Diabetic Emergencies: Diabetic Ketoacidosisand Hyperglycemic Hyperosmolar SyndromeALISHA WORTHNCSU CVM C/O 2015

Diabetes Mellitus Overview

Impaired carbohydrate metabolism due to inadequate insulin Pancreas: exocrine and endocrine function

Exocrine: digestive enzymes Glucagon: ↑ [glucose]: glycogenolysis, gluconeogenesis Insulin: ↓ [glucose]: promotes glycogen formation;

glucose uptake into cells

Diabetes Mellitus Types

Type I: Insulin-Dependent Diabetes Mellitus (IDDM) Immune-mediated destruction of beta cells

Genetic or chronic pancreatitis 50% of diabetic dogs Absolute insulin deficiency

Type II: Non Insulin-dependent Diabetes Mellitus (NIDDM) Insulin resistance, decreased insulin secretion

Obesity, inactivity, amyloid deposition in beta cells Most diabetic cats Relative insulin deficiency

Quick Review: Normal Cellular Respiration

• ATP: currency of life!• From breakdown of

glucose• From Kreb’s cycle• From electron

transport chain

Glucose Behaving Badly: Cellular Metabolic Derangements

Too much of a good thing↑ glucose + ↑ fatty acids = too much acetyl coA

Kreb’s cycle says “I can’t handle this!”

Acetyl coA says “Well, I have to go somewhere!”

Liver says “I got your back bro, let me convert you into ketone bodies for an alternative source of energy!”

DKA Pathophysiology, Redux

↓ insulin and ↑ glucagon

↑ lipolysis for energy → ↑ free fatty acids ↑ glucose release from liver: glycogenolysis, gluconeogenesis

Mitochondrial B oxidation of FA → acetyl- CoA

Accumulation of acetyl- CoA

acetyl- CoA → ketones: B-hydroxybutyrate, acetoacetate, acetone

Dissociation of these anions → ↑ [H+] → ketotic acidosis

↑ [glucose] in blood

Glucose spillover into urineKitties: 250 mg/dL [RR: 60-125 mg/dL]Dogs: 200 mg/dL [RR: 60-125 mg/dL]

Osmotic diuresis → dehydration, urinary electrolyte losses: Na, Cl, K, Phos

Clinical Pathology of DKA

Metabolic acidosis with a increased anion gapBonus NAVLE review time: Anion Gap! Body fluids are electrically neutral, aka equal amounts of anions and

cations. Commonly measured cations: Na+, K+ Commonly measured anions: Cl-, HCO3- Sum of the commonly measured cations < sum of commonly measured anions.

Aka, there are more unmeasured anions (UA) than unmeasured cations (UC) anion gap!

Anion gap = (Na+ + K+) – (Cl- + HCO3-) = UA –UC Ketoacids are anions; ↑ ketoacid levels ↑ the anion gap! Other causes of ↑ AG: lactic acidosis, uremic acidosis, toxins: ethylene

glycol, ethanol, aspirin

Clinical Pathology of DKA: Chemistry

High serum osmolality. Due to hyperglycemia, azotemia, ketones.Bonus NAVLE Review time: Osmolality! Osmolality = osmoles per kg of solvent. Vs. Osmolarity = osmoles per L of

solution. Osmole = something that draws H2O toward it: Alcohols, sugars, lipids, proteins. Effective osmole = something that generates osmotic pressure b/c it draws and keeps

H2O on its side of a semipermeable membrane. Osmolality is both measured (osmometer), and calculated. The difference between

these two is the osmol gap, which is normally < 10 mOsm/kg. Calculated Osmlality = 2 (Na+ + K+) + BUN/2.8 + Glucose/18

Why do I care about this? If you have a high osmolal gap, this raises your suspicion for unsuspected osmols in the

serum (MAE DIE), because you didn’t account for them in your calculated osmol gap. Reference Values: Dogs: 308-335 mOsm/kg. Cats: 290-310 mOsm/kg.

Osmole MnemonicMethanolAcetoneEthanolDiuretics (mannitol, sorbitol)IsopropanolEthylene glycol

Clinical Pathology of DKA: Chemistry

Hyponatremia True hyponatremia: urinary loss. Pseudohyponatremia: due to hyperglycemia. Correct for this below:

Corrected Na: Measured Na + 0.016 x (serum glucose – 100) Corrected Na if glucose > 600 mg/dL: Measured Na + 0.024 x (serum glucose – 100)

Potassium Low: urinary loss, vomiting, anorexia, or binding to ketoacids. High: due to intracellular to extracellular shifting to correct for acidemia: H+ in,

K+ out.

Clinical Pathology of DKA: Chemistry

Hypophosphatemia: urinary loss, hemolysis (in cats: Heinz body anemia) Other Electrolytes: Hypochloremia, Hypomagnesemia, Hypocalcemia Hyperlactatemia: poor tissue perfusion 2o to hypovolemia from dehydration Azotemia: dehydration ↑ ALT, ALP, GGT, tibili (hepatocellular damage d/t altered metabolism; hepatic lipid

infilitration and 2o cholestasis or hemolysis of Heinz bodies) Hyperlipidemia ↑ amylase and lipase (pancreatitis)

Clinical Pathology of DKA: CBC, UA CBC:

Stress or an inflammatory leukogram ↑ HCT/PCV and TS (dehydration) Heinz bodies in kitty RBCs anemia (Heinz body formation associated with B-

hydroxybutyrate formation) Urine

Ketonuria and glucosuria Pyuria, proteinuria, hematuria (diabetic animals are prone to UTIs) Low USG (medullary washout 2o to osmotic diuresis)

Clinical Signs: What DKA looks like!

Runs the gamut: from BAR to severe Mentally dull Dehydrated (gums, skin tent, eyes) Vomiting/Anorexia Body condition: under or overweight Cranial organolmegaly Remember, this might be the first presentation for a previously

unknown diabetic animal.

Diabetes Comorbidities and DDX

Dogs: Hyperadrenocorticism Acute pancreatitis Urinary tract infections Cataracts

Cats: Hepatic lipidosis Chronic renal failure Acute pancreatitis Bacterial/viral infections neoplasia

DKA Treatment: Fluids and Elytes

Fluid TherapyReplacement fluids Consider a buffered solution like LRS or Normosol-R; fine to use 0.9% NaCl, too

Lactate converted into bicarbonate in the liver. How handy! Time over which to replace? Look at your patient!Maintenance Fluids: 0.45% NaCl +/- 2.5% or 5% dextrose once BG ~250 mg/dLElectrolyte Abnormality CorrectionsPotassium: If low, supplement with a potassium CRI, not to exceed 0.5 mEq/kg/hr. Hyperkalemia will often resolve as the acidemia improves with rehydration and insulin.Phosphorus: potassium phosphate CRI (has 4.4 mEq of K and 3 mM/ml of Phos)Magnesium: magnesium sulfate CRI 0.5-1 mEq/kg q24h

DKA: Insulin TherapyInsulin Therapy Why: stops ketogenesis, ↑ utilization of ketones, ↓ gluconeogenesis, ↑ glucose

utilization. Most effective if tissue perfusion has been restored

When: 1-4 hours after you start your rehydration; wait longer (4-8 hours) if patient was hypokalemic. Supplement your fluids with potassium.

What: Regular insulin CRI, initially @ 10 ml/hr, in a separate line from fluids. Dogs: 2.2 U/kg of regular insulin added to a 250 ml bag of 0.9% NaCl Cats: 1.1 U/kg of regular insulin added to a 250 ml bag of 0.9% NaCl Recheck BG q2h; when <250, switch fluid to 0.45% NaCl + 2.5% dextrose and slow your

insulin rate to 7 ml/hr; see next slide. Run 50 ml of the insulin solution through the administration set first (insulin can adhere to the

plastic).

Handy Insulin CRI Protcol courtesy of Dibartola

Blood Glucose Conc (mg/dL)

Intravenous Fluid Solution

IV Insulin Solution Rate

250 0.9% saline 10200-250 0.9% saline, 2.5%

dextrose7

150-200 0.9% saline, 2.5% dextrose

5

100-150 0.9% saline, 5% dextrose

5

<100 0.9% saline, 5% dextrose

Stop the insulin

DKA Therapy Monitoring

Monitoring plan BG q2h-4h Blood pressure Electrolytes q8-12h PCV/TS q8-12h: assess rehydration Body weight q24h: is your hydration plan working? mentation

Other therapies: NUTRITION! We want these guys eating on their own again. Anti-emetics Heat support

Hyperglycemic, Hyperosmolar State

What makes a patient HHS?

Extreme hyperglycemia: >600 mg/dl

Serum osmolality: > 350 mOsm/kg

Little or no ketonuria

Decreased GFR severe dehydration

Pathophysiology of HHS

Similar to DKA: ↓ insulin; ↑ glucagon, cortisol, growth hormone Small amounts of insulin help prevent ketone formation

HyperglycemiaAnd

hyperosmolality

Osmotic diuresis

dehydration

Reduced GFR

HHS Therapy and Monitoring

Similar to DKA Therapy: Treat hypovolemic shock: 20 ml/kg bolus for cats; 30 ml/kg bolus for dogs of an

isotonic fluid Decrease sodium slowly to avoid cerebral edema: 1 mEq/L/hr or less! Nutrition Anti-emetics

Monitoring, as before for DKA: BG q2h-4h Blood pressure Electrolytes q8-12h PCV/TS q8-12h: assess rehydration Body weight q24h: is your hydration plan working? mentation

Prognostic Information

DKA: 70% of dogs and cats survive until discharge Median time in hospital 6 days dogs; 5 days cats

7% of dogs have a recurrence of DKA 40% of cats have a recurrence of DKA

HHS: Very little data in veterinary patients One study in cats: 64% mortality in hospital; 38% in dogs Human children: 72% mortality

References

Ettinger, SJ & Feldman, EC. (2009). Textbook of Veterinary Internal Medicine, vol 7. St. Louis, MO: Saunders Elsevier.

Hopper, K & Silverstein D. (2015). Small Animal Critical Care Medicine. St. Louis, MO: Elsevier Saunders.