Andjela Drincic, MD and Marcel Devetten, MD

Andjela Drincic, MD and Marcel Devetten, MD

At the completion of this presentation participants should: 1. Know some of the common errors encountered with high-risk medications in the in-patient environment, and best practice recommendations to reduce these risks 2. Incorporate evidence-based practice guidelines for management of insulin and anticoagulants in the inpatient environment 3. Be able to use the standardized orders and protocols available through One Chart

TJC requires that hospitals identify high-alert medications used in the hospital environment, and have a policy describing their risk reduction strategies Anticoagulants and insulin have been identified as high-alert medications at TNMC and BMC, based on the frequency of errors associated with their use, the likelihood of serious harm as a result of an error, and the frequency of use in day-to-day patient care.

Best data come from Pennsylvania Patient Safety Authority, where all hospitals centrally report medication safety incidents (still subject to reporting bias) 2012: 42,898 medication errors reported, 235 errors resulted in patient harm (including 5 deaths) 2004 data: 16.7% off all reported medication errors involve insulin products (25% omission, 14% wrong product, 13% wrong dose) 1.8% off reported insulin errors result in patient harm

2010 study on heparin errors reported to three major patient safety reporting programs in 2005: 284,383 errors and near misses reported 10,359 (3.6%) involved heparin 0.1% resulted in patient harm When applied to a hospital like TNMC (approximately 3400 medication error reports/year) we would expect 120 heparin errors per year and 500 insulin errors per year 3 heparin errors and 60 insulin errors resulting in patient harm/year (harm may vary from increased monitoring requirement to irreversible harm) Grissinger et al. Joint Commission J. Qual. Patient Safety 36:195-202 (2010)

Limit number of formulations (insulin) or concentrations (heparin) available on formulary Use evidence-based standardized protocols when possible Independent double checks for high-risk situations Education for providers and staff Investigate extreme hypo- and hyperglycemia, with feedback to involved providers/staff

T1/2 (hr) use reversible? renal dose adjustmen t warfarin 40 PO Vitamin K (slow) FFP (rapid) therapeuti c monitoring cost s no INR $ dabigatran 14 PO no yes none $$$ rivaroxaban 8.5 PO no yes none $$$ unfractionated heparin 1.5 subcut protamine no none $ enoxaparin 5-7 subcut protamine (partial) yes none $$ fondaparinux 20 subcut no yes none $$

Meaningful Use (MU) criteria require that every patient admitted to the hospital is considered for DVT/PE prophylaxis No prophylaxis is recommended for patients with an anticipated brief stay who will remain ambulatory during the majority of their stay (e.g. uncomplicated delivery). Provider has to document that patient meets the criteria for not requiring any prophylaxis For all other patients provider should consider thrombosis risk and bleeding risk, and decide on the use of mechanical prophylaxis, pharmacologic prophylaxis, or a combination of both.

Mechanical: Graduated Compression Stockings: no high-quality data to support their effectiveness Sequential Compression Devices: moderate quality data for some efficacy, however several studies (including one at TNMC) show that in many cases not worn for the required number of hours Pharmacologic For most patients in an in-patient environment (where rapid change in clinical condition is common) the preferred agent is either unfractionated heparin or enoxaparin, because of the relatively short half-life, reversibility, proven efficacy, and costs

T1/2 (hr) use reversible? renal dose adjustmen t therapeuti c monitoring argatroban 0.5 IV FFP no aptt $$$ bivalirudin 0.5 IV FFP yes aptt $$$ unfractionated heparin 1.5 IV protamine no aptt or anti-xa enoxaparin 5-7 subcut protamine (partial) cost s yes none $$ fondaparinux 20 subcut no yes none $$ $ Although warfarin can be used for treatment of DVT/PE, and is often started at the same time as initial IV or subcut therapy, the time required to achieve a therapeutic INR and the long half-life make warfarin less attractive as a treatment option in the acute care setting.

Because of it s short half-life, easy reversibility, and low costs, IV unfractionated heparin remains the work horse for treatment of most newly diagnosed DVT/PE Because of it s narrow therapeutic window, nonlinear pharmacokinetics, and non-specific mechanism of action unfractionated heparin also remains a significant medication safety risk

1. UFH for continuous IV infusion should be ordered in a weight based fashion All heparin dosing guidelines (both FDA approved and non-fda approved indications) are weight based Pharmacokinetics is non-linear: a fixed dose of heparin will not predictably result in a fixed response Allows for uniform use of smart pump drug libraries Non weight-based dosing for small and pediatric patients is dangerous!

2. UFH administered by continuous IV infusion requires laboratory monitoring Anti-Xa assay (heparin assay). This is the gold standard used to define a therapeutic aptt aptt. Therapeutic aptt is assay dependent! ACT. Not suitable for use in monitoring DVT/PE therapy, most useful for monitoring brief infusions aimed at achieving high levels of heparin (graded response for heparin levels 1-5 units/ml) The heparin assay is the only test that is useful in situations where the aptt is prolonged for reasons unrelated to heparin administration (anti-phospholipid antibodies, DIC, congenital coagulation factor deficiency, etc.)

Anti-Xa assay is gold standard: therapeutic aptt is defined as aptt that corresponds to anti-xa level of 0.3-0.7 units/ml six hours after start of UFH administration Anti-Xa assay less sensitive to some confounders that can affect aptt Presence of lupus anticoagulant, coagulation factor deficiency, or coagulation factor inhibitor Heparin resistance (usually due to high levels of FVIII, often in patients with high levels of inflammatory cytokines)

3. Use a standard order set whenever possible - Standard order sets are available within OneChart for treatment of DVT/PE with continuous infusion of UFH, and for continuous infusion of UFH for patients with an acute coronary syndrome

Achieving therapeutic anticoagulation within 24 hours of starting UFH improves outcomes (recurrent/progressive DVT/PE, death from PE, post-thrombotic syndrome) when treating DVT/PE 1 Use of algorithm that uses weight based heparin dosing + standardized dose adjustments more likely to achieve therapeutic anticoagulation in first 24 hours 2 Exceptions might be necessary for patients with high bleeding risk (thrombocytopenia, additional anti-platelet agents, etc.) 1. Hull et al. Arch Intern Med 1992; 152: 1589 2. Raschke et al. Ann Intern Med 1993; 119: 874

4. Other laboratory parameters to monitor All patients receiving unfractionated heparin should have a platelet count obtained prior to heparin treatment, and should have their platelet count checked regularly to detect possible heparin-induced thrombocytopenia (HIT) Regular monitoring of hemoglobin levels is recommended for all hospitalized patients receiving therapeutic anticoagulation If the aptt wil be used for therapeutic monitoring it should be checked prior to heparin administration to confirm that it is within the normal range. An abnormal aptt prior to heparin administration indicates a concurrent condition, and use of the heparin assay is recommended for therapeutic monitoring.

Most patients receive additional agents that affect coagulation system (anti-platelet agents, GPIIb/IIIa inhibitors, etc); therefore doses and therapeutic targets generally lower than for PE/DVT Bleeding risks often higher because of concomitant anticoagulants Use of standard doses with nomograms for dose adjustments not shown to directly affect outcome (survival, recurrent MI, bleeding), but most studies are preceding modern interventions Because most studies using UFH are older, almost all studies used aptt for monitoring and it is therefore not possible to firmly recommend a particular anti-xa level for optimal therapy

Unfractionated heparin is often used for other indications, such as maintenance of line or device patency, prevention of arterial thrombosis after device placement or thrombolysis, etc. A dose of 5 units/kg/hour is often used to prevent clotting of devices or extracorporeal circuits There are no evidence-based protocols or nomograms that can guide clinicians in decisions about dosing, dose adjustment, etc. Physicians will have to use clinical judgment, and will have to decide on an individual basis if therapeutic anticoagulation is desired, and what therapeutic target to aim for. The 4 basics of safe heparin administration still apply! The One Chart order set xxx should be used for this purpose

Use of anticoagulants other than heparin or enoxaparin may be required for specific indications There are no studies supporting the use of a specific dose-adjustment algorithm with therapeutic use of argatroban or bivalirudin. General recommendations are available and incorporated in the order sets, but individual patient adjustments might be necessary Consultation with a hematologist is highly recommended prior to starting therapeutic anticoagulation with argatroban or bivalirudin.

Hematology-oncology consultation widely available and strongly recommended for complex cases Dedicated anticoagulation pharmacist Brian Trevarrow available for assistance with ordering, dosing, therapeutic monitoring, etc. Phone: 552-3088 Pager: 402-888-3424

A 67-year-old man with known Factor XII deficiency (hemophilia C) is diagnosed with an acute iliac vein thrombosis. His baseline laboratory studies include: PT = 12.4 sec. (normal 12.0 15.1 sec.) INR = 1.1 (normal 0.8 1.2) aptt = 63 sec. (normal 22 36 sec.) You want to treat him with intravenous UFH. What test should be used for laboratory monitoring? A. aptt B. ACT C. aptt after infusion of 4 units FFP D. anti-xa (heparin assay)

D: anti-xa (heparin assay) This patient has a prolonged aptt due to his underlying coagulation factor deficiency, therefore the usual therapeutic aptt interval does not apply to this patient The ACT is not suitable to monitor heparin effects at the doses commonly used to treat DVT/PE Infusion of fresh frozen plasma might temporarily correct the aptt, but the effect will only last for a few hours.

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Hospital hyperglycemia Stress hyperglycemia A1C value >6.5% Hypoglycemia Severe hypoglycemia Any BG >140 mg/dl Elevations in blood glucose levels that occur in patients with no prior history of diabetes and A1C levels that are not significantly elevated (<6.5%) Suggestive of prior history of diabetes Any BG <70 mg/dl Any BG <40 mg/dl 33

Maintain fasting and preprandial BG <140 mg/dl Modify therapy when BG <100 mg/dl to avoid risk of hypoglycemia Maintain random BG <180 mg/dl More stringent targets may be appropriate in stable patients with previous tight glycemic control Less stringent targets may be appropriate in terminally ill patients or in patients with severe comorbidities Moghissi ES, et al. Endocrine Pract. 2009;15:353-369. Umpierrez GE, et al. J Clin Endocrinol Metab. 2012;97:16-38. 34

Antihyperglycemic Therapy SC Insulin Recommended for most medical-surgical patients OADs Not generally recommended Continuous IV Infusion Selected medical-surgical patients Moghissi ES, et al. Endocrine Pract. 2009;15:353-369. Umpierrez GE, et al. J Clin Endocrinol Metab. 2012;97:16-38. Smiley D, et al. J Hosp Med. 2010;5:212-217. 35

Insulin therapy preferred regardless of type of diabetes Discontinue noninsulin agents at hospital admission of most patients with type 2 diabetes with acute illness Use scheduled SC insulin with basal, nutritional, and correction components Modify insulin dose in patients treated with insulin before admission to reduce risk for hypoglycemia and hyperglycemia Avoid prolonged therapy with sliding scale insulin alone Umpierrez GE, et al. J Clin Endocrinol Metab. 2012;97:16-38. 36

Basal insulin Nutritional (prandial) insulin Correction insulin Controls blood glucose in the fasting state Detemir (Levemir), glargine (Lantus), NPH Blunts the rise in blood glucose following nutritional intake (meals, IV dextrose, enteral/parenteral nutrition) Rapid-acting: aspart (NovoLog), glulisine (Apidra), lispro (Humalog) Short-acting: regular (Humulin, Novolin) Corrects hyperglycemia due to mismatch of nutritional intake and/or illness-related factors and scheduled insulin administration 37

Insulin Onset Peak Duration Nutritional Rapid-acting analog (aspart, glulisine, lispro) 5-15 min 1-2 hours 4-6 hours Regular 30-60 min 2-3 hours 6-10 hours Basal Detemir 2 hours Relatively peakless 16-24 hours Glargine 2-4 hours Relatively peakless 20-24 hours NPH 2-4 hours 4-10 hours 12-18 hours Hirsch I. N Engl J Med. 2005;352:174-183. Porcellati F, et al. Diabetes Care. 2007;30:2447-2552. 38

Obtain patient weight in kg Calculate total daily dose (TDD) as 0.2-0.4 units per kg/day Choose the dosing schedule Give 50%-60% of TDD as basal insulin Give 40%-50% of TDD as nutritional insulin Use correction insulin for BG above goal range Adjust according to results of bedside glucose monitoring Adjust dose for NPO status or changes in clinical status 39

Umpierrez GE, et al. Diabetes Care. 2007;30:2181-2186. 40

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Blood glucose target: 140-180 mg/dl Intravenous insulin infusion prefered Hypoglycemia Reassess the regimen if blood glucose level is <100 mg/dl Modify the regimen if blood glucose level is <70 mg/dl Moghissi ES, et al. Endocr Pract. 2009;15:353-369. 43

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Which patients on IV insulin will need a transition to scheduled SC insulin? Type 1 DM Type 2 DM on insulin prior to admission Type 2 DM (or new hyperglycemia) requiring 2 units/hour of insulin Umpierrez G, et al. J Clin Endocrinol Metab. 2012;97:16-38. 45

IV insulin should be transitioned to SC basal bolus insulin therapy When patient begins to eat and BG levels are stable What are the concomitant therapies? Glucocorticoids? Inotropes? Vasoconstrictors? Because of short half-life of IV insulin, SC basal insulin should be administered at least 1-2 hours prior to discontinuing the drip Umpierrez G, et al. J Clin Endocrinol Metab. 2012;97:16-38. 46

Umpierrez G, et al. J Clin Endocrinol Metab. 2012;97:16-38. 47

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1. Basal + correction insulin [Detemir or glargine QD or NPH BID] + [regular or rapid-acting analogue] 2. Basal + fixed dose nutritional + correction insulin [Detemir or glargine QD or NPH BID] + [regular or rapid-acting analogue Q6 h] + [regular or rapid-acting analogue as needed] 50:50 ratio 50

Continuous EN Basal: 40%-50% of TDD as long- or intermediate-acting insulin given once or twice a day Short acting 50%-60% of TDD given every 6 h Cycled EN Intermediate-acting insulin given together with a rapid- or short-acting insulin with start of tube feed Rapid- or short-acting insulin administered every 4-6 hours for duration of EN administration Correction insulin given for BG above goal range Bolus enteral nutrition Rapid-acting analog or short-acting insulin given prior to each bolus BG, blood glucose; EN, enteral; TDD, total daily dose of insulin. 51

1. Calculate total carbohydrate calories being given as tube feeds 2. Assess BG every 1 h 3. If BG <100 mg/dl, give dextrose as D5W or D10W IV Example 100cc=5g Patient receiving 80 cc/h of Jevity enterally Jevity = 240 cc/8 oz can, containing 36.5 g carb 1 cc Jevity 0.15 g (150 mg) carbohydrate @ 80 cc/h 12 g Give 120 cc/h D10W or 240 cc/h D5W 100cc=10g 52

Issue: Continuous IV delivery of high concentrations of dextrose (20-25 gm/100 cc) Solutions: 1. Basal + correction insulin [Detemir or glargine QD or NPH BID] + [regular or rapid-acting analogue] 2. Basal + fixed dose nutritional + correction insulin [Detemir or glargine QD or NPH BID] + [regular or rapid-acting analogue Q6 h] + [regular or rapid-acting analogue as needed] 1. Regular insulin in TPN bag may be safest approach Limited flexibility (wait 24-48 h for next bag) Not appropriate for type 1 diabetes 50:50 ratio 53

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Patients without prior diabetes or hyperglycemia or those with diabetes controlled with oral agents Begin BG monitoring with low-dose correction insulin scale administered prior to meals Patients previously treated with insulin Increase total daily dose by 20% to 40% with start of high-dose steroid therapy Increase correction insulin by 1 step (low to moderate dose) Adjust insulin as needed to maintain glycemic control (with caution during steroid tapers) 55

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Patients on basal or basal-bolus insulin Give ~50% of usual NPH dose that morning or ~80% of usual dose of NPH, glargine, or detemir the night before Goal: Avoid hypoglycemia during NPO periods but also prevent presurgical BG >180 mg/dl if possible Patients on premix insulin (70/30 or 75/25) Give 1/3 of total dose as NPH only prior to procedure Patients undergoing prolonged procedures (eg, CABG) Hold SC insulin and start IV insulin infusion (which will also be needed post-op) 57

You are rounding in the ICU. Your patient is doing well, extubated, on no pressors or steroids, tolerating diet. He is on the insulin drip and needs to be switched to SC insulin. His insulin requirement was variable over the past few days when he was sick and varied between 60 80 Units daily. Patient has received an average of 2 U/h IV during previous 6 h. How will you transition him from IV to SC therapy?

a) sliding scale regular insulin b) 19 Units of Glargine and 6 units of Aspart with meals and correction insulin dose dose level 1 (which assumes that 1 unit of insulin will decrease blood sugar for ~ 50 points) c) 40 Units of glargine d) 38 units of Glargine and correction insulin dose level 1 ( which assumes 1 unit of insulin will decrease blood sugar for ~ 50 points)

Example: Patient has received an average of 2 U/h IV during previous 6 h. Recommended doses are as follows: SC TDD ( total daily dose) is 80% of 24-h insulin requirement: 80% of (2 U/h x 24) = 38 U Basal dose is 50% of SC TDD: 50% of 38 U = 19 U of long-lasting analogue Bolus total dose is 50% of SC TDD: 50% of 38 U = 19 U of total prandial rapid-acting analogue or ~6 U with each meal Correction dose is actual BG minus target BG divided by the C ( correction factor) CF ( an estimate of how much will one unit of insulin bring the sugar down) CF equal to 1700 divided by TDD: CF = 1700 38 = ~40 mg/dl Correction dose = (BG - 100) 40 BG, blood glucose; CF, correction factor; IV, intravenous; SC, subcutaneous; TDD, total daily dose. Bode BW, et al. Endocr Pract. 2004;10(suppl 2):71-80. 60