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neuromuscular and mild GI symptoms. Cardiac and renal complications typically occur later in disease

progression.

Treatment. Serum calcium concentration >14 mg/dL requires prompt treatment. If combined with

hyperphosphatemia, this situation is even more concerning due to the potential for metastatic

calcification. Initial treatment should include aggressive hydration with 0.9% normal saline with 20

mEq/L potassium with a goal of hydration to promote a urine output greater than 200 mL/hr. Once the

patient is adequately hydrated a trial of furosemide can be performed as long as a positive fluid balance

is maintained and potassium and magnesium are adequately replaced. Other adjuncts include calcitonin

(especially for inhibition of bone resorption), bisphosphonates (especially to treat malignancy), and in

patients with renal failure the use of low-calcium dialysate. Patients with hematologic malignancies and

granulomatous disease can be considered for treatment with steroids. Lastly, for those with

hyperparathyroidism, parathyroidectomy of some form is clearly indicated, with operation type

dependent upon whether the etiology is adenoma or hyperplasia. In medically refractory secondary or

tertiary hyperparathyroidism, total parathyroidectomy with parathyroid autotransplantation or sub-total

parathyroidectomy should be considered.46

Hypocalcemia

There are many causes of hypocalcemia (Table 11-15). Other factors can affect the serum calcium level

as mentioned previously, namely pH and albumin. In critically ill patients the incidence of hypocalcemia

can be up to 85%. From a surgical perspective the most common causes are postsurgical, including

hungry bone syndrome and loss of calcium from circulation.

Table 11-14 Signs and Symptoms of Hypercalcemia

Postsurgical hypocalcemia can occur in any neck surgery, although the incidence is higher with

parathyroidectomy. In non-neck surgery hypocalcemia can occur because of hypoalbuminemia; this does

not affect ionized calcium levels. Other postsurgical causes of hypocalcemia include atrophy of the

remaining parathyroid glands (i.e., after removal of a large parathyroid adenoma), venous congestion,

devascularization or hungry bone syndrome. Transient hypoparathyroidism is seen in up to 20% of

thyroid cancer surgery; this is permanent in 1% or less of cases.

Other surgery-related etiologies include pancreatitis, small bowel fistula, renal failure, massive

transfusion of blood, and severe hypomagnesemia. Pancreatitis-induced hypocalcemia occurs due to

calcium precipitation in peripancreatic tissue. Small bowel fistula can lead to hypocalcemia by loss of

calcium-rich effluent and vitamin D deficiency from malnutrition. Renal failure hypocalcemia is due to

deficiency in 1,25-dihydroxyvitamin D and hyperphosphatemia. Massive transfusion hypocalcemia does

not affect total calcium but decreases ionized calcium as a result of citrate binding to ionized calcium.

Symptoms typically do not occur until calcium levels are below 8 mg/dL. Chronic symptoms include

cataracts, dental changes, and extrapyramidal disorders. Symptoms of acute hypocalcemia are tetany,

papilledema, and seizures. Tetany is defined as repetitive discharges after a single stimulus. Tetany

usually does not occur until ionized calcium is less than 4.3 mg/dL or serum total calcium is less than

7.0 mg/dL. Alkalosis also plays a strong role in the development of tetany, even beyond its association

with hypocalcemia, as tetany is rarely seen in renal failure patients despite low calcium levels. This is

likely due to the protective effect of concurrent metabolic acidosis. The earliest symptoms of

hypocalcemia are perioral and acral paresthesias. Motor symptoms such as Trousseau sign (induction of

carpopedal spasm by inflation of sphygmomanometer above systolic pressure for 3 minutes) and

Chvostek sign (tap facial nerve and ipsilateral facial muscles twitch) occur later. Of note, Chvostek sign is

seen in up to 10% of normal patients. The last findings to occur are cardiac, in the form of ST segment

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prolongation (Table 11-16).44

Table 11-13 Differential Diagnosis of Hypercalcemia

Table 11-15 Causes of Hypocalcemia

Asymptomatic hypocalcemia needs no treatment as it is most commonly attributed to

hypoalbuminemia with normal ionized calcium. Symptomatic hypocalcemia is best treated with

intravenous infusion of calcium gluconate or calcium chloride. Calcium chloride is faster acting as it

does not require hepatic metabolism to dissociate into an active form, hence is usually the drug of

choice if severely symptomatic. A study during the anhepatic stage of liver transplantation found

equally rapid increase in calcium after administration of calcium chloride and gluconate.47 Calcium

chloride carries a higher risk of irritation of veins and tissue damage should extravasation occur; hence

calcium gluconate should be the drug of choice except in emergent situations. In order to minimize

caustic damage to veins, any form of calcium should be administered at a rate not to exceed 1.5

mEq/min. If prolonged calcium replacement is needed it is recommended to check vitamin D levels and

replace any deficiency with calcitriol, in addition to giving an oral form of calcium such as calcium

carbonate, calcium citrate, or calcium lactate.

Table 11-16 Clinical Manifestations of Hypocalcemia

Magnesium

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Half of the total body magnesium is confined to bone. Most of the remaining magnesium is

intracellular, with less than 1% of total body magnesium found extracellular. Magnesium is primarily

absorbed in the small intestine and is influenced by 1,25-dihydroxyvitamin D3. The other source of

magnesium is bone.

Hypermagnesemia

Outside of renal failure, hypermagnesemia is rare, as the kidneys have a strong ability to excrete large

amounts of magnesium. Instances do occur with severe burns, crush injuries, or other causes of

rhabdomyolysis but usually in the setting of renal insufficiency. Symptoms of hypermagnesemia include

loss of deep tendon reflexes at levels greater than 8 mg/dL. Once levels are greater than 12 mg/dL

paralysis can occur. Cardiac arrest can occur if levels exceed 18 mg/dL. The mainstay of treatment is

intravenous calcium to antagonize the effect of magnesium, volume expansion or loop diuretic

depending on volume status, correction of acid–base disturbances and if needed, hemodialysis.

Hypomagnesemia

Kidneys are also able to conserve magnesium quite well with about 40% reabsorption in the proximal

tubule. Most instances of hypomagnesemia occur with chronic malnutrition, prolonged intravenous fluid

replacement without magnesium, and loop diuretics. Other causes include pancreatitis and diabetic

ketoacidosis (DKA). Magnesium functions as a cofactor for many neuromuscular functions, thus

deficiency can lead to muscle fasciculation or tetany. The treatment depends on the severity, which

includes taking into account symptoms and magnesium level. For instance, if serum magnesium level is

less than 1 mEq/L or if the patient is hemodynamically unstable or is in a torsade de pointes arrhythmia

then immediate infusion of intravenous magnesium sulfate is indicated. The maximum recommended

rate would be 150 mg/min excluding the above emergent situations where it can be given as IV push or

over 5 minutes for torsade de pointes. If the patient has chronic or mild hypomagnesemia, oral doses of

magnesium should be used, with options including magnesium oxide, magnesium chloride, and

magnesium hydroxide (milk of magnesia) depending on side-effect profiles. It should be noted that

doses greater than 80 mEq/day can become cathartic.

ACID–BASE

An acid is defined as a chemical that can donate a hydrogen ion (H+), for example, HCl and H2CO3

. A

base is a chemical that can accept an H+, for example, OH− and HCO3−. Ampholytes are both acids and

bases; an example is H2PO4−, which can donate an H+ to become HPO4

2− but can also accept H+ to

become H3PO4

. Bases are commonly anions, but neutral substances can also function as bases (e.g.,

ammonia and creatinine). Some chemicals do not fit the classic definition of an acid, although they

retain acidic properties when dissociated in water. For example, when CaCl2

is dissolved in water, the

Ca2+ accepts OH− to form Ca(OH)2

.

The concentration of hydrogen ions [H+] determines the acidity of a solution. The pH is the negative

logarithm of [H+] expressed in moles per liter (mol/L). The concentration of H+ in biologic systems is

in the range of nanomoles (10−9 mol) per liter (nmol/L). The degree to which an acid dissociates

determines its strength.

Table 11-17 HCO3

− and PCO2 Derangements in Primary and Secondary Acid–Base

Disturbances

The Henderson–Hasselbalch equation describes pH as a measure of acidity in a biologic system.

pH = pKa + log10

([A-]/[HA])

pKa = Negative log of the acid dissociation constant

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A- = Conjugate base

HA = Acid–base pair

Buffer Systems

Buffers are chemicals in solution that tend to minimize changes in pH that would otherwise occur after

the addition of acid or alkali. For instance, if a strong base is added to a weak acid, the base is

neutralized:

NaOH - H2CO3 → NaHCO3 + H2O

One type of buffer is a mixture of a weak acid and its salt. The presence of such buffer systems in the

body is crucial in minimizing changes in pH, which can be deleterious to cell function.

The principal intracellular buffers are organic phosphates, bicarbonate, and peptides. In addition,

hemoglobin functions as a significant buffer in red blood cells. The major extracellular buffer is

bicarbonate. An approximation of the total body buffer capacity is 15 mEq/kg. More than half of the

total body alkaline buffer content is located outside the ECF and may in large part reside in bone.50 The

buffer pair carbonic acid/bicarbonate (H2CO3/HCO3−) is the primary buffer system of the body.

From a chemical point of view, the ideal buffer should have a pKa that allows normal physiologic pH.

The H2CO3/HCO3− buffer system has a pKa of only 6.1, which is not the normal body pH. That said,

this buffer system is efficient because of the presence of large amounts of bicarbonate, the conversion of

its acid H2CO3

to CO2

that is rapidly excreted through the lungs, and an inexhaustible supply of CO2

from metabolism.

Acid–Base Disturbances

9 There are four primary acid–base disturbances, each of which are related to changes in either

[HCO3−] or PCO2

. These are categorized as metabolic and/or respiratory (Table 11-17). A metabolic

acidosis is a decrease in pH as a result of a relative decrease in [HCO3−], whereas a metabolic alkalosis

is an increase in pH caused by a relative increase in [HCO3−]. A respiratory acidosis is a decrease in pH

secondary to a relative increase in PCO2

, and a respiratory alkalosis is an increase in pH caused by a

relative decrease in PCO2

. In each of these disorders, compensatory changes occur to minimize changes

in the relative ratio of [HCO3−] to PCO2 and thereby blunt the effect of the primary disturbance on

pH.48,49

Metabolic Acidosis

Anion Gap

The difference in the measured serum cations and anions yields the anion gap. This can be utilized to

identify the etiology of a metabolic acidosis. The most common equation used in practice is as follows:

Anion gap = [Na+] - ([Cl

-] + [HCO3])

The normal value of serum anion gap is approximately 3 to 10; however, each laboratory should

establish its own normal. If one includes potassium in the equation then the normal value should be

increased by about 4 mEq/L. The differential for an elevated anion gap acidosis includes: lactic acidosis,

salicylate poisoning, acute or chronic kidney disease, chronic acetaminophen ingestion, ketoacidosis

(i.e., diabetic), and acute or chronic kidney disease. A common mnemonic used to address etiologies is

the acronym: MUDPILES: methanol, uremia, diabetic ketoacidosis, propylene glycol, isoniazid, lactic

acidosis, ethylene glycol, and salicylates.

Mechanisms of Metabolic Acidosis

Four mechanisms result in a decrease in extracellular bicarbonate concentration and metabolic acidosis:

1. Dilutional acidosis. Rapid infusion of an alkali-free solution results in dilution of the bicarbonate

concentration.

2. Increased acid generation (e.g., lactic acidosis, ketoacidosis, salicylate poisoning).

3. Diminished renal acid excretion (e.g., renal failure or type I renal tubular acidosis [RTA]).

4. Decreased body bicarbonate content (e.g., severe diarrhea, fistula, type II RTA).

Table 11-18 Compensatory Mechanisms

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