HYPERGLYCEMIC EMERGENCIES

1. HYPERGLYCEMIC EMERGENCIES Boston University School of Medicine July, 2013 Marie McDonnell, MD marie.mcdonnell@bmc.org

2. Outline • Definitions: DKA , HHS and HK • Why do they require ICU in most cases? (and when don’t they) • Relevant Epidemiology • Simple overview of normal insulin physiology and severe insulin deficiency • What is going on? • Clinical features of acute insulin deficiency • Hyperglycemic crisis: diagnosis and management • Big picture: Treat hypovolemia agressively while avoiding iatrogenic complications of therapy

3. Case • 28 yo man with no prior medical history • Polyuria, polydipsia for 1 month, severe in last week • Subjective fever, flu-like illness for one week • Drinking fluids to exhaustion – water, juice, coca cola • Unable to easily wake patient one morning – EMS called

4. 132 92 52 1478 4.5 14 3.2 Data • Awake but lethargic on admission to ER • BP 92/50, pulse 128, T 99, 90 kg • Dry membranes • Stat labs: • Anion gap = 26 Arterial pH= 7.29 Urine ketones = 2+ Plasma ketones = Moderate Phos = 0.9 Mg = 2.0 WBC = 10, 000, 80% lymph HCT = 44

5. Definitions Cause of Death in Adults: Hypokalemic Cardiac Arrest (rare) • DKA • Blood glucose >250 mg/dl • Metabolic acidosis with ph <7.3 or serum bicarbonate <15mM • “MILD DKA” is Bicarb 15-18 • “MODERATE DKA” is Bicarb 15 or above with ph >7.0 • “SEVERE DKA” is Bicarb <15 with ph 7.0 or below • “EARLY DKA” is any Bicarb deficit in the setting of insulin deficiency, a non-official term • Ketonemia • note: most patients with ketonemia have + urine ketones, or ketonuria • HHS • Blood glucose >600mg/dl • arterial ph>7.3 • bicarbonate >15 • effective serum osmolality >320 mOsm/kg H20 • mild ketonuria or ketonemia may be present Cause of Death in Adults: Underlying illness (not uncommon)

6. Hyperosmolar Ketoacidosis • DKA and HHS occur simultaneously • Worse prognosis • Implication: • Much more severe water deficit • Much more severe insulin deficiency • Generally more ill overall (underlying illness) • Requires more aggressive therapies, and hence increased “iatrogenic” complications • Identifying this condition is powerful

7. Hyperosmolality • Causes progressive depressed mental function as osmolality rises. • If serum total osmolality is <340-350 mOsm/kg, or effective osmolality <320 (doesn’t include urea), stupor or coma should suggest another cause • Correction yields a very predictable improvement in mental status. If you don’t see this...?LP, toxic ingestion, etc.

8. Make the correct diagnosis • EO is the same as tonicity and excludes the BUN ... = 2 ( sodium + potassium) + glucose/18, normal = 280-90 Patient’s effective osm: = 2 ( 132 + 4.5) + 1478/18 = 273+82 = 355

9. Epidemiology • DKA prevalence is rising • Since 1996, 50% increase in No. diagnoses in the US • HHS (when diagnosed properly) is still much less common • DKA is still the most common cause of death in children and adolescents with type 1 diabetes • But death from DKA has declined substantially in last 20-40 years • Mortality: • HHS+DKA >> HHS>>>>DKA • 10-35% >> 5-20% >>>> 1% • HHS+DKA is often called Hyperosmolar Ketoacidosis (HK)

10. Epidemiology • Initial presentation of type 1 diabetes • Less and less common. Office diagnoses increasing • Negrato CA. Temporal changes in the diagnosis of type 1 diabetes by diabetic ketoacidosis in Brazil: A nationwide survery. Diabet Med 2012 Jan. • Initial presentation of type 2 diabetes • Overall represents a larger proportion of presentations given high prevalence of this disease • More common in patients of Afro-Caribbean ancestry. • Mauvis-Jarvis F. Ketosis-prone type 2 diabetes in patients of Sub-Saharan African origin. Diabetes 2004) (Balasubramanyam A. New profiles of diabetic ketoacidosis. Type 1 vs. type 2 diabetes and the effect of ethnicity. Arch Intern Med 1999

11. Epidemiology: Why? • Insulin non-adherence: Most likely reason in all studies • 68% of patients in a large, urban, inner city US location • Why does insulin non-adherence happen? • Financial constraint, feeling unwell, being away from insulin supply and trying to extend the insulin supply. Over 30% of patients give no reason for discontinuation. However, factors such as alcohol and substance abuse, younger age at the time of diagnosis, depression, longer duration of diabetes and homelessness contribute substantially to cases of recurrent DKA • Randall L. Recurrent diabetic ketoacidosis in inner city minority patients: behavioral, socio-economic, and psychosocial factors. Diabetes Care. 2011) • DKA may be more common in young immigrants, and of these, girls are 20% more likely to present compared with boys. • Fritsch M, Predictors of diabetic ketoacidosis in children and adolescents with type 1 diabetes. Experience from a large multicenter database. Pediatr Diabetes 2011 June)

12. HHS • Mortality 10-30% depending on institution • Depends on complications: • In adults, documented major complications include thrombosis, rhabdomyolysis, renal failure, and irreversible cardiac arrhythmias • Younger patients have higher mortality in some studies • Unique syndrome of hyperthermia, rhabdomyolysis and HHS in Young AA adults reported, >75% mortality, survivors with evidence of CPM • Yale report 2007, pts aged 10 to 30 yo • Out of 629 cases with glucose >600, only 10 met criteria for pure HHS (DKA-HHS excluded) • 10% mortality • Deaths limited those with unreversed shock over the first 24 hours of admission and who received <40 ml/kg of intravenous fluids over the first 6 hours of treatment. • Children’s hospital: advocating aggressive volume resuscitation • http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2842888/

13. Blood glucose >250 mg/dl Altered MentalStatus Electrolyte disturbances Marked hypovolemia +/- Acidosis/ Acidemia Underlying illness: Infection, MI, Stroke

14. Type 1 DM & DKA Insulin Production: Suboptimal Insulin Production: Severely impaired Insulin Action: Severely impaired Insulin Action: Normal or suboptimal Type 2 DM & HHS

15. HHS DKA

16. The diabetes landscape is changing DKA? HHS?

17. INSULIN ACTION: Cellular level

18. Overview of Insulin Function INSULIN MUSCLE LIVER ADIPOCYTE Forms triglycerides to store fat; inhibits lipolysis Transports glucose, amino acids and ions (K &phos) inhibits glucose production; allows glycogen storage

19. Insulin: the “fed state” hormone INSULIN glucagon Glucose and amino acids are actively transported into cells; normal K and Phos transport Hormone-Sensitive Lipase Inhibited Insulin inhibits glycogen breakdown Lipolysis is inhibited; triglycerides are formed for fat storage and fatty acids are not released Insulin increases malonyl coA, inhibiting CPT-1, and fatty acids are unable to enter mitochondria for oxidation

20. INSULIN MUSCLE LIVER ADIPOCYTE Can’t use glucose & Aas (starvation); K & Phos not normally transported More glucose is made; fatty acids oxidized for ATP Lipolysis goes unchecked, fatty acids fill the bloodstream…

21. Fatty Acid Oxidation Overload Product: Acetyl CoA, which has to enter TCA cycle to produce ATP TCA cycle can only do so much Enzymes become saturated What happens to TCA cycle “overflow”? =Ketone bodies

22. Overwhelmed TCA cycle Acetoacetyl-Coa

23. So many ketone bodies with nowhere to go…

24. …Acidemia impairs the ability of hemoglobin to bind oxygen

25. GH, EPINEPHRINE, CORTISOL INSULIN GLUCAGON Overwhelming FA oxidation takes place…acetyl Coa overwhelms the TCA cycle & Ketone Bodies are released into the blood Hormone-Sensitive Lipase Activated LIPOLYSIS GOES UNCHECKED… TRIGLYCERIDES BREAK DOWN TO FFAs… Increased glucagon/low insulin decreases malonyl coA, allows CPT-1 to transport FFAs into Liver mitochondria for oxidation

26. How to measure metabolic acidosis? • Blood pH: measures acidemia • “Anion Gap” • Normal extracellular anions = • Measurable: Cl- and HCO3- • Unmeasurable: proteins • Normal measureable extracellular cation = • Na++ • Electric “balance” • Anions must =Cations • Na++ - [Cl- + HCO3-] – (unmeasurable anions) = 0 The normal “Gap”

27. “Polyuria” in Hyperglycemic Crisis • Glycosuria • Glucose delivery to nephron exceeds ability of kidney to reabsorb glucose • Excess osmoles of glucose are excreted, along with water and sodium • The “threshold” probably varies in the population, but is around 220 mg/dl, and with rising glucose excretion increases Rave K, et al. Nephrol Dial Transplant. 2006 • Renal Concentrating Defect • Many patients with diabetes have a defective ability to concentrate urine • This is likely related to glycosuria progressing to “renal wash out” where the normal electrolyte gradients are lost • End result: more renal water loss Spira, et al. Am J Kidney Dis. 1997

28. Cortisol, Epi, Norepi, GH Cortisol, Epi, Norepi... GLUCAGON: INSULIN GLUCOSE SEVERE DEHYDRATION HYPEROSMOLALITY & CONFUSION GLUCAGON: INSULIN GLUCOSE LIPOLYSIS KETOACIDOSIS 1-4 days 2-6 weeks PATIENT WITH TYPE I DM MILD TO SEVERE ILLNESS+/- MISSED INSULIN DOSES PATIENT WITH TYPE 2 DM SEVERE ILLNESS + LIMITED ACCESS TO WATER HYPERGLYCEMIA >220 MG/DL GLUCOSURIA DEHYDRATION DEC. PO INTAKE TO HOSPITAL

29. Insulin, Potassium and H+ in DKA SLUGGISH H+ K+

30. Degree of Dehydration Water deficit on avg. 9L HHS DKA Water deficit on avg. 3-5L

31. Mortality Q: Which has a higher associated mortality DKA or HHS? A: HHS Recent rates are approximately 15%, whereas in DKA, it’s <5%

32. Diabetic Ketoacidosis: extreme insulin deficiency

33. DKA: clinical presentation Polyuria, polydipsia Fatigue Nausea, vomiting Abdominal pain Increased respiratory rate/dyspnea Dry membranes + ketones on breath (sweet) – unreliable sign Infection +/- fever

34. DKA… and? • Common complicating factors • Pancreatitis • Idiopathic “benign” Amylasemia/Lipasemia • Toxic Ingestion/Withdrawal • Renal Dysfunction • Other severe “stressor”: MI, PE • A second cause of acidosis (above, + others…) • Lactic acidosis was seen in 68% of adult pts with DKA (lactate >2.5 mmol/L) and 40% had lactate >4. It may not be associated with mortality or other relevant factors (LOS). Correlates with glucose level, so related to hypoperfusion AND altered glucose metabolism? • Journal of Critical Care. BI Deaconess, April 2012

35. Suspected DKA – initial assessment • Airway, Breathing, Circulation • IV access: • Most require central venous line due to severe hypovolemia, for frequent lab draws, and multiple drips • Arterial line not necessary in most cases • Venous blood gas measurements are reliably 0.03 Ph points higher than arterial..get both at the same time initially and compare

36. Suspected DKA – initial assessment Laboratory: • ABG with stat electrolytes (include phos and Ca) • Chem 7 for Anion Gap (normal is <10) • CBC with differential • Urine analysis, micro, culture • Ecg, consider troponin • Serum and urine toxicology screen • Serum and calculated osmolality • Serum Acetone • Lipids • Amylase/lipase

37. DKA: CLINICAL MANAGEMENT

38. DKA pathophysiology • Treatment is crystal clear • But what is the best approach? X X

39. Insulin effect can be slow • Ketosis causes insulin resistance • But insulin stops ketosis (so you have to give a LOT at first) • Need to stop the ketosis before insulin will work well • You know insulin is working if glucose starts to fall • Glucose transport is an accurate surrogate marker of insulin receptor overall function (and the only one we really have) • When glucose is falling, ketosis is resolving • At this point, risk of hypoglycemia is high given rapid improvement in glucose transportation. This likely involves improved GLUT4 translocation as ketosis resolves

40. Insulin, Potassium and H+ in DKA SLUGGISH H+ K+

41. Insulin, Potassium and H+ In HSS or DKA, never give insulin or bicarbonate until you know the potassium level…always start fluids first... Insulin NaHCO3 (and other measures to correct acidosis) H+ K+

42. Start Fluids First!

43. Priority 1: Reperfusion • BP 92/50, pulse 128 • Renal function: 52/3.2 • Urine output: 50cc in 2 hours • What is the fluid of choice? 0.9% NORMAL SALINE RATE: WIDE OPEN to start, reduce as perfusion improves

44. Complete Initial Evaluation. Start 1 Liter of 0.9% NaCl/hour initially (15-20ml/kg/hr) IV FLUIDS INSULIN POTASSIUM Use 0.9% saline 1L/hr in all cases to restore plasma volume: 1) urine output at least 30cc/hour, 2) mental status improved, 3) blood pressure and pulse normalizing To continue hydration, use serum Na as a guide: Na high - 0.45% NaCL Na normal - 0.45% NaCl Na low - 0.9% NaCl When serum glucose reaches 250, change fluid to d51/2 NS and continue with insulin drip, keep glucose 150-200 mg/dl until anion gap closed

45. Mortality in DKA • HYPOKALEMIC CARDIAC ARREST = giving insulin before knowing K and/or poor monitoring • Cerebral Edema • Pulmonary Edema

46. Complete Initial Evaluation. Start 1 Liter of 0.9% NaCl/hour initially (15-20ml/kg/hr) IV FLUIDS INSULIN POTASSIUM Use 0.9% saline 1L/hr in all cases to restore plasma volume: 1) urine output at least 30cc/hour, 2) mental status improved, 3) blood pressure and pulse normalizing To continue hydration, use serum Na as a guide: Na high - 0.45% NaCL Na normal - 0.45% NaCl Na low - 0.9% NaCl When serum glucose reaches 250, change fluid to d51/2 NS and continue with insulin drip, keep glucose 150-200 mg/dl until anion gap closed If serum K+ is <3.3 mEq/L Hold insulin and give 40meq K+ until K>3.3 If serum K >5.5, check K q2hours If K >3.3,<5.5 give 20-30 meq in each liter IVF to keep K 4-5 Check chem7 q2-4hr until stable.

47. Complete Initial Evaluation. Start 1 Liter of 0.9% NaCl/hour initially (15-20ml/kg/hr) IV FLUIDS INSULIN POTASSIUM Use 0.9% saline 1L/hr in all cases to restore plasma volume: 1) urine output at least 30cc/hour, 2) mental status improved, 3) blood pressure and pulse normalizing To continue hydration, use serum Na as a guide: Na high - 0.45% NaCL Na normal - 0.45% NaCl Na low - 0.9% NaCl When serum glucose reaches 250, change fluid to d51/2 NS and continue with insulin drip, keep glucose 150-200 mg/dl until anion gap closed Regular, 0.15u/kg as IV bolus *** sc/IM if mild DKA If serum K+ is <3.3 mEq/L Hold insulin and give 40meq K+ until K>3.3 0.1 u/kg/h IV infusion If serum K >5.5, check K q2hours If K >3.3,<5.5 give 20-30 meq in each liter IVF to keep K 4-5 Check serum glucose hourly, if doesn’t fall by 50-70 in first hour, then double hourly insulin dose until glucose falls by 50-70 mg/dl Check chem7 q2-4hr until stable.

48. Add screen shot

50. Coexisting Illness • Often serious and “masked” • Patients with Diabetes have more infections and more serious infections than the general population • After you start fluids, the search begins for underlying disease…