ICU: Case Presentation Diabetic Ketoacidosis Heparin Induced Thrombocytopenia

1. ICU: Case PresentationDiabetic KetoacidosisHeparin Induced Thrombocytopenia Hani Ramadan PharmD Candidate 2007 Oakwood Hospital Dearborn, MI

2. CC:Weakness and Shortness of Breath. 2/23/07 (ER) HPI: CC is a 42 year-old male with a known history of insulin dependent dabetes for the last eight years and previous history of diabetic ketacidosis. Patient has been having symptoms of SOB and lethargy for a week. PMH: Insulin dependent diabetes mellitus since 1999, DVT two years ago in the left common femoral vein, diabetic ketoacidosis, cellulitis with abscess in 2004 which required incision and drainage.

3. Allergies:NKDA SH:Patient rarely smokes. Social drinker. Does not use drugs. Medications at Home: Insulin 70/30 Physical assessment: VS:H=5’10” W=84kg T= 93.3, P= 94, RR=28,BP=102/60 HEENT:conjunctivae and lids have no pallor and no jaundice. Pupils equal, round and reactive to light and accomodation. Ears, nose and throat normal. Dry oropharynx and oral mucosa. Using some accessory muscles for breathing. Small abscess behind left ear.

4. Lungs:decreased breath sounds on the right CV:S1 and S2 plus tachycardic. Abd:no n/v/d. Neuro:lethargic. Incomplete assessment. Labs: Na 124 WBC 39.3 Scr 2.1 pH 6.8 Glu 372 K 5.1 HGB 16.3 BUN 20 HCO3 3 Anion Gap 13 Cl 99 HCT 48 plt 271 pCO2 20 acetone +2 X-Ray: Right sided pneumothorax with some tension with midline shift to the left as well as collapse of the RLL. EKG:NSR with intraventricular block.

5. Physician’s assessment/plan: • Diabetic ketoacidosis: Due to abscess and noncompliance. Patient started on insulin drip. Patient received 2 liters fluid bolus and placed on 0.9 normal saline at 150 ml/h. 2 ampules of bicarbonate per iv push and 3 ampules of bicarbonate and 1 liter of D5 half normal saline run at the rate of 150 ml/h. 2. Pneumothorax: Patient had a chest tube placed and pus in the chest tube has been collected. 3. Abscess of the right thigh: X-ray has been ordered. Patient has been placed on Vancomycin and Zosyn.

6. 4. Hyponatremia: Will get corrected as the hyperglycemia resolves. 5. Leukocytosis: secondary to underlying sepsis. 6. Hypothermia: probably from sepsis. Will place warm blankets 7. Acute renal failure probably prerenal: Replace fluids and recheck creatinine. 8. Gastrointestinal and DVT px.

7. DKA Diagnostic Criteria

8. Common Precipitating Factors • Infection (pneumonia, UTI, etc.) • Noncompliance with insulin therapy • Medications • Pancreatitis • Stroke • Alcohol/Drug abuse

9. Clinical Presentation • Early symptoms: Polyuria, Polydypsia, Polyphagia. • Neurologic symptoms: Effective Posm =2 X PNa +([glucose]/18) • N/V/Abdominal pain* • Hypotension, Dry mucus membranes, Hypothermia. • Kussmaul respirations

10. Fluid Repletion • Lowers plasma glucose by 35-70mg/dL per hour. • Due to hemodilution and urinary losses • Combined effect with insulin therapy causes plasma glucose lowering of 100-200mg/dL per hour.

11. Determine Hemodynamic Status Hypovolemic shock Cardiogenic shock Mild Hypotension Administer 0.9% NaCl (1L/h) Hemodynamic monitoring Evaluate Corrected serum Na2+ Serum Na2+ High Serum Na2+ Normal Serum Na2+ Low 0.45% NaCl 0.9% NaCl When serum glucose reaches 250mg/dL Change to 5% Dextrose with 0.45% NaCl (at 150-20mL/h) Keep serum glucose between 150-200 mg/dL

12. Insulin Therapy • Lowers hepatic glucose production • May lower plasma glucose by 65-125mg/dL per hour. • Slower response due to to resistance • Diminishes ketone production • Augments ketone metabolism • Antilipolytic action

13. Insulin IV Route SC/IM Route Insulin: Regular 0.15 units/kg as IV bolus Insulin: Regular 0.4 units/kg 1/2 IV bolus, ½ IM or SC 0.1 units.kg-1.h-1 IV insulin infusion 0.1 units.kg-1.h-1 Regular insulin SC or IM Change to 5% dextrose with 0.45% NaCl at 150-250 ml/h with adequate insulin (0.05-0.1 units.kg-1.h-1 IV infusion or 5-10 units SC every 2h) to keep the serum glucose between 150 to 200 mg/dl until metabolic control is achieved. If serum glucose does not fall by 50-70 mg/dl in first hour Double insulin infusion hourly until glucose falls by 50-70 mg/dl Give hourly IV insulin bolus (10 units) until glucose falls by 50-70 mg/dl When serum glucose reaches 250 mg/dl

14. Plasma Sodium • Increased plasma osmolality => Na+ • (1meq/L:62mg/dl) [pGlu < 400 mg/dl] • (1meq/L:25mg/dl) [pGlu > 400 m/dl] • Glycosuria-induced osmotic diuresis => Na+, K+ • Attenuated in CKD or maintenance dialysis

15. Plasma Potassium • Paradoxical hyperkalemia at presentation. • Acidemia • Insulin deficiency • Glucosuria induced osmotic diuresis

16. Potassium If serum K+ is <3.3 mEq/L: Hold insulin and give 40 mEq K+ per h (2/3 KCL and 1/3 KPO4) until K3.3 mEq/L If serum K+5.0 mEq/L do not give K+ but check K+ every 2 hrs If serum K+ 3.3 but < 5.0 mEq/L: Give 20-30 mEq K+ in each liter of IV fluid (2/3 as KCL and 1/3 as as KPO4) to keep serum K+ at 4-5 mEq/L

17. Plasma Bicarbonate and Anion Gap • Severity of MA depends on: • Rate of ketoacid production. • Duration of increased ketoacid production. • Rate of acid excretion in the urine.

18. Assess Need For Bicarbonate pH <6.9 pH 6.9-7.0 pH >7.0 NaHCO3 (100 mmol) Dilute in 400 ml H20 Infuse at 200 ml/h. NaHCO3 (50 mmol) Dilute in 200 ml H20 Infuse at 200 ml/h. No HCO3 Repeat HCO3 administration Every 2 h until pH > 7.0. Monitor serum K+.

19. Plasma Phosphate • Masked hyperphosphatemia. • Insulin deficiency • Acidosis

20. Monitoring Strategies • Plasma glucose • Every 1 to 2 hours • Electrolytes, Phosphate, Arterial pH • Every 2 to 6 hours

21. Warkentin TE, Greinacher A et al. Heparin-induced thrombocytopenia: recognition, treatment and prevention: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004 Sep;126(3 Suppl):311s-337s.

22. Day#5 (03/02/07) O: Patient has empyema and had a thoracotomy. Patient was found to have extensive occlusive and nonocclusive disease of his lower extermities with DVT. Patient today underwent successful placement of IVC filter. Vitals: Afebrile, BP:90/40, HR:86, RR:16-18. Labs: Na 141 pH: 7.41 Scr: 5.56 K 3.7 pCO2: 32 BUN: 61 Mg 2.2 HCO3-:20 Glu: 189 P 3.7 Hgb 8.9 Plt: 169 Ca 1.10 Hct 25 INR: 1.1 Antiplatelet F4: +ve Chest: no wheezing or rales. Heart: no murmurs, S2 or S3. Abdomen: Soft and nontender. No masses or organomegaly. Extremities: 1-2+ peripheral edema. Swelling suggestive of DVT. Patient is on CPAP trials of pressure 4-12, CPAP of 5 appears to be doing well. A: Bilateral lower extremity DVT. Heparin Induced Thrombocytopenia. P: Initiate Argatroban therapy.

23. Heparin Induced Thrombocytopenia Type 1: (HAT) Type 2: • Typical onset • Rapid onset • Delayed onset

24. Presentation of HIT • A fall in platelet count of  50% from baseline. • Platelet count fall may be less in some patients. • Coagulopathy.

25. Incidence of HIT • Higher in patients with previous heparin exposure than no previous exposure. • Surgical > medical. • Highest amongst patients undergoing orthopedic surgery tx with UFH (3-5%). • Adults undergoing cardiac surgery tx with UFH (1-2%). • Intermediate risk in general medical patients (0.8-3.0%) • Rare amongst obstetrics, pediatric patients, patients undergoing chronic hemodialysis.

26. Atypical manifestations • Thrombosis few days before thrombocytopenia • Skin lesions/necrosis at heparin injection sites • Anaphylaxis • Venous gangrene of limbs

27. Management of HIT • Diagnosis of exclusion • Discontinue all sources of heparin. • Confirm diagnosis with laboratory testing. • Consider alternative anticoagulant. • Monitor for thrombosis. • Monitor platelet count recovery.

28. Laboratory Diagnosis • Eliza PF4-heparin antibody test. (Immunoassay) • Positive predictive value range: 10-93% • Negative predictive value is high: >95% • Functional assays • Positive predictive value: 89-100% • Negative predictive value: 81%

29. Arepally et al. Heparin-induced Thrombocytopenia. NEJM august 2006; 809-817

30. Pharmacotherapy

31. Drug Lab Interactions • INR change is thought to depend on the argatroban dose and the thromboplastin agent used for measurement. • In order to calculate actual INR from measured INR • Reduce the dose of Argatroban to a dose of 2mcg/kg/min. • Repeat INR level 4-6 hours after reduction. • Based on the thromboplastin ISI utilized the following equations are used to calculate actual INR value: 0.19 + 0.57 (INRwa) = INRw (Innovin, Dade) 0.18 + 0.45 (INRwa) = INRw (Thromboplastin Cplus)

32. Treatment • For patients who have HIT and thrombosis: • Therapy with alternative anticoagulant. (DTI) • Transition to warfarin therapy once platelets recover to above 100 000 mm3 (preferably >150 000 mm3) • Oral Anticoagulants are initiated with DTI for at least 5 days until the INR is therapeutic for at least 48hrs. • Continue warfarin therapy for 6 months. • Monitor aPTT*, INR, PT, platelet count.

33. A Comparison of Lepirudin and Argatroban Outcomes. Smythe MA, et al. Clin Appl Thrombosis/Hemostasis. 2005 Oct;11(4):371-374. Objective: To compare the efficacy and safety outcomes of lepirudin and argatroban.

34. Study Design • Retrospective cohort study. • Baseline demographic/clinical recording. • Randomization to Argatroban or Lepirudin. • Argatroban n = 29 • Lepirudin n = 61

35. Outcome Measures • Primary Efficacy Outcome: • Effective anticoagulation: aptt > 1.5, fewer dose increase. • Primary Safety outcome: • In hospital major bleeding. • Secondary Efficacy Outcome: • Time to first therapeutic aPTT. • Percent of aPTTS that were therapeutic. • Number of hold orders for a supratherapeutic aPTT. • % of patients requiring a dose adjustment. • Number of dose titration requirements.

36. Results • Time to first therapeutic aPTT was the only efficacy outcome that differed between the groups. (P<0.05)

37. Limitations • Patient heterogeneity. • Sample size. • Time of follow up.

38. Conclusions • Lepirudin and Argatroban demonstrated comparable safety and efficacy. • To identify if clinically meaningful differences exist, a large prospective study is needed to compare outcomes of lepirudin and argatroban.

39. Argatroban Anticoagulation in Patients with Heparin-induced Thrombocytopenia. Lewis BE, et al. Arch Intern. Med. 2003;163:1849-1856.

40. Study Design • Multicenter, nonrandomized, prospective study using a historical control cohort. • Study group (n = 418): HIT (189), HITTS(229) study arms. • Control (n = 185) • Baseline demographic/clinical features comparable.

41. Selection • Inclusion: • Men and non-pregnant women  18 years clinically diagnosed with HIT. • Exclusion: • Unexplained activated aPTT > 2 times the control value at baseline. • Bleeding diathesis unrelated to HIT. • Lumbar puncture in the past 7 days. • Hx of previous aneurysm/ hemorrhagic stroke. • Recent thrombotic stroke unrelated to HIT • A known bleeding site • Current pregnancy or breastfeeding. • Terminal illness with a life expectancy of < 2 weeks. • Documented coagulation disorder

42. Outcome Measures • Primary efficacy end point: • Composite of all-cause mortality, all-cause amputation, new thrombosis in 37 days. • Secondary efficacy endpoints: • Death due to thrombosis. • Increased platelet count. • Bleeding.

43. Results • In the HIT arm the primary end point was significantly reduced in the treatment arm compared with controls. P=0.04 • In the HITTS study arm, the composite end point occurred in 95 patients (45%) and 26 (56%) controls. P=0.07 • Argatroban compared with control resulted in significant reductions in new thrombosis. • Patients with HIT (5.8% vs.23%, p<0.001) • Patients with HITTS (12.1% vs. 34.8%; p<0.001)

44. Limitations • Historical control. • Risk factors not completely assessed. • Incidence of confirmed HIT unknown. • Median aptt value unknown. • Disease severity unknown. • Liver function unknown. • Confounding variables not addressed.

45. Conclusion • Argatroban therapy compared to historical control improves outcomes particularly new thrombosis and death due to thrombosis in patients with HIT.

46. CC:Weakness and Shortness of Breath. 2/23/07 (ER) HPI: CC is a 42 year-old male with a known history of insulin dependent dabetes for the last eight years and previous history of diabetic ketacidosis. Patient has been having symptoms of SOB and lethargy for a week. PMH: Insulin dependent diabetes mellitus since 1999, DVT two years ago in the left common femoral vein, diabetic ketoacidosis, cellulitis with abscess in 2004 which required incision and drainage.

47. Allergies:NKDA SH:Patient rarely smokes. Social drinker. Does not use drugs. Medications at Home: Insulin 70/30 Physical assessment: VS:H=5’10” W=84kg T= 93.3, P= 94, RR=28,BP=102/60 HEENT:conjunctivae and lids have no pallor and no jaundice. Pupils equal, round and reactive to light and accomodation. Ears, nose and throat normal. Dry oropharynx and oral mucosa. Using some accessory muscles for breathing. Small abscess behind left ear.

48. Lungs:decreased breath sounds on the right CV:S1 and S2 plus tachycardic. Abd:no n/v/d. Neuro:lethargic. Incomplete assessment. Labs: Na 124 WBC 39.3 Scr 2.1 pH 6.8 Glu 372 K 5.1 HGB 16.3 BUN 20 HCO3 3 Anion Gap 13 Cl 99 HCT 48 plt 271 pCO2 20 acetone +2 X-Ray: Right sided pneumothorax with some tension with midline shift to the left as well as collapse of the RLL. EKG:NSR with intraventricular block.

49. Summary

50. References • Lewis BE, et al. Argatroban Anticoagulation in Patients with Heparin-induced Thrombocytopenia. Arch Intern. Med. 2003;163:1849-1856. • Smythe MA, et al. A comparison of Lepirudin and Argatroban Outcomes. Clin Appl Thrombosis/Hemostasis 2005 Oct;11(4):371-374. • Warkentin TE, et al. Management of heparin-induced thrombocytopenia: a cirtical comparison of lepirudin and argatroban. Thrombosis Research. 2003;110: 72-82. • Warkentin TE, Greinacher A et al. Heparin-induced thrombocytopenia: recognition, treatment and prevention: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004 Sep;126(3 Suppl):311s-337s. • Dang CH et al. Evaluation and Treatment with Diret-Thrombin Inhibitors in patients with Heparin-Induced Thrombocytopenia. Pharmacotherapy 2006;26(4):461-468. • Argatroban package insert. GlaxoSmithKline. • Gowthami M. et al. Heparin-Induced Thrombocytopenia. NEJM 2006;355:809-17. • Phathogenesis of Diabetic Ketoacidosis, Treatment of Diabetic Ketoacidosis; Uptodate 2006. • ADA position statement. Hyperglycemic Crises in Patients with Diabetes Mellitus. Diabetes Care;jan 2003;26(1):S109. • Herbst et al. Insulin Strategies for Primary Care Providers. Clinical Diabetes 2002;20:11-16.