Diabetic ketoacidosis by a physcian for educational purpose

Diabetic ketoacidosis by a physcian for educational purpose

1. Hyperglycemic Crises: Diabetic Ketoacidosis and Hyperglycemic Hyperosmolar State Melaku T, MD Endocrinology fellow

2. Outline Epidemiology Pathogenesis Clinical and lab features Treatment Complications of therapy

3. Case #1 AB, 20 y/o, T1DM/2years on MDI, he ran out of insulin 2 days ago. Presented with abdominal pain, nausea, and vomiting with increasing polyuria, polydipsia, and drowsiness since the day before. BP 106/67 mmHg, PR 123 bpm, RR 32 breaths per minute, T 37.1°C. He is drowsy, mild generalized abdominal tenderness RBS 450 mg/ dL , WBC 18,500/microliter , sodium 128 mEq /L, potassium 5.2 mEq /L, chloride 97 mEq /L, BUN 32 mg/ dL , creatinine 1.7 mg/ dL , urine ketones strongly positive, arterial pH 7.24, pCO ₂ 25 mmHg, bicarbonate 12 mEq /L

4. Case #2 AD, 47 y/o, T2DM/10 years on metformin and dapagliflozin . He has been on strict diet for weight loss. Presented with several days of dysuria and poor oral intake . He had a UTI 2 weeks prior, which had resolved with a course of antibiotics. Afebrile , RR 30 , PR 130 beats per minute, BP 160/89  mmHg, and SpO2 95% on room air. RBS 215 mg/dl, Cr 1.21  mg/dl, pH level of 6.94, bicarbonate 5   mmol /L, 3+ urinary ketones, a beta- hydroxybutyrate level of 8.9  mmol /L GAD-65 antibody test negative, C-peptide 2.3   ng/ml

5. Case #3 AD, 67 y/o, T2DM/20 years metformin and Glibenclamide . He presented with foot ulcer of 1 month duration accompanied by polyuria, polydypsia , generalized weakness and vomiting. BP : 90/60 mmHg, T 36.1°C, right heel ulceration with purulent discharge, obtunded RBS >600 mg/dl

6. Hyperglycemic Crises Acute metabolic complications of diabetes mellitus. DKA: hyperglycemia (or a diagnosis of diabetes), ketonemia and metabolic acidosis. HHS: severe hyperglycemia , high serum osmolality, and dehydration. Common features: absolute or relative insulin deficiency, volume depletion, and acid-base abnormalities .

7. History of DKA Dhatariya et al. Diabetic ketoacidosis. Nat Rev Dis Primers 6, 40 (2020)

8. Epidemiology DKA characteristically associated with T1DM, + can occur in T2DM with severe stressor or less often, as a presenting manifestation of T2D (KPDM ) HHS characteristically occur in elderly, T2DM DKA mortality <1% HHS mortality 10-20 % Severe dehydration, older age, and the presence of comorbid conditions

9. DKA hospitalization and mortality, US 2000-2014 Benoit et al. MMWR Morb Mortal Wkly Rep 2018; 67:362-365 per 1000 persons with diabetes

10. DKA hospitalization and mortality, US 2017 Diabetes care. 2020;43(12):e196–e197.

11. Decompensated diabetes imposes a heavy burden in terms of economics Diabetes Care. 2018;41(8):1631-1638

12. ↑Glucose ↑Insulin ↑Glucose uptake ↓Glucose production ↓ Gluconeogenesis ↓ Glycogenolysis Normoglycemia Normal response to hyperglycemia ↓Glucagon ↑Insulin

13. Pathogenesis of DKA/HHS Diabetes care. 2009;32(7):1335–1343

14. Decreased ratio of insulin to glucagon Insulin Glucagon, Adrenaline , Cortisol , Growth hormone

15. Glucagon is contributory , but not essential, for DKA N Engl J Med 1977; 296:1250-1253 N = 6 T1D, 4 pancreatectomized patients

16. Why hyperglycemia in DKA <HHS? Earlier presentation in DKA with symptoms of ketoacidosis (SOB, abdominal pain, nausea and vomiting ) Patients with DKA tend to be younger, higher glomerular filtration rate  higher glycosuria capacity limits the severity of the hyperglycemia

17. Why not ketosis in HHS? Differential sensitivity of fat metabolism and glucose metabolism to the effects of insulin + smaller decrease in the insulin/glucagon ratio Suppression of lipolysis and ketogenesis is more sensitive to insulin than the inhibition of gluconeogenesis The residual insulin secretion and its systemic activity in HHS is sufficient to minimize the development of ketoacidosis but not adequate to control hyperglycemia

18. Precipitant factors Initial presentation in T1DM/KPDM Inadequate insulin therapy Infection Ischemia/infarction Infant (pregnancy) Intraoperative Intoxication/illicit drug use Iatrogenic: GCs, SGLT2i, thiazides , Immune checkpoint inhibitors

19. Clinical features of DKA

20. Clinical features

21. Initial laboratory evaluation RBS CBC [leukocytosis with left shift] Serum electrolytes Serum ketones, urine ketones BUN, sCr Venous blood gases, ABG [metabolic acidosis] ECG Culture (blood, urine ), CXR

22. Typical total body deficits of water and electrolytes

23. The biochemical diagnostic criteria and typical electrolyte deficits in DKA and HHS

24. DKA consists of the biochemical triad of hyperglycemia , ketonemia , and high anion gap metabolic acidosis Kitabchi and Wall. Med Clin North Am. 1995;79(1):9–37

25. HHS consists of the biochemical triad of severe hyperglycemia , elevated serum osmolality and volume depletion with no significant acidosis

26. Euglycemic DKA DKA with euglycemia or modest elevation of Blood Glucose <250 mg/ dL Can occur in type 1 and 2 DM 2-5% of DKA Less polydipsia and polyuria and may rather initially present with non-specific symptoms such as fatigue and malaise

27. Etiologies of euglycemic ketoacidosis General state of starvation ( carb deficit ) resulting in ketosis while maintaining normoglycemia Fasting, starvation, ketogenic diet, anorexia/ vomiting , gastroparesis, alcoholism Partial treatment Increased rate of glycosuria: SGLT2i, pregnancy CLD Glycogen storage disease

28. Goal of therapy Volume Repletion Correct Electrolyte: hypokalemia Insulin Therapy Address Precipitants Manage Complication

29. Vigilant monitoring Secure air way, O2 (±ventilate), secure large bore IV line V/S, urine out put , ECG monitor, neurologic status q1hr Serum glucose q1hr Serum ketone q2hr Serum electrolyte, PH q2-4hr

30. Fluid therap y Fluid repletion is usually initiated with isotonic  saline Use 5% dextrose if blood sugar <250   mg/ dL Hydration alone may also reduce the level of counter-regulatory hormones and hyperglycemia.

31. Fluid therapy Optimal rate of initial hour isotonic saline infusion Hypovolemic shock: bolus fast Hypovolemia without shock: 10-20 ml/kg/ hr (~1000 ml in first hour) Euvolemic : slower rate of infusion Optimal rate of subsequent fluid therapy Depends upon the state of hydration, serum electrolyte levels, and the urine output Corrected [Na] <135 meq /l, isotonic saline should be continued at a rate of approximately 250-500 mL/hour Corrected [Na] normal or elevated, give electrolyte free water with ½ NS 250-500 ml/ hr

32. Potassium replacement K <3.3 meq /l, give KCl 20-40 meq /hour K 3.3-5.3 meq /l, give KCl 20-30 meq /hour K >5.3 meq /l, delay K supplementation Ensure adequate urine output

33. Insulin therapy Initiate treatment with low-dose IV insulin if K≥ 3.3 mEq /L. In most adults with DKA, a continuous intravenous infusion of regular insulin is the treatment of choice There is no advantage of rapid-acting insulin analogs over  regular insulin

34. The optimum route of insulin therapy in DKA Direct comparison of intramuscular, subcutaneous, and IV insulin therapy, for hemodynamically stable DKA patients, shows similar efficacy and safety Intravenous insulin achieved immediate pharmacologic level with more rapid decline in blood glucose and ketone bodies in the first 2 hours of treatment IV loading dose of insulin would be beneficial regardless of the subsequent route of insulin administration The role of IV bolus/priming dose of insulin when using intravenous infusion of insulin, is not clear N Engl J Med. 1977;297(5):238–241. Annals of internal medicine. 1979;90(1):36–42. Diabetes care. 1980;3(1):15–20

35. Intravenous regular insulin Give IV bolus of 0.1 IU/kg initially then continuous infusion of 0.1 IU/kg per hour Effect: reduces RBS by 50-70 mg/dl per hour If no RBS lowering, the insulin infusion rate should be doubled every hour until a steady decline in serum glucose of this magnitude is achieved If RBS <200-250 mg/dl, lower insulin infusion rate and change fluid to DNS Continue insulin infusion until ketoacidosis is resolved, serum glucose <200 mg/ dL and subcutaneous insulin is begun

36. The IV use of fast-acting insulin analogs in severe DKA No studies to support their use. Not recommended for patients with moderate to severe DKA or HHS These agents may not be effective given subcutaneously in patients with severe fluid depletion.

37. Subcutaneous insulin in mild DKA is possible Subcutaneous regular insulin Subcutaneous rapid-acting insulin analogs (insulin lispro , aspart , and glulisine ) in the management of mild DKA has been demonstrated to be safe and cost effective Potential absorption problems in severely dehydrated patients

38. Use of subcutaneous rapid acting insulin

39. Treat precipitants Antibiotics [infection] Adequate Rx of physical stress [surgery, burn, trauma…] P Ψ therapy [puberty, body image; social stressors, school exam ] Quality health education [dosing, omission]

40. Resolution of DKA Serum glucose level <200 mg/ dL Ketoacidosis has resolved: normalization of AG (<12 mEq /L) and blood beta- hydroxybutyrate levels Normalization of mental status and able to eat Urinary ketone testing should not be used for monitoring resolution of DKA [nitroprusside test reacts to the slowly cleared acetone]

41. Initiating SC insulin The IV insulin infusion should be continued for 1-2 hours after initiating the subcutaneous insulin because abrupt discontinuation of IV insulin acutely reduces insulin levels and may result in recurrence of hyperglycemia and/or ketoacidosis. If the patient is unable to eat, it is preferable to continue the IV insulin infusion

42. How to initiate SC insulin? A MDI with basal-bolus insulin regimen at a dose of 0.5 IU/kg per day in insulin-naive patients The pre-DKA or pre-HHS insulin regimen may be restarted in previously treated patients

43. DKA/HHS management: national algorithm

44. DKA/HHS management: algorithm

45. Complications of DKA Cerebral edema Hypoglycemia Hypokalemia, hyperkalemia, hypophosphatemia, Metabolic acidosis AKI Sepsis, aspiration pneumonia, Mucormycosis