Management of Hyperglycemic Crises

Transcription

1 Management of Hyperglycemic Crises Guillermo E. Umpierrez, MD, CDE, FACP, FACE Professor of Medicine Director Clinical Research, Diabetes & Metabolism Center Emory University School of Medicine Chief, Endocrinology Section, Grady Health System

2 Dr. Guillermo Umpierrez, Personal/Professional Financial Relationships with Industry January 2017 External Industry Relationships * Equity, stock, or options in biomedical industry companies or publishers Industry funds to Emory University for my research Industry Advisory/Consultant activities Company Name(s) BMJ Open Diabetes Research & Care American Association Clinical Endocrinologists Endocrine Society Merck, Sanofi, Novo Nordisk Boehringer Ingelhein Astra Zeneca Sanofi Role Editor-in-Chief Board of Director Council At Large Investigator-Initiated Research Projects Consultant/Advisory Boards

3 Hyperglycemic Crises in Adult Patients with Diabetes: DKA and HHS Epidemiology Pathogenesis Precipitating factors Diagnosis Treatment Prevention

4 Hyperglycemic Crises DKA HHS Hyperglycemia DKA HHS

5 Hyperglycemic Crises DKA 4Most common hyperglycemic emergency in patients with type 1 and type 2 diabetes 4DKA accounts for 4-9% of all hospital discharge summaries among patients with diabetes 4Annual average of > 135,000 hospitalizations for DKA in the United States 4Mortality rate <5% HHS 4Hospitalization rate lower than DKA, ~ less than 1% of all primary diabetic admissions 4Mortality rates ~15%

6 DKA Incidence from NHDS Growth in incidence since 1980 (primary diagnosis) Number (in Thousands) Year 2006 Incidence: 134,663 episodes CDC/NCHS, National Hospital Discharge Survey (NHDS). Accessed: 12/2011.

7 Type 1 Diabetes Accounts for the Majority of Primary DKA Episodes T1D - Children T1D - Adults T2D Primary DKA Episodes 134,633 ( % 48% 34% 66% 34% 34% of episodes are Type 2 ~46,000 cases Longer Hospital Stays 4.2 vs average of 3.5 Very few have CV issues or serious infections => Less than 15% T2D accounts for 34% of primary DKA cases and more than 50% of secondary causes National Hospital Discharge Survey (NHDS); 2006.

8 DKA-related Mortality Rates Have Been in Decline Since the 90s Mortality due to DKA (per annum) DKA Death Rates per 100,000 pop Overall 2006 mortality rate for DKA: 0.41% Centers for Disease Control and Prevention.

9 Death Rates for Hyperglycemic Crises as Underlying Cause, By Age, United States, 2009 Age (years) Accessed

10 Hospitalization cost of DKA has risen significantly since the 90 s Hospitalisation Charges US estimated at $2.4 billion in 2006 Key Statistics (Source: HCUP) Number of DKA episodes 136,510 - Mean Length of Stay 3.5 days - Mean charges per episode $17,559 - Total DKA-related Hospitalisation Cost $2.4 billion Source: Center for Disease Control

11 Pathogenesis of Hyperglycemic Crises DKA HHS Hyperglycemia osmotic diuresis Dehydration Lipolysis- Increased FFA Increased glucose production Insulin Deficiency Counterregulatory Hormones Increased ketogenesis Decreased glucose uptake Electrolyte abnormalities Hypertonicity Metabolic acidosis Umpierrez & Korytkowski. Nat. Rev. Endocrinol. 2016

12 Pathogenesis of Hyperglycemia in DKA Relative or absolute insulin deficiency Liver Muscle glucose output glycogenolysis glucose uptake

13 Increased Glucose Production in DKA Gluconeogenesis Glucose Activity of gluconeogenic enzymes (PEPCK, PC, PFK) Glycerol Amino acids Lactate TG Lipolysis Glucotoxicity Protein breakdown

14 Increased Production of Ketones in DKA Ketogenesis Insulin Glucagon B-OH-B Acetoacetate FFA Glycerol TG reduction of malonyl-coa Inhibition of CPT-I Lipolysis

15 Pathogenesis of DKA Liver Peripheral tissue Adipose tissue Liver Increased glucose production Decreased glucose uptake Increased release FFA Increased ketogenesis HYPERGLYCEMIA Osmotic diuresis KETOACIDOSIS Decreased alkali reserve Volume depletion Metabolic acidosis Pasquel & Umpierrez G. DKA & HHS Pathogenesis, In: DeGroot Endocrinology Textbook. 2014

16 Diagnostic Criteria for DKA and HHS DKA Mild Moderate Severe HHS Plasma glucose (mg/dl) >250 >250 >250 > 600 ph <7.24 <7.0 >7.30 Bicarbonate (meq/l) <15 <10 > 15 Urine ketones* positive positive positive small Serum ketones* positive positive positive small Effective serum Osmol variable variable variable >320 (mosm/kg) Alteration in sensoria alert alert/ stupor/ stupor/ or mental obtundation drowsy coma coma * Nitroprusside reaction method Calculation: 2[measured Na (meq/l)] + glucose (mg/dl)/18 ADA. Diabetes Care 24: , 2001

17 Precipitating Causes for DKA and HHS Umpierrez GE et al. Arch Intern Med. 1997;157:

18 Precipitating causes of DKA Australia Brazil China Korea Spain Syria Nigeria USA New Dx NR NR 12.8 NR NR Infection Poor Compliance Other Unknown Thuzar, et al. Diabetes research and clinical practice. 2014;104(1):e8-e11. Weinert, et al. Diabetes research and clinical practice. 2012;96(1): Tan, et al. Diabetes research and clinical practice. 2012;97(2): Ko, et al. Diabet Med. 2005;22(4): Guisado-Vasco, et al. Endocrinol Nutr. 2015;62(6): Alourfi, et al. Avicenna J Med. 2015;5(1): Edo AE. Niger Med J. 2012;53(3): Umpierrez, et al. Arch Intern Med. 1997;157(6): Randall, et al. Diabetes Care. 2011;34(9):

19 Diabetic Ketoacidosis (DKA) In Urban African Americans Precipitating Cause First episode of DKA Recurrent DKA Randall et al. Diabetes Care 34:1 6, 2011

20 Peters et al. Diabetes Care. 38(9): , 2015

21 SGLT2-I Associated DKA in T1D Any ketone-related AEs, n (%)* Serious DKA AEs, n (%)** Non-Serious AEs, n (%)*** Placebo CANA 100 mg CANA 300 mg 0 6 (5.1) 11 (9.4) 0 5 (4.3) 7 (6.0) 0 1 (0.9) 5 (4.3) * DKA, ketoacidosis, urine ketones ** Requiring hospitalization *** Increased urine ketones, mild moderate DKA or acidosis Henry et al. Diabetes Care 2015; 38:

22 Pathogenesis of SGLT2-Induced DKA Taylor et al. J Clin Endocrinol & Metabol 2015

23 Clinical Presentation of DKA Symptoms Polydipsia Polyuria Weakness Weight loss Nausea Vomiting Abdominal pain Signs Hypothermia Tachycardia Tachypnea Kussmaul breathing Ileus Acetone breath Altered sensorium The onset of DKA is usually relative short, ranging from hours to a day or two.

24 Mental Status at Presentation in DKA Level of Consciousness Mental Status and Osmolality Serum Osmolality (mosm/l) Umpierrez GE et al. Arch Intern Med. 1997;157:

25 Correlation Between Admission Mental Status and Serum Osmolality in 144 Patients with DKA Serum Osmolality (mosm/l) n= 71 n= 55 n= 18 Alert Lethargy/ Coma stupor Umpierrez et al, Arch Int Med157: , 1997

26 DKA and Abdominal Pain DKA with DKA without abdominal pain abdominal pain Number of patients Age (years) 37 ± 1 41 ± 2 Gender (M/F) 47/43 64/39 History of alcohol use 44 (51) * 25 (24) History of cocaine use 11(13) 2 (2) Blood glucose (mg/dl) 596 ± ± 24 Bicarbonate (mmol/l) 9 ± 1 * 15 ± 1 PH 7.12 ±.02 * 7.24 ±.09 Sodium (mmol/l) 133 ± ± 1 Serum osmolality (mmol/l) 307 ± ± 2 Data are means ± SEM or n (%) p < 0.05 p < 0.01 * p < Umpierrez et al, Critical Care J, 17:63-67,2002.

27 Admission Clinical characteristics Abdominal Pain Admission bicarbonate, glucose and osmolality in patients with DKA and abdominal pain Total # # cases (%) DKA cases with abdominal pain Bicarbonate (mmol/l) < (86) 5 - < (66) 10 - < (36) (13) Glucose (mg/dl) < (36) (48) > (50) Serum Osmolality (mmol/kg)* < (48) (40) > (54) Umpierrez et al, Critical Care J, 17:63-67,2002. Umpierrez et al, Critical Care J, 17:63-67,2002.

28 Initial Laboratory Studies Immediate determination of blood glucose by finger stick, and serum ketones (3-BH) by finger stick or urinary ketones. Laboratory studies: 4ABG s 4CBC with differential 4CMP (glucose, electrolytes, bicarbonate, PO4, Mg, BUN, creatinine) 4Serum ketones 4Urinalysis 4Bacterial cultures* 4Cardiac enzymes* * If clinically indicated

29 Useful Formulas for the Evaluation of DKA and HHS 1. Calculation of anion gap (AG): AG= [Na + ] [Cl - + HCO 3- ] 2. Total and effective serum osmolality: Total= 2[Na + ] + glucose (mg/dl) + BUN (mg/dl) Effective= 2[Na + ] + glucose (mg/dl) 18 Pasquel & Umpierrez G. DKA & HHS Pathogenesis, In: DeGroot Endocrinology Textbook. 2014

30 Serum Sodium 4Hyponatremia is common in patients with DKA Serum glucose H 2 O H 2 O H 2 O H 2 O Na + Correction of Serum sodium: Corrected Na + = [Na + ] = 1.6 x glucose (mg/dl) Pasquel & Umpierrez G. DKA & HHS Pathogenesis, In: DeGroot Endocrinology Textbook. 2014

31 Serum Potassium 4Admission serum potassium is frequently elevated (due to a shift of K - from the intracellular to the extracellular space) Osmolality Acidosis K + K + K + K + K + Na + K - Insulin regulates Activity of Na + /K + pump Serum Phosphorus 4Admission serum phosphorus is frequently elevated (due to a shift of K - from the intracellular to the extracellular space) Pasquel & Umpierrez G. DKA & HHS Pathogenesis, In: DeGroot Endocrinology Textbook. 2014

32 Can Serum β-hydroxybutyrate Be Used to Diagnose Diabetic Ketoacidosis? Children A HCO3 level of 18 meq/l corresponded with BOHB levels of 3.0 and 3.8 mmol/l in children and adults, respectively. Adults SHEIKH-ALI et al. Diabetes Care 31: , 2008

33 Clinical Utility of β-hydroxybutyrate Determined by Reflectance Meter in the Management of DKA Serum/urinary ketones 4Key diagnostic feature of DKA 4Nitroprusside reaction (semiquantitative estimation of acetoacetate and acetone, but fails to measure B-OH-B) 4Direct measurement of B-OH-B is preferable - Ketosite test - Precision Xtra Umpierrez et al, Diabetes Care 18:137, 1995

34 Blood β-ohb Levels in DKA β-ohb concentrations >0.5 mmol/l are considered abnormal Patients presenting with DKA can range between 3-12 mmol/l β-ohb β-ohb 1.0 mmol/l treat blood glucose level appropriately β-ohb 1.1 to 3.0 mmol/l insulin and fluids; retest in 1 hr and, if no improvement, contact physician β-ohb >3.0 mmol/l insulin, fluids, urgent medical attention Wallace TM, et al. Q J Med. 2004;97: Guerci B, et al. Diabetes Metab. 2005;31:

35 Management of DKA and HHS Replacement of fluids losses Correction of hyperglycemia/metabolic acidosis Replacement of electrolytes losses Detection and treatment of precipitating causes Conversion to a maintenance diabetes regimen (prevention of recurrence) Diabetes Care, Vol 32 (7) , 2009

36 Management of Adult Patients with DKA IV Fluids Insulin Potassium Bicarbonate Kitabchi, Umpierrez et al. Diabetes Care 26:S109-S117, 2009

37 Fluid Therapy in DKA Normal saline, 1-2 L over 1-2 h Calculate corrected serum sodium High or normal serum sodium Low serum sodium ½ NS at ml/h NS at ml/h Glucose < 250 mg/dl ADA. Diabetes Care 26:S109-S117, 2009 Change to D5% NS or 1/2NS

38 Suggested Initial Rate of Fluid Replacement* Hours 1st hour 2nd hour 3rd-5th hours 6th-12th hours Volume 1,000 2,000 ml 1,000 ml 500 1,000 ml/hour ml/hour *average replacement after initial hemodynamic resuscitation with normal saline when indicated Chaithongdi N, et al. Hormones (Athens). 2011;10(4):

39 Intravenous Insulin Therapy in DKA I.V. Bolus: 0.1 U/kg body Wgt I.V. drip: 0.1 U/kg/h body Wgt Glucose < 250 mg/dl I.V. drip: U/kg/h Until resolution of ketoacidosis

40 Insulin Uncomplicated DKA- SC route IV Route (DKA and HHS) Regular Insulin 0.3 U/kg B. Wt., then 0.2 U/kg every 2 hr 0.14 U/kg Bwt/hr as IV continuous insulin infusion When serum glucose reaches 250 mg/dl Adapted from Kitabchi et al, 31: , 2008 ADA Position Statement. Diabetes Care 26:S109-S117, 2009 DKA When serum glucose reaches 200 mg/dl, reduce regular insulin infusion to U/kg/hr IV, or give rapid-acting insulin at 0.1 U/kg SC every 2 hrs. Keep glucose between 150 and 200 mg/dl until resolution of DKA. HHS When serum glucose reaches 300 mg/dl, reduce regular insulin infusion to U/kg/hr IV. Keep glucose between 200 and 300 mg/dl until patient is mentally alert.

41 Intravenous Insulin Therapy in DKA 800 Bolus: 0.1 U/kg, + drip at 0.1 U/kg/h Normal saline Glucose mg/dl Decrease drip at 0.05 U/kg/h Change to D5%1/2 NS Hours of Treatment

42 Potassium Replacement K + = > 5.5 meq/l; no supplemental is required K + = 4-5 meq/l; 20 meq/l of replacement fluid K + = 3-4 meq/l; 40 meq/l of replacement fluid If admission K + = <3 meq/l give meq/h until K + >3 meq/l, then add 40 meq/l to replacement fluid

43 Bicarbonate Administration ph > 7.0 no bicarbonate ph < 7.0 and bicarbonate < 5 meq/l 44.6 meq in 500 ml 0.45% saline over 1 h until ph > 7.0 ADA. Diabetes Care 26:S109-S117, 2009

44 Phosphorus Administration Not routinely recommended. If serum phosphorus < 1 mg/dl mmol K-Phos over 24 h. Monitor serum calcium level. ADA. Diabetes Care 26:S109-S117, 2009

45 IV - Regular Insulin SQ - Lispro Insulin Bolus: 0.1 u/kg, i.v. infusion 0.1 u/kg/hr until BG <250 mg Then, decrease insulin rate to 0.05 u/kg/h until resolution Bolus: 0.2 u/kg/sq, then 0.1 u/kg/hr until BG <250 mg Then, decrease s.q. insulin to 0.05 u/kg/h until resolution Umpierrez et al. Am J Med 117: , 2004

46 Changes in Metabolic and Acid-Base Parameters During Treatment of DKA 800 Glucose (mg/dl) Bicarbonate (meq/l) FFA (mmol/l) 24 3 Glucose (mg/dl) IV Regular SC Lispro Bicarbonate (meq/l) FFA (mmol) Duration of Therapy (hr) Druartion of Therapy (hr) Duration of Therapy (hr) 12 B-OH-B (mmol) ph Insulin (µu/ml) B-OH-B (mmol) ph Insulin (uu/ml) Duration of Therapy (hr) Duration of Therapy (hr) Duration of Therapy (hr) Umpierrez et al. Am J Med 117: , 2004

47 Treatment of DKA with SQ aspart insulin every 1 and 2 hours versus IV regular insulin Aspart SC-1hr (n=15): Initial dose SC: 0.3 u/kg, then 0.1 U/kg/hr until BG<250 mg/dl Thereafter, 0.05 U/kg SC-1hr until resolution of DKA. Aspart SC-2hr (n=15): Initial dose SC: 0.3 U/kg,then 0.2 U/kg 1 hr later and Q 2 hr until BG<250 mg/dl. Then, 0.01 U/kg SC-2hr until resolution of DKA IV Regular (n=15): Initial dose IV: 0.1 unit/kg, then 0.1 U/kg/hr until BG<250 mg/dl. Thereafter, 0.05 U/kg/il resolution of DKA Umpierrez et al. Diabetes Care 27: , 2004

48 Changes in Metabolic Profile in Patients Treated with Aspart SC-1hr and SC-2hr, or with IV Regular Insulin Aspart SC-1hr Aspart SC-2hr Regular IV 1000 Glucose (mg/dl) Bicarbonate(mmol/L) Venous ph Glucose (mg/dl) Bicarbonate (meq/l) Venous ph Duration of Treatment (hours) Duration of Treatment (hours) Duration of Treatment (hours) 12 B-OH-B (mmol/l) 2.0 FFA (µmol/l) 10 B-OH-B (mmol) FFA (umol/l) Duration of Treatment (hours) Umpierrez et al. Diabetes Care 27: , Duration of Treatment (hours)

49 Response To Medical Treatment and Cost of Hospitalization Aspart Aspart Regular SC-1hr SC-2hr Intravenous L.O.S. (days) 3.4 ± ± ± 0.8 Duration of therapy until BG<250 mg/dl (hr) 6.9 ± ± ± 1 Duration of therapy until Resolution of DKA (hr) 9.9 ± ± ± 0.7 Amount of insulin until BG<250 mg/dl (units) 67 ± 4 65 ± 7 62 ± 8 Amount of insulin until resolution of DKA (units) 85 ± 4 94 ± 8 82 ± 9 Episodes of hypoglycemia Hospitalization Cost ($) 10,733 ± 2,017 10,173 ± 1,738 16,828 ± 2,563* Data are means ± SE * P < 0.01

50 Summary of studies comparing SC injections of insulin lispro vs continuous infusion of regular insulin in DKA patients Vincent and Nobecourt. Diabetes & Metabol 39: , 2013

51 Criteria for Resolution of Hyperglycemic Crises Ketoacidosis 4Blood glucose <200 mg/dl 4Two of the following criteria: a serum bicarbonate level 15 meq/l a venous ph >7.3 a calculated anion gap of 12 meq/l HHS 4Normal osmolality 4Normal mental status Umpierrez GE, Jones S, Smiley D, et al. Diabetes Care. 2009;32:

52 Transition to Subcutaneous Insulin after Resolution of DKA After Initial IV or SQ therapy (ph>7.3, HCO3 >18, AG < 14) Give SQ basal insulin 2 4 hours before stopping IV insulin Start multi-dose insulin (basal bolus) regimen Insulin analogs are preferred over human insulin Basal: glargine / detemir Rapid-acting insulin analogs (lispro, aspart, glulisine) Analogs results in similar BG control, but less hypoglycemia than human insulin (15% vs. 41%) Use early glargine insulin during treatment of DKA may prevent rebound hyperglycemia during insulin infusion Umpierrez & Korytkowski. Nat. Rev. Endocrinol. 2016

53 Insulin Analogs versus Human Insulin in the Treatment of Patients with Diabetic Ketoacidosis 68 subjects with DKA Open-labeled randomization Insulin Analogs (n= 34) Human Insulin (n= 34) IV Glulisine insulin therapy until resolution of DKA IV regular insulin therapy until resolution of DKA Transition to SC glargine once daily and glulisine before meals Transition to SC NPH and regular insulin twice daily Umpierrez et al, Diabetes Care 32: , 2009

54 Insulin Glulisine vs Regular Insulin 800 Glucose 7.40 ph Blood Glucose (mg/dl) ph Admit Duration of Treatment (hours) Duration of Treatment (hours) 22 Bicarbonate 22 Anion Gap Bicarbonate (meq/l) Anion Gap (meq/l) Duration of Treatment (hours) Umpierrez et al, Diabetes Care 32: , Duration of Treatment (hours)

55 Mean Daily Glucose and Hypoglycemia During Transition to SC Insulin NPH/ Regular Glargine/G lulisine P value Day ± ± Day ± ± Day ± ± Day ± ± Day ± ± Hypoglycemia Umpierrez et al, Diabetes Care 32: , 2009 NPH/ Regular Glargine/G lulisine P value Patients with BG <70 mg/dl, n (%) 14 (41) 5 (15) 0.03 Episodes of BG <70 mg/dl, n Patients with BG <40 mg/dl, n (%) 2 (6) 1 (3) NS Episodes of BG <40 mg/dl, n 2 1 NS Data for glucose levels are means ± SD.

56 Summary DKA and HHS are common, serious and expensive complications in patients with type 1 and type 2 diabetes Prevention of metabolic decompensation through patient education, strict surveillance of glucose homeostasis and aggressive diabetes management might reduce the high morbidity and mortality associated with DKA and HHS Recent treatment protocols have improved clinical outcome in patients with DKA and HHS

57 Thank you! Guillermo E. Umpierrez, MD