better to response to limit that change. replete mild to moderate hypomagnesemia. Causes of acid-base disorders can be determined by using blood gas pH, Pco,, serum bicarbonate measurements, and the serum anion gap. Arterial blood provides the most accurate e Significant symptoms of hypomagnesemia usually measurement, although venous blood gases may be useful in develop when the serum magnesium level is <1.2 mg/dL following response to therapy. Venous gases are least useful in (0.5 mmol/L); these include tremors, fasciculations, patients with shock, due to lower pH and higher Pco, values muscle weakness, carpopedal spasm, Chvostek and than in arterial gases. Trousseau signs, seizures, and cardiac arrhythmias. Primary acid-base disorders are classified according to the e Treatment of significant symptoms of hypomagnesemia underlying mechanism (metabolic or respiratory) and their includes magnesium sulfate infusions; less severe symp- effect on acid-base balance (acidosis or alkalosis) (Figure 10). toms can be treated with slow-release oral magnesium. Expected compensatory response to the primary disorder is then assessed (Table 8). A mixed acid-base disorder is present

includes magnesium sulfate infusions; less severe symp- effect on acid-base balance (acidosis or alkalosis) (Figure 10). toms can be treated with slow-release oral magnesium. Expected compensatory response to the primary disorder is then assessed (Table 8). A mixed acid-base disorder is present Hypermagnesemia when measured values fall outside the range of the predicted compensatory response. The primary disorder is usually Hypermagnesemia is defined by a serum magnesium level of reflected by the blood pH, although a normal pH may occur in >2.4 mg/dL (0.99 mmol/L). the context of a mixed disorder. Appropriate compensation Evaluation may result in near-normal pH.

Hypermagnesemia when measured values fall outside the range of the predicted compensatory response. The primary disorder is usually Hypermagnesemia is defined by a serum magnesium level of reflected by the blood pH, although a normal pH may occur in >2.4 mg/dL (0.99 mmol/L). the context of a mixed disorder. Appropriate compensation Evaluation may result in near-normal pH. Hypermagnesemia occurs infrequently and most commonly results from excessive intake in the setting of decreased kidney e Primary metabolic acidosis is defined by low serum function. Antacids and laxatives contain magnesium, and bicarbonate and primary metabolic alkalosis by elevated therapeutic infusions of magnesium sulfate for refractory serum bicarbonate. asthma and prevention of eclampsia are potential causes of e In primary respiratory acidosis, arterial Pco, is above hypermagnesemia. normal; in primary respiratory alkalosis, Pco, is below Symptoms of hypermagnesemia do not occur until levels are normal. 4.8 mg/dL (1.98 mmol/L). Early symptoms include loss of deep tendon reflexes, progressing to flaccid paralysis at higher levels. Hypermagnesemia also results in hypotension from loss of vascu- TABLE 7. Physiologic Levels of Tests Used in the lar tone. Laboratory analysis often shows hypocalcemia. Assessment of Acid-Base Status

Hypermagnesemia occurs infrequently and most commonly results from excessive intake in the setting of decreased kidney e Primary metabolic acidosis is defined by low serum function. Antacids and laxatives contain magnesium, and bicarbonate and primary metabolic alkalosis by elevated therapeutic infusions of magnesium sulfate for refractory serum bicarbonate. asthma and prevention of eclampsia are potential causes of e In primary respiratory acidosis, arterial Pco, is above hypermagnesemia. normal; in primary respiratory alkalosis, Pco, is below Symptoms of hypermagnesemia do not occur until levels are normal. 4.8 mg/dL (1.98 mmol/L). Early symptoms include loss of deep tendon reflexes, progressing to flaccid paralysis at higher levels. Hypermagnesemia also results in hypotension from loss of vascu- TABLE 7. Physiologic Levels of Tests Used in the lar tone. Laboratory analysis often shows hypocalcemia. Assessment of Acid-Base Status pH Pco, Bicarbonate | Management Prevention is the key to management of hypermagnesemia. | Arterial —-7.37-7.44 -36-44mmHg =. 22-26 mEq/L_—sid | blood (4.8-5.9 kPa) (22-26 mmol/L) | Hypermagnesemia is usually self-limited; magnesium-containing agents should be limited or avoided in individuals with kidney | Venous 7.32-7.38 42-50 mm Hg 23-27 mEq/L | blood (5.6-6.7 kPa) (23-27 mmol/L) | disease. Magnesium excretion can be enhanced with saline 19

Acid-Base Disorders <7.37 CT | >7.44 i ‘ | Acidemia | | Alkalemia | | | t + t t J HCO, TCO, T HCO, ; co, : FIGURE 10. Classification of primary acid-base Metabolic acidosis Respiratory acidosis Metabolic alkalosis Respiratory alkalosis disorders

i ‘ | Acidemia | | Alkalemia | | | t + t t J HCO, TCO, T HCO, ; co, : FIGURE 10. Classification of primary acid-base Metabolic acidosis Respiratory acidosis Metabolic alkalosis Respiratory alkalosis disorders Metabolic Acidosis If the corrected anion gap is increased, patients should next be assessed for coexistent normal anion gap acidosis or General Approach metabolic alkalosis. One method for detection of a coexistent A stepwise approach to assessment provides appropriate diag- additional acid-base disorder is to assess the ratio of the nosis of the underlying acid-base disorder. First, both pH and amount of anion gap abnormality (A anion gap) to the amount Pco, are needed to confirm the primary disorder because low of bicarbonate abnormality (A bicarbonate), also known as the serum bicarbonate may be a compensatory response to res- “delta-delta (A-A) ratio,” as follows: piratory alkalosis. A—A Ratio= A Anion Gap/A Bicarbonate = (Anion Gap — 12)/ Next, the serum anion gap is calculated to assess whether (25 — Bicarbonate) the low serum bicarbonate is due to loss of serum bicarbonate (no anion gap) or is a result of unmeasured anion (increased anion A A-A ratio of <0.5 to 1 may reflect the presence of con-

Metabolic Acidosis If the corrected anion gap is increased, patients should next be assessed for coexistent normal anion gap acidosis or General Approach metabolic alkalosis. One method for detection of a coexistent A stepwise approach to assessment provides appropriate diag- additional acid-base disorder is to assess the ratio of the nosis of the underlying acid-base disorder. First, both pH and amount of anion gap abnormality (A anion gap) to the amount Pco, are needed to confirm the primary disorder because low of bicarbonate abnormality (A bicarbonate), also known as the serum bicarbonate may be a compensatory response to res- “delta-delta (A-A) ratio,” as follows: piratory alkalosis. A—A Ratio= A Anion Gap/A Bicarbonate = (Anion Gap — 12)/ Next, the serum anion gap is calculated to assess whether (25 — Bicarbonate) the low serum bicarbonate is due to loss of serum bicarbonate (no anion gap) or is a result of unmeasured anion (increased anion A A-A ratio of <0.5 to 1 may reflect the presence of con- gap metabolic acidosis). The anion gap is calculated as follows: current normal anion gap metabolic acidosis; a ratio between 1 and 2 generally confirms the primary high anion gap meta- Anion Gap = Serum Sodium (mEq/L) — (Serum Chloride bolic acidosis; and a ratio of >2 may indicate the presence of [mEq/L] + Serum Bicarbonate [mEq/L]) metabolic alkalosis. The normal range for the anion gap is 8.0 to 10 mEq/L + Patients with metabolic acidosis due to acute or chronic 2 mEq/L (8-10 mmol/L + 2 mmol/L). In normal subjects, nega- kidney disease may have either a normal anion gap (more tively charged albumin is a major contributor to the anion gap. modest disease) or an increased anion gap (more severe chronic Therefore, changes in albumin need to be taken into account. kidney disease). When the glomerular filtration rate (GFR) This is most important in the context of a low albumin wherein decreases to <45 mL/min/1.73 m2, decreased urine ammonium failure to correct the anion gap will result in underestimation of excretion leads to a normal anion gap metabolic acidosis, often the true anion gap. The albumin-corrected anion gap (with nor- associated with hyperkalemia. When the GFR decreases to mal albumin being 4.0 g/dL [40 g/L]) is calculated as follows: <15 mL/min/1.73 m?, retention of sulfates, phosphates, and Albumin-Corrected Anion Gap = Anion Gap + 2.5 x (Normal organic acids results in an increased anion gap metabolic Albumin - Measured Albumin [g/dL]) acidosis.

gap metabolic acidosis). The anion gap is calculated as follows: current normal anion gap metabolic acidosis; a ratio between 1 and 2 generally confirms the primary high anion gap meta- Anion Gap = Serum Sodium (mEq/L) — (Serum Chloride bolic acidosis; and a ratio of >2 may indicate the presence of [mEq/L] + Serum Bicarbonate [mEq/L]) metabolic alkalosis. The normal range for the anion gap is 8.0 to 10 mEq/L + Patients with metabolic acidosis due to acute or chronic 2 mEq/L (8-10 mmol/L + 2 mmol/L). In normal subjects, nega- kidney disease may have either a normal anion gap (more tively charged albumin is a major contributor to the anion gap. modest disease) or an increased anion gap (more severe chronic Therefore, changes in albumin need to be taken into account. kidney disease). When the glomerular filtration rate (GFR) This is most important in the context of a low albumin wherein decreases to <45 mL/min/1.73 m2, decreased urine ammonium failure to correct the anion gap will result in underestimation of excretion leads to a normal anion gap metabolic acidosis, often the true anion gap. The albumin-corrected anion gap (with nor- associated with hyperkalemia. When the GFR decreases to mal albumin being 4.0 g/dL [40 g/L]) is calculated as follows: <15 mL/min/1.73 m?, retention of sulfates, phosphates, and Albumin-Corrected Anion Gap = Anion Gap + 2.5 x (Normal organic acids results in an increased anion gap metabolic Albumin - Measured Albumin [g/dL]) acidosis. TABLE 8. Compensation in Acid-Base Disorders : Condition Expected Compensation

gap metabolic acidosis). The anion gap is calculated as follows: current normal anion gap metabolic acidosis; a ratio between 1 and 2 generally confirms the primary high anion gap meta- Anion Gap = Serum Sodium (mEq/L) — (Serum Chloride bolic acidosis; and a ratio of >2 may indicate the presence of [mEq/L] + Serum Bicarbonate [mEq/L]) metabolic alkalosis. The normal range for the anion gap is 8.0 to 10 mEq/L + Patients with metabolic acidosis due to acute or chronic 2 mEq/L (8-10 mmol/L + 2 mmol/L). In normal subjects, nega- kidney disease may have either a normal anion gap (more tively charged albumin is a major contributor to the anion gap. modest disease) or an increased anion gap (more severe chronic Therefore, changes in albumin need to be taken into account. kidney disease). When the glomerular filtration rate (GFR) This is most important in the context of a low albumin wherein decreases to <45 mL/min/1.73 m2, decreased urine ammonium failure to correct the anion gap will result in underestimation of excretion leads to a normal anion gap metabolic acidosis, often the true anion gap. The albumin-corrected anion gap (with nor- associated with hyperkalemia. When the GFR decreases to mal albumin being 4.0 g/dL [40 g/L]) is calculated as follows: <15 mL/min/1.73 m?, retention of sulfates, phosphates, and Albumin-Corrected Anion Gap = Anion Gap + 2.5 x (Normal organic acids results in an increased anion gap metabolic Albumin - Measured Albumin [g/dL]) acidosis. TABLE 8. Compensation in Acid-Base Disorders : Condition Expected Compensation | Metabolic acidosis Maximally compensated: expected PCO, = (1.5) [HCO3]+ 8 +2 (Winter's formula)

TABLE 8. Compensation in Acid-Base Disorders : Condition Expected Compensation | Metabolic acidosis Maximally compensated: expected PCO, = (1.5) [HCO3]+ 8 +2 (Winter's formula) Measured PCO, > expected: complicating primary respiratory acidosis Measured PCO; < expected: complicating primary respiratory alkalosis Metabolic alkalosis For each T 1.0 mEq/L (1.0 mmol/L) in [HCO3], PCO, T 0.7 mm Hg (0.09 kPa) Respiratory acidosis Acute: 1.0 mEq/L(1.0 mmol/L) T [HCO3] for each 10 mm Hg (1.3 kPa) T in PCO> Chronic: 3.5 mEq/L (3.5 mmol/L) T [HCOs3] for each 10 mm Hg (1.3 kPa) Tin PCO [HCO3] < expected value: complicating metabolic acidosis [HCO3] > expected value: complicating metabolic alkalosis Respiratory alkalosis Acute: 2.0 mEq/L (2.0 mmol/L) | [HCO] for each 10 mm Hg (1.3 kPa) J in Peo, Chronic: 4.0-5.0 mEq/L (4.0-5.0 mmol/L) [HCO ] for each 10 mm Hg (1.3 kPa) J in PCO, [HCO ] < expected value: complicating metabolic acidosis [HCO3] > expected value: complicating metabolic alkalosis — = j 20

Acid-Base Disorders Most of the adverse effects that occur in patients with (diabetic, alcoholic, or starvation), acute or chronic kidney metabolic acidosis arise from the underlying cause rather injury, or poisoning (methanol, ethylene glycol, salicylate, or than the low pH. But with severe acidosis, patients are sus- propylene glycol). The plasma osmolal gap may assist in iden- ceptible to life-threatening arrhythmia and impaired cardiac tifying a cause. The plasma osmolal gap is the difference function. between the measured and calculated plasma osmolality. The calculated plasma osmolality is determined as follows:

Most of the adverse effects that occur in patients with (diabetic, alcoholic, or starvation), acute or chronic kidney metabolic acidosis arise from the underlying cause rather injury, or poisoning (methanol, ethylene glycol, salicylate, or than the low pH. But with severe acidosis, patients are sus- propylene glycol). The plasma osmolal gap may assist in iden- ceptible to life-threatening arrhythmia and impaired cardiac tifying a cause. The plasma osmolal gap is the difference function. between the measured and calculated plasma osmolality. The calculated plasma osmolality is determined as follows: Plasma Osmolality (mOsm/kg H,0) = (2 x Serum Sodium e The serum anion gap assesses whether the metabolic [mEq/L]) + Plasma Glucose (mg/dL)/18 + Blood Urea Nitrogen acidosis is due to an unmeasured organic anion (mg/dL)/2.8 (increased anion gap metabolic acidosis) or to a loss of bicarbonate (normal anion gap metabolic acidosis). A high osmolal gap (>10 mOsm/kg H,O) indicates the presence of unmeasured osmoles such as alcohol, methanol, e In the presence of an increased anion gap metabolic or ethylene glycol, which are metabolized to organic acids, acidosis, a delta-delta (A-A) ratio of <0.5 to 1 may indi- thereby increasing the anion gap. The patient’s history should cate a concurrent normal anion gap metabolic acidosis, guide further testing for unmeasured anions. and a ratio of >2 may indicate a concurrent metabolic Diabetic ketoacidosis usually presents with an increased alkalosis. anion gap metabolic acidosis due to accumulation of B-hydroxybutyrate and acetoacetate, although it may present Increased Anion Gap Metabolic Acidosis with a normal anion gap due to excretion of ketoacids. Urine Increased anion gap metabolic acidosis occurs when unmeas- dipstick assays for ketones detect acetoacetate using the nitro- ured anions accumulate. Lactic acidosis is the most common prusside assay; however, B-hydroxybutyrate is the dominant cause (Table 9). Less common causes include ketoacidosis ketoacid in diabetic ketoacidosis, so urine dipstick results can

Plasma Osmolality (mOsm/kg H,0) = (2 x Serum Sodium e The serum anion gap assesses whether the metabolic [mEq/L]) + Plasma Glucose (mg/dL)/18 + Blood Urea Nitrogen acidosis is due to an unmeasured organic anion (mg/dL)/2.8 (increased anion gap metabolic acidosis) or to a loss of bicarbonate (normal anion gap metabolic acidosis). A high osmolal gap (>10 mOsm/kg H,O) indicates the presence of unmeasured osmoles such as alcohol, methanol, e In the presence of an increased anion gap metabolic or ethylene glycol, which are metabolized to organic acids, acidosis, a delta-delta (A-A) ratio of <0.5 to 1 may indi- thereby increasing the anion gap. The patient’s history should cate a concurrent normal anion gap metabolic acidosis, guide further testing for unmeasured anions. and a ratio of >2 may indicate a concurrent metabolic Diabetic ketoacidosis usually presents with an increased alkalosis. anion gap metabolic acidosis due to accumulation of B-hydroxybutyrate and acetoacetate, although it may present Increased Anion Gap Metabolic Acidosis with a normal anion gap due to excretion of ketoacids. Urine Increased anion gap metabolic acidosis occurs when unmeas- dipstick assays for ketones detect acetoacetate using the nitro- ured anions accumulate. Lactic acidosis is the most common prusside assay; however, B-hydroxybutyrate is the dominant cause (Table 9). Less common causes include ketoacidosis ketoacid in diabetic ketoacidosis, so urine dipstick results can TABLE 9. Causes of Lactic Acidosis

Plasma Osmolality (mOsm/kg H,0) = (2 x Serum Sodium e The serum anion gap assesses whether the metabolic [mEq/L]) + Plasma Glucose (mg/dL)/18 + Blood Urea Nitrogen acidosis is due to an unmeasured organic anion (mg/dL)/2.8 (increased anion gap metabolic acidosis) or to a loss of bicarbonate (normal anion gap metabolic acidosis). A high osmolal gap (>10 mOsm/kg H,O) indicates the presence of unmeasured osmoles such as alcohol, methanol, e In the presence of an increased anion gap metabolic or ethylene glycol, which are metabolized to organic acids, acidosis, a delta-delta (A-A) ratio of <0.5 to 1 may indi- thereby increasing the anion gap. The patient’s history should cate a concurrent normal anion gap metabolic acidosis, guide further testing for unmeasured anions. and a ratio of >2 may indicate a concurrent metabolic Diabetic ketoacidosis usually presents with an increased alkalosis. anion gap metabolic acidosis due to accumulation of B-hydroxybutyrate and acetoacetate, although it may present Increased Anion Gap Metabolic Acidosis with a normal anion gap due to excretion of ketoacids. Urine Increased anion gap metabolic acidosis occurs when unmeas- dipstick assays for ketones detect acetoacetate using the nitro- ured anions accumulate. Lactic acidosis is the most common prusside assay; however, B-hydroxybutyrate is the dominant cause (Table 9). Less common causes include ketoacidosis ketoacid in diabetic ketoacidosis, so urine dipstick results can TABLE 9. Causes of Lactic Acidosis | Condition Cause Clinical and Laboratory Treatment Comments | Manifestations

Plasma Osmolality (mOsm/kg H,0) = (2 x Serum Sodium e The serum anion gap assesses whether the metabolic [mEq/L]) + Plasma Glucose (mg/dL)/18 + Blood Urea Nitrogen acidosis is due to an unmeasured organic anion (mg/dL)/2.8 (increased anion gap metabolic acidosis) or to a loss of bicarbonate (normal anion gap metabolic acidosis). A high osmolal gap (>10 mOsm/kg H,O) indicates the presence of unmeasured osmoles such as alcohol, methanol, e In the presence of an increased anion gap metabolic or ethylene glycol, which are metabolized to organic acids, acidosis, a delta-delta (A-A) ratio of <0.5 to 1 may indi- thereby increasing the anion gap. The patient’s history should cate a concurrent normal anion gap metabolic acidosis, guide further testing for unmeasured anions. and a ratio of >2 may indicate a concurrent metabolic Diabetic ketoacidosis usually presents with an increased alkalosis. anion gap metabolic acidosis due to accumulation of B-hydroxybutyrate and acetoacetate, although it may present Increased Anion Gap Metabolic Acidosis with a normal anion gap due to excretion of ketoacids. Urine Increased anion gap metabolic acidosis occurs when unmeas- dipstick assays for ketones detect acetoacetate using the nitro- ured anions accumulate. Lactic acidosis is the most common prusside assay; however, B-hydroxybutyrate is the dominant cause (Table 9). Less common causes include ketoacidosis ketoacid in diabetic ketoacidosis, so urine dipstick results can TABLE 9. Causes of Lactic Acidosis | Condition Cause Clinical and Laboratory Treatment Comments | Manifestations Lactic Acidosis See below Serum lactate level >4.0 Treat underlying cause; Most common cause of mEq/L (4.0 mmol/L) sodium bicarbonate increased anion gap when arterial pH is <7.1 metabolic acidosis to raise to 7.2

Lactic Acidosis See below Serum lactate level >4.0 Treat underlying cause; Most common cause of mEq/L (4.0 mmol/L) sodium bicarbonate increased anion gap when arterial pH is <7.1 metabolic acidosis to raise to 7.2 Type A lactic Tissue hypoperfusion Multisystem organ Correct cause of acidosis dysfunction typically present hypoperfusion Type B lactic Absent tissue Often related to drug/ Discontinue/remove acidosis hypoperfusion toxin-related impairment toxin of metabolism Propofol Propofol >4 mg/kg/h for —§ Rhabdomyolysis; Discontinue propofol; Seen with continuous >24h hyperlipidemia; hemodialysis infusion, not bolus dosing cardiogenic shock Metformin Metformin use in Most likely to occur in those Hemodialysis Contraindicated if eGFR patients with impaired with acute kidney injury <30 mL/min/1.73 m2 kidney function

Metformin Metformin use in Most likely to occur in those Hemodialysis Contraindicated if eGFR patients with impaired with acute kidney injury <30 mL/min/1.73 m2 kidney function HIV Mitochondrial toxicity Possible myopathy, Discontinue medication; Risk factors: female sex, nucleoside peripheral neuropathy, supportive care pregnancy, obesity, poor | reverse hepatic steatosis liver function, lower CD4 transcriptase count; mostly: ddl, d4T > inhibitor AZT; rare: TFV, ABC, FTC, SiC Hematologic Thought to be due to Hypoglycemia Treat underlying Portends very poor malignancy anaerobic metabolism malignancy prognosis; seen in high- in cancer cells grade B-cell lymphomas

Hematologic Thought to be due to Hypoglycemia Treat underlying Portends very poor malignancy anaerobic metabolism malignancy prognosis; seen in high- in cancer cells grade B-cell lymphomas D-Lacticacidosis | Short-bowel syndrome?; __ Intermittent confusion; Antibiotics (e.g., Diagnosis requires undigested slurred speech; ataxia; metronidazole or measurement of D-lactate carbohydrates in the increased anion gap neomycin) directed because D-isomer is not colon are metabolized metabolic acidosis with toward bowel flora; measured by conventional to D-lactate by bacteria normal serum lactate level restriction of dietary assays for serum lactate carbohydrates | 3TC=lamivudine; ABC = abacavir; AZT = zidovudine; d4T = stavudine; ddl = didanosine; eGFR = estimated glomerular filtration rate; FTC = emtricitabine; TFV = tenofovir. | ?After jejunoileal bypass or small-bowel resection. ki