Chapter 20 Fluid Therapy in Endocrine and Metabolic Disorders
Metabolic disorders such as complicated diabetes mellitus, hypoadrenocorticism, and heatstroke are associated with marked disturbances in fluid homeostasis, electrolyte balance, and acid-base status. Prompt recognition of the complications associated with these and other metabolic disorders is essential for effective management. The dynamic nature of these illnesses during treatment requires the attending clinician to be vigilant in monitoring and to recognize when therapy needs to be altered. An understanding of the pathophysiology of the metabolic abnormalities encountered in each disorder is necessary for proper management.
Diabetic ketoacidosis (DKA) is a life-threatening complication of diabetes mellitus that results from a combination of factors, including insulin resistance (counter-regulatory hormones), fasting, a lack of insulin, and dehydration in an animal with diabetes mellitus. Dehydration, electrolyte disturbances, and metabolic acidosis are consistent findings in affected patients that must be addressed during treatment. Most animals with DKA have concurrent diseases, including pancreatitis, urinary tract infection, hyperadrenocorticism, neoplasia, hepatic disease, and renal failure. In addition to clinical signs typical of diabetes mellitus, dogs and cats with ketoacidosis frequently exhibit lethargy, anorexia, vomiting, weakness, depression, dehydration, tachypnea, and weight loss. Other clinical signs may be present depending on the underlying illness. A tentative diagnosis is made by documenting ketonuria in a diabetic animal with clinical signs of systemic illness and diabetes mellitus. Many dogs with uncomplicated diabetes mellitus will have ketonuria at the time of initial diagnosis,56 and it is important to distinguish ketosis that does not necessitate the aggressive treatment described below from dogs with true ketoacidosis. The prognosis more often is determined by the nature and severity of the concurrent disease than by the ketoacidotic state.
A combination of events must take place for ketoacidosis to occur. Insulin deficiency, presence of counter-regulatory hormones, fasting, and dehydration combine to create the metabolic aberrations that result in the syndrome of DKA.43 The insulin deficiency may be relative or absolute. The diagnosis of diabetes mellitus is most often made at the time of presentation for DKA, but a minority of dogs and cats are receiving insulin at the time of diagnosis. The concurrent illness present in the majority of cases of DKA is the cause of insulin resistance and contributes to the increase in counter-regulatory hormones.
Hyperglycemia occurs as a result of insulin deficiency, increases in counter-regulatory hormones, and dehydration. Increased hepatic glucose output primarily caused by increased gluconeogenesis appears to be the primary factor causing hyperglycemia.18,43 Gluconeogenic substrates include amino acids derived from proteolysis and decreased protein synthesis, lactate from glycolysis, and glycerol from lipolysis. Increased glucagon and β-adrenergic activation by catecholamines in the face of inadequate insulin stimulate glycolysis and gluconeogenesis. The osmotic diuresis induced by glycosuria contributes to dehydration and subsequent hyperglycemia.18,43 Dehydration also may cause decreased insulin delivery to sensitive tissues such as skeletal muscle and therefore may reduce insulin action. In addition, antagonism of the cellular actions of insulin by growth hormone and cortisol contribute to insulin resistance.
Ketoacids are derived from the increased free fatty acids that are present as a consequence of increased lipolysis. An increase in catecholamines results in activation of hormone-sensitive lipase in adipose tissue, liberating free fatty acids and glycerol.18,43 In the liver, the large quantity of free fatty acids is oxidized to ketone bodies under the influence of glucagon, although cortisol, epinephrine, and growth hormone also play a role in stimulating ketogenesis. Anorexia that is usually present in patients with DKA contributes to the hormonal changes mentioned above and lack of substrate for anabolic functions. Use of ketones is impaired in DKA as well, contributing to their increased concentration. Low serum insulin and elevated serum glucagon concentrations are correlated with increasing serum ketone concentrations in dogs with diabetes mellitus.23
Dehydration is a consistent finding in dogs and cats with DKA.15,17,20,53 It occurs because of osmotic diuresis secondary to glycosuria and ketonuria, and as a result of gastrointestinal losses associated with vomiting and diarrhea. Electrolyte loss also occurs in these patients because of the diuresis and the cation excretion that accompanies ketoacid excretion.43 Insulin deficiency also results in loss of electrolytes because insulin is required for normal sodium, chloride, potassium, and phosphorus reabsorption in tubular epithelial cells. Loss of sodium, potassium, chloride, magnesium, phosphorus, and calcium occur to a substantial degree in DKA. However, the resulting electrolyte abnormalities are reflected variably in plasma concentrations.15,17,20,53 Hyponatremia is reported in 40% to 54% of dogs and 34% to 81% of cats with DKA,15,20,37,45,69 but correction of the serum sodium concentration for hyperglycemia reduces the prevalence of this finding.45 Because glucose has an osmotic effect in the plasma, hyperglycemia results in a shift of water into the intravascular space, diluting the plasma sodium. This effect can be corrected by adding 1.6 mEq/L to the measured sodium concentration for each 100 mg/dL that the plasma glucose exceeds 100 mg/dL.
Loss of ketoacids in urine results in buffering by plasma bicarbonate. Urinary bicarbonate excretion contributes to the metabolic acidosis induced by accumulation of ketoacids.43 Retention of these unmeasured anions results in an increased anion gap. The prognosis of dogs with DKA is negatively affected by a worsening base deficit.37
The goals of fluid therapy in DKA are to restore circulating volume, replace water and sodium deficits, correct electrolyte imbalances, improve tissue delivery of nutrients, and decrease the blood glucose concentration. Initial fluid therapy should improve intravascular volume, reduce secretion of counter-regulatory hormones, and enhance tissue delivery of insulin. It is recommended that insulin administration be delayed for 1 to 2 hours after fluid therapy is instituted, particularly when hyperglycemia is severe, hypotension is present, or clinically relevant hypokalemia exists. Reduction of blood glucose concentration before replacement of intravascular volume could result in loss of water from the intravascular space along with glucose and worsening of hypotension. Severe hyperglycemia and hypotension are likely. A substantial reduction of blood glucose will occur despite a delay in insulin administration because fluid therapy alone reduces insulin resistance, increases insulin availability at peripheral tissues such as skeletal muscle, dilutes the blood glucose, and enhances urinary loss subsequent to an increase in glomerular filtration rate (GFR).76 After initial rehydration, consideration should be given to the decrease in the plasma effective osmolality and thus the plasma volume that occurs after reduction of the blood glucose concentration, necessitating administration of fluids at a higher rate than would be needed in a euglycemic patient. After hydration status has been normalized and blood glucose concentration reduced, additional fluid administration should be based on the calculation of maintenance needs plus ongoing losses from the gastrointestinal tract (e.g., vomiting, diarrhea) and in urine (i.e., polyuria caused by continued glycosuria). Aggressive treatment is not necessary in dogs or cats with ketonuria if metabolic acidosis and signs of systemic illness are not present. The presence of a concurrent disease, present in most dogs and cats with DKA, may necessitate modification of the fluid therapy plan.
Because of the marked deficits of water and sodium present in animals with DKA, 0.9% saline is the fluid of choice for initial management. Administration of an isotonic solution allows for rapid expansion of intravascular volume in patients with severe dehydration or hypovolemic shock.
Serum osmolality usually is high in animals with DKA, often moderately to markedly so. The median measured osmolality in 23 cats with DKA was 353 mOsm/kg (reference range, 280 to 300 mOsm/Kg), and the median calculated osmolality in 19 other cats was 333 mOsm/kg.15 An increase in the calculated osmolality was confirmed in another recent study of 13 cats with DKA.45 The hyperosmolality is attributable primarily to hyperglycemia, azotemia, and ketone bodies. Because treatment rapidly resolves these abnormalities, the osmolality would be expected to decrease predictably without the use of hypotonic solutions. Cerebral edema has been documented in humans, particularly children during treatment of DKA. Clinical signs of cerebral edema are rare despite its common occurrence.46 Rapid reduction in plasma osmolality is a major factor in development of cerebral edema. Cerebral edema is caused in part by the accumulation of idiogenic osmoles in the central nervous system (CNS) secondary to chronic hyperosmolality.25 Idiogenic osmoles are produced in response to plasma hyperosmolality, and they increase the osmolality of the brain to prevent cerebral dehydration. If the plasma osmolality decreases quickly, the idiogenic osmoles will persist and cause water accumulation in the cerebrum because of the difference in osmolality between the brain and plasma. Because of this, administration of hypotonic fluids such as 0.45% saline is discouraged during initial treatment.18,43 The importance of this pathophysiology in dogs and cats is unknown and cerebral edema occurring during treatment has not been reported, but it seems prudent to avoid rapid reduction in plasma osmolality during treatment of DKA. Serum tonicity, calculated from corrected serum sodium and glucose concentrations, did not change significantly during treatment of diabetic ketosis in cats despite a decrease in serum glucose concentration.45 This is because serum sodium concentration increased in most cats, and sodium contributes considerably more to plasma tonicity and osmolality than glucose. Attention to replacement of sodium deficits will offset reduction in plasma osmolality that occurs when the blood glucose and ketoacid concentrations decrease in initial management of patients with DKA.73 Although 0.45% saline approximates the composition of electrolytes lost as a result of osmotic diuresis and has been recommended for administration after rehydration, the author rarely uses it for treatment of DKA. However, if hypernatremia is noted during ongoing treatment and rehydration, one could consider administration of 0.45% NaCl.
Once the blood glucose concentration decreases to less than 250 mg/dL, 50% dextrose should be added to the 0.9% saline to make a 2.5% to 5% dextrose solution.17,52,53 Adjustments in the dextrose content of the fluids should be made based on Table 20-1. The addition of dextrose will prevent hypoglycemia and allow for continued insulin administration to stop ketoacid formation.
|Blood Glucose Concentration (mg/dL)||Intravenous Fluid Solution||Rate of Intravenous Insulin Solution (mL/hr)*|
|200-250||0.9% saline, 2.5% dextrose||7|
|150-200||0.9% saline, 2.5% dextrose||5|
|100-150||0.9% saline, 5% dextrose||5|
|<100||0.9% saline, 5% dextrose||Stop insulin infusion|
Adapted from Macintire DK. Treatment of diabetic ketoacidosis in dogs by continuous low-dose intravenous infusion of insulin. J Am Vet Med Assoc 1993;202:1266–1272.
The primary goal of initial fluid therapy is to restore intravascular fluid volume to improve tissue perfusion, including GFR. Fluids should be administered at a rate sufficient to replace volume deficits in 12 to 24 hours, with 50% of the estimated deficit replaced in the first 4 to 6 hours. An estimated volume of fluid to account for ongoing losses should be added to the maintenance and replacement fluid volume, with special consideration of urine output in the presence of polyuria. Fluids should be administered cautiously to animals with impaired cardiac function or the potential for oliguric renal failure. Monitoring should consist of estimates or quantitation of urine output, serial body weights, packed cell volume, total solids, and serum concentrations of creatinine, electrolytes, and glucose. Urine output should be evident within 2 to 4 hours of initiating fluid therapy unless oliguric renal failure is present.
Intravenous fluid therapy will decrease the blood glucose concentration and reduce lactic acidosis, but insulin administration is required to halt ketogenesis, increase ketone body use, decrease gluconeogenesis, promote glucose use, and decrease proteolysis.18,43 Ketogenesis will be decreased by an insulin concentration 50% less than that required for promotion of peripheral use of glucose, and consequently ketoacid formation is decreased rapidly after insulin administration. For insulin to be most effective, tissue perfusion must be restored, so intravenous fluid therapy should be instituted first. Insulin sensitivity is increased by a reduction in hyperosmolality and decreased concentrations of counter-regulatory hormones that is accomplished by fluid administration. An additional important effect of insulin is its action on electrolyte transport and resolution of acidosis that cause a transcellular shift of potassium into cells, causing hypokalemia. In patients with serum potassium concentrations less than 3.5 mEq/L, insulin administration ideally should be delayed until potassium supplementation has successfully increased the serum potassium concentration above this limit to avoid worsening of hypokalemia. In addition, hypotensive animals should receive fluid therapy sufficient to stabilize the circulatory status before insulin administration to prevent the decrease in plasma volume that occurs when glucose and water are translocated into cells in response to insulin.
Administration of small doses of regular insulin has a clear advantage over large doses because the smaller doses are less likely to cause severe hypokalemia or hypoglycemia.42 In addition, if the reduction in the blood glucose concentration is too rapid, the associated decrease in osmolality has the potential to contribute to development of cerebral edema. Two methods of delivering low-dose insulin therapy to dogs have been described: the low-dose intramuscular technique and the continuous low-dose intravenous infusion.17,53 With either technique, regular insulin is administered with a desired effect of decreasing the blood glucose by not more than 50 to 75 mg/dL/hr. Similar treatment has been used in cats with DKA.52
The low-dose intramuscular insulin protocol is an effective and straightforward, but somewhat time-consuming, method for insulin administration in DKA.17 Intramuscular administration is recommended because absorption from subcutaneous sites may be reduced or inconsistent in the presence of dehydration. However, absorption is similar from the two administration sites in humans with DKA.30 Regular insulin is the only product that has been reported to be used in dogs. Recently, subcutaneous administration of the insulin analogs insulin lispro and insulin aspart, have been shown to be as effective as intravenous regular insulin in humans with uncomplicated DKA.74,75 These analogs have a more rapid onset of action (10 to 20 minutes) compared with regular insulin (1 to 2 hours) and a shorter duration of effect. Any advantages over the use of regular insulin in veterinary medicine await investigation. In dogs the initial dose of regular insulin is 0.2 U/kg intramuscularly, followed by hourly measurement of blood glucose concentrations.17 Subsequent insulin administration continues hourly at 0.1 U/kg intramuscularly until the blood glucose concentration is 250 mg/dL or less. Dogs weighing less than 10 kg are given 2 U and cats are given 1 U initially, followed by 1 U every hour unless diluted insulin is available.17 If the blood glucose concentration decreases by more than 100 mg/dL/hr, the dosage is decreased. Once the blood glucose concentration is less than 250 mg/dL, the hourly insulin injections are stopped, and 50% dextrose is added to the intravenous fluid solution in a quantity sufficient to make a 5% dextrose solution. Additional doses of regular insulin are administered every 4 to 6 hours at 0.1 to 0.4 U/kg subcutaneously with the dosage and dosing interval determined by measurement of blood glucose concentration every 1 to 2 hours to maintain blood glucose concentration between 200 and 300 mg/dL. The primary disadvantage of the low-dose intramuscular protocol is that it requires considerable technical effort to accomplish hourly injections and blood glucose measurements. In addition, the decrease in blood glucose concentration seems to occur more rapidly and less predictably than with the continuous intravenous infusion method.
The continuous low-dose intravenous infusion protocol involves administration of regular insulin diluted in normal saline using an intravenous infusion pump.53 It is my preferred technique of insulin administration to dogs with DKA because of the predictable and consistent response, the gradual decrease in blood glucose concentration (mean of 28 mg/dL/hr in dogs), and the ease of use.53 Unlike the low-dose intramuscular protocol, treatment is not dependent on hourly injections, and the decrease in blood glucose concentration is more gradual using the intravenous protocol. An insulin solution is made by adding regular insulin at 2.2 U/kg for dogs and 1.1 U/kg for cats to 250 mL 0.9% saline.52,53 This solution is administered as a constant-rate infusion at 10 mL/hr to deliver a dosage of 0.09 U/kg/hr in dogs and 0.045 U/kg/hr in cats. Because insulin may adhere to plastic in the administration set, it is recommended that 50 mL of the insulin solution be allowed to flow through the administration set before use. During insulin administration, intravenous fluid therapy with 0.9% saline is continued through a separate line as indicated for rehydration and maintenance needs. Blood glucose concentration is measured every 60 to 90 minutes. When the blood glucose is less than 250 mg/dL, the infusion rate is decreased according to Table 20-1, and dextrose is added to the hydration fluids to a final concentration of 2.5% to 5% (see Table 20-1).53 The primary disadvantage of the continuous low-dose intravenous infusion protocol is the need for an infusion pump and the time required to monitor blood glucose serially.
The high-dose intramuscular or subcutaneous insulin protocol is the simplest for management of DKA, requiring the least amount of monitoring and equipment.12 However, it has some shortcomings, including a rapid decrease in blood glucose concentration that predisposes to hypoglycemia, a greater magnitude of hypokalemia, and a substantial decrease in osmolality over a short period. It is for these reasons that this technique is no longer used in humans and is considered less desirable for use in dogs and cats. Regular insulin is administered at 0.25 U/kg every 4 hours intramuscularly until the patient is rehydrated, followed by subcutaneous administration every 6 to 8 hours.12 The dosage and frequency of insulin administration are based on monitoring blood glucose concentration hourly, with a goal of decreasing the glucose concentration by approximately 50 mg/dL/hr. Once the glucose concentration is near 250 mg/dL, dextrose is added to the intravenous saline solution to a final concentration of 5%, and the subsequent insulin dosage is decreased by 25% to 50%.
Regardless of the serum potassium concentration, almost all patients with DKA have a deficit of total body potassium.18,43 Before treatment, hypokalemia is found in approximately 30% to 45% of dogs and 55% to 67% of cats, whereas hyperkalemia is found in less than 10% of cases.* Hypokalemia occurs because of urinary potassium losses caused by osmotic diuresis, deficient renal tubular potassium absorption caused by insulin deficiency, and excretion with ketoacids, as well as through gastrointestinal losses from vomiting and diarrhea. Treatment of DKA rapidly lowers plasma potassium concentration because correction of acidosis causes a transcellular shift of potassium into cells, insulin enhances transport of potassium into cells, and intravenous fluid administration causes diuresis and dilution of plasma potassium. Hypokalemia is present at sometime during hospitalization in over 90% of cases.15,37 Hypokalemia can cause muscle weakness, arrhythmias, and impaired renal function.
Potassium should be supplemented in virtually all animals with DKA, but the initial dose rate is dependent on the pretreatment serum potassium concentration. If the serum potassium concentration is above the reference range, intravenous fluids should be administered without the addition of potassium for 2 hours, at which time the serum potassium concentration should be rechecked if possible. If the serum potassium concentration has decreased into the normal range, supplementation is given according to Table 20-2. The dose rate of KCl should not exceed 0.5 mEq/kg/hr because of the risk of cardiac arrhythmia. If a serum potassium measurement is not available after initial treatment and urine output appears adequate, 30 to 40 mEq KCl should be added to each liter of fluids. Urine production should be monitored closely to ensure that oliguric renal failure is not present. In humans with hypokalemia before treatment, it is recommended that insulin administration be delayed until the serum potassium concentration can be increased into the normal range because the potassium concentration will decrease during insulin administration.43 A similar recommendation is made for veterinary patients with substantial hypokalemia (<3.5 mEq/L). Serum potassium concentration should be monitored 4 hours after initiating potassium supplementation and at least every 8 to 12 hours thereafter, with dosage adjustments to maintain normokalemia (see Table 20-2).
|Serum Potassium Concentration (mEq/L)||Potassium Supplement (mEq) in 1 L Intravenous Fluid|
Similar to potassium, phosphate is deficient in animals with DKA regardless of the serum phosphorus concentration. Phosphorus is lost in patients with DKA because of a shift from the intracellular to the extracellular compartment secondary to hyperosmolality that is followed by urinary loss, decreased cellular uptake caused by insulin deficiency, inhibition of renal tubular phosphate absorption caused by acidosis, and osmotic diuresis.33,43 During treatment of DKA, the reduction in osmolality and insulin administration result in translocation of phosphate into the cell from the extracellular compartment. This translocation frequently causes a marked decrease in the plasma phosphorus concentration. However, clinically important consequences of hypophosphatemia are noted only when the serum phosphorus concentration is less than 1.0 to 1.5 mg/dL, and these signs are observed inconsistently. Hemolysis, muscle weakness, seizures, depression, and decreased leukocyte and platelet function leading to infection and bleeding can result from hypophosphatemia. The only abnormalities documented as caused by hypophosphatemia in veterinary DKA patients are hemolytic anemia in cats and possibly stupor and seizures in a dog.1,15,77 Hemolysis can occur despite phosphate supplementation and may have causes other than hypophosphatemia including oxidative injury.15,19 Hypophosphatemia is present at initial evaluation in 13% to 48% of cats and in 29% of dogs with DKA.15,20,37 Careful monitoring of serum phosphorus concentration during the initial 24 to 48 hours of management is important to identify severe hypophosphatemia necessitating phosphorus supplementation.
Treatment of hypophosphatemia is indicated when the serum phosphorus concentration before treatment is less than 1.5 mg/dL or if the serum phosphorus concentration is less than 1.0 mg/dL in the dog and less than 1.5 mg/dL in the cat at any time. Potassium phosphate typically is the treatment of choice because potassium supplementation is also necessary in most cases, but sodium phosphate is also available for use. Potassium phosphate is available as a solution containing 3 mmol/mL of phosphorus (99 mg/dL) and 4.36 mEq/mL of potassium. Excessive phosphate supplementation can cause hypocalcemia, hyperphosphatemia, tetany, soft tissue mineralization, and renal failure.29,33 Because phosphate deficits vary widely and are not necessarily reflected by serum phosphorus concentrations, phosphate administration should be guided by repeated serum phosphorus measurements during treatment. Potassium phosphate should be administered by constant-rate infusion at an initial dosage of 0.01 to 0.06 mmol/kg/hr. Higher infusion rates can be administered as necessary. Monitoring should consist of measurement of serum potassium, phosphorus, and calcium concentrations every 8 to 12 hours during phosphate administration. Hyperphosphatemia, clinically relevant hypocalcemia, and hyperkalemia are indications to discontinue phosphate administration. Treatment also should be discontinued when the serum phosphorus concentration is normal and the animal is eating. Some have suggested that potassium phosphate be routinely administered to animals with DKA regardless of the initial serum phosphorus concentration, but there is no evidence in veterinary or human medicine that such treatment is beneficial.29