Disorders of Water, Electrolytes & Acid–Base Metabolism

1. Disorders of Water, Electrolytes & Acid–Base Metabolism Lecture 5

2. Introduction • A complex system of chemical buffers together with highly specialized mechanisms of the lungs and kidneys continuously work together to ensure a precise balance of water, electrolytes, and pH in both the intracellular and extracellular compartments of the human body. • Although these systems display impressive flexibility and responsiveness to perturbation by illness or injury, they do have limits, at which point medical evaluation and treatment are required.

3. TOTAL BODY WATER: VOLUMEAND DISTRIBUTION

4. TOTAL BODY WATER: VOLUMEAND DISTRIBUTION • The minimum daily requirement for water can be estimated from renal & insensible losses: • renal (1200 to 1500 mL in urine) and • “insensible” losses (≈400 to 700 mL) • evaporation from the skin and respiratory tract. • Activity, environmental conditions, and disease all have dramatic effects on daily water (and electrolyte) requirements. • On average, an adult must take in ≈1.5 to 2.0 L of water daily to maintain fluid balance. • Because primary regulatory mechanisms are designed to first maintain intracellular hydration status, imbalances in TBW are initially reflected in the ECF compartment.

5. TOTAL BODY WATER: VOLUME AND DISTRIBUTIONChanges in Extracellular Fluid Volume

6. WATER AND ELECTROLYTES: COMPOSITION OF BODY FLUIDS • The primary cationic (positively charged) electrolytes are: • Sodium (Na+), potassium (K+), calcium (Ca2+), and magnesium (Mg2+), • Whereas the anions (negatively charged) include: • Chloride (Cl-), bicarbonate ( HCO3- ), phosphate (HPO24- , H2PO24- ), sulfate ( SO24- ), organic ions such as lactate, and negatively charged proteins. • Na+, K+, Cl-, and HCO3- in the plasma or serum are commonly analyzed in an electrolyte profile because their concentrations provide the most relevant information about the osmotic, hydration, and acid-base status of the body.

7. WATER AND ELECTROLYTES: COMPOSITION OF BODY FLUIDS • Any increase in the concentration of one anion is accompanied by a corresponding decrease in other anions, or by an increase in one or more cations or both because total electrical neutrality must be maintained. • Similarly, any decrease in the concentration of anions involves a corresponding increase in other anions, a decrease in cations, or both. • In the case of polyvalent ions (eg, Ca2+, Mg2+), it is important to distinguish between the substance concentration of the ion itself and the concentration of the ion charge. • Thus, although the concentration of total calcium ions in normal plasma is ≈2.5 mmol/L, the concentration of the total calcium ion chargeis 5.0 mmol/L (also called 5 milliequivalents per liter [mEq/L]).

8. WATER AND ELECTROLYTES: COMPOSITION OF BODY FLUIDSSodium • Disorders of Na+ homeostasis can occur because of: • Excessive loss, gain, or retention of Na+, or as • The result of excessive loss, gain, or retention of H2O. • It is difficult to separate disorders of Na+ and H2O balance because of their close relationship in establishing normal osmolality in all body water compartments. • Homeostasis within a narrow window is necessary for life, and the body must defend against excessive gains or losses.

9. WATER AND ELECTROLYTES: COMPOSITION OF BODY FLUIDSSodium: Hyponatremia • Hyponatremiais defined as a decreased plasma Na+ concentration (sodium level goes below 135  mmol/L). • Hyponatremia typically manifests clinically as: • Nausea, generalized weakness, • Mental confusion at values below 120 mmol/L, & • Severe mental confusion plus seizures at less than 105 mmol/L. • The rapidity of development of hyponatremia influences the Na+ concentrations at which symptoms develop • ie, clinically apparent symptoms may manifest at higher Na+ concentrations [≈125 mmol/L] when hyponatremia develops rapidly.

10. WATER AND ELECTROLYTES: COMPOSITION OF BODY FLUIDSSodium: Hyponatremia • Symptoms are due to changes in osmolality rather than to the Na+ concentration by itself. • CNS symptoms are due to movement of H2O into cells to maintain osmotic balance and subsequent swelling of CNS cells. • These symptoms can occur more rapidly in children, so there is a need to be particularly aware in the pediatric population. • Hyponatremia can be: • hypo-osmotic, hyperosmotic, or iso-osmotic. • Thus measurement of plasma osmolality is animportant initial step in the assessment of hyponatremia. • the most common form is hypo-osmotic hyponatremia.

13. WATER AND ELECTROLYTES: COMPOSITION OF BODY FLUIDSSodium: HyponatremiaHyperosmotic Hyponatremia • Hyponatremia in the presence of increased quantities of other solutes in the ECF is the result of an extracellular shift of water or an intracellular shift of Na+ to maintain osmotic balance between ECF and ICF compartments. • The most common cause of this type of hyponatremia is severe hyperglycemia. • As a general rule, Na+ is decreased by ≈1.6 to 2.0 mmol/L for every 100 mg/dL increase in glucose above 100 mg/dL. • Correction of hyperglycemia will restore normal blood Na+. • It also may occur when mannitol and glycine, used for irrigation during certain surgical procedures, enter the intravascular fluid compartment.

14. WATER AND ELECTROLYTES: COMPOSITION OF BODY FLUIDSSodium: HyponatremiaIsosmotic Hyponatremia • If the measured Na+ concentration in plasma is decreased, but measured plasma osmolality,glucose, and urea are normal, the most likely explanation is pseudohyponatremia caused by the electrolyte exclusion effect. • This occurs when Na+ is measured by an indirect ion-selective electrode in patients with severe hyperlipidemia or hyperproteinemia. • Pseudohyponatremia is confirmed if direct ISE value is normal. • If direct ISE is not available, simultaneous calculation and measurement of plasma osmolarity is very useful. • Measured osmolarity is normal in pseudohyponatremia but calculated osmolarity – based as it is on erroneously low plasma sodium result – is reduced.

15. Predicted influence of water (H20) content on sodium measurements for a 100-mmol/L sodium chloride solution by direct ion-selective electrode versus flame emission photometry or indirect ion-selective electrode. Red areas represent nonaqueous volumes, which could consist of lipids, proteins Indirect ISE

16. WATER AND ELECTROLYTES: COMPOSITION OF BODY FLUIDSSodium: HyponatremiaHypo-Osmotic Hyponatremia • Typically, when plasma Na+concentration is low, calculated or measured osmolality alsowill be low. • This type of hyponatremia can be due to: • Excess loss of Na+(depletional hyponatremia)or • increased ECF volume (dilutional hyponatremia). • Differentiating these initially requires clinical assessment of TBW and ECF volume by history and physical examination.

17. WATER AND ELECTROLYTES: COMPOSITION OF BODY FLUIDSSodium: HyponatremiaHypo-Osmotic Hyponatremia • Depletional hyponatremia results from a loss of Na+ from the ECF space that exceeds the concomitant loss of water. • The net loss of Na+ from the ECF space also stimulates thirst and production of vasopressin, both of which contribute to the maintenance of hyponatremia. • Hypovolemia is apparent in the physical examination (orthostatic hypotension, tachycardia, decreased skin turgor). • If urine Na+is low (<10 mmol/L), the kidneys are properly retaining filtered Na+ and the loss is extrarenal, most commonly from the GIT or skin.

18. WATER AND ELECTROLYTES: COMPOSITION OF BODY FLUIDSSodium: HyponatremiaHypo-Osmotic Hyponatremia • Alternatively, if urine Na+is increased in this setting (generally >20 mmol/L), renal loss ofNa+ likely. • Renal loss of Na+ occurs with: • Use of diuretics (which inhibit reabsorption of Cl- and Na+ in the ascending loop), • Adrenal insufficiency (no aldosterone), or • Salt-wasting nephropathies, as can occur with interstitial nephritis.

19. WATER AND ELECTROLYTES: COMPOSITION OF BODY FLUIDSSodium: HyponatremiaHypo-Osmotic Hyponatremia • Renal loss of Na+ in excess of H2O can also occur in metabolic alkalosis from prolonged vomiting, because increased renal HCO3- excretion is accompanied by Na+ ions. • In this case, urine sodium is increased (>20 mmol/L), but urine chloride remains low. • In proximal renal tubular acidosis (RTA) type 2, bicarbonate is lost because of a defect in HCO3- reabsorption, and Na+ is coexcreted to maintain electrical neutrality. • As with extrarenal Na+ loss, management is centered around the reversal of underlying cause and restoration of ECF volume.

20. WATER AND ELECTROLYTES: COMPOSITION OF BODY FLUIDSSodium: HyponatremiaHypo-Osmotic Hyponatremia • Dilutional hyponatremia is a result of excess H2O retention and often can be detected during the physical examination as edema. • In advanced renal failure, water is retained because of decreased filtration and H2O excretion. • When ECF is increased but the circulating blood volume is decreased, as occurs in hepatic cirrhosis and nephrotic syndrome, a vicious cycle is established. • The decreased blood volume is sensed by baroreceptors and results in increased aldosterone and vasopressin, even though ECF volume is excessive. • The kidneys reabsorb Na+ and H2O in response to increased aldosterone and vasopressin in an attempt to restore the blood volume, resulting in further increases in ECF and further dilution of Na+.

21. WATER AND ELECTROLYTES: COMPOSITION OF BODY FLUIDSSodium: HyponatremiaHypo-Osmotic Hyponatremia • In hypo-osmotic hyponatremia with a normal or euvolemic volume status, the most common causes are the syndrome of inappropriate antidiuretic hormone (ADH) (vasopressin) (SIADH), primary polydipsia, and endocrine disorders such as adrenal insufficiency and hypothyroidism. • Hypothyroidism impairs free H2O excretion. • Free water restriction is the mainstay of therapy in SIADH.

22. WATER AND ELECTROLYTES: COMPOSITION OF BODY FLUIDSSodium: HyponatremiaHypo-Osmotic Hyponatremia • However, in severe or symptomatic hyponatremia from any cause, the use of hypertonic saline solutions may be required to correct serum Na+ concentrations. • In such cases, the hyponatremia must be corrected cautiously because too rapid correction can lead to brain demyelination. • Current recommendations are to increase Na+ by 0.5 to 2.0 mmol/L per hour and not to exceed a total increase in Na+ greater than 18 to 25 mmol/L over 48 hours.

23. WATER AND ELECTROLYTES: COMPOSITION OF BODY FLUIDSSodium: HyponatremiaHypo-Osmotic Hyponatremia • Finally, euvolemic hyponatremia also can be found in primary polydipsia when water intake is greater than the renal capacity to excrete excess H2O. • This can be the result of psychiatric illness, but diseases that cause hypothalamic disorders, such as sarcoidosis, also may cause polydipsia by altering the thirst reflex.

24. WATER AND ELECTROLYTES: COMPOSITION OF BODY FLUIDSSodium: Hypernatremia • Hypernatremia is generally defined as a serum sodium level of more than 145 mmol/L. • Symptoms of hypernatremia are primarily neurologic (because of neuronal cell loss of H2O to the ECF) and include tremors, irritability, ataxia, confusion, and coma. • As with hyponatremia, the rapidity of development of hypernatremia will determine the plasma Na+ concentration at which symptoms occur. • Acute development may cause symptoms at 160 mmol/L, although in chronic hypernatremia, symptoms may not occur until Na+ exceeds 175 mmol/L. • In chronic hypernatremia, the intracellular osmolality of CNS cells will increase to protect against intracellular dehydration.

25. WATER AND ELECTROLYTES: COMPOSITION OF BODY FLUIDSSodium: Hypernatremia • Because of this, rapid correction of hypernatremia can cause dangerous cerebral edema because CNS cells will take up too much water if the ICF is hyperosmotic when normonatremia is achieved. • In many cases, the symptoms of hypernatremia may be masked by underlying conditions. • Hypernatremia rarely occurs in an alert patient with a normal thirst response and access to water. • Most cases are observed in patients withaltered mental status or infants, both of whom may not be capable of rehydrating themselves.

26. WATER AND ELECTROLYTES: COMPOSITION OF BODY FLUIDSSodium: Hypernatremia • Hypernatremia arises in the setting of: • Hypovolemia (excessive water loss or failure to replace normal water losses), • Hypervolemia (a net Na+ gain in excess of water gain), or • Normovolemia. • Again, assessment of TBW status by physical examination and measurement of urine Na+ and osmolality are important steps in establishing a diagnosis.

28. WATER AND ELECTROLYTES: COMPOSITION OF BODY FLUIDSSodium: Hypernatremia Hypovolemic Hypernatremia • Hypernatremia in the setting of decreased ECF is caused by renal or extrarenal loss of hypo-osmotic fluid, leading to dehydration. • Thus, once hypovolemia is established by physical examination, measurement of urine Na+ and osmolality is used to determine the source of fluid loss. • Patients who have large extrarenal losses will have concentrated urine (often >800 mOsmol/L) with low urine Na+(<20 mmol/L), reflecting a proper renal response to conserve Na+ and water to restore ECF volume. • Extrarenal causes include diarrhea, skin losses (burns, fever, or excessive sweating), and respiratory losses coupled with failure to replace the water.

29. WATER AND ELECTROLYTES: COMPOSITION OF BODY FLUIDSSodium: Hypernatremia Hypovolemic Hypernatremia • When gastrointestinal loss is excluded, and the patient has normal mental status and access to H2O, a hypothalamic disorder (tumor or granuloma) inducing diabetes insipidus (DI) should be suspected. • In patients with poorly controlled diabetes with glucose values greater than 600 mg/dL, an osmotic diuresis can occur that results in extreme dehydration and hypernatremia. • This condition is referred to as hyperosmolarhyperglycemic nonketotic syndrome and occurs most commonly in elderly individuals with type 2 diabetes.

30. WATER AND ELECTROLYTES: COMPOSITION OF BODY FLUIDSSodium: HypernatremiaNormovolemic Hypernatremia • Hypernatremia in the presence of normal ECF volume is often a prelude to hypovolemic hypernatremia. • Insensible losses through the lung or skin must be suspected and are characterized by concentratedurine as the kidneys conserve water. • Another cause of normovolemic hypernatremia is water diuresis, which is manifested by polyuria. • The differential for polyuria (generally defined as >3 L urine output/d) is a water or solute diuresis. • Solute diuresis is exemplified by the osmotic diuresisof diabetes mellitus and generally is characterized by urine osmolality greater than 300 mOsmol/L and hyponatremia. • Water diuresis, a manifestation of DI, is characterized by dilute urine (osmolality <250 mOsmol/L) and hypernatremia.

31. WATER AND ELECTROLYTES: COMPOSITION OF BODY FLUIDSSodium: HypernatremiaNormovolemic Hypernatremia • DI can be central or nephrogenic. • Central DI is due to decreased or absent vasopressin secretion resulting from head trauma or pituitary tumor • Nephrogenic DI is due to renal resistance to vasopressin as a result of drugs (eg, lithium) or electrolyte disorders. • When thirst and access to water are uncompromised, many patients with DI will remain normonatremic because their free water losses are compensated by intake.

32. WATER AND ELECTROLYTES: COMPOSITION OF BODY FLUIDSSodium: HypernatremiaNormovolemic Hypernatremia • Such patients display symptoms of only polyuria and polydipsia. • However, overt hypernatremia can become manifest with progression of underlying causes,impaired thirst, or restricted access to water. • Administration of vasopressin can be used to treat central DI, although patients with nephrogenic DI may be resistant to it. • Correction of underlying disorders or discontinuation of offending drugs may be required to normalize Na+ concentrations innephrogenic DI.

33. WATER AND ELECTROLYTES: COMPOSITION OF BODY FLUIDSSodium: HypernatremiaHypervolemic Hypernatremia • The presence of excess TBW and hypernatremia indicates a net gain of water and Na+, withNa+ gain in excess of water. • This rare condition is observed most commonly in hospitalized patients receiving hypertonic saline or sodium bicarbonate.

34. WATER AND ELECTROLYTES: COMPOSITION OF BODY FLUIDSPotassium • The total body potassium of a 70-kg subject is ≈3.5 mol (40 to 59 mmol/kg), of which only 1.5 to 2% is present in the ECF. • Nevertheless, plasma K+ is often a good indicator of total K+ stores. • Disturbance of K+ homeostasis has serious consequences. • For example, a decrease in extracellular K+ (hypokalemia) is characterized by muscle weakness, irritability, and paralysis. • Plasma K+ concentrations < 3.0 mmol/L are often associated with marked neuromuscularsymptoms andindicate a critical degree of intracellular depletion. • At lower concentrations, tachycardia and cardiac conduction defects are apparent on electrocardiogram (ECG) and can lead to cardiac arrest.

35. WATER AND ELECTROLYTES: COMPOSITION OF BODY FLUIDSPotassium

36. WATER AND ELECTROLYTES: COMPOSITION OF BODY FLUIDSPotassium • High extracellular K+ (hyperkalemia) concentrationsmay produce symptoms of mental confusion, weakness, and weakness of the respiratory muscles. • Cardiac effects of hyperkalemia include bradycardia and conduction defects. • Prolonged, severe hyperkalemia >7.0 mmol/L can lead to peripheral vascular collapse and cardiac arrest. • Symptoms or ECG abnormalities are almost always present at K+ concentrations above 6.5 mmol/L. • Concentrations greater than 10.0 mmol/L in most cases are fatal, although fatalities can occur at significantly lower values.

37. WATER AND ELECTROLYTES: COMPOSITION OF BODY FLUIDSPotassium: Hypokalemia • Causes of hypokalemia (plasma K+ <3.5 mmol/L) are classified as: • Redistribution of extracellular K+ into ICF, or • True K+ deficits, caused by: • decreased intake or • loss of potassium-rich body fluids.

39. WATER AND ELECTROLYTES: COMPOSITION OF BODY FLUIDSPotassium: Hypokalemia Redistribution • Insulin promotes acute entry of K into skeletal muscle and liver by increasing Na, K-ATPase activity. • In alkalosis, K+ moves from ECF into cells in exchange with H+. • Pseudohypokalemia can occur in cases of very high white blood cell or platelet counts. • when the blood sample is kept at room temp. for a relatively long period.

40. WATER AND ELECTROLYTES: COMPOSITION OF BODY FLUIDSPotassium: Hypokalemia • Autosomal dominant channelopathy characterized by muscle weakness or paralysis when there is a fall in potassium levels in the blood • caused most commonly by mutations in the alpha subunit of the skeletal muscle calcium channel gene Cav1.1 • Clinically, redistributive hypokalemia is generally a transient phenomenon that is reversed once underlying conditions are corrected.

41. WATER AND ELECTROLYTES: COMPOSITION OF BODY FLUIDSPotassium: Hypokalemia True Potassium Deficit • Hypokalemia reflecting true total body deficits of K+ as a consequence of potassium loss can be classified into renal and nonrenal losses, based on daily excretion of K+ in the urine. • If urine excretion of K+ is < 25 mmol/d, it can be concluded that the kidneys are functioning properly and are attempting to reabsorb K+. The cause may be: • decreased K+ intake • Causes of decreased intake include chronic starvation and postoperative intravenous fluid therapy with K+-poor solutions. • extrarenal loss of K+-rich fluid • Gastrointestinal loss of K+ occurs most commonly with diarrhea and loss of gastric fluid through vomiting.

42. WATER AND ELECTROLYTES: COMPOSITION OF BODY FLUIDSPotassium: Hypokalemia • Urine excretion exceeding 25 mmol/d in a hypokalemic setting is inappropriate and indicates that the kidneys are the primary source of K+ loss. • Renal losses of K+ may occur: • during the diuretic (recovery) phase of acute tubular necrosis and • Magnesium deficiency also can lead toincreased renal loss of K+, which is attributable to a reduction in the inhibitory effect of magnesium on luminal potassium channels • Due to metabolic acidosis (renal tubular acidosis)

43. WATER AND ELECTROLYTES: COMPOSITION OF BODY FLUIDSPotassium: Hypokalemia • In addition to redistribution of K+ into cells in an alkalotic setting, K+ can be lost from the kidneys in exchange for reclaimed H+ ions. Metabolic alkalosis

44. WATER AND ELECTROLYTES: COMPOSITION OF BODY FLUIDSPotassium: Hyperkalemia • Hyperkalemia (plasma K+ >5.0 mmol/L) is a result of (singly or in combination) • Redistribution, • Increased intake, or • Increased retention. • In addition, preanalytical conditions—such as: • Hemolysis, • Thrombocytosis (>106/µL), and • Leukocytosis (>105/µL together with delayed sample analysis)—have been known to cause marked pseudohyperkalemia

46. WATER AND ELECTROLYTES: COMPOSITION OF BODY FLUIDS Chloride • In the absence of acid-base disturbances, Cl-concentrations in plasma generally will follow those of Na+. • However, determination of plasma Cl- concentration is useful in the differential diagnosis of acid-base disturbances and is essential for calculating the anion gap. • Fluctuations in serum or plasma Cl- have little clinical consequence, but do serve as signs of an underlying disturbance in fluid or acid-base homeostasis. • The specific replacement of chloride is rarely targeted at chloride deficit independently, but it is a corner stone of management for metabolic alkalosis.

47. WATER AND ELECTROLYTES: COMPOSITION OF BODY FLUIDS Chloride: Hypochloremia • Hypochloremia is defined as a chloride level less than 95 mmol/L. • In general, causes of hypochloremia parallel causes of hyponatremia. • Persistent gastric secretion and prolonged vomiting result in significant loss of Cl- and ultimately in hypochloremic alkalosis and depletion of total body Cl- with retention of HCO3- . • Respiratory acidosis, which is accompanied byincreased HCO3- , is another common cause of decreased Cl- with normal Na+.

48. WATER AND ELECTROLYTES: COMPOSITION OF BODY FLUIDS Chloride: Hyperchloremia • Increased plasma Cl- concentration, similar to increased Na+ concentration, occurs with dehydration, prolonged diarrhea with loss of sodium bicarbonate, DI, and overtreatment with normal saline solutions, which have a Cl- content of 150 mmol/L. • In fact, mounting evidence suggests that use of saline (NaCl) solution for maintenance, intraoperative, and resuscitative therapy can result in a host of hyperchloremia induced side effects. • A rise in Cl- concentration also may be seen in respiratory alkalosis because of renal compensation for excreting HCO3-.

49. Case Studies Disorders of Water, Electrolytes

50. Case 1 • A 45‐year‐old man was brought into the A&E department late at night in a comatose state. It was impossible to obtain a history from him, and clinical examination was difficult, but it was noted that he smelt strongly of alcohol.The following analyses were requested urgently.