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Home , Metastatic calcification, Vitamin D toxicity

METABOLIC EMERGENCIES J.S. Wohl, DVM, ACVIM, ACVECC D.K. Macintire, DVM, MS, ACVIM, ACVECC Auburn University Critical Care Program Auburn University, AL

DISORDERS OF SODIUM AND CHLORIDE Sodium and chloride are the major extracellular ions and are regulated under strict homeostatic mechanisms. Sodium regulation is closely regulated with total body water and as such, changes in sodium concentration can be thought of as changes in free water. For example, is essentially relative free water excess and signifies free water deficit. Chloride derangements can also be affected by free water balance but can also denote changes in metabolic acid-base status. The most common abnormality of sodium and chloride is concurrent hyponatreemia and in vomiting animals that are allowed to drink water. In this derangement, animals experience isotonic fluid loss through vomiting and replace the volume deficit with hypotonic water. This phenomenon can also result from third space diseases (eg. ascites, plural effusion, vasculitis) where again, animals replace isotonic fluid loss into the third spaces by drinking hypotonic water. Hyponatremia Free water excess is a disturbance of the renal hypothalamic/pituitary axis or in rare cases primary polydipsia. Sodium, as the major extracellular cation, is the major determinant of plasma osmolality. In hypo-osmolar states, the expected response would be suppression of anti diuretic hormone (ADH) and increased free water excretion by the kidneys resulting in dilute, hyposomolar urine. The increased water excretion normalizes plasma osmolality and sodium concentrations. Severe volume depletion can override the effects of hypo-osmolality on pituitary and stimulate ADH secretion. With increased ADH release, water is conserved by the kidneys and hypo-osmallity, hyponatremia, and free water excess can persist or become exacerbated. In some cases of renal failure, hyponatremia may occur if the kidneys are unable to excrete excess water due to decreased glomerular filtration rate or severe volume depletion as described above. Primary polydipsia is a rare behavioral disorder characterized by excessive drinking. Usually, animals are able to maintain normal sodium concentration because renal concentrating ability is not impaired. In extreme cases, the renal hypothalamic/pituitary access is overwhelmed and hyponatremia can result. Hormonal causes of hyponatremia include hypoadrenocorticism and syndrome of inappropriate ADH secretion (SIADH). Aldosterone insufficiency accompanies hypoadrenocorticism and is largely responsible for hyponatremia commonly seen in this disease. Hyponatremia may be complicated in the Addisonian patient by severe volume depletion (and secretion of ADH) resulting from vomiting and diarrhea. Inappropriate ADH secretion is a rare disorder characterized by increased ADH release independent of abnormal plasma osmolar or volume states. SIADH has been reported in intracranial neoplasia and heartworm disease but is very rare. Drugs such as vincristine and barbiturates may stimulate ADH secretion. Dilutional hyponatremia can occasionally occur iatrogrenically during intravenous fluid therapy. Dilutional hyponatremia is more likely to occur with hyperosmolar fluid administration though, generally, animals with normal function are resistant to hyponatremia. Hyponatremia may result from hyperosmolar states such as severe diabetic hyperglycemia where water is drawn into the intravascular space from interstitial and intracellular compartments. Diagnosis of hyponatremia is based on measurement of plasma sodium concentration. When severe hyperlipidemia is present, sodium concentration may be artificially low. Therefore serum should be evaluated for lipemia or elevated triglyceride concentration prior to confirming pathologic hyponatremia. Clinical signs such as depression, muscular weakness, and central abnormalities are usually absent unless hyponatremia is severe (< 130mEq/L). When true hyponatremia (< 140 mEq/L) is confirmed, the patient should be evaluated for signs of severe volume contraction, other disease processes that can be associated with markedly decreased renal perfusion (eg. hypoadrenocortism, congestive failure, liver disease, renal disease) or hyperosmolar states (eg. diabetes) and third space fluid accumulation (eg. ascites, pleural effusion, vasculitis). Volume deficits should be replaced by intravenous isotonic sodium chloride administration. Identified primary diseases should be treated appropriately. In cases where no underlying mechanism can be identified on physical exam or initial blood work or when hyponatremia is severe and associated with clinical signs, plasma and urine osmolality should be measured. If urine osmolality is markedly dilute in the presence of plasma hyposmolality, primary polydipsia should be suspected. Primary polydipsia is manageged with behavior modicifcation and gradual water restricition. Urine osmolality greater than serum osmolality is consistent with a mechanism of inappropriate ADH secretion. Adminsitration of 3% sodium chloride can be used if severe hyponatremia and clinical signs are present. Adminsitration of hypertonic saline infusions should be administered judiciously and plasma sodium concentration should be monitored frequently. Hypernatremia Hypernatremia (> 160 mEq/L) or free water deficit is most commonly associated with excessive hypotonic fluid loss. The most common example of hypotonic fluid loss is diarrhea but may also occur during osmotic diuresis (eg. diabetes, mannitol administration). In diabetes insipidus (DI), an inability to secrete ADH during hyperosmolar states can result in progressively severe hypernatremia. However, severe hypernatremia and hyperosmolality usually do not occur unless the DI patient is deprived of oral water intake. In the absence of ADH, DI patients will continue to loose free water through the kidney despite volume contraction and urine osmolality will be dilute while plasma osmolality and sodium concentration progressively elevate. Without volume repletion, DI patients can rapidly undergo vascular collapse and renal shutdown. Patients with hypernatremia may exhibit seizures, twitching, coma, muscular weakness, and varying signs of volume contraction and interstitial dehydration. Neurons are susceptible to intracellular dehydration during severe hyperosmolar states and lead to intracranial hemorrhage and thrombosis. Pateints should be treated with intravenous administration of isotonic sodium chloride until hemodynamic stability is restored. Following initial fluid therapy, half-strength saline with 5% dextrose can be administered. If the onset of hypernatremia has been associated with chronic free water loss disorders (eg. diabetes insipidus, prolonged diarrhea) plasma osmolality should not be reduced faster than 2 mOsm/hr over the first 48 hours. In chronic states of hyperosmolality, brain neurons develop ideogenic osmoles from intracellular amino acids to combat the extracellular hypertonicity. Rapid shifts in extracellular osmolality can therefore result in rapid influx of fluid into brain neurons and cerebral edema. Chloride abnormalities Chloride is the major extracellular anion. As it is a physiologic necessity to maintain electronuetrality, chloride ion will typically change in correspondence to changes in sodium (and hence free water). However, changes in acid-base status can affect the degree to which extracellular chloride ion serves as the major anion in balance with sodium. Blood gas and acid-base analysis and evaluation of the anion gap is used to distinguish chloride disorders due to acid-base derangements from changes in free water. However, chloride concentration changes in the presence of normal sodium concentration typically denote an acid base disturbance. For example, an elevated chloride concentration in the presence of normal sodium concentration and normal calculated anion gap suggests metabolic acidosis. Metabolic acidosis associated with loss of bicarbonate ion (eg. diarrhea, renal tubular acidosis) will result in compensating renal retention of chloride and subsequent increases in plasma chloride ion concentration independent of changes in plasma sodium concentration. In contrast, metabolic alkalosis due to chronic vomiting of gastric contents leads to whole body chloride depletion and volume contraction. The resultant renal retention of sodium induced by volume contraction is accompanied by bicarbonate ion rather than chloride ion due to concurrent chloride depletion. Metabolic alkalosis can also result from chloride depletion during loop and thiazide diuretic administration by a similar mechanism. As volume contraction and reduced whole body chloride are elements in the propagation of metabolic alkalosis, volume expansion with isotonic sodium chloride is effective in reestablishing acid-base homeostasis.

DISORDERS OF POTASSIUM HOMEOSTASIS Hypokalemia is probably the most common electrolyte abnormality recognized in critical veterinary patients. Clinical signs include muscle weakness, cramping, lethargy, myocardial depression, ileus, urine retention, inability to concentrate urine, and mild hypoglycemia from decreased insulin secretion. Severe potassium depletion can result in death from paralysis of respiratory muscles. Hypokalemia can be caused by conditions of decreased intake, excessive losses, or translocation of potassium to the intracellular space. Animals with , vomiting and diarrhea are prone to hypokalemia, especially if they are given intravenous fluids deficient in potassium. Animals with pancreatitis, peritonitis, parvo viral enteritis and another causes of vomiting will generally require potassium supplementation to maintain normal serum levels. Fluids containing 14-20 mEq/L will usually keep potassium levels from falling below the normal range in conditions where decreased intake or excessive losses are expected. Excessive renal losses can be seen in patients with chronic renal failure, the recovery or diuretic phase of acute renal failure, and the post obstructive diuresis which commonly occurs in male cats after they are unobstructed. Serum potassium levels should be checked frequently in these patients. If hypokalemia occurs, potassium supplementation can be administered according to the sliding scale in Table 1. It is important not to exceed the rate of 0.5 mEq/kg/L when administering potassium supplementation IV, as serious arrhythmias or asystole can occur if it is given too rapidly. Diabetic animals, particularly those which are ketoacidotic, are also prone to hypokalemia. Sick diabetic animals are often depleted of total potassium body stores through increased urinary and GI losses and decreased intake. Serum potassium levels will appear falsely elevated in animals with acidosis, because potassium has moved extracellularly. For each change in blood pH of 0.1 units, an inverse change in serum potassium of approximately 0.6 mEq/L can be expected because of translocation. Serum potassium levels can drop precipitously following treatment with insulin and correction of acidosis. Therefore, potassium levels must be monitored closely in sick diabetic patients, and if hypokalemia is present, potassium supplementation should be instituted before aggressive treatment with insulin is begun. A condition in cats referred to as feline hypokalemic polymyopathy syndrome was first reported in 1984. Clinical signs included generalized muscle weakness, cervical ventroflexion, elevated CPK levels, severe hypokalemia, and remission of signs with potassium supplementation. Most affected cats were geriatric and had evidence of chronic renal disease. It was determined that many commercial feline diets did not contain adequate levels of potassium for cats with increased losses from chronic renal disease. Most diets today contain adequate amounts (0.6 - 0.7% potassium/dry matter) and this syndrome has become infrequent. However, cats with chronic renal disease and other causes of increased losses or decreased intake are at risk for developing hypokalemia. Potassium depletion can worsen progressive renal damage through decreased ability to autoregulate GFR and increased ammoniagenesis which can be toxic to tubular and interstitial cells. Therefore cats with chronic renal failure and other conditions associated with increased potassium losses should receive oral supplementation of potassium gluconate at a dose of 2-4 mEq/cat/day. Cats accept the potassium gluconate gel fairly readily, but oral potassium chloride liquid is generally unpalatable to cats and may cause vomiting. Enteric tablets are poorly absorbed and also cause GI irritation. Potassium supplementation can also be safely given in subcutaneous fluids at concentrations up to 30 mEq/L.

Table 1. Potassium Replacement

Serum K (mEq/L) KCl Added to 1 L of Fluids Max. Rate (ml/lb/hr)* (mEq/L)

3.6-5.0 20 12

3.1-3.5 30 8

2.6-3.0 40 5.5

2.1-2.5 60 4

<2.0 80 3 * So as not to exceed 0.5 mEq/kg/h Elevated serum potassium levels can be a life-threatening emergency because of effect on the myocardium. Progressive abnormalities on the electrocardiogram are noted. Mild hyperkalemia is associated with peaked T waves, decreased amplitude of the R wave and prolongation of the P-R interval. As serum potassium levels increase, flattening of the P wave, bradycardia, prolongation of the QT interval and widening of the QRS complex can occur. Severe life-threatening hyperkalemia can cause a sinoventricular rhythm, ventricular fibrillation, asystole, and cardiac arrest. Causes of hyperkalemia in veterinary patients include hypoadrenocorticism (Addison's disease), acute origuric renal failure, ruptured bladder or urethral tear, urethral obstruction, severe crushing injuries, heatstroke, or massive cellular destruction (, tumor lysis syndrome, overwhelming infections, thromboembolism). Hyperkalemia can also be caused by iatrogenic factors including overdosage of potassium sparing diuretics and overzealous potassium supplementation. Treatment of life-threatening hyperkalemia involves removal of the underlying cause and implementation of immediate steps to stabilize cell membranes and promote intracellular translocation of potassium. This can be accomplished through 3 different mechanisms. First, a slow intravenous bolus of sodium bicarbonate (1 - 2 mEq/kg) can be administered. This is the treatment of choice in animals with Addison's disease. It is also effective in most obstructed cats, but in some may promote . Obstructed cats often have low serum levels secondary to high levels. Administration of sodium bicarbonate lowers ionized calcium levels and may cause signs of tetany or muscle tremors. The preferred method for lowering serum potassium in these patients is to administer an insulin/dextrose combination by IV bolus (0.25 - 0.5 U/kg regular insulin with 2 g glucose per unit insulin). This is diluted to a 5 - 10% solution and given by IV push. Dextrose (2.5 - 5%) should be added to subsequent fluids to prevent hypoglycemia. A final treatment which can be used in animals with life-threatening hyperkalemia is 10% calcium gluconate (50-100 mg/kg) given by slow IV bolus while monitoring heartrate and electrocardiogram. Calcium protects the myocardium from the arrhythmogenic effects of hyperkalemia. Some animals may require all 3 treatments to stabilize the myocardium. Animals without life-threatening cardiac abnormalities generally do not require specific therapy for reducing hyperkalemia, other than removal of the underlying cause and dilutional fluid therapy. After the underlying cause is removed, continued diuresis is generally required to enhance renal potassium excretion. Animals with acute oliguric renal failure may require peritoneal dialysis or hemodialysis if urine flow can not be initiated by pharmacologic means. The best fluid choice for hyperkalemic animals is somewhat controversial. Potassium free fluids are often recommended (5% Dextrose in water, 0.9% sodium chloride) but these may worsen sodium imbalance and are not buffered solutions which will help correct acidosis. For severe hyperkalemia (> 10 mEq/L), a potassium free fluid should be chosen for initial fluid therapy. Otherwise, lactated Ringer's solution, which contains 4 mEq K+/L, appears to be the most physiologic choice for animals with normal renal function once the underlying cause of hyperkalemia is removed.

DISORDERS OF PHOSPHORUS BALANCE Like magnesium and potassium, phosphorus is present in the body primarily as an intracellular ion. It is important for energy production (co-factor for gycolysis, needed to form ATP) and cell membrane maintenance (component of phospholipid membrane). Serum phosphorus concentration is regulated by dietary intake; renal excretion; insulin, glucose, alkalosis and other factors which promote transcellular movement; and interactions of the regulatory hormones D and PTH. Severe aberrations must be recognized and corrected, or death may result.

Hypophosphatemia Until recently clinically significant decreases in serum phosphorus levels have been considered uncommon. Now is increasingly being recognized as a problem in critically ill humans and animals. Clinical sequelae of hypophosphatemia include hemolysis, skeletal muscle weakness, leukocyte dysfunction, and poor oxygenation of tissues due to reduced 2,3 DPG levels. "Nutritional recovery syndrome" was first recognized in prisoners of war following World War II. Aggressive feeding following prolonged malnutrition resulted in a syndrome of lethargy, depression, diarrhea, and multiple electrolyte abnormalities. It was later determined that malnourished patients are very prone to hypophosphatemia with re-feeding. Glucose and phosphorus are transported into the cell as a result of insulin secretion. Phosphorus is a co-factor for glycolysis and is rapidly consumed, sometimes dropping to dangerously low levels. The same syndrome can be seen in veterinary patients who receive enteral nutrition or intravenous dextrose solutions following a period of malnutrition. Hypophosphatemia can be prevented by gradually increasing feeding over several days to eventually achieve full caloric requirements and avoiding overzealous feeding with high carbohydrate diets. Another cause of clinically significant hypophosphatemia is insulin therapy in patients with diabetic ketoacidosis. The problem usually occurs as acute hemolysis, lethargy, and weakness several days after beginning treatment with insulin and intravenous fluids. Hypophosphatemia may be caused by or enhanced by aluminum hydroxide products which bind phosphorus absorption in the gut. Sucralfate also binds phosphorus. These agents should be discontinued in hypophosphatemic patients and should not be used in animals prone to hypophosphatemia. For example, male cats with post obstructive diuresis may initially present with and azotemia, but can develop hypophosphatemia from excessive renal losses. Therefore, the use of phosphate binders should be avoided in these animals. Although the mechanism is not clear, hypophosphatemia can be an early sign of sepsis, and unexplained decreases in serum phosphorus levels should prompt a search for infection. The decline in phosphorus may be secondary to the hypermetabolic state or the respiratory alkalosis which both occur early in sepsis. Hypophosphatemia should be treated with intravenous replacement when serum phosphorus levels drop below 1.0 mg/dl or when clinical signs attributable to hypophosphatemia are evident. Complications of intravenous replacement can include hyperphosphatemia, hypocalcemia, tetanic seizures, soft tissue mineralization. and hypotension secondary to rapid infusion. To avoid risk, phosphorus must be administered slowly and cautiously, and serum levels should be monitored q 6 hours. Replacement can be discontinued when serum levels reach 2.0 - 2.5 mg/dl. Potassium phosphate is available in a solution containing 3 mmols/ml phosphate (93 mg/ml) and 4.3 mEq/ml potassium. Most veterinary references recommend a dosage of 0.01-0.03 mmol/kg to be given over 6 hours and continued for another 6 hours if the phosphorus levels remain low. This dosage is safe but may be inadequate for animals with severe depletion. A recommended dose for humans is 7.7 mg/kg (0.025 mmol/kg) administered over 4 hours. Potassium phosphate must be administered in calcium free solutions, such as 0.9% NaCl instead of lactated Ringer's). Although some texts recommend giving half of the potassium requirement as potassium phosphate, this protocol can result in overdosage of phosphorus because the potassium deficit greatly exceeds the phosphorus deficit in most patients. Phosphorus replacement can safely be accomplished by the oral route in patients not exhibiting severe clinical signs at a dosage of 0.5-2 mmol/kg/day. Cow's milk contains 0.029 mmol/ml of phosphorus.

Hyperphosphatemia Increases in serum phosphorus levels are most commonly seen in veterinary patients with renal failure. Decreased GFR results in phosphorus retention. Other causes include massive cellular damage (tumor lysis syndrome, rhabdomyolysis, snakebite, thromboembolism), hypoparathyroidism, and from hypertonic sodium phosphate enemas or . Iatrogenic causes include over-zealous phosphorus replacement or overdosage of phosphorus containing urinary acidifiers. Mild elevation of phosphorus is considered normal in young growing dogs. Clinical findings include diarrhea, hypocalcemia, tetany, hyperosmolality, hypernatremia, and metastatic of soft tissues when the calcium/phosphorus product exceeds 58. Hyperphosphatemia also contributes to the progression of renal disease by stimulating renal secondary . Hyperphosphatemia is treated with intravenous fluids to correct acidosis and promote phosphorus excretion. Fluids containing dextrose promote intracellular translocation. Animals with renal failure should receive a low phosphorus diet, and intestinal phosphate binders should be administered with food to prevent gastrointestinal absorption.

DISORDERS OF MAGNESIUM BALANCE Recent reports in human critical care patients indicate a very high incidence (>50%) of hypomagnesemia. Although serum magnesium is infrequently measured in veterinary patients it is likely that certain populations of critically ill animals would be at risk for magnesium imbalance as well. A report of 101 critically ill dogs admitted to the Intensive Care Unit at Colorado State documented that magnesium imbalance was the most common electrolyte abnormality, with 30% exhibiting and 20% hypomagnesemia. Magnesium is the second most abundant intracellular cation. Most of the total body Mg++ is present in and skeletal muscle with only 1% present in the serum. Unfortunately, because of the dynamic nature of Mg++ homeostasis, serum Mg++ measurements may not accurately reflect total body stores. Magnesium is a co-enzyme for the Na/K ATPase, calcium ATPase, and proton pumps. It is essential for many metabolic functions including ATP production and synthesis of nucleic acids and proteins. It helps regulate smooth muscle vascular tone and may influence lymphocyte activation and cytokine production.

Hypomagnesemia The primary causes of include decreased intake, increased losses, and alteration of distribution. Factors which may predispose critical patients to hypomagnesemia include stress, catabolic illness, nasogastric suctioning, peritoneal dialysis, TPN, diuretics, massive blood transfusions, and aggressive IV fluid therapy with Mg++ deficient fluids. Because similar conditions cause hypokalemia and/or hypophosphatemia Mg++ deficiency may be unrecognized and over looked. In fact, concurrent hypokalemia may be refractory to treatment with aggressive K+ replacement until the Mg++ deficit is corrected. Clinical signs of hypomagnesemia include cardiac arrhythmias, muscle weakness, tremors, seizures, altered mentation, esophageal motility disorders, and respiratory muscle paralysis. Normal serum Mg++ concentrations range from 1.89 - 2.51 mg/dl. If an animal exhibits clinical signs (cardiac arrhythmias, muscle tremors, refractory hypokalemia) and serum Mg++ levels are <1.2 mg/dl, magnesium supplementation can be considered. Mild deficits can be corrected by intravenous fluids which contain Mg++ (Normasol-R, Plasmalyte). In cases of severe Mg++ depletion, magnesium chloride or magnesium sulfate can be added to 5% Dextrose in water at an initial dose of 0.75 - 1.0 mEq/kg/day and continued at half of the initial dosage for 3-5 days. For life-threatening ventricular arrhythmias, digitalis- induced arrhythmias, or cardiac arrest, a dose of 0.15 - 0.3 mEq/kg (50-100 mg/kg) can be diluted in 5% Dextrose or 0.9% saline and administered slowly IV over 5-15 minutes to raise the ventricular fibrillation threshold. The side effects or risk of intravenous magnesium therapy include hypocalcemia, hypotension, and cardiac conduction abnormalities (atrioventricular and bundle-branch blocks). Overdoses can be treated with calcium gluconate (10-50 mg/kg IV). Magnesium can also be given orally at a suggested dose of 1-2 mEq/kg/day. It is available as oxide or hydroxide salts. At the present time, disorders of hypermagnesemia are not considered to be clinically significant in critical patients, unless they are associated with signs of hypocalcemia. Obviously, magnesium supplementation is contraindicated in animals with elevated serum Mg++ levels.

DISORDERS OF CALCIUM METABOLISM Calcium is involved in vital metabolic functions such as membrane transport, coagulation, nerve conduction, muscle contraction, vascular tone, hormone release, bone formation and remodeling, hepatic glycogen metabolism, and cellular growth and division. Homeostatic control mechanisms involve bone, the kidneys, and the gastrointestinal tract. The hormones (PTH), (or Vitamin D), and calcitonin have direct effects on these target organs to maintain serum calcium concentrations within physiologic limits. Diseases affecting hormone secretion or release or hormone target organs can result in hypo or hypercalcemia. . Extracellular calcium exists in 3 fractions: 50% ionized or free calcium, 10% complexed to phosphate, bicarbonate sulfate, citrate or lactate, and 40% protein bound calcium. Ionized calcium is considered the most important biologically active fraction of extracellular calcium. Despite this, most laboratories report a serum total calcium concentration because it is more easily preserved than ionized calcium. Most clinicians correct or adjust reported total calcium concentrations relative to serum albumin concentration. This manipulation is based on the observation that 80-90% of protein bound calcium is bound albumin. The assumption is that serum total calcium concentrations that correct into the normal range are associated with normal ionized calcium concentrations. While this formula has never been validated by concurrent ionized calcium measurements, the formula remains a useful technique to disclose physiologic hyper or hypocalcemia that would otherwise remain unrecognized. It is important to remember that this formula is not valid for cats as there is not a linear relationship between serum protein and total calcium concentration. Recent technological advances have allowed direct measurement of the ionized calcium fraction. Ionic calcium concentration in the ECF has the greatest affect on PTH secretion by the parathyroid gland. Hypocalcemia induces PTH secretion and hypercalcemia suppresses PTH secretion. The target organs of PTH are the bone, and kidney and indirectly on the intestine. At the kidney, PTH binds to a membrane receptor and increases tubular resorption of calcium and increased conversion of vitamin D (25- hydroxy 6 calcitriol). In addition, PTH induces excretion (or decreased resorption) of phosphate. There is no direct effect of PTH on the intestine to increase calcium absorption. A powerful indirect effect however is exerted following PTH enhanced renal synthesis of calcitriol - the active form of vitamin D. Calcitriol increases gut absorption of dietary calcium. Both calcium and phosphorous resorption from bone is facilitated by calcitriol. Bone is the most important source of calcium for acute changes in serum concentration and serves as a reservoir when intestinal absorption and renal resorption fail to maintain normal serum calcium concentrations. Calcitonin is a polypeptide hormone secreted by C cells in the thyroid gland. Its major role is thought to limit the degree of postprandial hypercalcemia. The major target site of calcitonin is bone where it inhibits resorption. Clinical Signs Clinical signs of hypercalcemia and hypocalcemia can be similar and include weakness, twitching, seizures, anorexia, and hyperthermia. Clinical signs more suggestive of hypercalcemia include polyuria and polydypsia, vomiting, and depression. The severity of clinical signs depends on the degree of hypercalcemia as well as the underlying disease manifestations, and the rate and duration of the development of increased calcium levels. Most animals will show systemic signs when the serum calcium concentration is greater than 15 mg/dl. Concentrations above 20 mg/dl should be considered as being a life- threatening crisis. Excess calcium ions exert toxicity to cells by altering cell membrane permeability and cell membrane pump activity. This phenomena has its greatest affects on excitable tissues such as nerve and the heart. Neurons become less excitable in hypercalcemic states because they are less dermeable to sodium ions. Conversely, in hypocalcemic states, neurons become more permeable to sodium ions and therefore more excitable and even tetanic. Because of cell membrane sensitivity to ionic calcium concentrations, other metabolic derangements such as changes in serum sodium and potassium can magnify toxic signs of hypercalcemia due to their own effects in cell membrane function. Acidosis will increase the proportion of total calcium that is ionized and so may also exacerbate signs of hypercalcemia. Mineralization of soft tissues, often the heart and kidneys, can occur when the calcium phosphorous product is greater than 60. Etiology The most common cause of persistent pathologic hypercalcemia is malignancy. Other causes which are less common include hypoadrenocorticism, chronic or acute renal failure, primary hyperparathyroidism, bone lesions due to metastatic neoplasia, osteomyelitis, fungal infections most commonly blastomycosis or other granulamatous disease, and intoxication from vitamin D ingestion. If history and physical exam findings are not helpful in determining an etiologic diagnosis, ancillary testing is required. An expanded diagnostic plan to include repeat physical examinations, blood work, PTH and PTHrP assays, and diagnostic imaging should be undertaken to search for occult disease - particularly malignancy and paraneoplastic hypercalcemia. The most common causes of hypocalcemia are due to other systemic process rather than to failure of parathyroid hormone or calcium intake or loss. These include hypoalbuminemia, chronic and acute renal failure, acute pancreatitis, and ethylene glycol intoxication. Hypocalcemia can also occur due to primary failure of calcium homestatic mechanisms. Eclampsia or puerperal tetany usually occurs 1 to 3 weeks postpartum in small bitches. Hypocalcemia is attributed to excessive egress of calcium into milk production during lactation. Because of the sporadic incidence of this disease, parathyroid gland dysfunction may be involved. These bitches may also be mildly hypophosphatemic. Primary hypoparathyroidism seems to occur most commonly in female dogs. Hypoparathyroidism usually involves a lymphoplasmacytic infiltrates suggesting an immune mediated destruction of the gland. PTH concentrations are undetectable in the presence of hypocalcemia in cases of primary hypoparathyroidism. Treatment of Hypercalcemia Symptomatic therapy of clinical manifestations of hypercalcemia (dehydration, azotemia, seizures, cardiac arrhythmias) should be initiated immediately. Rapid rehydration followed by dieuresis with normal saline is indicated in animals with serum calcium concentrations greater than 13.5 mg% or when the calcium phosphorous product is greater than 60. Saline diuresis induces calciuresis by affecting the sodium gradient in favor of excretion in the thick ascending loop of henle. In persistently hypercalcemic patients, furoisemide will potentiate calciuresis by further inhibiting renal tubular calcium resorption. Furosemide should not be administered prior to intravascular volume repletion. Glucocorticoids decrease calcium absorption in the intestine and can be instituted in cases where hypercalcemia cannot be controlled with saline infusion and diuretic therapy. As many cases of hypercalcemia involve primary lymphoma, attempts should be made to identify neoplasia prior to instituting glucocorticoid therapy. Calcitonin (4-8 U/kg SQ q sid-tid) therapy has been used in severe hypercalcemia associated with cholecalciferol intoxication. Treatment of Hypocalcemia Tetanic signs of severe hypocalcemia warrant intravenous replacement therapy. Calcium gluconate 10% is recommended and is administered to effect (1.0-1.5 ml/kg over 20-30 minutes). Electrocardiography is recommended during calicium gluconate infusion and administration should be discontinued if bradycardia, ventricular ectopic beats or prolongation of the Q-T interval is observed. Hyperthermia usually resolves with resolution of tetany. Oral therapy with vitamin D and calcium should be instituted upon resolution of clinical signs. Repeated IV calcium gluconate administration may required in the first 12 hours of therapy as oral therapy requires 1 – 4 days for effect. Alternatively, subcutaneous administration of calcium gluconate every 8 hours can be administered. Calcium chloride should avoided as it is caustic and may result in phlebitis or cellulitis when administered IV and subcutaneously, respectively. Serum calcium should be monitored and therapy titrated to maintain concentrations between 8 –9 mg%. In animals with hypocalcemia secondary to pancreatitis or eclampsia oral maintencnce therapy may be discontinued within days to weeks. Primary hypoparathyroidism requires long term oral therapy with vitamin D (usually dihydrotachysterol or calcitriol) and may also require supplementation with calcium carbonate therapy. MANAGEMENT OF DIABETIC KETOACIDOSIS J.S. Wohl, DVM, ACVIM, ACVECC D.K. Macintire, DVM, MS, ACVIM, ACVECC Auburn University Critical Care Program Auburn University, AL

Pathophysiologic Review The pancreas secretes four hormones: insulin, glucagon, somatostatin, and pancreatic polypeptide. Though the exact role of pancreatic polypeptide is not understood, glucagon and insulin regulate carbohydrate metabolism. Somatostatin regulates islet cell secretion. A-cells secrete glucagon, D-cells secrete somatostatin, and F- cells secrete pancreatic polypeptide. The islet cells responsible for the synthesis and secretion of insulin are referred to as Beta cells. The immediate effects of insulin secretion include increased intracellular transport of glucose, amino acids, potassium in muscle, fat, and other insulin sensitive cells. (Glucose uptake by hepatic, intestinal, renal, brain, and red blood cells is independent of insulin). Later effects include inhibition of protein degradation and gluconeogenic enzymes, increased glycogen synthase and lipogenic enzyme activity, and increased protein synthesis. Insulin receptor number and affinity are affected by insulin secretion (down regulation with excessive insulin secretion), starvation (upregulation of receptors), exercise (increased receptor affinity), and endogenous or exogenous hypercortisolism (down regulation). Insulin secretion by beta cells is stimulated during hyperglycemia and inhibited during periods of euglycemia or hypoglycemia. Insulin has a half-life of ~ 5 minutes and is primarily degraded by the liver and kidney. Diabetes mellitus is an absolute or relative deficiency of insulin. Type II diabetes is most common in obese cats where down regulation of insulin receptors, impaired receptor binding, and post receptor defects in insulin action are present. Type II diabetes is referred to noninsulin dependent (NIDDM) as the defect is in insulin effect rather than insulin secretion. Type I diabetes mellitus is insulin dependent and characterized by an absolute deficiency in insulin secretion. Insulin dependent dibetes mellitus is characterized by more severe lack of intracellular glucose, hyperglycemia, and metabolic dysfunction. Glucoagon, norepinephrine, corticsol, and growth hormone are considered counterregulatory hormones and are gluconeogenic, lipolytic, and ketogenic. During diabetes mellitus, glucagon secretion increases and exacerbates hyperglycemia. Counterregulatory hormones are further increased during stress associated with metabolic derangements and infections. Glycogen stores in the liver are rapidly depleted resulting in accelerated protein catabolism to liberate amino acids for gluconeogenesis. Inabiltiy of stored, absorbed, and converted glucose to enter skeletal, smooth, and cardiac muscle forces cells to rely on fat stores for energy. The presence of glucagon and the absence of insulin facilitate hormone sensitive lipase activity. Hormone sensitive lipase liberates free fatty acids from fat stores. Free fatty acids are catabolized to acetyl CoA and excess of acetyl CoA are converted to ketone bodies, such as acetoacetate and beta-hydroxybutyrate. Hydrogen ions dontated by these ketone bodies exceed the buffering capacity of the plasma and acidosis results. The kidneys respond by excreting negatively charged ketones. Because the kidneys ability to excrete cations such as hydrogen and ammonium ions is exceeded, sodium and potassium are excreted and lead to plasma electrolyte derangements. These renal effects are exacerbated by the osmotic diuresis, hyperosmolality, and dehydration associated with hyperglycemia. Diabetes most commonly occurs in middle-aged female dogs and in older male cats and is characterized by four hallmark clinical signs: polyuria, polydipsia, polyphagia, and weight loss. Diabetes is most likely to progress to ketoacidosis when there is excessive counterregulatory hormones (infection, concurrent diseae) fasting, or dehydration. Ketones exacerbate osmotic diuresis and induce sodium, potassium depletion and further dehydration. Metabolic acidosis mediates nausea, inappetence, vomiting, diarrhea, and hyperventilation – all of which cause further dehydration. Decreased glomerular filtration rate secondary to volume contraction magnifies the acidosis via retention of blood glucose, ketones, and other organic acids. Historical and clinical signs in ketoacidosis may include polyuria, polydypsia, weight loss, anorexia, weakness, ataxia, severe depression, stupor, coma, or seizures.

Management Diabetic ketoacidosis is a medical emergency involving extreme alterations of metabolic parameters. The syndrome is characterized by hyperglycemia, metabolic acidosis, ketonemia, dehydration, and loss of electrolytes. Treatment goals include: (1) Restoration of electrolyte and acid-base balances, (2) Replacement of body fluids, (3) Reduction of blood glucose and (4) Identification of underlying or precipitating factors in the disease process. As DKA commonly occurs when there is a relative excess of stress hormones in an insulin deficient animal, every effort should be made to detect underlying disease factors contributing to stress. The work-up should include bloodwork (CBC, chemistry panel, blood gases, electrolytes, osmolality); chest radiographs if dyspneic (rule out congestive heart failure, neoplasia, dirofilariasis, pneumonia); abdominal radiographs (rule out pancreatitis, pyometra, urolithiasis, etc.); urinalysis (including culture and sensitivity); and amylase and lipase in vomiting dogs. Fluid therapy The initial fluid of choice is 0.9% NaCl. Isotonic saline prevents the rapid fall in osmolality which may occur if hypotonic fluids are used. Fluid requirements should be calculated to restore hydration over 10-12 hours (see Table I). Hypokalemia is a common problem in animals with anorexia and vomiting. In addition, potassium levels may drop precipitously with insulin therapy and correction of metabolic acidosis. Clinical signs associated with hypokalemia include muscle weakness, paralytic ileus, respiratory paralysis, and cardiac arrhythmias. Ideally, potassium should be monitored closely during therapy and added to the fluids as described in Table II. If monitoring equipment is not available and renal function is normal, potassium can usually be safely added to the fluids (20-40 mEq/L) after the first 4 hours. The use of sodium bicarbonate to correct acidosis in DKA is controversial. Treatment with insulin and fluids will correct the acidosis via oxidation of ketone bodies and excretion of hydrogen ions in the urine. Administration of sodium bicarbonate may cause decreased serum potassium, hyperosmolality, rebound alkalosis, or impaired oxygen delivery to tissues by increasing hemoglobin affinity for oxygen. Therefore, bicarbonate therapy is not recommended unless the pH < 7.100, and a conservative approach is always justified. Hypophosphatemia may occur in some animals being treated for DKA. Clinical signs include muscle weakness, rhabdomyolysis, hemolysis, respiratory failure, and impaired cardiac function. Phosphate replacement is not indicated in asymptomatic animals, however, since over-supplementation may be dangerous if hypocalcemia occurs. Diabetic cats with prolonged anorexia are predisposed to hypophosphatemia. If serum P values are < 2.0 g/dl or CPK values are very high (>1500), the patient will likely benefit from phosphate replacement. The recommended dosage for phosphorus supplementation is 0.01-0.03 mmol/kg/hr administered IV for 6-12 hours. Serum P levels should be rechecked before continuing the infusion. Some texts recommend giving half the potassium requirement as KPO4, but this practice is not recommended as serious phosphate overdosage can occur. Potassium phosphate solution contains 3 mmol/ml of phosphorus (93 mg/ml) and 4.4 mEq/ml of potassium. The recommended human dosage for phosphorus supplementation is 7.7-15 mg/kg IV over 6-12 hours. This dosage range has been used frequently by the author to treat animals with DKA induced hypophosphatemia. Insulin therapy Regular insulin is used at an initial dosage of 2.2 U/kg/24 h as a continuous intravenous infusion. Low dose continuous intravenous insulin infusion affords a safe and effective treatment by providing a gradual but consistent reduction in blood glucose while acid-base, electrolyte, and hydration abnormalities are corrected. The method is particularly efficacious for treating dogs with concurrent acute pancreatitis, or other causes of vomiting and anorexia, since the insulin infusion may be continued for several days with no adverse effects. When ketones are negative and the animal is eating, therapy can be initiated with longer acting insulin as in routine uncomplicated diabetics. The drip is very easy to prepare. For a 20 lb dog, 20 units of regular crystalline insulin are added to 250 ml of 0.9% NaCl. Since insulin binds to the plastic IV tubing, the first 50 ml should be run through and discarded. The drip is administered at 10 ml/hr in a separate line from the fluids, preferably through an infusion pump. The rate of insulin infusion is adjusted according to Table III. When the blood glucose drops to ≤ 250 mg/dl, 2.5% dextrose is added to the intravenous fluids and the infusion rate is slowed by 25-50%. Blood glucose should be monitored q 2 hours, and hematocrit, total protein, and electrolytes every 4 hours. Hypokalemia and hypoglycemia are potential problems that can be avoided with careful monitoring and appropriate supplementation. The mortality rate for DKA in animals is 25-30%, even with aggressive treatment. There is a high incidence of serious underlying disease factors, such as acute pancreatitis and hyperadrenocorticism, which undoubtedly contribute to the high mortality rate. An alternate method to treating animals with DKA is the intermittent IM technique of insulin administration. Regular crystalline insulin is given at an initial dosage of 0.2 U/kg IM. Then 0.1 U/kg IM is administered hourly until the blood glucose level is ≤250 Mg/dl. Once the animal is well hydrated and no longer ketoacidotic, subcutaneous insulin injections can be initiated. A starting dose of 0.5-1 U/kg of regular insulin is chosen and administered q 6-8 hours. A “mini” glucose curve can be charted. If regular insulin lasts 8 hours, then NPH or Lente insulin should be given once daily. If regular insulin lasts only 4-6 hours, twice daily insulin with NPH or Lente is required. The use of the “mini-curve” allows for more frequent adjustments of insulin dosage to “fine tune” the glucose control. Once a dosage of regular insulin is found that maintains blood glucose values between 80 and 300 mg/dl, that same dosage is administered using a longer acting insulin (usually NPH or Lente insulin twice daily). The owner’s schedule should be considered when determining times for insulin injections and feeding. A high fiber/low carbohydrate diet is generally recommended. Stable animals can be discharged and return in one week for a 24 hour glucose curve. Cats should be checked weekly at the time of peak insulin effect to avoid the pitfalls of hypoglycemia. Cats can be transient diabetics and may no longer require insulin once blood glucose levels have been normalized and the diet controlled.

Table 1 - Diabetic Ketoacidosis Emergency Treatment Protocol

I. Initial data base 1. Immediate PCV, TS, Azostick, Dextrometer, Na, K, UA (dipstick and specific gravity), osmolality, blood gases 2. CBC, chemistry panel 3. Rule out underlying infection - (radiographs, urine culture, amylase/lipase, etc.)

II. Fluid therapy 1. Place IV catheter - preferably central venous to allow for periodic blood sampling to monitor glucose. 2. Calculate fluid requirements and replace 80% of the deficit over 10 hours. a. BW (kg) x % dehydration x 1000 ml x 0.8 = # ml to rehydrate b. 2.2 ml/kg/hr x 10 h = maintenance c. Estimate # ml lost from vomiting in a 10 h period. Add (a) + (b) + (c) and divide by 10 to determine the hourly fluid rate for the initial 10 hours. 3. After 10 hours, reassess hydration and decrease infusion rate to 4 ml/kg/h 4. The initial fluid of choice is 0.9% NaCl supplemented with potassium according to Table 2. If serum potassium concentration is unknown, add 20 mEq/L KCl until it can be measured. 5. When serum glucose levels decrease to ≤250 mg/dl, change fluid to 0.45% NaCl and 2.5% dextrose. 6. If pH <7.000, give NaHCO3 0.1 x base deficit x BW(kg) = # ml slowly over 2 hours, or 0.1 x (18 - venous TCO2) x BW (kg) = # ml slowly over 2 hours 7. If serum phosphorus <2 mg/dl, and related clinical signs (hemolysis, myopathy, respiratory paralysis, encephalopathy) are evident, give 0.01-0.03 mmol phosphate/kg/hr over 6 hours and recheck phosphorus. Alternatively, a total replacement dose of 7.7-15 mg/kg can be given over 6-12 hours. (Potassium phosphate solution contains 93 mg/ml of phosphorus and 4.4 mEq/ml of potassium.)

III. Insulin Therapy 1. Use regular crystalline insulin in separate IV drip. 2. Dose: 2.2 U/kg/24h (dog) or 1.1 U/kg/24h (cat). 3. Add insulin to 250 ml NaCl or Ringer's solution. Run 50 ml through IV tubing and discard. Begin drip at 10 ml/h with infusion pump. 4. Slow insulin infusion rate by 25-50% according to insulin therapy chart (Table 3) when glucose ≤ 250 mg/dl. 5. Continue IV insulin infusion until ketones are negative and patient is eating. 6. Switch to subcutaneous regular insulin (0.5-1 U/kg) or begin long acting insulin (NPH, Lente, or Ultralente) at 0.5 U/kg SQ when ketones are negative and patient is stable. 7. Alternate IM method (instead of IV infusion): a. Initial dose, 0.2 U/kg IM; then 0.1 U/kg IM hourly until blood glucose level ≤250 mg/dl. Then switch to regular insulin SC (0.5-1 U/kg) q 6-8 h once the patient is well hydrated. IV. Miscellaneous 1. Antibiotics if fever/systemic infection. 2. NPO if pancreatitis 3. Monitor Dextrometer q 1-2 h initially - PCV, T.S., Na, K, osmolality q 4 h - Blood gases q 6 h - Urine output q 2 h

Table 2 - Potassium Replacement* Serum K (mEq/L) KCl added to 1 L Maximum rate of Fluids (mEq) (ml/lb/hr) 3.6 - 5.0 20 12 3.1 - 3.5 30 8 2.6 - 3.0 40 5.5 2.1 - 2.5 60 4 < 2.0 80 3 * Rate of supplementation should not exceed 0.5 mEq/kg/hr.

Table 3 - Insulin Therapy Adjustments

If glucose is: Fluids Insulin (2 U/kg in 250 ml)

> 250 mg/dl 0.9% NaCl 10 ml/hr 200 - 250 mg/dl 0.45% NaCl + 2.5% 7 ml/hr Dextrose 150 - 200 mg/dl 0.45% NaCl + 2.5% 5 ml/hr Dextrose 100 - 150 mg/dl 0.45% NaCl + 5% 5 ml/hr Dextrose < 100 mg/dl 0.45% NaCl + 5% Stop insulin infusion Dextrose Hyperosmolar Diabetes Mellitus HODM This syndrome is characterized by severe dehydration, abnormal brain function, marked hyperglycemia, and lack of significant ketoacidosis. Central nervous system signs associated with hyperosmolality include restlessness, convulsions, hyperthermia, ataxia, muscle twitching, nystagmus, and death. In human beings, NKHD generally develops in older nursing home residents with underlying renal or cardiovascular disease. They are commonly type II, maturity onset, non-insulin dependent diabetics. It is thought that endogenous insulin secretion in these patients maintains anti-lipolytic and anti-ketogenic effects, but is too low to allow for adequate glucose uptake. The most striking feature of NKHD is marked dehydration. Persistent hyperglycemia results in osmotic diuresis. When dehydration is of such magnitude that urine flow is impaired, serum glucose levels rise sharply. In addition, pre-renal azotemia develops. The extremely elevated blood glucose and hyperosmolality which develop cause an alteration of sensorium. NKHD is uncommon in dogs, but may occur in up to 50% of diabetic cats. Normal serum osmolality is between 285-310 mOsm/kg. Neurologic signs occur when the osmolality is greater than 350 mOsm/kg. Serum osmolality can be measured directly with a freezing point depression osmometer, or osmolality can be calculated by the following formula:

serum osmolality (mOsm/kg) = 2(Na) + glucose/18 + BUN/2.8

The object of therapy is to slowly and steadily lower the blood glucose and correct dehydration and electrolyte imbalances. Basically, the treatment is similar to the DKA protocol, but the insulin dosage is lower and the rate of rehydration is slower. Insulin - Regular insulin is administered in a continuous intravenous infusion at 1 U/kg/24 h. The blood glucose should be monitored closely, and should not drop below 250 mg/dl within the first 12 hours, since rapid decreases have been associated with cerebral edema and worsening of neurologic status. Generally, the insulin infusion is not initiated until 2 - 4 hours after the start of fluid therapy. Even without insulin, the blood glucose will drop as hyperglycemia is diluted and renal perfusion is restored. Fluids - The fluid of choice is again 0.9% NaCl, unless the serum sodium is very elevated. Caution must be exercised if a hypotonic fluid such as 0.45% NaCl is chosen, since it may lower the serum osmolality too rapidly, resulting in cerebral edema. Fluid requirements are estimated, and 80% of the calculated dose should be given over 12 hours.