Potassium, phosphorus, and calcium treatment of severe abnormalities (Proceedings)

Potassium

Potassium concentration is very commonly abnormal in critically ill patients. Most of the potassium in the body is located in the intracellular fluid compartment (140 mEq/L; 55 mEq/kg) while very little of it is located in the extracellular fluid compartment (4 mEq/L; 1 mEq/kg). Repolarization of electrically excitable cells is largely attributed to the rapid efflux of potassium. Resting membrane potential is determined by the equilibrium between potassium moving out of the cell in response to the intracellular-to-extracellular potassium gradient, and potassium moving back into to the cell in response to the extracellular-to-intracellular electronegativity.

Hyperkalemia

Hyperkalemia is primarily caused by oliguric/anuric renal disease, hypo-adrenocorticism, and iatrogenic causes. It may also be caused by rhabdomyolysis, metabolic (inorganic)/respiratory acidosis, periodic familial hyperkalemia. It may also be falsely elevated if the blood sample is not analyzed for a period of time due to hemolysis (only in the Akita dog) or from platelet or white cell degradation (only in severe thrombocytosis or leucocytosis).

Causes of hyperkalemia

• Oliguric or anuric renal disease

-Post-renal obstruction or perforation

• Hypomineralocorticism

-Iatrogenic

• Extracellular redistribution

-Metabolic (inorganic)/respiratory acidosis

--Hypoinsulinemia

--Beta2-adrenergic blockade

--Familial periodic hyperkalemic paralysis

• Tissue damage or catabolism

-Trauma, burns

--Rewarming and washout of ischemic tissues

--Severe exercise

--Succinylcholine

-False hyperkalemia

--In-vitro hemolysis (only Akita dog)

--In-vitro platelet/white cell degeneration (only very severe thrombocytosis or leucocytosis)

Hyperkalemia causes membrane hypopolarization which may result in extrasystoles/fibrillation if the resting membrane potential is slightly more negative than threshold potential or asystole when resting membrane potential is slightly less negative. Hyperkalemia also increases potassium permeability which augments the repolarization phases of the electrocardiograph (tall, tented, narrow T-wave) and diminishes the depolarization phases (small P waves; prolonged P-R intervals; bradycardia, and widened QRS complexes). Hyperkalemia may also be associated with peripheral muscle weakness, decreased contractility, and weak pulse quality. Finally there is a blending of the QRS and T waves (a sinusoidal pattern), hypotension, and either ventricular asystole or fibrillation.

The plasma potassium measurement defines the plasma potassium concentration (normal, hyperkalemia, hypokalemia). The ECG changes define whether or not the animal is having any electrical problems from the potassium imbalance. There is considerable individual variation is this association. Severe hyperkalemia, for instance, that is associated with a fairly normal ECG complexes and at least "fair" pulse quality suggest that the animal's condition is not life-threatening and that therapy can be conservative. Moderate hyperkalemia associated with severe ECG changes suggests a life-threatening emergency requiring immediate and effective therapy.

Life-threatening hyperkalemia, defined by severe electrocardiographic disturbances, should be treated specifically. Calcium (0.2 ml of 10% calcium chloride or 0.6 ml or 10% calcium gluconate per kilogram of body weight , administered intravenously), by virtue of its effect on membrane threshold potential, antagonizes the effect of hyperkalemia and immediately returns the electrical performance toward normal. The effects of calcium are, however, short-lived, lasting only until the calcium is redistributed. Insulin and glucose (0.1 to 0.25 units of regular insulin/kg, administered as an intravenous bolus and 0.5 to 1.5 G of glucose/kg, respectively, administered as an intravenous infusion over two hours) is the common treatment for hyperkalemia. Patients should be monitored to make sure that they do not get excessively hypoglycemic. Bicarbonate will also cause the intracellular redistribution of potassium if it is going to be administered for acidosis. It is not a common choice for the treatment of hyperkalemia because animals commonly do not need to be alkalinized. Sympathomimetic drugs with beta2-agonist activity will also cause the intracellular redistribution of potassium but their therapeutic margin is narrow. Specific beta2 drugs (terbutaline) are associated with tachycardia and hypotension; while general beta1&2 drugs (epinephrine, dopamine) are associated with tachycardia, arrhythmias, and hypertension.

Hypokalemia

Hypokalemia is primarily attributed to excessive abnormal losses (vomiting, diarrhea, diuresis), dehydration (aldosterone-mediated renal losses), and lack of intake. It may also be caused by hypochloremia, hyperadrenocorticism, metabolic (inorganic)/respiratory alkalosis), bicarbonate therapy, beta2-agonist administration, and familial periodic hypokalemia.

Hypokalemia causes membrane hyperpolarization (electrical paralysis) and decreases potassium permeability (diminishes repolarization processes and enhances depolarization processes. Hypokalemia is associated with general muscle weakness (skeletal, gastrointestinal, and myocardial) and may be associated with ECG changes opposite to those of hyperkalemia (although the changes are not as characteristic as they are with hyperkalemia): flattened T-wave, U waves (a positive deflection following the T wave), elevated P wave, increased R wave amplitude, and depressed S-T segment. Hypokalemia is also associated with CNS depression and an impaired ability of the renal nephrons to concentrate urine.

A severely hypokalemic patient needs to be potassium loaded. The general rule is that potassium should not be administered faster than 0.5 mEq/kg/hour. The concentration of potassium in the fluid may vary between 10 and 50 mEq/L, or higher, but matters little as long as safeguards are in place to prevent iatrogenic hyperkalemia (continuous ECG; serial plasma potassium measurements). There are two ways to get into trouble with potassium administration: 1) give too much; 2) administer it faster than in can redistribute into the intracellular space.

Causes of hypokalemia

• Insufficient intake

-Anorexia; Maintenance fluids with low potassium concentrations

• Excessive losses

-Vomiting; diarrhea; diuresis; dialysis with potassium-free fluids

-Aldosterone-mediated urinary losses during dehydration

• Hypermineralocorticism

-Appropriate - dehydration

-Inappropriate - Addison's disease

• Hypochloremia

• Diuretic therapy

• Carbonic anhydrase inhibitors

• Renal tubular acidosis (proximal and distal)

• Carbenicillin and some other penicillin derivatives (due to renal tubular sodium reabsorption with a nonreabsorbable anion)

• Intracellular redistribution

-Insulin and glucose; Bicarbonate, B2-agonists

-Metabolic alkalosis (Hydrogen loss or bicarbonate retention)

-Familial periodic hypokalemic paralysis

Potassium supplementation guideline

Phosphorus

Phosphorus is the major intracellular anion and is an important constituent of cell membranes. It is the "P" in ATP (stored energy for all metabolic processes), 3,5 DPG (which is an important modulator of hemoglobin affinity for oxygen), cyclic AMP (which is a major intracellular second messenger), and NADP+ (which is an essential proton carrier in glycolysis and for the mitochondrial electron transport chain). Phosphate is essential for fat, carbohydrate, and amino acid metabolism. It is also an important urinary buffer for urinary excretion of hydrogen ion. Hyperphosphatemia stimulates the activity of glutamase in ammoniagenesis. Hypophosphatemia stimulates the activity of 1α-hydroxylase in the renal tubules which converts inactive calcidiol to the active calcitriol (which functions to increase plasma calcium concentration).

Phosphorus exist as organic phosphate when combined with lipids in cell membranes or proteins in nucleic acids. It also exists as inorganic phosphate as hydroxyapatite in bone and when combined with hydrogen ion (phosphoric acid) or other cations (sodium, calcium, or magnesium). The phosphate anion is readily exchangeable between its organic and inorganic forms. Plasma inorganic phosphate exists in three forms: ionized (55%); nonionized, chelated forms (33%), and albumin-bound (12%) . The ionized form is the biologically active form. Phosphate is primarily an intracellular anion and plasma concentrations may bear little correlation to total body content.

Phosphorus has a molecular weight of 31. It is usually measured in mg/dl. It is occassionally useful to convert the measured phosphate concentration to mM/L or mEq/L.

a) phosphate in mg/dl x 10 dl/L x 1 mM/31 mg = phosphate in mM/L

b) phosphate in mM/L x 1.8 mEq/mM = phosphate in mEq/L

The 1.8 reflects the fact that, at pH 7.4, approximately 90% of the plasma phosphate is in the divalent form HPO4 2- , while about 10% is in the univalent form H2PO4 1- ; it does not quite have a valence of two.

Inorganic phosphorus is absorbed by passive paracellular diffusion and by a calcitriol stimulated, sodium-dependent, active transport across the luminal membrane of the intestinal epithelial cells. Phosphorus is primarily excreted by in the kidney. Parathyroid hormone diminishes proximal tubular reabsorption and increases urinary phosphate loss. Phosphate is cotransported with sodium in the proximal tubule and a saline diuresis also enhances urinary phosphate loss. Plasma phosphate concentration is regulated by proximal tubular reabsorption. Disease/drugs which cause diuresis are associated with urinary phosphate loss. PTH also decreases phosphate reabsorption.

Hypophosphatemia

Hypophosphatemia may be associated with depletion of intracellular ATP. In the red blood cell, this accounts for increased cell fragility and hemolysis. Depletion of membrane phospholipids may also contribute. Depletion of erythrocytic 2,3 DPG increases hemoglobin affinity for oxygen (shifts the oxyhemoglobin dissociation curve to the right). Depletion of white blood cell ATP impairs all phases of leucoactivation. There may also be widespread reduced cellular activity, function and integrity leading to a metabolic encephalopathy (progressive obtundation), muscle weakness/cramps; muscle tremors; respiratory and skeletal muscle weakness; myocardial weakness and hypotension; renal tubular dysfunction, platelet dysfunction, and rhabdomyolysis.

Normal serum phosphate concentrations range between 3 and 6 mg/dl in the dog and cat. Therapy should be considered if the measured plasma phosphate is below 2.0 mg/dl and must be implemented if it is below 1.5 mg/dl. Oral sodium or potassium phosphate preparations are available for mild hypophosphatemia; severe hypophosphatemia should be treated intravenously. Intravenous sodium or potassium phosphate is dosed at a rate of 0.02 up to 0.1 mM (0.6 mg]) per kilogram per hour until the plasma phosphate concentrations stabilize, which may take from a few hours to a day to accomplish. Inadvertent hyperphosphatemia may be associated with hypocalcemia and soft tissue mineralization.

Causes of hypophosphatemia

• Reduced GI uptake

- Malnutrition; malabsorption

-Vitamin D deficiency

-Antacids, phosphate binders and sucralfate

• Increased renal losses

-Diabetes mellitus and ketoacidosis

-Renal tubular defects

-Hyperparathyroidism

-Hypomagnesemia

-Hypokalemia

-Acidosis

-Proximal nephron diuretics (carbonic anhydrase inhibitors) but not distal nephron diuretics

• Intracellular redistribution and increased phosphate utilization in glycolysis

-Insulin therapy

-Carbohydrate therapy and refeeding, especially with intravenous nutrition solution

-Respiratory alkalosis and bicarbonate therapy

• Hypercalcemia of malignant neoplasia

• Septicemia

• Calcitonin therapy

Hyperphosphatemia

Hyperphosphatemia decreases calcium concentration by a mass action effect promoting soft tissue mineralization. Soft tissue mineralization is reputed to be more likely to occur when the calcium x phosphorus product is greater than 60. Hyperphosphatemia also inhibits 1a-hydroxylase (converts inactive calcidiol to active calcitriol). The resultant decrease in calcitriol levels further decreases serum calcium concentrations and promotes secondary hyperparathyroidism. Hyperphosphatemia is not associated with any specific clinical signs.

The mainstay of treatment for hyperphosphatemia is effective treatment of the underlying disease process. There is no absolute agreement with regard to when more aggressive therapy should be implemented, but one guideline is when the calcium x phosphorus product exceeds 60. Extracellular volume expansion and diuresis enhances phosphaturia. Insulin and glucose therapy (as for hyperkalemia) could temporarily decrease extracellular phosphorus concentration by increasing intracellular redistribution. Oral or rectal phosphate binders could also be administered. Aluminum or calcium and hydroxide, carbonate, or acetate are common phosphate binding compounds. The dosage ranges between 50 and 100 mg/kg/day, divided into 2 or 3 doses.

Causes of hyperphosphatemia

• Reduced renal excretion

-Oliguria/anuria

-Hypoparathyroidism

-Hyperthyroidism

• Enhanced cellular translocation

-Hemolysis; tumor lysis

-Rhabdomyolysis

-Tissue trauma; heat stroke

-Metabolic acidosis

• Increased GI uptake

-Phosphate enemas

-Hypervitaminosis D

• Iatrogenic

• Rapid growth

Calcium

Most of the calcium is located in the skeleton bound with phosphorus as hydroxyapatite [Ca10 (PO4)6 (OH)2]. Most of it is not readily exchangeable with the extracellular fluid compartment, however, there is a small amount within the bone extracellular fluid matrix that is readily exchangeable. Calcium is an important intracellular messenger for many intracellular functions. Most of the intracellular calcium is sequestered in organelles such as the endoplasmic reticulum, or bound to cell membranes or proteins (calbindin, calmodulin, troponin C); cytoplasmic calcium concentrations are generally very low. Sustained high cytoplasmic calcium concentrations, by several different mechanisms, are cytotoxic. It is required for muscle contraction and smooth muscle tone, nerve conduction and neurotransmitter release, hormone secretion, cell division and motility, enzyme activity, blood coagulation, and plays an important role in the action potential of excitable cells as well as pacemaker automaticity.

Plasma calcium exists in three forms: ionized (55%); nonionized, chelated forms (10%), and albumin-bound (35%) . The ionized is physiologically the most important and the form which is regulated by the body.

Calcium has a molecular weight of 40. It is usually measured in mg/dl. It is occassionally useful to convert the measured calcium concentration to mM/L or mEq/L.

a) calcium in mg/dl x 10 dl/L x 1 mM/40 mg = calcium in mM/L

b) calcium in mM/L x 2 mEq/mM = calcium in mEq/L

Calcium is regulated by the balance between gastrointestinal absorption, bone mineralization or demineralization, and renal excretion. Calcium balance is primarily regulated by the balance between calcitriol (day to day control) and parathormone (minute to minute control).

Calcitriol (1,25 dihydroxyvitamin D3) (the active form) is produced in the proximal tubules by the action of 1a-hydroxylase on calcidiol (25 hydroxyvitamin D3) (the inactive form) which was produced in the liver by hydroxylation of vitamin D3 (cholecalciferol) which, in dogs and cats, is primarily derived via GI absorption. 1 a -hydroxylase activity (and calcitriol production) is stimulated by hypocalcemia, hypophosphatemia, parathormone, calcitonin, and low plasma levels of calcitriol, and vice-versa. The net effect of calcitriol is to increase plasma calcium concentration. Calcitriol does this by enhancing GI calcium absorption by several different mechanisms, by stimulating osteoclastic bone demineralization, and by enhancing renal reabsorption of calcium and phosphorus. Calcitriol also decreases parathyroid hormone production and that of itself.

Parathyroid hormone is produced by the chief cells of the parathyroid gland. It is produced as it is needed and has a very short plasma half-life (minutes). Production is stimulated by hypocalcemia and inhibited by hypercalcemia and calcitonin. Azotemia impairs chief cell responsiveness to calcium and calcitonin which contributes to the overproduction of parathormone in renal secondary hyperparathyroidism. The net effect of parathyroid hormone is to increase plasma calcium concentration. It does this by increasing GI absorption, by increasing renal distal tubular reabsorption, by increasing osteoclastic bone demineralization, and by stimulating calcitriol production.

Normal total calcium concentrations in the dog and cat are about 9 to 11 mg/dl (2.2 to 2.8 mM/L); ionized calcium concentrations are about 1.1 to 1.4 mM/L (4.4 to 5.6 mg/dl).

Hypocalcemia

Hypocalcemia lowers (more negative) threshold transmembrane potential and increases the excitability of the nervous system and muscles. This may be manifested by muscle tremors, fasciculations, and twitching; muscle contractions, cramps, and tetany; disorientation, restlessness, hypersensitivity to external stimuli, and parasthesias and facial rubbing; panting and hyperthermia; prolapse of the third eyelid; and arrhythmias and hypotension.

Hypocalcemia may be attributed to a variety of problems (Table 13-4). Hyperphosphatemia promotes hypocalcemia by calcium precipitation (mass action) and inhibition of calcitriol production. Severe hypomagnesemia and hypermagnesemia inhibit parathyroid hormone (PTH) release and action. Pancreatitis causes hypocalcemia by saponification of calcium and by other, poorly understood, mechanisms. Total calcium concentrations are decreased in hypoalbuminemia but the ionized calcium would be expected to remain fairly constant. Acidosis decreases the protein-bound portion (increases the ionized calcium). Alkalosis has the opposite effect. An increase in plasma free fatty acids (sepsis, severe pancreatitis, ketoacidosis, heparin anticoagulaiton, and intravenous lipid emulsions) increase the protein binding of calcium.

Calcium therapy must be implemented if there are any clinical signs of hypocalcemia. Therapy is also indicated prior to the development of clinical signs when the measured plasma calcium is very low, although there is no broad agreement as to when this should be considered. It seems appropriate to consider calcium therapy when the measured calcium is 20% below normal and to provide therapy when the measured calcium is 30% below normal. This would correspond to about 7.0 and 6.0 mg/dl for total calcium, respectively, and 0.9 and 0.75 mM/L for ionized calcium, respectively. There are many oral calcium and vitamin D preparations available for long-term treatment of hypocalcemic patients. The two common calcium concentrates available for intravenous use are 10% calcium gluconate (9.3 mg Ca/ml; 0.47 mEq/ml) and 10% calcium chloride (27.2 mg Ca/ml; 1.36 mEq/ML). Either form can be used, however calcium chloride can cause tissue necrosis if given undiluted perivascularly or subcutaneously. If the animal is in tetany or a hypotensive crisis, administer 1.0 ml of 10% calcium gluconate/kg intravenously over about one minute. Repeat as necessary to effect. If the animal is not in a crisis, or once the crisis is stabilized, continue with the calcium administration at a rate of 0.5 to 1.0 ml of 10% calcium gluconate/kg per hour. Individual requirements vary widely. It generally does not take more than a few hours to achieve normal blood calcium levels. A maintenance infusion of 0.25 ml 10% calcium gluconate (0.23 mg calcium/kg) per hour may be required to maintain blood calcium concentrations thereafter. Oral supplementation should be implemented, if necessary, as soon as possible.

Causes of hypocalcemia

• Lack of parathyroid hormone

-Primary hypoparathyroidism

-Acquired hypoparathyroidism

--Parathyroid gland dysfunction (surgical removal; trauma; neoplasia; radioiodine)

--Hypo/hypermagnesemia

• Hypovitaminosis D

-Lack of intake; malabsorption

-Liver/renal disease (impaired hydroxylation of vitamin D to calcitriol)

• Chelation

-Hyperphosphatemia (mass action effect)

-Citrate; EDTA; large-dose heparin

-Necrotizing pancreatitis

-Ethylene glycol poisoning

-EDTA or citrate or large-dose heparin anticoagulation of test blood sample

-Infusion of large amounts of citrate anticoagulated blood

• Other

-Alkalosis or bicarbonate therapy Eclampsia; Lymphangectasia; Dietary

-Hemodialysis with a low-calcium dialysates; Hypoalbuminemia;

-"Hungry bone syndromes" (after parathyroidectomy; osteoblastic malignancy)

Hypercalcemia

Hypercalcemia impairs the function of most cells in the body by decreasing threshold potential (less negative transmembrane potential) for excitable cells (making them less excitable and slows conduction), by increasing the contractile state of smooth and skeletal muscle, by increasing ATP utilization by cell membrane and endoplasmic reticulum membrane calcium pumps, by interfering with ATP production associated with the mitochondrial accumulation of the calcium. This is manifested clinically by obtundation, poor diastolic heart function, increased arteriolar vasomotor tone, impaired nephron concentrating ability, lethargy and muscle weakness, arrhythmias, muscle twitching, and seizures. Chronic hypercalcemia is also associated with gastric hyperacidity and vomiting, and calciuresis, urolithiasis, and renal failure

Causes of hypercalcemia

• Primary hyperparathyroidism

• Hypervitaminosis D (rodenticides)

• Humoral hypercalcemia of malignancy (PTH related protein)

-Lymphosarcoma, anal sac apocrine gland carcinoma, other carcinomas

• Hypoadrenocorticism

• Chronic renal failure

• Osteolysis

• Iatrogenic

• Granulomatous diseases (Blastomycosis, Histoplasmosis, Coccidiomycosis)

• Thiazide diuretics

The most common causes of hypercalcemia are hyperalbuminemia, hypoadrenocorticism, malignancy (lymphoma, anal sac apocrine gland adenocarcinoma, and other carcinomas), and chronic renal failure. Lymphoma and some adenocarcinomas secrete a PTH-like related protein which has the similar effects of increasing serum calcium concentrations. Neoplasias also release inflammatory mediators which enhance bone demineralization. Thiazides, unlike the other diuretics, may enhance renal calcium reabsorption.

The mainstay of hypercalcemia treatment is effective therapy of the underlying disease process. There is no absolute agreement with regard to when more aggressive therapy should be implemented, but one guideline is when the calcium x phosphorus product exceeds 60. Hypercalcemia should be treated with volume augmentation and saline diuresis. The latter can be augmented by furosemide. Thiazides should be avoided. Sodium bicarbonate therapy, notwithstanding alkalemia, will decrease the ionized calcium concentration. Corticosteroids may lower serum calcium if it is elevated due to neoplasia, hypoadrenocorticism, or granulomatous disease. Corticosteroids decrease intestinal resorption and increase renal excretion of calcium, and decrease bone demineralization. Life-threatening hypercalcemia could be treated with chelating agents such as sodium or potassium phosphate (0.25 to 0.5 mM/kg IV over 4 hours) , EDTA (50 mg/kg/hr IV to effect), sodium citrate, or calcium-channel blockers. Peritoneal or hemodialysis could also be used to remove calcium from the body. Calcitonin(4 units/kg intramuscular every 12 hours) and mithramycin (25 mg/kg over 4 hours every 2 - 7 days) inhibit bone reabsorption and could be used for longer term management of hypercalcemia .