Elke Rudloff, DVM, DACVECC

Transcription

1 THE DIABETIC-KETOTIC DISASTER Elke Rudloff, DVM, DACVECC EMERGENCY AND CRITICAL CARE Hyperglycemic ketoacidosis is a syndrome that can cause severe illness and death. Serum hyperosmolarity, osmotic diuresis, and vomiting can result in hypovolemia and severe dehydration. Altered mentation from serum hyperosmolarity and cytotoxic edema, ketosis and increased capillary permeability, vasogenic edema, acidosis, and electrolyte disturbances can increase the risk for aspiration, nervous tissue injury, and seizure activity. The mainstay for resuscitation is careful volume replacement. Reestablishing and maintaining intravascular and interstitial fluid homeostasis requires glycemic control and elimination of ketonemia with insulin therapy. Treatment of the sick diabetic patient does not end until there has been correction of the underlying process that instigated the release of counter-regulatory hormones and/or resolution of the ketosis with insulin. When an animal is hyperglycemic (unrelated to a stress response), they may have an absolute insulin deficiency or insulin resistance. They may exhibit signs associated with hyperglycemia, such as an increase in drinking and urination, and signs associated with cellular hypoglycemia, such as weight loss, and polyphagia. Concurrent conditions (infection, pancreatitis, hepatic lipidosis, inflammatory bowel disease, renal insufficiency, heart disease, cholangiohepatitis, pyoderma, exocrine pancreas insufficiency, pituitary macrotumors, neoplasia, etc.) can result in excess secretion of counter-regulatory hormones such as glucagon, catecholamines, cortisol, and growth hormone. Counter-regulatory hormones restrict glucose transport into the cell, and the glucose-starved cell will convert freefatty acids into ketone bodies for energy. Although hyperglycemia and ketosis most commonly signify a cellular insulin deficiency, other conditions, such as malnutrition, can produce ketosis, and in the presence of elevated blood sugar (e.g., during stress), the combined syndromes may be mistaken for an absolute insulin deficiency. Finally, severe hyperglycemia in the absence of ketosis can also result in severe illness (hyperosmolarity). Nevertheless, therapeutic intervention during the resuscitation and stabilization will be the same for all syndromes. Commonly the presenting complaint may include signs of lethargy, incoordination, altered mentation, vomiting, and anorexia if the critically ill animal has developed significant dehydration, electrolyte abnormalities, and hyperosmolar changes with or without ketoacidosis. Occasionally, seizure activity is also reported. A complete history may uncover more classical signs of hyperglycemia including increased drinking, urination, and appetite, with weight loss. Physical examination of the ill hyperglycemic animal typically finds severe dehydration, altered mentation, poor body condition (either obese or cachexic), and (if you have the nose for it) a sweet-smelling odor in the breath when ketosis is advanced. Keys to successful treatment include restoration of water balance (perfusion and hydration) and electrolyte balance, and reducing hyperglycemia and ketone production with insulin infusion. Equally important will be the investigation and identification of the underlying condition that resulted in the production of counter-regulatory hormones and the exacerbation of ketosis. Whenever a critically ill animal presents, the primary survey will identify any immediate, life-threatening problems. The breathing effort is characterized, and the lungs are carefully ausculted for evidence of increased sounds. Perfusion is assessed and body temperature obtained. It is common for poor perfusion to manifest as pale mucous membranes, prolonged capillary refill time, bradycardia, hypotension, and hypothermia. When altered mentation exists, the patient must be carefully handled to minimize stress and increases in intracranial pressure. Oxygen is supplied while immediate placement of a peripheral catheter and collection of blood and urine for analysis is performed. Use of mg/kg butorphanol IV/intramuscular (IM) may reduce anxiety associated with restraint. Resuscitation from hypotension always involves the use of a balanced isotonic solution. Some clinicians prefer to use 0.9% sodium chloride (308 mosm/l) to provide the least degree of osmolar shift when severe hyperglycemia is present and to treat hyponatremia. Hyponatremia can be a pseudo finding when hypertrygliceridemia exists, or due to shift of water intravascularly due to increased osmolality. An acidic fluid, such as 0.9% sodium chloride, may not correct an acidemia as effectively as a balanced buffered isotonic solution, such as Plasmalyte-7.4 or Normosol- R (~295 mosm/l). Sodium bicarbonate is never administered during fluid resuscitation. When the animal is hypothermic, they must be actively warmed during the resuscitation process to reestablish vascular reactivity. Bolus infusions of warmed 20 ml/kg isotonic crystalloid solution and 5 ml/kg hydroxyethyl starch (HES) are administered and the arterial blood pressure is monitored. Repeated boluses are administered until the systolic blood

2 pressure is at least mmhg. Fluid administration is continued at maintenance and rehydration rate until the rectal temperature reaches 98 degrees Fahrenheit. If hypotension still exists after rewarming, additional crystalloid and colloid boluses are continued. If hypotension persists in the normothermic animal following the infusion of ml/kg buffered isotonic crystalloid and ml/kg HES have been administered, causes of non-responsive hypotension must be investigated for, and vasopressors may be indicated. Stat analysis of packed cell volume (PCV), total solids (TS), electrolytes, venous blood gas, glucose, osmolality, lactate, and urinalysis is performed. Samples for a complete blood count, biochemical profile, urine culture, and thyroid profile are submitted. If urine cannot be obtained, plasma can be tested for ketones using urine reagent strips. Ketostix use a calorimetric method measuring a nitroprusside reaction for detecting acetoacetate and acetone in blood or urine. Because it does not measure beta-hydroxybutyrate, it is an insensitive method for monitoring severity of ketoacidosis. Ketone testing using Precision Xtra and Abbott Optium will measure betahydroxybutyrate which can be present before detectable acetoacetic acid and acetone. Blood measurements are more precise than urine. Once the animal is reperfused, rehydration therapy is instituted using a balanced, buffered isotonic crystalloid. Rehydration rates are calculated based on the estimated level of dehydration. If the patient is conscious, rehydration can safely occur over 4 6 hours. If the patient is stuporous, it may be more desirable to reduce rapid osmolar shifts across the blood-brain barrier and rehydrate over 6 24 hours. The rehydration rate is added to the maintenance fluid rate (30 X Body Weight (kg) + 70 per day) and to replacement volumes of ongoing fluid losses (e.g., in vomitus, gastric suction, diarrhea, body effusions, osmotic diuresis). Once perfusion is restored and rehydration has commenced, placement of a multilumen central venous catheter in the jugular or saphenous vein will facilitate blood collection and central venous pressure monitoring. When potassium supplementation is necessary, it may be supplemented in the form of potassium chloride with or without potassium phosphate. The need for phosphate supplementation will be determined with repeated evaluation of the electrolyte concentrations. Potassium supplementation is calculated according to serum level and, in general, the rate should not exceed 0.5 meq/kg/h. Magnesium can decrease with insulin therapy and may be associated with poor glycemic control and insulin resistance. Placing fluids in a buretrol permits adjustment of additives without sacrificing an entire bag of fluids. Hypokalemia: Hypomagnesemia: Hypophosphatemia: Low HCO3: meq/l: give 2 3 meq KCl/kg/24h meq/l: give 3 5 meq KCl/kg/24h <2.5 meq/l: give 5 10 meq KCl/kg/24h <2.0 meq/l: Ideal [K+]-Pt [K+] x vascular volume (L)= meq meq/kg/day or meq/kg if life-threatening KPO 4: mmol of phosphate/kg/h if serum PO 4 <1.5mg/dL (<9 meq/l) despite volume replacement: NaHCO 3 (meq)= (Desired HCO 3 Patient HCO 3) x 0.3 x BW(kg) Administer ¼ ½ dose over 1 2 hours and recheck value It may be difficult to regulate fluid balance in the critically ill patient with hyperglycemia. They typically will not drink, and underlying conditions may cause nausea, gastrointestinal dysfunction, and ongoing fluid losses. Osmotic diuresis may be profound. Frequent reevaluation and adjustment of the fluid rates may be necessary. Use of HES during fluid maintenance therapy ( ml/kg/h) may promote intravascular fluid retention. Insulin infusion is started after perfusion has been restored, and rehydration has been initiated. Intermittent IM administration of regular insulin can be successfully employed at an initial dosage of 0.1 U/kg IM followed by 0.05 U/kg IM administered hourly until the blood glucose level is <250 mg/dl. Inadequate perfusion and absorption from depot sites may make this method of administration less predictable. Using constant rate infusion of regular crystalline insulin (cat or dog) or lispro (dog) permits a more regulated decline in serum glucose levels and osmolarity because adjustments in infusion rates can be made. The following protocol is one that has proven to be easy to use for the critically ill hyperglycemic animal. The daily dose of insulin

3 is calculated: dog 2.2 units/kg/day, cat unit/kg/day. The insulin is added to an isotonic saline solution. The first 50 ml is drained through the line because insulin binds to the plastic. Example 5kg cat, using a 250ml fluid bag: 1.1 unit insulin x 5.5 kg per day = 5.5 units/24 h = 11 units/48 h. To compensate for the fluid and insulin drained from the 250 ml bag, place units in 250 ml and drain out first 50 ml. This leaves 11 units in 200 ml to be delivered over 48 hours (~4 ml/h) Patient monitoring includes checking a blood glucose q 2 4 hours; electrolytes, venous blood gases, fluid ins and outs, and vital signs q 4 8 hours; perfusion/hydration parameters and mentation q 1 6 hours; testing for ketones q hours; urine sediment for casts q 4 8 hours; and body weight q hours on same scale. Insulin therapy may be adjusted according to glucose levels as follows: BLOOD GLUCOSE (mg/dl) TREATMENT CHANGES > 400 If glucose is not declining after 2 3 rechecks, increase insulin by 0.5 unit/kg/day Continue as initially planned Reduce insulin by 25% Reduce insulin by 25% Reduce insulin by 25% <100 Stop insulin infusion, start 2.5% dextrose in half-strength buffered solution. If clinical signs exist, slowly bolus g/kg 50% dextrose (0.5 1 ml/kg) and repeat blood glucose after 30 minutes Once the patient is cardiovascularly stable, additional diagnostic evaluation is necessary for identifying conditions (listed above) associated with ketosis. Thoracic and abdominal radiographs and abdominal ultrasound are necessary for uncovering evidence supporting liver disease, pancreatitis, renal abnormalities, infection, and neoplasia. When liver enzymes are elevated and/or biliary changes exist, liver biopsy collection for histopathological and culture analysis may be indicated. A common concurrent disease finding in cats, hepatic lipidosis, may require additional therapeutic measures. When chronic gastrointestinal (GI) signs occur, endoscopic biopsy collection of GI mucosa may uncover infiltrative diseases. Potential Complications Acidosis Avoid administering bicarbonate (rarely needed!) until the patient is reperfused and rehydrated. If the serum bicarbonate level remains (HCO 3) < 10.0 mmol/l and pco 2 is normal or low after reperfusion and rehydration, consider adding sodium bicarbonate to drip. Administer over 1/2 1 hour and then repeat venous blood gas. The goal is not to restore serum bicarbonate levels to normal, only increase to a more acceptable level (>12 mmol/l). Anorexia/Malnutrition Administration of partial parenteral nutrition with nasogastric tube feedings is necessary to preserve enterocyte function, reverse protein catabolism and promote hepatic function until the patient is eating voluntarily. It also limits the development of food aversion and the cephalic and gastric phases of digestion that can promote vomiting in nauseated patients. Nasogastric tube placement permits evaluation of gastric emptying function with periodic suctioning, as well as immediate administration of liquid nutrition. CliniCare can be infused as a constant infusion starting with a 50% solution at 0.5 ml/kg/h. Over a 48 hour period, this is increased to a 100% solution at 2 ml/kg/h provided that suctioned volumes are minimal. FreAmine is an intravenous 3% amino acid solution that can be administered at a maintenance fluid rate once the patient has started insulin therapy. ProcalAmine is another intravenous amino acid solution that contains glycerin as a carbohydrate source (administered as a 3 4% amino acid solution). Insulin infusion rates may be adjusted according to patient glucose levels. Each contains potassium and other supplements and can be administered via peripheral catheter. Since they are administered at a constant rate, additives such as antiemetics and vitamin B can be added to these fluids facilitating adjustment rates of other fluids being administered. Hyponatremia In some cases, a reduction in measured sodium is a result of increased plasma glucose holding water in the vascular space and diluting the plasma sodium (pseudohyponatremia). The corrected sodium can be calculated by adding the

4 measured sodium with 1.6 (glucose mg/dl 100)/100. It corrects with fluid replacement and establishing normoglycemia. Hypernatremia. This can be a consequence of water loss in excess of solutes in the urine, or through the respiratory tract. Once the pet is reperfused and rehydrated, ½ strength solutions or amino acid solutions can be used at maintenance rates to replace water. Acute Kidney Injury Begin looking for renal tubular cell casts and make sure animal remains hydrated and perfused. If oliguria is suspected, place a urinary catheter with a closed collection system to better quantify urine volumes, and consider use of furosemide mg/kg/hr. AVOID MANNITOL since this might exacerbate serum hyperosmolarity. Hypokalemia This is especially prominent after insulin has been initiated and acidosis corrected, when potassium will move back into the cell. Using potassium phosphate for correction of hypokalemia is not recommended. However, should potassium phosphate be used for correction of hypophosphatemia, adjustments in potassium chloride infusion rates may be necessary. When potassium levels are difficult to restore, supplemental magnesium may be necessary. Hypophosphatemia As the acidemia is corrected and insulin therapy has been instituted, there will be a relocation of serum potassium into the cell and use of phosphate in the production of adenosine triphosphate. There is a serious risk for hemolysis should the serum phosphate levels fall <1.5 g/dl. If serum phosphate values are <2.0 g/dl or creatine phosphokinase (CPK) values are very high (>1500), the patient will likely benefit from phosphate replacement. Most potassium phosphate solutions contain 3 mmol/ml of phosphorus (93 mg/ml) and 4.4 meq/ml of potassium. When phosphate levels are difficult to restore, supplemental magnesium may be necessary. Infections Broad spectrum intravenous antibiotic therapy (e.g., cefazolin 20 mg/kg q 8h) may be indicated when a left shift is identified, a fever is present, gastrointestinal signs exist, or overt signs of a bacterial infection are identified. Thoracic radiographs and urine culture are used as a screening tool for identifying pulmonary or genitourinary infections. Thromboemboli These occasionally occur in the pulmonary and mesenteric vessels when diabetic/ketotic vasculitis exists. Patients with preexisting cardiomyopathy or lung tumors are also at risk. Hypoglycemia Any animal seen with change in mentation, shaking, trembling, or seizure should have an immediate electrolyte panel and glucose evaluated. When found, treat hypoglycemia with g/kg 50% dextrose IV ( ml/kg) and supplement infusion fluids with % dextrose. Discontinue insulin as instructed above. Refractory hypoglycemia can also be treated with glucagon injection. Once the patient is maintaining adequate hydration, the ketosis is cleared, and the patient is voluntarily eating or tolerating tube feedings, then long-term insulin therapy can be initiated. The continuous insulin infusion is discontinued at least four hours prior to starting long-acting insulin injections. The blood glucose is evaluated at the time insulin injections are to be given. If the serum glucose is <250 mg/dl, insulin is not administered. At the next scheduled time for insulin therapy, the glucose is checked. Once it is >250 mg/dl, unit NPH (canine), glargine (feline), or protamine zinc (feline) q 12 hours insulin is administered. This dose is also recommended in the previously diagnosed diabetic, since alterations in insulin requirements may have occurred. A glucose curve is evaluated over the following 12 hours and adjustments made in repeated insulin injections made as necessary. The goal is to have a glucose nadir no less than 150 mg/dl and a glucose peak no greater than 350 mg/dl in the hospital. The patient is discharged with instructions for feeding and at home urine glucose monitoring, with a glucose curve evaluation after one week. We instruct the pet owner to call a veterinarian if the urine glucose is repeatedly negative or >2000. A glucose curve is necessary to determine any adjustments in insulin therapy.

5 Suggested Reading Hume DZ, Drobatz KJ, Hess RS. Outcome of dogs with diabetic ketoacidosis: 127 dogs ( ). J Vet Intern Med 2006;20: Macintire DK. Treatment of diabetic ketoacidosis in dogs by continuous low-dose intravenous infusion of insulin. J Am Vet med Assoc 1993;202: Hess RS, Kass PH, Van Winkle TJ. Association between diabetes mellitus, hypothyroidism or hyperadrenocorticism, and atherosclerosis in dogs. J Vet Intern Med 2003;17: Sears KW, Drobatz KJ, Hess RS. Use of lispro insulin for treatment of diabetic ketoacidosis in dogs. J Vet Emerg Crit Care 2012;10:1 8. Claus MA, Silverstein DC, Shofer FS, Mellema MS. Comparison of regular insulin infusion doses in critically ill diabetic cats: 29 cases ( ). J Vet Emerg Crit Care 2010;20: