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CHAPTER 17:  Fluids and Electrolytes      81 mm CO2 X Y mm CO2 mm CO2 mm CO2 FIGURE 16-2. End-tidal capnogram. Capnogram A depicts a normal capnogram with inspiratory baseline (V), expiratory upstroke (W), expiratory plateau (X), end-tidal concentration (Y), and inspiratory downstroke (Z). Capnogram B represents apnea, which appears as serially decreasing end-tidal concentrations as little gas is expired. Capnogram C represents hypoventilation, which appears as an upward trend in the plateau and end-tidal concentration. Capnogram D represents rebreathing or air trapping, which appears as an increase in the baseline phase of the capnogram. In either case, the Petco 2 value will be lower than the arterial value. These errors may be exacerbated in the setting of obstructive pulmonary disease due to incomplete expiration of gases secondary to air trapping. In a study of ED patients with chronic obstructive pulmonary disease, end-tidal measurements did not significantly vary from presentation to admission and were not clinically different for patients discharged home as compared to those requiring admission. 27 Studies assessing the accuracy of Etco 2 measurements compared to arterial sampling are mixed. In one study of patients presenting to the ED with undifferentiated dyspnea, mainstream Petco 2 did correlate closely with Paco 2.28 In a comparison of healthy individuals, neither mainstream nor side stream sampling accurately predicted the arterial Pco 2.29 A convenience sample of ED patients with an indication for arterial blood gas did not have a close correlation of side stream Etco 2 with the Paco 2.30 Notwithstanding these specific limitations, capnography enjoys a multitude of welldescribed applications in the emergency setting. 31 It is most useful for identifying respiratory compromise in patients undergoing sedation, as hypoventilation appears in the capnogram long before the patient develops hypoxia. 32 Colorimetric carbon dioxide detectors have been used for over a decade to help identify tracheal intubation. End-tidal capnography has also been studied extensively for identification of the return of spontaneous circulation in patients suffering cardiac arrest. Numerous other applications are described in the literature, and further discussion of them is beyond the scope of this chapter. REFERENCES The complete reference list is available online at www.TintinalliEM.com. Fluids and Electrolytes Roberta Petrino Roberta Marino  FLUIDS AND SODIUM PATHOPHYSIOLOGY Total body water (TBW), which accounts for approximately 60% of total body weight, can be divided into intracellular fluid (ICF) and extracel lular fluid (ECF) compartments. The ECF is composed of intravascular fluid and extravascular, or interstitial, fluid. Three fundamental homeostatic equilibriums govern the behavior of fluids: the osmotic equilib rium, the electric equilibrium, and the acid-base equilibrium. CHAPTER Tintinalli_Sec03_p0053-0142.indd 81 8/2/19 2:57 PM

ECF) compartments. The ECF is composed of intravascular fluid and extravascular, or interstitial, fluid. Three fundamental homeostatic equilibriums govern the behavior of fluids: the osmotic equilib rium, the electric equilibrium, and the acid-base equilibrium. CHAPTER Tintinalli_Sec03_p0053-0142.indd 81 8/2/19 2:57 PM 82 SECTION 3: Resuscitation TABLE 17-1 Electrolyte Concentrations of Fluids Solution Plasma Interstitial Intracellular Normal Saline Lactated Ringer’s Solution Multiple Electrolyte Injection * Cations Sodium, mEq/L 142 144 10 154 130 140 Potassium, mEq/L 4 4.5 150 — 4 5 Magnesium, mEq/L† 2 1 40 — — 3 Calcium, mEq/L‡ 5 2.5 — — 3 — Total cations, mEq/L 153 152 200 154 137 148 Anions Chloride, mEq/L 104 113 — 154 109 98 Lactate, mEq/L# — — — — 28 Acetate, mEq/L — — — — — 27 Gluconate, mEq/L — — — — — 23 Phosphates, mEq/L 2 2 120 — — — Sulfates, mEq/L 1 1 30 — — — Bicarbonate, mEq/L 27 30 10 — — — Proteins, mEq/L 13 1 40 — — — Organic acids, mEq/L 6 5 — — — — Total anions 153 152 200 154 137 148 Osmolality, mOsm 285–295 285–295 285–295 286 254 *Multiple electrolyte injection, type 1, is the generic name for Plasma-Lyte 148®, Normosol®, and Isolyte® †Multiply by 0.411 to convert to International System of Units (SI) units in mmol/L. ‡Multiply by 0.25 to convert to SI units in mmol/L. #Multiply by 0.323 to convert to SI units in mmol/L. TABLE 17-2 Definition of Terms Term Definition Comments Mole 6.02 × 1023 molecules of a substance Unit measure used in International System of Units format. Equivalent Mass (in grams) of a mole of a substance divided by charge of substance Unit of measure used in conventional lab values. Osmole Amount of a substance (in moles) that dissociates to form 1 mole of osmotically active particles

molecules of a substance Unit measure used in International System of Units format. Equivalent Mass (in grams) of a mole of a substance divided by charge of substance Unit of measure used in conventional lab values. Osmole Amount of a substance (in moles) that dissociates to form 1 mole of osmotically active particles Osmolarity Measure of solute concentration per unit volume of solvent Osmolarity varies with changing temperature, because water changes its volume according to temperature. Osmolality Measure of solute concentration per unit mass of solvent Osmolality is the preferred measure because it remains constant with changes in temperature. Tonicity or effective osmolality Measure of the osmotic pressure gradient between two solutions, across a semipermeable membrane Tonicity is affected only by solutes that cannot cross a semipermeable membrane. For example, tonicity is not affected by urea or glucose as they cross semipermeable membranes. The key point is that sodium is much more concentrated in the ECF (approximately 140 mEq/L) than in the ICF (approximately 10 mEq/L), but is equal in both compartments of the ECF because the capillary membrane between intravascular fluid and interstitial fluid is permeable to water and electrolytes. In contrast, the cell membrane is permeable to water but not to electrolytes, which are moved through ionic pumps against gradient to keep the intracellular sodium concentration constant around 10 mEq/L and potassium at 150 mEq/L. Table 17-1 lists the electrolyte concentration of body fluids and the most commonly used therapeutic solutions. Table 17-2 defines commonly used terms that describe measures or characteristics of elec trolytes and/or disorders.1 When two solutions are separated by a membrane that is permeable only to water, water crosses into the compartment with the more con centrated solution to equalize the ion concentration in each. The force driving this movement is “osmotic pressure. ” 1 In human fluids, the substances that contribute the most to osmotic pressure in ECF are sodium (Na +) and the anions HCO 3 – and Cl –, plus glucose. In physiology, this force is called effective osmolality or tonicity. The formula to calculate effective osmolality or tonicity is 2 × [Na +] + glucose/18 (normal range, 275 to 290 mOsm/L) When 1 L of free water is added to the ECF , it crosses the cell membrane into the ICF to equalize ECF osmolality. The result is TBW expansion and slight reduction in osmolality ( Figure 17-1). When 1 L of isotonic saline solution 0.9% is added to the ECF , there is no movement of water into the cells, and the final result is ECF expan sion only. In contrast, when there is a fluid loss and a consequent increase in osmolality, osmoreceptors in the hypothalamus stimulate thirst and the release of antidiuretic hormone (ADH, known also as vasopressin) from the pituitary gland. With a decrease in circulating blood volume, low-pressure baroreceptors in the great veins and the right atrium aug ment the effect on the osmoreceptors, with a consequent urine water reabsorption and vasoconstriction. 1-5 The plasma sodium concentration, or tonicity, leads to changes in cell volume. Hypertonic plasma draws water out of the cell into the vascu lature, causing cell shrinkage. In the setting of hypotonic plasma, cells swell with water. DEHYDRATION Dehydration is a loss in TBW caused by either water loss (hyperos molality) or salt loss (hypo-osmolality). 6 Water loss may be caused by inadequate fluid intake to replace insensible loss or excessive diuresis, Tintinalli_Sec03_p0053-0142.indd 82 8/2/19 2:57 PM

of hypotonic plasma, cells swell with water. DEHYDRATION Dehydration is a loss in TBW caused by either water loss (hyperos molality) or salt loss (hypo-osmolality). 6 Water loss may be caused by inadequate fluid intake to replace insensible loss or excessive diuresis, Tintinalli_Sec03_p0053-0142.indd 82 8/2/19 2:57 PM CHAPTER 17:  Fluids and Electrolytes      83 due to hyperglycemia for example. Salt loss can be caused by vomiting, diarrhea, sweating, bleeding, or chronic kidney failure.7 Symptoms of dehydration include thirst, fatigue, dizziness, and ulti mately confusion; signs include sunken eyes, dry mouth and tongue, and tenting of the skin. In elderly patients, dehydration is a cause of delirium, cognitive deterioration, agitation, hallucinations, and delu sions. In these patients, rapid weight loss, dark (concentrated) urine, and behavioral change suggest a diagnosis of dehydration. 8 A combination of factors may precipitate an episode of dehydration, such as chronic antihypertensive medication or diuretic use combined with exposure to high outdoor temperature, an episode of fever, or an acute illness when water intake is insufficient. Table 17-3 lists the screening suggested by the Dehydration Council to evaluate the risk of dehydration.6 HYPONATREMIA Hyponatremia is defined as a serum [Na+] <138 mEq/L. However, symptomatic hyponatremia rarely occurs until [Na+] falls to ≤135 mEq/L. In the setting of normal water intake, high circulating levels of ADH with subsequent water retention are a prerequisite for the development of hyponatremia. 3,10,11 Urine osmolality is always >100 mOsm/L H 2O with the exception of samples from patients with psychogenic polydipsia, which drives down urine osmolality below the typical minimum. Mild hyponatremia is common, with an incidence of 15% to 30% in hospitalized patients; 1% to 4.5% of patients have sodium levels below 126 mEq/L. 10,12 Hyponatremia affects approximately 20% of patients with heart failure, whereas at least 50% of nursing home patients have had one or more episodes of hyponatremia. 8,11 The concentration of Na+ does not give information regarding volume status. Therefore, the first step in the evaluation should include a clinical evaluation of ECF volume status plus comparing measured and calculated plasma osmolalities.  HYPEROSMOLAR HYPONATREMIA (PLASMA OSMOLALITY [P OSM] >295 mOsm/kg H2O) Hyperosmolar hyponatremia occurs when large quantities of osmotically active solutes accumulate in the ECF space. In this setting, there is a net movement of water from the ICF to the ECF , thereby effectively diluting the ECF [Na +]. This happens commonly with severe hyper glycemia. Each 100 milligram/dL increase in plasma glucose above the normal level of 100 milligrams/dL decreases the serum [Na +] by 1.6 mEq/L.1 Other causes of hypertonic hyponatremia are administra tion of osmotic agents such as mannitol, glycerol, and maltose, causing an osmolar gap and hyponatremia. The osmolar gap is the difference between measured osmolality and calculated osmolality. Normally the difference is around 10 mOsm/L; if it is >15 mOsm/L, it means that a nondetectable agent with osmotic activity is present, causing an osmolar gap. A consequent osmotic diuresis will cause [Na +] deficit with volume depletion that should be treated with saline solution.  ISO-OSMOLAR HYPONATREMIA (P OSM 275 TO 295 mOsm/kg H2O) Pseudohyponatremia is a factitiously low value of [Na +] that occurs in the setting of severe hyperproteinemia or hyperlipidemia yielding a measurement error.

c diuresis will cause [Na +] deficit with volume depletion that should be treated with saline solution.  ISO-OSMOLAR HYPONATREMIA (P OSM 275 TO 295 mOsm/kg H2O) Pseudohyponatremia is a factitiously low value of [Na +] that occurs in the setting of severe hyperproteinemia or hyperlipidemia yielding a measurement error. High concentrations of lipids or protein can dis place serum water, which causes laboratory misinterpretation of normal [Na +]; some laboratories use instruments that avoid this laboratory InterstitialNormal Plasma ICFECF InterstitialAdd salt Plasma ICFECF InterstitialAdd water Plasma ICFECF InterstitialAdd isotonic saline Plasma ICFECF FIGURE 17-1. Distribution of total body water into the intracellular fluid (ICF) and extracellular fluid (ECF) compartments. Addition of water expands both compartments. Addition of isotonic saline expands only the ECF, whereas addition of salt without water expands the ECF at the expense of the ICF. [Reproduced with permission from Eaton DC, Poole JP (eds): Vander’s Renal Physiology, 8th ed. New York: McGraw-Hill, Inc.; 2013. Fig 6-1.] TABLE 17-3 Checklist for Evaluation of Dehydration Risk •  Diuretics •  End of life •  High fever •  Yellow urine turns dark •  Dizziness (orthostasis) •  Reduced oral intake •  Axilla dry •  Tachycardia •  Incontinence (fear of, reducing oral intake) •  Oral problems •  Neurologic impairment •  Sunken eyes Tintinalli_Sec03_p0053-0142.indd 83 8/2/19 2:57 PM

Dehydration Risk •  Diuretics •  End of life •  High fever •  Yellow urine turns dark •  Dizziness (orthostasis) •  Reduced oral intake •  Axilla dry •  Tachycardia •  Incontinence (fear of, reducing oral intake) •  Oral problems •  Neurologic impairment •  Sunken eyes Tintinalli_Sec03_p0053-0142.indd 83 8/2/19 2:57 PM 84 SECTION 3: Resuscitation TABLE 17-4 Classification, Differential Diagnosis, and Features of Hyponatremia According to Volume Status Clinical Conditions Orthostatic Hypotension Edema U[Na+], mEq/L UOSM, mOsm/L Hypervolemic hypernatremia CHF Cirrhosis Nephrotic syndrome Acute and chronic kidney disease Absent Yes Compensated: >20 Decompensated: <10 Compensated: <100 Decompensated: >100 Normovolemic hyponatremia Psychogenic polydipsia Glucocorticoid deficit Hypokalemia Drugs SIADH Absent No >20 >100 Renal hypovolemic hyponatremia Diuretics Mineralocorticoid deficit Salt-losing nephropathy Normally present No >20 >100 Extrarenal hypovolemic hyponatremia Vomiting Diarrhea Normally present No <10 >100 Abbreviations: CHF = congestive heart failure; SIADH = syndrome of inappropriate antidiuretic hormone excretion; U[Na+] = urine sodium; UOSM = urine osmolality. TABLE 17-5 Causes of Syndrome of Inappropriate Antidiuretic Hormone Secretion Neurologic and psychiatric disorders •  Infections:  meningitis, encephalitis, brain abscess •   Vascular: hemorrhagic or ischemic stroke, subdural hemorrhage, temporal arteritis, cavernous sinus thrombosis •   Malignancy: primary or metastatic •   Traumatic brain injury •   Psychosis, delirium tremens •   Other: Guillain-Barré syndrome, neurosurgery Drugs •  Cyclophosphamide •  Carbamazepine •  Vinca  alkaloids (chemotherapy agents) •  Thioridazine,  other phenothiazines, haloperidol •   Selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors •  Bromocriptine •  Narcotics,  opiate derivatives •  Amiodarone •  Desmopressin  overtreatment of diabetes insipidus or enuresis Lung diseases •  Tuberculosis •  Lung  abscess, empyema •  Acute  respiratory failure Non-CNS tumors with ectopic production of vasopressin •   Carcinoma of lung (small cell, bronchogenic), duodenum, pancreas, thymus, bladder, prostate, uterus; olfactory neuroblastoma •  Lymphoma,  leukemia •  Sarcoma error; check with your laboratory administrator. Patients are asymptomatic; treatment is not needed.  HYPO-OSMOLAR HYPONATREMIA (P OSM <275 mOsm/kg H2O) The different causes of hypo-osmolar (hypotonic) hyponatremia according to volume status are listed in Table 17-4.2,3 Osmol receptors in the hypothalamus react to low osmolality by secreting ADH, which limits water excretion and increases water reabsorption. In situations such as heart failure, 13,14 cirrhosis,15 and nephrotic syndrome, the effective arte rial blood volume is decreased because water is mainly distributed to the interstitial space. Thus, Na + and water reabsorption are increased, and water excretion is reduced. Two important hyponatremic disorders are the syndrome of inap propriate ADH secretion and the less common cerebral salt-wasting syndrome.1,2,11 Both conditions are diagnoses of exclusion after dis missing other causes of hyponatremia. The onset of both syndromes is linked to chronic cerebral disease, but syndrome of inappropriate ADH secretion may also be caused by noncerebral diseases and conditions as described in Table 17-5. In syndrome of inappropriate ADH secretion, volume status is normal, whereas in cerebral salt-wasting syndrome, there is hypovolemia; therefore, these two disorders are treated differ ently (see treatment section later in this chapter). Methylenedioxymethamphetamine (MDMA or Ecstasy) intoxication is an uncommon but important cause of hyponatremia that may be profound (see also Chapter 188, “Hallucinogens”).

alt-wasting syndrome, there is hypovolemia; therefore, these two disorders are treated differ ently (see treatment section later in this chapter). Methylenedioxymethamphetamine (MDMA or Ecstasy) intoxication is an uncommon but important cause of hyponatremia that may be profound (see also Chapter 188, “Hallucinogens”).  CLINICAL FEATURES The most important symptoms of hyponatremia are due to its effects on the brain; symptoms can be divided into moderately severe and severe, according to a European clinical practice guideline. 3,4 Moderately severe symptoms often start when a plasma [Na +] is <130 mEq/L and consist of headache, nausea, disorientation, confusion, agitation, ataxia, and areflexia. When [Na +] reaches levels <120 mEq/L, severe symptoms may develop including intractable vomiting, seizures, coma, and ultimately respiratory arrest due to brainstem herniation. Brain injury may become irreversible. The symptoms of hyponatremia can be due to many other conditions, and clinicians are cautioned to consider other etiologies before making treatment decisions. 4 The presence of hyponatremiarelated symptoms is directly related to the rapidity of onset. After a certain period, brain cells begin to adapt to hyponatremia. Initially the hypo-osmolality drives water into the brain cells, yielding swelling. 2,3 Due to the rigid skull, intracranial hypertension occurs and the described symptoms begin. After 48 hours, the brain cells start to adapt by extruding Na +, K+, Cl–, and organic osmolytes such as glycine and taurine from the cells, reducing cell osmolality and preventing further water uptake. In several clinical or physiologic conditions, this adaptation mechanism is impaired, as in the syndrome of inappropriate ADH secretion, in children, in menstruating women, and in hypoxia. In such cases, symptoms are more severe and persistent.  DIAGNOSIS The diagnosis of hyponatremia and its subtypes is based on the clinical findings of volume status in association with specific laboratory values Tintinalli_Sec03_p0053-0142.indd 84 8/2/19 2:57 PM

ion, in children, in menstruating women, and in hypoxia. In such cases, symptoms are more severe and persistent.  DIAGNOSIS The diagnosis of hyponatremia and its subtypes is based on the clinical findings of volume status in association with specific laboratory values Tintinalli_Sec03_p0053-0142.indd 84 8/2/19 2:57 PM CHAPTER 17:  Fluids and Electrolytes      85 TABLE 17-6 Syndrome of Inappropriate Secretion of Antidiuretic Hormone Diagnostic Criteria Diagnostic Criteria •  Hypotonic  hyponatremia with (POSM <275 mOsm/kg H2O) •  Inappropriately  elevated urinary osmolality (usually >200 mOsm/kg) •  Elevated  urinary [Na+] (typically >20 mEq/L) •  Clinical  euvolemia •  Normal  adrenal, renal, cardiac, hepatic, and thyroid functions Abbreviation: POSM = plasma osmolality. TABLE 17-7 Treatment of Hyponatremia Symptomatic With Seizures or Coma Step 1 Assess for indication for 3% hypertonic saline: severe symptoms of hyponatremia such as seizures or coma with suspected impending brainstem herniation in setting of acute* or chronic† hyponatremia. Step 2 Infuse 100–150 mL of 3% hypertonic saline IV over 15–20 min.‡ Step 3 Measure serum sodium level after each 3% hypertonic saline infusion. Step 4 Stop infusion when symptoms improve or a target of a 5 mEq/L (range, 4–6 mEq/L) increase in serum sodium concentration is achieved. Step 5 May repeat 150 mL of 3% hypertonic saline up to 3 total doses, or a total of 450 mL IV of 3% hypertonic saline. Step 6 Keep the IV line open with minimal volume of 0.9% normal saline until cause-specific treatment is started. Limit increase in sodium level to no more than 8–12 mEq/L during the first 24 h or 18 mEq/L over 48 h. *Both European guidelines and U.S. expert panel recommend 3% hypertonic saline infusion for acute life-threatening hyponatremia, which is most commonly due to self-induced water intoxication during endurance exercise, psychiatric illness, in association with methylenedioxymethamphetamine intoxication, or intracranial pathology or increased intracranial pressure. †European guidelines state that regardless of onset of acute or chronic hyponatremia, presence of seizures or coma is an indication for brief infusion of hypertonic saline to improve symptoms. ‡European guidelines recommend a prompt 150-mL 3% hypertonic saline infusion over 20 minutes, then checking the serum sodium concentration after 20 minutes while repeating an infusion of 150 mL 3% hypertonic saline for the next 20 minutes, repeating this sequence up to twice more, and stopping with clinical improvement or when target sodium level is reached. including serum [Na+], serum osmolality, volume status, urinary sodium (UNa+), and urine osmolality (U OSM). Acute and chronic hyponatremia are defined by an onset time of less than (acute) or greater than (chronic) 24 to 48 hours. Experts recommend that when duration is unknown, the hyponatremia should be assumed to be chronic and treated as chronic with a longer correction time. If U OSM is not readily available from the laboratory, it can be estimated using urinary specific gravity (π). Con sider the numerals in the hundredths and thousandths decimal places of the π as whole numbers and multiply them by 35 to obtain U OSM. As an example, for a π of 1.005, U OSM = 05 × 35 = 175 mOsm/L. 1 Table 17-4 lists the values of UNa+ and UOSM in different classifications of hyponatremia according to volume status and the differential diagnosis for each classification. As a rule, only in patients with edematous syndromes and in patients with vomiting and diarrhea will U Na+ be found to be <10 mEq/L. 16 The diagnostic criteria for syndrome of inappropriate ADH secretion are listed in Table 17-6. Use care when assessing patients with potential exercise-associated hyponatremia.

ication. As a rule, only in patients with edematous syndromes and in patients with vomiting and diarrhea will U Na+ be found to be <10 mEq/L. 16 The diagnostic criteria for syndrome of inappropriate ADH secretion are listed in Table 17-6. Use care when assessing patients with potential exercise-associated hyponatremia. Since the worldwide effort to encourage consuming fluids during endurance exercise beginning in the early 1980s, overhydration with hypotonic fluids is now being seen. If a postexercise athlete presents with bloating, nausea, vomiting, and edema (check wrists and fingers), consider hyponatremia. In contrast, dehydration presents with excessive thirst, sunken eyes, poor skin turgor, and postural hypotension.  TREATMENT Treatment of hyponatremia is guided by four variables: severity of symptoms, rate of onset, volume status, and the current serum [Na +]. Nevertheless, the most important guides for therapy are symptoms (defined also as hyponatremic encephalopathy) rather than the serum [Na +]. When the patient presents with severe neurologic symptoms (vomiting, seizures, reduced consciousness, cardiorespiratory arrest), the initial treatment includes infusion of 3% hypertonic saline as recommended by European guidelines 4,17 and U.S. experts10,18 (Table 17-7). Raising serum sodium by 5 mEq/L is typically all that is required to see an improvement in severe neurologic symptoms. 10,17,19 When symptoms are mild or moderate (nausea, confusion, headache) or in chronic hyponatremia, the [Na +] correction should be slower than for acute hyponatremia. Rapid correction increases risk for the most dangerous complication of treatment, the osmotic demyelination syndrome. For chronic hyponatremia [Na +], the correction rate should not exceed 6 mEq/24 h in high-risk patients and 12 mEq/24 h in low-risk patients (see “Osmotic Demyelination Syndrome” section later in this chapter for risks). 10 Hypertonic (3%) saline can be given at a low infusion rate, 0.5 to 1 mL/kg/h, with frequent [Na +] checks. Isotonic (0.9%) saline is fre quently used (sometimes before the [Na +] is known), especially for the treatment of mild hyponatremia; however, the additional fluid load must be accounted for in treatment calculations. Loop diuretics (primarily furosemide, starting with a small dose of 20 milligrams IV) may be used in addition to treatment with saline infusions. Urine volume and [Na +] should be strictly measured. Specific recommendations for hyponatre mia treatment are summarized in Table 17-8.2,7 There is no definitive consensus regarding the role of vaptans for patients with hyponatremia, their safety, or their tolerability. The major concerns remain the risk of overcorrection, the risk of precipitating osmotic demyelination syn drome, and the high cost.  COMPLICATIONS OF TREATMENT Osmotic Demyelination Syndrome Osmotic demyelination syndrome is caused by rapid correction of hyponatremia (>12 mEq/L/24 h) as water moves from cells to ECF yielding intracellular dehydration (Figure 17-2 ). Risk factors for osmotic demyelination syndrome include [Na +] <120 mEq/L, chronic heart failure, alcoholism, cirrhosis, hypokalemia, malnutrition, and treatment with vasopressin antagonists such as tolvaptan. Main symptoms are dysarthria, dysphagia, lethargy, paraparesis or quadriparesis, seizures, and coma. The treatment of [Na +] overcorrection is rarely done in the ED, but consists of giving 5% dextrose in water at 3 mL/kg/h, loop diuretics, and desmopressin.3,10 HYPERNATREMIA Hypernatremia is defined as serum or plasma [Na +] >145 mEq/L and hyperosmolality (serum osmolality >295 mOsm/L). Hypernatremia results from a deficit in TBW and/or a net gain of Na+ (less common).

e in the ED, but consists of giving 5% dextrose in water at 3 mL/kg/h, loop diuretics, and desmopressin.3,10 HYPERNATREMIA Hypernatremia is defined as serum or plasma [Na +] >145 mEq/L and hyperosmolality (serum osmolality >295 mOsm/L). Hypernatremia results from a deficit in TBW and/or a net gain of Na+ (less common). When [Na +] and osmolality increase, normal subjects become thirsty and drink free water, and the Na + level returns toward normal. Any clinical situation that impairs the patient’s sense of thirst, limits the availability of water, limits the kidney’s ability to concentrate urine, or results in increased salt intake predisposes the patient to hypernatremia. Elderly patients, decompensated diabetics, infants, and hospitalized patients are at particular risk of developing hypernatremia. In addition, hypernatremia may be the result of loss of free water in diarrheal stools or in the urine. 21,22 As in hyponatremia, symptoms will be more severe and evident when the onset is rapid; after the first 48 hours, there is an adaptation of brain cells with an increase in electrolytes and organic osmolytes and thus increased intracellular water partly correcting the initial cell shrinking (Figure 17-3). If severe hypernatremia develops in the course of minutes to hours, such as from a massive salt overdose in a suicide attempt, a suddenly shrinking brain may prompt intracranial hemorrhage. Based on volume status, hypernatremia may be classified as hypovolemic hypernatremia (decreased TBW and total body Na + with a relatively greater decrease in TBW), hypervolemic hypernatremia (increased total body Na + with normal or increased TBW), or normovolemic hypernatremia (near normal total body sodium and decreased TBW)1,2 (Table 17-9). Tintinalli_Sec03_p0053-0142.indd 85 8/2/19 2:57 PM

natremia (decreased TBW and total body Na + with a relatively greater decrease in TBW), hypervolemic hypernatremia (increased total body Na + with normal or increased TBW), or normovolemic hypernatremia (near normal total body sodium and decreased TBW)1,2 (Table 17-9). Tintinalli_Sec03_p0053-0142.indd 85 8/2/19 2:57 PM 86 SECTION 3: Resuscitation Slow correction of hypernatremia Too rapid correction of hypernatremia Sustained Acute Hypernatremia Adaptive increase in cell solutes Normal cell volume Cell swelling Cell shrinking FIGURE 17-3. Adaptation of brain volume to hypernatremia and effect of correction. Cell shrinking Slow correction of hyponatremia Too rapid correction of hyponatremia Sustained Acute Hypo-osmolar hyponatremia Adaptive decrease in cell solutes Cell swelling Normal cell volume FIGURE 17-2. Adaptation of brain volume to hyponatremia and effect of correction. TABLE 17-8 Cause-Specific Treatment for Hyponatremia Clinical Condition Therapy Cautions/Comments Chronic heart failure and cirrhosis Loop diuretics, water restriction. Consider vasopressin antagonists* if the above therapies fail for patients with chronic heart failure. When vasopressin antagonists* are used, serum [Na+] should be frequently measured to avoid hypernatremia. FDA recommends against vasopressin antagonists in patients with liver disease. Nephrotic syndrome Water restriction. Acute or chronic kidney disease Water restriction. Frequent assessment of creatinine. Psychogenic polydipsia Water restriction. Treat the underlying psychiatric disease. Hypothyroidism Levothyroxine. Several days of therapy are typically required to correct hyponatremia. Glucocorticoid deficiency Hydrocortisone. If neurologic symptoms, consider vasopressin antagonists* if resistant to hydrocortisone. When vasopressin antagonists* are used, [Na+] should be frequently measured. SIADH Water restriction. Enhanced Na+ and protein intake + furosemide. Vasopressin  antagonists * can be used for [Na+] <125 mEq/L. Demeclocycline. Lithium. Isotonic (0.9%) NaCl may worsen hyponatremia; when vasopressin antagonists* are used, [Na+] should be frequently measured. Diarrhea and vomiting Isotonic (0.9%) NaCl. Add KCl if hypokalemia is present. Treat the cause, monitor hemodynamic status. Diuretics (most commonly thiazides) Stop diuretic. KCl may be sufficient in patients with coexistent potassium depletion and normal dietary sodium intake. NaCl can be given orally. Slow correction is recommended. Do not overcorrect K+ deficit. Mineralocorticoid deficiency Replace volume deficit. Fludrocortisone therapy is indicated once diagnosis is confirmed. Mechanism: volume depletion →↑  ADH →  decreases water excretion, ↑ Na loss. Salt-losing nephropathies Isotonic (0.9%) NaCl. Cerebral salt wasting Isotonic (0.9%) NaCl. Fludrocortisone may be considered after the diagnosis is confirmed. NaCl orally at home. Abbreviations: ADH = antidiuretic hormone; FDA = Food and Drug Administration; KCl = potassium chloride; NaCl = sodium chloride; SIADH = syndrome of inappropriate antidiuretic hormone secretion. *Vasopressin antagonists or vaptans are rarely started in the ED; they are not indicated unless [Na+] <125 mEq/L; starting doses are tolvaptan, 15 milligrams PO daily; and conivaptan, 20 milligrams loading dose IV over 30 minutes, then continuous infusion of 20 milligrams over 24 hours for 2 to 4 days.  CLINICAL FEATURES History depends on hypernatremia type and may reveal nausea and vomiting, lethargy, weakness, increased thirst, low water intake, salt intake, polyuria (>3000 mL of urine/24 h), diabetes, hypercalcemia, hypokalemia, medications such as lactulose, loop diuretics, lithium, demeclocycline (may cause nephrogenic diabetes insipidus), or NSAIDs (may cause interstitial nephritis).

sea and vomiting, lethargy, weakness, increased thirst, low water intake, salt intake, polyuria (>3000 mL of urine/24 h), diabetes, hypercalcemia, hypokalemia, medications such as lactulose, loop diuretics, lithium, demeclocycline (may cause nephrogenic diabetes insipidus), or NSAIDs (may cause interstitial nephritis). Physical exam may reveal hypoten sion, tachycardia, orthostatic blood pressures, sunken eyes, dry mucous membranes (symptoms of hypovolemia), altered mental status (may be Tintinalli_Sec03_p0053-0142.indd 86 8/2/19 2:57 PM CHAPTER 17:  Fluids and Electrolytes      87 TABLE 17-9 Hypernatremia Classification and Features According to Volume Status Volume Status Clinical Conditions Diagnosis UOSM, mOsm/kg H2O U[Na+], mEq/L Hypervolemic hypernatremia Cushing’s syndrome Primary hyperaldosteronism Salt water intake Iatrogenic Hemodialysis Cortisol test History of hypertension and hypokalemia Psychiatric disorder Hypertonic saline, enteral feeding, bicarbonate infusion Clinical history >100 >20 Normovolemic hypernatremia Central DI Partial DI Nephrogenic DI Hypodipsia Medications History of CNS lesion, urinary concentration after desmopressin History of nephrotoxic drugs, no response to desmopressin History of poor oral intake Amphotericin, aminoglycosides, lithium, phenytoin Central DI <300 Partial DI >300 but <800 <200 >100 <200 >20 Renal hypovolemic hypernatremia Osmotic diuretics Loop diuretics Postobstructive diuresis Hyperglycemia. High sodium level after correction Clinical history Clinical history >100

Central DI Partial DI Nephrogenic DI Hypodipsia Medications History of CNS lesion, urinary concentration after desmopressin History of nephrotoxic drugs, no response to desmopressin History of poor oral intake Amphotericin, aminoglycosides, lithium, phenytoin Central DI <300 Partial DI >300 but <800 <200 >100 <200 >20 Renal hypovolemic hypernatremia Osmotic diuretics Loop diuretics Postobstructive diuresis Hyperglycemia. High sodium level after correction Clinical history Clinical history >100 >20 Extrarenal hypovolemic hypernatremia Vomiting Diarrhea GI fistulas Sweating Burns Clinical history >800 <10 Abbreviations: DI = diabetes insipidus; U[Na+] = urine sodium; UOSM = urine osmolality. present in any of the hypernatremia classifications), poor skin turgor, or edema in hypervolemic hypernatremia. Without intervention, coma, seizures, and shock may occur. Signs of Cushing’s syndrome may be present, including moon facies, fatty deposits between the shoulders and upper back, and thinning of the skin. Severe hypernatremia (i.e., a [Na +] >150 to 160 mEq/L) yields a mortality of 75%. 23  DIAGNOSIS The diagnosis of hypernatremia and its classification are based on the clinical evaluation including volume status and specific laboratory tests, such as serum electrolytes and osmolality, urine osmolality, urea/creatinine ratio, and free water deficit. A BUN/creatinine ratio >40 is indicative of hyperosmolar dehydration. Urine osmolality can be used to suggest the type of hypernatremia (Table 17-10). A patient’s free water deficit can be calculated with the aid of a phone application or Internet calculator.  TREATMENT First, shock, hypoperfusion, or volume deficits should be treated with isotonic (0.9%) saline. Second, treat any existing underlying cause, such as diabetes insipidus (see “Diabetes Insipidus” section later in this chapter), vomiting, diarrhea, or fever. Third, correct the patient’s free water deficit at a rate reflecting the acuity or duration time of the hypernatremia onset (Table 17-11). 15,24 In cases of a lethal sodium chloride ingestion/ load (0.75 to 3.0 grams/kg) less than 6 hours prior to presentation, the free water deficit may be replaced rapidly with no reported adverse events. 11,25 When the adaptation of brain cells is incomplete (onset over TABLE 17-10 Urine Osmolality Findings in Selected Hypernatremic States Urine Osmolality (UOSM) Potential Hypernatremic State UOSM <300 mOsm/kg H2O Central or nephrogenic diabetes insipidus UOSM >300, <800 mOsm/kg H2O Partial diabetes insipidus or osmotic diuresis UOSM >800 mOsm/kg H2O Hypertonic dehydration <48 hours), the correction rate of acute hypernatremia can be performed at a rate of 1 mEq/L/h. In an alert patient capable of safely drinking water, the route of administration should be two-thirds free water orally and one-third IV . If hypernatremia is chronic (onset over >48 hours), the rate of correction should be slower to avoid the risk of cerebral edema, at no more than 0.5 mEq/L/h or 10 to 12 mEq/24 h. DIABETES INSIPIDUS Diabetes insipidus is a disease where the ability of the kidney to reab sorb free water is compromised. 2,27 The disorder is characterized by polyuria, polydipsia, and an increased volume of hypo-osmolar urine. TABLE 17-11 Treatment of Hypernatremia Treatment Indication and Comments Isotonic (0.9%) saline Use for correction of volume deficits. Etiology-specific therapy Treat fever with antipyretics, vomiting with antiemetics, and diabetes insipidus with desmopressin (see “Diabetes Insipidus” section). D5W or oral free water to replace free water deficit over 2–3 d In cases of chronic hypernatremia, it is suggested that correcting (lowering) the sodium level should occur at a rate of no more than 0.5 mEq/L/h or 10–12 mEq/24 h. 0.45% normal saline at 100 mL/h Correct volume deficits first. A commonly used infusion for mild to moderate hypernatremia, but this therapy adds sodium to total body.

chronic hypernatremia, it is suggested that correcting (lowering) the sodium level should occur at a rate of no more than 0.5 mEq/L/h or 10–12 mEq/24 h. 0.45% normal saline at 100 mL/h Correct volume deficits first. A commonly used infusion for mild to moderate hypernatremia, but this therapy adds sodium to total body. D5W to replace free water deficit over 1–2 h Reserved only for those cases where acuity is known to be <6 h and the salt load is known to be lethal (0.75–3.0 grams/kg of body weight). Hemodialysis An alternative or as a supplement to D5W to replace free water deficit in life-threatening acute cases of salt ingestion. Abbreviation: D5W = 5% dextrose in water. Tintinalli_Sec03_p0053-0142.indd 87 8/2/19 2:57 PM

known to be <6 h and the salt load is known to be lethal (0.75–3.0 grams/kg of body weight). Hemodialysis An alternative or as a supplement to D5W to replace free water deficit in life-threatening acute cases of salt ingestion. Abbreviation: D5W = 5% dextrose in water. Tintinalli_Sec03_p0053-0142.indd 87 8/2/19 2:57 PM 88 SECTION 3: Resuscitation Hypernatremia is present only when the thirst center is impaired or water intake is reduced. Diabetes insipidus can be central (also called neurogenic), due to inadequate ADH secretion, or renal (also called nephrogenic), when ADH secretion is normal or increased but the v2R receptors of the kidney’s collecting duct cells do not respond appro priately to ADH. Diabetes insipidus may be congenital or acquired. In Table 17-12, the main causes of diabetes insipidus are listed. Congenital forms of diabetes insipidus present during infancy. Eventually, recur rent cellular dehydration causes cerebral calcifications that manifest as delayed intellectual advancement. Central diabetes insipidus is acquired in most cases, associated with various disorders that cause destruction of ADH-secreting neurons. When a diagnosis is not possible, despite imaging and other diagnostic tests, diabetes insipidus will be defined as idiopathic diabetes insipidus. The most common clinical symptoms and signs are excessive thirst, polydipsia, and polyuria plus several nonspecific symptoms including weakness, lethargy, myalgias, and irritability. In infancy, congenital forms of diabetes insipidus present with fatigue and weakness often manifested by less activity or tiring with feeding, vomiting, polyuria, and sometimes fever. Diagnosis can be suspected in the ED by clinical presentation, but the diagnosis requires a prolonged test, requiring 4 to 18 hours. Urine osmolality is assessed after water deprivation; many cases require another assessment after a dose of desmopressin, the “water deprivation test. ” A spot check in the ED without water deprivation will typically reveal a U OSM of <300 mOsm/L. In central diabetes insipidus, a cerebral MRI is indicated (on a nonurgent outpatient basis) to evaluate the hypothalamic–pituitary area. Central diabetes insipidus is treated with the synthetic hormone des mopressin, as a nasal spray, 10 micrograms (0.1 mL) every 12 hours, or PO, 0.05 milligrams every 12 hours, as starting doses. Therapy of neph rogenic diabetes insipidus includes a low-salt, low-protein diet, adequate hydration, and the careful use of one to three agents that act together to concentrate urine in these patients: a thiazide diuretic, the potassiumsparing diuretic amiloride, and indomethacin. Exogenous ADH, 5 to 10 micrograms SC, two to four times daily, is also used in noncongenital nephrogenic diabetes insipidus, as these patients have a partial response to ADH. Patients with significant electrolyte abnormalities should be admitted to the hospital, whereas stable patients suspected of having diabetes insipidus should be referred for testing.  POTASSIUM PATHOPHYSIOLOGY Potassium (K +) is the major intracellular cation of the body: 98% of total body K+ in healthy subjects is intracellular, and 70% to 75% of total K+ is in muscle tissues. The normal intracellular concentration averages 150 mEq/L, and the normal extracellular concentration is 3.5 to 5.0 mEq/L. + is excreted predominantly by the kidneys (80% to 90%) and is fil tered freely through the renal glomerulus and then reabsorbed in the proximal and ascending tubules. It is secreted in the distal tubule in exchange for Na +. In healthy individuals, the kidneys are able to excrete up to 6 mEq/kg /d. The several mechanisms of K + handling along the nephron are the targets of diuretic therapy.

reely through the renal glomerulus and then reabsorbed in the proximal and ascending tubules. It is secreted in the distal tubule in exchange for Na +. In healthy individuals, the kidneys are able to excrete up to 6 mEq/kg /d. The several mechanisms of K + handling along the nephron are the targets of diuretic therapy. Being mostly intracellular, an accurate calculation of total body K + is difficult, but an estimation of the K+ deficit can be determined using the following equation: estimated K+ deficit in mEq/L = (expected serum [K+] in mEq/L – measured serum [K +] in mEq/L) × ICF (calculated as 40% of total body weight).1 However, this equation is reliable only for healthy subjects, because critical patients sustain significant and rapid intracellular to extracel lular shifting in response to severe injury (e.g., surgical stress, trauma, or burns), acid-base imbalance, catabolic states, increased extracellular osmolality, or insulin deficiency. So it is possible to have hyperkalemia in patients with a total body K + deficit (e.g., diabetic ketoacidosis) and hypokalemia with total body K + surplus.2 These shifts are crucial con sidering the role of K + in maintaining the resting membrane potential, as the ratio of intracellular to extracellular K + is the most important determinant of neuromuscular and cardiovascular excitability.28,29 Acid-base imbalance plays an important role in critically ill patients: there is an inverse proportionality between serum pH and [K +], with [K+] rising about 0.6 mEq/L for every 0.1 decrease in pH and vice versa, through an exchange between H+ and K+.1,30 In addition, the duration of both hypo- and hyperkalemia influences the clinical response: chronic potassium depletion or surplus allows adaptation through shifts in intra-/extracellular K + concentration to maintain the resting membrane potential, thus mitigating neuromuscular and cardiac electrophysiologic effects. Potassium derangements are becoming more and more frequent in the ED (up to 11%)31 and should be promptly and correctly addressed.32 HYPOKALEMIA Hypokalemia is defined as a serum [K +] of <3.5 mEq/L. The most fre quent causes of hypokalemia are insufficient dietary intake (e.g., fasting, eating disorders, alcoholism), intracellular shifts (e.g., alkalosis, insulin, 2-agonists, hypokalemic periodic paralysis), and increased losses, mainly GI (vomiting, nasogastric suction, diarrhea) or renal (diuretics,33 hyperaldosteronism, osmotic diuresis, toxins)34 (Table 17-13). The clinical manifestations result from abnormalities in membrane polarization and affect almost every body system but are particularly dangerous in the excitable myocardium. Hypokalemia makes the resting potential more electronegative, thus enhancing depolarization; the reduction in [K +] conduction delays repolarization, causing prolonged QTc, flattened T waves, and the appearance of U waves in the ECG (Figure 17-4).  CLINICAL FEATURES Symptoms of hypokalemia (Table 17-14) usually start when serum concentrations reach 2.5 mEq/L, although they may appear sooner with rapid decreases in concentration or appear later (i.e., at even lower [K +]) for chronic depletion. Particular attention must be paid to cardiac arrhythmias, usually tachyarrhythmias (atrial fibrillation, 35 torsadess de pointes, ventricular tachycardia, and ventricular fibrillation), which can be life threatening. TABLE 17-12 Classification of Diabetes Insipidus Class Acquisition Pathophysiology Central or neurogenic diabetes insipidus

must be paid to cardiac arrhythmias, usually tachyarrhythmias (atrial fibrillation, 35 torsadess de pointes, ventricular tachycardia, and ventricular fibrillation), which can be life threatening. TABLE 17-12 Classification of Diabetes Insipidus Class Acquisition Pathophysiology Central or neurogenic diabetes insipidus Congenital Structural malformations affecting the hypothalamus or pituitary Autosomal dominant (or rarely recessive) mutations in the gene encoding AVP-NPII precursor protein Acquired Primary tumors (craniopharyngioma) or metastases Infection (e.g., meningitis, encephalitis) Histiocytosis and granulomatous diseases Trauma Surgery Idiopathic Nephrogenic diabetes insipidus Congenital X-linked: inactivating mutations in AVPR2 gene Autosomal: recessive or dominant mutations in AQP-2 gene Acquired Primary renal disease Obstructive uropathy Metabolic causes (e.g., hypokalemia, hypercalcemia) Sickle cell disease Drugs (e.g., lithium, demeclocycline) Primary polydipsia or dipsogenic diabetes insipidus Acquired Psychogenic illness characterized by excessive fluid intake. Treatment is aimed at the psychiatric disease. Tintinalli_Sec03_p0053-0142.indd 88 8/2/19 2:57 PM CHAPTER 17:  Fluids and Electrolytes      89 TABLE 17-13 Causes of Hypokalemia Transcellular shifts Alkalosis * Increased plasma insulin (treatment of diabetic ketoacidosis) β-Adrenergic agonists Hypokalemic periodic paralysis (congenital) Thyrotoxic hypokalemic periodic paralysis Decreased intake Fasting Alcoholism (worsened by hypomagnesemia) Eating disorders GI loss Vomiting *, nasogastric suction Diarrhea* (including laxative, enema abuse) Malabsorption Ureterosigmoidostomy Enteric fistula Villous adenoma Renal loss Diuretics (carbonic anhydrase inhibitors, loop diuretics, and thiazide-like diuretics)* Primary hyperaldosteronism Secondary hyperaldosteronism Licorice ingestion Excessive use of chewing tobacco Renal tubular acidosis Postobstructive diuresis Osmotic diuresis Bartter’s syndrome (mimics loop diuretic use) Gitelman’s syndrome (mimics thiazide diuretic use) Apparent mineralocorticoid excess and related syndromes (Conn’s, Liddle’s) Drugs and toxins (aminoglycosides, echinocandins, carbenicillin, penicillins, amphotericin B, levodopa, lithium, thallium, cesium, barium, toluene, theophylline, chloroquine, steroids, etc.) Sweat loss Heavy exercise Heatstroke Fever Other

Diuretics (carbonic anhydrase inhibitors, loop diuretics, and thiazide-like diuretics)* Primary hyperaldosteronism Secondary hyperaldosteronism Licorice ingestion Excessive use of chewing tobacco Renal tubular acidosis Postobstructive diuresis Osmotic diuresis Bartter’s syndrome (mimics loop diuretic use) Gitelman’s syndrome (mimics thiazide diuretic use) Apparent mineralocorticoid excess and related syndromes (Conn’s, Liddle’s) Drugs and toxins (aminoglycosides, echinocandins, carbenicillin, penicillins, amphotericin B, levodopa, lithium, thallium, cesium, barium, toluene, theophylline, chloroquine, steroids, etc.) Sweat loss Heavy exercise Heatstroke Fever Other Hypomagnesemia Acute leukemia and lymphomas IV hyperalimentation Recovery from megaloblastic anemia Hypothermia (accidental or induced) *Frequently encountered etiologies in the ED.  DIAGNOSIS Diagnosis of hypokalemia is made with serum chemistry measurement; the etiology is investigated with additional testing. An ECG should be obtained from hypokalemic patients in the ED (Figure 17-4). Obtain blood gas analysis when alkalosis is suspected. If the cause of hypo kalemia is not apparent from history, spot urinary electrolytes can be obtained before starting K + replacement (see Table 17-15 for interpretation of urine K+ values1); also UNa+, UOSM, and POSM should be measured, because a UNa+ value <30 mEq/L and a UOSM value less than POSM suggest polyuria. Polyuria can increase K + excretion even if total body K + is depleted; thus urinary K+ may be misleading for diagnosis in the setting of polyuria.2 Another useful tool for differential diagnosis is transtubular K+ gradient = (Urinary K+ × POSM)/(UOSM × Plasma K+), with normal values of 8 to 9 mEq/L. Values <5 mEq/L suggest hyperaldosteronism; if paralysis is present, values <3 mEq/L suggest hypokalemic periodic paralysis. A calcium/phosphate ratio >1.7 on a spot urine is 100% sensitive and 96% specific for thyrotoxic hypokalemic periodic paralysis. 36,37  TREATMENT The treatment of hypokalemia is replacement of K+. This should be done orally in stable patients with mild hypokalemia (>3.0 mEq/L) who are able to tolerate oral intake. 2 Foods rich in K + (fruits, dried fruits, nuts, vegetables, and meat) can be suggested at discharge from ED, as well as salt substitutes or K + supplements that should be prescribed with abundant fluids and/or food to prevent gastric irritation. Additional treatment targeted to the underlying cause should be considered. For example, it is possible to treat (and prevent) chronic hypokalemia induced by loop or thiazide diuretics by adding an adequate amount of spironolactone to the patient’s chronic therapy 38; however, the primary care physician should be aware of or guide such a change in medication. Whenever modifying diuretics or other drugs at ED discharge, recom mend follow-up within 1 week for repeat assessment of renal function and [K +]. In hypokalemia secondary to respiratory alkalosis (as caused by an acute anxiety disorder), the simple correction of the acid-base imbalance (through reassurance or anxiolytics) can correct [K +] without administering exogenous potassium. IV replacement is indicated in patients with severe (<2.5 mEq/L) hypokalemia and in symptomatic patients with moderate (2.5 to 3 mEq/L) hypokalemia. Treat patients with cardiac arrhythmias or prolonged QT or when oral replacement is not tolerated or not feasible (see Table 17-16 for common medications known to prolong QTc). Monitor the patient’s rhythm when treating with IV K+. Monitor closely those patients who sustain rapid [K +] changes due to their illness (e.g., postobstructive polyuria) or IV treatment. An example is diabetic ketoacidosis treatment, where rapid hypokale mia (including life-threatening arrhythmias) should be prevented by adequate IV K + administration prior to the detection of a rapid fall in serum potassium. The following are general principles in hypokalemia correction: 1. Use potassium chloride and avoid administering K + in glucose solu tions, to reduce insulin-induced K+ transfer into cells. 2.

arrhythmias) should be prevented by adequate IV K + administration prior to the detection of a rapid fall in serum potassium. The following are general principles in hypokalemia correction: 1. Use potassium chloride and avoid administering K + in glucose solu tions, to reduce insulin-induced K+ transfer into cells. 2. Potassium is irritating to the endothelium; adequate dilution is mandatory to prevent pain and phlebitis (maximum recommended [K +] in 500 mL of a saline solution is 40 mEq, to be infused in 4 to 6 hours in a peripheral line). If a more aggressive correction is needed, an identical solution can be administered in a second peripheral line. Higher concentrations can be administered through a central line, but infusion rates should never exceed 20 mEq/h. 3. Reassessing serum [K+] should be adjusted to infusion rate and coexisting factors (e.g., concomitant acid-base imbalance, volume deple tion, cardiac arrhythmias). 4. ECG monitoring is recommended. 5. In most cases, hypokalemic patients are also hypomagnesemic. Thus, magnesium (20 to 60 mEq/24 h) may be added to the infusion both to optimize tubular reuptake of potassium and to contrast proar rhythmic effect of hypokalemia. HYPERKALEMIA  PATHOPHYSIOLOGY Hyperkalemia is defined as measured serum [K +] of >5.5 mEq/L. The most common cause is factitious hyperkalemia due to release of intracellular potassium caused by hemolysis during phlebotomy. Other causes are listed in Table 17-17. Clinical manifestations of hyperkalemia result from disordered membrane polarization (Figure 17-5). Cardiac manifestations are the most serious. In hyperkalemia, the resting potential of the excitable myocardium becomes less electronegative, with a consequent partial depolarization that reduces the activation of voltage-dependent sodium channels; this results in a slower and reduced amplitude of action potential. Table 17-18 summarizes the ECG effects that may lead to arrhyth mic complications, such as sinoatrial and atrioventricular blocks and atrial paralysis (Figure 17-5). Calcium administration does not affect potassium levels; rather, calcium antagonizes the effects of hyperkalemia Tintinalli_Sec03_p0053-0142.indd 89 8/2/19 2:57 PM

18 summarizes the ECG effects that may lead to arrhyth mic complications, such as sinoatrial and atrioventricular blocks and atrial paralysis (Figure 17-5). Calcium administration does not affect potassium levels; rather, calcium antagonizes the effects of hyperkalemia Tintinalli_Sec03_p0053-0142.indd 89 8/2/19 2:57 PM 90 SECTION 3: Resuscitation TABLE 17-14 Symptoms and Signs of Hypokalemia Cardiovascular Hypertension Orthostatic hypotension Potentiation of digitalis toxicity Dysrhythmias (usually tachyarrhythmias) T-wave flattening, QT prolongation, U waves, ST depression Neuromuscular Malaise, weakness, fatigue Hyporeflexia Cramps Paresthesias Paralysis Rhabdomyolysis Nausea, vomiting Abdominal distention Ileus Renal Increased ammonia production Urinary concentrating defects Metabolic alkalemia, paradoxical aciduria Nephrogenic diabetes insipidus Endocrine Glucose intolerance 10 mm/mV 10 mm/mV V1 V2 V3 V4 V5 V6 aVL aVF aVR FIGURE 17-4. ECG of a patient with potassium of 1.4 mEq/L, with leg paralysis and deep fatigue. The patient had been taking a thiazide-like diuretic for hypertension. Notice the prolonged QTc and a flattened T wave with a U wave visible in V2 to V5. at the level of the cell membrane, raising the threshold potential, thus restoring the membrane potential and myocyte excitability close to normal (Figure 17-6).  CLINICAL FEATURES Cardiac dysrhythmias, such as ventricular fibrillation, sinoatrial and atrioventricular blocks until complete heart block, and asystole, may occur. Death from hyperkalemia is usually the result of diastolic arrest or ventricular fibrillation. Other common symptoms include neuromuscular dysfunctional weakness, paresthesias, areflexia, ascending paralysis, and GI effects (nausea, vomiting, and diarrhea).  DIAGNOSIS A stat ECG is essential in all hyperkalemic patients (Table 17-18); if ECG changes are present, emergency treatment of hyperkalemia should start immediately. In addition, if ECG changes are detected in a patient whose electrolyte levels are not yet known (e.g., a dialysis patient), hyperkalemia should be suspected and treated. A symptomatic TABLE 17-15 Interpretation of Urinary Potassium Spot Urinary Potassium Possible Mechanism UK+ <10 mEq/L Decreased K+ intake, nonrenal losses GI losses Sweat losses Nasogastric suction (↓UCl–) Transcellular shift Alkalosis (↓UCl–) Hypomagnesemia (↑UCl–) Hypokalemic periodic paralysis Thyrotoxic hypokalemic periodic paralysis (calculate TTKG) UK+ >20 mEq/L Renal losses If hypernatremia coexists consider: hyperaldosteronism (calculate TTKG) Massive GI losses (secondary to metabolic alkalosis) Abbreviations: TTKG = transtubular K+ gradient; UCl– = urinary chloride; UK+ = urinary potassium. Tintinalli_Sec03_p0053-0142.indd 90 8/2/19 2:57 PM

is (calculate TTKG) UK+ >20 mEq/L Renal losses If hypernatremia coexists consider: hyperaldosteronism (calculate TTKG) Massive GI losses (secondary to metabolic alkalosis) Abbreviations: TTKG = transtubular K+ gradient; UCl– = urinary chloride; UK+ = urinary potassium. Tintinalli_Sec03_p0053-0142.indd 90 8/2/19 2:57 PM CHAPTER 17:  Fluids and Electrolytes      91 TABLE 17-16 Common Medications Known to Prolong QTc Antiarrhythmics Amiodarone, sotalol, flecainide, quinidine, dronedarone, dofetilide Vasopressors/inotropes Epinephrine, norepinephrine, dopamine, dobutamine Neuroleptics Haloperidol, droperidol, chlorpromazine, olanzapine, quetiapine, risperidone, paliperidone, clozapine, aripiprazole Antidepressants Amitriptyline, nortriptyline citalopram, escitalopram, fluoxetine, paroxetine, sertraline, venlafaxine Antibiotics Macrolides, quinolones, metronidazole, cotrimoxazole GI prokinetics Domperidone, cisapride, metoclopramide Antiemetics Ondansetron, granisetron, dolasetron, promethazine Antifungals Fluconazole, itraconazole, voriconazole, ketoconazole, posaconazole Antivirals Foscarnet, amantadine, atazanavir, nelfinavir, rilpivirine, ritonavir, saquinavir, telaprevir Antiparasitics Chloroquine, mefloquine, quinine, hydroxychloroquine, pentamidine Antihistamines Terfenadine, hydroxyzine, diphenhydramine Others Cocaine, lithium, methadone, tamoxifen, vardenafil, tacrolimus, pseudoephedrine TABLE 17-17 Causes of Hyperkalemia Pseudohyperkalemia Tourniquet use Hemolysis (in vitro)* Leukocytosis Thrombocytosis Intracellular to extracellular potassium shift Acidosis* Heavy exercise β-Blockade Insulin deficiency Digitalis intoxication Hyperkalemic periodic paralysis Potassium load Potassium supplements Potassium-rich foods IV potassium Potassium-containing drugs Transfusion of aged blood Hemolysis (in vivo) GI bleeding Cell destruction after chemotherapy Rhabdomyolysis/crush injury* Extensive tissue necrosis Decreased potassium excretion Renal failure* Drugs—potassium-sparing diuretics,* β-blockade, NSAIDs, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, cyclosporine, tacrolimus Aldosterone deficiency* Selective defect in renal potassium excretion (pseudohypoaldosteronism, systemic lupus erythematosus, sickle cell disease, obstructive uropathy, renal transplantation, type IV renal tubular acidosis) *Frequent or important ED diagnostic considerations. patient with a relatively small elevation of [K+] (5.0 to 6.0 mEq/L) requires identification and treatment of the underlying cause. A spot urine K+ may identify the diagnosis. An elevated spot urine K+ (>20 mEq/L) suggests an extrarenal cause (and will more likely be responsive to therapy). A low urine K + output (<10 mEq/L) suggests oliguric kidney failure or drug effect, such as angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers.  TREATMENT Emergency treatment includes continuous ECG monitoring and immediate intervention with several therapeutic medications, which based on the action mechanism can be divided into three modali ties: membrane stabilization (crucial for cardiac tissue, must be done immediately), intracellular shift of K +, and removal/excretion of K + from the body. All three modalities should be administered sequen tially in rapid succession. Each mode has a different onset time and duration 40 (Table 17-19). A blood gas is essential to identify metabolic acidosis. A 2015 Cochrane review does not recommend the routine administration of sodium bicarbonate for hyperkalemia unless there is concomitant metabolic acidosis. 41 In this Cochrane review, the effectiveness of sodium bicarbonate alone, or in combination with other therapies listed in Table 17-19, could not be clearly demonstrated, even at a variety of time points.

the routine administration of sodium bicarbonate for hyperkalemia unless there is concomitant metabolic acidosis. 41 In this Cochrane review, the effectiveness of sodium bicarbonate alone, or in combination with other therapies listed in Table 17-19, could not be clearly demonstrated, even at a variety of time points. Treatment should correct the underlying cause of the acid-base imbalance. If pH is normal or alkaline, the therapeutic measures that act to promote an intracellular to extracellular shift of [K +] will be less effective, and treatment should be aimed at improving renal excretion. Until recently, sodium polystyrene sulfonate was the only oral agent that lowered potassium levels by enhancing excretion (rather than shifting K+ into cells). This agent has recently been associated with intestinal necrosis.43 Two new oral binding agents, patiromer and sodium zir conium cyclosilicate, have proven useful to lower potassium levels for patients with mild hyperkalemia in a few randomized controlled trials (some still ongoing); however, although the onset of action for patiromer is too slow to be of benefit in life-threatening hyperkalemia, sodium zirconium cyclosilicate, which is still in development, seems to provide an effective reduction in [K +] in a few hours, thus making it valuable for ED use.44 The following are general principles in treatment of hyperkalemia: 1. Immediate cessation of further K + administration, reduction of dietary intake, and suspension of drugs impairing K + renal excre tion directly (angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, K +-sparing diuretics) or indirectly through worsening of renal function (e.g., NSAIDs, iodine contrast, antibiotics). 2. Fluid administration enhances K+ renal excretion through increasing urine output. 3. If a patient is on digitalis,45 hypercalcemia enhances the toxic cardiac effects of digitalis. However, in severe hyperkalemia secondary to digitalis intoxication with advanced intraventricular conduction impairment (wide, low-voltage QRS complexes), calcium administration must be considered, in association with antidigoxin antibodies. 4. ECG continuous monitoring should be used to confirm the effects of therapy, thus reducing the frequency of rechecking [K +].  MAGNESIUM The total body content of magnesium (Mg2+) is 24 grams, or 2000 mEq, 50% to 70% of which is fixed in bone and only slowly exchange able. Most of the remaining Mg 2+ is found in the ICF space, with a concentration of approximately 40 mEq/L. The distribution of Mg 2+ is similar to that of K +, with the major portion being intracellular. It is the second most abundant intracellular cation. Normal serum [Mg2+] ranges between 1.5 and 2.5 mEq/L (0.7 to 1.1 mmol/L or 1.7 to 2.7 milligrams/dL). Circulating Mg 2+ is 25% to 35% bound to proteins (mainly albumin), 10% to 15% complexed, and 50% to 60% ionized, which is the active portion. The normal dietary intake of Mg 2+ is approximately 240 to 336 milligrams/d and is found in vegetables such as dry beans and leafy greens, meat, and cereals. Sixty percent of excreted Mg 2+ is through stool, with the remainder via the urine. Tintinalli_Sec03_p0053-0142.indd 91 8/2/19 2:57 PM

hich is the active portion. The normal dietary intake of Mg 2+ is approximately 240 to 336 milligrams/d and is found in vegetables such as dry beans and leafy greens, meat, and cereals. Sixty percent of excreted Mg 2+ is through stool, with the remainder via the urine. Tintinalli_Sec03_p0053-0142.indd 91 8/2/19 2:57 PM 92 SECTION 3: Resuscitation TABLE 17-18 ECG Changes Associated with Hyperkalemia [K+] (mEq/L) ECG Changes* 6.5–7.5 Prolonged PR interval, tall peaked T waves, short QT interval 7.5–8.0 Flattening of the P wave, QRS widening 10–12 QRS complex degradation into a sinusoidal pattern *In chronic or slowly developing hyperkalemia, ECG changes may not occur until higher [K+] levels are reached. 10 mm/mV 10 mm/mV 10 mm 10 mm/aV73/min 87/min aVRaVR aVLaVL aVF V1 V2 V3aVF V4 V5 V6 0.15-35 Hz 0.15-3 P80 1E91 25 mm/s 10 mm/aV 10 mm/aV 10 mm/aV10 0.1 96/min 111/min III III 94/min /s 25 mm/s 25 mm/s F50 0.15-35 Hz 0.15-35 Hz F50 0.15-35 H P80 P81E91 0.15-35 Hz F50 0.15-35 Hz F50 79/min FIGURE 17-6. The same patient as in Figure 17-5 during calcium chloride infusion. She regained a pulse and became conscious. The QRS and T wave narrowed, as compared with Figure 17-5. FIGURE 17-5. Monitor strip (V1– V3) of a 35-year-old patient in critical condition, who was hypotensive and fatigued and rapidly deteriorated into cardiac arrest. Potassium level was 9.1 mEq/L. She was on spironolactone and steroid therapy. Tintinalli_Sec03_p0053-0142.indd 92 8/2/19 2:57 PM

s compared with Figure 17-5. FIGURE 17-5. Monitor strip (V1– V3) of a 35-year-old patient in critical condition, who was hypotensive and fatigued and rapidly deteriorated into cardiac arrest. Potassium level was 9.1 mEq/L. She was on spironolactone and steroid therapy. Tintinalli_Sec03_p0053-0142.indd 92 8/2/19 2:57 PM CHAPTER 17:  Fluids and Electrolytes      93 TABLE 17-19 Emergency Therapy of Hyperkalemia Therapy Dose and Route Onset of Action Duration of Effect Mechanism Calcium chloride (10%)* 5–10 mL IV 1–3 min 30–50 min Membrane stabilization Calcium gluconate (10%)* 10–20 mL IV 1–3 min 30–50 min Membrane stabilization NaHCO3 † 50–150 mEq IV if accompanying metabolic acidosis 5–10 min 1–2 h Shifts [K+] into cell Albuterol (nebulized) 10–20 milligrams in 4 mL of normal saline, nebulized over 10 min 15–30 min 2–4 h Upregulates cyclic adenosine monophosphate, shifts [K+] into cell Insulin‡ and glucose# 5–10 units regular insulin IV Glucose 25 grams (50% solution) IV 30 min 4–6 h Shifts [K+] into cell Furosemide 40–80 milligrams IV Varies Varies Renal [K+] excretion Sodium polystyrene sulfonate 25–50 grams PO or PR 1–2 h 4–6 h GI [K+] excretion Hemodialysis — Minutes Varies Removes [K+] *Calcium chloride has three times the elemental calcium when compared to calcium gluconate. 10% calcium chloride = 27.2 milligrams [Ca2+]/mL; 10% calcium gluconate = 9 milligrams [Ca2+]/mL. Due to its short duration, calcium administration (both chloride and gluconate) can be repeated up to four times per hour. †May be institutional variations in treatment with sodium bicarbonate; refer to Batterink et al41 and Rossignol et al42 for full discussion. ‡Reduce dose of insulin in patients with renal failure. #Glucose infusion should be administered after initial bolus to prevent hypoglycemia. Glucose should not be administered in hyperglycemic patients. TABLE 17-20 Causes of Hypomagnesemia Redistribution IV glucose Correction of diabetic ketoacidosis IV hyperalimentation Refeeding after starvation Acute pancreatitis Postparathyroidectomy (hungry bone syndrome) Osteoblastic metastasis (hungry bone syndrome) Extrarenal loss Nasogastric suction (infrequent) Lactation Profuse sweating, burns, sepsis Intestinal or biliary fistula Diarrhea Decreased intake Alcoholism (cirrhosis) Malnutrition, poor intake Small bowel resection Malabsorption (steatorrhea) Renal loss

IV glucose Correction of diabetic ketoacidosis IV hyperalimentation Refeeding after starvation Acute pancreatitis Postparathyroidectomy (hungry bone syndrome) Osteoblastic metastasis (hungry bone syndrome) Extrarenal loss Nasogastric suction (infrequent) Lactation Profuse sweating, burns, sepsis Intestinal or biliary fistula Diarrhea Decreased intake Alcoholism (cirrhosis) Malnutrition, poor intake Small bowel resection Malabsorption (steatorrhea) Renal loss Ketoacidosis Saline or osmotic diuresis Potassium depletion Phosphorus depletion Familial hypophosphatemia Tubulointerstitial renal disease Drugs Loop diuretics Aminoglycosides Amphotericin B Vitamin D intoxication Alcohol Cisplatin Theophylline Proton pump inhibitors Calcineurin inhibitors (cyclosporine, tacrolimus) Endocrine disorders

Ketoacidosis Saline or osmotic diuresis Potassium depletion Phosphorus depletion Familial hypophosphatemia Tubulointerstitial renal disease Drugs Loop diuretics Aminoglycosides Amphotericin B Vitamin D intoxication Alcohol Cisplatin Theophylline Proton pump inhibitors Calcineurin inhibitors (cyclosporine, tacrolimus) Endocrine disorders Syndrome of inappropriate antidiuretic hormone secretion Hyperthyroidism Hyperparathyroidism Hypercalcemic states Primary or secondary aldosteronism Renal reabsorption is carried out with sodium and water and is unidirectional; that means that it is impaired by volume overload, osmotic diuresis, and diuretics. About 300 enzymes have their activities regulated by Mg 2+; it assists the production of adenosine triphosphate, participates in nucleic acid and protein synthesis, and is involved in coagulation, platelet aggregation, and neuromuscular activity, as well as in cardiac action potential. 1,2,47 Mg2+ homeostasis is very complex and finely regulated by many fac tors, such as parathyroid hormone, calcitonin, ADH, glucose, insulin, glucagon, catecholamines, sodium, potassium, calcium, and phosphorus levels. Mg 2+ is effective therapy in severe asthma when added to standard therapy48 (see Chapter 69, “ Acute Asthma and Status Asthmaticus”). HYPOMAGNESEMIA Table 17-20 lists the different causes of hypomagnesemia. IV hyperalimentation or treatment of diabetic ketoacidosis without adequate provision of Mg2+, especially in a previously malnourished patient, can cause an abrupt fall in plasma Mg2+ levels. Acid-base imbalance affects the levels of ionized Mg 2+; a typical example is respiratory alkalosis that enhances neuromuscular activity (thus provoking tremors and cramps) by rapidly decreasing ionized [Mg 2+] and [Ca2+] at the same time. Among the iatrogenic causes, proton pump inhibitors may cause hypomagnesemia,49 especially in association with diuretic therapy, probably through the inhibition of intestinal absorption. Concomitant hypomagnesemia and hypokalemia may coexist.  CLINICAL FEATURES Due to the essential role of Mg 2+ in enzyme regulation in multiple body systems, hypomagnesemia may result in a wide variety of neuromuscu lar, GI, and cardiovascular effects (Table 17-21).  DIAGNOSIS Hypomagnesemia is common in acute illness; it has been found in 12% of hospitalized patients and in up to 65% of medical intensive care patients. 50 It is likely underdiagnosed because few hospitalized patients have levels drawn.51 The diagnosis of hypomagnesemia in the presence of normal serum calcium levels is suggested by increased neuromuscular irritability, shown by hyperreflexia tremor, tetany, or even convulsions. Chvostek sign and Trousseau sign, findings traditionally associated with hypocalcemia, may be elicited in hypomagnesemic patients. Hypomagnesemia Tintinalli_Sec03_p0053-0142.indd 93 8/2/19 2:57 PM

um levels is suggested by increased neuromuscular irritability, shown by hyperreflexia tremor, tetany, or even convulsions. Chvostek sign and Trousseau sign, findings traditionally associated with hypocalcemia, may be elicited in hypomagnesemic patients. Hypomagnesemia Tintinalli_Sec03_p0053-0142.indd 93 8/2/19 2:57 PM 94 SECTION 3: Resuscitation TABLE 17-21 Symptoms and Signs of Hypomagnesemia Neuromuscular Tetany Muscle weakness Chvostek and Trousseau signs Cerebellar (ataxia, nystagmus, vertigo) Confusion, obtundation, coma Seizures Apathy, depression Irritability Paresthesias GI Dysphagia Anorexia, nausea Cardiovascular Heart failure Dysrhythmias Hypotension Miscellaneous Hypokalemia Hypocalcemia Anemia should be suspected in patients with alcoholism or cirrhosis or those requiring IV fluids or hyperalimentation for prolonged periods. Low total [Mg 2+] can also be secondary to hypoalbuminemia. The ECG changes may be similar to those caused by hypokalemia and/or hypocalcemia because they may be due to Mg 2+ deficiency altering cardiac intracellular potassium content. As for hypokalemia, low [Mg 2+] levels enhance digitalis toxicity, so hypomagnesemia should be searched in ECG disturbances associated with digoxin intake, especially when both digoxin and K + levels are normal.52  TREATMENT Hypokalemia, hypocalcemia, and hypophosphatemia are often present with severe hypomagnesemia and must be monitored carefully. Hypocalcemia does not develop until [Mg 2+] falls below 1.2 milligrams/dL. The following are general principles in treatment of hypomagnesemia: 1. Treat or stop the cause of hypomagnesemia. 2. For asymptomatic patients (including ECG changes), magnesium supplements should be administered orally, in multiple low doses during the day, to avoid diarrhea. Magnesium lactate, chloride, glu conate, and proteinate are the formulations with minimum effect on intestinal motility. 3. For severe and symptomatic hypomagnesemia, urgent IV replacement is mandatory. The formulation most commonly used is magnesium sulfate (MgSO 4). In life-threatening conditions (torsades de pointes, eclampsia), 1 to 4 grams or 8 to 32 mEq diluted in at least 100 mL of 5% dextrose or normal saline (0.9%) solution can be administered in 10 to 60 minutes under continuous monitoring: ECG (risk of hypo kinetic arrhythmias), noninvasive blood pressure (risk of hypotension), and ventilatory pattern (risk of respiratory depression, usually preceded by areflexia, that can be monitored as an alarm sign). As a minor side effect, flushing due to vasodilatation is common. 4. Patients with chronic Mg 2+ deficiency may require >50 mEq of oral Mg 2+ (6 grams of MgSO 4 per day). In chronic alcoholics with delirium tremens and in patients with severe hypomagnesemia, up to 8 to 12 grams of MgSO 4 may be given IM (possible, but very painful) or IV the first day. The first 10 to 15 mEq (1.5 to 2.0 grams) of IV MgSO 4 can be given over 1 to 2 hours. This may be followed by up to 4 to 6 grams/d. Approximately half of the administered Mg 2+ will be lost in the urine. 5. Spironolactone is effective in maintaining [Mg 2+] homeostasis as well as in reducing the incidence of arrhythmias in congestive heart failure patients. HYPERMAGNESEMIA Hypermagnesemia is rarely encountered in emergency medicine prac tice, because the kidney can increase the fractional excretion of Mg 2+ up to nearly 100%. A small elevation in serum concentration has little clinical significance. The most common cause for hypermagnesemia can be found in patients with renal insufficiency or renal failure who ingest Mg 2+-containing drugs.54 Hypermagnesemia is more commonly seen in the perinatal setting secondary to the treatment of preeclampsia or eclampsia.

serum concentration has little clinical significance. The most common cause for hypermagnesemia can be found in patients with renal insufficiency or renal failure who ingest Mg 2+-containing drugs.54 Hypermagnesemia is more commonly seen in the perinatal setting secondary to the treatment of preeclampsia or eclampsia. It has been described as a serious, life-threatening conse quence of Mg 2+-containing laxative abuse in patients with normal renal function.55 Other causes of hypermagnesemia include lithium ingestion, volume depletion, or familial hypocalciuric hypercalcemia (Table 17-22).  CLINICAL FEATURES Hypermagnesemia rarely produces symptoms. Mg2+ decreases the transmission of neuromuscular messages and thus acts as a CNS depressant and decreases neuromuscular activity. Signs and symptoms related to [Mg 2+] can be found in Table 17-23.  DIAGNOSIS Serum [Mg 2+] is usually diagnostic. The possibility of hypermagnesemia should be considered in patients with hyperkalemia or hypercalcemia. Hypermagnesemia also should be suspected in patients with renal failure, particularly in those who are taking magnesiumcontaining antacids or laxatives.  TREATMENT Immediate cessation of Mg2+ administration is required. If renal failure is not evident, dilution by IV fluids followed by furosemide (40 to 80 milligrams IV) may be indicated. Calcium directly antagonizes the cardiac effects of magnesium because it reverts the calcium channel blockade provoked by elevated [Mg 2+]. Severe symptomatic hypermag nesemia can be treated with 10 mL of 10% calcium chloride IV over 2 to 3 minutes. Further infusion of 40 to 60 mL during the next 24 hours can be administered. Patients with renal failure may benefit from dialysis using a decreased [Mg 2+] bath that lowers serum [Mg2+]. TABLE 17-22 Causes of Hypermagnesemia Renal Failure Acute or Chronic Increased magnesium load Magnesium-containing laxatives, antacids, or enemas* Treatment of preeclampsia/eclampsia (mothers and neonates) Diabetic ketoacidosis (untreated)* Tumor lysis Rhabdomyolysis* Increased renal magnesium absorption Hyperparathyroidism Familial hypocalciuric hypercalcemia Hypothyroidism Mineralocorticoid deficiency, adrenal insufficiency (Addison’s disease) *Most likely presentations relevant to the ED. TABLE 17-23 Symptoms and Signs of Hypermagnesemia Magnesium Level (mEq/L) Clinical Manifestations 2.0–3.0 Nausea 3.0–4.0 Somnolence 4.0–8.0 Loss of deep tendon reflexes 8.0–12.0 Respiratory depression 12.0–15.0 Hypotension, heart block, cardiac arrest Tintinalli_Sec03_p0053-0142.indd 94 8/2/19 2:57 PM

levant to the ED. TABLE 17-23 Symptoms and Signs of Hypermagnesemia Magnesium Level (mEq/L) Clinical Manifestations 2.0–3.0 Nausea 3.0–4.0 Somnolence 4.0–8.0 Loss of deep tendon reflexes 8.0–12.0 Respiratory depression 12.0–15.0 Hypotension, heart block, cardiac arrest Tintinalli_Sec03_p0053-0142.indd 94 8/2/19 2:57 PM CHAPTER 17:  Fluids and Electrolytes      95 TABLE 17-24 Selected Causes of Hypocalcemia Cause Mechanism(s) Decreased calcium absorption Vitamin D deficiency Decreased oral intake Decreased intestinal absorption Decreased production of 25(OH)D3 Decreased synthesis of 1,25(OH2)D3 Malabsorption syndromes Malnutrition Intestinal bypass, gastrectomy Liver failure Renal failure, hyperphosphatemia Malabsorption Increased calcium excretion/reduced bone resorption Alcoholism Hypomagnesemia causing inhibition of PTH secretion, PTH resistance to bone resorption Hypoparathyroidism Genetic, autoimmune, surgical, tumoral Pseudohypoparathyroidism Resistance to PTH action Hypomagnesemia Inhibition of PTH secretion, PTH resistance to bone resorption Drugs (Table 17-25) Malignancy Pseudohypocalcemia, hyperphosphatemia, hypomagnesemia, vitamin D or PTH deficiency, osteoblastic metastasis Sepsis Acute pancreatitis Fatty acids combine with [Ca2+] to form insoluble Ca2+ soaps and lead to a reduction of serum [Ca2+] Massive transfusions Rhabdomyolysis Abbreviations:  25(OH)D3 = 25-hydroxyvitamin  D3; 1,25(OH2)D 3 = 1,25-dihydroxyvitamin  D3; PTH = parathyroid  ho rmone. TABLE 17-25 Drugs That Can Cause Hypocalcemia •  Phosphates  (e.g., enemas, laxatives) •  Phenytoin,  phenobarbital •  Gentamicin,  tobramycin, dactinomycin, foscarnet •  Cisplatin •  Citrate •  Loop  diuretics •  Glucocorticoids •  Magnesium  sulfate •  Bisphosphonates,  calcitonin, denosumab •  Cinacalcet  CALCIUM PATHOPHYSIOLOGY Calcium (Ca2+) is the most abundant mineral in the body. The total body [Ca2+] is 15 grams/kg of body weight, or about 1 kg in an average-sized adult. Ca2+ is 99% bound in bone as phosphate and carbonate (mineral apatite), with the remainder in the teeth, soft tissues, plasma, and cells. The normal daily intake of Ca 2+ is 800 to 3000 milligrams, one third of which is absorbed primarily in the small bowel by active (vitamin D–dependent) and passive (concentration-dependent) absorption. Excretion of Ca 2+ is primarily via the stool. The cell content of Ca2+ is 10,000 times lower than the plasma content, and this gradient is maintained by Ca-ATPase, Ca 2+-specific channels, and Na/Ca exchangers. Plasma [Ca2+] is between 8.5 and 10.5 milligrams/dL (4.3 to 5.3 mEq/L or 2.2 to 2.7 mmol/L) and is present in three different forms: ionized calcium, 50% of total (4.5 to 5.6 milligrams/dL; 1.1 to 1.4 mmol/L), which is the only active fraction; protein-bound calcium, 40% of total, which is inactive and not filtered by glomerulus; and complexed calcium, 10% of total, which is bound to anions such as phosphate, carbonate, and citrate. It is necessary to be aware of standard units used by different laboratories to express Ca 2+ value: 1 mEq/L = 2 milligrams/dL = 0.5 mmol/L. The ionized fraction is the only biologically active fraction; a decrease in albumin decreases the total [Ca 2+] but does not change the ionized fraction. On average, 0.8 milligram of Ca 2+ binds to 1 gram of protein. Therefore, total serum [Ca2+] is equal to ionized [Ca2+] plus the product of 0.8 and total protein. Alkalosis produces a decrease in ionized frac tion with no change in the total serum [Ca2+]. Each 0.1 rise in pH lowers ionized [Ca2+] by about 3% to 8%. The opposite effect is produced by acidosis.

to 1 gram of protein. Therefore, total serum [Ca2+] is equal to ionized [Ca2+] plus the product of 0.8 and total protein. Alkalosis produces a decrease in ionized frac tion with no change in the total serum [Ca2+]. Each 0.1 rise in pH lowers ionized [Ca2+] by about 3% to 8%. The opposite effect is produced by acidosis. The role of Ca 2+ is crucial for muscle and cardiac contraction, nerve conduction, cell growth, enzyme activation, and coagulation, and consequently, any hypo- or hypercalcemia leads to severe dysfunctions.  HOMEOSTASIS OF CALCIUM The organs involved in the homeostasis of calcium are bones, kidneys, and the intestines, whereas the major determinants are three hormones and one receptor. 1,2,56,57 1. 1,25-Dihydroxycholecalciferol (active vitamin D 3)57 is formed in the distal tubule. It promotes Ca2+ absorption from intestine, but this activity is modulated by physiologic conditions that may enhance it (pregnancy and growth) or reduce it (oxalates and phytates in food and aging). 2. Parathyroid hormone (PTH) is secreted by parathyroid glands when [Ca 2+] is low and is regulated by Ca 2+-sensing receptor, vitamin D 3, and Mg2+ (hypomagnesemia inhibits PTH secretion). PTH stimulates bone demineralization by activating osteoclasts and by increasing the synthesis of vitamin D 3 and increasing Ca 2+ reabsorption from kidney.58 3. Calcitonin is a peptide secreted by C-cells of the thyroid gland when [Ca 2+] is high. It inhibits the activity of osteoclasts and thus bone resorption. 4. Ca2+-sensing receptor58,59 is mainly present on plasma membranes of parathyroids, kidney, bones, and thyroid. It becomes active in case of hypercalcemia and inhibits the production of PTH. In the kidney, activated Ca 2+-sensing receptor provokes hypercalciuria and polyuria, preventing nephrocalcinosis. The activation of the recep tor also stimulates the secretion of calcitonin and inhibits osteoclast formation. Urinary secretion of Ca 2+ is variable and influenced by many differ ent factors. Hypercalcemia, metabolic acidosis, hypervolemia, and loop diuretics increase urinary secretion of [Ca 2+]. PTH, vitamin D 3, metabolic alkalosis, hypovolemia, and the chronic use of thiazides reduce secretion. HYPOCALCEMIA Hypocalcemia is defined by an ionized [Ca2+] level <2.0 mEq/L (<4 milligrams/dL or <1.1 mmol/L). Homeostasis is regulated by the maintenance of the gradient between cells and ECF , is controlled by the previously described mechanism, and is mediated intracellularly by phosphates, cyclic adenosine monophosphate, and ion pumps. 56 Any process that interferes with cell metabolism, such as shock or sepsis, will tend to reduce ionized [Ca 2+] by allowing increased net movement of Ca2+ across the cell membrane into the cytoplasm of the poorly functioning cells. Table 17-2459-61 lists the most common causes of hypocalcemia and the primary mechanism of each. Table 17-25 lists the principal drugs that cause hypocalcemia.2  CLINICAL FEATURES The severity of signs and symptoms depends greatly on the rapidity of the decrease in [Ca 2+]. Table 17-26 lists the different signs and symp toms that can be seen in the course of hypocalcemia. 1,2,62 Tintinalli_Sec03_p0053-0142.indd 95 8/2/19 2:57 PM

s the principal drugs that cause hypocalcemia.2  CLINICAL FEATURES The severity of signs and symptoms depends greatly on the rapidity of the decrease in [Ca 2+]. Table 17-26 lists the different signs and symp toms that can be seen in the course of hypocalcemia. 1,2,62 Tintinalli_Sec03_p0053-0142.indd 95 8/2/19 2:57 PM 96 SECTION 3: Resuscitation TABLE 17-26 Symptoms and Signs of Hypocalcemia Muscular Weakness, fatigue Spasms, cramps Neurologic Seizures Tetany Chvostek sign, Trousseau sign Circumoral and digital paresthesias Impaired memory, confusion Hallucinations, dementia Extrapyramidal disorders Dermatologic Hyperpigmentation Coarse, brittle hair Dry, scaly skin Cardiovascular Heart failure Ventricular arrhythmias, QTc prolongation leading to torsades de pointes Vasoconstriction Skeletal Osteodystrophy Rickets Osteomalacia Miscellaneous Dental hypoplasia Cataracts Decreased insulin secretion Neuromuscular and cardiovascular signs and symptoms predomi nate. As serum [Ca 2+] falls, neuronal membranes become increasingly more permeable to sodium, thereby enhancing excitation and causing smooth and skeletal muscle contractions. Irritability, confusion, dementia, extrapyramidal symptoms, seizures, and hallucination may occur. V1 III aVL aVR aVF V2 V3 V4 V5 V6 FIGURE 17-7. ECG of a patient with severe hypocalcemia (Ca2+ 4.5 milligrams/dL) who was complaining of chest and abdominal pain, pain in the legs, and Trousseau sign. A very long QTc and T-wave abnormalities mimicking ischemia are evident. Decreased ionized [Ca2+] reduces the strength of myocardial contraction primarily by inhibiting relaxation. The most characteristic ECG finding in hypocalcemia is a prolonged QTc interval.28,29 The T wave may be of normal width, and it is the ST segment that is actually prolonged. In very severe hypocalcemia, T waves may present abnormalities that may mimic ischemia (Figure 17-7). This finding is usually seen with total serum calcium levels <6.0 milligrams/dL. A positive Chvostek sign (twitch at the corner of the mouth when the examiner taps over the facial nerve just in front of the ear) and Trousseau sign (carpal spasm produced when the examiner applies a blood pressure cuff to the upper arm and maintains a pressure above systolic for 2 to 3 minutes; the fingers are spastically extended at the interphalangeal joints and flexed at the metacarpophalangeal joints with wrist flexion and forearm pronation) are classically associated with hypocalcemia (but also may occur in respiratory alkalosis, which shifts ionized Ca 2+ to the proteinbound form). These diagnostic signs have not been subjected to rigorous assessment, and there is no agreement on sensitivity or specificity. 63,64  DIAGNOSIS In addition to total serum [Ca 2+], a full electrolyte panel, renal function tests, ionized [Ca 2+], and magnesium levels aid in the diagnosis. An albumin level should be obtained because hypoalbuminemia may falsify the diagnosis. In cases where acid-base abnormalities are suspected, a blood gas analysis to evaluate pH should be obtained. Also consider a phosphate level. Blood samples for PTH and vitamin D 3 levels should be drawn (but results are not required) before starting therapy.  TREATMENT Treatment of hypocalcemia is tailored to the individual patient and directed toward the underlying cause. If a patient is asymptomatic or if the hypocalcemia is not severe or prolonged for >10 to 14 days, oral 2+ therapy with or without vitamin D may be sufficient. Ca 2+ lactate, Tintinalli_Sec03_p0053-0142.indd 96 8/2/19 2:57 PM

f hypocalcemia is tailored to the individual patient and directed toward the underlying cause. If a patient is asymptomatic or if the hypocalcemia is not severe or prolonged for >10 to 14 days, oral 2+ therapy with or without vitamin D may be sufficient. Ca 2+ lactate, Tintinalli_Sec03_p0053-0142.indd 96 8/2/19 2:57 PM CHAPTER 17:  Fluids and Electrolytes      97 ascorbate, carbonate, and gluconate are available in oral preparations and contain variable percentages of elemental Ca2+; 1 mEq of elemental Ca2+ is equal to 20 milligrams of elemental Ca 2+. Regimens can be 500 to 3000 milligrams of elemental Ca 2+ by mouth daily, in one dose or up to three divided doses. The dose must be individualized for each patient, according to the cause and severity of hypocalcemia. IV Ca 2+ is recommended only in cases of symptomatic or severe hypocalcemia2 (ionized [Ca 2+] <1.9 mEq/L or <0.95 mmol/L), because IV Ca2+ administration causes vasoconstriction and possible ischemia, especially in patients with low cardiac output who already have sig nificant peripheral vasoconstriction. IV Ca 2+ gluconate is preferred over IV calcium chloride (CaCl 2) in nonemergency settings due to the dangers of extravasation with CaCl2 (calcinosis cutis). With severe acute hypocalcemia, 10 mL of 10% CaCl2 (or 10 to 30 mL of 10% Ca2+ gluconate) may be given IV over 10 to 20 minutes and repeated every 60 minutes until symptoms resolve or followed by a continuous IV infusion of 10% CaCl 2 at 0.02 to 0.08 mL/kg/h (1.4 to 5.6 mL/h in a 70-kg patient). 65 The serum [Ca 2+] should then be rechecked before continuing parenteral Ca 2+. IV Ca 2+ should be used with caution in patients taking digitalis because hypercalcemia can potentiate digitalis toxicity. 66 Symptomatic patients after thyroid or parathyroid surgery are often treated with parenteral Ca2+. During massive transfusions, if the blood is being given faster than 1 unit every 5 minutes, 10 mL of 10% CaCl 2 can be given after every 4 to 6 units of blood if a patient is in shock or has heart failure despite adequate volume replacement therapy. Hypocalcemia is difficult to correct if hypomagnesemia is also present because of reduction of PTH and Ca 2+ releases from bone. Therefore, magnesium should be replaced before, or in conjunction with, Ca 2+ replacement.56,57 HYPERCALCEMIA Hypercalcemia is relatively common. It is defined as a total [Ca 2+] >10.5 milligrams/dL or an ionized [Ca 2+] level >2.7 mEq/L. Because Ca2+ is necessary for cellular functions, every organ and system is affected by hypercalcemia, and clinical manifestations are dependent on the level of [Ca2 +]: mild hypercalcemia, 10.5 to 11.9 milligrams/dL; moderate, 12 to 13.9 milligrams/dL; severe, >14 milligrams/dL.2,67 Neuromuscular changes include decreased sensitivity, responsive ness, and strength of muscular contraction and nerve conduction. The conduction of the heart is slowed and automaticity is decreased with a shortening of the refractory period. Increased sensitivity to cardiac glycosides may be seen. Loss of concentrating ability is the most frequent renal effect of hypercalcemia. This is a reversible tubular defect, which results in polyuria and volume depletion even in the presence of thirst. Potassium wasting resulting in hypokalemia may occur in up to one third of patients. Nephrocalcinosis and nephrolithiasis may result from hypercalcemia and can be exacerbated by volume depletion. As the hypercalcemia persists, increasing microscopic Ca 2+ deposits in the kidney can lead to progres sive renal insufficiency. More than 90% of occurrences are associated with hyperparathyroidism2,68 or malignancy, the latter being the most likely presentation in the ED.

ia and can be exacerbated by volume depletion. As the hypercalcemia persists, increasing microscopic Ca 2+ deposits in the kidney can lead to progres sive renal insufficiency. More than 90% of occurrences are associated with hyperparathyroidism2,68 or malignancy, the latter being the most likely presentation in the ED. A list of potential causes of hypercalcemia and the relative mecha nism of onset are provided in Table 17-27.  CLINICAL FEATURES Hypercalcemic patients with plasma total [Ca2+] below 12.0 milligrams/dL are usually asymptomatic, but higher levels can cause a wide variety of symptoms (Table 17-28). Patients with total [Ca 2+] >14 to 16 milligrams/dL are usually very weak, lethargic, and confused. Polyuria and polydipsia are due to impaired renal tubular reabsorption of water and result in volume depletion. Total [Ca 2+] >15.0 milligrams/dL may cause somnolence, stupor, and even coma. A mnemonic sometimes used for the signs and symp toms of hypercalcemia is stones (renal calculi), bones (osteolysis), moans (psychiatric disorders), and groans (peptic ulcer disease, pancreatitis, and constipation). Hypercalcemia should be investigated in patients with extensive metastatic bone disease, particularly if the primary site involves the breast, lungs, or kidneys, and in individuals with combinations of clini cal problems, such as renal calculi, pancreatitis, or ulcer disease. On ECG, hypercalcemia may be associated with depressed ST segments, widened T waves, and shortened ST segments and QT intervals. In severe hypercalcemia, ST-segment elevation mimicking myocardial infarction may be seen. 69 Bradyarrhythmias may occur, with bundle branch patterns TABLE 17-27 Causes of Hypercalcemia Cause Mechanism Hypercalcemia due to increased bone Ca2+ resorption Primary hyperparathyroidism Malignancy Pseudohyperparathyroidism Renal failure Addison’s disease Hyperthyroidism Immobilization ↑ PTH Osteolysis, PTH-related protein (PTHrP) production PTH from non–parathyroid tissue source Secondary and tertiary hyper-PTH due to chronic hypocalcemia ↑ Albumin, bone resorption Increased bone resorption Osteoclast activation Hypercalcemia due to decreased urinary Ca2+ excretion Familial hypercalcemic hypocalciuria Thiazides

ysis, PTH-related protein (PTHrP) production PTH from non–parathyroid tissue source Secondary and tertiary hyper-PTH due to chronic hypocalcemia ↑ Albumin, bone resorption Increased bone resorption Osteoclast activation Hypercalcemia due to decreased urinary Ca2+ excretion Familial hypercalcemic hypocalciuria Thiazides Mutation of CaSR Increased kidney Ca2+ reabsorption in proximal tubule Hypercalcemia due to increased GI Ca2+ absorption Granulomatous diseases (sarcoidosis, tuberculosis, coccidioidomycosis, histoplasmosis) Milk (calcium)-alkali syndrome Vitamin D intoxication 1α-Hydroxylase activity ↑Ca2+ intake (calcium carbonate) and absorption Increased calcium absorption and bone resorption Abbreviations: CaSR = Ca2+-sensing receptor; PTH = parathyroid hormone. TABLE 17-28 Signs and Symptoms of Hypercalcemia General Malaise, weakness Polydipsia, dehydration Cardiovascular Hypertension Dysrhythmias Vascular calcifications ECG abnormalities QT shortening Coving of ST-T wave Widening of T wave Digitalis sensitivity Neurologic Confusion Apathy, depression, stupor Decreased memory Irritability Hallucinations Headache Ataxia Hyporeflexia, hypotonia Mental retardation (infants) Anorexia, weight loss Nausea, vomiting Constipation Abdominal pain Peptic ulcer disease Pancreatitis Urologic Polyuria, nocturia Renal insufficiency Nephrolithiasis Metastatic calcification Band keratopathy Conjunctivitis Pruritus Skeletal Fractures Bone pain Deformities Tintinalli_Sec03_p0053-0142.indd 97 8/2/19 2:57 PM

orexia, weight loss Nausea, vomiting Constipation Abdominal pain Peptic ulcer disease Pancreatitis Urologic Polyuria, nocturia Renal insufficiency Nephrolithiasis Metastatic calcification Band keratopathy Conjunctivitis Pruritus Skeletal Fractures Bone pain Deformities Tintinalli_Sec03_p0053-0142.indd 97 8/2/19 2:57 PM 98 SECTION 3: Resuscitation that may progress to second-degree block or complete heart block. Levels of [Ca2+] above 20 milligrams/dL may cause cardiac arrest.  DIAGNOSIS True hypercalcemia must be confirmed by measuring ionized [Ca 2+]70; then electrolytes, CBC, phosphate, magnesium, BUN, creatinine, and alkaline phosphatase will help determine the cause. The acuity of hypercalcemia can be determined or suggested using the medical history together with an ECG, chest radiograph, and laboratory investigation. Normally, acute, severe hypercalcemia is not caused by hyperparathy roidism. Malignancies, in particular lymphoma, leukemia, and meta static bone cancer, are common causes of severe, acute hypercalcemia. A corrected Ca 2+ level should be calculated if albumin is not in the normal range: corrected Ca 2+ (milligrams/dL) = measured total Ca 2+ (milligrams/dL) + 0.8 (4.0 – serum albumin [grams/dL]), where 4.0 represents the average albumin level in grams/dL. If the reference lab reports val ues in mmol/L, use the following formula: corrected Ca 2+ (mmol/L) = measured total Ca2+ (mmol/L) + 0.02 (40 – serum albumin [grams/L]), where 40 represents the average albumin level in grams/L. If the values listed in the corrected Ca 2+ formulas for normal albumin do not match your institution’s lab, adjust this value accordingly.  TREATMENT Symptomatic patients or asymptomatic patients with [Ca 2+] levels >14 milligrams/dL should receive treatment starting with volume repletion. Administer 0.9% normal saline at 500 to 1000 mL/h for 2 to 4 hours as tolerated by the patient. In general, 3 to 4 L should be given over the first 24 hours, then 2 to 3 L per 24 hours until a urine output of 2 L/d is achieved. 71 Furosemide is recommended to promote a diuresis of 150 to 200 mL/h, which increases the calciuric effect, 1,71 with an initial dose of 20 to 40 milligrams. Caution should be used for possible paradoxical hypercalcemia due to bone resorption, and for hypokalemia and/or hypomagnesemia occurrence, when furosemide is being used. Decreased mobilization of [Ca 2+] from bone through reduction of osteoclastic activity can be obtained with corticosteroids, such as prednisone, 1 to 2 milligrams/kg PO, or hydrocortisone, 200 to 300 milligrams IV initial dose, in Addison’s disease or in steroidresponsive malignancies. In very severe cases, it will be necessary to receive hemodialysis to quickly remove Ca 2+ from blood. 67,72 In the ED, initiating bisphos phonates or calcitonin is not mandatory. However, for hypercalcemia associated with malignancy, IV bisphosphonates are now considered first-line therapy 71; examples are pamidronate or zoledronate (zole dronic acid). Zoledronic acid is recommended; for a corrected [Ca 2+] level of 12 milligrams/dL or higher, 4 milligrams as a single dose can be given IV over 15 minutes. Calcitonin works more rapidly than bisphosphonates and can be given at a dose of 4 units/kg SC or IM.  PHOSPHORUS As phosphorus is a highly reactive mineral, it is found as phosphate (PO 3–) existing mainly as hydroxyapatite (85%) or as an intracellular constituent (10% to 15%). Only about 1% is in the ECF , so serum mea surements may not accurately reflect total body stores. It is involved in oxidative phosphorylation and mitochondrial respiration, and it is the essential component of adenosine triphosphate, a requirement for cellular energy metabolism.

intracellular constituent (10% to 15%). Only about 1% is in the ECF , so serum mea surements may not accurately reflect total body stores. It is involved in oxidative phosphorylation and mitochondrial respiration, and it is the essential component of adenosine triphosphate, a requirement for cellular energy metabolism. 2,73 Serum [PO4 3–] decreases with age from a range of 4.0 to 7.0 milligrams/dL in newborns to 2.5 to 5.0 milligrams/dL in adults. The total body phosphorus store in a normal man is approximately 700 grams (10 to 15 grams/kg). Metabolism of phosphorus is strictly linked to that of calcium. The only active status of PO 3– is in biological fluids. Homeostasis of PO 4 3– is mainly regulated by gut absorption and urine excretion. Gut absorption is localized in two different sites. The first is the duodenum, which is inhibited by calcitonin and is stimulated by vitamin D 3 and low phosphate intake. The second is the jejunum and ileum, where absorption is passive and dependent on PO 4 3– concentration in the gut. Excretion is predominantly in the urine by the glomerulus, with the majority reabsorbed in the proximal tubules. Excretion is regulated by PTH, which lowers serum phosphate by increasing renal excretion, and by a hormone secreted by osteoclasts and osteoblasts, the fibroblast growth factor-23, which increases PO 3– excretion and inhibits intestinal absorption. Proximal tubule absorption increases when serum [PO 4 3–] levels drop and with hypoparathyroidism, volume depletion, hypocalcemia, or the presence of growth hormone. Excretion increases in the presence of volume expansion, hypercalcemia, acidosis, hypomagnesemia, hypokalemia, glucocorticoids, diuretics, calcitonin, or PTH. HYPOPHOSPHATEMIA Hypophosphatemia is defined as serum [PO 4 3–] <2.5 milligrams/dL, but severe symptoms may not occur until the [PO 4 3–] level drops to <1 milligram/dL. Because phosphorus is abundant in many foods and readily absorbed, hypophosphatemia is relatively unusual. Mechanisms include a shift of phosphate into cells, increased renal excretion, and decreased GI absorption (Table 17-29). Only when depletion is present will clinical manifestations occur and require treatment. It is important to understand pseudohypophosphatemia, which occurs when a patient is treated with mannitol, which binds to molybdate in the serum, caus ing an artificially low value when [PO 3–] is measured by the laboratory. Severe hypophosphatemia can occur in patients with prolonged use of antacids, such as aluminum hydroxide, magnesium hydroxide, or calcium carbonate. Several other drugs may cause hypophosphatemia with different mechanisms (Table 17-30). Critically ill patients are particularly at risk for hypophosphatemia, which occurs in up to 30% of those admitted to the intensive care unit with sepsis, trauma, and pulmonary diseases. It has also been associated with cardiac surgery. 74,75 The mechanism is glucose infusions, starvation, refeeding, shock, acidosis, alkalosis, diuretics, and catecholamine treatment.  CLINICAL FEATURES Symptoms are due to the depletion of adenosine triphosphate and the reduction of erythrocyte 2,3-diphosphoglycerate.

It has also been associated with cardiac surgery. 74,75 The mechanism is glucose infusions, starvation, refeeding, shock, acidosis, alkalosis, diuretics, and catecholamine treatment.  CLINICAL FEATURES Symptoms are due to the depletion of adenosine triphosphate and the reduction of erythrocyte 2,3-diphosphoglycerate. The final outcome will TABLE 17-29 Causes of Hypophosphatemia Shift from ECF to ICF without depletion of PO4 3– Glucose Insulin Catecholamines Respiratory alkalosis Shift from ECF to ICF with depletion of PO4 3– Hyperalimentation Refeeding syndrome Decreased intestinal absorption Low intake Malabsorption Chronic use of calcium acetate or bicarbonate, aluminum hydroxide Vitamin D deficiency Increased renal loss Hyperparathyroidism Increased fibroblast growth factor-23 (FGF-23) Genetic hypophosphatemia mutations Tubular acidosis Fanconi’s syndrome Hypokalemia Hypomagnesemia Polyuria Acidosis Miscellaneous causes Alcoholism (poor intake, vitamin D deficiency) Diabetic ketoacidosis (osmotic diuresis) Toxic shock syndrome Drugs See Table 17-30 Abbreviations: ECF = extracellular fluid; ICF = intracellular fluid. Tintinalli_Sec03_p0053-0142.indd 98 8/2/19 2:57 PM