Chapter 16 Electrolytes

Hypophosphatemia

1-5% of hospitalized patients 20-40% of patients with diabetic ketoacidosis, chronic obstructive pulmonary disease, asthma, malignancy, long-term parenteral nutrition, inflammatory bowel disease, anorexia nervosa and alcoholism 60-80% of ICU patients with sepsis Caused by increased renal secretion (in hyperparathyroidism) and decreased intestinal absorption (vitamin D deficiency or antacid use)

Electrolytes, what are they?

Ions capable of carrying an electric charge Two types 1. *Anions* have negative charge & move toward anode 2. *Cations* have positive charge & move toward cathode Electrolytes are an essential component in many processes: Volume & osmotic regulation (Na+, Cl-, K+) Myocardial rhythm & contractility (K+, Mg2+, Ca2+) Cofactors in enzyme activation (Mg2+, Ca2+, Zn2+) Blood coagulation (Ca2+, Mg2+) Body needs electrolyte concentrations within narrow ranges Complex systems for monitoring and maintenance

What is the "Normal" Anion Gap ?

Many textbooks say 8 - 16 mmol/L However, reference interval is *method dependent* Some instruments yield reference interval of 4 - 12 mmol/L Others yield range of 8-16 mmol/L

Determination of Osmolality

May be measured in serum or urine most commonly by freezing point depression and vapor pressure (see Chapter 5) Can also be calculated as an estimate of true osmolality or to determine the osmolal gap Difference between measured and calculated osmolality Indirectly indicates presence of other osmotically active substances e.g. ethanol, methanol, ethylene glycol, lactate, β-hydroxybutyrate There are 2 formulas: See associated figure

How is hypernatremia related to urine osmolality

Measurement of urine osmolality is necessary to evaluate the cause of hypernatremia

Methods for the Determination of Calcium

Methods Ionized calcium - ion selective electrode (ISE; see Chapter 5) *Total calcium* - ISE or dye binding method Use either ortho-cresolphthalein complexone (CPC) or arsenazo III dye to form a complex with Ca2+ after acidification to remove Ca2+ from proteins Atomic absorption spectroscopy is reference method but rarely used in clinical laboratories

Magnesium Methods and reference ranges

Methods (all spectrophotometric) Calmagite: bind together to form reddish-violet complex (532 nm) Formazan dye: bind together to form colored complex (660 nm) Methylthymol blue: bind together to form colored complex

Water, what does it have to do with the body.

Water = 40-75% of human body weight Declines with age & obesity Less in women than in men, due to higher % of body fat in women Water is *solvent for all processes* in human body: Transports nutrients to cells Determines cell volume by its transport into & out of cells Removes waste products by way of urine Acts as body's coolant by way of sweating Intracellular (2/3) - ICF Extracellular (1/3) - ECF Intravascular ECF - plasma (93% water) Interstitial cell fluid - surrounds cells in tissue

Calcium regulation

Three hormones regulate calcium: PTH, vitamin D, calcitonin by altering their secretion rate in response to changes in ionized calcium

Four other factors affect blood volume:

*Atrial natriuretic peptide (ANP)* Released from myocardial atria in response to increased volume and promotes Na+ and water excretion from kidney *Volume receptors independent of osmolality* Stimulate release of ADH conserving water by renal reabsorption *Glomerular filtration rate (GFR)* Increases with increased volume and decreases with decreased volume *Increased serum Na+* will increase urine Na+ excretion and vice versa if everything else is "normal"

Anion Gap, What is it useful for? What's the cause of elevation or decrease?

*Causes of AG elevation* Uremia/renal failure (causing phosphate and sulphate retention) Ketoacidosis (as seen in cases of starvation, diabetes) Methanol, ethanol, ethylene glycol or salicylates poisoning Lactic acidosis Hypernatremia Instrument error Causes of AG decrease Rare, seen in hypoalbuminemia (causes decrease in unmeasured anions) or severe hypercalcemia (causes increase in unmeasured cations)

What does Potassium regulate

*Kidneys regulate potassium balance* Proximal tubules reabsorb nearly all K+ Under influence of aldosterone, additional K+ secreted into urine in exchange for Na+ in distal tubules and collecting ducts Excess K+ from diet is excreted into urine but in kidney failure, may accumulate toxic levels in plasma *Potassium uptake from ECF into cells normalizes acute rise* *Factors that influence distribution of potassium between ICF and ECF:* 1. Inhibition of Na+ K+-ATPase pump by certain conditions 2. Insulin promotes potassium ions entering muscle & liver 3. Catecholamines (e.g. epinephrine) promote cellular entry of potassium

Potassium

*Major intracellular cation* in body Concentration 20 times greater inside cells than outside Many cellular functions require the body maintain a low ECF concentration of K+ Only 2% of body's K+ circulates in plasma Functions include: Regulation of neuromuscular excitability Contraction of skeletal and cardiac muscles ICF volume Hydrogen ion concentration

Sodium (Na+) What's its relevance.

*Most abundant cation in ECF* (90%) Largely determines osmolality of serum Sodium concentration in ECF is much larger than inside cells Active transport systems, such as ATPase ion pumps, prevent sodium equilibrium in all cells Counteract passive diffusion *Regulation of sodium concentration* Intake of water in response to thirst (determined by osmolality) Excretion of water (determined by ADH secretion) Blood volume status (affects Na+ excretion through aldosterone, angiotensin II and ANP)

Regulation of Blood Volume Regulation of water and Na+ is interrelated in controlling blood volume What controls this

*Renin-angiotensin-aldosterone system* primarily responds to *decrease* in blood volume (detected by stretch receptors) Renin secreted in response to *decreased renal blood flow* Converts angiotensinogen to angiotensin I which then becomes angiotensin II Angiotensin II causes vasoconstriction increasing blood pressure and secretion of aldosterone which *increases retention of Na+ and water*

What's used for the determination of sodium concentration

*Specimen*: serum, plasma, whole blood, urine, sweat *Methods*: Ion-selective electrodes (ISE) method is most common *Direct ISE method:* Undiluted sample interacts with ISE membrane *Indirect ISE method:* Diluted sample is used for measurement *No significant difference, except:* Hyperlipidemic Hyperproteinemic Displacement of plasma H2O

Distribution of Phosphate

Inorganic/free phosphate ion (~25%) Organic phosphate (bound) (~75%) 80% in bone, 20% soft tissues, <1% serum/plasma of total phosphate

Magnesium

4th most abundant cation in body, 2nd intracellularly Average human body contains 1 mole (24 g) of magnesium 53% in bone 46% in muscle, organs and soft tissue < 1% in serum and red blood cells of which ~ 33% is bound to albumin , 61% exists in free or ionized state (physiologically active form) and 5% is complexed with other ions (e.g. PO4- and citrate) Widespread role in body; *essential cofactor* of > 300 enzymes involved in: Glycolysis Transcellular ion transport Neuromuscular transmission Synthesis of carbohydrates, proteins, lipids, nucleic acids Release of & response to certain hormones

Calcium Distribution

99% of body calcium is in bone 1% is in blood & other ECF Concentration of calcium in blood is approximately 5000 - 10000 times higher than that of cytosol of cardiac or smooth muscle This *large gradient* is vital to maintain the essential rapid influx of calcium if required 45% circulates as free calcium ions *Ionized calcium = physiologically active form* 40% is bound to protein (mostly albumin) 15% is bound to anions (HCO3-, citrate and lactate)

Calcium during a Disease state

During disease, surgery or critical care, this distribution can change dramatically so calculation of ionized calcium from a total calcium measurement is not reliable Total calcium and ionized calcium measurements are available Ionized calcium is more sensitive and specific marker of calcium disorders

Osmolality, what is it?

A physical property of a solution based on concentration of solutes (millimoles) dissolved per kilogram of solvent (w/w) Related to changes in properties of solution relative to pure water (decreases in freezing point & vapor pressure) *Clinical significance* of osmolality Parameter to which *hypothalamus* responds Antidiuretic hormone (ADH) secretion and thirst stimulation Regulation of osmolality affects *plasma sodium* concentration Regulation of sodium & water controls *blood volume*

Decrease in Anion Gap

AG = ([Na+] + [K+]) - ([Cl-] + [HCO3-]) Increased unmeasured cations leading to increase Cl- monoclonal protein with + charge in some *multiple myeloma* hypermagnesemia, hypercalcemia, lithium intoxication,etc. Decreased unmeasured anions hypoalbuminemia (anion gap by 2.5 mmol/L for each 1 g/dL in albumin) Laboratory error falsely high chloride or bicarbonate falsely low sodium

High Anion Gap Acidosis

AG results from increase in unmeasured anions in the plasma. MUDPILES Methanol Uremia DKA/AKA Paraldehyde/phenformin Iatrogenic Lactic acidosis Ethylene glycol Salicylates Rarely, the AG is not related to acidosis Decrease in unmeasured cations (Ca2+, Mg2+, K+)

Phosphate Regulation

Absorbed in intestine from dietary sources, released from cells into blood, lost from bone Loss of regulation by kidneys has *most profound effect* and is controlled by PTH Lowers blood phosphate concentration by increasing renal excretion Vitamin D (increases phosphate in blood), calcitonin, growth factor (if secreted excessively, GH causes increases in blood phosphate due to decreased renal excretion) and acid-base status can also affect renal regulation of phosphate

Clinical applications of Bicarbonate

Acid-base imbalances cause changes in HCO3- and CO2 levels Metabolic acidosis may decrease HCO3- as it combines with H+ to produce CO2 Metabolic alkalosis increases total CO2 concentrations as HCO3- is retained

Lactate, what is it?

Byproduct of an emergency mechanism that produces a small amount of ATP when *oxygen is severely diminished* i.e. during anaerobic metabolism, excess lactate is released into blood

Clinical applications of Chloride

Cl- disorders often a result of same causes of Na+ disturbances because Cl- passively follows Na+ Few exceptions Hyperchloremia (increased Cl-) May result with loss of HCO3- as a result of GI losses, renal tubular acidosis or metabolic acidosis Hypochloremia (decreased Cl-) May result from prolonged vomiting, diabetic ketoacidosis, aldosterone deficiency, salt-losing renal disease such as pyelonephritis, conditions associated with high HCO3- such as compensated respiratory acidosis or metabolic acidosis

Clinical Applications of Lactate

Clinical applications Metabolic monitoring in critically ill patients *Type A lactic acidosis*: associated with hypoxic conditions such as shock, myocardial infarction, severe congestive heart failure, pulmonary edema or sever blood loss *Type B acidosis*: of metabolic origin such as with diabetes mellitus, severe infection, leukemia, liver or renal disease and toxins (ethanol, methanol or salicylate poisoning)

Collection of sample precautions for Potassium

Collection of samples: Proper collection and handling is extremely important as a number of causes of artifactual hyperkalemia Serum K+ 0.1-0.7 mmol/L higher than plasma due to release of K+ from platelets during coagulation If patient's platelet count is high, may be even higher Storing whole blood on ice releases K+ from cells Store at room temperature *Hemolysis* falsely elevates K+ due to release from red cells *Most common pre-analytical issue*

Hypermagnesemia

Concentration of serum Mg2+ is higher-than-normal Less frequent than hypo- Most common cause is renal failure (GFR < 30 mL/min) Symptoms Asymptomatic until > 1.5 mmol/L Treatment Discontinue source of Mg2+ If severe can administer supportive therapy for cardiac, neuromuscular, respiratory or neurologic abnormalities Patients with renal failure - hemodialysis Normal renal function - diuretic and IV fluid

Hypomagnesemia

Concentration of serum Mg2+ is lower-than-normal Often seen in hospitalized individuals and rare in non-hospitalized individuals Symptoms Asymptomatic until < 0.5 mmol/L Treatment Oral intake of magnesium lactate, oxide or chloride or a Mg2+ containing antacid; in severely ill patients, a MgSO4 solution is given IV.

Hyperkalemia

Concentration of serum potassium is higher-than-normal (<5.3 mmol/L) Symptoms: muscle weakness (> 8 mmol/L), tingling, numbness or mental confusion by altering neuromuscular conduction Treatment: immediately initiated if K+ 6-6.5 mmol/L or greater or if there are ECG changes. Ca2+ given to protect myocardium against effects of hyperkalemia. Sodium bicarbonate and insulin with glucose can be given to shift K+ into cells. Diuretics can also be given so excess K+ is excreted

Hypokalemia

Concentration of serum potassium is lower-than-normal (<3.5 mmol/L) Symptoms: muscle weakness that can interfere with breathing, increased risk of arrhythmia, fatigue, constipation Treatment: oral KCl replacement of K+, IV replacement, food with high K+ content in mild cases (dried fruit, nuts, bran cereals, bananas)

Hypernatremia and the table associated with it

Concentration of serum sodium is higher-than-normal (>145 mmol/L) *Symptoms:* altered mental status, lethargy, irritability, restlessness, seizures, muscle twitching, difficult respiration, increased thirst *Treatment:* correction of underlying condition gradually

Hyponatremia

Concentration of serum sodium is lower-than-normal (<135 mmol/L) Clinically significant <130 mmol/L *Symptoms:* nausea, vomiting, muscular weakness, headache, lethargy, ataxia up to and including seizures, coma and respiratory depression *Treatment:* correction of condition that caused either water loss or Na+ loss Mostly through appropriate fluid management

Lab Values of an anion gap

Demonstration of anion gap from concentrations of anions and cations in normal state and in lactate acidosis

Determination of calcium Specimens

Determination of calcium Specimen *Total calcium:* serum or lithium heparin plasma (EDTA or oxalate anticoagulants bind calcium and so are unacceptable tube types) and urine (preferably 24 hour sample acidified with HCl) *Ionized calcium:* samples must be collected *anaerobically* to keep CO2 and maintain pH Heparinized plasma is preferred sample but can use serum if clotting and centrifugation are done quickly

Specimen and methods for Phosphate

Determination of inorganic phosphorus *Specimen* Serum, lithium heparin plasma, urine (24 hour sample) Oxalate, citrate or EDTA anticoagulants should not be used as they interfere with analytical method (see below) Hemolysis should be avoided RBCs have higher concentrations of phosphorus than serum or plasma Subject to circadian rhythm with highest levels in late morning, lowest in evening Methods: formation of an ammonium phosphomolybdate complex (365 nm)

Determination of Lactate, specimen and methods

Determination of lactate *Specimen handling* Special care required Avoid using tourniquet and fist clenching = it will increase lactate levels After sample collection, glucose is converted to lactate by way of anaerobic glycolysis and should be prevented Iodoacetate and fluoride (glycolysis inhibitors) containing tubes should be used, delivered to lab on ice as quickly as possible for centrifugation and analysis *Methods:* Most common today are enzymatic methods

Anion Gap (AG) What is it?

Difference between unmeasured anions & unmeasured cations AG = ([Na+] + [K+]) - ([Cl-] + [HCO3-]) Created by concentration difference between commonly measured cations (Na++ K+) & anions (Cl-+ HCO3-) Approximation of anions other than HCO3- and Cl- present in ECF (e.g. proteins, albumin, lactate and other organic anions) *Useful for* Indicating an increase in 1 or more unmeasured anions in serum Quality control for analyzer used to measure electrolytes

Calcium Physiology

Essential for myocardial contraction Decreased ionized calcium concentrations impairs myocardial function Blood-ionized (free) calcium is closely regulated & has mean concentration in humans of about *1.18 mmol/L* Important to maintain normal ionized levels during surgery & in critically ill patients Decreased levels of ionized calcium Neuromuscular irritability can occur which may become clinically apparent as irregular muscle spasms called tetany

Water Load Osmolality Regulation

Excess intake of water lowers serum osmolality ADH excretion and thirst are suppressed and dilute urine is excreted If renal excretion of water is impaired, hypoosmolality and hyponatremia can occur

Potassium Regulation

Exercise increases plasma potassium as K+ is released from muscle cells ~0.3 - 1.2 mmol/L in moderate exercise ~ 2 - 3 mmol/L in exhaustive exercise Reverses after several minutes of rest Hyperosmolality causes water diffusion out of cells carrying K+ with it Gradual depletion of K+ if kidney function is normal Cellular breakdown releases K+ into ECF leading to increased plasma concentrations Severe trauma, tumor lysis syndrome and massive blood transfusions *Pre-analytical causes of falsely increased K+* Clenching and unclenching fist with or without tourniquet during venipuncture Use of tourniquet for prolonged period during venipuncture (> 1 minute after blood has started flowing into tube)

Phosphate

Found everywhere in living cells Participate in *key biochemical processes* DNA and RNA are phosphodiesters Most important cellular energy reservoirs are ATP, creatine phosphate and phosphoenolpyruvate (PEP)

Summary of Electrolyte excretion and Conversation for Electrolytes and Renal Function

Glomerulus: filters out large proteins & protein-bound particles Renal tubules Phosphate: reabsorption inhibited by PTH Calcium: reabsorbed under influence of PTH Magnesium: reabsorption occurs in Henle's loop Sodium: reabsorbed through 3 mechanisms Chloride: reabsorbed by passive transport in proximal tubule Potassium: reabsorbed by 2 mechanisms Bicarbonate: recovered from glomerular filtrate

Hypocalcemia: calcium depletion

In absence of PTH in primary hypoparathyroidism, Ca2+ levels are not properly regulated Surgery and intensive care - commonly seen in patients with sepsis, burns, renal failure or cardiopulmonary insufficiency Neonatal monitoring - may occur as infant may lose calcium rapidly and not be able to readily reabsorb it Symptoms (if total <1.88 mmol/L) Neuromuscular irritability (muscle cramps, parathesia, tetany and seizures) and cardiac irregularities (arrhythmia or heart block) Treatment Oral or parenteral administration sometimes with vitamin D and magnesium if also low

Hyperphosphatemia

Increased risk if have acute or chronic renal failure Increased intake of phosphate or increased release of cellular phosphate Neonates particularly susceptible due to immature PTH and vitamin D metabolism and increased intake in cow's milk or laxatives Also increased breakdown of cells, severe infections, intensive exercise, neoplastic disorders, intravascular hemolysis Patients with lymphoblastic leukemia Patients with hypoparathyroidism

Hypercalcemia: elevated calcium concentrations

Primary hyperparathyroidism is main cause (excess secretion of PTH) Malignancy is second leading cause Symptoms If mild (total 2.62 - 3 mmol/L), often asymptomatic Moderate or severe, can cause neurologic, GI and renal symptoms Neurologic: mild drowsiness, weakness, depression, lethargy, coma GI: constipation, nausea, vomiting, anorexia, peptic ulcer disease Renal: nephrolithiasis and nephrocalcinosis Treatment Estrogen replacement, parathyroidectomy, increased salt and water intake

Bicarbonate Regulation What are the different conditions?

Reabsorbed by proximal (85%) & distal (15%) tubules in kidneys as CO2 as tubules only slightly permeable to HCO3- In alkalosis, relative increase in HCO3- compared with CO2 Kidneys increase excretion of HCO3- into urine carrying a cation too (e.g. Na+) to help correct pH In acidosis, increased excretion of H+ into urine with almost complete reabsorption of HCO3-

Lactate Regulation

Regulation Not specifically regulated Levels rise rapidly when oxygen delivery decreases below a critical level and indicate tissue hypoxia earlier than pH Liver removes lactate by converting it back to glucose by gluconeogenesis

Magnesium Regulation

Rich sources of magnesium: raw nuts, dry cereal, hard drinking water, vegetables, meats, fish, & fruit Consumption of processed foods can lead to inadequate intake Regulation of body magnesium controlled largely by kidneys, which can reabsorb it in deficiency states or excrete excess Regulation appears to be related to Ca2+ and Na+

Chloride

The *major extracellular anion* (i.e. in ECF) Ingested in diet and almost completely absorbed by intestinal tract *Functions* Maintains osmolality, blood volume, electric neutrality Shifts secondarily to movement of Na+ or HCO3- (bicarbonate) Electroneutrality is maintained by: Cl- filtered out by glomerulus and passively reabsorbed in conjunction with Na+ by proximal tubules Cl- is rate-limiting component Excess Cl- is excreted in urine and sweat; excessive sweating stimulates aldosterone secretion which acts on sweat glands to conserve Na+ and Cl- "Chloride shift" (see link below)

Bicarbonate What about it?

Second most abundant anion in ECF Total CO2 comprises HCO3-, H2CO3 (carbonic acid) and dissolved CO2 HCO3- comprises >90% of total CO2 at physiological pH Major component of *buffering system in blood* Carbonic anhydrase in RBCs converts CO2 and H2O to H2CO3 which dissociates into H+ and HCO3-'

Water deficit Osmolality Regulation

Serum osmolality increases ADH secretion and thirst are activated Hypernatremia rarely occurs with normal thirst mechanism so it is a concern in infants and elderly as thirst decreases once >60 years old

Specimen and method for the determination of Chloride

Specimen Serum, plasma (lithium heparin is anticoagulant of choice), urine (24 hour collection), sweat, whole blood on some analyzers Method ISE most commonly used with ion-exchange membrane For sweat chloride determinations, coulometric titration by chloridometer is also common

Magnesium specimen

Specimen Nonhemolyzed serum (Mg2+ concentrations inside RBCs is 10x higher than ECF) Lithium heparin plasma (cannot use oxalate, citrate or EDTA tubes as they will bind Mg2+) 24-hour urine is preferred due to diurnal variation and it should be acidified with HCl to avoid precipitation Methods (all spectrophotometric) Calmagite: bind together to form reddish-violet complex (532 nm) Formazan dye: bind together to form colored complex (660 nm) Methylthymol blue: bind together to form colored complex

Determination of potassium concentration

Specimen: serum, plasma, urine Methods: Ion-selective electrodes (ISE) method is most common with valinomycin membrane (chapter 5)

Determinations of carbon dioxide (CO2) Specimen and Methods

Specimen: venous serum or plasma (lithium as anticoagulant) Samples should be kept capped so CO2 does not escape - if left uncapped, level can decrease by 6 mmol/L/hour Methods: ISE (Chapter 5) & enzymatic (340 nm) Reference interval Total CO2, venous 23-29 mmol/L (plasma, serum)