Electrolytes and Acid-Base Balance


By the end of this session the reader should be able to:

  • Identify proper specimen collection for electrolyte analysis
  • Describe the effect of blood clotting on the serum potassium
  • Discuss the effect of refrigeration of whole blood on serum potassium concentrations
  • Describe the role of antidiuretic hormone and aldosterone in electrolyte balance
  • Describe the functioning of the renin-angiotensin system
  • Calculate the serum "anion gap"
  • Discuss causes of an increased "anion gap"
  • Discuss causes of a decreased "anion gap"
  • Calculate the serum osmolality from serum sodium, urea-nitrogen, and glucose
  • Calculate the "osmolal gap"
  • Discuss causes of an increased serum osmolality
  • Discuss causes of a decreased serum osmolality
  • Describe the application of the Henderson-Hasselbalch in maintenance of acid-base balance
  • Understand the major clinical causes for electrolyte and acid-base disturbances
  • Interpret blood gas data in terms of acid-base status
  • Differentiate acidosis from alkalosis and to determine if the primary cause is respiratory or metabolic
  • Discuss renal compensatory mechanisms for elimination of hydrogen ion in respiratory acidosis and retention of hydrogen ion in respiratory alkalosis
  • Discuss pulmonary compensatory mechanisms operative in metabolic acidosis and metabolic alkalosis
  • Discuss the criteria for determining renal compensation in chronic respiratory acidosis and chronic respiratory alkalosis
  • Discuss the criteria for determining pulmonary compensation in metabolic acidosis and in metabolic alkalosis
  • Describe the major causes of increased and decreased serum bicarbonate
  • Describe the major causes of increased and decreased serum chloride
  • Describe the major causes of increased and decreased serum sodium
  • Describe the major causes of increased and decreased serum potassium


Acidosis - a pathological condition resulting from accumulation of acid in the blood or loss of base from the blood; arterial blood pH < 7.35

Aldosterone - a mineralocorticoid hormone secreted by the adrenal cortex that influences sodium and potassium metabolism; released through action of angiotensin II.

Alkalosis - a pathological condition resulting from accumulation of base or loss of acid from the body; arterial blood pH > 7.45

Angiotensin - a vasoconstrictive polypeptide produced by the enzymatic action of renin on angiotensinogen, forming angiotensin I; angiotensin converting enzyme from the lung removes two C-terminal amino acids from the inactive decapeptide angiotensin I to form the biologically active octapeptide angiotensin II

Anion gap - the difference between the measured cations and measured anions (Na+ + K+) - (Cl- + HCO3-)

Antidiuretic hormone (ADH; vasopressin) - a hormone produced by the hypothalamus and stored in the pituitary; causes water to be reabsorbed by the renal collecting ducts and ascending loop of Henle; release regulated by serum osmolality

Apnea - cessation of breathing

Cirrhosis - progressive disease of the liver characterized by damage to hepatic parenchymal cells.

Diabetes insipidus - the chronic excretion of very large amounts of hyposmotic urine caused by inability to concentrate urine because of the lack of antidiuretic hormone (ADH) production, secretion, or effect; pituitary form is caused by inadequate ADH synthesis or secretion; nephrogenic form is caused by unresponsiveness of the renal tubules to ADH

Edema - an increase in the interstitial fluid volume

Henderson-Hasselbalch equation - describes the relationship among pH, the pKa of a buffer system, and the ratio of the conjugate base to its corresponding weak acid

Hypercapnia - a condition of excess carbon dioxide in the blood

Hypochloremic alkalosis - a metabolic alkalosis resulting from increased blood bicarbonate secondary to loss of chloride from the body

Hypovolemia - an abnormally low blood volume

Hypoxia - a condition of low oxygen content in tissues.

Juxtaglomerular cells - smooth muscle cells that synthesize and store renin and release it in response to decreased renal perfusion pressure, increased sympathetic nerve stimulation of the kidneys, or decreased sodium concentration in fluid in the distal tubule.

Metabolic acidosis - primary deficit of bicarbonate; pathological accumulation of acid or loss of base from the body

Metabolic alkalosis - primary excess of bicarbonate; pathological accumulation of base or loss of acid in the body

Osmol gap - the difference between the measured osmolality and the calculated osmolality

Osmolality - the number of particles dissolved in a kg of water

Polyuria - excessive urine output (more than 1 to 2 L/day in the adult)

Pseudohyperkalemia - abnormally high plasma potassium concentration in the sample obtained from a patient in the absence of true elevation of plasma potassium concentration in that patient

Renin - an enzyme produced, stored, and secreted by the juxtaglomerular cells of the kidney, which acts on circulating angiotensinogen to form angiotensin I

Respiratory acidosis - primary excess of dCO2; pathological retention of CO2 caused by respiratory change

Respiratory alkalosis - primary deficit of dCO2; pathological decrease in CO2 caused by respiratory change

Syndrome of inappropriate antidiuretic hormone secretion (SIADH) – a grouping of findings, including hypotonicity of the plasma, hyponatremia, and hypertonicity of the urine with continued sodium excretion, that is produced by excessive ADH secretion and that improves with water restriction


A basic understanding of renal and lung physiology is assumed for this chapter. Electrolyte analyses are among the most frequently ordered laboratory tests and an understanding acid-base balance is important to every clinician. Many drugs have a direct effect on acid-base balance while others influence pH through pharmacological mechanisms. Understanding how to interpret blood gas and electrolytes forms the core for the diagnosis and treatment of a variety of pathological states.


Plasma: Ammonium heparinate is the preferred anticoagulant. Do not use EDTA, citrate, oxalate or fluoride anticoagulants since these may elevate sodium or potassium if these salts are used; also, some bind Ca++ and Mg++.

Serum: Potassium values are slightly higher in serum (0.1 - 0.6 mmol/L) than in plasma because of release of potassium from platelets during clotting. Consequently spuriously high potassium values may be seen in severe thrombocythemia (3 million/μL). In this condition, plasma potassium rather than serum potassium should be used.

Long storage of whole blood specimens results in release of potassium from leukocytes and erythrocytes. Refrigeration of the clotted sample will result in elevation of serum potassium and depression of serum sodium due to inhibition of the Na/K-ATPase pump. This process does not produce hemolysis.

Hemolysis and Plasma Potassium Values

For each 30 mg/dL increase of plasma hemoglobin, potassium rises 0.1 mmol/L due to release of K+ from erythrocytes

  • 30 mg of hemoglobin/dL of plasma = barely pink
  • 60 mg of hemoglobin/dL of plasma = red
  • 90 mg of hemoglobin/dL of plasma = burgundy


ADH (Vasopressin)

  • Produced in hypothalamus, stored in pituitary
  • Causes water to be reabsorbed by collecting ducts and ascending loop
  • Release regulated by osmolality
  • Diabetes insipidus
    • Hypothalamic / pituitary: lack of production / storage
    • Nephrogenic: kidneys do not respond to ADH


  • Promotes retention of Na+ and HCO3- and excretion of K+ and H+ with retention of water
  • Promotes retention of Na+ and Cl- from sweat gland
  • Released by angiotensin II (renin released due to decreased renal perfusion and hyponatremia)
  • Addison’s disease - destruction of adrenal cortex leading to deficit of aldosterone and cortisol
  • Conn’s syndrome (primary hyperaldosteronism: bilateral hypertrophy of zona glomerulosa; adrenal adenoma; adrenal carcinoma) - high serum aldosterone leading to low serum renin
  • Secondary hyperaldosteronism (hepatic cirrhosis, congestive heart failure, nephrosis) - high serum renin leading to high serum aldosterone

Renin-Angiotensin System

Renin is an enzyme produced, stored, and secreted by the juxtaglomerular cells of the kidney in response to low sodium concentration and decreased renal perfusion. Renin acts on angiotensinogen to produce the biologically inactive angiotensin I. Angiotensin-converting enzyme from the lung converts angiotensin I to the biologically active angiotensin II, which, in turn, stimulates the release of aldosterone. Aldosterone causes retention of sodium and water and excretion of potassium and hydrogen ion.


Figure 1: "Gamble-Gram" shows that the Intravascular Concentrations of Cations are balanced by Anions


In clinical practice, only sodium, potassium, chloride, and bicarbonate are routinely measured in order to evaluate the electrolyte balance in the patient. This leaves approximately 7 mmol/L of “undetermined cations” (calcium, magnesium), as well as approximately 23 mmol/L of “undetermined anions” (phosphate, sulfate, organic acids, proteins - see “Gamble-Gram”). When only the cations sodium and potassium and the anions chloride and bicarbonate are balanced against each other, a difference in unmeasured ions, the so-called “anion gap” results, which normally ranges from 10-20 mmol/L (average ~16). “Gap” is a misnomer since there is always a balance. The anion gap is simply a reflection of the difference in the number of “measured cations” and “measured anions” and therefore also of “unmeasured cations” and “unmeasured anions.”

\begin{align} ({Na}^{+} \ + \ {K}^{+}) \ - \ ({Cl}^{-} \ + \ {HC{O}_{3}}^{-}) \end{align}

Using the values of the illustration (Gamble-Gram):

(142 + 4) - (103 + 27)
=146 - 130
(range: 10-20)

Alternative formula:(2)
\begin{align} {Na}^{+} \ - \ ({Cl}^{-} \ + \ {HC{O}_{3}}^{-}) \end{align}

142 - (103 + 27)
(range: 7-16)

The anion gap is influenced by changes of the unmeasured ions. The most frequent change is an increase of the anion gap, indicating acidosis due to accumulation of acid metabolites (organic acids such as ketoacids; inorganic acids such as phosphoric acid, sulfuric acid) as in renal disease or uncontrolled diabetes. Less frequently a decrease of the anion gap is seen, which may be due to hypoproteinemia, the presence of a cationic paraprotein as in multiple myeloma, or an increase in calcium or magnesium (“undetermined cations”).

Calcium, magnesium, phosphate, and protein are usually determined for reasons other than their role in electrolyte or acid-base balance.

Major Clinical Causes of an Increased Anion Gap

  • Ketoacidosis (diabetic, alcoholic, starvation) caused by acetoacetate and β-hydroxybutyrate
  • Renal failure (accumulation of organic acids, sulfuric acid, phosphoric acid)
  • Lactic acidosis
  • Treatment with substances that are unmeasured anions at physiological pH, e.g. citrate, lactate, carbenicillin, penicillin
  • Poisonings (all yield unmeasured anions)
    • Aspirin, salicylic acid, and other organic acids
    • Methanol (formic acid metabolite)
    • Ethylene glycol (glycolic and oxalic acid metabolites)
    • Paraldehyde (acetic acid metabolite)

Major Clinical Causes of a Decreased Anion Gap

  • Hypoalbuminemia (decrease in negative charge)
  • Hemodilution
    • Normal anion gap: (140 + 4) - (100 + 25) = 144 - 125 = 19
    • But with 20% dilution: (112 + 3.2) - (80 + 20) = 115.2 - 100 = 15.2
  • Paraproteins increase unmeasured cations, due to positive charge


Osmolality (not osmolarity) is the number of particles of solute (osmolutes) dissolved in a kilogram of water. It is measured in units of milliosmoles per kilogram of water. For a nondissociable, water-soluble compound (e.g., glucose, urea, ethanol), one “osmole” equals one mole, and one “milliosmole” equals one millimole. In the case of a dissociable, water-soluble compound the number of particles yielded per mole must be considered, e.g. 1 mole of NaCl yields theoretically 2 moles of solute. Actually, in serum, dissociation is incomplete, and the yield is 1.86 Osm/kg H2O. Thus:

For glucose (MW 180):

\begin{align} \frac{1 \ milliosmole}{L \ of \ serum \ water} = \ \frac{180 \ mg}{L} = \frac{18 \ mg}{dL} \end{align}

RULE OF THUMB: For non-dissociable, water-soluble substance, MW/10 = mg/dL yielding 1 mosmol/kg

For urea measured as urea-N (2 nitrogens per molecule of urea; AW of N =14; 2 N=28):

\begin{align} \frac{1 \ milliosmole}{L \ of \ serum \ water} = \ \frac{28 \ mg}{L} = \frac{2.8 \ mg}{dL} \end{align}

For ethanol (MW 46):

\begin{align} \frac{1 \ milliosmole}{L \ of \ serum \ water} = \ \frac{46 \ mg}{L} = \frac{4.6 \ mg}{dL} \end{align}

In healthy persons the osmolality may be calculated as follows based on measured values (assuming normal Na 140, glu 90, and SUN 14):

\begin{align} 2 \ (Na) \ + \ \frac{(Glu)}{18} \ + \ \frac{SUN}{2.8} \\ = 2 \left( 140\right) \ + \ \frac{90}{18} \ + \ \frac{14}{2.8} \\ = \ 290 \ mOsm/kg \end{align}

Measurement of Osmolality

This analysis is based on the measurement of the freezing-point depression of water due to solutes in solution. Freezing-point depression is linearly related to solute concentration. When one mole of any nonionic solute is dissolved in a kilogram of water, the freezing point is lowered by 1.858°C. A mole of an electrolyte or ionic substance will lower the freezing point a multiple of this amount depending on how many ions are formed when the substance is dissolved.

Reference Range: 275-298 mOsm/kg

It must be emphasized that osmolality is usually measured on serum, not plasma, since anticoagulants such as EDTA, oxalate, fluoride, etc. contribute to osmolality (some as much as 155 mOsm/kg!). Heparinized plasma, however, can be used.

Major Clinical Causes of Hyperosmolality

  • Dehydration
  • Hyperglycemia/diabetic ketoacidosis
  • Diabetes insipidus (serum osmolality high, but urine osmolality low)
  • Uremia
  • Ethanol ingestion
  • Improper specimen collection (use of anticoagulants - this effect is enhanced in a partially filled tube)

Major Clinical Causes of Hyposmolality

  • Overhydration
  • Inappropriate antidiuretic hormone (ADH) secretion (SIADH) - serum osmolality low but urine osmolality high
  • Compulsive water drinking (psychogenic polydipsia)

Osmolal Gap

The difference between measured osmolality and calculated osmolality is called the osmolal gap, which reflects unmeasured osmotically active substances that are present. A high osmolal gap suggests either the presence of another compound (e.g., ethanol) whose identity should be sought, or elevation of endogenous constituents that may not have been measured (e.g., proteins, ketoacids).


The bicarbonate/carbonic acid buffer system is the most important buffer system in plasma for maintenance of physiological pH. The Henderson-Hasselbalch (H-H) equation may be used to appreciate the concepts of respiratory and metabolic acidosis and alkalosis:

\begin{align} pH \ = \ p {{K}}_{a} \ + \ log \ \frac{[base]}{[acid]} \ = \ p {{K}}_{a} \ + \ log \ \frac{[HC{{O}_{3}}^{-}]}{[ {H}_{2}C {O}_{3}]} \ \\ = \ 6.1 \ + \ log \ \frac{24 \ mmol/L}{1.2 \ mmol/L} \end{align}

where [H2CO3] (in mmol/L) = (0.03 x pCO2), when pCO2 is expressed in mm Hg (0.03 x 40 = 1.2)

=6.1 + log20 = 6.1 + 1.3 = 7.4

Also recall that:

\begin{align} (Renal) \ {H}^{+} \ + \ HC {{O}_{3}}^{-} \ \Longleftrightarrow \ {H}_{2}C {O}_{3} \ \Longleftrightarrow \ {H}_{2}O \ + \ C {O}_{2} \uparrow \ (Pulmonary) \end{align}

The H - H equation indicates that the ratio of HCO3- / H2CO3 (which is normally 20/1) determines the blood pH. Any change, whether in the numerator (HCO3-) or in the denominator (H2CO3), will cause a change in pH.

In metabolic acidosis, the H+ reacts with the bicarbonate component of the buffer system to form carbonic acid, which forms CO2 + H2O. The CO2 is removed by increased ventilation. In this reaction, HCO3- is lost (= bicarbonate deficit).

\begin{align} (Renal) \ {H}^{+} \ + \ HC {{O}_{3}}^{-} \ \longrightarrow \ {H}_{2}C {O}_{3} \ \longrightarrow \ C {O}_{2} \uparrow \ + \ {H}_{2}O \ (Pulmonary) \end{align}

In metabolic alkalosis, the OH- reacts with the carbonic acid component of the buffer system to form HCO3- (= bicarbonate excess)

\begin{align} O {H}^{-} \ + \ {H}_{2}C{O}_{3} \longrightarrow \ HC { {O}_{3} }^{-} \ + \ {H}_{2}O \end{align}

Compensatory Mechanisms (Renal): (to eliminate hydrogen ion)

  • Sodium-hydrogen ion exchange (renal tubules)
  • Hydrogen phosphate formation
  • Bicarbonate reclamation (formation)
  • Ammonia production

Compensatory Mechanisms (Pulmonary):

  • Hyperventilation (to decrease pCO2)
  • Hypoventilation (to increase pCO2)

Figure 2: Renal Reclamation of Bicarbonate


Figure 3: Renal Excretion of Acid, Sodium/Hydrogen Ion Exchange and Formation of Ammonia

Assessing Compensation (Renal and Pulmonary Mechanisms):

Respiratory acidosis (retention of carbon dioxide)

Acute (no renal compensation)

RULE: for every 10 mm increase in pCO2 above normal of 40 mm, there is 1 mmol/L increase in bicarbonate above the normal of 24 mmol/L (mass action). Review Equation 9.

Chronic (renal compensation)

RULE: for every 10 mm increase in pCO2 above normal of 40 mm, there is 3.5 mmol/L increase in bicarbonate above the normal of 24 mmol/L. Review Equation 9.

(via loss of hydrogen ion by increased sodium-hydrogen ion exchange, increased ammonia formation, increased bicarbonate formation/reclamation, and increased hydrogen phosphate formation)

Metabolic acidosis (retention of hydrogen ion OR loss of bicarbonate)

Review Equation 9.

RULE: pulmonary compensation (via hyperventilation) has occurred if

pCO2 = (1.5 X bicarbonate) + 8 (+/- 2)

INTERRELATIONSHIPS: Last 2 digits of pH = pCO2 (e.g., pCO2 = 28, pH = 7.28) AND bicarbonate + 15 = last 2 digits of pH (e.g., bicarbonate = 15, pH = 7.30)

Respiratory alkalosis (loss of carbon dioxide)

Acute (no renal compensation)

Review Equation 9.

RULE: for every 10 mm decrease in pCO2 from normal of 40, there is a 2 mmol/L decrease in bicarbonate from normal of 24 (mass action)

Chronic (renal compensation)

Review Equation 9.

RULE: for every 10 mm decrease in pCO2 from normal of 40, there is a 5 mmol/L decrease in bicarbonate from normal of 24

(via retention of hydrogen ion by decreased sodium-hydrogen ion exchange, decreased ammonia formation, decreased bicarbonate formation/reclamation, and decreased hydrogen phosphate formation)

Metabolic alkalosis (retention of bicarbonate OR loss of hydrogen ion)

RULE: pulmonary compensation (via hypoventilation) has occurred if, for every 10 mmol/L increase in bicarbonate (above normal of 24), there is an increase of 6 mm in pCO2 above normal of 40 AND if bicarbonate + 15 = last 2 digits of pH (e.g. if bicarbonate = 35, pH = 7.50)



Reference values:
Serum: 135-145 mmol/L
Erythrocytes: 16 mmol/L (thus, hemolysis lowers serum sodium by dilution)


  • Dehydration
  • Diarrhea (water loss)
  • Hyperadrenalism (Cushing’s syndrome)
  • Aldosteronism


  • Over hydration
  • Diarrhea (sodium loss)
  • Intestinal fistula
  • Addison’s disease (hypoadrenalism)
  • Renal disease, tubular dysfunction
  • Salt losing nephritis
  • Uncontrolled diabetes (cations lost with keto-acids in urine)
  • Dilutional hyponatremia associated with hyperglycemia (osmotic effect); for each 100 mg/dL glucose over normal, sodium is lowered 1.6 mmol/L
  • Prolonged use of potassium-sparing diuretics (e.g., spironolactone)
  • Inappropriate antidiuretic hormone secretion (SIADH)

Hyponatremia with increased total body sodium

  • Water retention, edema from:
    • Renal insufficiency
    • Congestive heart failure
    • Hepatic cirrhosis with ascites
    • Nephrotic syndrome
    • Protein deficiency


Reference values:
Serum: 3.5-5.0 mmol/L
Erythrocytes: 125 mmol/L (thus, hemolysis increases serum potassium


  • Tissue damage or impairment of renal clearance of K+
  • Shock
  • Uncontrolled diabetes mellitus (tissue breakdown, utilization of protein for calories)
  • Dehydration
  • Adrenocortical insufficiency (Addison’s disease)


  • Poor food intake
  • Prolonged intravenous glucose or NaCl (without K+)
  • Vomiting
  • GI fistulas (mostly intestinal)
  • Diarrhea
  • Large intestinal adenomas (mucus-producing)
  • Aldosteronism
  • Hyperadrenalism
  • Over dosage with ACTH and cortisone
  • Familial periodic paralysis (intracellular K+ high)
  • Diuretic abuse
  • Laxative abuse


Reference values: 22-28 mmol/L
Newborns: 19-23 mmol/L, adult level reached by 2-6 months

Increased plasma bicarbonate

Respiratory acidosis (primary imbalance is dCO2 excess)

  • Prolonged hypoventilation (CO2 retention, increased H2CO3, decreased pH)
  • Central nervous system depression (e.g., opiate usage)
  • Pulmonary disease (e.g., emphysema, fibrosis, pulmonary obstruction)
  • Cardiac disease
Compensatory mechanisms (to lose hydrogen ion)
  • Hemoglobin and protein buffer systems
  • Hyperventilation
  • ↑ Na+ - H+ exchange
  • ↑ H2PO4- formation
  • ↑ HCO3- reclamation
  • ↑ NH3 production
Laboratory findings
  • Plasma pCO2 ↑, pH ↓
  • After compensation HCO3- ↑, tCO2
  • Urine pH ↓

Metabolic alkalosis (primary imbalance is HCO3- excess)

  • Loss of acid from stomach (prolonged vomiting, pyloric or high intestinal obstruction —> loss of hydrogen ion, causing increased HCO3-)
  • Excessive drainage of stomach (iatrogenic —> loss of hydrogen ion, causing increased HCO3-)
  • Cushing’s syndrome (hyperadrenalism —> loss of KCl and hydrogen ion, causing increased HCO3-)
  • Excessive ACTH or cortisone (KCl and hydrogen ion are lost in excess in urine, causing increased HCO3-)
  • Use of diuretics (loss of potassium and hydrogen ion in urine, causing increased HCO3-)
Compensatory mechanisms (to retain hydrogen ion)
  • HCO3- /H2CO3 buffer system
  • Hypoventilation
  • ↓ Na+ - H+ exchange
  • ↓ NH3 production
  • ↓ HCO3- reclamation
  • ↓ H2PO4 formation
Laboratory findings
  • HCO3- ↑, tCO2 ↑; pH ↑
  • After compensation: pCO2 ↑; pH → ↑

Decreased plasma bicarbonate

Respiratory alkalosis (primary imbalance is decrease in dCO2)

  • Increased rate and depth of respiration (fever, high external temperatures, hysteria, anoxia; an early phase of salicylate poisoning)
Compensatory mechanisms (to retain hydrogen ion)
  • ↓ NH3 production
  • ↓ Na+ - H+ exchange
  • ↓ HCO3- reclamation
  • ↓ H2PO4 formation
Laboratory findings
  • pCO2 ↓, pH ↑
  • After compensation: HCO3- ↓, tCO2 ↓, pH → ↑

Metabolic acidosis (primary imbalance is decrease in HCO3-)

  • Overproduction of acids (diabetes, lactic acidosis)
  • Reduced H+ excretion (renal failure, renal tubular acidosis, decreased Na+ - H+ exchange)
  • Excessive loss of base (diarrhea, GI fistula)
Compensatory mechanisms (to lose hydrogen ion)
  • HCO3- / H2CO3 buffer system
  • Hyperventilation
  • ↑ Na+ - H+ exchange
  • ↑ H2PO4- formation
  • ↑ NH3 production
  • ↑ HCO3- reclamation
Laboratory findings
  • HCO3- ↓, tCO2 ↓, pH ↓
  • After compensation: pCO2 ↓, pH → ↓


Reference values:
Serum: 97-107 mmol/L
Erythrocytes: 52 mmol/L (thus, hemolysis lowers serum chloride)


  • Dehydration
  • Hyperchloremic acidosis (loss of HCO3- due to diarrhea or renal tubular acidosis with compensatory increase in chloride)
  • Stimulation of respiratory center (drugs, hysteria, anxiety, fever, hyperventilation) causes loss of CO2 and decrease in HCO3-, with compensatory increase in chloride
  • High altitudes (small effect which is due to hyperventilation), causing loss of CO2 and decrease in HCO3-, with compensatory increase in chloride


  • Overhydration
  • Hypoventilation (CO2 retention), with increased CO2 and HCO3- and compensatory decrease in chloride
  • Depression of central nervous system (CO2 retention), with increased CO2 and HCO3- and compensatory decrease in chloride
  • Pulmonary disease (CO2 retention), with increased CO2 and HCO3- and compensatory decrease in chloride
  • Chronic renal disease
  • Diabetic ketosis
  • Adrenal insufficiency (Cl- lost from kidney together with Na+)
  • Hyperfunction of adrenal cortex (Cl- lost from kidney with K+)
  • Over dosage with ACTH and cortisone (hypochloremic alkalosis) with loss of potassium and hydrogen ion, causing increase in HCO3- and compensatory decrease in chloride
  • Metabolic alkalosis (increased HCO3- with compensatory decrease in chloride)
  • Vomiting (loss of hydrogen ion, causing increased HCO3- and compensatory decrease in chloride); also loss of chloride in gastric fluid
  • Fistulas of GI tract (gastric) with loss of hydrogen ion, causing HCO3- and compensatory decrease in chloride; also loss of chloride in gastric acid

Note: The compensatory increase/decrease in chloride “offsets” the corresponding changes in bicarbonate, thereby preserving electroneutrality.



  • 5th most common element in body
  • Average human has 1 kg of Ca
  • Three compartments, skeletal (99% of Ca), soft tissue, and extracellular
  • Three forms, free Ca++ (50%, ionized), protein bound (40%), complexed to small anions (10%)
  • Ionized calcium is regulated by 1,25-dihydroxyvitamin D, parathyroid hormone (PTH) and calcitonin
  • Reference range 8.5-10.4 mg/dL

Interpretation of Calcium

  • Since extensively bound to albumin, need to consider albumin concentrations when interpreting Ca++
  • Monitored for a variety of reasons including: bone disease, malignancy, hyper- and hypoparathyroidism, renal disease, and endocrine disorders


  • Adults have 600 g (85% in bone)
  • Reference range 2.5-4.5 mg/dL
  • Critical role in high energy compounds (e.g., ATP, NADP)
  • Essential element in phospholipids
  • Phosphorylation controls a variety of enzymatic and nuclear transcription factors


  • Total body content of about 25 g (55% in skeleton)
  • Reference range 1.7-2.6 mg/dL
  • A co-factor for over 300 enzymes
  • Estimated that 10% of patients admitted to hospitals have low magnesium
  • Hypokalemia commonly present with low magnesium


Parathyroid Hormone

  • Synthesized and secreted by parathyroid glands
  • Increases serum Ca by increasing bone resorption
  • Decreases serum phosphate by increasing excretion
  • Increases 1,25-dihydroxyvitamin D3
  • Release regulated by ionized Ca++

1,25-Dihydroxyvitamin D3

  • Dietary vitamin D3 is sequentially hydroxylated in liver to form 25-hydroxyvitamin D3 and then in the kidney to form the active hormone 1,25-dihydroxyvitamin D3
  • Increases Ca++ and phosphate absorption in gut
  • With PTH increases osteoclast activity
  • Increases kidney reabsorption of Ca++ and phosphate


  • Secreted by parafollicular cells of thyroid gland
  • Reduces concentrations of Ca++ and phosphate
  • Inhibits osteoclastic bone reabsorption
  • Exact physiological role is uncertain


Case 1

A febrile 84-year-old woman is brought from a nursing home to the emergency department of a local hospital. She is severely cachectic, confused, has sagging skin folds, and extremely dry skin. Admission chemistry tests are: serum sodium 168 mmol/L, serum potassium 6.2 mmol/L, chloride 130 mmol/L, and HCO3- 26 mmol/L. The serum osmolality is found to be 360 mOsm/kg of water. A urea nitrogen drawn at admission is 38 mg/dL and the patient’s hematocrit is 58%.

  1. Explain the elevated serum sodium and the elevated serum osmolality.
  2. Explain the elevated urea-N.
  3. What other laboratory studies are indicated?
  4. Explain the high hematocrit in this patient.
  5. Propose possible reasons for this patient’s abnormal laboratory data.

Case 2

A 40-year-old male presents to the emergency department confused and with the odor of alcohol on his breath. Chemistry tests performed at the time of admission show the following: serum sodium 137 mmol/L, potassium 4.2 mmol/L, chloride 100 mmol/L, and HCO3- 26 mmol/L. The urea-N was 14 mg/dL and glucose was 90 mg/dL. The serum osmolality, however, is 360 mOsm/kg of water.

  1. Propose a reason for the patient’s elevated serum osmolality.
  2. How would you test your hypothesis?
  3. Discuss reasons for serum hyperosmolality in the emergency department patient.
  4. Calculate the osmolality based on the above data.
  5. Assuming the elevated osmolality is due to ethanol, calculate the patient’s expected blood ethanol concentration.

Case 3

An 8-year-old girl was brought to the hospital with a 4-day history of profuse diarrhea. She was listless and responded rather incoherently to questions. Her skin turgor was poor for a child her age, and her eyes were soft and sunken. Pulse was 114 beats/minute with a BP of 98/66 mmHg. Respirations were deep and at a rate of 26/minute. Hematocrit was 58%. Lungs were clear, and the abdomen was soft without evidence of significant local tenderness. The following laboratory data were obtained:

ABG pH = 7.13 pCO2 = 18 mmHg
pO2 = 96 mmHg HCO3 = 6 mmol/L
Serum Electrolytes Na+ = 133 mmol/L K+ = 3.1 mmol/L
Cl- = 115 mmol/L total CO2 = 7 mmol/L
  1. What is the nature and etiology of the acid-base disorder in this patient?
  2. Is there evidence for and expected degree of compensation for this disorder?
  3. Explain the low serum potassium.
  4. Is there evidence for abnormalities of electrolyte fluid balance? If so, how might such a disturbance impact serum potassium?
  5. Is serum K+ a good indicator of total body K+ for patients with acid-base abnormalities?
  6. What are the causes of the high pulse rate, low blood pressure, and high respiratory rate?
  7. Why is the serum chloride increased?

Case 4

A 21-year-old woman with an eight-year history of juvenile onset diabetes was brought to the hospital in a coma. She had required 92 units of insulin daily to maintain her blood glucose concentration in an acceptable range and prevent excessive glucosuria. On admission she had a BP of 92/20 mmHg, a pulse of 122 beats/min, and deep respirations of 32/min. Lab data showed:

ABG: pH = 7.10 pCO2 = 15 mmHg
pO2 = 90 mmHg HCO3 = 4 mmol/L
Serum Chemistry Values: Na+ = 129 mmol/L K+ = 6.4 mmol/L
Cl- = 95 mmol/L total CO2 = 5 mmol/L
glucose = 1200 mg/dL urea nitrogen = 74 mg/dL
creatinine = 2.3 mg/dL

The serum was strongly positive for ketones.

Eight units of regular insulin were given IV and 8 units/h were given by IV infusion pump. Her serum glucose concentration fell at a rate of approximately 100 mg/dL each hour. In seven hours her ventilation and blood pH were normal following IV injection of NaHCO3 and vigorous fluid and electrolyte replacement.

  1. What is the nature and etiology of the acid-base disturbance?
  2. Is there indication for a normal compensatory response?
  3. What are serum ketones (ketone bodies)? How are they frequently detected?
  4. Explain the abnormal serum potassium result.
  5. Explain the low serum sodium result.
  6. What is the cause of the low BP upon admission? How does the low BP affect GFR (glomerular filtration rate)?
  7. Calculate the patient’s anion gap. Explain.
  8. Calculate the patient’s osmolality. Interpret.

Case 5

(Nephrol. Dial. Transplant. 14(1):226-230, 1999)

A 54-year-old male was admitted to emergency department with progressive weakness, somnolence, and shortness of breath 5 days after receiving chemotherapy (ifosfamide 2 g/m2) for recurrence of sarcoma. Past medical history included diabetes mellitus type II that was diet controlled.

Initial labs: creatinine 3.5 mg/dL, K+ 2.3 mmol/L, Na+ 147 mmol/L, Cl- 122 mmol/L, glucose 400 mg/dL.

Initial therapy included isotonic saline, 60 mmol of KCl and subcutaneous insulin. On day 2 similar labs as above were obtained. Blood gases were measured and an initial diagnosis of ketoacidosis was made.

Patient was admitted to ICU with blood pressure of 120/60 mmHg and heart rate regular at 120/min. Respiration rate was 36/min, deep, and labored.

Analyte Units Day 3 Day 4 Reference Range
Na+ mmol/L 160 162 135 - 145
K+ mmol/L 2.3 4.0 3.5 - 5.2
Cl- mmol/L 140 132 97 - 108
Glucose mg/dL 300 307 76 - 110
Creatinine mg/dL 3.7 4.4 0.3 - 1.2
pH 7.24 7.46 7.34 - 7.44
pCO2 mmHg 12 20 35 - 46
pO2 mmHg 122 87 69 - 116
HCO3 mmol/L 5 14 22 - 26
  1. The initial therapy included KCl and insulin. Why was the KCl necessary?
  2. Were any important lab results missing from the initial studies?
  3. How do you interpret the creatinine values?
  4. Calculate the anion gap for day 3. Does this support the initial diagnosis of ketoacidosis?
  5. What is the nature of this acid-base disturbance?
  6. Is there evidence of compensatory mechanisms?
  7. Propose a drug-induced mechanism for these laboratory results. Is this adverse reaction typical of this class of drugs?

Case 6

A 25-year-old woman with a history of surgical removal of an adenoma of the pituitary returns to her internist complaining of unquenchable thirst, and excretion of voluminous amounts of urine daily. Laboratory studies drawn in the physician’s office reveal the following: serum sodium 160 mmol/L, potassium 4.8 mmol/L, chloride 125 mmol/L and HCO3- 24 mmol/L. The patient’s serum osmolality is found to be 335 mOsm/kg of water.

  1. What further laboratory studies are indicated?
  2. What is the most likely diagnosis?

Case 7

A 14-year-old boy who had never been immunized against poliomyelitis contracted the disease late in the summer. He was hospitalized and required the use of a respirator during the acute phase of his illness. When he appeared to be recovering, he was taken off the respirator with no apparent ill effects. Several days later an analysis of his blood revealed the following:

ABG: pH = 7.32 pCO2 = 70 mmHg
pO2 = 52 mm Hg HCO3- = 35 mmol/L
Serum Na+ = 136 mmol/L K+ = 4.5 mmol/L
Electrolytes Cl- = 92 mmol/L total CO2 = 36 mmol/L
  1. What is the nature and cause of the acid-base disturbance in this boy? What are other causes of this type of acid-base disorder?
  2. What are the normal compensatory mechanisms in response to this acid-base disturbance?
  3. Is there evidence that these compensatory mechanisms are operative in this case?
  4. Differentiate compensatory responses in acute and chronic respiratory abnormalities of acid-base metabolism.
  5. What is included in the measurement of total CO2 in serum?
  6. Bicarbonate is generally included in the test panel: pH/blood gases. How is the bicarbonate value determined and what is its relationship to total CO2 in serum?
  7. Why is serum chloride decreased?
Table 1: Classification and Characteristics of Simple Acid-Base Disorders
Primary Change Compensatory Response Expected Compensation
Acidosis ↓↓↓ cHCO3- ↓↓ pCO2 pCO2 = 1.5 (cHCO3-) + 8 ± 2, pCO2 falls by 1-1.3 mmHg for each mmol/L fall in cHCO3-, Last 2 digits of pH = pCO2 (e.g., if pCO2 = 28, pH = 7.28), cHCO3- + 15 = last 2 digits of pH, cHCO3- = 15, pH = 7.30
Alkalosis ↑↑↑ cHCO3- ↑↑ pCO2 pCO2 increases 6 mmHg for each 10 mmol/L rise in cHCO3- , cHCO3- + 15 = last 2 digits of pH (cHCO3- = 35, pH = 7.50)
Acute ↑↑↑ pCO2 ↑ cHCO3- cHCO3- increases by 1 mmol/L for each 10 mmHg rise in pCO2
Chronic ↑↑↑ pCO2 ↑↑ cHCO3- cHCO3- increases by 3.5 mmol/L for each 10 mmHg rise in pCO2
Acute ↓↓↓ pCO2 ↓ cHCO3- cHCO3- falls by 2 mmol/L for each 10 mmHg fall in pCO2
Chronic ↓↓↓ pCO2 ↓↓ cHCO3- cHCO3- falls by 5 mmol/L for each 10 mmHg fall in pCO2

Modified from Narins RG and Gardner LB, Simple acid-base disturbances, Med. Clin. North Am. 65:321-346, 1981 [Tietz Textbook of Clinical Chemistry, 3rd edition, table 32-4, p. 1115].


Figure 4: Acid-Base Map: area of normal values is labeled N; map actually extends further up than shown (to a pH of 6.6) and further to right than shown (to a pCO2 of 180 mmHg); numbered lines represent isopleths for bicarbonate (in milliequivalents per liter); from Goldberg M et al., Computer-based instruction and diagnosis of acid-base disorders: a systematic approach, JAMA 223:269-275, 1973, p. 270


Figure 5: The Siggaard-Anderson Alignment Nomogram for the Calculation of Acid-Base Parameters

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