1. Management of hyperglycaemic emergencies Ukandu Igwe, Senior Registrar, Endocrinology, Diabetes and Metabolism Unit, Lagos University Teaching Hospital.

2. Outline Goals of management Fluid therapy Insulin Electrolytes General measures Summary

3. Goals of management Fluid therapy Insulin Electrolytes General measures Summary

4. Goals of management Rehydrating the patient Correcting hyperglycaemia Correcting acidosis and ketonaemia Correcting electrolyte abnormalities Identifying and managing precipitants Avoiding and managing complications

5. Typical deficits DKAHHSCorresponding losses (in a 70-kg man) DKA HHS Water (ml/kg)100100-2007l 7-14l Na + (meq/kg)7-105-13490-700meq 490-980meq Cl - (meq/kg)3-54-6210-350meq 280-420meq K + (meq/kg)3-53-7210-350meq 210-490meq PO4 (meq/kg)5-71-2350-490meq 70-140meq Mg ++ (meq/kg)1-2 70-140meq Ca ++ (meq/kg)1-2 70-140meq

6. Severe DKA Features of severe DKA: Ketones > 6mmol/l HC0 3 - > 5mmol/l K + < 3.5mmol/l Glasgow Coma Score <12 O 2 < 92% Systolic blood pressure < 90mmHg Pulse rate > 100/mn or < 60/mn Anion gap > 16mmol/l Manage in Intensive Care Unit

7. Severe DKA

8. Fluid therapy Intravascular, interstitial and intracellular fluid are all depleted Typical deficits 100-200ml/kg Estimated deficits should be corrected within 24h Pass 2 wide bore intravenous cannulas

9. Fluid therapy Fluid replacement alone will lower the blood glucose Typical fluid regimen (through intravenous route) 1l in first hour 1l over next 1h 1l over next 2h 1l over next 3h 1l over next 4h If patient able to drink, give 20ml/kg of the fluid (water) orally Modify regimen based on input/output, cardiac status

10. Fluid 0.9% saline is fluid of choice Change to 5% or 10% glucose when RBS < 250mg/dl If patient still volume depleted 0.9% saline may be continued concurrently If random blood glucose > 250mg/dl after changing, continue glucose infusion and increase insulin. Do not revert to normal saline If acidosis slow to resolve and RBG < 180mg/dl (euglycaemic ketoacidosis) change 5% to 10% dextrose to allow faster insulin rate

11. Insulin therapy Insulin therapy is effective regardless of route of administration Should be instituted about 1h after commencing fluid therapy Continuous intravenous infusion is preferred route Short half life Easy titration Start at 0.1unit/kg/h (e.g. 6 units for 60kg man) Target blood glucose reduction 50-75mg/dl per hour If reduction rate is slower, increase insulin infusion rate till steady decline by 50% Continue long-acting insulin analogues

12. Insulin infusion pump

13. Buretrol

14. Insulin therapy In DKA, when serum glucose falls to ≤250 mg/dl The insulin infusion is decreased to 0.02 to 0.05 units/kg/h 5% dextrose with 0.45% NaCl is initiated at a rate of 150 to 250 mL/h Titrate to keep serum glucose between 150 and 200 mg/dl until DKA is resolved

15. Insulin therapy In HHS, when the glucose falls to ≤300 mg/dl The rate of insulin is switched to 0.02 to 0.05 units/kg/h And 5% dextrose with 0.45% NaCl is infused at a rate of 150 to 250 mL/h Titrate to keep serum glucose between 200 and 300 mg/dl until HHS has resolved

16. Insulin therapy Transition to subcutaneous insulin Run continuous intravenous insulin till: For DKA, RBS < 200mg/dl and 2 of HCO 3 - ≥ 15mmol/l Venous pH > 7.3 Anion gap ≤ 12mmol/l For HHS Normal osmolality Regaining of normal mental status

17. Insulin therapy Transition to subcutaneous insulin When ketosis is resolved and patient eating, change to subcutaneous Overlap with IV 1-2h Basal-bolus regimen Lispro/aspart + glargine have lower incidence of hyperglycaemia than regular + NPH Same dose as pre-crisis, or 0.5-0.8 units/kg/day

18. Insulin therapy 32 patients with hyperglycaemic emergencies in Lagos (Anumah-Ehusani, Ohwovoriole) 40.6% DKA 34.4% HHS 25% non-ketotic normoosmolar hyperglycaemic state

19. Insulin therapy Mean time to RBS < 250mg/dl IV: 3.2h IM: 4.2h Longer in HHS Rate of reduction more gradual and more predictable in IM Another study in Cameroun: IM insulin and careful rehydration leads to reduced mortality

20. Insulin therapy Hourly subcutaneous lispro insulin vs hourly intramuscular regular insulin No difference in outcome, hypoglycaemia, mortality (Adesina et al) Sc lispro or aspart insulin in mild-moderate HE are as safe as IV regular insulin in non-ICU patients But use only IV regular insulin in ICU Hypotension Anasarca Severe critical illness

21. Insulin therapy

23. Potassium correction Total K + depleted but hyperkalaemia common at presentation K + replacement when < 5.0mmol/l, target 4-5mmol/l Generally, add 20-30meq to each litre of IVF If hypokalaemia, omit till > 3.5mmol/l Hypokalaemia can result from Insulin therapy Correction of acidosis Volume expansion

24. Potassium correction Serum potassiumAction <3.5mmol/lWithhold insulin Add 30mmol KCl to each litre of IVF 3.5-5.2mmol/lAdd 20-30mmol KCl to each litre of IVF >5.2mmol/lWithhold KCl and reassess every 2h

25. Bicarbonate correction Usually no replacement Self-correction in mild-moderate Adequate fluid and insulin usually will resolve acidosis But severe acidosis causes Impaired myocardial contractility Cerebral vasodilatation Coma If pH < 6.9 100mmol of 1.4% NaHCO 3 in 400ml sterile water + 20mmol KCl Run at 200ml/h until pH >7.0

26. Phosphate correction Normal at presentation Reduced by insulin therapy No benefit of replacement. Can cause hypocalcaemia But replace if: anaemia, respiratory depression, cardiac dysfunction 20-30meq/l of IVF, at 4-5mmol/h No role in HHS

27. Metabolic treatment targets Reduce capillary blood glucose by 50-75mg/dl per hour Reduce blood ketones by 0.5mmol/l per hour Increase HC0 3 - by 3mmol/l per hour Maintain K + 4-5mmol/l Reduce Na + by 10mmol/l in 24h

28. General measures Diabetologist’s involvement shortens hospital stay Weight-based, fixed rate insulin infusion better than sliding scale

29. General measures Management of DKA focused on ketones, not glucose Portable ketone metres for bedside ketone (β-hydroxybutyrate) Resolution of DKA depends on suppression of ketonaemia So measurement of blood ketones now represent best practice

30. Monitoring Monitor blood glucose hourly Serum electrolytes, urea and creatinine 2-6 hourly Cardiac monitoring Use blood ketone metre (bedside) Monitor fluid input/output Routine catheterisation not advised

31. Other measures Identify and treat precipitating factors Routine anticoagulation (unless contraindication) Treat complications Prevent recurrence

32. Treat complications Hypoglycaemia. Can result to: Rebound ketosis (increased counter-regulatory hormones) Arrhythmia, brain injury Cerebral oedema: Intravenous mannitol, dexamethasone Cardiac arrhythmias: correct precipitant (hypokalaemia, acidosis…), cardiac monitoring Pulmonary oedema: cautious fluid correction, diuretics, oxygen

33. Prevention Proper patient education Early access to medical care effective communication with a health care provider during intercurrent illness Education of family members on sick day rule Self blood glucose monitoring Urine ketone testing Better access to medical care Provision of guidelines reduce mortality

34. Summary… Early involvement of diabetologist Adequate hydration initial therapeutic intervention Continuous intravenous insulin therapy preferred Emphasis on serum ketones over glucose (in DKA) Correction of electrolyte abnormalities

35. References Kitbachi AE, Milez JM, Umpierrez GE, Fisher JN. Hyperglycaemic crises in adult patients with diabetes. Diabetes Care 2009; 32(7): 1335-1343 Sobngwi E, Lekoubou Al, Dehayem MY, Nouthe BE, Balti EV, Nwastock F, et al. Evaluation of a simple management protocol for hyperglycaemic crises using intramuscular insulin in a resource- limited setting. Diabetes & Metabolism 2009 (35) 404-409. Ehusani_Anumah FO, Ohwovoriole AE. Plasma glucose response to insulin in hyperglycaemic crisis. Int J Diabetes & Metabolism 2007 (15): 17-21

36. References Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Hyperglycemic emergrncies in adults. Can J Diabetes 2013 (37): S72-S76 Chinenye S, Ofoegbu EN, Onyemelukwe GC, Uloko AE, Ogbera AO. Clinical practice guidelines for diabetes management in Nigeria. Published by Diabetes Association of Nigeria, 2013. Accessed at diabetesnigeria.org on 14-02-15 Joint British Diabetes Societies Inpatient Care Group. The management of diabetic ketoacidosis in adults, 2013. Available at http://www.diabetologists-abcd.org.uk/JBDS/JBDS.htm and the Diabetes UK website at www.diabetes.org.ukwww.diabetes.org.uk

37. References Anumah FO. Management of hyperglycaemic emergencies in the tropics. Ann Afr Med 2007;6:45-50 Fasanmade OA, Odeniyi IA, Ogbera AO. Diabetic ketoacidosis: diagnosis and management. Afr J Med Sci 2008; 37 (2): 99-105 Joint British Diabetes Societies Inpatient Care Group. The management of the hyperosmolar hyperglycaemic state in adults with diabetes, 2012. Available at http://www.diabetologists- abcd.org.uk/JBDS/JBDS_IP_HHS_Adults.pdf.

38. References Adesina OF, Kolawole BA, Ikem RT, Adebayo OJ, Soyoye DO. Comparison of lispro insulin and regular insulin in the management of hyperglycaemic emergencies. Afr J Med Sci 2011; 40(1): 59-66

39. Thank you