ELECTROLYTES
























  • References [3,22,23]
Estimates of body fluid distribution
Compartment Estimated volume
(Based on total body weight)
Intravascular fluid 0.08 L/kg
Plasma 0.048 L/kg
Extracellular fluid 0.20 L/kg
Intracellular fluid 0.40 L/kg
Whole body fluid
(extracellular + intracellular)
0.60 L/kg (men and children)
0.50 L/kg (women and elderly men)
0.45 L/kg (elderly women)
Body fat 0.2 - 0.35 L/kg

















  • References [1,2,5,6,7,9]
Causes of hypokalemia
Potassium shift into cells - see acute control
  • Increase in plasma pH
  • Insulin
    • May occur with intravenous insulin or IV dextrose infusions that stimulate insulin release
  • Beta-2 adrenergic agonists
    • Epinephrine
    • Pseudoephedrine, phenylpropanolamine - in large amounts
    • Terbutaline
    • Albuterol, levalbuterol
      • One dose of nebulized albuterol reduces serum potassium levels by 0.2 - 0.4 mEq/L, and a second dose within an hour will reduce it by 1 mEq/L. The effects can last for up to 4 hours.
  • Theophylline - stimulates release of sympathetic amines
  • Caffeine - stimulates release of sympathetic amines. The caffeine in 2 cups of coffee can decrease potassium by up to 0.4 mEq/L
  • Verapamil overdose - increases cellular uptake
  • Chloroquine overdose - blocks exit of potassium from cells
Excessive renal loss
  • Thiazide and loop diuretics - see diuretic-induced potassium loss
  • Excessive mineralocorticoid activity - see aldosterone / renal control
    • Adrenal hyperplasia
    • Conn's syndrome (aldosterone-secreting tumor)
    • 17-Hydroxylase deficiency - rare genetic disorder that causes decreased glucocorticoids and sex hormones and increased mineralocorticoid
    • Fludrocortisone
    • High-dose or prolonged therapy with glucocorticoids
      • Some glucocorticoids have mineralocorticoid activity at high doses or with prolonged therapy. See corticosteroid properties.
    • Cushing's syndrome / disease
      • Excess corticosteroids have mineralocorticoid activity
    • High dietary sodium intake - increases delivery of sodium to the distal nephron
    • Licorice
      • Licorice contains a chemical called glycyrrhizic acid that inhibits the 11βHSD2 enzyme thus increasing cortisol and mineralocorticoid activity
  • Diabetic ketoacidosis
  • Renal tubular acidosis type I (Classic distal) and type II (Proximal)
  • Carbonic anhydrase inhibitors (e.g. acetazolamide)
  • Metabolic alkalosis - may occur from diuretics, vomiting, nasogastric suctioning, Bartter and Gitelman syndrome
  • Glucagon - promotes secretion of potassium
  • Antibiotics - intravenous antibiotics that contain a large amount of sodium
    • Penicillin
    • Nafcillin
    • Ampicillin
  • Drugs that deplete magnesium - see hypomagnesemia
    • Aminoglycosides
    • Cisplatin
    • Foscarnet
    • Amphotericin B - may also cause renal tubular acidosis
Other loss
  • Extrarenal loss
    • Vomiting - particularly if metabolic alkalosis occurs. Only a small amount of potassium is lost in vomitus.
    • Diarrhea / Laxatives / Enemas - colonic fluid contains about 30 mEq/L of potassium so profuse diarrhea can cause significant loss
    • Potassium-binding resins (e.g. Kayexalate, Paritomer)
  • Dilutional
    • IV fluids without potassium
  • Decreased intake
    • Alcoholism
    • Eating disorders (e.g. anorexia)
  • Hypomagnesemia - see hypomagnesemia
  • Hyperthyroidism
    • Hyperthyroidism is a rare cause of hypokalemia. Mostly seen in Asian patients. Mechanism is unclear but may occur from thyroid hormone stimulating the Na-K ATPase pump.
  • Treatment of severe pernicious anemia
    • Rapid uptake of potassium by newly formed RBCs can cause hypokalemia
  • Familial hypokalemic periodic paralysis
    • Rare disorder marked by sudden onset of weakness and hypokalemia. Hypokalemia occurs secondary to skeletal muscle uptake. Attacks may be precipitated by high carbohydrate intake or exertion.
  • Transfusion with previously frozen RBCs - transfused RBCs may take up potassium and cause hypokalemia
  • Pseudohypokalemia
    • Leukocytosis - significant leukocytosis (> 75,000 WBCs/mm3) can cause pseudohypokalemia when WBCs take up potassium in the sample
    • Recent IV insulin administration
    • Storage of blood samples at high room temperature (seasonal pseudohypokalemia) - heat stimulates Na-K ATPase activity



  • References [5,6,7,11]
Steps for evaluating hypokalemia
Step 1 - measure urinary potassium excretion
  • Measuring urine potassium is the first and most important step in analyzing hypokalemia because it helps to determine if potassium loss is renal or extrarenal. The most direct method for measuring urinary potassium excretion is with a 24-hour urine. 24-hour urine collections are tedious, so a spot urine potassium or a spot urine potassium-to-creatinine ratio is often performed instead. All 3 methods are discussed below.

  • 24-hour urine potassium - this is the best method because it directly measures the amount of potassium excreted in a day. Method is tedious, particularly on an outpatient basis. A 24-hour creatinine should also be measured to ensure that a full and accurate sample has been obtained.
    • 24-hour potassium < 20 mEq - suggests proper conservation of potassium by the kidneys and makes an extrarenal source of potassium loss more likely
    • 24-hour potassium > 20 mEq - suggests renal potassium wasting

  • Urine potassium-to-creatinine ratio - this test is easier to perform than a 24-hour urine because it only requires that the patient give a urine sample. Creatinine is excreted at a constant rate, so taking the ratio of potassium to creatinine in the sample helps to correct for variations in urine dilution.
    • Ratio ≤ 1.5 mEq/mmol (13 mEq/gram) - suggests proper conservation of potassium by the kidneys and makes an extrarenal source of potassium loss more likely
    • Ratio > 1.5 mEq/mmol (13 mEq/gram) - suggests renal potassium wasting

  • Spot urine potassium - a spot urine potassium is easy to perform. The main drawback to the test is that it does not correct for variations in urine dilution. A urine osmolality can be drawn with a spot potassium to evaluate urine concentration. High urine osmolality (> 700 mOsm/kg) suggests that a high potassium may be secondary to concentrated urine as opposed to excessive potassium excretion.
    • Spot potassium < 20 mEq/L - suggests proper conservation of potassium by the kidneys and makes an extrarenal source of potassium loss more likely
    • Spot potassium > 40 mEq/L - suggests renal potassium wasting
Step 2 - based on results from Step 1, consider the following:
Step 3 - for renal potassium loss, consider the following testing:
  • Arterial blood gas (ABG) - an ABG is necessary to identify metabolic acidosis or alkalosis
    • Alkalosis - consider diuretics, vomiting, nasogastric suctioning, excessive mineralocorticoid activity, Bartter syndrome, and Gitelman syndrome
    • Acidosis - consider renal tubular acidosis type I and II, DKA, and carbonic anhydrase inhibitors

  • Serum Magnesium - hypomagnesemia can contribute to renal potassium loss

  • Urine chloride - in patients with metabolic alkalosis, urine chloride measurements can help determine the etiology
    • Spot urine chloride < 20 mEq/L or 24-hour urine chloride < 10 mEq - diuretics, vomiting, nasogastric suctioning
    • Spot urine chloride > 40 mEq/L or 24-hour urine chloride > 20 mEq - excessive mineralocorticoid activity, Bartter syndrome, and Gitelman syndrome

  • Urine sodium - a spot urine sodium level that is < 20 mEq/L with a high urine potassium suggests excessive mineralocorticoid activity

  • Aldosterone and renin levels - elevated aldosterone levels are consistent with mineralocorticoid excess. The aldosterone-to-renin ratio (ARR) can help identify if the hyperaldosteronism is primary or secondary.
    • ARR > 30 - consistent with primary aldosteronism (Conn's syndrome)
    • ARR < 10 - consistent with secondary aldosteronism which is caused by decreased renal blood flow (e.g. dehydration, CHF, anasarca)

  • Cortisol level - a high cortisol level suggests glucocorticoid excess (e.g. Cushing's syndrome) may be the cause of excessive mineralocorticoid activity















  • One milliquivalent (mEq) of potassium is equal to one millimole (mmol)
  • References [10, Manufacturer's PI]
Potassium supplements
Potassium salt Conversion
(mEq of K+ per mg of salt)
Products
Potassium chloride
(KCL)
1 mEq = 75 mg Immediate-release products
  • Effervescent tablet - 25 mEq ($)
  • Powder for oral solution - 20 mEq/packet ($)
  • Solution - 10% (20 mEq/15 ml) and 20% (40 mEq/15 ml). Comes in a 473 ml bottle. ($-$$)
Extended-release products
  • Tablet (K-tab®, Klor-Con®) - 8, 10, 15, 20 mEq ($)
  • Capsule (Klor-Con®) - 8, 10 mEq ($)
Potassium citrate
(K3C6H5O7*H2O)
1 mEq ∼ 108 mg Tablet (Urocit-K®)
  • 5, 10, 15 mEq tablet ($$-$$$)
  • Used to prevent kidney stones. See kidney stones for more.
Potassium bicarbonate (KHCO3) 1 mEq = 100 mg
  • Found in antacids and dietary supplements
Potassium gluconate (KC6H11O7) 1 mEq = 234 mg
  • Found in dietary supplements


  • Reference: USDA food database
Potassium content of select foods
Food Potassium content per 100 gram or 100 ml of select food
CONDIMENTS
Salt substitutes (e.g. No-Salt)
  • Contains potassium chloride
16.4 mEq per 1/4 tsp
FRUITS
Apricots, dried 30 mEq (1162 mg)
Prunes, dehydrated, uncooked 27 mEq (1058 mg)
Raisins, seedless 19 mEq (749 mg)
Plums, dried, uncooked 19 mEq (732 mg)
Dates, medjool 18 mEq (696 mg)
Avocados, raw 13 mEq (507 mg)
Bananas, raw 9 mEq (358 mg)
Orange juice 5 mEq (208 mg)
Grapefruit juice 4 mEq (142 mg)
VEGETABLES
Yam, cooked, boiled, drained, or baked 17 mEq (670 mg)
Spinach, fresh 14 mEq (558 mg)
Parsley, fresh 14 mEq (554 mg)
Potatoes, white, flesh and skin, baked 14 mEq (544 mg)
Mushrooms, Chanterelle, raw 13 mEq (506 mg)
Beets, cooked, boiled 8 mEq (305 mg)
Carrots, raw 8 mEq (320 mg)
Mushrooms, Shiitake, raw 8 mEq (304 mg)
Tomatoes, raw, red, ripe 6 mEq (237 mg)
Radishes, raw 6 mEq (233 mg)
NUTS AND SEEDS
Pistachio nuts, dry roasted 26 mEq (1007 mg)
Sunflower seed kernels, dry roasted 22 mEq (850 mg)
Pumpkin and squash seed kernels, roasted 20 mEq (788 mg)
Almonds, dry roasted 18 mEq (713 mg)
Brazil nuts, dried 17 mEq (659 mg)
Cashews, dry roasted 14 mEq (565 mg)
Walnuts, English 11 mEq (441 mg)
Pecans 11 mEq (410 mg)
BEANS
Soybeans, mature, boiled 13 mEq (515 mg)
Lima beans, mature, boiled 13 mEq (508 mg)
Black beans, mature, boiled 9 mEq (355 mg)
Chickpeas (garbanzo beans), mature seeds, boiled 7 mEq (291 mg)
Peas, green, raw 6 mEq (244 mg)
Beans, snap, green, raw 5 mEq (211 mg)
DAIRY PRODUCTS
Yogurt, low fat, plain 6 mEq (234 mg)
Milk, 2% 5 mEq (182 mg)
Egg, whole, cooked, omelet 3 mEq (117 mg)
Cheese, cheddar 2 mEq (76 mg)
BEEF
Beef, round cut, pan fried 12 mEq (484 mg)
Beef, tenderloin steak, grilled 11 mEq (443 mg)
Beef, ground, 90% lean meat, pan-browned 11 mEq (433 mg)
Beef, top sirloin steak, broiled 10 mEq (380 mg)
Beef, rib, roasted 8 mEq (319 mg)
Beef, brisket, braised 7 mEq (275 mg)
POULTRY
Chicken, breast, grilled 11 mEq (420 mg)
Turkey, breast, roasted 6 mEq (249 mg)
FISH
Mahimahi, cooked, dry heat 14 mEq (533 mg)
Trout, cooked, dry heat 12 mEq (463 mg)
Salmon, coho, wild, cooked, moist heat 12 mEq (455 mg)
Tuna, white, canned in water 6 mEq (237 mg)




  • References [7,13,9]
Causes of hyperkalemia
Potassium shift out of cells - see acute control
  • Decrease in plasma pH - metabolic acidosis
  • Insulin deficiency
  • Tissue ischemia / trauma / toxicity
    • Burns
    • Rhabdomyolysis
  • Cellular damage / lysis
    • Tumor lysis syndrome
    • Hemolytic anemia
    • Large hematomas
    • Transfusion reactions
  • Medications
    • Digoxin - can inhibit the Na-K ATPase pump
    • Beta-adrenergic blockers
    • Somatostatin
    • Succinylcholine
  • Hyperosmolality - hyperglycemia, mannitol
  • Strenuous exercise
Decreased renal excretion
  • Decreased mineralocorticoid production - see aldosterone / renal control
    • Addison disease - condition where adrenal glands produce insufficient amount of corticosteroids
    • Heparin - blocks production of aldosterone in adrenal gland
    • Ketoconazole - blocks production of aldosterone in adrenal gland
  • RAAS inhibitors
    • ACE inhibitors
    • Angiotensin II receptor blockers (ARBs)
    • Renin inhibitors (aliskiren)
    • Aldosterone antagonists (spironolactone)
    • NSAIDs
  • Epithelial sodium channel (ENaC) inhibitors - see aldosterone / renal control
    • Amiloride
    • Triamterene
    • Trimethoprim - has similar structure and action as amiloride
    • Pentamidine
  • Other medications
    • Tacrolimus - suppresses renin release and interferes with potassium excretion in the collecting duct
    • Cyclosporine - suppresses renin release and interferes with potassium excretion in the collecting duct
  • Renal tubular cell damage
    • Amyloidosis
    • Diabetic nephropathy
    • HIV / AIDS
    • Kidney transplant rejection
    • Lower urinary tract obstruction
    • Sickle cell disease
    • Systemic lupus erythematosus
  • Decreased renal perfusion
    • CHF
    • Cirrhosis
    • Renal artery stenosis
Other
  • Increased intake (foods and supplements)
    • Herbs high in potassium - alfalfa, dandelion, horsetail, nettle
    • High potassium foods - see dietary potassium
    • Noni juice (56 mEq/Liter)
    • Salt substitutes (e.g. No-Salt) - 16.4 mEq per 1/4 tsp
  • Medications
    • Penicillin G potassium (1.68 mEq per 1 million units)
    • Potassium supplements
    • Red blood cell transfusions - leakage of potassium into supernatant due to decreased Na-K ATPase activity
  • Pseudohyperkalemia
    • Mechanical hemolysis - can occur if tourniquet during blood draw is too tight or left on too long. Also may occur if sample is left sitting too long.
    • Excessive milking of extremities - seen in infant heel and finger sticks. Introduces interstitial fluid into sample.
    • Fist clenching during sample draw - can cause hemolysis and an acidotic sample
    • Potassium-containing IV infusions - if blood is drawn upstream of the infusion site
    • Thrombocytosis (> 500,000/µL ) - for every 100,000/µL elevation in platelet count, serum potassium increases by 0.15 mEq/L. This occurs secondary to potassium release from platelets during the clotting process. Whole blood and plasma potassium levels (obtained from a heparinized sample) are not affected by thrombocytosis and should be drawn to confirm hyperkalemia in patients with platelet counts > 500,000/µL.
    • Leukocytosis (> 70,000/µL) - elevated serum potassium may occur secondary to potassium release from WBCs during the clotting process. Whole blood and plasma potassium levels (obtained from a heparinized sample) are not affected by leukocytosis and should be drawn to confirm hyperkalemia in patients with WBC counts > 70,000/µL.
    • Reverse pseudohyperkalemia - reverse pseudohyperkalemia is a phenomenon where plasma potassium levels are spuriously higher than serum potassium levels. It can occur in patients with leukemia because leukemic leukocytes are fragile and can release potassium during processing. Measuring potassium levels from an arterial blood gas sample can prevent reverse pseudohyperkalemia.



  • References [7,11,12,13]
Laboratories for evaluating hyperkalemia
Serum creatinine and GFR / CrCl
  • Since the kidneys are the primary site of potassium excretion, decreased renal function is a major cause of hyperkalemia
  • In chronic kidney disease, hyperkalemia does not typically occur until the GFR falls below 30 ml/min. Patients who have other risk factors for decreased renal function (e.g. CHF, diabetes, advanced age) may experience hyperkalemia at levels > 30 ml/min. These patients are also frequently prescribed RAAS inhibitors which compound the risk.
  • See GFR / CrCl and serum creatinine for a review of these measures

Urine potassium
  • Measuring urine potassium can help to determine if the kidneys are excreting potassium appropriately. The most direct method for measuring urinary potassium excretion is with a 24-hour urine. 24-hour urine collections are tedious, so a spot urine potassium or a spot urine potassium-to-creatinine ratio is often performed instead. All 3 methods are discussed below.

  • 24-hour urine potassium - this is the best method because it directly measures the amount of potassium excreted in a day. Method is tedious, particularly on an outpatient basis. A 24-hour creatinine should also be measured to ensure that a full and accurate sample has been obtained.
    • 24-hour potassium < 20 mEq - suggests impaired renal excretion
    • 24-hour potassium > 20 mEq - suggests appropriate renal elimination

  • Urine potassium-to-creatinine ratio - this test is easier to perform than a 24-hour urine because it only requires that the patient give a urine sample. Creatinine is excreted at a constant rate, so taking the ratio of potassium to creatinine in the sample helps to correct for variations in urine dilution.
    • Ratio ≤ 1.5 mEq/mmol (13 mEq/gram) - suggests impaired renal excretion
    • Ratio > 1.5 mEq/mmol (13 mEq/gram) - suggests appropriate renal elimination

  • Spot urine potassium - a spot urine potassium is easy to perform. The main drawback to the test is that it does not correct for variations in urine dilution. A urine osmolality can be drawn with a spot potassium to evaluate urine concentration. High urine osmolality (> 700 mOsm/kg) suggests that a high potassium may be secondary to concentrated urine as opposed to appropriate potassium excretion.
    • Spot potassium < 20 mEq/L - suggests impaired renal excretion
    • Spot potassium > 40 mEq/L - suggests appropriate renal elimination

Urine sodium
  • Spot urine sodium > 25 mEq/L - suggests decreased mineralocorticoid activity or direct renal cell damage
  • Spot urine sodium < 25 mEq/L - suggests appropriate mineralocorticoid activity. Consider decreased renal perfusion (e.g. cirrhosis, CHF).

Other labs that may be helpful depending on the presentation / risk factors
  • Arterial blood gas (ABG) - an ABG can identify acidosis
  • Serum glucose - to look for diabetes and insulin deficiency
  • Urinalysis - to look for nephropathy and glomerulonephritis
  • Serum cortisol and aldosterone levels - to look for adrenal insufficiency
  • Serum uric acid and phosphorus - elevated in tumor lysis syndrome
  • Serum creatinine phosphokinase (CPK) - to look for rhabdomyolysis
  • Urine myoglobin - present in rhabdomyolysis and crush injuries
  • Potassium level from plasma or whole blood - if thrombocytosis or leukocytosis are present (see pseudohyperkalemia above)
  • Potassium level from ABG - in patients with leukemia to rule out reverse pseudohyperkalemia (see pseudohyperkalemia above)



























  • References [2,19,20,21,22]
Hypotonic hyponatremia (serum osmolality < 275 mOsm/kg)
Hypovolemic causes - total body water decreases more than the decrease in total body sodium
  • Gastrointestinal fluid loss (diarrhea or vomiting)
  • Diuretic therapy
    • Thiazide diuretics are prone to cause hyponatremia with long-term use because they promote sodium excretion while reducing the diluting capacity of the nephron. In contrast, loop diuretics promote both sodium excretion and urine dilution. This occurs because the hyperosmolarity of the medullary region of the kidney that is responsible for water reabsorption in the collecting duct is mostly a product of sodium, potassium, and chloride that is reabsorbed in the ascending Loop of Henle by the Na-K-2Cl transporter. Loop diuretics block this transporter causing medullary osmolality to decrease. Reduced medullary osmolality causes less free water to be drawn from the collecting duct. Thiazide diuretics do not lower the medullary osmolality, and therefore, free water reabsorption remains normal while solute excretion is increased.
  • Salt-wasting nephropathies - rare sequelae of interstitial kidney disease, polycystic kidney disease, and urinary obstruction
  • Cerebral salt wasting - condition where intracranial disorders (e.g. subarachnoid hemorrhage, meningitis) disrupt the normal sympathetic stimulation of the kidneys which leads to suppression of the RAAS and decreased reabsorption of sodium along the nephron

Euvolemic causes - total body water increases with stable total body sodium
  • Syndrome of inappropriate ADH secretion (SIADH)
    • SIADH is the most common cause of hyponatremia in hospitalized patients. In SIADH, inappropriate ADH secretion increases the absorption of free water at the renal collecting duct causing serum sodium concentrations to fall. Most patients with SIADH are euvolemic despite the increased reabsorption of free water. This occurs because intravascular volume expansion inhibits the RAAS and stimulates natriuretic peptides. A suppressed RAAS and the natriuretic effects of ANP and BNP help to reduce intravascular volume, but they also promote sodium excretion which can worsen SIADH. Because of this, SIADH is best treated with fluid restriction as opposed to normal saline because infused sodium is excreted at a greater rate than the infused water, and the net effect is the addition of more electrolyte-free water.
    • Causes of SIADH include the following:
      • Medications (see medications associated with SIADH below)
      • CNS disorders (e.g. trauma, encephalitis, stroke, TIA, hydrocephalus)
      • Ectopic production (e.g. small cell carcinoma of the lung, lymphoma)
      • Pulmonary diseases (e.g. pneumonia, tuberculosis, bronchiectasis)
      • HIV
      • Other (e.g. pain, postsurgery, mechanical ventilation)
  • Psychogenic polydipsia - drinking > 18 liters of water a day or > 750 ml/hour
  • Potomania - excessive beer drinking which provides high amount of fluid and a relatively low amount of solutes
  • Reset osmostat - condition seen in elderly patients and pregnancy where the brain regulates serum osmolality around a reduced set point. This condition differs from SIADH in that patients are able to dilute their urine in response to a water load.
  • Severe hypothyroidism - mechanism is unclear but possibly due to reduced cardiac output and GFR
  • Cortisol deficiency (e.g. Addison's disease) - cortisol inhibits ADH release. When it is deficient, ADH release is increased.

Hypervolemic causes - total body water increases more than total body sodium. Water retention is driven by a decrease in effective circulating volume.
  • Congestive heart failure
  • Cirrhosis
  • Renal failure (acute and chronic)
  • Nephrotic syndrome
  • Severe hypoproteinemia (albumin < 2 g/dl)
Isotonic hyponatremia (serum osmolality 275 - 290 mOsm/kg)
Pseudohyponatremia
  • Under normal conditions, serum is composed of about 93% water. When levels of fats and proteins are significantly elevated, they can displace water from a serum sample so that the fraction of water may fall below 80%. The displaced water contains sodium, and when serum sodium concentrations are measured, they may come back spuriously low. If a lab uses direct ion-selective electrode measurement techniques, this phenomenon does not occur and the measured sodium will be correct.
    • Causes of Pseudohyponatremia include the following:
      • Hypertriglyceridemia
      • Hypercholesterolemia
      • Cholestasis
      • Hypergammaglobulinemia (e.g. monoclonal gammopathy, multiple myeloma)
      • IVIG administration

Absorption of solutions used in procedures
  • Solutions used for irrigation during urological (e.g. TURP) and gynecological procedures (e.g. hysteroscopy) can be absorbed. These solutions contain glycine, sorbitol, and mannitol which are nonionic solutes that pull free water into the serum through osmosis. The increase in serum water can lower sodium concentrations while osmolality remains normal or elevated.

Sucrose and maltose in IVIG infusions
  • Sucrose and maltose are present in some IVIG solutions. Sucrose and maltose are nonionic solutes that pull free water into the serum through osmosis. The increase in serum water can lower sodium concentrations while osmolality remains normal or elevated.
Hypertonic hyponatremia (serum osmolality > 290 mOsm/kg)
Overview
  • Hypertonic hyponatremia occurs when the presence of osmotically active solutes in the serum pull free water into the serum through osmosis. Total body sodium levels are normal, but the shift of water into the serum lowers sodium concentrations and causes a "dilutional hyponatremia." Some examples of hypertonic hyponatremia are discussed below.

Hyperglycemia
  • Abnormally high glucose concentrations can cause hypertonic hyponatremia. The following correction factors can be used to estimate serum sodium concentrations if glucose levels were normal.
    • Glucose 100 - 400 mg/dl - sodium levels drop 1.6 mEq/L for every 100 mg/dl increase in glucose above 100 mg/dl
    • Glucose > 400 mg/dl - sodium levels drop 2.4 mEq/L for every 100 mg/dl increase in glucose above 400 mg/dl

Mannitol
  • Mannitol is given to patients with brain edema because it elevates plasma osmolality, but it does not cross the blood-brain barrier. The osmolality gradient it creates between the brain and the periphery causes fluid to shift from the brain to the periphery and dilutional hyponatremia may occur.

Absorption of solutions used in procedures
  • Solutions used for irrigation during urological (e.g. TURP) and gynecological procedures (e.g. hysteroscopy) can be absorbed. These solutions contain glycine, sorbitol, and mannitol which are nonionic solutes that pull free water into the serum through osmosis. The increase in serum water can lower sodium concentrations while osmolality remains normal or elevated.

Sucrose and Maltose in IVIG infusions
  • Sucrose and maltose are present in some IVIG solutions. Sucrose and maltose are nonionic solutes that pull free water into the serum through osmosis. The increase in serum water can lower sodium concentrations while osmolality remains normal or elevated.



  • Reference [19,20]
Steps for evaluating hyponatremia
Step 1 - check serum osmolality
Step 2 - check urine osmolality
  • Urine osmolality < 100 mOsm/kg indicates proper renal response (dilute urine). Consider psychogenic polydipsia, reset osmostat, and malnutrition.
  • Urine osmolality > 100 mOsm/kg indicates a high ADH state. Assess patient volume status and proceed to Step 3.
Step 3 - check a spot urine sodium and/or calculate the fractional excretion of sodium
  • Fractional excretion of sodium is calculated with the following formula:
    • Fractional excretion of sodium (FENa) = (UNa x PCr x 100) / (PNa x UCr)
    • where UNa is urine sodium, PCr is plasma creatinine, PNa is plasma sodium, and UCr is urine creatinine
    • Diuretics can increase FENa to > 20% so they must be discontinued for at least 24 hours before measuring
  • Urine sodium < 10 mEq/L or FENa < 1% indicates proper renal response (increased sodium reabsorption). Consider extrarenal causes (e.g. diarrhea, vomiting, CHF, cirrhosis)
  • Urine sodium > 20 mEq/L or FENa > 2% indicates renal sodium loss. Consider renal disease (e.g. nephropathy), diuretics, and SIADH

  • Diagnostic criteria for SIADH
    • Normal hepatic, renal, and cardiac function
    • Normal thyroid and adrenal function
    • Hypotonic hyponatremia
    • Urine osmolality > 100 mOsm/kg (typically > 400 - 500 mOsm/kg)
Other tests that may be helpful in select patients
  • TSH - severe hypothyroidism
  • Cortisol - adrenal insufficiency
  • Liver function tests - cirrhosis
  • BNP - CHF
  • Urine protein - nephropathy
  • Chest imaging - ADH-secreting lung cancer; other lung disease
  • Brain imaging - CNS disorders associated with SIADH
  • Serum protein electrophoresis (SPEP) - monoclonal gammopathy
  • Serum lipids - pseudohypokalemia
  • Serum glucose - hyperglycemia
  • HIV - cause of SIADH











  • Reference [24,25,26]
Causes of hypernatremia
Free water loss or unreplaced loss
  • Impaired thirst mechanism - may occur from lesions to the hypothalamus, granulomatous diseases, vascular abnormalities, and trauma
  • Inadequate intake (e.g. altered mental status, infants)
  • Central diabetes insipidus (DI) - central diabetes insipidus occurs when the brain does not secrete adequate amounts of ADH. Interestingly, most patients with DI and an intact thirst mechanism do not present with hypernatremia. This occurs because the thirst mechanism is so strong that patients with DI often consume enough water to offset the loss of up to 15 liters of free water a day. Central DI can occur secondary to the following conditions:
    • Idiopathic
    • Head trauma
    • Cranial neoplasm (e.g. craniopharyngioma, pinealoma, meningioma, germinoma, lymphoma, metastatic disease)
    • Pituitary damage (e.g. sarcoidosis, histiocytosis, surgery, trauma)
    • Aneurysms - particularly anterior communicating
    • Meningitis / Encephalitis
    • Guillain–Barré syndrome
    • Drugs (e.g. ethanol, phenytoin)
  • Nephrogenic diabetes insipidus (DI) - nephrogenic DI occurs when the kidneys do not have an adequate response to ADH. Nephrogenic DI may be congenital or acquired, and it is a side effect of some medications. Interestingly, most patients with DI and an intact thirst mechanism do not present with hypernatremia. This occurs because the thirst mechanism is so strong that patients with DI often consume enough water to offset the loss of up to 15 liters of free water a day. Causes of acquired nephrogenic DI include the following:
    • Intrinsic kidney disease (e.g. medullary cystic disease, polycystic kidney disease, nephrocalcinosis, Sjögren’s syndrome, lupus, papillary necrosis, sarcoidosis, sickle cell nephropathy)
    • Obstructive kidney disease
    • Hypercalcemia
    • Hypokalemia
    • Medications
Hypotonic fluid loss
  • Renal loss
    • Loop diuretics
    • Osmotic diuresis (e.g. mannitol, hyperglycemia)
    • Postobstructive diuresis
    • Acute tubular necrosis
  • Gastrointestinal loss
    • Vomiting
    • Diarrhea
    • Nasogastric suctioning
    • Enterocutaneous fistula
    • Osmotic laxatives
  • Cutaneous loss
    • Burns
    • Excessive sweating
Sodium gain
  • Hypertonic fluids (e.g. sodium bicarbonate infusions, hypertonic saline)
  • Ingestion of seawater - seawater is about 3 - 3.5% NaCl
  • Sodium chloride tablets
  • Hypertonic dialysis
  • Hypertonic feeding preparations
  • Hyperaldosteronism - promotes retention of sodium in the collecting duct
  • Cushing's syndrome - excess corticosteroids have mineralocorticoid activity




  • References [24,25,26,27]
Evaluating hypernatremia
Evaluating patient volume status
  • Spot urine sodium - a spot urine sodium < 10 mEq/L suggests renal sodium retention secondary to intravascular volume contraction
  • BUN to serum creatinine ratio - a BUN to serum creatinine ratio of > 20:1 usually indicates dehydration
Evaluating renal concentrating ability
  • Urine osmolality
    • Hypovolemic patients - urine osmolality > 600 mOsm/kg with a low spot urine sodium (< 10 mEq/L) indicates renal fluid retention and suggests an extrarenal source of water loss (e.g. gastrointestinal, dermal). Urine osmolality < 300 mOsm/kg with a high spot urine sodium (> 20 mEq/L) suggests renal fluid loss (e.g. diuretics, osmotic diuresis, intrinsic renal disease)
    • Euvolemic patients - urine osmolality > 600 mOsm/kg indicates appropriate renal fluid retention and suggests decreased water intake or increased insensible losses. Urine osmolality < 300 mOsm/kg suggests diabetes insipidus.
Evaluating for diabetes insipidus
  • Water deprivation test
    • A water deprivation test can help differentiate central from nephrogenic DI. To perform the test, water is withheld from the patient and urine osmolality is checked hourly. Once the osmolality varies by less than 30 mOsm/kg on 2 sequential tests, the patient is given ADH. One hour later, the urine osmolality is rechecked. Results are interpreted as follows:
      • Central DI - urine osmolality < 300 mOsm/kg after water deprivation and > 750 mOsm/kg after ADH administration
      • Nephrogenic DI - urine osmolality < 300 mOsm/kg after water deprivation and there is no rise in urine osmolality after ADH administration
      • Partial DI - urine osmolality of 300 - 750 mOsm/kg after water deprivation and < 750 mOsm/kg after ADH administration
      • Primary polydipsia - urine osmolality > 750 mOsm/kg after water deprivation and < 750 mOsm/kg after ADH administration

  • ADH (vasopressin) level - a low ADH level after water deprivation indicates central DI. A normal or high level after water deprivation suggests nephrogenic DI.
  • Urine specific gravity - urine specific gravity is < 1.005 in DI


















  • References [32,34,35]
Causes of hypocalcemia
  • Kidney disease
    • Hypocalcemia in kidney disease typically occurs when the GFR falls below 30 ml/min. It is primarily driven by 2 processes: (1) decreased renal conversion of calcidiol to calcitriol, (2) decreased renal excretion of phosphate. Loss of calcitriol decreases calcium absorption in the intestines, and rising serum phosphate levels bind ionized calcium and render it inactive. Reduced ionized calcium levels stimulate PTH production and bone resorption is increased. The end result is bone resorption that outpaces bone formation causing weakened bones and an increased risk of fractures. Another possible adverse effect is an increased risk of cardiovascular disease from calcium phosphate deposition in the vasculature.
  • Vitamin D deficiency - vitamin D deficiency leads to decreased calcium absorption in the intestines. Vitamin D deficiency may occur from inadequate intake or malabsorption (e.g. celiac disease, shortened bowel, Crohn's disease)
  • Hypomagnesemia - severe hypomagnesemia (< 1 mg/dl) can affect the release of PTH from the parathyroid gland and lead to hypocalcemia
  • Acute pancreatitis - the exact cause of hypocalcemia in pancreatitis is unknown but may involve the following: (1) generation of free fatty acids that bind calcium salts in the pancreas, (2) release of lipase that degrades omental fat causing calcium binding in the peritoneum, (3) hypoparathyroidism, (4) hypomagnesemia
  • Hypoparathyroidism
    • Hypoparathyroidism can be hereditary or acquired. Hereditary hypoparathyroid syndromes are rare. Acquired hypoparathyroidism is more common and may be caused by the following:
      • Neck irradiation
      • Radioiodine therapy for Graves' disease
      • Parathyroid surgery (transient hypocalcemia - 33% | permanent hypocalcemia - 2%)
      • Thyroidectomy (transient hypocalcemia - 27% | permanent hypocalcemia - 1%)
      • Infiltrative diseases of the thyroid (e.g. hemochromatosis, granulomatous, metastatic)
      • Autoimmune destruction (e.g. polyglandular autoimmune disease)
  • Pseudohypoparathyroidism - pseudohypoparathyroidism occurs when PTH receptors are resistant to the effects of PTH. Receptor defects are inherited, and these syndromes are rare.
  • Liver disease - vitamin D2 and D3 are converted in the liver to calcidiol. Significant liver disease can impair this process. See vitamin D metabolism.
  • Hungry bone syndrome - after surgical correction of hyperparathyroidism, a sudden decrease in PTH levels can cause bones to undergo rapid remodeling. These "hungry" bones take up lots of calcium which can lead to hypocalcemia.
  • Sepsis - hypocalcemia is sometimes seen in severe sepsis. The mechanism is not completely understood, but may be related to impaired PTH secretion, decreased calcitriol production, and/or hypomagnesemia.
  • Hyperphosphatemia - phosphorus binds calcium and lowers its active levels. Hyperphosphatemia can occur from decreased excretion (kidney disease) and in conditions where there is a sudden release of phosphorus from cells (e.g. tumor lysis syndrome, rhabdomyolysis).
  • Pseudohypocalcemia - gadolinium-based contrast agents (e.g. gadodiamide, gadoversetamide) used in MRI scans can interfere with calcium assays and cause false-low readings. This usually occurs if a calcium level is drawn within 24 hours of the agent being given.
  • Medications (see below)



  • References [2,32,34,35]
Steps for evaluating hypocalcemia
Step 1 - Confirm that hypocalcemia is real
  • In plasma, about 50% of calcium circulates in its ionized (free) form which is also its active form. Ten percent is complexed with anions, and the remaining 40% is bound to protein, mainly albumin. If albumin levels are low, total calcium levels will not reflect the true amount of ionized calcium. In these cases, ionized calcium levels can be measured directly. Another widely used method for estimating the correct calcium level is with the formula below:
    • Corrected calcium (mg/dL) = measured total Ca (mg/dL) + 0.8 (4.0 - serum albumin [g/dL])
    • where 4 represents the normal albumin level
Step 2 - Depending on the patient, consider the following
  • Medications associated with hypocalcemia
  • Serum creatinine and GFR - to look for kidney disease
  • 25-hydroxy vitamin D (calcidiol) and 1,25-dihydroxy vitamin D (calcitriol)
    • Reduced 25-hydroxy vitamin D suggests dietary deficiency, lack of sunlight, or malabsorption
    • Reduced 1,25-dihydroxy vitamin D suggests kidney disease (see vitamin D metabolism)
  • Magnesium level - to look for hypomagnesemia
  • PTH level - low levels are seen in hypoparathyroidism and severe hypomagnesemia
  • Phosphorus level
    • Hyperphosphatemia is seen in kidney disease, tumor lysis syndrome, rhabdomyolysis, hypoparathyroidism and pseudohypoparathyroidism
    • Hypophosphatemia is seen in vitamin D deficiency and hungry bone syndrome
  • Amylase and lipase - if pancreatitis is suspected
  • Liver function tests - to look for liver disease





















  • References [28,29,30,31,32,33]
Causes of hypercalcemia
PTH disorders
  • Primary hyperparathyroidism
    • Primary hyperparathyroidism is the most common cause of hypercalcemia accounting for > 50% of cases. Hyperactive benign adenomas are the most common reason.
    • Multiple endocrine neoplasia type 1 (MEN1) is an rare inherited disorder that can cause primary hyperparathyroidism
  • Malignancy
    • Malignancy is the second most common cause of hypercalcemia accounting for 33 - 50% of cases
    • Hypercalcemia secondary to malignancy may result from direct osteolytic bone destruction (20% of cases), but more often, it occurs secondary to tumors that produce PTH-related peptide, a protein that mimics the activity of PTH (80% of cases). Other malignant causes that are very rare include vitamin D-secreting lymphomas and ectopic PTH secretion.
    • Hypercalcemia secondary to PTH-related peptide is most commonly seen in squamous cell carcinomas of the head and neck, multiple myeloma, lymphomas, and cancers of the breast, kidney, lung, ovary, bladder, and prostate.
  • Familial hypocalciuric hypercalcemia (FHH)
    • Familial hypocalciuric hypercalcemia is a rare disorder caused by inherited (autosomal dominant) mutations in the calcium-sensing receptors that are found in the parathyroid glands and kidneys. The mutations decrease the calcium-sensing ability of the receptors, and the parathyroid gland does not respond appropriately to calcium levels.
    • Patients with FHH typically have mild asymptomatic hypercalcemia with normal or slightly elevated PTH levels. A severe form of the disease called "neonatal severe hyperparathyroidism" can present right after birth with extreme hypercalcemia, respiratory distress due to hypotonia, fractures, and bone mineralization deficiencies.
    • After excluding more common causes of hypercalcemia, FHH can be diagnosed with a 24-hour urine test. In FHH, urinary calcium excretion is < 100 mg/24 hours, and the calcium-creatinine excretion ratio (see formula below) is < 0.020. Genetic testing for calcium-sensing receptor (CaSR) mutations is also available.
    • In most cases, FHH is considered a benign disease and treatment is not indicated. In rare cases, patients may develop pancreatitis that requires parathyroidectomy.
    • Calcium-creatinine excretion ratio = [UCa × SCr] / [SCa × UCr], where UCa is the urinary calcium concentration, SCr is the serum creatinine, SCa is the serum calcium concentration, and UCr is the urinary creatinine concentration, all in mg/dl
  • PTH analogs (Abaloparatide, Teriparatide) - PTH analogs used to treat osteoporosis may cause hypercalcemia
  • Lithium - lithium can inhibit the PTH-suppressing effects of calcium on the parathyroid gland, and it can increase calcium reabsorption in the kidneys
  • Renal transplant - patients with hyperparathyroidism from renal failure can develop hypercalcemia after they receive a renal transplant
Bone disorders
  • Malignancy
    • Malignancy is the second most common cause of hypercalcemia accounting for 33 - 50% of cases
    • Hypercalcemia secondary to malignancy may result from direct osteolytic bone destruction (20% of cases), but more often, it occurs secondary to tumors that produce PTH-related peptide, a protein that mimics the activity of PTH (80% of cases). Other malignant causes that are very rare include vitamin D-secreting lymphomas and ectopic PTH secretion.
    • Cancers that are often associated with osteolytic bone lesions include multiple myelomas, leukemia, and breast cancer
  • Hyperthyroidism - excess thyroid hormone can stimulate osteoclastic bone resorption and lead to hypercalcemia
  • Paget's disease - rare disorder that causes abnormal bone remodeling
Vitamin D disorders
  • Excessive vitamin D intake
  • Granulomatous diseases - granuloma macrophages possess an enzyme (25-hydroxyvitamin D–1α-hydroxylase) that converts calcidiol to its more active form, calcitriol. This can lead to increased calcium absorption and hypercalcemia. Granulomatous diseases include the following:
    • Sarcoidosis
    • Tuberculosis
    • Fungal infections
    • Leprosy
Other
  • Thiazide diuretics - increase renal calcium reabsorption
  • Calcium-containing antacids - consuming large amounts of calcium-containing antacids (calcium carbonate) can lead to the "milk-alkali syndrome." Milk-alkali syndrome is marked by hypercalcemia, metabolic alkalosis, and renal failure.
  • Prolonged immobilization - prolonged immobilization can cause increased bone resorption, especially in person's with Paget's disease
  • Hypervitaminosis A - probably through stimulation of osteoclasts
  • Adrenal insufficiency - possibly through increased calcium reabsorption in the kidneys
  • Hypophosphatasia - hypophosphatasia is a rare genetic disorder that is marked by defects in the tissue-nonspecific alkaline phosphatase (TNSALP) enzyme. TNSALP is involved in bone and tooth mineralization, and affected individuals have weakened bones, skeletal abnormalities, and hypercalcemia.
  • Subcutaneous fat necrosis

  • References [28,33]
Hypercalcemia levels
Degree Total calcium
(mg/dl)
Ionized calcium
(mg/dl)
Mild 10.5 - 11.9 5.6 - 7.9
Moderate 12 - 13.9 8 - 9.9
Severe ≥ 14 ≥ 10


  • References [28,29,30,31,33]
Steps for evaluating hypercalcemia
Step 1 - Evaluate for hyperparathyroidism (> 50% of cases)
  • Confirm that hypercalcemia is real with a repeat calcium level and an ionized calcium
  • Consider medications associated with hypercalcemia (e.g. lithium, thiazide diuretics, abaloparatide, teriparatide, vitamin D and A supplements, antacids)
  • Check serum PTH, phosphorus, and kidney function
  • Elevated or high-normal PTH and high calcium
    • Most patients with hyperparathyroidism will have an elevated PTH, but up to 15% can have a high-normal PTH
    • An elevated PTH in the presence of a high ionized calcium level is diagnostic for primary hyperparathyroidism. A low phosphorus level is also consistent with primary hyperparathyroidism.
    • Refer affected patients for surgical evaluation. Imaging with ultrasound, CT scan, MRI, and nuclear medicine can be performed to locate involved glands. The preferred study depends upon the specialist and availability.

If the PTH level is low or low-normal or the above testing is not definitive, proceed to Step 2
Step 2 - Evaluate for malignancy (33 - 50% of cases)
  • Depending on the individual, consider the following cancers and testing:
    • Breast cancer - mammogram or MRI
    • Lung cancer - Chest X-ray or CT scan
    • Renal cancer - ultrasound, CT, or MRI
    • Lymphoma and leukemia - CBC and peripheral smear
    • Multiple myeloma - serum and urine protein electrophoresis
    • Head and neck cancers - CT scan
    • Bone scan - to look for bone metastasis
    • Parathyroid hormone-related peptide (PTHrP) - elevated levels are consistent with malignancy

If the above testing is not definitive move to Step 3
Step 3 - Look for less common causes
  • Familial hypocalciuric hypercalcemia - check 24-hour urine for calcium and creatinine.
  • Hyperthyroidism - check TSH
  • Hypervitaminosis A - check vitamin A level
  • Hypervitaminosis D - check calcidiol (25-hydroxyvitamin D) levels
  • Paget's disease - check alkaline phosphatase and order bone scan
  • Granulomatous diseases - chest X-ray and calcitriol levels
  • Adrenal insufficiency - check cortisol level





























  • There is limited data on the bioavailability of magnesium supplements, and absorption may vary widely between individuals
  • References [47,48,49]
Magnesium supplements
Magnesium supplement Percent elemental magnesium Comments
Magnesium oxide 60%
  • Magnesium oxide has relatively low bioavailability (only 4% in some studies)
  • Comes in many dosage forms over-the-counter
  • One small study found that 613 mg of magnesium oxide solution once daily for 3 months raised serum magnesium levels by 0.21 mg/dl (average baseline level 1.7 mg/dl) [PMID 28297698]
  • Another study found that a magnesium oxide 400 mg tablet once daily for 10 weeks raised magnesium levels by 0.073 mg/dl (average baseline level 2.1 mg/dl) [PMID 31968571]
Magnesium carbonate 45%
  • Magnesium carbonate has relatively low bioavailability
  • Comes in many dosage forms over-the-counter
Magnesium hydroxide 42%
  • Magnesium hydroxide has relatively low bioavailability (only 4% in some studies)
  • Comes in many dosage forms over-the-counter
Magnesium citrate 16%
  • Magnesium citrate has relatively good bioavailability (12% in some studies)
  • Comes in many dosage forms over-the-counter
Magnesium lactate 12%
  • Magnesium lactate has relatively good bioavailability (12% in some studies)
  • Comes in many dosage forms over-the-counter
Magnesium chloride 12%
  • Magnesium chloride has relatively good bioavailability (12% in some studies)
  • Comes in many dosage forms over-the-counter
  • One small study found that 2500 mg of magnesium chloride solution once daily for 16 weeks raised serum magnesium levels by 0.24 mg/dl (average baseline level 1.55 mg/dl) [PMID 12663588]
Magnesium aspartate 10%
  • The bioavailability of magnesium aspartate has not been studied extensively
  • Comes in many dosage forms over-the-counter
Magnesium sulfate 10%
  • Also referred to as "Epsom salt" which comes from the name of the town where it was discovered
  • Magnesium sulfate has relatively low bioavailability (only 4% in some studies)
  • Comes in many dosage forms over-the-counter
Magnesium gluconate 5%
  • Magnesium gluconate has relatively good bioavailability
  • Comes in many dosage forms over-the-counter