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Fluid and Electrolyte Therapy in Diabetic Ketoacidosis
F l u i d an d E l e c t ro l y t e T h e r a p y in D i a b e t i c Ketoacidosis Elizabeth Thomovsky,
DVM, MS
KEYWORDS Diabetic ketoacidosis Insulin Crystalloid fluid Hyperglycemia Acidosis Sodium Potassium Phosphorus KEY POINTS Treatment of diabetic ketoacidosis is relatively straightforward in its approach. The difficulty comes in fine-tuning the basic treatment protocol to each animal. Using crystalloid fluids in addition to insulin therapy with frequent rechecks of blood glucose, electrolytes, and blood pH, resolution of the hyperglycemia and other abnormalities is almost always successful.
INTRODUCTION
Diabetic ketoacidosis (DKA) is a complication of diabetes mellitus commonly encountered in dogs and cats. This article presents an approach to fluid and electrolyte therapy for DKA. Although an extensive discussion of the pathophysiology and clinical presentation is beyond the confines of this article, this article will briefly touch on the important points related to this disease before discussing details of fluid and electrolyte management. PATHOPHYSIOLOGY OF DIABETIC KETOACIDOSIS
Diabetes mellitus refers to a deficiency of insulin in the body that can be relative or absolute.1,2 Regardless of the exact reason for the deficiency of insulin, the result is that the diabetic dog or cat is unable to move glucose from the bloodstream into the cells to fuel cellular metabolic processes. In response, the cells of the body begin to mobilize alternative energy sources such as fats and proteins to provide fuel for metabolism. See Fig. 1A, B for more details.3,4
The author has nothing to disclose. Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Purdue University, 625 Harrison Street, West Lafayette, IN 47906, USA E-mail address: [email protected] Vet Clin Small Anim - (2016) -–http://dx.doi.org/10.1016/j.cvsm.2016.09.012 0195-5616/16/ª 2016 Elsevier Inc. All rights reserved.
vetsmall.theclinics.com
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In this climate of cellular demand for energy, the body is initially able to supply enough energy to the cells, largely through metabolism of fats. However, in the process of breaking down fats to make energy, ketoacids are also formed in excess.2 Although some of the ketoacids are used by the myocardium, skeletal muscle, kidney cells, and brain, those remaining need to be excreted by the kidneys.2 In most cases, ketoacids are formed in excess when cellular energy demand increases above normal.5 In diabetic patients, this often occurs when hormones such as epinephrine, glucagon, cortisol, and growth hormone are produced. These hormones may be produced when there is a concurrent disease process but can simply be produced when the body perceives that it requires more energy in the cells.5 Concurrent diseases range from the relatively benign (urinary tract infection) to more severe disorders such as pancreatitis or neoplasia. These ketogenic hormones increase fatty acid breakdown (glucagon), further decrease insulin’s efficacy (growth hormone, epinephrine, and cortisol), and increase protein breakdown (cortisol and epinephrine).5 Oxidation of fats to form ketone bodies liberates carboxylic acids that release hydrogen ions.2 Therefore, overproduction of ketone bodies also leads to an overproduction of hydrogen ions, thus decreasing the blood pH and leading to acidosis. A diabetic patient can be ketotic without acidosis if the bicarbonate buffering system in the body can bind to and buffer the hydrogen ions. When the amount of hydrogen ions created exceeds the bicarbonate buffering system’s ability to bind hydrogen, acidosis results.2 Contributing to the development of acidosis (and hence DKA) is the mechanism of ketoacid excretion in the kidneys. To be excreted from the kidneys, the ketoacids combine with sodium found in the extracellular fluid (blood and interstitial fluid).6 Hydrogen ions are then used by the body to replace the sodium ions in the extracellular fluid, further decreasing the pH of the bloodstream and interstitial tissues.1,6 NONPHARMACOLOGIC TREATMENT OPTIONS FOR DIABETIC KETOACIDOSIS
Once a patient has been diagnosed with DKA by a combination of documented hyperglycemia, glucosuria, ketonuria, and acidemia, the first order of business is to initiate treatment. The mainstays of treatment of ketoacidosis are fluids and insulin therapy. Obviously, if there is another concurrent disorder in the dog or cat that has led to the development of DKA, such as a urinary tract infection, pancreatitis, or any other disease, specific treatment of that condition should be instigated as well. This article focuses on the fluid therapy aspects and briefly touches on insulin therapy; veterinarians are urged to consult other resources for information about treating disorders concurrent with DKA. OVERVIEW OF FLUID THERAPY IN DIABETIC KETOACIDOSIS
Fluids are given to patients with DKA for several reasons: Dehydration (see Box 1 for the mechanism of this change in DKA) Hypovolemia (see Box 1) Improve glomerular filtration in the kidneys (see Box 1) Increase excretion of glucose through the kidneys Increase excretion of ketoacids and hydrogen ions through the kidneys Decreases acidosis Resolve hypernatremia (see Box 2 for mechanism of electrolyte changes) Supply potassium (see Box 2) Supply phosphorus if indicated (see Box 2).
DKA Fluids–Electrolytes
Box 1 Effects of diabetes mellitus on fluid and electrolytes in the body Increased concentrations of glucose in the blood will remain either in the intravascular space or diffuse into the interstitial space. The cell membrane is relatively impermeable to glucose and, therefore, the glucose does not enter the cells. Instead, the glucose will draw fluid from the intracellular space into the vascular and interstitial spaces. This dehydrates the intracellular space. Glucose contained the blood is filtered at the glomeruli and excreted through the renal tubules. Glucose contained in the renal tubules holds water in the tubules and decreases tubular water reabsorption. Water is lost in large quantities through the kidneys causing polyuria (osmotic diuresis). Lack of water reabsorption in the kidney / decreased vascular volume / fluid shifts from the interstitium into the vascular space (interstitial dehydration) / fluid shifts from the intracellular space into the vasculature (intracellular dehydration) / when no more fluid can leave either the intracellular or interstitial space, the vascular volume decreases (hypovolemia). Diabetes can cause both intracellular and interstitial dehydration. Diabetes can also lead to hypovolemia in untreated cases, especially when an animal is unable to take in water (polydipsia) to compensate for the loss of water from the interstitial and intracellular spaces. Ketoacids filtered at the glomeruli and excreted through the renal tubules / cotransported with sodium / sodium holds water in the tubules and decreases tubular reabsorption of fluid / excrete sodium, water, and ketoacids. Adapted from Hall JE. Insulin, glucose and diabetes mellitus. In: Guyton and Hall textbook of medical physiology 12th edition. Philadelphia: Saunders Elsevier; 2011.
Fluid Type
The first order of business is determining which fluid type is best for an animal with DKA. Because animals with DKA are dehydrated in the interstitial and intracellular spaces on presentation, giving a crystalloid fluid is indicated because up to 75% of these fluids naturally shift from the intravascular space into the interstitial and intracellular spaces within 20 to 30 minutes of administration. Therefore, fluid is returned quickly to the dehydrated spaces. In addition, because hypovolemia in DKA results from dehydration of the interstitial and intracellular spaces (thus causing loss of fluid that would normally be used to replenish the intravascular space), hypovolemia will also be improved by refilling those deficient compartments, allowing for return of fluid to the vascular space.10 Human (and older veterinary) resources have recommended 0.9% sodium chloride (NaCl) as the fluid of choice. The reasons for this were largely because this fluid has the highest sodium concentration and, therefore, can treat the hyponatremia often observed in DKA patients (see Box 2). However, due to the increased chloride in these fluids and the lack of a buffer, they have been shown to cause hyperchloremic metabolic acidosis in DKA patients, all of whom already have a high anion gap metabolic acidosis from the ketone body production.11 Therefore, using a balanced crystalloid with a buffer (such as lactated Ringer solution or plasmalyte-148) is recommended in veterinary medicine. Plasmalyte-148 was shown to improve resolution of acidosis within the first 12 hours of infusion versus 0.9% NaCl in adult human patients with DKA.11 Additionally, humans receiving
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Box 2 Mechanisms of electrolyte disorders in diabetic ketoacidosis Hyponatremia7 Increased concentration of ketoacids in blood / sodium (Na1) excreted with ketoacids in kidneys via a cotransporter. Hyperglycemia / increased osmolality in blood / fluid shifts from interstitium and intracellular space into blood / decreases the sodium concentration by dilution of existing sodium. - For every 100 mg/dL increase in glucose in blood, there is at least a 1.6 mEq/L decrease in Na1 concentration. Increased renal filtration of glucose / retain Na1 and water in renal tubules (osmotic diuresis) / Na1 loss in urine. Hypokalemia8 Loss in kidneys 1 1 - Lack of insulin / potassium (K ) remains in blood / K filtered through glomeruli / K1 lost through renal tubules with excessive water and glucose (osmotic diuresis). 1 1 - Acidosis / hydrogen (H ) ions shift into cells and K moves into bloodstream from cells / potassium filtered at kidney / K1 lost through renal tubules with excessive water and glucose (osmotic diuresis). Insulin therapy / movement glucose and potassium into cells / hypokalemia. Epinephrine release / shifts glucose and potassium into cells / hypokalemia. Hypophosphatemia6,9 Phosphate (PO4) deficit - Loss of muscle mass during amino acid breakdown (see Fig. 1B) / less stored PO4 in the body. - Loss of phosphorus in the urine Decreased insulin concentration / decreased movement PO4 into cells / more PO4 filtered at glomeruli and into renal tubules / loss of PO4 in urine. Decreased insulin concentration / decreased reabsorption PO4 in the kidney / loss of PO4 in urine. Fluid therapy / increased renal PO4 excretion (with sodium phosphorus cotransporter). Movement phosphorus into cells - Insulin therapy during treatment shifts PO4 into cells with glucose / hypophosphatemia.
plasmalyte-148 do not have increases in their chloride concentrations contributing to metabolic acidosis.11 Insulin Therapy
The goal of giving insulin to a diabetic patient is to resolve hyperglycemia by storing circulating serum glucose in the liver as glycogen (increase glycogen synthesis) and as triacylglycerols in the adipose tissue (increase fatty acid synthesis).1,2 Additionally, the insulin transports glucose into the cells to be used in glycolysis and the tricarboxylic acid (TCA) cycle (ie, re-establish normal metabolism, Fig. 1A) so that further fat and protein breakdown for energy and, therefore, ketone body production is not necessary.2 Because insulin allows for improvement of blood glucose concentration, and decreased ketonemia and concurrent acidemia, one of the goals of treatment is to continuously and consistently administer insulin as long as possible to a patient. There has been much published on various techniques of insulin administration. Historically, in both human and veterinary medicine, regular insulin (a short-acting insulin) is indicated in the acute period.12–15 There are multiple ways to administer regular insulin with routes ranging from intravenous to intramuscular, with frequencies reported
DKA Fluids–Electrolytes
from continuous to every 1 to 4 hours.12 Veterinarians are urged to use whatever regular insulin protocol they are most comfortable with. The goal of any insulin regimen is to maintain serum glucose concentration between 100 to 250 g/dL. Table 1 is a sample treatment chart. The frequency of blood glucose monitoring depends on the exact insulin protocol initiated. Typically, continuous infusions of insulin have blood glucose monitoring every 1 to 2 hours, whereas intramuscular injection protocols call for monitoring of blood glucose every 4 hours. Regardless of the frequency of glucose monitoring, note that when the animal’s blood glucose decreases, dextrose is added to the crystalloid fluids so as to continue to allow administration of insulin without causing hypoglycemia. In recent years, 2 publications have reported using different short-acting human insulin products in dogs with DKA.16,17 One product is called lispro and it was administered at a dosage of 2.2 U/kg/d mixed in 0.9% saline and given as a continuous infusion (see Table 1). In a study of 12 dogs, 6 dogs received lispro insulin and their ketonemia, hyperglycemia, and acidemia were normalized in a median of 26 hours (range 26–50 hours), whereas 6 dogs received regular insulin and had resolution of signs in a median of 51 hours (range 50–82 hours).16 The second product is called insulin aspart. It was used in 6 dogs and given intravenously continuously at a dosage of 2.2 U/kg/d mixed in 0.9% saline (see Table 1).17 The dogs given insulin aspart had a median time to resolution of ketonemia, hyperglycemia, and acidemia of 28 hours (range 20–116 hours).17 Therefore, the use of any short-acting insulin product (regular, lispro, or aspart) continuously intravenously is effective in decreasing the blood sugar in dogs. Neither lispro nor aspart insulin has been tested in cats. Fluid Rates and Administration
Guidelines for humans assume that all DKA patients presenting at the hospital have a 5% to 10% dehydration (corresponding to a deficit of 6–9 L of fluid).13 Recommendations for humans specify that 50% of this deficit is replaced within 8 to 12 hours, with the total dehydration deficit given over 24 to 36 hours.13 Veterinary medicine lacks such specific guidelines and allows for more individualized treatment. The author presents a potential way to approach fluid therapy. Step 1. Initial treatment (0–6 hours postpresentation) Examine the patient and estimate dehydration paying attention to whether there is concern that the animal is hypovolemic (Table 2 shows guidelines on estimating dehydration and calculating the dehydration deficit).
Table 1 A sample protocol for continuous intravenous administration of short-acting insulin (regular insulin, lispro insulin, or insulin aspart in dogs; or regular insulin in cats) Measured Blood Glucose (mg/dL)
Dextrose in Crystalloid Fluids
Insulin Rate (mL/h)a
250
None
10
200–250
2.5% dextrose
7
150–200
2.5% dextrose
5
100–150
5% dextrose
5
<100
5% dextrose
No insulin
a All insulin administered is created in the following way: 250 mL bag of 0.9% saline 1 2.2 U/kg of short-acting insulin (dogs) or 1.1 U/kg regular insulin only (cats). Data from Refs.12,16,17
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Table 2 Guidelines for estimation of dehydration based on physical examination findings in dogs and cats Percent Dehydration Compartment Involved Clinical Signsa <5%
ISF
History of anorexia Decreased or absent drinking Vomiting, diarrhea
5%
ISF
Tacky mucous membranes 1/ skin tent
7%–8%
ISF / IC
Skin tent Dull corneas
10%
IC
Sunken eyes Depressed mentation
10%–12%
IC / IV
Tachycardia Decreased blood pressure Severe depression
12%–15%
IV
Worsening signs of hypovolemia (die at 15%)
Calculating dehydration deficit: (wt in kg) (% dehydration) 5 L of fluid. Abbreviations: IC, intracellular compartment; ISF, interstitial fluid compartment; IV, intravascular space. a Only new findings that occur at that level of dehydration are listed; it is assumed that all previous findings are still present.
Administer a portion of this dehydration deficit in the first 2 to 6 hours of treatment with the timing and amount based on clinical judgment of this particular patient’s condition. Use a balanced crystalloid solution such as lactated Ringer solution or plasmalyte-148. An example is to give one-half of the dehydration deficit over 4 hours. Factors to take into account include the degree of dehydration (hypovolemic or severely dehydrated patients need more fluid faster) and comorbidities (animals with heart disease often require slower more deliberate fluid administration). No insulin is administered during this rehydration period because the goal is to restore hemodynamic stability (ie, treat hypovolemia if present) and improve filtration in the kidneys. Fluid therapy itself will decrease the initial presenting glucose concentration; therefore, withholding insulin therapy until the fluid-induced decrease in glucose concentration in the blood occurs is wise. Fluid therapy will potentially cause alterations in the presenting concentrations of potassium, phosphorus, and sodium. Therefore, specific treatment of the electrolyte abnormalities noted on initial bloodwork should not be implemented until after this initial fluid therapy period. Step 2. Correction of remaining dehydration, acidosis, and electrolyte abnormalities (the first 24 hours of hospitalization) After the initial fluid administration (roughly 2–6 hours after presentation), take a blood sample to determine the animal’s electrolytes, blood pH, and blood glucose concentration. Depending on the animal’s blood glucose concentration, initiate regular insulin therapy using the veterinarian’s preferred technique and dosing (see Table 1 of regular and other short-acting insulins).
DKA Fluids–Electrolytes
Determine the remaining amount of fluid required to replace the animal’s dehydration (ie, subtract what has been given thus far from the initial estimated amount). Give what remains over the next 12 to 24 hours, depending on the animal’s comorbidities (ie, animals with heart disease or heart murmurs might receive fluids at a slower rate than those without). Provide maintenance fluids to the animal in addition to the dehydration fluids. Consider supplementing dextrose or electrolytes to the animal (see subsequent sections). Step 3. Reassess fluid rate, insulin administration, and electrolyte supplementation (every 6–12 hours during hospitalization) When the calculated dehydration deficit has been completely administered, reassess the patient to ensure that the animal no longer seems to be dehydrated (see Table 2). If the animal is still clinically dehydrated, recalculate the dehydration deficit and administer it over the next 4 to 12 hours. If the animal is no longer clinically dehydrated, decrease the crystalloid fluid rate to maintenance (ie, 60 mL/kg/d) or to an amount that matches the urine production in severely polyuric animals. If the animal has ongoing losses, such as vomiting or diarrhea, estimate that amount. Administer fluids to replace the ongoing losses in addition to the maintenance fluids. Recheck blood glucose concentration regularly as dictated by the insulin regime (usually every 1–4 hours). Administer insulin as dictated by the blood glucose concentration (see Table 1). At least every 12 hours (often every 4–6 hours depending on how sick the animal is), recheck the electrolytes and blood pH. Adjust supplementation as indicated (see subsequent sections). Other Considerations When Administering Fluids
It is important to remember that frequent reassessment of patients is important to ensure that enough but not too much fluid is being given. The author typically does a physical examination at least every 12 hours on these animals, paying particular attention to whether or not the physical findings consistent with dehydration have improved. In the author’s experience, it is not uncommon to underestimate the animal’s dehydration, especially because many of the clinical findings can be affected by age or breed, as well as behaviors such as panting or hypersalivating from nausea. Also, these animals are losing large amounts of fluid in their urine due to osmotic diuresis, which can lead to continued dehydration despite fluid therapy. Interestingly, studies of humans using standard levels of dehydration at which every patient receives the same amount of fluid (without a physical examination or personalized recommendation) lead to overzealous volumes of fluid administration in up to 2 out of 3 of patients.18 Using serial body weights is very helpful when determining if the animal is properly rehydrated. Remember that correction of a 10% dehydration deficit should correspond to an approximately 10% body weight gain (ie, a 10 kg animal becomes an 11 kg animal after fluid therapy). Additionally, properly rehydrated animals should be urinating frequently. Animals with DKA and osmotic diuresis obviously have polyuria and if you do not see frequent urination, the animal is still dehydrated. Urine specific gravities with glucosuria and osmotic diuresis should not be higher than 1.015. Higher specific gravities are likely consistent with persistent dehydration.
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Human pediatric patients with DKA are at a high risk of developing cerebral edema. This has led to recommendations in children in which fluid therapy is limited in the initial 3 to 4 hours and fluid rates in general are more restricted and aimed at giving fluid with lower amounts of sodium (0.45% saline vs 0.9% saline) over longer periods of time (48 hours rather than 24 hours) in children.14 However, newer information suggests that cerebral edema is due to reperfusion of ischemic brain tissue and increased vascular permeability rather than shifting of water into brain cells, making fluid therapy rarely, if ever, a contributing factor.14 There is nothing in the veterinary literature that indicates veterinary patients are at a significant risk of developing cerebral edema when treated for DKA. Supplementation of Electrolytes and Dextrose
Sodium7 There are no concerns about improving sodium concentrations through administration of sodium. - Any crystalloid fluid will have enough sodium. - Older recommendations of 0.9% saline are not absolute requirements. As ketone body production decreases, concurrent loss of sodium with ketones through the kidney will decrease. Volume resuscitation alone will decrease hyperglycemia. - Decreases osmolarity in the blood vessel / decreases movement of water into the vascular space from the extravascular space / decreases dilution of sodium. - Decreases osmolarity in the renal tubule / decreases movement of sodium and water out of the kidneys / more sodium retained by the kidneys. Potassium8 All DKA patients require potassium supplementation regardless of measured serum potassium concentration. - Potassium has been lost through kidneys. - Potassium has shifted from storage inside cells into the bloodstream secondary to acidosis and insulin therapy. Falsely increases serum potassium concentration. Total body potassium concentrations are decreased as intracellular stored potassium shifts out of cells. If serum potassium concentrations are in the normal range (generally 3.5–5.5 mEq/L) - Add 20 mEq/L of potassium chloride (KCl) to crystalloid fluids or infuse approximately 0.1 mEq/kg/h to patient. If serum potassium concentrations are low, use Sliding Scale of Scott (Table 3) or administer 0.1 to 0.5 mEq/kg/h KCl (with rate depending on sequentially measured serum potassium concentrations). - Be careful exceeding 0.5 mEq/kg/h of potassium supplementation. - Hyperkalemia can cause cardiac arrhythmias, including atrial standstill and asystole. - Be sure to thoroughly mix all supplemental potassium in crystalloid fluid bags to prevent excessively high concentrations (potentially life-threatening) of potassium in the initial milliliters of fluids administered from un-mixed bags.19 Phosphorus9 Typically, even normal serum phosphorus concentrations are expected to decrease when insulin therapy initiated. - Insulin moves phosphate (PO4) into the cells.
DKA Fluids–Electrolytes
Table 3 Sliding Scale of Scott for potassium supplementation Measured Serum Potassium Concentration (mEq/L)
mEq KCl Added to 1 L Crystalloid Fluid
Maximum Daily Fluid Rate (mL/Kg/d)a
<2.0
80
144
2.1–2.5
60
192
2.6–3.0
40
288
3.1–3.5
28
432
3.6–5.0
20
600
a
If crystalloid fluid rate exceeds the listed rate, decrease the mEq KCl added to the 1 L bag so as to not exceed 0.5 mEq/kg/h of potassium administration. Data from DiBartola SP, De Morais HA. Disorders of potassium: hyperkalemia and hypokalemia. In: DiBartola SP, editor. Fluid, electrolyte and acid base disorders in small animal practice, 4th edition. St Louis (MO): Elsevier Saunders; 2012. p. 92–119.
It is important to serially evaluate serum PO4 concentration during the course of treatment. - The author suggests obtaining baseline serum phosphorus concentrations and then checking serum phosphorus between 6 to 12 hours after initiating insulin therapy, even if the serum phosphorus concentration was initially normal. Hypophosphatemia requiring treatment is usually considered to be lower than 1.5 mg/dL. - Supplement phosphorus (potassium phosphate [KPO4] solution) intravenously. - Administer 0.01 to 0.06 mmol/kg/h diluted in 0.9% saline. - Be aware that KPO4 will also supply potassium to the animal. Decrease KCl administered so as to limit the amount of potassium given to the animal. Determine potassium supplementation using the Sliding Scale of Scott (see Table 3). Give one-half of the potassium requirement as KCl and one-half as KPO4. Typically, this will be an adequate amount of PO4 for the animal while giving appropriate amounts of potassium. Alternatively, determine potassium supplementation by calculation (0.1–0.5 mEq/kg/h). Give one-half of the potassium requirement as KCl and one-half as KPO4. Typically, this will be an adequate amount of PO4 for the animal while giving appropriate amounts of potassium. Dextrose Most DKA patients require dextrose supplementation at some point in their treatment. - Most dogs and cats do not eat food during the initial stages of treatment due to nausea resulting from acidosis or other underlying diseases such as pancreatitis. - Administration of insulin will decrease serum glucose concentration, especially in anorexic patients. Insulin helps to move ketones as well as glucose into the cells. - Glucose is converted into glycogen that can then be broken down via glycolysis to yield acetyl coenzyme A (A-CoA) (see Fig. 1A). -
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Fig. 1. Normal cellular energy usage versus cellular energy production in diabetes mellitus/ DKA.2–4 (A) In the normal setting glucose enters cells under the influence of insulin and is converted to A-CoA via glycolysis. The A-CoA is then incorporated into the citric acid (TCA)
DKA Fluids–Electrolytes
Box 3 Mechanism of bicarbonate to resolve metabolic acidosis while potentially leading to other complications HCO3- 1 H1 4 H2CO3 4 H2O 1 CO2 HCO3- 5 bicarbonate. H1 5 hydrogen ion. H2CO3 5 carbonic acid. H2O 5 water. CO2 5 carbon dioxide. The administration of HCO3- will bind to H1 and reduce acidemia. However, giving extra bicarbonate will lead to increased production of CO2 (the equation shifts to the right). If the patient is unable to increase respiratory rate and effort to remove the excess CO2, carbon dioxide will accumulate in the blood. Examples of patients who cannot compensate to remove CO2 via the respiratory system include those with severe hypokalemia with concurrent respiratory muscle weakness, recumbent animals, or those with concurrent respiratory diseases. Excess CO2 diffuses into the central nervous system (CNS) more readily than HCO3- / CNS acidosis (paradoxic CNS acidosis) Excess CO2 can cause the equation to shift back to the left, increasing serum H1 concentration and further decreasing blood pH (respiratory acidosis). Excess HCO3- created when the equation shifts back to the left must be removed by the kidneys (a problem when there is concurrent renal disease) / can lead to metabolic alkalosis. Adapted from DiBartola SP. Metabolic acid-base disorders. In: DiBartola SP, editor. Fluid, electrolyte and acid base disorders in small animal practice, 4th edition. St Louis (MO): Elsevier Saunders; 2012.
Ketones are removed from the blood and shifted into cells / more rapidly resolves the acidosis. A goal of treatment is to be able to administer as much insulin to a DKA patient as possible during the animal’s hospitalization. Many animals will receive concurrent insulin and dextrose supplementation as indicated in Table 1 to avoid hypoglycemia while receiving insulin therapy. Bicarbonate This is given to improve blood pH. Box 3 lists its effects. -
= cycle. The resulting electrons liberated in the TCA cycle are transported to the electron transport chain in the mitochondrion where they fuel oxidative phosphorylation and make adenosine triphosphate (ATP). (B) In the diabetic patient, the lack of insulin limits the amount of glucose that is transported into the cell from the bloodstream, causing the body to make use of primarily fatty acids and secondarily amino acids from protein breakdown to provide the A-CoA needed for the TCA cycle and eventual production of ATP. This beta-oxidation of fatty acids primarily takes place in the liver using coenzyme A. As the diabetic continues to break down fat to make A-CoA, the rate of this conversion is limited by the amount of coenzyme A in the liver, eventually leading to a maximal rate of fatty acid breakdown. In addition, the TCA cycle becomes saturated with A-CoA and cannot operate faster despite being faced with increased amounts of A-CoA. One of the intermediates in the TCA cycle (oxaloacetate) is also converted back to glucose in an attempt to provide cellular energy, further limiting the ability of the TCA cycle to take up and convert A-CoA. Thus, there is an excess of A-CoA. It is this excess of A-CoA that the body uses to form ketone bodies. Conversion to ketone bodies liberates coenzyme A to continue fatty acid breakdown in the liver. Ketone bodies can be used in the heart, skeletal muscle, kidney, and brain to provide energy or can be excreted through the kidney.
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Bicarbonate is not recommended in humans for blood pH greater than 7.013,20 and veterinarians have followed this recommendation.12,15 - There is no evidence that even human patients with severe acidosis (blood pH <6.9) had improved time to resolution of acidosis or time to hospital discharge or time to hospital discharge when given bicarbonate.20 - There is a concern for reflex respiratory acidosis in patients treated with bicarbonate (see Box 3). Decrease in ketones via renal excretion (administration of intravenous fluids) and insulin therapy will improve acidosis, negating the need for bicarbonate therapy in most patients. In the author’s experience, unless the kidneys are unable to reabsorb bicarbonate on their own to resolve the acidosis and waste the ketoacids, therapy with exogenous bicarbonate is not needed. SUMMARY
Treatment of DKA is relatively straightforward in its approach. The difficulty comes in fine-tuning the basic treatment protocol to each animal. However, if veterinarians remember to use crystalloid fluids in addition to insulin therapy, with frequent rechecks of blood glucose, electrolytes, and blood pH, resolution of the hyperglycemia and other abnormalities is almost always successful. REFERENCES
1. Hall JE. Insulin, glucose and diabetes mellitus. In: Guyton and Hall textbook of medical physiology 12th edition. Philadelphia: Saunders Elsevier; 2011. p. 939–54. 2. Nelson DL, Cox MM. Hormonal regulation and integration of mammalian metabolism. In: Lehninger principles of biochemistry 6th edition. New York: Freeman, WH & Company; 2012. p. 929–75. 3. Nelson DL, Cox MM. The citric acid cycle. In: Lehninger principles of biochemistry 6th edition. New York: Freeman, WH & Company; 2012. p. 633–65. 4. Nelson DL, Cox MM. Fatty acid catabolism. In: Lehninger principles of biochemistry 6th edition. New York: Freeman, WH & Company; 2012. p. 667–93. 5. Hall JE. Lipid metabolism. In: Guyton and Hall textbook of medical physiology 12th edition. Philadelphia: Saunders Elsevier; 2011. p. 819–30. 6. Eaton DC, Pooler JP. Regulation of calcium, magnesium and phosphate. In: Vander’s renal physiology 8th edition. New York: McGraw-Hill Education; 2013. p. 172–86. 7. DiBartola SP. Disorders of sodium and water: hypernatremia and hyponatremia. In: DiBartola SP, editor. Fluid, electrolyte and acid base disorders in small animal practice. 4th edition. St Louis (MO): Elsevier Saunders; 2012. p. 45–79. 8. DiBartola SP, De Morais HA. Disorders of potassium: hyperkalemia and hypokalemia. In: DiBartola SP, editor. Fluid, electrolyte and acid base disorders in small animal practice. 4th edition. St Louis (MO): Elsevier Saunders; 2012. p. 92–119. 9. DiBartola SP, Willard MD. Disorders of phosphorus: hyperphosphatemia and hypophosphatemia. In: DiBartola SP, editor. Fluid, electrolyte and acid base disorders in small animal practice. 4th edition. St Louis (MO): Elsevier Saunders; 2012. p. 195–211. 10. Wellman ML, DiBartola SP, Kohn CW. Applied physiology of body fluids. In: DiBartola SP, editor. Fluid, electrolyte and acid base disorders in small animal practice. 4th edition. St Louis (MO): Elsevier Saunders; 2012. p. 2–25.
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11. Chua H, Venkatesh B, Stachowski E, et al. Plasma-Lyte 148 vs 0.9% saline for fluid resuscitation in diabetic ketoacidosis. J Crit Care 2012;27:138–45. 12. Kerl ME. Diabetic ketoacidosis: treatment recommendations. Compend Contin Educ Vet 2001;23:330–40. 13. Gosmanov AR, Gosmanova EO, Dillard-Cannon E. Management of adult diabetic ketoacidosis. Diabetes Metab Syndr Obes 2014;7:255–64. 14. Watts W, Edge JA. How can cerebral edema during treatment of diabetic ketoacidosis be avoided? Pediatr Diabetes 2014;15:271–6. 15. Boysen SR. Fluid and electrolyte therapy in endocrine disorders: diabetes mellitus and hypoadrenocorticism. Vet Clin North Am Small Anim Pract 2008;38: 699–717. 16. Sears KW, Drobatz KJ, Hess RS. Use of lispro insulin for treatment of diabetic ketoacidosis in dogs. J Vet Emerg Crit Care 2012;22:211–8. 17. Walsh ES, Drobatz KJ, Hess RS. Use of intravenous insulin aspart for treatment of naturally occurring diabetic ketoacidosis in dogs. J Vet Emerg Crit Care 2016;26: 101–7. 18. Fagan MJ, Avner J, Khine H. Initial fluid resuscitation for patients with diabetic ketoacidosis: how dry are they? Clin Pediatr 2008;47:851–5. 19. Hoehne SN, Hopper K, Epstein SE. Accuracy of potassium supplementation of fluids administered intravenously. J Vet Intern Med 2015;24:834–9. 20. Duhon B, Attridge RL, Franco-Martinez AC, et al. Intravenous sodium bicarbonate therapy in severely acidotic diabetic ketoacidosis. Ann Pharmacother 2013; 47:970–5.
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KEYWORDS Diabetic ketoacidosis Insulin Crystalloid fluid Hyperglycemia Acidosis Sodium Potassium Phosphorus KEY POINTS Treatment of diabetic ketoacidosis is relatively straightforward in its approach. The difficulty comes in fine-tuning the basic treatment protocol to each animal. Using crystalloid fluids in addition to insulin therapy with frequent rechecks of blood glucose, electrolytes, and blood pH, resolution of the hyperglycemia and other abnormalities is almost always successful.
INTRODUCTION
Diabetic ketoacidosis (DKA) is a complication of diabetes mellitus commonly encountered in dogs and cats. This article presents an approach to fluid and electrolyte therapy for DKA. Although an extensive discussion of the pathophysiology and clinical presentation is beyond the confines of this article, this article will briefly touch on the important points related to this disease before discussing details of fluid and electrolyte management. PATHOPHYSIOLOGY OF DIABETIC KETOACIDOSIS
Diabetes mellitus refers to a deficiency of insulin in the body that can be relative or absolute.1,2 Regardless of the exact reason for the deficiency of insulin, the result is that the diabetic dog or cat is unable to move glucose from the bloodstream into the cells to fuel cellular metabolic processes. In response, the cells of the body begin to mobilize alternative energy sources such as fats and proteins to provide fuel for metabolism. See Fig. 1A, B for more details.3,4
The author has nothing to disclose. Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Purdue University, 625 Harrison Street, West Lafayette, IN 47906, USA E-mail address: [email protected] Vet Clin Small Anim - (2016) -–http://dx.doi.org/10.1016/j.cvsm.2016.09.012 0195-5616/16/ª 2016 Elsevier Inc. All rights reserved.
vetsmall.theclinics.com
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In this climate of cellular demand for energy, the body is initially able to supply enough energy to the cells, largely through metabolism of fats. However, in the process of breaking down fats to make energy, ketoacids are also formed in excess.2 Although some of the ketoacids are used by the myocardium, skeletal muscle, kidney cells, and brain, those remaining need to be excreted by the kidneys.2 In most cases, ketoacids are formed in excess when cellular energy demand increases above normal.5 In diabetic patients, this often occurs when hormones such as epinephrine, glucagon, cortisol, and growth hormone are produced. These hormones may be produced when there is a concurrent disease process but can simply be produced when the body perceives that it requires more energy in the cells.5 Concurrent diseases range from the relatively benign (urinary tract infection) to more severe disorders such as pancreatitis or neoplasia. These ketogenic hormones increase fatty acid breakdown (glucagon), further decrease insulin’s efficacy (growth hormone, epinephrine, and cortisol), and increase protein breakdown (cortisol and epinephrine).5 Oxidation of fats to form ketone bodies liberates carboxylic acids that release hydrogen ions.2 Therefore, overproduction of ketone bodies also leads to an overproduction of hydrogen ions, thus decreasing the blood pH and leading to acidosis. A diabetic patient can be ketotic without acidosis if the bicarbonate buffering system in the body can bind to and buffer the hydrogen ions. When the amount of hydrogen ions created exceeds the bicarbonate buffering system’s ability to bind hydrogen, acidosis results.2 Contributing to the development of acidosis (and hence DKA) is the mechanism of ketoacid excretion in the kidneys. To be excreted from the kidneys, the ketoacids combine with sodium found in the extracellular fluid (blood and interstitial fluid).6 Hydrogen ions are then used by the body to replace the sodium ions in the extracellular fluid, further decreasing the pH of the bloodstream and interstitial tissues.1,6 NONPHARMACOLOGIC TREATMENT OPTIONS FOR DIABETIC KETOACIDOSIS
Once a patient has been diagnosed with DKA by a combination of documented hyperglycemia, glucosuria, ketonuria, and acidemia, the first order of business is to initiate treatment. The mainstays of treatment of ketoacidosis are fluids and insulin therapy. Obviously, if there is another concurrent disorder in the dog or cat that has led to the development of DKA, such as a urinary tract infection, pancreatitis, or any other disease, specific treatment of that condition should be instigated as well. This article focuses on the fluid therapy aspects and briefly touches on insulin therapy; veterinarians are urged to consult other resources for information about treating disorders concurrent with DKA. OVERVIEW OF FLUID THERAPY IN DIABETIC KETOACIDOSIS
Fluids are given to patients with DKA for several reasons: Dehydration (see Box 1 for the mechanism of this change in DKA) Hypovolemia (see Box 1) Improve glomerular filtration in the kidneys (see Box 1) Increase excretion of glucose through the kidneys Increase excretion of ketoacids and hydrogen ions through the kidneys Decreases acidosis Resolve hypernatremia (see Box 2 for mechanism of electrolyte changes) Supply potassium (see Box 2) Supply phosphorus if indicated (see Box 2).
DKA Fluids–Electrolytes
Box 1 Effects of diabetes mellitus on fluid and electrolytes in the body Increased concentrations of glucose in the blood will remain either in the intravascular space or diffuse into the interstitial space. The cell membrane is relatively impermeable to glucose and, therefore, the glucose does not enter the cells. Instead, the glucose will draw fluid from the intracellular space into the vascular and interstitial spaces. This dehydrates the intracellular space. Glucose contained the blood is filtered at the glomeruli and excreted through the renal tubules. Glucose contained in the renal tubules holds water in the tubules and decreases tubular water reabsorption. Water is lost in large quantities through the kidneys causing polyuria (osmotic diuresis). Lack of water reabsorption in the kidney / decreased vascular volume / fluid shifts from the interstitium into the vascular space (interstitial dehydration) / fluid shifts from the intracellular space into the vasculature (intracellular dehydration) / when no more fluid can leave either the intracellular or interstitial space, the vascular volume decreases (hypovolemia). Diabetes can cause both intracellular and interstitial dehydration. Diabetes can also lead to hypovolemia in untreated cases, especially when an animal is unable to take in water (polydipsia) to compensate for the loss of water from the interstitial and intracellular spaces. Ketoacids filtered at the glomeruli and excreted through the renal tubules / cotransported with sodium / sodium holds water in the tubules and decreases tubular reabsorption of fluid / excrete sodium, water, and ketoacids. Adapted from Hall JE. Insulin, glucose and diabetes mellitus. In: Guyton and Hall textbook of medical physiology 12th edition. Philadelphia: Saunders Elsevier; 2011.
Fluid Type
The first order of business is determining which fluid type is best for an animal with DKA. Because animals with DKA are dehydrated in the interstitial and intracellular spaces on presentation, giving a crystalloid fluid is indicated because up to 75% of these fluids naturally shift from the intravascular space into the interstitial and intracellular spaces within 20 to 30 minutes of administration. Therefore, fluid is returned quickly to the dehydrated spaces. In addition, because hypovolemia in DKA results from dehydration of the interstitial and intracellular spaces (thus causing loss of fluid that would normally be used to replenish the intravascular space), hypovolemia will also be improved by refilling those deficient compartments, allowing for return of fluid to the vascular space.10 Human (and older veterinary) resources have recommended 0.9% sodium chloride (NaCl) as the fluid of choice. The reasons for this were largely because this fluid has the highest sodium concentration and, therefore, can treat the hyponatremia often observed in DKA patients (see Box 2). However, due to the increased chloride in these fluids and the lack of a buffer, they have been shown to cause hyperchloremic metabolic acidosis in DKA patients, all of whom already have a high anion gap metabolic acidosis from the ketone body production.11 Therefore, using a balanced crystalloid with a buffer (such as lactated Ringer solution or plasmalyte-148) is recommended in veterinary medicine. Plasmalyte-148 was shown to improve resolution of acidosis within the first 12 hours of infusion versus 0.9% NaCl in adult human patients with DKA.11 Additionally, humans receiving
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Box 2 Mechanisms of electrolyte disorders in diabetic ketoacidosis Hyponatremia7 Increased concentration of ketoacids in blood / sodium (Na1) excreted with ketoacids in kidneys via a cotransporter. Hyperglycemia / increased osmolality in blood / fluid shifts from interstitium and intracellular space into blood / decreases the sodium concentration by dilution of existing sodium. - For every 100 mg/dL increase in glucose in blood, there is at least a 1.6 mEq/L decrease in Na1 concentration. Increased renal filtration of glucose / retain Na1 and water in renal tubules (osmotic diuresis) / Na1 loss in urine. Hypokalemia8 Loss in kidneys 1 1 - Lack of insulin / potassium (K ) remains in blood / K filtered through glomeruli / K1 lost through renal tubules with excessive water and glucose (osmotic diuresis). 1 1 - Acidosis / hydrogen (H ) ions shift into cells and K moves into bloodstream from cells / potassium filtered at kidney / K1 lost through renal tubules with excessive water and glucose (osmotic diuresis). Insulin therapy / movement glucose and potassium into cells / hypokalemia. Epinephrine release / shifts glucose and potassium into cells / hypokalemia. Hypophosphatemia6,9 Phosphate (PO4) deficit - Loss of muscle mass during amino acid breakdown (see Fig. 1B) / less stored PO4 in the body. - Loss of phosphorus in the urine Decreased insulin concentration / decreased movement PO4 into cells / more PO4 filtered at glomeruli and into renal tubules / loss of PO4 in urine. Decreased insulin concentration / decreased reabsorption PO4 in the kidney / loss of PO4 in urine. Fluid therapy / increased renal PO4 excretion (with sodium phosphorus cotransporter). Movement phosphorus into cells - Insulin therapy during treatment shifts PO4 into cells with glucose / hypophosphatemia.
plasmalyte-148 do not have increases in their chloride concentrations contributing to metabolic acidosis.11 Insulin Therapy
The goal of giving insulin to a diabetic patient is to resolve hyperglycemia by storing circulating serum glucose in the liver as glycogen (increase glycogen synthesis) and as triacylglycerols in the adipose tissue (increase fatty acid synthesis).1,2 Additionally, the insulin transports glucose into the cells to be used in glycolysis and the tricarboxylic acid (TCA) cycle (ie, re-establish normal metabolism, Fig. 1A) so that further fat and protein breakdown for energy and, therefore, ketone body production is not necessary.2 Because insulin allows for improvement of blood glucose concentration, and decreased ketonemia and concurrent acidemia, one of the goals of treatment is to continuously and consistently administer insulin as long as possible to a patient. There has been much published on various techniques of insulin administration. Historically, in both human and veterinary medicine, regular insulin (a short-acting insulin) is indicated in the acute period.12–15 There are multiple ways to administer regular insulin with routes ranging from intravenous to intramuscular, with frequencies reported
DKA Fluids–Electrolytes
from continuous to every 1 to 4 hours.12 Veterinarians are urged to use whatever regular insulin protocol they are most comfortable with. The goal of any insulin regimen is to maintain serum glucose concentration between 100 to 250 g/dL. Table 1 is a sample treatment chart. The frequency of blood glucose monitoring depends on the exact insulin protocol initiated. Typically, continuous infusions of insulin have blood glucose monitoring every 1 to 2 hours, whereas intramuscular injection protocols call for monitoring of blood glucose every 4 hours. Regardless of the frequency of glucose monitoring, note that when the animal’s blood glucose decreases, dextrose is added to the crystalloid fluids so as to continue to allow administration of insulin without causing hypoglycemia. In recent years, 2 publications have reported using different short-acting human insulin products in dogs with DKA.16,17 One product is called lispro and it was administered at a dosage of 2.2 U/kg/d mixed in 0.9% saline and given as a continuous infusion (see Table 1). In a study of 12 dogs, 6 dogs received lispro insulin and their ketonemia, hyperglycemia, and acidemia were normalized in a median of 26 hours (range 26–50 hours), whereas 6 dogs received regular insulin and had resolution of signs in a median of 51 hours (range 50–82 hours).16 The second product is called insulin aspart. It was used in 6 dogs and given intravenously continuously at a dosage of 2.2 U/kg/d mixed in 0.9% saline (see Table 1).17 The dogs given insulin aspart had a median time to resolution of ketonemia, hyperglycemia, and acidemia of 28 hours (range 20–116 hours).17 Therefore, the use of any short-acting insulin product (regular, lispro, or aspart) continuously intravenously is effective in decreasing the blood sugar in dogs. Neither lispro nor aspart insulin has been tested in cats. Fluid Rates and Administration
Guidelines for humans assume that all DKA patients presenting at the hospital have a 5% to 10% dehydration (corresponding to a deficit of 6–9 L of fluid).13 Recommendations for humans specify that 50% of this deficit is replaced within 8 to 12 hours, with the total dehydration deficit given over 24 to 36 hours.13 Veterinary medicine lacks such specific guidelines and allows for more individualized treatment. The author presents a potential way to approach fluid therapy. Step 1. Initial treatment (0–6 hours postpresentation) Examine the patient and estimate dehydration paying attention to whether there is concern that the animal is hypovolemic (Table 2 shows guidelines on estimating dehydration and calculating the dehydration deficit).
Table 1 A sample protocol for continuous intravenous administration of short-acting insulin (regular insulin, lispro insulin, or insulin aspart in dogs; or regular insulin in cats) Measured Blood Glucose (mg/dL)
Dextrose in Crystalloid Fluids
Insulin Rate (mL/h)a
250
None
10
200–250
2.5% dextrose
7
150–200
2.5% dextrose
5
100–150
5% dextrose
5
<100
5% dextrose
No insulin
a All insulin administered is created in the following way: 250 mL bag of 0.9% saline 1 2.2 U/kg of short-acting insulin (dogs) or 1.1 U/kg regular insulin only (cats). Data from Refs.12,16,17
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Table 2 Guidelines for estimation of dehydration based on physical examination findings in dogs and cats Percent Dehydration Compartment Involved Clinical Signsa <5%
ISF
History of anorexia Decreased or absent drinking Vomiting, diarrhea
5%
ISF
Tacky mucous membranes 1/ skin tent
7%–8%
ISF / IC
Skin tent Dull corneas
10%
IC
Sunken eyes Depressed mentation
10%–12%
IC / IV
Tachycardia Decreased blood pressure Severe depression
12%–15%
IV
Worsening signs of hypovolemia (die at 15%)
Calculating dehydration deficit: (wt in kg) (% dehydration) 5 L of fluid. Abbreviations: IC, intracellular compartment; ISF, interstitial fluid compartment; IV, intravascular space. a Only new findings that occur at that level of dehydration are listed; it is assumed that all previous findings are still present.
Administer a portion of this dehydration deficit in the first 2 to 6 hours of treatment with the timing and amount based on clinical judgment of this particular patient’s condition. Use a balanced crystalloid solution such as lactated Ringer solution or plasmalyte-148. An example is to give one-half of the dehydration deficit over 4 hours. Factors to take into account include the degree of dehydration (hypovolemic or severely dehydrated patients need more fluid faster) and comorbidities (animals with heart disease often require slower more deliberate fluid administration). No insulin is administered during this rehydration period because the goal is to restore hemodynamic stability (ie, treat hypovolemia if present) and improve filtration in the kidneys. Fluid therapy itself will decrease the initial presenting glucose concentration; therefore, withholding insulin therapy until the fluid-induced decrease in glucose concentration in the blood occurs is wise. Fluid therapy will potentially cause alterations in the presenting concentrations of potassium, phosphorus, and sodium. Therefore, specific treatment of the electrolyte abnormalities noted on initial bloodwork should not be implemented until after this initial fluid therapy period. Step 2. Correction of remaining dehydration, acidosis, and electrolyte abnormalities (the first 24 hours of hospitalization) After the initial fluid administration (roughly 2–6 hours after presentation), take a blood sample to determine the animal’s electrolytes, blood pH, and blood glucose concentration. Depending on the animal’s blood glucose concentration, initiate regular insulin therapy using the veterinarian’s preferred technique and dosing (see Table 1 of regular and other short-acting insulins).
DKA Fluids–Electrolytes
Determine the remaining amount of fluid required to replace the animal’s dehydration (ie, subtract what has been given thus far from the initial estimated amount). Give what remains over the next 12 to 24 hours, depending on the animal’s comorbidities (ie, animals with heart disease or heart murmurs might receive fluids at a slower rate than those without). Provide maintenance fluids to the animal in addition to the dehydration fluids. Consider supplementing dextrose or electrolytes to the animal (see subsequent sections). Step 3. Reassess fluid rate, insulin administration, and electrolyte supplementation (every 6–12 hours during hospitalization) When the calculated dehydration deficit has been completely administered, reassess the patient to ensure that the animal no longer seems to be dehydrated (see Table 2). If the animal is still clinically dehydrated, recalculate the dehydration deficit and administer it over the next 4 to 12 hours. If the animal is no longer clinically dehydrated, decrease the crystalloid fluid rate to maintenance (ie, 60 mL/kg/d) or to an amount that matches the urine production in severely polyuric animals. If the animal has ongoing losses, such as vomiting or diarrhea, estimate that amount. Administer fluids to replace the ongoing losses in addition to the maintenance fluids. Recheck blood glucose concentration regularly as dictated by the insulin regime (usually every 1–4 hours). Administer insulin as dictated by the blood glucose concentration (see Table 1). At least every 12 hours (often every 4–6 hours depending on how sick the animal is), recheck the electrolytes and blood pH. Adjust supplementation as indicated (see subsequent sections). Other Considerations When Administering Fluids
It is important to remember that frequent reassessment of patients is important to ensure that enough but not too much fluid is being given. The author typically does a physical examination at least every 12 hours on these animals, paying particular attention to whether or not the physical findings consistent with dehydration have improved. In the author’s experience, it is not uncommon to underestimate the animal’s dehydration, especially because many of the clinical findings can be affected by age or breed, as well as behaviors such as panting or hypersalivating from nausea. Also, these animals are losing large amounts of fluid in their urine due to osmotic diuresis, which can lead to continued dehydration despite fluid therapy. Interestingly, studies of humans using standard levels of dehydration at which every patient receives the same amount of fluid (without a physical examination or personalized recommendation) lead to overzealous volumes of fluid administration in up to 2 out of 3 of patients.18 Using serial body weights is very helpful when determining if the animal is properly rehydrated. Remember that correction of a 10% dehydration deficit should correspond to an approximately 10% body weight gain (ie, a 10 kg animal becomes an 11 kg animal after fluid therapy). Additionally, properly rehydrated animals should be urinating frequently. Animals with DKA and osmotic diuresis obviously have polyuria and if you do not see frequent urination, the animal is still dehydrated. Urine specific gravities with glucosuria and osmotic diuresis should not be higher than 1.015. Higher specific gravities are likely consistent with persistent dehydration.
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Human pediatric patients with DKA are at a high risk of developing cerebral edema. This has led to recommendations in children in which fluid therapy is limited in the initial 3 to 4 hours and fluid rates in general are more restricted and aimed at giving fluid with lower amounts of sodium (0.45% saline vs 0.9% saline) over longer periods of time (48 hours rather than 24 hours) in children.14 However, newer information suggests that cerebral edema is due to reperfusion of ischemic brain tissue and increased vascular permeability rather than shifting of water into brain cells, making fluid therapy rarely, if ever, a contributing factor.14 There is nothing in the veterinary literature that indicates veterinary patients are at a significant risk of developing cerebral edema when treated for DKA. Supplementation of Electrolytes and Dextrose
Sodium7 There are no concerns about improving sodium concentrations through administration of sodium. - Any crystalloid fluid will have enough sodium. - Older recommendations of 0.9% saline are not absolute requirements. As ketone body production decreases, concurrent loss of sodium with ketones through the kidney will decrease. Volume resuscitation alone will decrease hyperglycemia. - Decreases osmolarity in the blood vessel / decreases movement of water into the vascular space from the extravascular space / decreases dilution of sodium. - Decreases osmolarity in the renal tubule / decreases movement of sodium and water out of the kidneys / more sodium retained by the kidneys. Potassium8 All DKA patients require potassium supplementation regardless of measured serum potassium concentration. - Potassium has been lost through kidneys. - Potassium has shifted from storage inside cells into the bloodstream secondary to acidosis and insulin therapy. Falsely increases serum potassium concentration. Total body potassium concentrations are decreased as intracellular stored potassium shifts out of cells. If serum potassium concentrations are in the normal range (generally 3.5–5.5 mEq/L) - Add 20 mEq/L of potassium chloride (KCl) to crystalloid fluids or infuse approximately 0.1 mEq/kg/h to patient. If serum potassium concentrations are low, use Sliding Scale of Scott (Table 3) or administer 0.1 to 0.5 mEq/kg/h KCl (with rate depending on sequentially measured serum potassium concentrations). - Be careful exceeding 0.5 mEq/kg/h of potassium supplementation. - Hyperkalemia can cause cardiac arrhythmias, including atrial standstill and asystole. - Be sure to thoroughly mix all supplemental potassium in crystalloid fluid bags to prevent excessively high concentrations (potentially life-threatening) of potassium in the initial milliliters of fluids administered from un-mixed bags.19 Phosphorus9 Typically, even normal serum phosphorus concentrations are expected to decrease when insulin therapy initiated. - Insulin moves phosphate (PO4) into the cells.
DKA Fluids–Electrolytes
Table 3 Sliding Scale of Scott for potassium supplementation Measured Serum Potassium Concentration (mEq/L)
mEq KCl Added to 1 L Crystalloid Fluid
Maximum Daily Fluid Rate (mL/Kg/d)a
<2.0
80
144
2.1–2.5
60
192
2.6–3.0
40
288
3.1–3.5
28
432
3.6–5.0
20
600
a
If crystalloid fluid rate exceeds the listed rate, decrease the mEq KCl added to the 1 L bag so as to not exceed 0.5 mEq/kg/h of potassium administration. Data from DiBartola SP, De Morais HA. Disorders of potassium: hyperkalemia and hypokalemia. In: DiBartola SP, editor. Fluid, electrolyte and acid base disorders in small animal practice, 4th edition. St Louis (MO): Elsevier Saunders; 2012. p. 92–119.
It is important to serially evaluate serum PO4 concentration during the course of treatment. - The author suggests obtaining baseline serum phosphorus concentrations and then checking serum phosphorus between 6 to 12 hours after initiating insulin therapy, even if the serum phosphorus concentration was initially normal. Hypophosphatemia requiring treatment is usually considered to be lower than 1.5 mg/dL. - Supplement phosphorus (potassium phosphate [KPO4] solution) intravenously. - Administer 0.01 to 0.06 mmol/kg/h diluted in 0.9% saline. - Be aware that KPO4 will also supply potassium to the animal. Decrease KCl administered so as to limit the amount of potassium given to the animal. Determine potassium supplementation using the Sliding Scale of Scott (see Table 3). Give one-half of the potassium requirement as KCl and one-half as KPO4. Typically, this will be an adequate amount of PO4 for the animal while giving appropriate amounts of potassium. Alternatively, determine potassium supplementation by calculation (0.1–0.5 mEq/kg/h). Give one-half of the potassium requirement as KCl and one-half as KPO4. Typically, this will be an adequate amount of PO4 for the animal while giving appropriate amounts of potassium. Dextrose Most DKA patients require dextrose supplementation at some point in their treatment. - Most dogs and cats do not eat food during the initial stages of treatment due to nausea resulting from acidosis or other underlying diseases such as pancreatitis. - Administration of insulin will decrease serum glucose concentration, especially in anorexic patients. Insulin helps to move ketones as well as glucose into the cells. - Glucose is converted into glycogen that can then be broken down via glycolysis to yield acetyl coenzyme A (A-CoA) (see Fig. 1A). -
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Fig. 1. Normal cellular energy usage versus cellular energy production in diabetes mellitus/ DKA.2–4 (A) In the normal setting glucose enters cells under the influence of insulin and is converted to A-CoA via glycolysis. The A-CoA is then incorporated into the citric acid (TCA)
DKA Fluids–Electrolytes
Box 3 Mechanism of bicarbonate to resolve metabolic acidosis while potentially leading to other complications HCO3- 1 H1 4 H2CO3 4 H2O 1 CO2 HCO3- 5 bicarbonate. H1 5 hydrogen ion. H2CO3 5 carbonic acid. H2O 5 water. CO2 5 carbon dioxide. The administration of HCO3- will bind to H1 and reduce acidemia. However, giving extra bicarbonate will lead to increased production of CO2 (the equation shifts to the right). If the patient is unable to increase respiratory rate and effort to remove the excess CO2, carbon dioxide will accumulate in the blood. Examples of patients who cannot compensate to remove CO2 via the respiratory system include those with severe hypokalemia with concurrent respiratory muscle weakness, recumbent animals, or those with concurrent respiratory diseases. Excess CO2 diffuses into the central nervous system (CNS) more readily than HCO3- / CNS acidosis (paradoxic CNS acidosis) Excess CO2 can cause the equation to shift back to the left, increasing serum H1 concentration and further decreasing blood pH (respiratory acidosis). Excess HCO3- created when the equation shifts back to the left must be removed by the kidneys (a problem when there is concurrent renal disease) / can lead to metabolic alkalosis. Adapted from DiBartola SP. Metabolic acid-base disorders. In: DiBartola SP, editor. Fluid, electrolyte and acid base disorders in small animal practice, 4th edition. St Louis (MO): Elsevier Saunders; 2012.
Ketones are removed from the blood and shifted into cells / more rapidly resolves the acidosis. A goal of treatment is to be able to administer as much insulin to a DKA patient as possible during the animal’s hospitalization. Many animals will receive concurrent insulin and dextrose supplementation as indicated in Table 1 to avoid hypoglycemia while receiving insulin therapy. Bicarbonate This is given to improve blood pH. Box 3 lists its effects. -
= cycle. The resulting electrons liberated in the TCA cycle are transported to the electron transport chain in the mitochondrion where they fuel oxidative phosphorylation and make adenosine triphosphate (ATP). (B) In the diabetic patient, the lack of insulin limits the amount of glucose that is transported into the cell from the bloodstream, causing the body to make use of primarily fatty acids and secondarily amino acids from protein breakdown to provide the A-CoA needed for the TCA cycle and eventual production of ATP. This beta-oxidation of fatty acids primarily takes place in the liver using coenzyme A. As the diabetic continues to break down fat to make A-CoA, the rate of this conversion is limited by the amount of coenzyme A in the liver, eventually leading to a maximal rate of fatty acid breakdown. In addition, the TCA cycle becomes saturated with A-CoA and cannot operate faster despite being faced with increased amounts of A-CoA. One of the intermediates in the TCA cycle (oxaloacetate) is also converted back to glucose in an attempt to provide cellular energy, further limiting the ability of the TCA cycle to take up and convert A-CoA. Thus, there is an excess of A-CoA. It is this excess of A-CoA that the body uses to form ketone bodies. Conversion to ketone bodies liberates coenzyme A to continue fatty acid breakdown in the liver. Ketone bodies can be used in the heart, skeletal muscle, kidney, and brain to provide energy or can be excreted through the kidney.
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Bicarbonate is not recommended in humans for blood pH greater than 7.013,20 and veterinarians have followed this recommendation.12,15 - There is no evidence that even human patients with severe acidosis (blood pH <6.9) had improved time to resolution of acidosis or time to hospital discharge or time to hospital discharge when given bicarbonate.20 - There is a concern for reflex respiratory acidosis in patients treated with bicarbonate (see Box 3). Decrease in ketones via renal excretion (administration of intravenous fluids) and insulin therapy will improve acidosis, negating the need for bicarbonate therapy in most patients. In the author’s experience, unless the kidneys are unable to reabsorb bicarbonate on their own to resolve the acidosis and waste the ketoacids, therapy with exogenous bicarbonate is not needed. SUMMARY
Treatment of DKA is relatively straightforward in its approach. The difficulty comes in fine-tuning the basic treatment protocol to each animal. However, if veterinarians remember to use crystalloid fluids in addition to insulin therapy, with frequent rechecks of blood glucose, electrolytes, and blood pH, resolution of the hyperglycemia and other abnormalities is almost always successful. REFERENCES
1. Hall JE. Insulin, glucose and diabetes mellitus. In: Guyton and Hall textbook of medical physiology 12th edition. Philadelphia: Saunders Elsevier; 2011. p. 939–54. 2. Nelson DL, Cox MM. Hormonal regulation and integration of mammalian metabolism. In: Lehninger principles of biochemistry 6th edition. New York: Freeman, WH & Company; 2012. p. 929–75. 3. Nelson DL, Cox MM. The citric acid cycle. In: Lehninger principles of biochemistry 6th edition. New York: Freeman, WH & Company; 2012. p. 633–65. 4. Nelson DL, Cox MM. Fatty acid catabolism. In: Lehninger principles of biochemistry 6th edition. New York: Freeman, WH & Company; 2012. p. 667–93. 5. Hall JE. Lipid metabolism. In: Guyton and Hall textbook of medical physiology 12th edition. Philadelphia: Saunders Elsevier; 2011. p. 819–30. 6. Eaton DC, Pooler JP. Regulation of calcium, magnesium and phosphate. In: Vander’s renal physiology 8th edition. New York: McGraw-Hill Education; 2013. p. 172–86. 7. DiBartola SP. Disorders of sodium and water: hypernatremia and hyponatremia. In: DiBartola SP, editor. Fluid, electrolyte and acid base disorders in small animal practice. 4th edition. St Louis (MO): Elsevier Saunders; 2012. p. 45–79. 8. DiBartola SP, De Morais HA. Disorders of potassium: hyperkalemia and hypokalemia. In: DiBartola SP, editor. Fluid, electrolyte and acid base disorders in small animal practice. 4th edition. St Louis (MO): Elsevier Saunders; 2012. p. 92–119. 9. DiBartola SP, Willard MD. Disorders of phosphorus: hyperphosphatemia and hypophosphatemia. In: DiBartola SP, editor. Fluid, electrolyte and acid base disorders in small animal practice. 4th edition. St Louis (MO): Elsevier Saunders; 2012. p. 195–211. 10. Wellman ML, DiBartola SP, Kohn CW. Applied physiology of body fluids. In: DiBartola SP, editor. Fluid, electrolyte and acid base disorders in small animal practice. 4th edition. St Louis (MO): Elsevier Saunders; 2012. p. 2–25.
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11. Chua H, Venkatesh B, Stachowski E, et al. Plasma-Lyte 148 vs 0.9% saline for fluid resuscitation in diabetic ketoacidosis. J Crit Care 2012;27:138–45. 12. Kerl ME. Diabetic ketoacidosis: treatment recommendations. Compend Contin Educ Vet 2001;23:330–40. 13. Gosmanov AR, Gosmanova EO, Dillard-Cannon E. Management of adult diabetic ketoacidosis. Diabetes Metab Syndr Obes 2014;7:255–64. 14. Watts W, Edge JA. How can cerebral edema during treatment of diabetic ketoacidosis be avoided? Pediatr Diabetes 2014;15:271–6. 15. Boysen SR. Fluid and electrolyte therapy in endocrine disorders: diabetes mellitus and hypoadrenocorticism. Vet Clin North Am Small Anim Pract 2008;38: 699–717. 16. Sears KW, Drobatz KJ, Hess RS. Use of lispro insulin for treatment of diabetic ketoacidosis in dogs. J Vet Emerg Crit Care 2012;22:211–8. 17. Walsh ES, Drobatz KJ, Hess RS. Use of intravenous insulin aspart for treatment of naturally occurring diabetic ketoacidosis in dogs. J Vet Emerg Crit Care 2016;26: 101–7. 18. Fagan MJ, Avner J, Khine H. Initial fluid resuscitation for patients with diabetic ketoacidosis: how dry are they? Clin Pediatr 2008;47:851–5. 19. Hoehne SN, Hopper K, Epstein SE. Accuracy of potassium supplementation of fluids administered intravenously. J Vet Intern Med 2015;24:834–9. 20. Duhon B, Attridge RL, Franco-Martinez AC, et al. Intravenous sodium bicarbonate therapy in severely acidotic diabetic ketoacidosis. Ann Pharmacother 2013; 47:970–5.
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