Fluids / AB / Electrolytes Flashcards

Question

________ includes all osmoles in solution, whereas ________ refers solely to effective osmoles, which do not freely permeate most cell membranes.

Answer 1

Osmolarity Tonicity It is changes in tonicity that will drive fluid movement in or out of cells.

Answer 2

o Na+ and its associated anions (Cl-) are the predominant extracellular effective osmoles o K+ and its associated anions are the predominant intracellular effective osmoles.

Answer 3

o The Na+/K+-ATPase pumps on the cell membrane are the primary regulators of cell volume by maintaining an appropriate distribution of intracellular potassium and extracellular sodium. o Most sodium ions of the body stay extracellular because of these Na+/K+-ATPase pumps

Answer 4

o Starling’s forces (i.e., hydrostatic and colloid osmotic pressures [COP] in the intravascular and interstitial spaces). o Vascular endothelial permeability o They govern the magnitude of fluid filtration through the capillary into the interstitial compartment.

Answer 5

o Volume overload (e.g., pulmonary, peripheral tissue and other organ edema), inappropriate fluid shifts (e.g., cerebral edema as an example of intracellular overhydration), and electrolyte and acid-base derangements. o Large volumes of fluid therapy may lead to a coagulopathy secondary to hemodilution and functional disturbances of primary hemostasis (synthetic colloidal fluids). o Aggressive volume resuscitation may exacerbate hemorrhage in bleeding patients.

Answer 6

o They are fluids containing small solutes with molecular weights less than 500 g/mole (1 g/mole = 1 dalton [Da]). o The majority of solutes are electrolytes (<50 g/mole), which readily cross the capillary endothelium and equilibrate throughout the extracellular fluid compartment. There is a lag time of 20 to 30 minutes for electrolytes to distribute evenly in the extracellular fluid compartments (i.e., intravascular and interstitial fluid compartments). o The net result of fluid shifts (i.e., osmosis) is dictated by the relative tonicity between different fluid compartments.

Answer 7

Na and Cl Other small solutes such as glucose and lactate are readily metabolized; hence 5% dextrose in water is considered “free water” because it does not contain an effective osmole

Answer 8

o Based on their tonicity - isotonics, hypotonics and hypertonic

Answer 9

o The osmolarity and sodium concentration of isotonic fluids are similar to that of plasma and extracellular fluid. o Normal plasma osmolarity is 290 to 310 mOsm/L for dogs and 311 to 322 mOsm/L for cats, and isotonic fluids generally have an osmolality in the range of 270 to 310 mOsm/L. o These fluids are therefore useful for treatment of hypovolemic shock when rapid intravascular volume expansion is desired. o Strictly speaking, isotonic fluid does not cause significant fluid shifts between intracellular and extracellular fluid compartments in normal animals (tonicities of the intracellular and extracellular fluids are unchanged; therefore there is no net osmotic shift).

Answer 10

o Isotonic fluids are also commonly used for treating interstitial dehydration. o Normal or abnormal body fluid losses are generally hypotonic or isotonic in nature. o Although isotonic crystalloids are best suited for the treatment of dehydration secondary to isotonic fluid loss, they are commonly used to replace hypotonic loss as well. o Although excess electrolytes are typically excreted by the kidneys, patients with compromised renal function should have their electrolytes closely monitored. o Examples of isotonic fluids include P- Lyte 148, P-Lyte A, Normosol-R, LRS, and 0.9% NaCl. o 0.9% NaCl contains a much higher chloride concentration (154 mmol/L) than canine or feline plasma. It is useful for treating animals with a hypochloremic metabolic alkalosis, as in the case of pyloric obstruction. Conversely, patients with normal chloride concentration may develop a hyperchloremic metabolic acidosis when 0.9% saline is administered in large volumes.

Answer 11

o In comparison to ECF and plasma, the osmolarity and sodium concentration of hypotonic fluids are much lower (0.45% saline has an osmolarity of 154 mOsm/L with a sodium [and chloride] concentration of 77 mEq/L). o Five percent dextrose in free water is a unique isoosmotic solution (250 mOsm/L) with hypotonic effects because dextrose is rapidly metabolized and free water remains (tonicity of 0mOsm/L). o Sterile water with an osmolarity of 0 mOsm/L should never be administered directly into the vascular system because of the risk of intravascular hemolysis and endothelial damage. o Hypotonic fluids replenish free water deficits and are useful for treating animals with hypernatremia secondary to hypotonic fluid loss (although bolus therapy is contraindicated). o Hypotonic fluids distribute throughout both intracellular and extracellular fluid compartments, with less remaining extracellularly (both intravascular and interstitial space) in comparison to isotonic fluids. o The large volume of distribution and free water content make hypotonic fluid a safer choice for slowly treating animals that have a decreased ability to excrete excess sodium or tolerate an elevated intravascular volume (e.g., kidney and heart diseases, respectively). o Additionally, the low chloride content minimizes bromide loss in animals receiving potassium bromide therapy for seizure control. o Hypotonic fluids should never be used as bolus therapy for intravascular volume resuscitation. Not only are these fluids ineffective at expanding the intravascular volume, they may also lead to life- threatening cerebral edema. o A rapid intravenous administration of hypotonic fluids drops plasma and extracellular fluid osmolarity (mainly determined by sodium level) quickly; as a consequence, water shifts from the extracellular fluid space to the intracellular space. Frequent sodium level monitoring during hypotonic fluids administration is recommended.

Answer 12

o The high osmolarity and sodium concentration of hypertonic solutions, such as 7.5% saline, causes a free water shift (i.e., osmosis) from the intracellular space to the extracellular space, expanding the extracellular fluid volume by 3 to 5 times the volume administered. o Osmotic fluid shifts from the interstitial space into the intravascular space start immediately after intravenous administration of hypertonic solution, even sooner than the uniform distribution of the electrolytes throughout the extracellular space. o Free water from the intracellular fluid compartment then moves into the extracellular fluid compartment as the interstitial fluid osmolarity rises.

Answer 13

o Hypertonic saline ranging from 3% to 7.5% is used for the therapy of hypovolemic shock, intracranial hypertension, and severe hyponatremia. o It is often administered for patients with both hypovolemic shock and concerns for intracranial hypertension such as the head trauma patient. o Similar to isotonic and hypotonic crystalloids, the intravascular volume expansion effect of hypertonic saline is transient (<30 minutes) because of the redistribution of electrolytes (i.e., sodium and its associated anions) throughout the extravascular space. o The ensuing osmotic diuresis also facilitates excess sodium excretion. To prolong the intravascular volume–expanding effect of hypertonic saline, it is often combined with a colloidal solution.

Answer 14

o Hypertonic saline has several beneficial effects on the cardiovascular system beyond increasing vascular volume. It transiently improves cardiac output and tissue perfusion via arteriolar vasodilation (decreased afterload), volume loading (increased preload), reduced endothelial swelling, and a weak positive inotropic effect. o It is important that administration rates do not exceed 1 mL/kg/min because hypotension may result from central vasomotor center inhibition or peripheral vasomotor effects mediated by the acute hyperosmolarity (bradycardia and vasodilation). o Also has immune-modulatory effects including suppression of neutrophil respiratory burst activity and cytotoxic effects. The antiinflammatory effects of hypertonic saline may be especially advantageous in trauma patients. o Improves cerebral perfusion pressure in head trauma patients by augmenting mean arterial blood pressure and decreasing intracranial pressure. At equal osmolar dosages, similar osmotic effects are achieved with either hypertonic saline or mannitol to reduce cerebral edema.

Answer 15

o A dose of 4 ml/kg of 7.5% saline will expand intravascular volume by 12 to 16 ml/kg (a fraction of total shock dose), but the effect is transient secondary to the fluid redistribution to the interstitial space and osmotic diuresis that follows. o Therefore additional volumes of isotonic crystalloids, colloids, or blood products are required to stabilize a patient suffering from hypovolemic or distributive shock. o Hypernatremia is a potential side effect that prevents the safe use of repeated doses of hypertonic saline o Repeated administration of hyperosmotic solutions may lead to hemolysis and phlebitis if given into small peripheral veins.

Answer 16

o The pH of intravenous fluids is usually acidic; largely this is due to dissolved CO2 and the acidic nature of dextrose solutions. o This low pH does not influence the acid-base balance of patients because of the lack of titratable acidity. o Essentially, the total quantity of free H+ in an intravenous fluid is small and easily buffered in the body and should not be considered as relevant to the acid-base effects of fluid therapy. o Acetate, gluconate, and lactate are weak buffers included in some crystalloids such as Normosol-R, lactated Ringer’s solution, and Plasma-Lyte 148. Metabolism of these buffers consumes H+, yielding an alkalinizing effect. As such they are considered beneficial when treating patients with a metabolic acidosis.

Answer 17

LRS solution may be the ideal fluid for neonates because lactate is the preferred metabolic fuel in early life.

Answer 18

o The lactate anion found in crystalloids such as LRS does not contribute to metabolic acidosis; it can, however, cause falsely elevated lactate meter readings if it is not yet metabolized.

Answer 19

o Acetate is metabolized primarily in the skeletal muscle and most cells in the body metabolize gluconate. o Hypotension due to vasodilation is associated with rapid infusion of acetate and has been reported in humans and experimental dogs. This has led to concerns of use of acetate containing crystalloids for shock resuscitation.

Answer 20

o Most synthetic starch colloid solutions are hyperoncotic relative to plasma and polydiverse (i.e., contain a wide spectrum of molecular weights). o These solutions effectively increase and maintain intravascular COP; fluids are pulled into the vascular space because of the increased intravascular/ interstitial COP ratio. o Hydroxyethyl starch molecules are branched polymers of glucose derived from hydrolysis of amylopectin.

Answer 21

o Concentration in the solution o Molecular weight o Degree of hydroxyl substitutions by hydroxyethyl groups o Ratio of hydroxyethyl group substitutions at the C2 versus C6 position.

Answer 22

o Larger MW, higher degree of substitutions, and higher C2:C6 ratio o For example, VetStarch, a veterinary formulation of Voluven, is a 6% tetrastarch solution with a weight average MW of 130,000 Da, 4 hydroxyethyl group substitutions per 10 glucose molecules (designated as 130/0.4), and a C2:C6 ratio of 9:1. The molecular weight range of VetStarch and Voluven is 110,000 to 150,000 Da. o In comparison to Hextend (670/0.75,4:1), the half-life of VetStarch and Voluven is shorter (38h vs. 10h in healthy humans). A high cumulative dosage can also prolong the half-life of synthetic starch colloids because of a saturable degradation process. o Dextrans are another example of synthetic starch colloid solutions but are currently off the market, primarily because of their propensity to cause AKI and allergic reactions in humans.

Answer 23

o On the number of colloidal molecules. o Small starch colloid molecules (e.g., hetastarch < 50,000 Da) are filtered through the glomeruli and rapidly excreted, causing a transient osmotic diuresis. o Colloidal molecules in the urine increase urine viscosity and specific gravity measurement by the refractometer. Urine osmolality is a more accurate measure of urine concentration in animals receiving colloidal fluids. o Larger starch molecules are metabolized slowly to smaller molecules. Synthetic starch molecules are degraded by the reticuloendothelial system (i.e., liver, spleen, and lymph nodes). Also, amylase in the blood metabolizes hydroxyethyl starches. o If colloid molecules leak into the interstitial space, especially in patients with increased vascular permeability, they are returned to the circulation by the lymphatics or engulfed by macrophages. o Kidneys are the main route for excretion of synthetic starch colloids.

Answer 24

o Synthetic starch colloids interfere with the function of platelets, von Willebrand’s factor, and factor VIII, leading to a primary hemostatic coagulopathy and prolonged activated partial thromboplastin time, all of which are dose dependent. o Hetastarch solutions typically prolong bleeding times when administered at doses greater than 20 ml/kg/day. o The same characteristics of hydroxyethyl starches that enable a longer half-life also confer the greatest coagulopathic effects (higher molecular weight, degree of hydroxyethyl group substitution, and C2 : C6 ratio of hydroxyethyl group substitution). o Clinical bleeding is not typically observed with the available commercial hydroxyethyl starch solutions in stable, noncoagulopathic animals, even with doses greater than 40ml/kg/day; however, caution is advised when using higher doses in critically ill or coagulopathic animals. o LMW hydroxyethyl starch solutions may be preferable in patients with a higher risk of bleeding (e.g., surgical or coagulopathic patients) because of their decreased coagulopathic effects. o Allergic reaction to the synthetic starches is a possible side effect of synthetic colloids in humans but has not been reported in veterinary medicine. o Evidence for the increasing concern regarding AKI secondary to synthetic starch colloid use in the critically ill humans is accumulating and has led to their withdrawal from the market in some countries. o Decreased glomerular filtration, hypertonicity of glomerular filtrate, and direct hydroxyethyl starch deposits are thought to contribute to the renal toxicity of these products. o A direct association between hydroxyethyl starches and the occurrence of AKI has not been reported in VM; however, similar risks are possible in the critically ill animals.

Answer 25

o 66 - 69 kDa. Has a negative charge o Colloid osmotic pressure hepatocytes is what will stimulate its synthesis. o 30-40% intravascular / 60-70% extravascular, minimal amount intracellularly o Albumin contributes to a large portion of COP in animals (80%). Other essential physiologic functions of albumin involve wound healing, coagulation, and scavenging of free radicals. o Albumin serves as a carrier for multiple substrates, including hormones, bilirubin, fatty acids, divalent cations, toxins, and drugs. Additionally, albumin also exerts a weak buffer effect via binding of hydrogen ions.

Answer 26

o Several colloidal blood products are derived from canine or feline donors. o FFP provides all the clotting factors and plasma protein. o Plasma that remains at room temperature for > 8h or is stored frozen for > 1 year loses the labile clotting factors (FV and FVIII) and is then considered frozen plasma. o Frozen plasma provides plasma proteins and clotting factors II, VII, IX, and X. o Cryosupernatant is the top portion of partially thawed fresh plasma after a hard spin (5000× g for 7 minutes) and contains albumin, globulin, antithrombin, protein C, protein S, and clotting factors II, VII, IX, X, XI and XII. o The remaining portion is cryoprecipitate, which is rich in fibrinogen, fibronectin, factor VIII, and von Willebrand’s factor. o Fresh whole blood transfusion provides platelets and red blood cells in addition to plasma proteins and clotting factors.

Answer 27

1g/dL 40 to 50mL/Kg

Answer 28

o Pooled HSA has been administered to CI dogs to raise serum albumin and COP. Five percent (5 g/dl) HSA is isoosmolar and isooncotic, whereas the most commonly used 25% (25 g/dl) HSA exerts 5 times the osmolar and oncotic effects of 5% human albumin. o As expected, the high oncotic pressure of 25% albumin expands intravascular volume much more than the volume administered. Judicious dosing and close monitoring for volume overload are crucial for patient safety. o Human and canine albumin molecules share only 79% homology -> the xenogenic transfusion of HSA comes with the potential life-threatening risk of an immediate or delayed hypersensitivity reaction. Naturally occurring antibodies against HSA have also been documented in healthy dogs with no prior HSA transfusion. o Several retrospective studies have found that the rate of severe adverse reaction is rare when used once in critically ill animals.It is hypothesized that the immune system is compromised in severely ill animals and therefore unable to mount an immune response to the antigenic HSA. o Therefore HSA is reserved only for critically ill animals with severe hypoalbuminemia, after carefully weighing the benefit and risks of human albumin administration. o Because immunoglobulin G (IgG) formation is well documented in dogs after exposure to human albumin, repeated administration within the lifetime of a given animal is not advised. o Hypoalbuminemia is associated with poor clinical outcomes, but the effect of human albumin on mortality in small animals is currently unknown.

Answer 29

o Oxyglobin is the only veterinary FDA-approved HBOC for the treatment of canine anemia. It contains 13 g/dl of polymerized bovine hemoglobin that is ultrapurified and free of antigenic red blood cell stroma and is suspended in a modified LRS solution. o Has a P50 of 34 mm Hg, similar to that of canine and feline hemoglobin (P50 of canine and feline hemoglobin in red blood cells are 31.5 and 35.6 mm Hg, respectively). o Polymerization of bovine hemoglobin tetramers creates a more stable, larger molecule, which prolongs its half-life and eliminates renal toxicity associated with hemoglobin dimers (derived from rapid breakdown of individual hemoglobin tetramers). o Oxyglobin is a polydiverse colloidal solution with an average weight molecular weight of 200 kDa (molecular weight range of 64 to 500 kDa). It is isoosmotic (300 mOsm/kg) and hyperoncotic (COP of 43 mm Hg). The viscosity of Oxyglobin is low (<2 cP). o Increased preload, stroke volume, and cardiac output are observed after Oxyglobin administration. However, the hemodynamic effect of Oxyglobin is complicated by its NO scavenging effect. o NO has a vasodilatory effect. Peripheral vasoconstriction subsequent to the decrease in NO with Oxyglobin therapy may ironically compromise tissue perfusion and oxygen delivery. In addition, the local regulatory response to improved tissue oxygenation may also lead to peripheral vasoconstriction after Oxyglobin administration. o Blood typing and cross-matching are not necessary before Oxyglobin administration. Hematocrit is no longer a useful measure of blood carrying capacity and may actually decrease after Oxyglobin administration because of its dilutional effect. o The most concerning side effect of Oxyglobin is volume overload.

Answer 30

o The most prevalent cation in the ICF is potassium, with much smaller contributions made by magnesium and sodium. o The most prevalent anions in the ICF are phosphate and the polyanionic charges of the intracellular proteins.

Answer 31

o The primary cation in the ECF is sodium and the most prevalent anions are Cl– and HCO3– o The proteins in plasma and the interstitial space also contribute to the negative charges.

Answer 32

o Larger molecules ( >20,000Da) do not easily cross the vascular endothelial membrane and may attract small, charged particles, thus creating the colloid osmotic pressure (COP). o There are three main natural colloid particles: albumin, globulins, and fibrinogen.

Answer 33

The pressure of fluid within a compartment that pushes against a membrane

Answer 34

o In health, fluid distribution within the ECF is determined by the balance between forces that favor reabsorption of fluid into the vascular compartment (increased COP or decreased hydrostatic pressure) and those that favor filtration out of the vascular space (decreased COP or increased hydrostatic pressure). o Changes in the osmolality between any of the fluid compartments within the body will cause free water movement across the respective membrane.

Answer 35

o Isotonic fluid losses, as seen in animals with polyuric renal failure, vomiting, diarrhea, or bleeding, will lead to depletion of the ECF compartment and dehydration. o If severe ECF losses are not replaced, hypovolemia may become clinically apparent. o Because isotonic losses will not alter ECF osmolality, there will be no movement of water across the cell membrane and ICF volume will remain unchanged. o In order to replace the ECF deficit, isotonic crystalloids should be administered. However, if the animal has been drinking water to replace the isotonic fluid losses, hyponatremia may result.

Answer 36

o Hypotonic fluid losses, as seen with DI or excessive panting, will cause hypernatremia and an increase in ECF osmolality. o This leads to movement of water out of the ICF space. Consequently, there is a depletion of both the ICF and ECF compartments. o Isotonic fluid therapy may be sufficient if the hypernatremia is not severe, but in animals with significant hypotonic fluid losses, free water administration is indicated. o Care must be taken to lower serum Na slowly to avoid causing potentially life-threatening cerebral edema.

Answer 37

o Loss of hypertonic fluid occurs infrequently in small animals. o Excessive loss of solutes in the urine may occur with diseases such as hypoadrenocorticism but more commonly hyponatremia results from excessive free water intake or retention. o Hyponatremia caused by hypertonic fluid loss is often exacerbated by electrolyte losses combined with hypotonic fluid replacement (i.e., oral water intake). o If a hypertonic fluid loss does occur, a drop in ECF osmolality results and provides a gradient for water to move into the ICF compartment, leading to cell swelling. o Significant hyponatremia or hypoosmolality requires careful fluid therapy to avoid rapid (>0.5 mEq/L increase per hour) changes in sodium concentration and subsequent central pontine myelinolysis (also known as osmotic demyelination syndrome).

Answer 38

o Disease processes that cause an increase in vascular permeability may lead to high-protein fluid extravasation from the intravascular space. o This can lead to a decrease in intravascular volume, possibly associated with interstitial edema. Because this will not alter the osmolality of the ECF compartment, increased vascular permeability alone is not expected to alter the ICF volume. o Patient history, physical examination, and laboratory data can provide useful information concerning the route of fluid losses, timeline of these losses, food and water consumption, and current clinical status. This will guide formulation of an appropriate fluid therapy plan.

Answer 39

o Disease processes that cause an increase in vascular permeability may lead to high-protein fluid extravasation from the intravascular space. o This can lead to a decrease in intravascular volume, possibly associated with interstitial edema. Because this will not alter the osmolality of the ECF compartment, increased vascular permeability alone is not expected to alter the ICF volume. o Patient history, physical examination, and laboratory data can provide useful information concerning the route of fluid losses, timeline of these losses, food and water consumption, and current clinical status. This will guide formulation of an appropriate fluid therapy plan.

Answer 40

o Estimated dehydration o Maintenance needs o Anticipated ongoing losses

Answer 41

[Body weight (kg)×1000]×[percentage dehydration/100] = deficit (ml) + estimated ongoing losses (ml) + maintenance (ml) = amount to be given over next 4 to 24 hours

Answer 42

o ICF deficits lead to cerebral obtundation, hypernatremia, and hyperosmolality. ICF deficits alone will not cause clinical evidence of dehydration. o Interstitial volume deficits are typically associated with a decrease in skin turgor (increased skin tenting) and dry mucous membranes. Skin turgor provides only a rough estimate of dehydration, and severe emaciation or obesity can make this assessment difficult. Serial body weight measurements may also be a useful and more objective indicator of dehydration. o Intravascular volume deficits are commonly associated with compensatory vasoconstriction, pale mucous membranes, poor pulse quality, tachycardia, prolonged capillary refill time, and cold extremities. These symptoms are suggestive of poor tissue perfusion and require rapid intervention.

Answer 43

It takes into account the sensible and insensible ongoing fluid losses (feces, urine, panting, sweating)

Answer 44

o Daily maintenance fluid volume requirements have been shown to parallel RER; thus, calculations of RER are often used to estimate fluid requirements (1 kcal of energy = 1ml of water). o The resting energy requirement (RER) is the amount of energy (or water) needed to maintain homeostasis in the fed state in a thermoneutral environment and is equal to 70(BWkg)^0.75 -> this one more accurate for patients <2kg or >40kg o Additional commonly used formulas for calculating daily fluid needs are as follows: Formula 1: 30(BWkg) + 70/day Formula 2: 60(BWkg) + 140/day o Because there is less water in fat than in muscle, most calculations overestimate the maintenance needs of overweight patients.

Answer 45

o Ongoing fluid losses are estimated from an understanding of the underlying disease process and historical data. For example, when treating animals with GI losses, the approximate volume and frequency of vomiting and diarrhea is estimated. o Obviously this predicted volume may be inaccurate; it allows calculation of an initial fluid therapy plan, but close patient monitoring and reevaluation are imperative. If the estimate of ongoing fluid losses is significantly inaccurate, the fluid plan should be altered accordingly.

Answer 46

o Although SQ fluid administration can be effective in the management of fluid deficits, it is not adequate for the critically ill patient. o Fluid therapy should be administered via an intravenous or intraosseous catheter that is assessed regularly for evidence of phlebitis (if venous) or inadvertent subcutaneous fluid administration. o In general, fluids with an osmolality less than 600 mOsm/L can be given safely through a peripheral venous catheter; those with an osmolality greater than 700mOsm/L should be given through a central catheter to decrease the risk of phlebitis or thrombosis.

Answer 47

o Replacement fluids, also known as isotonic crystalloids, are electrolyte-containing fluids with a composition similar to that of the ECF. They have a similar osmolality as plasma (290 to 310 mOsm/L). They may also contain buffer compounds and dextrose. o Isotonic crystalloids are commonly used to expand the intravascular and interstitial spaces and maintain hydration. Additional electrolytes, such as potassium, may be added to maintenance or replacement fluids as needed for an individual patient.

Answer 48

o After infusion of isotonic crystalloids into the vascular space, the small electrolytes and water pass freely across the capillary vascular endothelium. These are extracellular-expanding fluids; 75% redistributes to the interstitial space, and only 25% remains in the vascular space after 30 minutes. o Although so-called replacement fluids are used commonly for maintenance of hydration, most animals are able to easily excrete the electrolyte constituents that are in excess of the body’s needs. This practice is common because most hospitalized animals have ongoing electrolyte losses and poor enteral intake, and it is much easier to hang one bag of isotonic crystalloids than two separate bags (one for replacement and one for maintenance).

Answer 49

o Isotonic crystalloids can cause harm, especially in critically ill animals. The interstitial fluid gain can lead to interstitial edema, pulmonary edema, and cerebral edema. Patients with a low COP, pulmonary contusions, cerebral trauma, fluid-unresponsive renal disease, or cardiac disease/failure are at highest risk for complications. o In addition, substantial hemodilution of blood constituents that are not found in the crystalloids can occur. Anemia, hypoproteinemia, electrolyte derangements, and hypocoagulability can occur after large-volume crystalloid administration.

Answer 50

o Animals with diabetic ketoacidosis or liver disease should not receive lactate-containing fluids because of their decreased ability to convert the lactate to bicarbonate in the liver. o Lactated Ringer’s solution may be preferred in very young animals because lactate is the preferred metabolic fuel in neonates with hypoglycemia. o Patients with a hypochloremic metabolic alkalosis will benefit from 0.9% sodium chloride because this is the highest chloride-containing fluid, but animals with a severe acidosis may benefit from an alkalinizing fluid containing lactate, acetate, or gluconate. o Animals with head trauma or increased intracranial pressure may benefit from 0.9% sodium chloride because this isotonic crystalloid is least likely to cause a decrease in osmolality that might promote water movement into the brain interstitium.

Answer 51

o Maintenance fluids refers to the volume of fluid and amount of electrolytes that must be consumed on a daily basis to keep the volume of total body water and electrolyte content within the normal range. o Obligate fluid losses are hypotonic and low in sodium but contain relatively more potassium than does the ECF. o Maintenance fluids are therefore hypotonic crystalloids that are low in sodium, chloride, and osmolality but high in potassium compared with normal plasma concentrations. o The inclusion of dextrose may make the fluid isoosmotic to plasma, but the dextrose is metabolized rapidly to carbon dioxide and water, so these fluids are still hypotonic in nature. o Maintenance-type fluids are distributed into all body fluid compartments and should never be administered as a rapid bolus because cerebral edema may result.

Answer 52

o In order to give free water (fluids with no electrolytes or buffers) IV without using a dangerously hypotonic fluid, sterile water is combined with 5% dextrose to yield an osmolality of 252 mOsm/kg (safe for intravenous administration). o This fluid is indicated in animals with a free water deficit (i.e., hypernatremia) or severe ongoing free water losses (e.g., diabetes insipidus). In order to safely lower the sodium concentration by 1 mEq/hr, a rate of 3.7 ml/ kg/h of free water is a good starting point and can be adjusted based on the patient’s response. o Alternatively, the patient’s free water deficit can be calculated by the formula: Free water deficit =([current[Na+]÷normal[Na+]]−1) × (0.6 × body weight in kg) o This formula will provide the total volume of free water to be replaced and can be administered as 5% dextrose in water over the number of hours calculated for safe reestablishment of normal plasma sodium concentration (Na+ change of no greater than 0.5 – 1.0 mEq/L/h). Close monitoring of electrolyte status is advised. o Dextrose 5% in water should never be administered as a rapid bolus because acutedecreases in osmolality will cause potentially fatal cerebral edema

Answer 53

TRUE The base solution is an isotonic crystalloid (e.g., 0.9% NaCl), and the colloidal particles are suspended within the crystalloid.

Answer 54

o Colloidal solutions contain large molecules (molecular weight > 10,000Da) that do not readily sieve across the vascular membrane. o These fluids are polydisperse (they contain molecules with a variety of molecular weights) and hyperoncotic to the normal animal and therefore cause the movement of fluid from the extravascular to the intravascular space.

Answer 55

40 ml/kg/day

Answer 56

Platelet function vWF FVIII An increase in the activated partial thromboplastin time (aPTT) may develop in animals that receive large amounts of synthetic colloid therapy, although the quantitative aPTT change is not predictive of clinical bleeding.

Answer 57

A 6% hydroxyethyl starch solution, with particles ranging from 10,000 to 1,000,000 Da in MW, a number average MW of 69,000Da, a mean average MW of 450,000Da, and a COP of 34mmHg in vitro.

Answer 58

A 6% tetrastarch solution, with particles ranging from 110,000 to 150,000 Daltons, a mean average molecular weight of 130,000 Daltons, and a COP of 40mmHg.

Answer 59

VetStarch Hetastarch

Answer 60

Used at a rate of 0.5 to 2 ml/kg/h in animals with acute decreases in COP or total protein levels.

Answer 61

o BW should be monitored daily (or more often if indicated). A physical examination should be performed at least twice daily to assess the animal’s mental status, skin turgor, heart rate and pulse quality, mucous membrane color, capillary refill time, extremity temperature, and respiratory rate and effort. o Serial lung auscultation should be performed to monitor for increased breath sounds, crackles or wheezes. o If an indwelling urinary catheter is present, urine output can be compared with fluid administered to help guide fluid therapy and prevent the administration of too much or too little fluid. Serum blood urea nitrogen and creatinine levels can be evaluated in con- junction with the urine specific gravity to determine whether there is prerenal or renal azotemia (or a combination of both). An increase in blood urea nitrogen and creatinine with an increase in USG would suggest that the animal is receiving insufficient fluid volume. o Lactate - inadequate tissue perfusion may result in an increase in blood lactate levels secondary to anaerobic metabolism. Serial lactate measurements may help guide fluid therapy as an indicator of tissue perfusion. Moderate to severely elevated lactate levels should alert the clinician that more aggressive treatment may be required. o If a central venous catheter is in place, central venous pressure monitoring may be used to help guide fluid therapy. o Additional monitoring techniques that might be helpful include arterial blood pressure; electrocardiogram; and repeated measurements of packed cell volume, total solids, blood glucose, electrolytes, lactate, and acid-base status. Pulmonary capillary wedge pressure monitoring, cardiac output monitoring, and mixed (or central) venous oxygen saturation measurements may be helpful in select patients.

Answer 62

o Clinical signs in animals receiving too much fluid include serous nasal discharge, chemosis, jugular venous distention, and interstitial pitting edema. o In the early stages of pulmonary edema, an increase in the respiratory rate will occur, followed by inspiratory crackles, wheezes, and dyspnea. o It is therefore of utmost importance to monitor the respiratory rate and effort of all patients receiving fluid therapy.

Answer 63

o In most animals, fluid therapy should not be discontinued abruptly, especially if high flow rates are being administered. o These animals may have renal medullary washout and therefore the urine-concentrating ability will be impaired for several days. This can lead to severe dehydration and hypovolemia in animals that are not drinking large amounts of water. o Ideally, intravenous fluid therapy should be decreased gradually over a 24h period. Some animals may require slower weaning protocols, especially those receiving high flow rates. o Owners should be informed that the animal may have increased water requirements for a few days after the discontinuation of intravenous fluid therapy.

Answer 64

4-6mL/kg/h assuming normal cardiac function + ongoing losses

Answer 65

Subglycocalyx space Contains about 2% of TBW

Answer 66

Because of the idiogenic osmoles that have developed in the brain

Answer 67

Brown port, it is the largest one

Answer 68

Causes vasoconstriction of afferent arteriole decreasing renal blood flow. This response can be magnified in hypovolemic patients.

Answer 69

LRS - 130mEq/L

Answer 70

Intrinsic primarily affected - aPTT

Answer 71

o Normal COP of albumin 20mmHg o Synthetic albumin 200mmHg - because it is also hypertonic, not only with the effects of high MW molecule.

Answer 72

Lactate clearance = (lactate initial − lactate delayed) / lactate initial × 100 (expressed as percentage).

Answer 73

TRUE Even sodium concentration changes within the reference interval have been associated with increased mortality risk.

Answer 74

o Osmolality is the concentration of osmoles in a mass of solvent. In biologic systems, osmolality is expressed as mOsm/kg of water and can be measured using an osmometer. o Osmolarity is the concentration of osmoles in a volume of solvent and in biologic systems is expressed as mOsm/L of water. o In physiologic systems there is no appreciable difference between osmolality and osmolarity, so the term osmolality os normally used.

Answer 75

o Every molecule dissolved in the total body water contributes to osmolality, regardless of size, weight, charge, or composition. o The most abundant osmoles in the extracellular fluid are sodium (and the accompanying anions chloride and bicarbonate), glucose, and urea. o Because they are the most plentiful, these molecules are the main determinants of plasma osmolality in healthy dogs and cats.

Answer 76

o Osmoles that do not cross the cell membrane freely are considered effective osmoles. o Osmoles that do cross freely are termed ineffective osmoles. o The water-permeable cell membrane is functionally impermeable to Na+,K+andglucose. As a result, Na,Kglucose are effective osmoles and they exert osmotic pressure across the cell membrane.

Answer 77

mOsm/kg = 2xNa + K + Glu / 18

Answer 78

o Is dictated by the osmotic pressure gradient. o Osmotic pressure causes water molecules from an area of lower osmolality (higher water concentration) to move to an area of higher osmolality (lower water concentration) until the osmolalities of the compartments are equal.

Answer 79

Hypothalamic osmoreceptors sense changes in plasma osmolality, and changes of only 2 to 3mOsm/kg induce compensatory mechanisms to return the plasma osmolality to its hypothalamic setpoint.

Answer 80

o ADH o Thirst

Answer 81

o ADH is a small peptide secreted by the posterior pituitary gland. o There are two major stimuli for ADH release: elevated plasma osmolality and decreased effective circulating volume. o Increased plasma osmolality causes shrinkage of a specialized group of cells in the hypothalamus called osmoreceptors. When their cell volume decreases, these hypothalamic osmoreceptors send impulses via neural afferents to the posterior pituitary, leading to ADH release. o When effective circulating volume is low, baroreceptor cells in the aortic arch and carotid bodies send neural impulses to the pituitary gland that stimulate ADH release. o In the absence of ADH, renal tubular collecting cells are relatively impermeable to water. When ADH activates the V2 receptor on the renal collecting tubular cell, aquaporin-2 molecules are inserted into the cell’s luminal membrane. o Aquaporins are channels that allow the movement of water into the renal tubular cell. Water molecules cross through these aquaporins into the hyperosmolar renal medulla down their osmotic gradient. o If the kidney is unable to generate a hyperosmolar renal medulla because of disease or diuretic administration, water will not be reabsorbed, even with high concentrations of ADH. o Circulating ADH concentration and ADH’s effect on the normal kidney are the primary physiologic determinants of free water retention and excretion.

Answer 82

o Hyperosmolality and decreased effective circulating volume also stimulate thirst. o The mechanisms by which hyperosmolality and hypovolemia stimulate thirst are similar to those that stimulate ADH release. o Thirst and the resultant water consumption are the main physiologic determinants of free water intake.

Answer 83

o Under normal physiologic conditions, the RAAAS monitors and fine tunes effective circulating volume, and the ADH system maintains normal plasma osmolality. o However, maintenance of effective circulating volume is always prioritized over maintenance of normal plasma osmolality. o Therefore patients with poor effective circulating volume will have increased thirst and ADH release regardless of their osmolality. The resultant increased free water intake (from drinking) and water retention (from ADH action at the level of the kidney) can lead to hyponatremia (and thus hypoosmolality) in patients with poor effective circulating volume. o An example of the defense of effective circulating volume at the expense of normal plasma osmolality is seen in patients with chronic congestive heart failure that present with hyponatremia.

Answer 84

o Plasma sodium concentration is different than, and independent of, total body sodium content. o Total body sodium content refers to the total number of sodium molecules in the body, regardless of the ratio of sodium to water. o Sodium content determines the hydration status of the animal. As it is used clinically, hydration is a misnomer, because findings such as skin tenting and moistness of the mucous membranes and conjunctival sac are determined by both the sodium content and the water that those sodium molecules hold in an animal’s interstitial space. o The Na/water ratio is independent of the total body Na content: patients may be normally hydrated, dehydrated, or overhydrated (normal, decreased, or increased total body sodium content) and have a normal plasma sodium concentration, hypernatremia, or hyponatremia.

Answer 85

o When patients have increased total body sodium, an increased quantity of fluid is held within the interstitial space and the animal appears overhydrated, regardless of the plasma sodium concentration. o Overhydrated patients may manifest a gelatinous subcutis; peripheral or ventral pitting edema; chemosis; or excessive serous nasal discharge.

Answer 86

o When patients have decreased total body sodium, a decreased quantity of fluid is held within the interstitial space and the animal appears dehydrated, regardless of the plasma sodium concentration. o Once a patient has lost 5% or more of its body weight in isotonic fluid (≥5% “dehydrated”), it may manifest decreased skin turgor, tacky or dry mucous membranes, decreased fluid in the conjunctival sac, or sunken eye position. Patients that are less than 5% dehydrated appear clinically normal. o Patients with dehydration can become hypovolemic as fluid shifts from the intravascular space into the interstitial space as a result of decreased interstitial hydrostatic pressure.

Answer 87

Plasma or serum sodium concentration above the reference interval.

Answer 88

Most dogs and cats with hypernatremia have excessive free water loss rather than increased sodium intake or retention.

Answer 89

o Normal animals can become severely hypernatremic if denied access to water for extended periods. o Animals with vomiting, diarrhea, or polyuria of low-sodium urine may also develop hypernatremia. o Hypernatremia can occur after administration of activated charcoal suspension containing a cathartic because the hypertonic cathartic draws electrolyte-free water into the GI tract. Osmotic diuresis with mannitol also causes an electrolyte-free water loss and thus can cause hypernatremia. o Diabetes insipidus (DI), a syndrome of inadequate release of or response to ADH, can cause hypernatremia. Animals with DI become severely hypernatremic when they do not drink water, because they cannot reabsorb free water in the renal collecting duct. Acute or critical illness can unmask previously undiagnosed DI. o A syndrome of hypodipsic hypernatremia has been reported in Miniature Schnauzers, one of which was diagnosed with congenital holoprosencephaly. This syndrome most likely is due to impaired osmoreceptor or thirst center function. o In other dog breeds and cats, hypodipsic hypernatremia has been associated with hypothalamic granulomatous meningoencephalitis, hydrocephalus,and other central nervous system (CNS) deformities and CNS lymphoma.

Answer 90

Severe hypernatremia can also occur with the introduction of large quantities of sodium in the form of hypertonic saline, sodium bicarbonate, sodium phosphate enemas, seawater, beef jerky, and saltflour dough mixtures

Answer 91

o Hypernatremia causes no specific clinical signs in many cases. o If it is severe (usually >180 mEq/L) or occurs rapidly, it may be associated with CNS signs such as obtundation, head pressing, seizures, coma, and death. o All cells that have Na+/K+-ATPase pumps shrink as a result of hypernatremia as water moves out of the cell down its osmotic gradient to the relatively hyperosmolar extracellular compartment, but neurons are clinically the least tolerant of this change in cell volume. Thus, neurologic signs are seen most commonly in patients with clinically significant hypernatremia. o Patients that develop hypernatremia slowly are often asymptomatic. o An experimental study found decreased myocardial contractility during injection of hypernatremic or hyperosmolar solutions in dogs (but hypertonic solutions increase CO by decreasing afterload - arteriolar vasodilation) o Hypernatremia has also been associated with hyperlipidemia, possibly a result of the inhibition of lipoprotein lipase.

Answer 92

o Hypernatremia causes free water to move out of the relatively hypoosmolar intracellular space into the hyperosmolar extracellular space, leading to decreased cell volume. o The brain has multiple ways to protect against and reverse neuronal water loss in cases of hypernatremia. In the early minutes to hours of a hyperosmolal state, as neuronal water is lost to the hypernatremic circulation, lowered interstitial hydraulic pressure draws fluid from the cerebrospinal fluid (CSF) into the brain interstitium. o As plasma osmolality rises, sodium and chloride also appear to move rapidly from the CSF into cerebral tissue, which helps minimize brain volume loss by increasing neuronal osmolality and thus drawing water back to the intracellular space. o These early fluid and ionic shifts appear to protect the brain from the magnitude of volume loss that would be expected for a given hyperosmolal state. o Additionally, within 24h, neurons begin to accumulate organic solutes to increase intracellular osmolality and help shift lost water back to the intracellular space. Accumulated organic solutes are called idiogenic osmoles, or osmolytes, and include molecules such as inositol, glutamine, and glutamate. o Generation of these idiogenic osmoles begins within a few hours of cell volume loss, but full compensation may take as long as 2 to 7 days. Restoration of neuronal cell volume is important for cellular function and is an important consideration during tx of hyperNa..

Answer 93

FALSE - patients with hyPERnatremia

Answer 94

o In patients with mild to moderate hypernatremia (Na+< 180 mEq/L), sodium concentration should be decreased no more rapidly than 1 mEq/L/hr. o In those with severe hypernatremia (Na+ ≥ 180 mEq/L), it should be decreased no more rapidly than 0.5 to 1 mEq/L/hr. o This slow decrease in plasma sodium concentration is important to prevent cellular swelling. Idiogenic osmoles are broken down slowly, so rapid drops in plasma sodium concentration (and thus plasma osmolality) cause free water to move back into the relatively hyperosmolar intracellular space and can lead to neuronal edema.

Answer 95

o The formula gives the total volume of free water that needs to be replaced. o This volume of free water, usually given as 5% dextrose in water, is infused over the number of hours calculated for safe reestablishment of normal plasma sodium concentration. o This rate of free water replacement may be inadequate in cases of ongoing free water loss, as seen with diuresis of electrolyte-free water in patients with DI or unregulated diabetes mellitus, but it is a safe starting point in most cases. o Plasma sodium concentration should be monitored no less often than every 4 hours to assess the adequacy of treatment, and CNS status should be monitored continuously for signs of obtundation, seizures, or other abnormalities. o The rate of free water supplementation should be adjusted as needed to ensure an appropriate drop in plasma sodium concentration, the goal being a drop of no more than 1mEq/hr and no clinical signs of cerebral edema. o Water may be supplemented intravenously (as 5% dextrose in water) or orally on an hourly schedule in animals that are alert, willing to drink, and not vomiting. o Free water replacement alone will not correct clinical dehydration or hypovolemia, because free water replacement does not provide the sodium required to correct these problems.

Answer 96

FALSE o Free water replacement in the hypernatremic patient is relatively safe, even in animals with cardiac or renal disease, because two thirds of the volume administered will enter the cells.

Answer 97

o Cerebral edema is the primary complication of therapy for hypernatremia. o Clinical signs of cerebral edema include obtundation, head pressing, coma, seizures, and other disorders of behavior or movement. If these signs develop during the treatment of hypernatremia, immediately stop the administration of any fluid that has a lower sodium concentration than the patient and disallow drinking. o The patient’s plasma sodium concentration should be measured to confirm that it is lower than it was when treatment was instituted. This is an important step because signs of worsening hypernatremia may be similar to those seen with cerebral edema. o If the plasma sodium concentration has decreased, even if it has dropped at less than 1mEq/L/hr, cerebral edema should be considered. o Cerebral edema is treated with a dose of mannitol at 0.5 to 1 g/kg intravenously (IV) over 20 to 30 minutes. Mannitol should be administered via a central vein if possible, but it may be diluted 1 : 1 in sterile water and given through a peripheral vein in an emergency situation. o If mannitol is not available, or if a single dose does not improve signs, consider a dose of 7.2% sodium chloride at 3 to 5 ml/ kg over 20 minutes. The administration method is similar to that used for mannitol. Hypertonic saline should not be administered as a rapid bolus because it can cause vasodilation.

Answer 98

The ratio of the amount of substance excreted relative to the filtered load Fex = Clearance / GFR Clearance = Ux x V / Px Normal for Na is <1%

Answer 99

Hyponatremia is defined as plasma or serum sodium concentration below the reference interval.

Answer 100

o Dogs and cats with hyponatremia almost always have free water retention in excess of sodium retention; they may have sodium loss as well. Generation of hyponatremia usually requires water intake in addition to decreased water excretion. o Decreased effective circulating volume o Hypoadrenocorticism o Diuretics o SIADH

Answer 101

o A common cause of hyponatremia in dogs and cats is decreased effective circulating volume, which causes ADH release and water intake in defense of intravascular volume and thus decreases plasma sodium concentration. o Possible causes include congestive heart failure, excessive gastrointestinal losses, excessive urinary losses, body cavity effusions, and edematous states. o Note that in the case of congestive heart failure, the patient has increased total body sodium (is “overhydrated”) because of activation of the RAAAS, yet is hyponatremic because of increased water retention in excess of sodium retention. o In the case of excessive salt and water losses from the GI or urinary tract, the patient is total body sodium depleted (is “dehydrated”) and is hyponatremic as a result of compensatory water drinking and retention to maintain effective circulating volume.

Answer 102

o Hypoadrenocorticism leads to hyponatremia through decreased sodium retention (caused by hypoaldosteronism) combined with increased water drinking and retention in defense of inadequate circulating volume. o Animals with atypical hypoadrenocorticism, whose aldosterone production and release are normal, may also develop hyponatremia, because low circulating cortisol concentration leads to increased ADH release and resultant water retention regardless of intravascular volume status.

Answer 103

o Thiazide or loop diuretic administration can lead to hyponatremia by induction of hypovolemia, hypokalemia that causes an intracellular shift of sodium in exchange for potassium, and the inability to dilute urine. o Renal failure can cause hyponatremia by similar mechanisms.

Answer 104

Syndrome of inappropriate ADH secretion (SIADH) causes hyponatremia through water retention in response to improperly high circulating concentrations of ADH. The syndrome has been reported in dogs and a cats and has many known causes in humans.

Answer 105

o Hyponatremia has been reported in animals with GI parasitism, infectious and inflammatory diseases, psychogenic polydipsia, and pregnancy. o It has also been reported in a puppy fed a low- sodium, home-prepared diet. o A syndrome of cerebral salt wasting (CSW) has been described in humans with CNS disease but has not been reported clinically in dogs or cats. o Patients with CSW have increased urinary sodium excretion in the face of intravascular volume depletion, which is inappropriate because a volume-depleted animal’s kidney should avidly conserve sodium. o The mechanisms— and even the syndrome’s actual existence—are unclear, but both brain natriuretic peptide (too much) and aldosterone (not enough) have been implicated. o Cerebral salt wasting is differentiated from SIADH by evaluation of hydration status: patients with CSW are clinically dehydrated because of a decrease in total body sodium content, and those with SIADH are usually adequately hydrated with excessive free water retention.

Answer 106

o Mild to moderate hyponatremia usually causes no specific clinical signs. If hyponatremia is severe (usually <120 mEq/L) or occurs rapidly, it may be associated with CNS signs such as obtundation, head pressing, seizures, coma, and death. o All cells that have Na+/K+- ATPase pumps swell as a result of hyponatremia as water moves into the relatively hyperosmolar cell from the hypoosmolar extracellular space, but brain cells are clinically the least tolerant of this change in cell volume. o An experimental study found increased myocardial contractility during injection of hyponatremic or hypoosmolar solutions in dogs. o Hyponatremia decreases renal concentrating ability in dogs.

Answer 107

o Hyponatremia causes free water to move into the relatively hyperosmolar cell from the hypoosmolar extracellular space, leading to increased cell volume. o Interstitial and intracellular CNS edema increases intracranial tissue hydrostatic pressure. This pressure enhances fluid movement into the cerebrospinal fluid, which flows out of the cranium, through the subarachnoid space and central canal of the spinal cord, and back into venous circulation. o Swollen neurons also expel solutes such as sodium, potassium, and organic osmolytes to decrease intracellular osmolality and encourage water loss to the extracellular fluid, returning cell volume toward normal. Ion expulsion occurs rapidly, but loss of organic osmolytes requires hours to days. o Therefore clinical signs associated with hyponatremia, and potential complications of management, are associated with both the magnitude and rate of sodium concentration change.

Answer 108

o Hyponatremia caused by decreased effective circulating volume is most often mild (Na+ ≥ 130 mEq/L) and usually self-corrects with appropriate treatment of the underlying disease. o Fluids with a sodium concentration less than that of the patient should be avoided. The plasma sodium concentration and the patient’s CNS status should be monitored regularly, but complications of hyponatremia or its treatment are unlikely to occur in these situations. o Patients with hyponatremia caused by congestive heart failure will likely remain hyponatremic as a result of diuretic administration, the resultant polydipsia, and ingestion of a low-sodium diet. o Asymptomatic patients that are edematous may be treated with water restriction alone, and those that are asymptomatic and normally hydrated or dehydrated may be treated with administration of fluids containing a higher sodium concentration than that of the patient.

Answer 109

o Symptomatic hyponatremia (acute or chronic) requires emergency therapy, although the best management approach is controversial. o These patients usually have a plasma sodium concentration of 120 mEq/L or lower. The aim is to raise the patient’s sodium concentration enough to resolve the clinical signs without causing complications. o One proactive method to achieve free water excretion is through administration of mannitol (0.5 to 1 g/kg IV over 20 to 30 minutes) along with furosemide (0.5 to 1 mg/kg IV) to ensure that electrolyte-free water is excreted along with the mannitol. o Fluid loss should be replaced with standard replacement intravenous fluids, unless the patient is overhydrated and the fluid loss desired. o The goal is to raise the plasma sodium concentration by no more than 10 mEq/L during the first 24 hours and by no more than 18 mEq/L during the first 48 hours of treatment, never to exceed the low end of the reference interval. The limit of 10 mEq/L during the first day of treatment is more important than the rate over a specific period within that day.

Answer 110

o When the patient’s sodium concentration cannot be raised adequately with diuretics, or if a different approach is desired, hypertonic saline can be administered. o In human medicine a common recommendation is to raise the symptomatic hyponatremic patient’s sodium concentration by 10% to 15% in the first day of treatment. o The rate of correction may be as high as 2 mEq/L/hr initially with a maximal increase of no more than 15 mEq/L in the first 24 hours. o The sodium deficit should first be calculated, using a target plasma sodium concentration of no more than 10% to 15% higher than the patient’s current sodium concentration. o The calculated sodium deficit determines the amount of hypertonic saline to be infused to raise plasma sodium no faster than 2 mEq/L/hr. The hypertonic saline is usually administered as a 3% solution. Co-administration of loop diuretics can further aid in excretion of free water and may be necessary in patients with concentrated urine.

Answer 111

When developing a treatment plan for dysnatremia, cases should be evaluated in the following categories: 1. Severe vs not severe: As a rule of thumb, severe dysnatremia is a sodium concentration of >15 mmol/L out of the normal range. Generally, strict guidelines for treatment of dysnatremia are only necessary for severe abnormalities. 2. Acute vs chronic: dysnatremia of < 48 hours duration is considered acute. If the duration of dysnatremia is unknown, it should be considered to be chronic (> 48 hours) for treatment purposes. 3. Symptomatic vs asymptomatic: Any neurologic abnormalities at the time of presentation in a patient with severe dysnatremia should be considered symptomatic. Neurologic signs reported include tremors, ataxia, seizures, obtundation and stupor 4. What is the underlying mechanism of the dysnatremia?

Answer 112

The concurrent change in osmolality. We can have hyponatremia with normal/increased plasma osmolality or with decreased plasma osmolality

Answer 113

o This mechanism of hyponatremia, also known as ‘dilutional hyponatremia’ occurs when osmotically active substances accumulate in the ECF causing water translocation from the ICF to the ECF. o This movement of water will dilute the ECF [Na]. The most common causes are hyperglycemia from diabetes mellitus or mannitol administration. o In diabetes mellitus there are correctional factors published to estimate ECF [Na] if the hyperglycemia is resolved. Correction factors of 1.6 to 2.0 mmol/L increase in serum [Na] for every 100 mg/dL decrease in blood glucose are commonly used, although it is recognized that the exact relationship between ECF glucose and sodium concentrations is not linear for different levels of hyperglycemia and may vary between disease states. o Treatment of hyperosmolar hyponatremia is focused on resolution of the primary disease. As ECF osmolality is not low, osmotic adaptation of brain cells does not occur and strict control of the rate of resolution of the hyponatremia is not necessary.

Answer 114

o Hypo-osmolar hyponatremia is always assumed to be due to a gain in free water as true sodium losing diseases almost never occur in clinical medicine. o The treatment plan for hypo-osmolar hyponatremia has two important components. An understanding of the disease mechanism by which the hyponatremia has developed will guide the nature of the treatment required and the duration and severity of the hyponatremia will guide the speed of resolution. o Assessment of the volume status of patients with hypo-osmolar hyponatremia will help determine the disease processes causing the hyponatremia.

Answer 115

o Hypovolemic hyponatremic can occur with gastrointestinal or third space losses with concurrent water ingestion or hypoadrenocorticism. o Hypovolemia is determined from the history, physical examination and other diagnostic tests such as point of care cardiac ultrasound and urine electrolytes. o When hyponatremia is due to hypovolemia, treatment of the hypovolemia will lead to normalization of plasma [Na]. o If large volume resuscitation is required, it is recommended to use a fluid that has a [Na] similar to the patient (within 10 mmol/L of the patient) to avoid sudden changes in plasma [Na]. o Plasma [Na] should be monitored frequently in these patients. It is challenging to regulate the speed at which the plasma [Na] will increase following volume resuscitation and if correction is too rapid, strategies such as administration of desmopressin +/- free water administration may be required.

Answer 116

o Normovolemic hyponatremia is due to a free water gain such as excessive water ingestion, iatrogenic administration of free water or syndrome of inappropriate antidiuretic hormone release. o Resolution of hyponatremia is often achieved by restriction of water intake. In order to avoid overly rapid correction in chronic cases, gradual reductions in free water intake should be performed over several days. o Administration of a loop diuretic will enhance free water excretion if urine osmolality is not already minimal. If free water restriction and diuretic administration will not resolve hyponatremia, hypertonic saline administration may be indicated.

Answer 117

Hypervolemic hyponatremic can occur with disease processes such as congestive heart failure and kidney failure. Treatment generally includes loop diuretics and addressing the primary disease process.

Answer 118

o Symptomatic hyponatremia – acute or chronic • 3% hypertonic saline 1 – 2 ml/kg IV over 10 to 60 minutes o Rate of administration depends on severity of clinical signs o Repeat until neurological signs resolve or plasma sodium increases by 4 to 6mmol/L • Once neurological signs are resolved, continue with care as appropriate dependent on chronicity of hyponatremia • The change in serum [Na] made in this acute period needs to be included in the total 24h allowance for [Na] change o Severe acute (<48 hours) hyponatremia • Correct plasma sodium concentration no faster than 8 – 10 mmol/L per 24h • Monitor plasma sodium every 2 – 4 hours until hyponatremia resolved • Provide specific treatment for underlying disease o Severe chronic (>48 hours) hyponatremia • Correct plasma sodium concentration at < 8 mmol/L per 24 hours • Monitor plasma sodium every 2 – 4 hours until hyponatremia resolved • Provide specific treatment for underlying disease

Answer 119

o In cases of excessive free water intake, water restriction will usually be successful in increasing plasma [Na]. If urine osmolality is not maximally dilute (< 100 mOsm/L), diuretic administration may also be of benefit. o In hypervolemic hyponatremia, loop diuretic administration such as furosemide in addition to water restriction is the cornerstone of treatment. ADH receptor antagonists have been used in human medicine in the treatment of hyponatremia. These drugs have been associated with overly rapid resolution of hyponatremia and are not recommended for treatment in severe hyponatremia at this time. o If free water restriction and diuretic administration will not resolve hyponatremia, hypertonic saline administration is indicated. In human medicine, 3% hypertonic saline is most commonly used for therapy. The dose is determined from the calculated sodium deficit and the time over which correction is desired. o These fluid plans for resolution of hyponatremia do not address maintenance fluid needs or the replacement of any deficits. Isotonic fluids (ideally a fluid with a [Na] within 10 mmol/L of the patient) should be provided as appropriate.

Answer 120

o A 10 kg dog with a normal plasma [Na] of 145 mmol/L has chronic, severe, asymptomatic hyponatremia with a [Na] of 120 mmol/L. o With a targeted rate of increase of 8 mmol/L per 24 hours, it would ideally take ~ 72 hours to correct the plasma [Na]. o The calculated sodium deficit is 150 mmol. Administration of 150 mmol over 72 hours would be a sodium administration rate of 2 mmol/hr. o 3% hypertonic saline has a [Na] of 0.5 mmol/ml, so the plan would be to give 4 ml/hr of 3% hypertonic saline for 72 hours and to monitor the plasma [Na] frequently. o The administration rate of hypertonic saline may need to be changed if the rate of change in sodium is too fast or slow. o If free water restriction and/or furosemide treatment is to be used, hypertonic saline therapy should be reduced or delayed until the impact of these interventions is assessed. Maintenance fluid therapy and other treatment should be given as indicated.

Answer 121

o Symptomatic hypernatremia – acute or chronic • Administer 5% dextrose solution, sterile water or oral water at a rate of 7-10 ml/kg/h for the initial 2-3 h or until the neurological signs are resolved. • Once neurological signs are resolved, continue with care as appropriate dependent on chronicity of hypernatremia • The change in serum [Na] made in this acute period needs to be included in the total 24 hour allowance for [Na] change o Severe acute (<48 hours) hypernatremia • Administer 5% dextrose solution (or other hypotonic solution including oral water) with a desired rate of change in [Na] of 1-2 mmol/L/h -> use calculation of free water deficit to determine rate or use an empiric rate of 3-6 ml/kg/h. • Monitor plasma sodium every 2 – 4 hours until hyponatremia resolved • Aim to resolve hypernatremia in < 24 hours • Provide specific treatment for underlying disease o Severe chronic (>48 hours) hypernatremia • Administer 5% dextrose solution (or other hypotonic solution including oral water) with a desired rate of change of [Na] of 0.5 mmol/L/hr o Use calculation of free water deficit to determine rate or use an empiric rate of 1-1.5 ml/kg/h • Monitor plasma sodium every 2 – 4 hours until hyponatremia resolved • Correct plasma sodium concentration no faster than 10-12 mmol/L per 24 hours • Provide specific treatment for underlying disease

Answer 122

o A 25 kg dog is found collapsed in its kennel. The owners report the dog was completely normal 24 hours earlier but is known to have diabetes insipidus which they have elected not to treat. The dog had been inadvertently confined without access to water for the last 24 hours. o On evaluation the dog is obtunded and has tremors. The serum [Na] is 183 mmol/L. The dog is assessed to have acute, severe symptomatic hypernatremia. o As the dog is symptomatic, an initial rapid decrease in [Na] is targeted with 10ml/kg/hr of D5W. After 3 hours the dog is awake and responsive and the tremors have resolved. o The [Na] is 171 mmol/L at this time and the dog is producing a moderate urine volume. The calculated free water deficit at this time is 2700ml. As it is acute, this deficit could be administered in <24 hours. o A rate of 150 ml/hr of free water would theoretically return the [Na] to normal in 18 hours. The challenge with this dog is that the untreated diabetes insipidus means there is an ongoing substantial free water loss in the urine. o One option is to give a greater volume of free water – enough to replace the volume lost in the urine in addition to replacing the deficit. Alternatively, a conservative dose of desmopressin could be used to increase renal water retention and help with resolution of the hypernatremia.

Answer 123

o The major complication of treatment for hyponatremia is osmotic demyelination syndrome (ODM). It is a result of neuronal shrinking away from the myelin sheath as water moves out of the neuron during correction of hyponatremia. o Clinical signs of ODM usually manifest many days after intervention, so the clinician cannot assume that a rapid change in plasma sodium concentration has been well tolerated simply because no CNS signs are present during initial treatment. o Clinical signs are paresis, ataxia, dysphagia, obtundation, and other neurologic signs in dogs. ODM lesions in dogs are commonly seen in the thalamus, rather than the pons as in humans. Patients with ODM may recover with intensive supportive treatment, although some do not. o Because the signs of ODM are delayed, it is rare for a patient to develop abnormal CNS signs during initial treatment of hyponatremia. If new neurologic signs develop during treatment, administration of any fluid that is hyperosmolar to the patient (mannitol, hypertonic or isotonic fluids) should be stopped. The patient’s plasma sodium concentration is checked to confirm that it has increased. o This is an important step, because signs of worsening hyponatremia may be similar to those seen with treatment. If the plasma sodium concentration is higher than it was at the initiation of treatment, even if the concentration has increased slowly, CNS damage should be considered. o Treatment of CNS signs caused by overly rapid correction of hyponatremia requires administration of free water. o Attempting to drop the sodium concentration to achieve no more than 10 mEq/L total correction during the first 24 hours and no more than 18 mEq/L total correction during the first 48 hours seems appropriate. The free water volume to administer can be calculated using the free water deficit equation, inserting the desired plasma sodium concentration in place of “normal [Na+].” o Decreasing sodium concentration in an already hyponatremic animal can be difficult unless the patient is treated with a loop diuretic such as furosemide to clamp urine osmolality, and water is replaced simultaneously.

Answer 124

o Pseudohyponatremia is the term used to describe hyponatremia in a patient with normal or elevated plasma osmolality. o The most common cause of pseudohyponatremia in dogs and cats is hyperglycemia. Glucose is an effective osmole, so when hyperglycemia is present, the excess glucose molecules cause an increase in ECF water, diluting sodium to a lower concentration. o For each 100 mg/dl increase in blood glucose, sodium concentration drops by approximately 1.6 mEq/L. o This effect is nonlinear, however; mild hyperglycemia leads to smaller changes in plasma sodium concentration than more severe hyperglycemia. o Pseudohyponatremia does not require specific treatment, and the sodium concentration will increase as the hyperglycemia resolves and water moves back into the cells. o The other common cause of pseudohyponatremia in dogs and cats is mannitol infusion with retention (rather than renal excretion) of mannitol molecules.

Answer 125

o Patients with moderate to severe abnormalities in sodium concentration ([Na+] < 130 or > 170) that require intravascular volume expansion should be resuscitated with a fluid that has a sodium concentration that matches that of the patient (±6 mEq/L). o Hyponatremic animals may be resuscitated with a balanced electrolyte solution containing 130 mEq/L sodium if appropriate, or with a maintenance solution that has sodium chloride added to bring the sodium concentration of the solution up to that of the patient. o Hypernatremic animals should be resuscitated with a balanced electrolyte solution with NaCl added in a quantity sufficient to bring the solution’s sodium concentration up to that of the animal. o The simplest way to add sodium to a bag of commercially available fluid is to add 23.4% NaCl to the bag. This product contains 4 mEq NaCl/ml solution, so it adds a significant quantity of sodium in a small volume.

Answer 126

o K is the predominant intracellular ion - 90-95% of total body K o K is strictly regulated by multiple mechanisms o K is responsible for resting membrane potential. HypoK hyperpolarizes the cell resulting in action potential duration prolongation, reduced repolarization reserve and a pro-arrhythmic state (early afterdepolarizations, delayed afterdepolarizations, and automaticity). HyperK depolarizes the cell resulting in action potential duration shortening, alterations in conduction velocity, and changes to the effective refractory period and a pro-arrhythmic state (bradycardia, atrial standstill, re-entrant tachyarrhythmias) o Also plays a role in: ▪ Hormone section and action ▪ Vascular tone ▪ Systemic blood pressure control ▪ Gastrointestinal motility ▪ Acid-Base homeostasis ▪ Glucose and insulin metabolism ▪ Renal concentrating mechanisms ▪ Fluid and electrolyte balance

Answer 127

o K is removed primarily by the kidney (90-95% in urine) - GI losses of K can occur, but most associated hypoK to GI loss is through RAAS activation o Kaliuresis is strongly tied to circadian rhythms - implications when measuring FE and timing emergency replacement o Despite meals containing large amounts of K, serum [K] is tightly regulated * Sequestration in liver and muscle occurs after meal - between meal fasting kaliuresis * Meals trigger increased kaliuresis (some mechanisms unknown)

Answer 128

o Serum [K] may be 0.5 mmol/L lower than plasma due to platelet release o Clinical signs associated with [K] < 3.5 mmol/L - Weakness, arrhythmias and polyuria occur [K] < 3.0 mmo/L - Rhabdomyolysis and respiratory muscle paralysis occur [K] < 2.0 mmol/L o Clinical signs vary depending on severity and acuity and don’t always correlate with serum [K] - Anorexia - Muscular weakness (generalized or mild) - Polyuria - Cats with severe can demonstrate flaccid ventroflexion of neck, forelimb hypermetria, and broad-based hindlimb stance - Ventricular and supraventricular tachyarrhythmias (possibly life-threatening)

Answer 129

o In life-threatening cases up to 1mEq/kg/h can be safely administered if monitoring carefully (continual ECG) for short periods 1-3 h before rechecking [K] o Supplementation rates > 0.25 mEq/kg/h usually required to increase [K] o Supplementation rates < 0.25 mEq/kg/h usually allow maintenance of current [K] ▪ Dependent on many factors so routine monitoring of [K] is critical ▪ Titration to effect is critical o Thorough mixing when added to IV fluid containers is critical to prevent ‘hotspots’ and dangerous K supplementation overdose o Oral supplementation is helpful when patient is eating or tolerating enteral feeding

Answer 130

Hyperkalemia occurs when the serum potassium concentration exceeds 5.5 mEq/L and is considered life threatening at serum concentrations greater than 7.5 mEq/L

Answer 131

Clinical signs vary depending on severity and acuity and don’t always correlate with serum [K] o Weakness o Cardiac conduction disturbances ▪ Bradycardia ▪ P-wave widening, prolonged P-Q interval, and decreased P amplitude until atrial standstill ▪ QRS widening and decreased amplitude ▪ Prolonged Q-T interval ▪ Tall tented T-waves ▪ May be observed when [K] > 6.5 mmol/L

Answer 132

Consider current medications for possible iatrogenic contributions (esp in compromised renal function) ▪ ACE inhibitors ▪ AGII receptor antagonists ▪ K sparing diuretics (spironolactone) ▪ NSAIDS ▪ Heparin ▪ Trimethoprim ▪ Cyclosporin or Tacrolimus ▪ NH4Cl ▪ Beta blockers o If azotemic concurrently consider ▪ Acute Kidney Injury (oligoanuria) ▪ Bladder rupture ▪ Urinary obstruction (bilateral ureteral, or urethral) ▪ Hypoadrenocorticism ▪ Pseudohypoadrenocorticism - severe acute GI losses (Trichuriasis, Salmonellosis), acute cavity effusions/Third space losses/Pyometra, late pregnancy

Answer 133

o Monitor ECG continuously o Consider calcium gluconate (0.5-1 mL/kg of 10% solution) slowly IV over 10 minutes (slow infusion if GI signs or bradycardia observed) to antagonize effects on conduction ▪ Caution if known hyperphosphatemia o Consider dextrose bolus (0.5-1 mL/kg of 50% solution) diluted or infused slowly into rapid IV fluid administration ▪ Consider administering regular insulin 0.1-0.25 U/kg IV in severe cases ▪ Monitor BG carefully-may need to supplement fluids with 2.5-5% dextrose to prevent hypoglycemia o Bicarbonate therapy is rarely indicated o Peritoneal dialysis, hemodialysis, or continuous renal replacement therapy will effectively treat hyperkalemia that is not responsive to medical management.

Answer 134

o They can be associated with hyperkalemia and a reduced sodium/potassium ratio (<27 : 1). o Chronic chylothorax managed by intermittent or continual drainage can also result in hyperkalemia and hyponatremia. o In addition, these abnormalities were reported in a dog with a lung lobe torsion, another with a neoplastic pleural effusion, and three at-term pregnant Greyhounds. o Although the mechanism of hyperkalemia in such patients is unclear, a reduction in effective circulating volume and subsequent reduced distal renal tubular flow could lead to deficient urinary potassium excretion.

Answer 135

o Potassium can be released from increased numbers of circulating blood cells, especially platelets and white blood cells, causing an artifactual increase in potassium termed pseudohyperkalemia. o This is seen primarily in animals with severe thrombocytosis or leukocytosis. o Pseudohyperkalemia can also be seen in Akita dogs (or other dogs of Japanese origin) secondary to in vitro hemolysis, because their erythrocytes have a functional sodium-potassium adenosine triphosphatase and, as such, have high intracellular potassium concentrations. This potassium is released and causes an artifactual hyperkalemia if hemolysis occurs in the serum blood tube. o Confirmation of pseudohyperkalemia can be made by determining the plasma potassium concentration (blood collected in a heparinized tube) because this should not be affected by changes in platelet or white blood cell numbers (unless the patient suffers from leukemia).

Answer 136

80% - decreases by 6 months approximately Always estimate fluids in lean body mass

Answer 137

o Larger molecules causing fluid shifts at the level of the glomerulus, decreasing GFR o Causes hypertonic filtrate and suspects that dehydrates the tubular cells. o This molecules can deposit into the renal cells and cause direct damage. o Cause increase of RRT in CI human patients

Answer 138

o Ionized (free) o Protein bound o Complexed (calcium bound to phosphate, bicarbonate, lactate, citrate, oxalate)

Answer 139

Total calcium routinely measured on serum automated biochemical analyzers measures all three types of calcium - ionized, protein bound and complexed.

Answer 140

The ionized form of calcium is the biologically active form in the body and is considered the most important indicator of functional calcium levels.

Answer 141

o Calcium regulation is a complex process involving primarily parathyroid hormone (PTH), vitamin D metabolites, and calcitonin. o These calcium regulatory hormones exert most of their effects on the intestine, kidney, and bone.

Answer 142

o PTH is synthesized and secreted by the chief cells of the parathyroid gland in response to hypocalcemia or low calcitriol levels (also known as 1,25(OH)2D3, the principal active vitamin D metabolite). o PTH is synthesized and secreted constantly at low rates to maintain serum ionized calcium levels within a narrow range in healthy animals. o PTH secretion is normally inhibited by increased serum ionized calcium levels, as well as by increased concentrations of circulating calcitriol. o The principal action of PTH is to increase blood calcium levels through increased tubular reabsorption of calcium, increased osteoclastic bone resorption, and increased production of calcitriol.

Answer 143

o Vitamin D and its metabolites also play a central role in calcium homeostasis. o Dogs and cats, unlike humans, photosynthesize vitamin D inefficiently in their skin and therefore depend on vitamin D in their diet. o After ingestion and uptake, vitamin D is first hydroxylated in the liver to 25(OH)D3 (calcidiol), and then it is further hydroxylated to calcitriol by the proximal tubular cells of the kidney. o This final hydroxylation by the 1α-hydroxylase enzyme system to form active calcitriol is under tight regulation and is influenced primarily by serum PTH, calcitriol, phosphorus, ionized calcium, and fibroblast growth factor 23 (FGF-23) concentrations. o Decreased levels of phosphorus, calcitriol, and calcium promote calcitriol synthesis, and increased levels of these substances all cause a decrease in calcitriol synthesis. Increased PTH has a potent effect to enhance calcitriol synthesis, whereas FGF-23 inhibits the synthesis of calcitriol.

Answer 144

o Calcitriol primarily acts on the intestine, bone, kidney, and parathyroid gland. o In the intestine, calcitriol enhances the absorption of calcium and phosphate at the level of the enterocyte. o In the bone, calcitriol promotes bone formation and mineralization by regulation of proteins produced by osteoblasts. In addition, calcitriol is also necessary for normal bone resorption because of its effect on osteoclast differentiation. o In the kidney, calcitriol acts to inhibit the 1α-hydroxylase enzyme system, as well as promote calcium and phosphorus reabsorption from the glomerular filtrate. o In the parathyroid gland, calcitriol acts to inhibit the synthesis of PTH.

Answer 145

o Although minor when compared with the effects of PTH and vitamin D metabolites, calcitonin also plays a role in calcium homeostasis. o It is produced by the parafollicular C cells in the thyroid gland in response to an increased concentration of calcium after a calcium- rich meal and also during hypercalcemia. o Calcitonin acts mostly on the bone to inhibit osteoclastic bone resorption activity but also decreases renal tubular reabsorption of calcium.

Answer 146

o The patient should be fasted before collection if possible to minimize postprandial increases in calcium. o Both serum and heparinized plasma samples can be used. When plasma samples are used, certain anticoagulants such as oxalate, citrate, and ethylenediamine- tetraacetic acid should not be used because they can dramatically lower calcium levels when measured in the laboratory. o When measuring ionized calcium, serum is preferred over whole or heparinized blood because of less variation in results. In addition, anaerobic samples are preferred for ionized calcium measurement because pH can alter the concentration. o In aerobic conditions, CO2 can be lost, thus raising the pH in the sample. o An alkalotic pH may increase the binding of calcium to protein, especially albumin, in the sample and therefore artificially decrease the amount of ionized calcium in the sample. o Aerobic samples can be used with reasonable diagnostic accuracy for ionized calcium measurement when sent to a referral laboratory, but species-specific correction formulas are needed that correct the sample pH to 7.40. o Handheld point-of-care analyzers consistently report ionized calcium values that are less than those from bench machines; this error increases with the magnitude of the calcium being measured.

Answer 147

o The calcium status of most animals is usually obtained first via measurement of total calcium. o However, this parameter often does not reflect the ionized calcium concentration of the diseased patient, especially in critically ill animals. o When attempts are made to predict ionized calcium concentrations in the cat based on total calcium measurements, hypercalcemia and normocalcemia are often underestimated, whereas hypocalcemia is often overestimated. o In dogs, the opposite appears to be true; the frequency of hypercalcemia and normocalcemia is overestimated and hypocalcemia underestimated. o In dogs with chronic renal failure the magnitude of error greatly increases, with hypercalcemia being overdiagnosed. o Therefore for accurate assessment of patient calcium status, measurement of ionized calcium is recommended. So-called correction formulas that are used to predict ionized calcium status from total serum calcium are quite inaccurate.

Answer 148

o Clinical signs associated with hypercalcemia loosely parallel the severity of the calcium elevation. o Common signs include PU/PD (dogs, not cats), anorexia, constipation, lethargy, and weakness. Severely affected animals may display ataxia, obtundation, listlessness, muscle twitching, seizures, or coma. o Bradycardia may be detected on physical examination, and ECG monitoring may reveal a prolonged PR interval, widened QRS complex, shortened QT interval, shortened or absent ST segment, and a widened T wave. Bradyarrhythmias may progress to complete heart block, asystole, and cardiac arrest in severely affected animals. o Other abnormalities may also be secondary to the underlying disease process causing the hypercalcemia.

Answer 149

o A diagnosis of hypercalcemia is confirmed with an ionized calcium measurement greater than 6 mg/dl or 1.5mmol/L in the dog or greater than 5.7 mg/dl or 1.4mmol/L in the cat. o The increase in ionized calcium typically parallels the increase in total serum calcium except in animals with renal failure, in which the increase in total calcium is caused by calcium binding with citrate, phosphate, or bicarbonate. o In cats, hypercalcemia is more commonly discovered when ionized calcium is measured compared with the total calcium measurement in the same cat.

Answer 150

o A thorough physical examination should be repeated. o The clinician should palpate the anal sacs (dogs) and peripheral lymph nodes for any enlargement, perform a fundic examination (e.g., systemic disease, mycoses, neoplasia), and do a thorough evaluation for any masses that may have been missed on initial examination (e.g., mammary tumors). o Further diagnostic maneuvers should be tailored to the individual patient based on clinical signs, physical examination findings, initial laboratory testing, and suspected etiology, but may include a complete blood cell count, chemistry panel, urinalysis, imaging (thoracic radiographs, abdominal radiographs, abdominal ultrasonography, parathyroid ultrasonography), FNA with cytologic evaluation of any masses found, PTH measurement, PTH-related protein measurement, calcidiol measurement, calcitriol measurement, bone biopsy, and bone marrow aspiration.

Answer 151

o Neoplasia associated hypercalcemia (specifically lymphoma) o Followed by renal failure, hyperparathyroidism, and hypoadrenocorticism. o In cats, neoplasia is thought to be the third most common cause of hypercalcemia behind idiopathic hypercalcemia and renal failure.

Answer 152

o There is no absolute calcium value that should serve as a guide for initiating aggressive treatment. o Intervention should be guided by multiple factors, including the magnitude of hyperCa, rate of development, stable or progressive disease, clinical signs associated with hyperCa, organ dysfunction (renal, cardiac, CNS), clinical condition of the patient, and suspected etiology of the hyperCa.

Answer 153

Evaluation of phosphorus concentrations may help in guiding therapy, because a calcium- phosphorus product greater than 60 represents increased risk for soft tissue mineralization.

Answer 154

o It is 0.9% sodium chloride because the additional sodium ions provide competition for renal tubular calcium reabsorption, resulting in enhanced calciuria. o In addition, 0.9% sodium chloride is calcium free, thus decreasing the calcium load on the body. o Intravenous fluid therapy should be used to correct dehydration over 4 to 6 hours (if stable) and then given at rates of at least 1.5 to 2 times maintenance. o Potassium supplementation is often needed with this fluid protocol (potassium 5 to 40 mEq/L) depending on serum potassium concentrations. o Judicious fluid therapy should be used in patients withcardiac disease or hypertension, because volume overload and pulmonary congestion may easily occur.

Answer 155

o Furosemide enhances urinary calcium loss but should not be used in volume-depleted animals. o Suggested dosages of furosemide are 1 to 2 mg/kg IV, SC, or PO q6-12h. o A constant rate infusion (CRI) of 0.2 to 1 mg/kg/hr may occasionally be needed for several hours during a hypercalcemic crisis. o Meticulous attention to fluid balance is essential when this method is used to avoid serious volume contraction. o It is beneficial to place a urinary catheter in order to match the amount of fluid administered with the amount of urinary losses and ensure adequate volume replacement during aggressive diuresis.

Answer 156

o Glucocorticoids lead to reduced bone resorption, decreased intestinal calcium absorption, and increased renal calcium excretion. o The magnitude of decline with therapy depends on the cause of the hypercalcemia. o Dexamethasone often is given at dosages of 0.1 to 0.22 mg/kg SC or IV q12h, or prednisone at dosages of 1 to 2.2 mg/kg PO, SC, or IV q12h. o However, in patients that have no definitive diagnosis for the hypercalcemia, calcitonin therapy should be considered instead of glucocorticosteroids because glucocorticosteroids may interfere with obtaining an accurate cytologic or histopathologic diagnosis as a result of cytolytic effects on lymphoid and plasma cells (e.g., lymphosarcoma, myeloma).

Answer 157

o Calcitonin acts to decrease serum calcium concentrations mostly by reducing the activity and formation of osteoclasts. o Calcitonin- salmon can be used at a dosage of 4 to 6 IU/kg SC q8-12h. o Vomiting may occur after several days of administration in dogs.

Answer 158

o Sodium bicarbonate can also be considered for crisis therapy because it decreases the ionized and total calcium; effects on the bound fractions of calcium have not been examined in this situation. o Sodium bicarbonate is given at a dosage of 1 mEq/kg IV as a slow bolus (up to 4 mEq/ kg total dose) when patients are at risk for death. o Acid-base status should be monitored closely to avoid inducing alkalemia or other complications of bicarbonate therapy (i.e., paradoxical cerebral acidosis, hypernatremia, hypokalemia).

Answer 159

o They decrease osteoclastic activity, thus decreasing bone resorption. o Bisphosphonates can take 1 to 3 days to maximally inhibit bone resorption, so they are not considered drugs of choice for acute or crisis therapy. o Pamidronate has been the most commonly used bisphosphonate in veterinary medicine for management of hypercalcemia; zoledronate is more potent than pamidronate and can be considered for use in selected patients. o Pamidronate can be given IV at dosages of 1.3 to 2 mg/kg in 150 ml 0.9% saline as a 2-hour to 4-hour infusion. This dose can be repeated in 1 week, if needed, but the salutary effect may last for 1 month in some instances. o Crisis management for idiopathic hypercalcemia in cats is almost never needed because of the insidious development of hypercalcemia. Oral alendronate starting at 1 to 3 mg/kg/wk has been used to treat it. This medication may provide more long-term control compared with other proposed treatments. o Oral alendronate is not as effective as intravenous bisphosphonate therapy in the acute setting. Oral bisphosphonates can cause esophageal irritation and have been reported to cause abdominal discomfort, nausea, and vomiting in humans.

Answer 160

o Calcimimetics belong to a new class of drugs that will likely have future use in veterinary medicine to treat some cases of hypercalcemia in which the underlying cause cannot be treated adequately by other means (tertiary hyperparathyroidism, primary hyperparathy- roidism caused by carcinoma). o These drugs activate the calcium sensing receptor and thus decrease PTH secretion. Cinacalcet has been marketed for use in humans to treat renal secondary hyperparathyroidism and nonsurgical primary hyperparathyroidism.

Answer 161

The prevalence of ionized hypocalcemia was 31% in sick dogs and 27% in cats.

Answer 162

< 6.5mg/dL < 4mg/dL < 1mmol/L

Answer 163

Severely affected animals may have decreased inotropy and chronotropy (bradycardia), and ECG abnormalities may include a prolonged QT interval (because of prolonged ST segment), deep, wide T waves, or atrioventricular block.

Answer 164

o A total calcium concentration less than 8 mg/dl in dogs and less than 7 mg/dl in cats. o When hypocalcemia is diagnosed via total calcium concentrations, it should always be confirmed with an ionized calcium measurement. o Using ionized calcium concentrations, hypocalcemia is defined as less than 5 mg/dl (1.25 mmol/L) in dogs and less than 4.5 mg/dl (1.1 mmol/L) in cats.

Answer 165

o The most common cause of a total serum hypocalcemia is hypoalbuminemia. However, the hypocalcemia associated with this is usually mild and typically no clinical signs result. o Renal dysfunction appears to be the second most common cause of hypocalcemia in dogs. o Primary hypoparathyroidism is the one condition that will require long-term calcium-specific treatment. If the serum phosphorus level is above the reference range at the same time that hypocalcemia is discovered, the most likely diagnoses to rule out include renal dysfunction, pancreatitis (with or without prerenal azotemia), excessive phosphorous intake, and primary hypoparathyroidism.

Answer 166

o Myocardial failure and respiratory arrest. o This may be particularly important in dogs with sepsis because the presence of ionized hypocalcemia has been shown to be a negative prognostic indicator. o Septic cats also have a high prevalence of ionized hypocalcemia; failure to normalize during hospitalization is associated with a longer length of hospitalization and ICU stay.

Answer 167

o Hypermagnesemia and hypomagnesemia can impair the secretion of PTH, and PTH actions on its receptor, so measurement of serum magnesium (preferably ionized magnesium) is important, especially in animals with refractory hypocalcemia.

Answer 168

o Ionized hypocalcemia, low serum 25-hydroxyvitamin D (25[OH] D) concentrations, and elevated PTH serum concentrations have been reported in dogs with PLE. o Many of these animals often undergo anesthetic procedures for diagnostic purposes (e.g., intestinal biopsy); therefore it may be warranted to treat ionized hypocalcemia, if present, because tachycardia, ECG alterations (i.e., prolonged QT interval), refractory hypotension, and respiratory arrest are all possible complications of ionized hypocalcemia.

Answer 169

FALSE o If the patient is stable, no clinical signs referable to hypocalcemia are documented, and the ionized calcium is not progressively decreasing, then it is reasonable to consider not treating these patients. o Patients with a severe decrease in ionized calcium concentration warrant calcium-specific treatment regardless of clinical signs. o Therapy may also be initiated in an asymptomaticpatient with moderate progressive ionized hypocalcemia to prevent the development of signs. o Patients with clinical signs attributed to hypocalcemia clearly should receive calcium-specific rescue therapy.

Answer 170

o It can be divided into acute and subacute to long term. o Attempts should always be made to treat the primary disease causing the disorder. o Most cases of hypocalcemia do not require long-term therapy, with hypoparathyroidism being the exception. o Many cases will require acute treatment, especially those with tetany, seizures, or muscle fasciculations.

Answer 171

o For acute therapy, calcium should be administered intravenously to effect over a 10- to 20-minute period. o Calcium gluconate and calcium chloride are both available for treatment, but calcium gluconate is preferred because it is not irritating if injected perivascularly (unlike calcium chloride). o Calcium salts should NEVER be given subcutaneously because they can cause skin necrosis and abscess formation severe enough to warrant euthanasia, even when diluted calcium preparations are administered. o Calcium gluconate (10% solution, calcium 9.3 mg/ml) can be given at dosages of 0.5 to 1.5ml/kg IV slowly to effect. o Heart rate and ECG should be monitored closely during administration to look for bradycardia; pro- longed PR interval; widened QRS complex; shortened QT interval; elevated, shortened, or absent ST segment; and widened T wave, all of which may indicate cardiac toxicity. o It is important to note that it may take up to 30 to 60 minutes for all clinical signs to resolve after correction of hypocalcemia, and some behavioral changes and panting may persist during this time.

Answer 172

o For subacute management, the initial bolus of calcium salts often needs to be followed with a CRI of calcium, especially if the hypocalcemia is expected to persist. o A CRI of elemental calcium can be delivered at a rate of 1 to 3 mg/kg/hr IV based on the severity of hypocalcemia to maintain normal calcium levels until oral calcium administration and or vitamin D metabolites can be used to control serum calcium concentrations. o Vitamin D metabolites should also be started early if the hypocalcemia is expected to persist, because it may take several days for intestinal calcium transport to be maximized. o Calcitriol is the preferred active vitamin D metabolite because it has a quick onset of action, short plasma half-life, and relatively short biologic effect half-life (important if overshoot hypercalcemia occurs). o Calcitriol is dosed at 20 to 30 ng/kg q24h PO divided twice a day for 3 to 4 days for induction, then 5 to 15 ng/kg q24h divided twice a day for maintenance therapy, and titrated to the desired level of serum calcium concentration.

Answer 173

o For long-term therapy (e.g., primary hypoparathyroidism), oral calcium usually is needed to control serum calcium levels. o It should be noted, however, that the goal of therapy with hypoparathyroidism is not to return calcium levels completely to normal, because this can have deleterious effects (hypercalciuria despite normocalcemia in the absence of basal effects that PTH normally has on renal tubules). o One should aim to control signs and correct calcium levels to just below normal. o Many forms of oral calcium are available (calcium carbonate, calcium lactate, calcium chloride, calcium gluconate) and all are dosed at 25 to 50 mg/kg q24h (divided and given twice a day). o Calcium carbonate is the most common form of calcium used and is generally well tolerated. Calcitriol can also be used.

Answer 174

o A relatively new class of drugs that antagonize the calcium-sensing receptor and thus stimulate PTH secretion. o They may have future use in VM to treat some cases of hypocalcemia that are refractory to current therapies. o Calcilytics are currently being investigated for their use in humans to treat osteoporosis and autosomal dominant hypocalcemia (familial hypercalciuric hypocalcemia).

Answer 175

Dogs - HARDONS neoplasia > primary hyperparathyroidism > CKD > hypoadrenocorticism ▪ H- hyperparathyroidism ▪ A- Addison’s ▪ R- Renal ▪ D- Vitamin D intoxication ▪ O- Osseus ▪ N- Neoplasia ▪ S- Spurious Cats - HARDIONS ▪ idiopathic > CKD > neoplasia ▪ I- Idiopathic

Answer 176

• Reported in 16% of dogs • Alkalosis and lactatemia can alter fractions of bound/complexed and ionized Ca • In patients with unknown causes for hypocalcemia. Speculation that may play a role: ▪ Vit D deficiency/resistance ▪ Acquired or relative hypoparathyroidism ▪ Hypomagnesemia • Difficult to determine if hypoCa is cause of poor outcome or a marker of illness severity • Some have speculated that critically ill patients with hypocalcemia should be treated ▪ Pros - Improved cardiovascular function ▪ Cons - Associated intracellular calcium induced injury

Answer 177

o Chloride is the most important extracellular anion and contributes approximately 70% of the total body anions. o It has many important functions in the body including contributions to body fluid osmolality, electroneutrality and electrical activity in neuromuscular cells. o Chloride channels exist in all cell types and the importance of chloride in normal physiology is highlighted by the impact of defects in chloride channels in diseases such as cystic fibrosis.

Answer 178

o Chloride concentration is mainly regulated by the kidneys and the gastrointestinal tract. o Chloride is freely filtered at the glomerulus and approximately 60-70% is reabsorbed in the proximal tubule in association with sodium and water reabsorption. o 15-25% of filtered chloride is reabsorbed in the thick ascending limb of the loop of Henle with the Na-K-2Cl pump. o The macula densa also has the Na-K-2Cl pump on the apical membrane and tubular chloride concentration is an important part of tubuloglomerular feedback and subsequent RAAAS activation. o In the distal tubule, the handling of chloride is complex and largely determined by potassium and acid-base balance. o In the gastrointestinal tract, significant quantities of chloride are secreted by gastric parietal cells in the production of hydrochloric acid for digestion. o Chloride is both reabsorbed and secreted in the intestinal tract where it plays an important role in regulating fluid secretion.

Answer 179

o The normal concentration of serum chloride in dogs is approximately 110 mmol/L and approximately 120 mmol/L in cats. o Venous samples have a chloride concentration of 3-4 mmol/L lower than arterial samples. o This is a result of chloride-bicarbonate exchange across the red blood cell membrane (known as the Hamburger shift). o In venous blood, CO2 diffuses into the plasma and then into the red blood cell cytoplasm. There CO2 is converted to bicarbonate with the aid of carbonic anhydrase. o Bicarbonate then leaves the red blood cell in exchange for chloride, resulting in a lower venous chloride concentration.

Answer 180

o Chloride concentration can change due to absolute changes in the quantity of chloride in the extracellular fluid or due to changes in the quantity of water in the system. o Changes in water balance are marked by changes in sodium concentration. o The ‘corrected chloride’ value is a calculated value of the chloride concentration normalized for water balance. Meaning, it is the value the chloride concentration would be if the animal’s water balance was normal. o The formula to calculate corrected chloride is: Corrected [Cl-] = Patient [Cl-] x (Mid-normal [Na+]/Patient [Na+]). o Determining the corrected chloride concentration is recommended when there is an abnormal sodium concentration to aid in identification of absolute loss or gain in chloride. This is particularly important in the semiquantitative approach to acid base analysis.

Answer 181

o Hypochloremia can be due to a free water gain or mechanisms of chloride loss (corrected hypochloremia) through the gastrointestinal or renal systems. o Corrected hypochloremia can be due to losses of chloride rich gastric fluid through vomiting or nasogastric tube suctioning or through renal chloride loss.

Answer 182

o There are no specific clinical signs associated with hypochloremia, clinical signs are generally attributed to the underlying disease process and/or concomitant metabolic alkalosis. o Treatment of hypochloremia depends largely on the underlying cause. For animals with hypochloremia from free water excess, restoration of a normal water balance will normalize the chloride concentration. o In diseases of chloride loss, resolution of the primary disease is the cornerstone of therapy. Corrected hypochloremia almost always occurs in association with metabolic alkalosis. o Many causes of metabolic alkalosis are very responsive to chloride supplementation Administration of chloride rich fluids such as 0.9% chloride is the treatment of choice of hypochloremic metabolic alkalosis if there is any volume deficit. o Fluid supplementation with potassium chloride is another method of chloride supplementation.

Answer 183

o Hyperchloremia can be due to free water loss or a true increase in chloride (corrected hyperchloremia). o Water loss can occur with loss of electrolyte poor or hypotonic fluids from the body in disease processes such as diarrhea, burns, and renal diseases. o Renal water loss can occur in DI, osmotic diuresis, diuretic administration and kidney disease. o Pseudohyperchloremia occurs in animals on bromide containing medications such as potassium bromide. This is an artifactual abnormality due to bromide interfering with chloride measurement and does not have the same clinical relevance as true hyperchloremia.

Answer 184

o Corrected hyperchloremia almost always occurs in conjunction with a metabolic acidosis. This is the result of electroneutrality. o If IV fluid therapy or disease processes lead to a gain in chloride, there will be a reciprocal decrease in bicarbonate concentration to maintain the charge balance between anions and cations. o As such, the clinical significance of hyperchloremia can be hard to distinguish from the effects of metabolic acidosis.

Answer 185

o There are no specific clinical signs described for hyperchloremia. o Treatment of hyperchloremia due to free water loss requires free water administration, either oral water administration or IV infusion of solutions such as D5W. o Treatment of corrected hyperchloremia is primarily based on resolution of the underlying disease. o The use of buffered crystalloid fluids such as Lactated Ringers Solution and avoiding high chloride fluids such as potassium chloride will be of benefit. o In diseases with bicarbonate loss such as some forms of diarrhea and renal tubular acidosis, sodium bicarbonate administration maybe indicated.

Answer 186

o There are now numerous studies that have shown that administration of chloride rich fluids and the resulting hyperchloremic metabolic acidosis is associated with worse clinical outcomes in human patients. o This association has been found in critically ill, septic and surgical patients. In a randomized clinical trial, the administration of balanced crystalloids resulted in a lower mortality rate and lower rates of renal replacement therapy or renal dysfunction in critically ill patients, when compared to saline administration. o In comparison, no difference in outcome could be demonstrated in a similar study of non-critically ill adults. o In a large veterinary study of all animals with a serum chloride measured, hyperchloremia was identified in 21% of dogs and 9% of cats was associated with a higher mortality than normochloremia in both species

Answer 187

o Altered cytokine responses, increased NO levels, hemodynamic instability and altered renal blood flow. o Hyperchloremic metabolic acidosis has been shown to decrease renal blood flow and some studies have found an association with acute kidney injury. o Rapid administration of 2 liters 0.9% saline to healthy human volunteers caused a significant reduction in renal arterial blood flow and renal cortical tissue perfusion, when compared to baseline and to the people who received Plasma-Lyte 148. o Results of experimental animal studies suggest that renal vasoconstriction is a direct result of hyperchloremia. Increased renal tubular chloride concentration has been shown to cause increased absorption of chloride by the macula densa leading to afferent arteriolar vasoconstriction. o Fluid retention in the interstitial space is also greater with 0.9% saline than with balanced solutions. This may further limit urine output and contribute to organ dysfunction. o Despite these concerns, the relationship between hyperchloremic metabolic acidosis and kidney injury is not clear. There appears to be a difference in the impact of hyperchloremia in the critically ill patient population. Avoiding iatrogenic hyperchloremia is a strong clinical recommendation at this time.

Answer 188

o The vast majority of magnesium is found in bone and muscle. o Sixty percent of the total body magnesium content is present in bone, incorporated into the crystal mineral lattice or in the surface-limited exchangeable pool. o This pool consists of magnesium that is in equilibrium with the magnesium ions in the extracellular fluid and serves as a reservoir for maintenance of the extracellular magnesium concentration. o Twenty percent is located in skeletal muscle and the remainder is located in other tissues, primarily the heart and liver. Less than 1% of total body magnesium is present in the serum.

Answer 189

o In the serum, magnesium exists in three distinct forms: ionized, anion-complexed, and protein-bound fractions. o The ionized fraction is thought to be the physiologically active component and accounts for approximately 66% and 63% of the total serum magnesium concentration in cats and dogs, respectively. o Approximately 4% and 6% are complexed to compounds such as phosphate, bicarbonate, sulfate, citrate, and lactate in cats and dogs, respectively. o The remaining 30% and 31% of total serum magnesium are bound to protein (primarily albumin) in cats and dogs, respectively

Answer 190

o Magnesium is required for many metabolic functions, most notably those involved in the production and use of adenosine triphosphate (ATP). o This electrolyte is a coenzyme for the membrane- bound sodium-potassium ATPase pump and functions to maintain the sodium-potassium gradient across all membranes. Calcium ATPase and proton pumps also require magnesium. o Magnesium is also essential for protein and nucleic acid synthesis, regulation of vascular smooth muscle tone, cellular second messenger systems, and signal transduction. o In addition, there are data to suggest that magnesium exerts an important influence on lymphocyte activation, cytokine production, and systemic inflammation.

Answer 191

o Magnesium homeostasis is achieved through intestinal absorption and renal excretion. o Absorption occurs primarily in the small intestine (jejunum and ileum) with little or none occurring in the large intestine. o The loop of Henle is the main site of magnesium reabsorption in the kidney. The kidney appears to be the main regulator of serum magnesium concentration and total body magnesium content. This is achieved by both glomerular filtration and tubular reabsorption. Renal magnesium excretion will increase in proportion to the load presented to the kidney; conversely, the kidney conserves magnesium in response to a deficiency. o Lactation appears to play a role in gastrointestinal (GI) and renal handling of magnesium. Increased concentrations of parathyroid hormone, in addition to calcium concentration, most likely participate in magnesium conservation during lactation to supply the mammary glands with a sufficient amount. o No primary regulatory hormone has been identified for magnesium homeostasis, although the parathyroid, thyroid, and adrenal glands are likely involved

Answer 192

o Most magnesium-related disorders are caused by conditions that lead to the depletion of total body stores. o Hypomagnesemia is a common electrolyte abnormality in both canine and feline intensive care unit patients. However, this electrolyte disorder appears to be less common in the general canine hospital population. o Ionized hypomagnesemia has been documented in perioperative feline renal transplant recipients, as well as cats with DM and DKA. o Other evidence suggests that animals on peritoneal dialysis, dogs with CHF receiving furosemide therapy, dogs with PLE, and lactating dogs are also at risk for hypomagnesemia.

Answer 193

Decreased intake (or absorption) Increased losses Alterations in distribution.

Answer 194

o Decreased dietary intake, if sustained for several weeks, can lead to significant magnesium depletion. o In addition, catabolic illness and prolonged intravenous fluid therapy or parenteral nutrition without sufficient magnesium supplementation can contribute to depletion.

Answer 195

o Magnesium losses can occur through the GI tract, kidneys, or both. o Because magnesium balance is primarily a function of intestinal absorption and urinary excretion, depletion is almost always caused by disturbances in one or both organ systems. o Increased GI losses can result from IBD, malabsorptive syndromes, cholestatic liver disease, or other diseases that cause prolonged diarrhea. Fluid from the intestinal tract contains a high concentration of magnesium. Patients with protracted episodes of large-volume diarrhea are prone to significant magnesium depletion. o The kidney often serves as a focal point for the development of hypomagnesemia through urinary loss. Acute renal dysfunction as a consequence of glomerulonephritis or the nonoliguric phase of acute tubular necrosis is often associated with a rise in the fractional excretion of magnesium. o A number of endocrinopathies are also associated with an increase in the fractional excretion of magnesium, including DKA and hyperthyroidism. o Numerous drugs that are commonly administered to critically ill patients can increase renal magnesium loss. Diuretic agents (furosemide, thiazides, mannitol) and cardiac glycosides induce hypomagnesemia by increasing urinary excretion. Aminoglycosides, amphotericin B, cisplatin, and cyclosporine, predispose to renal tubular injury and excessive magnesium loss. o Disease states or therapeutic modalities can cause the redistribution of circulating magnesium by producing extracellular to intracellular shifts, chelation, or sequestration. o Administration of glucose, insulin, or amino acids causes magnesium to shift intracellularly. Catecholamine elevations in animals with sepsis, trauma, or hypothermia may cause ionized hypomagnesemia. o β-adrenergic stimulation of lipolysis generates free fatty acids that chelate magnesium, thereby producing insoluble salts. Citrated blood products can avidly chelate magnesium ions when administered in large quantities. o In animals with acute pancreatitis, magnesium can form insoluble soaps, and magnesium sequestration may occur in areas of fat necrosis surrounding the pancreas.

Answer 196

o Are often related to its effects on the cell membrane that result in changes in resting membrane potential, signal transduction, and smooth muscle tone. o The effects of magnesium on the myocardium are linked to its role as a regulator of other electrolytes, primarily calcium and potassium. For this reason, one of the most dramatic clinical signs associated with hypomagnesemia is cardiac arrhythmias, including afib, SVT, VT, and VF. o Hypomagnesemia also predisposes patients to digoxin-induced arrhythmias. Magnesium depletion not only enhances digoxin uptake by the myocardium but also inhibits the myocardial sodium-potassium ATPase pump, as does digoxin. Before overt arrhythmia development, subtle ECG changes may be seen. These include prolongation of the PR interval, widening of the QRS complex, depression of the ST segment, and peaking of the T wave. In addition to these changes, hypomagnesemia can cause hypertension, coronary artery vasospasm, and platelet aggregation.

Answer 197

o Hypomagnesemia can cause various nonspecific neuromuscular signs. Concurrent hypocalcemia and hypokalemia may also contribute. o Magnesium deficiency increases acetylcholine release from nerve terminals and enhances the excitability of nerve and muscle membranes. It also increases the intracellular calcium content in skeletal muscle. o Clinical manifestations of magnesium deficiency can include generalized muscle weakness, muscle fasciculations, ataxia, and seizures. Esophageal or respiratory muscle weakness can be manifested as dysphagia or dyspnea, respectively.

Answer 198

o Because magnesium is necessary for the movement of Na, K, and Ca in and out of cells, other manifestations of hypomagnesemia include metabolic abnormalities such as concurrent hypokalemia, hyponatremia, and hypocalcemia. o Concurrent hypokalemia that is refractory to aggressive potassium supplementation may be due to magnesium deficiency causing excessive potassium loss through the kidneys. Assessment of magnesium status and subsequent magnesium supplementation are recommended. o Hypocalcemia is another manifestation of magnesium deficiency. Because hypomagnesemia impairs PTH release and enhances Ca movement from extracellular fluid to bone, total and ionized hypocalcemia often accompanies magnesium depletion. Therefore, clinical signs of hypocalcemia are often observed in patients with magnesium deficiency.

Answer 199

o Determination of total serum magnesium concentration is usually the most readily available technique for estimation of magnesium status. o Because more than 99% of total body magnesium is located in the IC compartment, total serum concentrations do not always reflect total body stores. Therefore a normal total serum Mg concentration can occur in an animal with a total body Mg deficiency. A low total serum concentration in a patient at risk for deficiency is usually significant. o The reported reference range for total serum magnesium is 1.89 to 2.51 mg/dl in dogs, and 1.75 to 2.99 mg/dl in cats.3 o The ionized magnesium concentration is thought to provide a more accurate reflection of intracellular ionized magnesium status and represents the “active” component. Ionized Mg appears to equilibrate rapidly across the cell membrane; thus extracellular ionized magnesium values may be more reflective of intracellular stores. The canine reference range for ionized magnesium is 0.43 to 0.6 mmol/L, and the feline reference range is 0.43 to 0.7 mmol/L.

Answer 200

o The amount and route of magnesium replacement depends on both the degree of hypomagnesemia and the patient’s clinical condition. o Mild hypomagnesemia may resolve with management of the underlying disorder and modification of intravenous fluid therapy. o Animals receiving long-term diuretic or digoxin therapy may benefit from oral magnesium supplementation. Supplementation should be considered if total serum magnesium concentrations are lower than 1.5 mg/dl and at any concentration if clinical signs (cardiac arrhythmias, muscle tremors, refractory hypokalemia) are present. o Renal function and cardiac conduction must be assessed before Mg administration. o Because magnesium is excreted primarily by the kidneys, the dosage should be reduced by 50% in azotemic patients and serum concentrations should be monitored frequently to prevent hypermagnesemia. o Magnesium prolongs conduction through the atrioventricular (AV) node. Therefore any patient with cardiac conduction disturbances should have judicious supplementation and continuous ECG monitoring.

Answer 201

o Both sulfate and chloride salts are available for parenteral supplementation. o The IV route is preferred for rapid repletion of Mg concentrations, the IM route is generally painful. o An initial dosage of 0.5 to 1 mEq/kg q24h can be administered by continuous rate infusion in 0.9% NaCl or D5W. A lower dosage of 0.25 to 0.5 mEq/kg q24h can be used for an additional 3 to 5 days. o For management of life-threatening ventricular arrhythmias, a dose of 0.15 to 0.3 mEq/kg of magnesium diluted in normal saline or D5W can be administered slowly over 5 to 15 minutes. o Parenteral administration of magnesium sulfate may result in hypocalcemia because of chelation of calcium with sulfate. Therefore magnesium chloride should be given if hypocalcemia is also present. o Other side effects of magnesium therapy include hypotension, atrioventricular block, and bundle branch blocks. Adverse effects usually are associated with intravenous boluses rather than continuous rate infusions. o Chloride, gluconate, oxide, and hydroxide magnesium salts are available for oral administration. The suggested dosage is 1 to 2 mEq/ kg q24h. The main side effect of oral administration is diarrhea.

Answer 202

o Many veterinary critical care diets contain low concentrations of magnesium (0.1 to 0.22 mg/kcal). o Given that many critically ill patients are fed at or below their resting energy requirement, the actual intake of magnesium may be well below the concentration needed to replete a magnesium deficient animal. o Additionally, magnesium supplementation in standard TPN formulations (0.13 to 0.22 mEq/kg/day) is also below the concentration recommended to treat hypomagnesemia (0.3 to 1.0 mEq/kg/day). o Based on the low concentrations of Mg in critical care diets and total parenteral nutrition formulations, animals with moderate to severe hypomagnesemia will likely require intravenous or oral Mg supplementation to normalize serum Mg concentrations, especially if they have diseases resulting in continued loss of Mg from the gastrointestinal tract or kidneys.

Answer 203

o Because large quantities of magnesium can be eliminated easily by the kidneys, it is unusual to encounter hypermagnesemia in the absence of azotemia. o Unlike magnesium depletion, normal serum concentrations cannot hide increased body stores.

Answer 204

o Conditions in which hypermagnesemia has been noted include renal failure, endocrinopathies, and iatrogenic overdose, especially in patients with impaired renal function. o It appears that absolute magnesium excretion falls as the GFR declines, so it is not surprising that most patients with hypermagnesemia have some degree of renal insufficiency. In general the degree of hypermagnesemia parallels the degree of renal failure. Acute renal failure is more likely to be associated with clinically significant hypermagnesemia than chronic renal failure, but it may occur in the latter. o Several endocrinopathies may be associated with hypermagnesemia, although the mechanisms are not well understood. These diseases include hypoadrenocorticism, hyperparathyroidism, and hypothyroidism. In comparison with renal failure, these diseases cause hypermagnesemia less often and to a milder degree. The prerenal azotemic state present in most patients with hypoadrenocorticism may contribute to hypermagnesemia. o Improper dosing of magnesium replacement therapy or lack of consideration of the underlying renal function generally plays a role in iatrogenic hypermagnesemia. Many cathartics, laxatives, and antacids contain magnesium, so care should be exercised if multiple doses are given to a patient with underlying renal disease. Sorbitol- containing cathartics are advised when patients have renal disease or require multiple doses to detoxify the GI tract.

Answer 205

o Nonspecific clinical signs of hypermagnesemia include lethargy, depression, and weakness. o Hypermagnesemia usually results in varying degrees of neuromuscular blockade. One of the earliest clinical signs of magnesium toxicity is hyporeflexia. o Profound magnesium toxicity has been associated with respiratory depression secondary to respiratory muscle paralysis. Severe respiratory depression can result in hypoventilation and subsequent hypoxemia. o An absent menace and palpebral reflex have been reported in one dog and one cat that developed acute hypermagnesemia secondary to iatrogenic overdose. o Hypermagnesemia can also lead to blockade of the ANS and vascular collapse. o Cardiovascular effects of hypermagnesemia result in ECG changes, including prolongation of the PR interval and widening of the QRS complex. This is due to delayed atrioventricular and interventricular conduction. Bradycardia can occur in hypermagnesemic patients. At severely high serum magnesium concentrations, complete heart block and asystole can occur. Ectopy does not appear to be enhanced by elevated serum magnesium concentrations. o Hypermagnesemia has also been reported to produce hypotension secondary to relaxation of vascular resistance vessels. o Hypermagnesemia may impair platelet function and coagulation.

Answer 206

o Total serum magnesium concentrations greater than 2.99 mg/dl in cats and 2.51 mg/dl in dogs are considered indicative of hypermagnesemia. o Ionized magnesium concentrations above 0.7 mmol/L in cats and 0.6 mmol/L in dogs are considered ionized hypermagnesemia.

Answer 207

o Therapy consists first and foremost of stopping all exogenous Mg administration. Further treatment is based on the degree of hypermagnesemia, clinical signs, and renal function. o A patient with mild clinical signs such as depression and hyporeflexia can be treated with supportive care and observation, provided that renal function is normal. o More severe cases that involve unresponsiveness, respiratory depression, and any degree of hemodynamic instability should be treated with intravenous Ca. o Calcium is a direct antagonist of Mg at the neuromuscular junction and may be beneficial in reversing the cardiovascular effects of hypermagnesemia. o Calcium gluconate (10%) can be given at 0.5 to 1.5 ml/kg as a slow intravenous bolus over 15 to 30 minutes. o Saline diuresis and furosemide can also be used to accelerate renal magnesium excretion. Furosemide should not be given to a dehydrated or hypovolemic patient. o Hypermagnesemic patients with severely impaired renal function may require peritoneal or hemodialysis. o In patients with severe clinical signs, anticholinesterase treatment may be administered to offset the neurotoxic effects of hypermagnesemia (increased Mg decreases release of Ach, giving anticholinesterase we decrease the Ach degradation) o Physostigmine can be given at 0.02 mg/kg intravenously [IV] q12h until clinical signs subside. o In severe cases complicated by cardiopulmonary arrest, intubation and mechanical ventilation are recommended. Hypermagnesemic shock may be refractory to epinephrine, norepinephrine, and other vasopressors, making resuscitation efforts extremely difficult.

Answer 208

Intracellular anion

Answer 209

o It is required in the production of ATP, GTP, cAMP, and phosphocreatine, which function to maintain cellular membrane integrity, energy stores, metabolic processes, and biochemical messenger systems. o A major role of phosphate is maintenance of normal bone and teeth matrix in the form of hydroxyapatite. o Other roles include regulation of tissue oxygenation by way of 2,3-DPG, which decreases the affinity of oxygen to hemoglobin, support of cellular membrane structure and ionic charge via phospholipids, mitochondrial production of ATP through the electron transport system by phosphoproteins, and buffering acidotic conditions in the body.

Answer 210

Technically, phosphorus is an element and phosphate is a molecular anion (e.g., HPO42−); however, the terms are often used interchangeably.

Answer 211

o 80% to 85% in the bone and teeth as inorganic hydroxyapatite o 14% to 15% in soft tissues o Less than 1% in the extracellular space.

Answer 212

o Phosphorus is present in the body as organic and inorganic phosphates. o Organic phosphate is mostly intracellular and inorganic phosphate is mostly extracellular. o Organic phosphates are components of phospholipids, phosphoproteins, nucleic acids, enzymes, cofactors, and biochemical intermediates. Approximately two thirds of organic phosphate is in the form of phospholipids. o Inorganic phosphate is further divided into orthophosphates and pyrophosphates. The quantity of pyrophosphates is insignificant; therefore most extracellular inorganic phosphate is in the form of orthophosphates. o Approximately 85% of orthophosphates are free in circulation as monohydrogen phosphate (HPO42−) or dihydrogen phosphate (H2PO4−) with a ratio of 4:1 (HPO42− : H2PO4−) at a normal blood pH of 7.4. o Alkalosis increases and acidosis decreases the ratio of divalent to monovalent phos- phates. The remaining 15% is either protein bound (10%) or complexed (5%) to magnesium, calcium, or sodium. o Inorganic phosphate in the form of 2,3-DPG accounts for 70% to 80% of phosphate in red blood cells.

Answer 213

o In plasma, both organic and inorganic phosphates are present. o Organic phosphates include phosphate esters and phospholipids. o Inorganic phosphates are composed primarily of the orthophosphates (free, protein bound, and complexed). o Only the inorganic phosphates are measured during blood chemistry analysis. o Units are usually expressed as mmol/L or mEq/L. Conversion of units results in a normal plasma phosphate concentration of 3.1 mg/dl = 1 mmol/L phosphate = 1.8 mEq/L phosphate. o Serum or heparinized plasma, separated from cells within 1 hour, can be used to measure inorganic phosphate. o Serum phosphate transiently peaks 6 to 8 hours after meals; therefore blood samples ideally should be collected after a 12h fast. o Spurious hyperphosphatemia can occur secondary to in vitro hemolysis or rupture of other blood cells, hypertriglyceridemia, and the presence of a monoclonal gammopathy

Answer 214

o Phosphate balance is a complex interaction between phosphate intake and phosphate excretion. o Intestinal absorption is linearly related to intake, and 60% to 70% of ingested phosphate is absorbed in the duodenum, jejunum, and ileum. o In states of phosphate deficiency, calcitriol (1,25-dihydroxycholecalciferol) can increase active transport of inorganic phosphate. o Serum phosphate balance is dependent on glomerular filtration rate and tubular reabsorption, which occurs primarily in the proximal convoluted tubule. Normally, 60% to 90% of filtered phosphate is reabsorbed in the proximal convoluted tubule. o The amount of phosphate reabsorbed is dependent on dietary intake, with maximal reabsorption occurring in animals consuming phosphate-deficient diets. o Parathyroid hormone (PTH) is considered phosphaturic because it decreases the tubular transport maximum for phosphate reabsorption. Growth hormone, insulin, insulinlike growth factor 1, and thyroxine increase tubular phosphate reabsorption. Growth hormone partially accounts for the expected hyperphosphatemia in young, growing animals. o Phosphatonins, calcitonin, atrial natriuretic peptide, supraphysiologic doses of vasopressin, high doses of dexamethasone, and ACTH increase urinary phosphate excretion. o Phosphatonins are relatively new in the understanding of phosphate physiology; they are circulating substances that increase phosphate excretion in the kidneys, and it is believed intestinal phosphatonins exist as well. o Fibroblast growth factor 23 is a phosphatonin thought to be heavily involved in the regulation of phosphate and vitamin D homeostasis. o The skeleton is the body’s phosphate reservoir. Provides a source of phosphate during periods of hypophosphatemia regulated by PTH and calcitonin. o PTH-mediated osteolysis is rapid and accounts for the acute changes (minutes to hours) in calcium and phosphate, whereas PTH- mediated activation of osteoclasts is a slower process (days to weeks). Hyperphosphatemia does not occur during this process because of the phosphaturic effects of PTH.

Answer 215

o Serum concentrations of phosphate measured by blood chemistry analyzers do not necessarily reflect whole-body phosphate balance. o Phosphate is the predominant intracellular anion; therefore rapids shifts from the extracellular to intracellular space, or vice versa, can occur. o Blood chemistry analyzers measure serum phosphate (normal approximate range 2.9 to 5.3 mg/dl). o Mild to moderate hypophosphatemia (1.0 to 2.5 mg/dl) may or may not be clinically significant and typically is not associated with phosphate depletion. Severe hypophosphatemia (<1 mg/dl) is generally clinically significant and associated with total body phosphate depletion. o A patient can suffer from phosphorous depletion despite a normal serum phosphate. The decision to treat should be based on clinical assessment of the individual patient and measured serum phosphate concentration.

Answer 216

o Decreased intestinal absorption o Transcellular shifts o Increased urinary excretion o The most common cause being transcellular shifts. o In many clinical situations of hypophosphatemia, the etiology is often multifactorial.

Answer 217

o Decreased intestinal absorption is associated with chronic malnourishment, malabsorptive conditions (severe infiltrative disease), steatorrhea, vitamin D (1,25-dihydroxychcolecalciferol) deficiency, and administration of phosphate binding antacids. o Steatorrhea (increased fat content in feces) and diseases causing chronic diarrhea result in decreased intestinal phosphate absorption and secondary hyperparathyroidism due to vitamin D deficiency. Both mechanisms contribute to hypophosphatemia in this subset of patients. o Iatrogenic hypophosphatemia can occur as a result of increased fecal excretion associated with phosphate-binding drugs such as aluminum hydroxide or lanthanum carbonate.

Answer 218

o Transcellular shifting of phosphate is associated with alkalemia, hyperventilation, refeeding syndrome, parenteral nutrition, insulin administration, glucose administration, catecholamine administration or release, and salicylate toxicity. o In critical care medicine, hypophosphatemia can occur as a result of hyperventilation caused by pain, anxiety, sepsis, heat stroke, and CNS disorders. Hyperventilation causes respiratory alkalosis, leading to rapid diffusion of carbon dioxide from the intracellular space to the extracellular space. The increase in intracellular pH activates phosphofructokinase and glycolysis, causing phosphate to rapidly shift into cells. o Hypophosphatemia is the most common and critical electrolyte disturbance associated with refeeding syndrome. During chronic malnutrition, phosphate depletion can occur and may not be reflected by a decrease in serum phosphate concentration. Administration of enteral or parental nutrition to a patient with chronic malnutrition stimulates insulin release, which promotes intracellular uptake of phosphate and glucose for glycolysis; this transcellular shift may result in severe hypophosphatemia. o Insulin and glucose administration can cause severe hypophosphatemia in a patient with total body phosphate depletion, such as patients being treated for DKA or HHS. o Insulin and glucose stimulate glycolysis, promoting the synthesis of phosphorylated glucose compounds and intracellular shifts of phosphate. o Catecholamines (endogenous or exogenous) such as epinephrine or norepinephrine and β-receptor agonists such as terbutaline may cause hypophosphatemia as a result of β-adrenergic receptor–mediated cellular uptake of phosphate. o Salicylate toxicity causes uncoupling of oxidative phosphorylation and inhibition of the Kreb’s cycle. Initially it causes hyperphosphatemia, which is thought to be a result of transcellular shifts from the intracellular to the extracellular compartment; however, this is rapidly (30 to 60 minutes) followed by hypophosphatemia caused by excessive urinary excretion.

Answer 219

o Excessive loss of phosphate through the kidneys can cause hypophosphatemia and phosphate depletion. This is more severe in patients with multifactorial causes of hypophosphatemia. o Patients with diabetes mellitus have a high risk for phosphate depletion because of osmotic diuresis promoting phosphate excretion, loss of muscle mass, and impaired tissue phosphate utilization as a result of insulin deficiency. o The severity of hypophosphatemia often worsens after treatment with insulin and intravenous fluid therapy because of transcellular shifts. o Primary or nutritional secondary hyperparathyroidism may result in hypophosphatemia. o Primary hyperaldosteronism causes renal loss of calcium, resulting in hypocalcemia, which stimulates secretion of PTH and may result in normal or low serum phosphate. o Hyperadrenocorticism is a reported cause of hypophosphatemia in humans; Initially it was thought that glucocorticoids decrease intestinal calcium absorption, leading to secondary hyperparathyroidism, and increase urinary excretion of phosphate, causing subsequent hypophosphatemia. However, in a prospective study, dogs with hyperadrenocorticism were found to have increased PTH concentrations and normal serum phosphate concentrations that were higher than the control group.

Answer 220

o In humans, induction of therapeutic hypothermia for treatment of head trauma has resulted in severe electrolyte abnormalities, including depletion of magnesium, phosphate, potassium, and calcium. o Increased urinary loss of electrolytes associated with hypothermia-induced diuresis is one possible mechanism of electrolyte depletion. o Hypophosphatemia occurs in patients with third-degree burns and is more significant in patients with higher total body surface area burns. The mechanism for hypophosphatemia is thought to be multifactorial; increased loss through the skin and increased urinary excretion during the recovery phase are likely mechanisms.

Answer 221

Mannitol administration could theo- retically also be associated with phosphate wasting because of its diuretic effects.

Answer 222

o Sepsis has been associated with hypophosphatemia in people and may be attributable to increased circulation of inflammatory cytokines, especially IL6 and TNF-α. o Currently the mechanism by which cytokines cause hypophosphatemia is unknown. o Acute respiratory alkalosis stimulates phosphofructokinase and glycolysis, which may play a role in the transcellular shift of phosphate during sepsis. o Septic human patients with severe hypophosphatemia (serum phosphate <1 mg/dl) are reported to have an eightfold increase in mortality.

Answer 223

o Mild to moderate hypophosphatemia is typically asymptomatic; however, severe hypophosphatemia and total body phosphate depletion can result in widespread cellular dysfunction. o Depletion of ATP and 2,3-DPG is responsible for most of the severe clinical signs and can affect most cells in the body. Intracellular inorganic phosphate concentration is the critical determinant of cellular injury because it is necessary for the synthesis of ATP from adenosine diphosphate. Decreased intracellular 2,3-DPG impairs release of oxygen by hemoglobin to tissues, leading to tissue hypoxia. o Hemolysis can occur with severe hypophosphatemia because of decreased concentrations of red blood cell ATP and 2,3- DPG, spherocytosis, red cell membrane rigidity, and shorted red blood cell survival in some cats and dogs. o Severe hypophosphatemia causes impaired chemotaxis, phagocytosis, and bactericidal activity of leukocytes, which increases the risk of infection in critically ill animals. Platelets have a shortened survival time with impaired clot retraction, which increases the risk of hemorrhage. o Reversible myocardial dysfunction occurs with phosphate depletion and is a proposed mechanism for cardiac dysrhythmias associated with induction of therapeutic hypothermia in humans. o Clinical signs of severe hypophosphatemia-induced skeletal muscle changes include generalized weakness, tremors, and muscle pain (which can manifest as difficulty in weaning patients from mechanical ventilation). o Rhabdomyolysis secondary to acute hypophosphatemia may occur during refeeding syndrome. Neurologic signs may include ataxia, seizures,and coma associated with metabolic encephalopathy. GI signs can include anorexia, nausea, functional ileus, vomiting, and diarrhea

Answer 224

o We should differentiate hypophosphatemia (decreased serum phosphate) from phosphate depletion (decreased total body phosphate). o Differentiation may be difficult because phosphate is predominately intracellular, a fluid compartment that cannot easily be sampled for analysis. o Hypophosphatemia refers to a decreased serum phosphate below the lower limit of the reference range and may occur with low, normal, or high total body phosphate. o Mild to moderate hypophosphatemia correlates with a serum phosphate concentration of 1 to 2.5 mg/dl, and severe hypophosphatemia correlates with a serum phosphate of less than 1 mg/ dl. o Phosphate depletion is a reduction in total body phosphate, usually resulting from decreased intake or increased loss through the kidneys, and can be compounded by transcellular shifts. o Phosphate depletion can occur in the face of normal or high measured serum phosphate; therefore, phosphate depletion should be suspected in patients with predisposing causes and associated clinical signs.

Answer 225

o It will depend on the severity of the phosphate deficit, whether total body phosphate depletion is suspected or impending, anticipated duration of illness, clinical signs of the patient, and presence of concurrent illnesses associated with decreased intake or increased loss of phosphate. o Focus should be on treating the 1ary disease and many cases of mild to moderate hypophosphatemia will subsequently resolve in this manner. Hypophosphatemia associated with respiratory alkalosis typically resolves when the patient’s ventilatory and acid-base status normalizes. o Phosphate replacement can be administered orally or intravenously. Oral replacement is indicated in asymptomatic patients with mild to moderate (1 to 2.5 mg/ dl) hypoPh. Bovine milk contains 0.032mmol/ml of elemental Ph and can be used as an oral phosphate supplement. o Parenteral replacement is indicated in patients with severe hypophosphatemia (<1 mg/dl) that are at high risk of phosphate depletion. Commercially available hypertonic sodium and potassium phosphate solutions are available for parenteral use; they require dilution, typically in 0.9% saline, before administration. Dilution of phosphate salts in lactated Ringer’s solution should be avoided because of potential for precipitation with calcium. o When using potassium phosphate, it is important to account for the total amount of potassium supplementation in the patient’s fluid therapy. Reported dose ranges for IV phosphate therapy are 0.01 to 0.12mmol/kg/h. o Serum phosphate, ionized calcium, and serum potassium concentrations should initially be rechecked every 4 to 6 hours after starting parenteral phosphate replacement therapy. o Potential adverse effects of overzealous supplementation include hyperphosphatemia, hypocalcemia with associated tetany, metastatic calcification, and renal failure.

Answer 226

o The definition of hyperphosphatemia should vary depending on the age of the patient. o A baseline normal serum phosphate range is 2.9 to 5.3 mg/dl; however, concentrations of 10 mg/dl have been reported in healthy puppies.

Answer 227

o Decreased renal excretion, increased intake or iatrogenic administration, and transcellular shifts. o The most common cause in veterinary medicine is decreased renal excretion associated with AKI or CKD.

Answer 228

o Hyperphosphatemia inhibits 1α-hydroxylase activity and stimulates secretion of PTH. Conversion of vitamin D to its active metabolite, calcitriol, is catalyzed by 1α-hydroxylase. o Decreased calcitriol reduces intestinal absorption of phosphate; however, increased PTH enhances intestinal absorption and urinary excretion of phosphate, resulting in a small net effect of increased phosphate excretion. o Calcitriol concentrations are subsequently restored by increased PTH. Initially, this restores serum phosphate; however, when PTH decreases, serum phosphate increases because of a decreased glomerular filtration rate and the cycle continues to preserve phosphate balance. o Eventually, as CKD progresses, maximal inhibition of phosphate tubular reabsorption is surpassed, causing persistent hyperphosphatemia. As the number of functional tubular cells decrease, renal calcitriol synthesis tapers, and the magnitude of hyperphosphatemia progresses in spite of increased PTH. o Renal secondary hyperparathyroidism occurs in 47% to 100% of dogs and cats with CKD, with a higher incidence in patients with more severe CKD (IRIS stage 3 and 4). o In the critical care setting, other common causes of hyperphosphatemia as a result of decreased excretion are AKI, acute-on-chronic kidney disease, urethral obstruction, and uroabdomen. Because of insufficient time for physiologic compensatory mechanisms to develop, AKI is often associated with significant hyperphosphatemia.

Answer 229

o The most notable causes of transcellular shifts of phosphate resulting in hyperphosphatemia occur with tumor lysis syndrome, rhabdomyolysis, and hemolysis. o Tumor lysis syndrome is the clinical manifestation and laboratory sequelae of acute death of tumor cells that release potassium, phosphate, and nucleic acids into circulation and may cause AKI. Renal tubular mineralization is thought to play a role in the pathogenesis of AKI associated with tumor lysis syndrome. Patients with a high tumor cell burden that respond rapidly to chemotherapy or radiation, such as stage IV and V lymphoma, are thought to be at higher risk for tumor lysis syndrome because these cells contain up to four times as much phosphate as normal cells. o Rhabdomyolysis is a syndrome of massive skeletal muscle tissue injury and can cause hyperphosphatemia directly from release of intracellular contents and indirectly by decreased renal excretion from resulting myoglobin-induced AKI (although this has never been reported in dogs or cats). o Release of intracellular phosphate is the mechanism by which hemolysis is thought to cause hyperphosphatemia.

Answer 230

o Iatrogenic overdose and toxicities are conditions related to increased intake of phosphate. o Parenteral administration of phosphate is not without risk and supplementation requires close monitoring to avoid iatrogenic overdose. Acute administration of large doses of parenteral phosphate can cause not only hyerphosphatemia but also hypomagnesemia, hypocalcemia, and hypotension. o Phosphate-containing enemas can cause severe hyperphosphatemia with the associated clinical consequences and can be fatal. o Ingestion of cholecalciferol rodenticides and vitamin D3 skin creams (e.g., calcipotriene) can rapidly increase serum phosphate concentration by increased intestinal absorption and release from bones.

Answer 231

o Hypoparathyroidism is rare in veterinary medicine but should be suspected in a patient presenting on emergency with acute tetany, muscle fasciculations, seizures, hypocalcemia, and normal kidney function (normal kidney values with appropriate urine specific gravity). In this disease, hyperphosphatemia may or may not bepresent. o Hyperthyroidism has also been associated with hyperphosphatemia because thyroxine increases renal tubular reabsorption of phosphate.

Answer 232

o Clinical signs of hyperphosphatemia include anorexia, nausea, vomiting, weakness, tetany, seizures, and dysrhythmias. o Hyperphosphatemia is often associated with hypocalcemia, hypomagnesemia, hypernatremia, and metabolic acidosis. o Clinical manifestations of hyperphosphatemia predominantly are due to hypocalcemia and metastatic soft tissue calcification. Tetany and seizures can develop in patients with severe hypocalcemia. Soft tissue calcium phosphate deposition occurs when the calcium phosphate product is greater than 58 to 70 mg^2/dl^2 and represents one mechanism for hypocalcemia. o Tissues primarily affected by ectopic calcification include cardiac, vasculature, renal tubules, pulmonary, articular, periarticular, conjunctival, skeletal muscle, and skin. o Arrhythmias, such as polymorphic ventricular tachycardia or torsades de pointes caused by prolongation of the Q-T interval, are also associated with subsequent hypocalcemia and hypomagnesemia.

Answer 233

o Is based on a serum phosphate greater than 5.3 to 6 mg/dl in an adult dog or cat. o Age of the patient should be considered when interpreting serum Ph concentrations. Puppies and kittens less than 8 weeks of age have the highest plasma phosphate concentrations; this value steadily decrease as the animal ages, with normal adult values expected at 1 year of age.

Answer 234

o A thorough investigation for the underlying cause should be sought to most effectively treat hyperphosphatemia. o If rapid correction of hyperphosphatemia is needed, treatment includes crystalloid fluid therapy and dextrose administration with a goal of correcting azotemia if present, and increasing intracellular uptake of phosphate. o For patients with hyperphosphatemia caused by oliguric or anuric AKI, continuous renal replacement therapy or hemodialysis likely will be necessary. Continuous renal replacement therapy has been reported to be effective in a single case report for treatment of AKI and multiple electrolyte disturbances, including hyperphosphatemia, that was associated with acute tumor lysis syndrome and did not respond to conventional therapy. o Feeding a low-phosphate diet and administering phosphate binders such as aluminum hydroxide, ipakitine, lanthanum carbonate, or sevelamer should be considered when treating animals with hyperphosphatemia caused by chronic kidney disease.

Answer 235

Ranges from 10 to 160 nanomoles/L, which correlates with a pH from 8 to 6.8, respectively.

Answer 236

Acidemia Alkalemia

Answer 237

o Clinical assessment of acid-base balance first evaluates the pH: normal, acidemia or alkalemia. o The system is then partitioned into the respiratory and metabolic components and each is evaluated separately. PCO2 represents the respiratory component universally, but there are numerous measures available for assessment of the metabolic component. o These include the Henderson-Hasselbalch, or traditional, approach; the Stewart approach; and a semi-quantitative approach that combines aspects of both the traditional and Stewart approaches.

Answer 238

o For two reasons. First, nearly all of the known LMW and water- soluble intermediary metabolites possess chemical groups that are completely ionized at neutral pH. These groups are phosphate, ammonium and carboxylic acid. Ionization of these compounds traps them and keeps them in or out of the cell. o Second, optimal protein function inside and outside the cell occurs when the net charge on the protein structure is kept constant; also occurring at a neutral pH.

Answer 239

o A substance capable of donating a hydrogen ion to another substance in water. o A substance that can accept a pair of electrons to form a covalent bond.

Answer 240

o Because of their reactivity, they exist only in association with other solvent molecules that surround them. In biological systems, this is typically water. o We think about hydrogen ions only out of convenience.

Answer 241

o Lewis developed the concept of effective concentration to assist in explaining the complex interactions of solutions depending on concentration and temperature and other factors. His concept in a formula can be described as: ax = g • [x] o ax is the effective activity of substance x in solution o g is the activity coefficient of x o [x] is the concentration of substance x in solution. o In an ideal solution the activity coefficient is 1, making activity and concentration roughly equivalent.

Answer 242

The use of pH is recommended by the international body of clinical chemistry because of its advantages: 1) Traditional and in wide use. 2) Relates to activity of H+ or more specifically the log of H+ activity and is what appears to drive physiological systems. 3) It is what is measured by the pH electrode (activity of H+). 4) The alternative [H+] is not correct because the activity coefficient is ignored. 5) Free protons do not exist in solution.

Answer 243

o Volatile - able to be exhaled- essentially this is CO2 o Volatile acid load is produced from metabolism of carbohydrates for energy and is significant (approximately 200 mmol/kg/day), often more than the amount of fixed acids produced daily. CO2 excretion in the lungs is a result of the reaction between bicarbonate and a proton. When CO2 is excreted the proton remains behind as water. o Fixed acids - that are non-volative and excreted through the kidney o In the early part of the twentieth century, fixed acid production was thought to be due to incomplete metabolism of carbohydrates (lactate), fats (ketones), or protein (sulfate, phosphate) and amounted to 1-1.5 mmol [H+]/kg/day. Today we recognize that there are other strong ions that also participate in acid base balance (Na, Cl, etc).

Answer 244

pH = pKa + log10 ([A-]/[HA]) Because of the unique and prominent role of carbonic acid and carbon dioxide plays, the equation is often remembered only with HCO3- (numerator) and H2CO3 (denominator) in the equation, but it is important to recognize that any acid system can be used in the equation. pH = 6.1 + log ([HCO3 − ] ÷ [0.03 × pCO2 ]) where 6.1 is the pKa in body fluids; HCO3− is the concentration of bicarbonate measured in mEq/L or mmol/L; 0.03 is the solubility coefficient for CO2 in plasma; and pCO2 is the partial pressure of CO2 in mmHg.

Answer 245

o Strong ions are cations and anions that exist as charged particles dissociated from their partner ions at physiologic pH. o These ions are “strong” because their ionization state is independent of pH.

Answer 246

o Siggaard-Anderson from Copenhagen developed his base excess approach in the 1950s and postulated that when a plasma sample was equilibrated to a pCO2 of 40 mmHg at 37C (removing contribution of the volatile acids to the pH of the sample), a titrated amount of acid/base can be added to return the pH of the sample to 7.4. o The amount of acid/base added must represent the non-volatile acid load, allowing clinicians to determine if there was a non-respiratory acidosis or alkalosis present and to comment on the magnitude.

Answer 247

o A buffer is a solution that can resist pH change upon the addition of an acidic or basic components. It is able to neutralize small amounts of added acid or base, thus maintaining the pH of the solution relatively stable. o To effectively maintain a pH range, a buffer must consist of a weak conjugate acid-base pair, meaning either a. a weak acid and its conjugate base, or a weak base and its conjugate acid. The use of one or the other will simply depend upon the desired pH when preparing the buffer. o Buffering typically occurs in a solution that contains a weak acid (HA) and the salt of that acid (eg NaA). In this sort of a system, the salt provides a reservoir of A- to replenish the [A-] when A- is consumed in a reaction with H+. o Mammals have an enormous buffering capacity as was illustrated by a classic experiment conducted by Swan and Pitts in the early 1950s where dogs were infused with 14,000,000nmol of protons (dilute hydrochloric acid) per L of body water. They measured the change in blood pH (7.44 to 7.14 or [H+] from 36 nmol/L to 72 nmol/L). One analogy that is used to explain this enormous buffering capacity is to liken this to depositing $14,000,000 into a bank account and having the balance increase by $36. Or in other words, although we measured a change in [H+] by 36 nmol/L, we did not measure the 13,999,964 nmol of H+ that were buffered in the system.

Answer 248

o ISF - interstitial fluid compartment

Answer 249

o The site of sample collection affects acid-base variables. o In healthy research dogs there was a statistically significant difference in pH, PCO2, PO2, and bicarbonate concentration when arterial values were compared with venous values. pH and PCO2 were also different between jugular and cephalic venous samples. o These differences are relatively small, and for the purpose of acid-base analysis, venous samples have been found to be an adequate replacement for arterial values in critically ill human patients. o In states of poor peripheral perfusion, peripheral venous samples can have elevations in PCO2 and lactate concentration, which will contribute to lower pH values that may not be representative of central venous or arterial values. o Other sources of preanalytical error for acid-base analysis include time delays between sample collection and sample analysis; exposure to air, which will allow PCO2 to equilibrate to a lower value; and inappropriate dilution of the blood sample with liquid anticoagulant such as sodium heparin. o Any bubbles in the sample should be immediately removed. If a delay of greater than 15 minutes between sample collection and analysis is anticipated, the sample should be maintained under airtight conditions and immersed in ice water.

Answer 250

o The traditional approach is based on the Henderson-Hasselbalch equation for carbonic acid and uses pH, the PCO2, and HCO3). o pH = 6.1 + log ([HCO3 − ] ÷ [0.03 × PCO2 ]) o From this equation it is clear that pH has a direct relationship with bicarbonate concentration and an inverse relationship with PCO2. o The base excess (BE) and anion gap (AG) parameters have been added to the traditional approach to improve its diagnostic utility. o The body relies on three major processes to maintain acid-base balance: regulation of PCO2 by alveolar ventilation, buffering of acids by bicarbonate and non-bicarbonate buffer systems, and changes in renal excretion of acid or base. o pCO2represents the respiratory component, and in the traditional approach changes in bicarbonate concentration (or BE) represent the metabolic component (influenced by both buffering systems and renal handling of acid). o As the HH equation describes, pH is not dependent on having a specific PCO2 and bicarbonate concentration. Rather, pH is the consequence of the ratio of bicarbonate to PCO2. A patient can have a high HCO3-, but as long as the PCO2 has increased by a similar magnitude, the HCO3− : PCO2 ratio will remain normal and hence pH will remain in the normal range. o Because maintenance of an acceptable pH is optimal to maintain physiologic processes, it is no surprise that when an abnormality in one system (respiratory or metabolic) occurs, changes are made in the opposing system in an attempt to return the ratio of HCO3- to PCO2 toward normal; hence pH is driven back toward a more normal value. o This process is known as compensation and tends to return pH toward normal, but it is generally accepted that compensation will not be complete. This means compensation will rarely result in a pH within the normal range and will not overcompensate.

Answer 251

o CO2 acts as an acid in the body because of its ability to react with water to produce carbonic acid. o With increases in pCO2, the ratio of bicarbonate to pCO2 is decreased, hence pH falls. o Another way to consider this process is that with an increase in PCO2 the carbonic acid equation (shown below) will be driven to the right, increasing the hydrogen ion concentration. CO2 +H2O←→H2CO3 ←→H+ +HCO3− o Because CO2 is a gas and its concentration in the blood is controlled by pulmonary ventilation, the lung plays an important role in controlling acid-base status. Changes in alveolar ventilation are rapid and can alter blood pH within minutes. An increased pCO2 -> respiratory acidosis. A decreased pCO2 -> respiratory alkalosis.

Answer 252

o Bicarbonate is a parameter calculated by blood gas machines, although some clinical laboratories do measure it directly. o Elevations in bicarbonate are consistent with a metabolic alkalosis, whereas decreases in bicarbonate concentration represent a metabolic acidosis. o One of the major criticisms of using bicarbonate as the measure of the metabolic component is that it is not independent of changes in PCO2. o Changes in PCO2 will alter the equilibration of the carbonic acid equation. Elevations of PCO2 will lead to elevations of bicarbonate, whereas decreases in PCO2 will lead to a decrease in bicarbonate. o As such it is important that changes in bicarbonate concentration are always evaluated in terms of the pH and PCO2.

Answer 253

o Base excess (BE) is the titratable acidity (or base) of the blood sample. o It is defined as the amount of acid or base that must be added to a sample of oxygenated whole blood to restore the pH to 7.4 at 37° C and at a pCO2 of 40 mmHg. o Theoretically a normal individual should not have an excess or deficit of acid or base and hence BE would equal 0. o An increased BE (more positive value) is consistent with an alkalotic process (either gain of bicarbonate or loss of acid). o A decreased BE (more negative value), also known as a base deficit, represents an acidotic process. o The BE is a parameter calculated by an algorithm programmed into blood gas machines. Herbivores tend to have a more positive “normal” BE than people, whereas carnivores tend to have a more negative “normal” BE than people. o The major advantage of using BE over bicarbonate concentration is that it is independent of changes in the respiratory system. When there are minimal changes in PCO2 present, the BE and bicarbonate should correlate well. o The BE can be estimated by the measured bicarbonate concentration minus the normal bicarbonate concentration. In the face of substantial abnormalities in PCO2, the BE is a more reliable measure of the metabolic component.

Answer 254

o Many blood gas machines and most diagnostic laboratories will provide a parameter called total carbon dioxide (TCO2). o This is a misleading name because this represents the metabolic acid-base component, not the respiratory system component. o The TCO2 is a measure of all the carbon dioxide in a blood sample, and the majority of carbon dioxide is carried as bicarbonate in the blood. o In general, TCO2 will be 1 to 2 mmol/L higher than the true bicarbonate concentration.

Answer 255

o The anion gap (AG) was developed to better define the cause of a metabolic acidosis. o Electroneutrality requires there to be an equal number of anions and cations in physiologic systems. o In reality there is no actual AG; the apparent AG exists because more cations in the system are readily measured than anions. o The AG is a reflection of unmeasured cations and unmeasured anions and is calculated according to the following equation: Anion gap = ([Na+ ]+ [K+ ])− ([HCO3− ]+ [Cl− ]) o The AG of a normal individual is primarily composed of negatively charged plasma proteins, mostly albumin.

Answer 256

o The first is the loss of bicarbonate from the body via the gastrointestinal tract or kidneys; this bicarbonate is produced by cells and involves the exchange of bicarbonate and chloride. o The result is a rise in serum chloride as bicarbonate is lost, a hyperchloremic metabolic acidosis. No change in AG would be expected. o The other common clinical cause of metabolic acidosis is the gain of acid. When there is excess acid in the system, hydrogen ions will titrate (combine) with bicarbonate, leading to a fall in bicarbonate concentration; the anion that accompanied the hydrogen ion will accumulate, maintaining electroneutrality and increasing the AG. Common acids associated with an increased AG include lactate, ketone bodies, sulfate, phosphate, and toxins such as ethylene glycol. o A useful mnemonic for increased AG metabolic acidosis in small animals is DUEL, standing for DKA, uremic acids (sulfates, phosphates), ethylene glycol, and lactic acidosis. o It is important to note that hypoalbuminemia can mask the presence of unmeasured anions. Albumin and phosphorus are the major contributors to the AG in the normal animal. In states of hypoalbuminemia, abnormal unmeasured anions (e.g., lactate or ketones) may be present but the calculated anion gap may still remain within the reported reference range. As a result the AG is not reliable in hypoalbuminemic patients.

Answer 257

o Traditional acid-base analysis can identify primary (or simple) AB disorders in which there is an abnormality of one system (respiratory or metabolic) and any changes evident in the opposing system are considered consistent with normal compensation. o A primary metabolic acidosis should have respiratory compensation. The respiratory response to a primary metabolic abnormality is rapid in onset and complete within hours (assuming a stable level of the metabolic abnormality). o In comparison, the metabolic compensatory response to a primary respiratory disorder takes hours to begin and 2 to 5 days to complete. o If the change observed in the secondary system is similar in magnitude to the calculated, expected response, it is consistent with compensation and the assessment is a simple acid-base disorder. The change in the secondary system is completely attributed to compensation and no other acid-base abnormality is suspected. o A mixed acid-base disorder is diagnosed when the changes in the secondary system are not within a range compatible with expected compensation for the primary disorder. The assumption is that there is some disturbance of the secondary system preventing appropriate compensation from occurring or causing the appearance of “overcom- pensation” (which does not occur).

Answer 258

TRUE o There is a single study in the literature reporting that cats do not develop respiratory compensation in response to a metabolic acidosis and there are no studies evaluating the respiratory response of adult cats to a metabolic alkalosis.

Answer 259

o Any situation where there is an abnormality in both the metabolic and respiratory components. o Mixed disorders are evident when both the respiratory and metabolic components have the same influence on acid-base balance (i.e., metabolic acidosis and respiratory acidosis or metabolic alkalosis and respiratory alkalosis). o A mixed disorder is also present when there are abnormalities evident in both the metabolic and respiratory components but the pH is in the normal range. o In this situation it is important to recall the rule that compensation does not return pH all the way back to normal. o A mixed disorder may be identified when the change in the opposing system is not consistent with expected compensation.

Answer 260

o Its failure to identify individual disease processes that are contributing to the acid-base abnormality. o Although the AG may help to determine causes of a metabolic acidosis, it is prone to error and only narrows the possible diagnoses but does not provide a definitive diagnosis.

Answer 261

o Elevations in pCO2 can represent a primary respiratory acidosis or can occur in an attempt to compensate for a primary metabolic alkalosis. o Respiratory acidosis results from an imbalance in CO2 production via metabolism and alveolar minute ventilation in the lung. This is best described by the equation PaCO2 ~ VCO2 / VA where VCO2 is the production of CO2 by the tissues and VA is alveolar minute ventilation. o A respiratory acidosis is the consequence of increased CO2 production or decreased VA. Clinically the most common causes of changes in PCO2 are a result of changes in VA. o When primary metabolic acid-base abnormalities alter pH, it is sensed by both central and peripheral chemoreceptors and there is a resultant alteration in VA to change pCO2 in a manner to reduce the magnitude of pH change (respiratory compensation).

Answer 262

o Because minute ventilation is the product of RR x TV, common causes of a respiratory acidosis are diseases that reduce respiratory rate, tidal volume, or both. o Airway obstruction can impair tidal volume. Depression of the respiratory center of the brainstem as a consequence of drugs (e.g., many anesthetics and sedatives), brain injury, mass lesion, and other conditions can lead to lack of stimulus for VA. o Diseases that prevent transmission of impulses from the respiratory center to the respiratory muscles, such as cervical spinal cord disease, peripheral neuropathies, and diseases of the neuromuscular junction, can all cause respiratory paralysis and respiratory acidosis. Myopathies or muscular fatigue can also occur, impairing respiratory muscle function. o Increases in CO2 production can occur in patients with hyperthermia, seizures, fever, and malignant hyperthermia. The awake, neurologically intact animal should increase VA to compensate for an increase in VCO2 , so generally these abnormalities cause respiratory acidosis in the compromised or anesthetized animal.

Answer 263

o The ideal treatment for respiratory acidosis is resolution of the underlying disease when possible. o In severe cases of hypoventilation that persists despite therapy, mechanical ventilation is indicated. o Elevated levels of CO2 can cause hypoxemia in patients breathing room air, and all animals with significant hypercapnia (>60 mm Hg) should receive oxygen therapy. o It is important to note that bicarbonate therapy is contraindicated in patients with a respiratory acidosis.

Answer 264

o A decreased PCO2 is the result of an increase in VA (decreased CO2 production is not a clinically relevant issue). o A low PCO2 may occur as an appropriate compensatory response to a metabolic acidosis. o Primary disease processes that may stimulate an increased RR or TV include significant hypoxemia, pulmonary parenchymal disease (causing stimulation of stretch receptors or nociceptors), and airway inflammation. o In addition, central stimulation of respiratory rate and effort by the respiratory center can occur. This can be a pathologic process resulting from brain injury or it could be behavioral as a result of pain or anxiety. o An animal’s respiratory rate cannot be used to determine if it is hyper or hypoventilating. o Dead space ventilation, as occurs with panting, can allow a very rapid rate without change to PCO2 while slow respiratory rates can be associated with hyperventilation if larger tidal volumes are generated. Ventilatory status can only be accurately determined by measurement of PCO2. o Treatment of respiratory alkalosis is focused on therapy for the underlying disease; specific therapy for the respiratory alkalosis itself is rarely attempted.

Answer 265

Metabolic acidosis occurs relatively commonly in small animal patients, identified in 43% of dogs and cats that had blood gas analysis at a university teaching hospital.

Answer 266

o Metabolic acidosis caused by bicarbonate loss, typified by hyperchloremia and a normal anion gap, can occur through the intestinal tract via diarrhea or can be due to renal losses. o Hyperchloremic metabolic acidosis in association with small bowel diarrhea has been well reported in human patients and large animal species but is an infrequent occurrence in dogs and cats. o Renal loss of bicarbonate can be an appropriate response to a persistent respiratory alkalosis (metabolic compensation). o When it occurs as a primary disease process, it is known as renal tubular acidosis (RTA). o It can be broadly categorized as proximal or distal tubular dysfunction. In animals with proximal RTA there is inadequate reabsorption of bicarbonate in the proximal nephron. Reported causes in dogs and cats include congenital abnormalities (Fanconi syndrome), as well as acquired abnormalities secondary to toxins, drugs, and various diseases (hypoparathyroidism and multiple myeloma). o Distal RTA is a disorder involving inadequate hydrogen ion secretion in the distal tubule that prevents maximal acidification of the urine; it is often accompanied by hypokalemia and is more rarely reported in the veterinary literature than proximal RTA. Potential causes include pyelonephritis and IMHA. o Hypoadrenocorticism not only leads to hypovolemia and a lactic acidosis but also impairs urine acidification, leading to metabolic acidosis.

Answer 267

o Treatment of metabolic acidosis caused by bicarbonate loss is primarily based on therapy of underlying diseases. o In addition, intravenous (IV) fluid therapy may speed the resolution of this disorder. Fluids containing a “buffer” such as lactated Ringer’s solution will aid in the metabolism of hydrogen ions. o When treating patients with a hyperchloremic metabolic acidosis, use of lower chloride containing fluids (avoiding 0.9% NaCl) will also be of benefit. o When the acidosis is severe or the compensatory respiratory alkalosis is considered detrimental to the patient, bicarbonate administration is indicated.

Answer 268

o Metabolic acidosis caused by a gain in acid is typified by normochloremia and an elevated AG. o The common causes in dogs and cats were mentioned previously (DKA, uremia, lactic acidosis, and ethylene glycol intoxication). Less common causes include D-lactic acidosis and various additional intoxications, including salicylates and methanol. o Treatment of metabolic acidosis caused by an acid gain is primarily focused on resolution of the underlying cause and appropriate selection of IV fluid therapy. o Bicarbonate administration may be beneficial in some uremic patients, but is not typically indicated for treatment of other acidoses. o In a retrospective study of metabolic acidosis in dogs and cats, 25% of dogs and 34% of cats had neither an elevated AG nor hyperchloremia, suggesting there are limitations to this categorization of metabolic acidosis.

Answer 269

o Metabolic alkalosis appears to be less common in small animal patients, in 15% of a population of dogs and cats compared with metabolic acidosis in 43% of these animals. o Metabolic alkalosis broadly can be considered to occur because of either acid loss or bicarbonate gain. o Causes of acid loss include selective gastric acid loss such as can occur with gastrointestinal obstructive processes (leading to sequestration or vomiting) and nasogastric tube suctioning. o Renal acid loss can occur as a result of loop diuretic administration, mineralocorticoid excess, and the presence of non- reabsorbable anions such as carbenicillins. o Acid loss invariably occurs along with chloride in the gastrointestinal tract and renal system and as a result many animals with metabolic alkalosis will also be hypochloremic o Increases in bicarbonate concentration can occur as an appropriate renal compensation to a respiratory acidosis. o Pathologic increases in bicarbonate concentration can also occur with contraction alkalosis, iatrogenic administration of an alkalinizing therapy (sodium bicarbonate), or metabolism of organic anions such as lactate, ketones, acetate, and citrate. o Hypokalemia can play a significant role in the generation and maintenance of metabolic alkalosis. Intracellular shifts of hydrogen ions in exchange for potassium ions leaving the cells will increase the pH of the extracellular fluid. Further, hypokalemia promotes renal acid loss - in A cells of distal tubule, K will be reabsorbed in exchange for H+ (acid loss, retention of K+). o The kidney has the ability to excrete large quantities of bicarbonate, such that metabolic alkalosis should be rectified rapidly. When metabolic alkalosis is persistent, there must be factors limiting renal bicarbonate excretion. o Decreased effective circulating volume and hypochloremia can both limit renal bicarbonate excretion. Hypokalemia and aldosterone excess further impair renal bicarbonate excretion.

Answer 270

It occurs when a large volume of sodium-rich, bicarbonate low fluid is lost from the body. This occurs with diuretic use, cystic fibrosis, congenital chloride diarrhea, among others. The net concentration of bicarbonate increases as a result. This pathology is easily counteracted by the release of H+ from intracellular space to balance the pH in most incidences.

Answer 271

1) Ensure there is adequate effective circulating volume. 2) Normalize electrolytes 3) When possible, correct the primary disease

Answer 272

Decreased myocardial contractility, arterial vasodilation, impaired coagulation, decreased renal and hepatic blood flow, insulin resistance, and altered central nervous function.

Answer 273

o Sodium bicarbonate is the most common alkali therapy used in veterinary medicine. o Alternative alkalinizing therapies include tris-hydoxymethyl aminomethane (also known as tromethamine [THAM]) and Carbicarb, an equimolar mixture of sodium bicarbonate and sodium carbonate. These alternative buffer therapies may have the advantage of having no (THAM) or less (Carbicarb) associated CO2 production than sodium bicarbonate.

Answer 274

o No o Sodium bicarbonate therapy does not reliably increase pH. After administration, the bicarbonate binds hydrogen ions (hence the alkalinizing effect) to form carbonic acid; this rapidly dissociates to CO2 and water. o If ventilation does not increase appropriately, an elevated pCO2 will cause a decrease in pH. For this reason, sodium bicarbonate therapy is strictly contraindicated in patients with evidence of hypoventilation.

Answer 275

o Of greater concern is the paradoxical intracellular acidosis that has been shown to occur after sodium bicarbonate administration. o Bicarbonate cannot freely cross cell membranes, but the CO2 produced as bicarbonate is metabolized can freely enter cells. o Once intracellular, the CO2 combines with water, leading to hydrogen ion release and causing intracellular acidosis. Many animal studies have demonstrated decreases in cellular and cerebrospinal fluid pH after bicarbonate therapy. o Bicarbonate therapy has also been associated with increases in blood lactate concentration in studies of lactic acidosis, hemorrhagic shock, and DKA. The exact mechanism for this response is not known, but left shifting of the oxygen-hemoglobin dissociation curve because of increases in blood pH may play a role.

Answer 276

o If a specific therapy exists for the underlying cause of a metabolic acidosis, this in combination with appropriate IV fluid therapy should be the focus of treatment and bicarbonate therapy is not indicated. o This is particularly relevant to animals with lactic acidosis or DKA, where bicarbonate therapy has been associated with no improvement in outcome or clinical deterioration despite severe acidemia. o It is likely that bicarbonate therapy will be beneficial in the treatment of diseases causing bicarbonate loss, such as chronic kidney disease and diarrhea (an uncommon cause of metabolic acidosis in small animal patients). o The role of bicarbonate therapy in the management of patients with acute kidney injury (AKI) is less well defined. o Because renal replacement therapy is rarely available for veterinary patients, the use of bicarbonate for management of metabolic acidosis and hyperkalemia is a reasonable option, although caution must be used to avoid volume overload in the oliguric or anuric patient.

Answer 277

o There is no exact method by which to determine a sodium bicarbonate dose. o An approximate dose can be calculated from the following formula: Sodium Bicarbonate Dose (mmol) = 0.3 × BW (kg ) × Base Deficit where 0.3 is an approximate value for the distribution of bicarbonate, BW(kg) is the patient body weight in kilograms, and base deficit (mmol/L) is a calculated value provided by the blood gas machine (or can be approximated by patient’s measured bicarbonate concentration minus the normal bicarbonate concentration). o This dose would theoretically return the blood bicarbonate concentration back to normal. It is common practice to only give a portion of this calculated dose (50% to 80%) in order to avoid causing an iatrogenic metabolic alkalosis. o This is of particular concern when other simultaneous therapies may contribute to resolution of the metabolic acidosis. Because there is no way to accurately determine an appropriate bicarbonate dose, bicarbonate therapy should be guided by frequent reevaluation of acid-base status.

Answer 278

o Hypertonic sodium bicarbonate should never be administered rapidly (other than in the cardiopulmonary resuscitation setting) because it can cause vasodilation and increases in intracranial pressure, which can be fatal. o It can be given slowly (over 30 minutes or longer) or diluted with sterile water to make it an isotonic solution. Dilution usually results in a significant volume for administration. o The rate of infusion should then be governed by the perceived fluid tolerance of the patient. If the hypertonic sodium bicarbonate solution is not diluted to an osmolality of less than 600 mOsm/L, it should be given via a central catheter to avoid phlebitis. o The commercially available 8.4% sodium bicarbonate solution has an osmolality of approximately 2000 mOsm/L, so a dilution of 1 part sodium bicarbonate to 3 parts diluent (sterile water for injection) would be appropriate for peripheral venous administration. o Before giving sodium bicarbonate, clinicians should consider their level of concern for the increase in intravascular volume and the potential for hypernatremia, hyperosmolality, hypercapnia, hypokalemia, and hypocalcemia (ionized) in the patient.

Answer 279

o Stewart approach and semi-quantitative o Evaluation of respiratory acid- base balance is similar across all diagnostic approaches. o The nontraditional or quantitative approaches to acid-base analysis provide alternative methods to evaluate the metabolic contribution. o The major criticism of the traditional approach to metabolic acid-base disorders is its failure to identify individual disease processes that contribute to a metabolic acid-base abnormality. The nontraditional approaches may provide greater insight to underlying causes of metabolic acid-base abnormalities.

Answer 280

o According to the Stewart approach there are three independent determinants of acid-base balance: - pCO2 - The difference between strong cations and strong anions, known as the strong ion difference (SID) - Total weak acids (ATOT). o The quantity of hydrogen (or bicarbonate) ions added to, or removed from, the system is not considered relevant to the final pH because hydrogen ion concentration is not an “independent” variable. o SID and ATOT are proposed to affect H+ concentration directly by altering the dissociation of water via electrochemical forces. o Ultimately the Stewart approach is able to identify five metabolic acid-base abnormalities

Answer 281

o Strong ions are ions that are fully dissociated at physiologic pH. o The major strong ions include sodium, potassium, calcium, magnesium, and chloride. Some authors include other anions as strong ions, such as lactate and ketoacids. o The formula used to calculate SID is based on the total quantity of strong cations minus the quantity of strong anions. The exact formula used varies depending on the ions included in the calculation. o Quantitatively, sodium and chloride are the most important strong ions in the body and SID is commonly simplified as the difference between serum sodium and chloride concentrations. o It is important to note that changes in SID will reflect changes in bicarbonate concentration if ATOT remains constant. o A decreased SID metabolic acidosis can be due to hyponatremia, hyperchloremia, or a combination of the two. o Conversely, an increased SID metabolic alkalosis may be due to hypernatremia, hypochloremia, or both. o Treatment of abnormalities in SID generally focuses on fluid therapy to restore SID to normal. o The SID of intravenous fluids can be determined as it is for plasma. This value can help guide fluid selection for patients with SID abnormalities. For example, a patient with an increased SID alkalosis may benefit from a fluid with a low SID such as 0.9% saline (SID = 0). o In contrast, a patient with a decreased SID acidosis may be best treated with an IV fluid with a higher SID such as lactated Ringer’s with an effective SID of approximately 28 mmol/L (after the lactate is metabolized). o Sodium bicarbonate is a fluid with a very high SID because bicarbonate is not counted as having any effect. As a result, sodium bicarbonate with a concentration of 2000mmol/L has a SID of approximately 2000mmol/L and is therefore considered an effective treatment of patients with a low-SID metabolic acidosis.

Answer 282

• Decreased SID metabolic acidosis • Increased SIG metabolic acidosis • Increased ATOT metabolic acidosis • Increased SID metabolic alkalosis • Decreased ATOT metabolic alkalosis

Answer 283

o Weak acids are only partially dissociated at physiologic pH. The major contributors to ATOT are albumin and phosphate. o Because the dissociation of these substances varies with pH, there are complex formulas to calculate ATOT. o Constable and colleagues have also developed simplified equations to estimate the plasma protein contribution to ATOT using a species-specific dissociation constant (Ka), for dogs and cats. o For dogs the net protein charge is 0.25 mEq/g for total protein or 0.42 mEq/g for albumin. The net protein charge for cats is 0.19 mEq/g of total protein or 0.41 mEq/g of albumin. o Because ATOT represents a value for weak acids, increases in ATOT indicate a metabolic acidosis and decreases in ATOT (primarily from decreased albumin) indicate a metabolic alkalosis. o Treatment of abnormalities of ATOT aim to normalize the levels of albumin and phosphate when possible.

Answer 284

o The strong ion gap (SIG) is the Stewart evaluation of unmeasured anions in a manner similar to the use of anion gap (AG) in traditional acid-base analysis. o The SIG can be calculated from the SID minus the contribution of bicarbonate and ATOT. o If there are no unmeasured anions (SIG = 0) in the system, the SID should equal the sum of the contributions of bicarbonate and ATOT. If unmeasured cations are present in the system, this reduces the value determined for SIG. A simplified formula for the calculation of SIG has been developed: for dogs as SIGsimplified = ([alb] × 4.9) − AG for cats it is SIGsimplified = ([alb] × 7.4) − AG. o This simplified approach does not account for changes in phosphate concentration; in the presence of hyperphosphatemia the SIGsimplified is determined by first modifying the AG equation with the following formula: AGphosphateadjusted = AG + (2.52−0.58×[phosphate]) o Increases in SIG, like increases in AG, reflect the presence of unmeasured anions (e.g., lactate, sulfates, ethylene glycol, ketones, etc.), which are assumed to have an acidifying influence on the system. o There are many different formulas for determination of SIG in the literature, some of which include additional anions, such as lactate, and therefore affect interpretation of the SIG. A major advantage of SIG over AG is that it is independent of changes in albumin concentration. As a result, SIG is more sensitive to the presence of unmeasured anions in hypoalbuminemic patients.

Answer 285

o Increases in SIG, like increases in AG, reflect the presence of unmeasured anions (e.g., lactate, sulfates, ethylene glycol, ketones, etc.), which are assumed to have an acidifying influence on the system. o A major advantage of SIG over AG is that it is independent of changes in albumin concentration. o As a result, SIG is more sensitive to the presence of unmeasured anions in hypoalbuminemic patients.

Answer 286

o It is a combination of the traditional and Stewart methods. o This approach has been variably called the Stewart-Fencl approach, the Stewart-Figge approach, semi-quantitative analysis, and base excess partitioning.

Answer 287

o Uses equations to estimate the magnitude of effect of individual acid-base processes on base excess (BE); each acid-base process is represented by one of five parameters. These parameters are: 1) A free water effect (marked by sodium concentration) 2) An effect represented by changes in chloride concentration 3) An albumin effect 4) A phosphate effect 5) A lactate effect. o Differences between the sum total of all these calculated effects and the BE are attributed to the presence of unmeasured (unknown) acids or bases. o Semi-quantitative acid-base analysis as presented here requires measurement of pH and PCO2, determination of BE, and measurement of as many of the following parameters as possible: sodium, chloride, albumin, lactate, and phosphate. From these measured parameters, 10 metabolic acid-base influences can be identified and the magnitude of their contribution to the overall BE estimated. o Negative contributions indicate an acidotic influence on BE, whereas a positive calculated effect indicates an alkalotic influence.

Answer 288

o The free water effect on BE is due to changes in the water balance. o Clinically, the free water concentration is marked by sodium concentration; a deficit of free water causing hypernatremia and an excess of free water causing hyponatremia. o An excess of free water (hyponatremia) will be evident by a negative free water effect indicating an acidotic effect (dilutional acidosis). o A deficit of free water (hypernatremia) will be evident by a positive free water effect indicating an alkalotic effect (contraction alkalosis). Free water effect Dogs - 0.25([Na+] − mid-normal [Na+]) Cats - 0.22([Na+] − mid-normal [Na+])

Answer 289

o In many processes within the body, chloride and bicarbonate are reciprocally linked (i.e., when a chloride ion is excreted, a bicarbonate ion is retained and vice versa). o Such processes include gastric acid secretion, intestinal bicarbonate secretion, renal acid-base handling, and transcellular ion exchange. o Evaluation of the change in chloride concentration can therefore be used to estimate the contribution to BE made by these processes. Because chloride concentration will also be altered by changes in free water concentration, it needs to be corrected before calculation of the chloride effect: Measured [Cl−] × (mid-normal [Na+]/ measured [Na+]) o The difference between this corrected chloride concentration and the patient’s normal chloride concentration (the mid- normal value for chloride for that species is usually used) estimates the contribution to BE by processes associated with the change in chloride concentration. Mid-normal [Cl−] − corrected [Cl−] o An increased (positive) chloride effect is associated with a process that increases bicarbonate concentration and is indicative of an alkalotic process; a decreased chloride effect (negative) marks an acidotic process.

Answer 290

o Albumin acts as a weak acid. o Hypoalbuminemia is equivalent to the removal of a weak acid from the system; it is evident as a positive effect and indicates an alkalotic effect. o Conversely, hyperalbuminemia will be evident as a negative effect, indicating an acidotic influence. 3.7(mid-normal [albumin] − measured [albumin])

Answer 291

o Phosphoric and sulfuric acids are products of protein metabolism and are normally excreted by the kidneys. o Patients with acute kidney injury or failure retain these acids, resulting in a metabolic acidosis. The phosphoric acid contribution toward BE, from a given inorganic phosphorus concentration can be determined: 0.58 (mid-normal [phosphate] − measured [phosphate]) o Elevated phosphorus will cause a negative effect and indicates an acidotic influence on BE. o Because serum phosphorus concentration is normally low, hypophosphatemia does not cause a clinically significant alkalosis. Sulfate is not usually measured and is therefore one of the unmeasured anions.

Answer 292

o In acute clinical scenarios of lactic acidosis caused by anaerobic metabolism, lactate has an equimolar effect on BE. o Elevations in lactate concentration will be evident as a negative calculated effect (acidotic influence). −1 × [lactate] o There are causes of hyperlactatemia that are associated with little or no acidosis, such as cytokine or catecholamine stimulation of glycolytic rate. o In addition, blood samples contaminated with sodium lactate (e.g., from lactated Ringer’s) will also show an increase in lactate with no acidosis. o As a result, some clinical judgment is required when including the lactate value in the calculations.

Answer 293

o The quantitative approach identifies many of the relevant contributors to the metabolic acid-base component. o The difference between the sum of these identified effects and the patient’s BE represents unidentified acids or bases contributing to the acid-base equilibrium. XA = Base excess − sum of effects o Unmeasured acids include ketoacids, sulfuric acid, ethylene glycol, salicylic acid, propylene glycol, and metaldehyde. o As with the SIG value, the parameter XA is not affected by changes in albumin concentration, making it a more sensitive measure of unmeasured anions.