Electrolytes and Diuretics

Sodium

Hyponatremia

Hyponatremia, defined as Na ⁺ less than135 mEq/L or mM, is the most common electrolyte disturbance in hospitalized patients with a prevalence reaching 30%. It is associated with a high mortality. In most cases of hyponatremic hospitalized patients, total body Na ⁺ is either normal or increased. The most common clinical associations with hyponatremia include the postoperative state, acute intracranial disease, malignant disease, medications, and acute pulmonary 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 mM) include anorexia, nausea, vomiting, cramps, weakness, altered level of consciousness, coma, and seizures. Acute central nervous system (CNS) manifestations relate to brain swelling. Because the blood-brain barrier is poorly permeable to Na ⁺ 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 ⁺ can lead to abrupt brain dehydration ( Fig. 42.1 ).

Hyponatremia can be classified as true hypoosmotic hyponatremia, pseudohyponatremia, or syndrome of inappropriate secretion of antidiuretic hormone (SIADH) ( Tables 42.2, 42.3, and 42.4 ). Pseudohyponatremia is an artifact associated with the use of flame photometry, now an obsolete technique, to measure plasma Na ⁺ in severely hyperproteinemic or hyperlipidemic patients. The current analytic method, direct potentiometry, directly measures Na ⁺ and is uninfluenced by plasma components such as proteins and lipids.

TABLE 42.2

Causes of True Hypo-osmotic Hyponatremia

Hypovolemia

Renal losses (urinary sodium > 20 mEq/L) Diuretic therapy Mineralocorticoid deficiency Cerebral salt-wasting syndrome (e.g., subarachnoid hemorrhage) Renal disease Renal tubular acidosis (bicarbonaturia with renal tubular acidosis and metabolic alkalosis) Renal tubular defect (salt-wasting nephropathy) External losses (urinary sodium <20 mEq/L) Gastrointestinal disease—vomiting, diarrhea, gastric suctioning Skin losses—burns, sweating, cystic fibrosis Pancreatitis Trauma

Hypervolemia

Renal causes (urinary sodium >20 mEq/L) Renal failure Other causes (urinary sodium <20 mEq/L) Congestive heart failure Hepatic cirrhosis Nephrotic syndrome Pregnancy

Euvolemia (Urinary Sodium >20 mEq/L)

Glucocorticoid deficiency

Hypothyroidism

Syndrome of inappropriate antidiuretic hormone Reset osmostat—psychosis, malnutrition

TABLE 42.3

Causes of Pseudohyponatremia

Normal Plasma Osmolality

Hyperlipidemia Hyperproteinemia Transurethral resection of prostate, hysteroscopy

Increased Plasma Osmolality

Hyperglycemia Mannitol administration

TABLE 42.4

Causes of Syndrome of Inappropriate Secretion of Antidiuretic Hormone

Malignancy

Lung (especially small cell carcinoma) Central nervous system Pancreas

Pulmonary

Pneumonia Tuberculosis Fungal Abscess

Neurologic

Infection Trauma Cerebrovascular accident

Drugs

Amitriptyline Chlorpropamide Cyclophosphamide Desmopressin Morphine Nicotine Nonsteroidal antiinflammatory drugs Oxytocin Selective serotonin reuptake inhibitors Vincristine

Hyponatremia can be isotonic (plasma osmolality [P _osm ] 280–295 mOsm/kg), hypotonic (P _osm < 280 mOsm/kg), or hypertonic (P _osm > 295 mOsm/kg). Calculated plasma osmolality is determined by the following formula:

$P_{osm}=2.0\times \left[{\text{Na}}^{+}\right]+\text{Glucose}/18+\text{BUN}/2.8,$

where serum Na ⁺ is measured in millimoles, and blood glucose and blood urea nitrogen (BUN) are expressed as milligrams per deciliter. Other minor solutes such as Ca ²⁺ , Mg ²⁺ , and K ⁺ make a small contribution to plasma osmolality. Considering plasma is 93% water and Na ⁺ is not completely dissociated into solution, these factors tend to cancel out.

Patients with disorders such as hypoproteinemia or hyperlipidemia that cause increased osmolality and pseudohyponatremia have an abnormal osmolality gap. These disorders highlight the importance of measuring plasma osmolality in hyponatremic patients. Hyponatremia with a normal or high serum osmolality results from the presence of a nonsodium solute, such as glucose or mannitol, that holds water within the extracellular space and results in dilutional hyponatremia. The presence of a nonsodium solute resulting in “factitious” hyponatremia can be inferred if measured osmolality exceeds calculated osmolality by more than 10 mOsm/kg. For example, plasma Na ⁺ decreases approximately 2.4 M for each 100-mg/dL rise in glucose concentration, with perhaps even greater decreases for glucose concentrations higher than 400 mg/dL.

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, glycine, or sorbitol) during transurethral resection of the prostate. 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, hypoosmolality can gradually develop and cerebral edema can appear as a late complication. Consequently, hypoosmolality is more important in generating symptoms than hyponatremia per se. The problem of excessive fluid absorption during transurethral resection of the prostate can be monitored by using small amounts of alcohol in the irrigating fluid; the level of alcohol can be detected in expired air as a quantitative measure of irrigating fluid absorption. True hyponatremia with a normal or elevated serum osmolality also can accompany renal insufficiency. BUN, included in the calculation of total osmolality, distributes throughout both ECV and intracellular volume (ICV). Calculation of effective osmolality (2 Na ⁺ + glucose/18) excludes the contribution of urea to tonicity and demonstrates true hypotonicity.

True hyponatremia ( Fig. 42.2 , Table 42.5 ) with low serum osmolality can be associated with a high, low, or normal total body Na ⁺ and PV. Therefore hyponatremia with hyposmolality is evaluated by assessing total body Na ⁺ content, BUN, serum creatinine (SCr), urinary osmolality, and urinary Na ⁺ . Hyponatremia with increased total body Na ⁺ is characteristic of edematous states—that is , congestive heart failure (CHF), cirrhosis, nephrosis, and renal failure. Aquaporin 2, the vasopressin-regulated water channel, is upregulated in experimental CHF and cirrhosis and decreased by chronic vasopressin stimulation. In patients with renal insufficiency, reduced urinary diluting capacity can lead to hyponatremia if excess free water is given.

TABLE 42.5

Classification of Hypotonic Hyponatremia by Volume Status

HYPOVOLEMIC		EUVOLEMIC	HYPERVOLEMIC
Extrarenal Na + Loss (FE Na < 1%, U Na < 20 mEq/L)	Renal Na + Loss (FE Na > 2%, U Na > 20 mEq/L)	(FE Na < 1%, U Na > 20 mEq/L)	(U Na < 20 mEq/L)
Dehydration Diarrhea Vomiting Gastrointestinal suctioning Skin losses Trauma Pancreatitis	Diuretics Osmotic diuresis Salt-losing nephropathy Mineralocorticoid deficiency	Glucocorticoid deficiency SIADH Hypothyroidism Psychogenic polydipsia (>15 L/day) Beer potomania/malnutrition (alcoholism, anorexia)	CHF Liver disease Nephrotic syndrome Pregnancy

CHF, Congestive heart failure; FE _Na , fractional excretion of sodium; SIADH, syndrome of inappropriate secretion of antidiuretic hormone; U _Na , urine sodium.

The underlying mechanism of hypovolemic hyponatremia is secretion of ADH in response to volume contraction with ongoing oral or IV intake of hypotonic fluid. 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 of the nephron. Hypovolemic hyponatremia associated with a urinary Na ⁺ greater than 20 mM suggests mineralocorticoid deficiency, especially if serum K ⁺ , BUN, and SCr are increased.

The cerebral salt-wasting syndrome is an often severe, symptomatic salt-losing diathesis that appears to be mediated by brain natriuretic peptide and is independent of SIADH. Patients at risk include those with cerebral lesions caused by trauma, subarachnoid hemorrhage, tumors, and infection.

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 Na ⁺ and ECV are relatively normal and edema is rarely evident. SIADH can be idiopathic but also is associated with CNS or pulmonary diseases (see Table 42.4 ). Euvolemic hyponatremia is usually associated with exogenous ADH administration, pharmacologic potentiation of ADH action, drugs that mimic the action of ADH in the renal tubules, or excessive ectopic ADH secretion. Tissues from some small cell lung cancers, duodenal cancers, and pancreatic cancers increase ADH production in response to osmotic stimulation.

At least 4.0 % of postoperative patients develop plasma Na ⁺ less than 130 mM. 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 herniation, attributable in part to IV administration of hypotonic fluids, secretion of ADH, and other factors, including drugs and altered renal function, that influence perioperative water balance. Menstruating women are particularly vulnerable to brain damage secondary to postoperative hyponatremia. Smaller patients change plasma Na ⁺ more in response to similar volumes of hypotonic fluids. Based on a report of apparent postoperative SIADH in a 30-kg, 10-year-old girl, it has been suggested that children receive no sodium-free water perioperatively. Postoperative hyponatremia can develop even with infusion of isotonic fluids if ADH is persistently increased. Twenty-four hours after surgery, mean plasma Na ⁺ in patients undergoing uncomplicated gynecologic surgery decreased from 140 to 136 mM. Although the patients retained Na ⁺ perioperatively, they retained proportionately more water (an average of 1.1 L of electrolyte-free water). Careful postoperative attention to fluid and electrolyte balance can minimize the occurrence of symptomatic hyponatremia.

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 (see Fig. 42.2 and Table 42.5 ). In hypovolemic patients or edematous patients, the ratio of BUN to SCr should be greater than 20 : 1. Urinary Na ⁺ is generally less than 20 mM in edematous states and volume depletion, and greater than 20 mM in hyponatremia secondary to renal salt wasting or renal failure with water retention.

Criteria for the diagnosis of SIADH include hypotonic hyponatremia, urinary osmolality greater than 100 to 150 mmol/kg, absence of ECV depletion, normal thyroid and adrenal function, and normal cardiac, hepatic, and renal function. Urinary Na ⁺ should be greater than 20 mM unless fluids have been restricted. The diagnosis of SIADH is inaccurately applied to functionally hypovolemic postoperative patients, in whom, by definition, ADH secretion would be “appropriate.”

Treatment of hyponatremia associated with normal or high serum osmolality requires reduction of the elevated concentrations of the responsible solute. Uremic patients are treated by free water restriction or dialysis. Treatment of edematous (hypervolemic) patients necessitates restriction of both sodium and water. Therapy is directed toward improving cardiac output and renal perfusion and using diuretics to inhibit Na ⁺ reabsorption. In hypovolemic, hyponatremic patients, blood volume must be restored, usually by infusion of 0.9 % saline solution, and excessive Na ⁺ losses must be curtailed. Correction of hypovolemia usually results in removal of the stimulus for ADH 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 total body water (TBW) by 0.5 to 1.0 l/day, decreases ECV even if excessive ADH secretion continues. The resultant reduction in glomerular filtration rate (GFR) enhances proximal tubular reabsorption of salt and water, thereby decreasing free water reabsorption, and stimulates aldosterone secretion. As long as free water losses (i.e., renal, skin, gastrointestinal) exceed free water intake, serum Na ⁺ will increase. During treatment of hyponatremia, increases in plasma Na ⁺ are determined by both the composition of the infused fluid and the rate of renal free water excretion. Free water excretion can be increased by administering furosemide. However, the correction of hyponatremia continues to generate controversy. When plasma Na ⁺ is less than 130 mM or hyponatremia is present together with cerebral symptoms, it is recommended to immediately administer one or more IV boluses of 2 mL/kg of 3% NaCl. This should result in a prompt response and should be followed by boluses every 5 to 10 minutes as needed. Symptoms should disappear when plasma Na ⁺ has risen by 4 to 6 mM.

This approach differs from a previously advocated focus on a separation between acute and chronic causes for hyponatremia. Apart from the fact that this can be very difficult to distinguish based on history and physical examination, when hyponatremia is seriously symptomatic the problem must be addressed expeditiously. When cerebral function has been restored, there is an inadvertent risk of overcorrection with the risk of osmotic demyelination. There are no prospective studies of the absolute safe speed for correction of hyponatremia. Goals can be set to 8 mM in 24 hours, 14 mM in 48 hours, and 16 mM in 72 hours. A formula for predicting changes of plasma Na ⁺ is shown in the following equation:

${\left[N{a}^{+}\right]}_2=\frac{{\left[N{a}^{+}\right]}_1\times TBW+\Delta (N{a}^{+}+K^{+})}{TBW+\mathrm{\Delta TBW}},$

where Na ⁺ ₁ is the initial plasma Na ⁺ and Na ⁺ ₂ is the concentration in plasma Na ⁺ that results from the change in the external balances of water (TBW + ΔTBW) and cations Δ Na ⁺ + K ⁺ ). Treatment should be interrupted or slowed when symptoms improve. Frequent determinations of Na ⁺ are important to prevent too rapid correction. It is also important to insert a bladder catheter for close tracking production of urine, which should be analyzed to determine Na ⁺ and K ⁺ .

Although delayed correction of hyponatremia can result in neurologic injury, inappropriately rapid correction can result in abrupt brain dehydration (see Fig. 42.1 ), permanent neurologic sequelae, cerebral hemorrhage, or CHF. The symptoms of the 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 syndrome is more likely when hyponatremia has persisted longer than 48 hours. Most patients in whom the syndrome is fatal have undergone correction of plasma Na ⁺ of more than 20 mM/day. Even a moderate decrease in Na ⁺ in pigs can cause significant brain edema. Other risk factors for development of the syndrome include alcoholism, poor nutritional status, liver disease, burns, and hypokalemia.

For patients who require long-term pharmacologic therapy of hyponatremia, demeclocycline is the drug of choice. Although better tolerated than lithium, demeclocycline can induce nephrotoxicity, a concern in patients with hepatic dysfunction. Hemodialysis is occasionally necessary in severely hyponatremic patients whose condition cannot be adequately managed with drugs or hypertonic saline solution. Once hyponatremia has improved, careful fluid restriction is necessary to avoid recurrence.

Vasopressin receptor antagonists (arginine vasopressin [AVP] antagonists) are a class of drugs that exert their effects by inhibiting 1 of 3 subtypes of vasopressin receptors. Vasopressin receptors V1 _a and V1 _b act via the inositol trisphosphate pathway to increase cytosolic Ca ²⁺ as a second messenger, whereas V2 receptors act via the adenylyl cyclase pathway to increase cyclic adenosine monophosphate (cAMP) as a second messenger. V1 _a activation produces vasoconstriction, platelet aggregation, inotropic stimulation, and myocardial protein synthesis. V1 _b activation leads to pituitary adrenocorticotrophic hormone secretion. V2 activation causes antidiuretic effects by activity on the renal collecting ducts. The ideal treatment would increase Na ⁺ free water clearance and increase serum Na ⁺ . Conivaptan is a dual antagonist of V1 _a and V2 receptors used for euvolemic or hypervolemic hyponatremia. Tolvaptan is an orally active, nonpeptide, selective V2 receptor antagonist. It increases free water clearance, decreases urine osmolality, and increases Na ⁺ and can be used for hyponatremic patients with heart failure and SIADH that resists water restriction.

Physiologic Role

Potassium ion (K ⁺ ) is perhaps the most frequently supplemented electrolyte. Potassium plays an important role in cell membrane physiology, especially in maintaining resting membrane potential and in generating action potentials in the nervous system and heart. Potassium is actively transported into cells by sodium potassium adenosine triphosphatase (Na,K-ATPase; Na ⁺ pump), which maintains intracellular K ⁺ at least 30-fold greater than extracellular K ⁺ . Intracellular K ⁺ concentration (K ⁺ ) is normally 150 mM, while the extracellular concentration is only 3.5 to 5.0 mM. Serum K ⁺ measures about 0.5 mM higher than plasma K ⁺ owing to cell lysis during clotting. Total body K ⁺ in a 70-kg adult is approximately 4256 mEq, of which 4200 mEq is intracellular; of the 56 mEq in the ECV, only 12 mEq is in the PV. Common causes of K ⁺ losses are shown in Table 42.7 . The ratio of intracellular to extracellular K ⁺ contributes to the resting potential difference across cell membranes and therefore to the integrity of cardiac and neuromuscular transmission.

Extracellular K ⁺ is determined by catecholamines, the renin-angiotensin-aldosterone system, glucose, and insulin, as well as direct release from exercising or injured muscle. The primary mechanism that maintains K ⁺ inside cells is transport of three Na ⁺ ions out of the cell for every two K ⁺ ions transported in by the Na,K-ATPase pump. Both insulin and β- adrenergic agonists promote K ⁺ entry into cells ( Fig. 42.3 ). In contrast, α-adrenergic agonists impair cellular K ⁺ uptake. Metabolic acidosis tends to shift K ⁺ out of cells, whereas metabolic alkalosis favors movement into cells.

Usual K ⁺ intake is 50 to 150 mEq/day. Freely filtered at the glomerulus, most K ⁺ excretion is urinary with some fecal elimination. Most filtered K ⁺ is reabsorbed; excretion is usually approximately equal to intake. As long as GFR is greater than > 8 mL/kg, dietary K ⁺ intake, unless greater than normal, can be excreted. Assuming plasma K ⁺ of 4.0 mM and normal GFR of 180 L/day, 720 mEq of K ⁺ 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 K ⁺ excretion is regulated. Excretion of K ⁺ ions is a function of open K ⁺ channels and the electrical driving force in the cortical collecting duct.

The two most important regulators of K ⁺ excretion are plasma K ⁺ and aldosterone, although there is some evidence to suggest involvement of the CNS and of an enteric reflex mediated by potassium-rich meals. 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 non-reabsorbable anions such as carbenicillin, phosphates, and sulfates. As Na ⁺ reabsorption increases, the electrical driving force opposing reabsorption of K ⁺ is increased. Aldosterone increases Na ⁺ reabsorption by inducing opening of the epithelial Na ⁺ channel ; potassium-sparing diuretics (amiloride and triamterene) and trimethroprim block the epithelial Na ⁺ channel, thereby increasing K ⁺ reabsorption. Magnesium depletion contributes to renal K ⁺ wasting.

Hypokalemia

Uncommon among healthy persons, hypokalemia (K ⁺ < 3.0 mM) is a frequent complication of treatment with diuretic drugs (see the “ Diuretics ” section) and occasionally complicates other diseases and treatment regimens. Generally, a chronic decrement of 1.0 mM in plasma K ⁺ corresponds to a total body deficit of approximately 200 to 300 mEq. In uncomplicated hypokalemia, the K ⁺ deficit exceeds 300 mEq if plasma K ⁺ is less than 3.0 mM and 700 mEq if plasma K ⁺ is less than 2.0 mM. Plasma K ⁺ poorly reflects total body K ⁺ ; hypokalemia can occur with normal, low, or high total body K ⁺ .

Hypokalemia causes muscle weakness and, when severe, even paralysis. With chronic K ⁺ loss, the ratio of intracellular to extracellular K ⁺ remains relatively stable; in contrast, acute redistribution of K ⁺ from the extracellular to the intracellular space substantially changes resting membrane potential.

Cardiac rhythm disturbances are among the most dangerous complications of hypokalemia. Acute hypokalemia causes hyperpolarization of cardiac cells that can lead to ventricular escape activity, reentrant phenomena, ectopic tachycardias, and delayed conduction. In patients taking 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 ⁺ less than 3.5 mM has been associated with an increased incidence of perioperative dysrhythmias, especially atrial fibrillation/flutter, in cardiac surgical patients.

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 might not improve for several months after treatment. If hypokalemia is sufficiently prolonged, chronic renal interstitial damage can occur. In experimental animals, hypokalemia is associated with intrarenal vasoconstriction and a pattern of renal injury similar to that produced by ischemia. Hypokalemia can result from chronic depletion of total body K ⁺ or from acute redistribution of K ⁺ from the ECV to the ICV. Redistribution of K ⁺ into cells occurs when the activity of the Na,K-ATPase pump is acutely increased by hyperkalemia or increased intracellular concentration of Na ⁺ , as well as by insulin, carbohydrate loading (which stimulates release of endogenous insulin), β ₂ -adrenergic agonists, or aldosterone. Both metabolic and respiratory alkalosis lead to decreases in plasma K ⁺ .

Causes of chronic hypokalemia include those associated with renal K ⁺ conservation (extrarenal K ⁺ losses; low urinary K ⁺ ) and those with renal K ⁺ wasting. Low urinary K ⁺ suggests inadequate dietary intake or extrarenal depletion (in the absence of recent diuretic use). Diuretic-induced urinary K ⁺ losses are frequently associated with hypokalemia secondary to increased aldosterone secretion, alkalemia, and increased renal tubular flow. Aldosterone does not cause renal K ⁺ wasting unless Na ⁺ is present (i.e., aldosterone primarily controls Na ⁺ reabsorption, not K ⁺ excretion). Renal tubular damage owing to nephrotoxins such as aminoglycosides or amphotericin B can also cause renal K ⁺ wasting.

Initial evaluation of hypokalemia includes a medical history (diarrhea, vomiting, diuretic or laxative use), physical examination (hypertension, cushingoid features, and edema), measurement of serum electrolytes (Mg ²⁺ ), arterial pH assessment, and evaluation of the electrocardiogram (ECG). Many trauma patients develop hypokalemia that returns to normal within 24 hours without specific therapy. Measurement of 24-hour urinary excretion of Na ⁺ and K ⁺ can 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 can be helpful in the differential diagnosis. Characteristic electrocardiographic changes associated with hypokalemia include flat or inverted T waves, prominent U waves, and ST-segment depression.

The treatment of hypokalemia consists of K ⁺ repletion, correction of alkalemia, and removal of offending drugs ( Table 42.8 ). Hypokalemia secondary only to acute redistribution might not require treatment. There is no urgent need for K ⁺ replacement therapy in mild to moderate hypokalemia (3–3.5 mM) in asymptomatic patients. If total body K ⁺ is decreased, oral K ⁺ supplementation is preferable to IV replacement. Potassium is usually replaced as the chloride salt because coexisting chloride deficiency can limit ability of the kidney to conserve K ⁺ .

Potassium repletion must be performed cautiously, usually at a rate of 10 to 20 mEq/hr or lower, because the magnitude of K ⁺ deficits is unpredictable. Plasma K ⁺ and the ECG must be monitored during rapid repletion (10–20 mEq/hr) to avoid hyperkalemic complications. Particular attention should be given to patients with concurrent acidemia, type IV renal tubular acidosis, diabetes mellitus (DM), or those receiving nonsteroidal antiinflammatory agents, angiotensin-converting enzyme (ACE) inhibitors, or β blockers, all of which delay movement of extracellular K ⁺ into cells.

In patients with life-threatening dysrhythmias secondary to hypokalemia, serum K ⁺ must be rapidly increased. Assuming PV in a 70-kg adult is 3.0 L, administration of 6.0 mEq of potassium over a minute will increase serum K ⁺ by no more than 2.0 mM because redistribution into interstitial fluid will decrease the quantity remaining in plasma.

Hypokalemia associated with hyperaldosteronemia (e.g., primary aldosteronism, Cushing syndrome) usually responds favorably to reduced Na ⁺ intake and increased K ⁺ intake. Hypomagnesemia, if present, aggravates the effects of hypokalemia, impairs K ⁺ conservation, and should be treated. Potassium supplements or potassium-sparing diuretics should be given cautiously to patients who have DM or renal insufficiency, which limit compensation for acute hyperkalemia. In patients who are both hypokalemic and acidemic, such as those who have diabetic ketoacidosis, K ⁺ administration should precede correction of acidosis to avoid a precipitous decrease in plasma K ⁺ as pH increases.

Hyperkalemia

The most lethal manifestations of hyperkalemia (K ⁺ > 5.0 mM) involve the cardiac conduction system: dysrhythmias, conduction abnormalities, and cardiac arrest. A classic example of hyperkalemic cardiac toxicity is associated with the administration of succinylcholine to paraplegic, quadriplegic, or severely burned patients. If plasma K ⁺ is less than 6.0 mM, cardiac effects are negligible. As K ⁺ increases further, the ECG 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. Hyperkalemic cardiotoxicity is enhanced by hyponatremia, hypocalcemia, or acidosis. Because progression to fatal cardiotoxicity is unpredictable and often swift, the presence of hyperkalemic electrocardiographic 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 mM and can progress to flaccid paralysis, inability to phonate, and respiratory arrest.

The most important diagnostic issues are history, emphasizing recent drug therapy, and assessment of renal function. If hyponatremia is also present, adrenal function should be evaluated. Although the ECG can 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.

Hyperkalemia can occur with normal, high, or low total body K ⁺ stores. Deficiency of aldosterone, a major regulator of K ⁺ excretion, leads to hyperkalemia in adrenal insufficiency and hyporeninemic hypoaldosteronism, a state associated with DM, renal insufficiency, and advanced age. Because the kidneys excrete K ⁺ , severe renal insufficiency commonly causes hyperkalemia. Patients with chronic renal insufficiency can maintain normal plasma K ⁺ despite markedly decreased GFR because urinary K ⁺ excretion depends on tubular secretion rather than glomerular filtration when the GFR exceeds 8 mL/min.

Drugs are now the most common cause of hyperkalemia, especially in elderly patients. Drugs that can limit K ⁺ excretion include nonsteroidal antiinflammatory 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 DM, renal insufficiency, advanced age, or hyporeninemic hypoaldosteronism. ACE inhibitors are particularly likely to produce hyperkalemia in patients who have CHF.

In patients with normal total body K ⁺ , hyperkalemia can accompany a sudden shift of K ⁺ from the ICV to the ECV because of acidemia, increased catabolism, or rhabdomyolysis. Metabolic acidosis and respiratory acidosis can also cause an increase in plasma K ⁺ . However, organic acidosis (lactic acidosis, ketoacidosis) has little effect on K ⁺ , whereas mineral acids cause significant cellular shifts. In response to increased hydrogen ion activity because of addition of acids, K ⁺ will increase if the anion remains in the extracellular volume. Neither lactate nor ketoacids remain in the extracellular fluid (ECF). Therefore hyperkalemia in these circumstances reflects tissue injury or lack of insulin. Pseudohyperkalemia, which occurs when K ⁺ 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 K ⁺ from the body. Emergent management of severe hyperkalemia is shown in Table 42.9 . Hyperkalemia is best treated with insulin plus glucose, β agonists (see Fig. 42.3 ), and furosemide. Mineralocorticoid deficiency can be treated with 9-αα-fludrocortisone (0.025–0.10 mg/day). Hyperkalemia secondary to digitalis intoxication can be resistant to therapy because attempts to shift K ⁺ from the ECV to the ICV are often ineffective. In this situation, use of digoxin-specific antibodies has been successful.

Membrane hyperexcitability can be antagonized by translocating K ⁺ from the ECV to the ICV, removing excess K ⁺ , or (transiently) by infusing calcium chloride to depress the membrane threshold potential. Pending definitive treatment, rapid infusion of calcium chloride (1 g over 3 minutes, or 2–3 ampoules of 10% calcium gluconate over 5 minutes) can stabilize cardiac rhythm. Calcium should be given cautiously if digitalis intoxication is likely. Acute alkalinization using sodium bicarbonate (50–100 mEq over 5-10 minutes in a 70-kg adult) transiently promotes movement of K ⁺ from the ECV to the ICV. Bicarbonate can be administered even if pH exceeds 7.40; however, it should not be administered to patients with congestive cardiac failure or hypernatremia. When used alone, bicarbonate is relatively ineffective and is no longer favored. Insulin, in a dose-dependent fashion, causes cellular uptake of K ⁺ by increasing the activity of the Na,K-ATPase pump. Insulin increases cellular uptake of K ⁺ best when high insulin levels are achieved by IV injection of 5 to 10 U of regular insulin, accompanied by 50 mL of 50% glucose. β ₂ -Adrenergic drugs such as salbutamol and albuterol also increase K ⁺ uptake by skeletal muscle and reduce plasma K ⁺ , an action that can explain hypokalemia with severe acute illness.

Potassium can also 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 Na ⁺ for K ⁺ , can be given orally (30 g) or as a retention enema (50 g in 200 mL of 20% sorbitol). However, Na ⁺ overload and hypervolemia are potential risks. Rarely, when temporizing measures are insufficient, emergency hemodialysis can remove 25 to 50 mEq/hr. Peritoneal dialysis is less efficient.

Physiologic Role

Calcium is a divalent cation found primarily in the ECF. The free calcium concentration Ca ²⁺ in ECV is approximately 1 mM, whereas the free Ca ²⁺ in the ICV approximates 100 nM, a gradient of 10,000 to 1. Circulating Ca ²⁺ consists of a protein-bound fraction (40%), a chelated fraction (10%), and an ionized fraction (50%), which is the physiologically active and homeostatically regulated component. Acute acidemia increases and acute alkalemia decreases ionized Ca ²⁺ . Because mathematical formulae that “correct” total Ca ²⁺ measurements for albumin concentration are inaccurate in critically ill patients, ionized Ca ²⁺ should be directly measured.

In general, Ca ²⁺ is essential for all movement that occurs in mammalian systems. Essential for normal excitation-contraction coupling, Ca ²⁺ is also necessary for proper function of muscle tissue, swallowing, mitosis, neurotransmitter release, enzyme secretion, and hormonal secretion. cAMP and phosphoinositides, which are major second messengers regulating cellular metabolism, function primarily through the regulation of Ca ²⁺ movement. Activation of numerous intracellular enzyme systems requires Ca ²⁺ . Calcium is important both for generation of cardiac pacemaker activity and for generation of the cardiac action potential for which it is the primary ion responsible for the plateau phase of the action potential. Calcium also plays vital functions in membrane and bone structure.

Serum Ca ²⁺ is regulated by multiple factors ( Fig. 42.4 ), including a Ca ²⁺ receptor and several hormones. Parathyroid hormone (PTH) and calcitriol, the most important neurohumoral mediators of serum Ca ²⁺ , mobilize Ca ²⁺ from bone, increase renal tubular reabsorption of Ca ²⁺ , and enhance intestinal absorption of Ca ²⁺ . 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 Ca ²⁺ intake, PTH and vitamin D can maintain a normal circulating Ca ²⁺ by mobilizing Ca ²⁺ from bone.

Hypocalcemia

Hypocalcemia occurs frequently in critical care, affecting 80% to 90% of patients, and is associated with increased mortality in this population. Hypocalcemia (ionized Ca ²⁺ < 4.0 mg/dL or < 1.0 mM) occurs as a result from failure of PTH or calcitriol action or because of Ca ²⁺ chelation or precipitation, not because of Ca ²⁺ deficiency alone. PTH deficiency can result from surgical damage or removal of the parathyroid glands or from suppression of the parathyroid glands by severe hypomagnesemia or hypermagnesemia. Burns, sepsis, and pancreatitis can suppress parathyroid function and interfere with vitamin D action. Vitamin D deficiency can result from lack of dietary vitamin D or vitamin D malabsorption in patients with low sunlight exposure.

Hyperphosphatemia-induced hypocalcemia can 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 calcium hydrogen phosphate (CaHPO ₄ ) complexes occurs with hyperphosphatemia. However, ionized Ca ²⁺ decreases only approximately 0.019 mM for each 1.0-mM increase in phosphate concentration. In massive transfusion, citrate can produce hypocalcemia by chelating Ca ²⁺ ; however, decreases are usually transient and produce no cardiovascular effects. A healthy, normothermic adult who has intact hepatic and renal function can metabolize the citrate present in 20 units of blood per hour without becoming hypocalcemic. However, when citrate clearance is decreased (e.g., by hepatic or renal disease or hypothermia) and when blood transfusion rates are rapid (e.g., >2 mL/kg per minute), hypocalcemia and cardiovascular compromise can occur. Alkalemia resulting from hyperventilation or sodium bicarbonate injection can acutely decrease Ca ²⁺ . Furthermore, resuscitation-induced hemodilution is an important causative factor of early hypocalcemia in trauma patients. This is an iatrogenic rather than adaptive complication of treatment and can have deleterious effects on blood coagulation and cardiovascular function.

The hallmark of hypocalcemia is increased neuronal membrane irritability and tetany ( Table 42.10 ). Early symptoms include sensations of numbness and tingling involving fingers, toes, and the circumoral region. In frank tetany, tonic contraction of respiratory muscles can 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 can impair cardiovascular function and has been associated with heart failure, hypotension, dysrhythmias, insensitivity to digitalis, and impaired β-adrenergic action.

Reduced ionized serum Ca ²⁺ occurs in as many as 88% of critically ill patients, 66% of less severely ill patients in intensive care units (ICUs), and 26% of non-ICU hospitalized patients. Patients at particular risk include patients after multiple trauma and cardiopulmonary bypass. In most patients, ionized hypocalcemia is clinically mild (Ca ²⁺ 0.8– 1.0 mM).

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 the 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 the Trousseau sign.

The differential diagnosis of hypocalcemia can be approached by addressing four issues: age, serum phosphate concentration, general clinical status, and duration of hypocalcemia. High phosphate concentrations suggest renal failure or hypoparathyroidism. In renal insufficiency, reduced phosphorus excretion results in hyperphosphatemia, which downregulates the 1α-hydroxylase responsible for renal conversion of calcidiol to calcitriol. This, combined with decreased production of calcitriol secondary to reduced renal mass, causes reduced intestinal absorption of Ca ²⁺ and hypocalcemia. Low or normal phosphate concentrations imply vitamin D or Mg ²⁺ deficiency. An otherwise healthy patient with chronic hypocalcemia probably is hypoparathyroid. Chronically ill adults with hypocalcemia often have disorders such as malabsorption, osteomalacia, or osteoblastic metastases.

The definitive treatment of hypocalcemia necessitates identification and treatment of the underlying cause ( Table 42.11 ). Symptomatic hypocalcemia usually occurs when serum ionized Ca ²⁺ is less than 0.7 mM. The clinician should carefully consider whether mild, asymptomatic ionized hypocalcemia requires therapy, particularly in ischemic and septic states in which experimental evidence suggests that Ca ²⁺ can increase cellular damage.

Unnecessary offending drugs should be discontinued. Hypocalcemia resulting from hypomagnesemia or hyperphosphatemia is treated by repletion of Mg ²⁺ or removal of phosphate. Treatment of a patient with tetany and hyperphosphatemia requires coordination of therapy to avoid the consequences of metastatic soft tissue calcification. Potassium and other electrolytes should be measured and abnormalities 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 can provoke tetany.

Mild, ionized hypocalcemia should not be overtreated. For instance, in most patients after cardiac surgery administration of Ca ²⁺ 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, Ca ²⁺ infusion significantly improves contractile performance and blood pressure. Therefore Ca ²⁺ infusions should be of limited value in surgical patients unless there is evidence of 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 (Ca ²⁺ < 0.7 mM) is Ca ²⁺ administration. In patients who have severe hypocalcemia or hypocalcemic symptoms, Ca ²⁺ should be administered intravenously. In emergency situations in an average-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 of 0.3 to 2 mg/kg per hour (i.e., 3–16 mL/h of 10 % calcium gluconate for a 70-kg adult). Calcium salts should be diluted in 50 to 100 mL of dextrose 5% in water (D ₅ W) (to limit venous irritation and thrombosis), should not be mixed with bicarbonate (to prevent precipitation), and must be given cautiously to patients using digoxin because Ca ²⁺ increases its toxicity. Continuous ECG monitoring during initial therapy will detect cardiotoxicity (e.g., heart block, ventricular fibrillation). During Ca ²⁺ replacement, serum Ca ²⁺ , Mg ²⁺ , phosphate, K ⁺ , and creatinine should be monitored. Once the ionized Ca ²⁺ is stable in the range of 4 to 5 mg/dL (1.0–1.25 mM), oral calcium supplements can substitute for parenteral therapy. Urinary Ca ²⁺ should be monitored in attempt to avoid hypercalciuria (>5 mg/kg per 24 hours) and possible urinary tract stone formation.

When supplementation fails to maintain normal serum Ca ²⁺ , or if hypercalciuria develops, vitamin D can be added. Although the principal effect of vitamin D is to increase enteric Ca ²⁺ absorption, osseous Ca ²⁺ 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 are preferable. Because the effect of vitamin D is not regulated, the dosages of Ca ²⁺ and vitamin D should be adjusted to raise serum Ca ²⁺ into the low normal range.

Adverse reactions to Ca ²⁺ and vitamin D include hypercalcemia and hypercalciuria. If hypercalcemia develops, Ca ²⁺ 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, 20–60 days; dihydrotachysterol, 5–15 days; calcitriol, 2–10 days). Glucocorticoids can antagonize the toxic effects of vitamin D metabolites.