The document discusses sepsis treatment bundles which include early goal directed therapy, corticosteroids, antibiotics, ARDSnet ventilator management, stress ulcer prophylaxis, deep vein thrombosis prophylaxis, and Drotrecogin alpha. It provides details on the components, goals, and guidelines for each bundle element aimed at improving outcomes for patients with sepsis.

1. Sepsis Treatment Members of the Midwest Critical Care Collaborative Led by: W. Christopher Bandy, MD Katie Burenheide, PharmD

2. Objectives Reviewing Sepsis Bundle Management Early Goal Directive Therapy Corticosteroids Antibiotics ARDSnet Stress Ulcer Prophylaxis Deep Vein Thrombosis Drotrecogin alpha (Xigris  )

3. What is a Bundle? Group of interventions that when performed together to treat a disease process results in better outcome then when performed individually Each component of the bundle should have a level of evidence-based research supporting its inclusion

4. Bundle Examples Sepsis Bundle Early Goal Directed Therapy Stress Ulcer Prophylaxis Deep Vein Thrombosis Prophylaxis Aggressive oral hygeine ARDsNet Steroids Adequate Glycemic Control Ventilator Associated Pneumonia (VAP) Bundle Head of bed > 30 degrees Ventilator Weaning Sedation Scale Use of Evac endotracheal Tube Aggressive oral hygiene Oral gastric tubes Stress Ulcer prophylaxis

5. Adapted from Univ of Ks. Hospital

6. Early Goal Directed Therapy: Adequate Resuscitation The Key to Hypoperfusion/Hypotension Management due to Sepsis!

7. EARLY GOAL DIRECTED THERAPY (within 6 hours of diagnosis) SvO2 capable central line or pulmonary artery catheter placement and arterial line are required immediately upon diagnosis of sepsis. CVP 8-12 mmHg Mean arterial pressure (MAP)  65 mmHg SBP  90 mmHg SvO2 > 70% UOP greater than 0.5mL/kg/hr

8. Optimization Of Central Venous Pressure (CVP) Check CVP. CVP <4 mmHg: Give albumin 5%, 250 ml X 1 CVP < 8 mmHg: Administer 500 ml, NS bolus. Recheck CVP every 15 minutes and repeat 500ml NS bolus q 15 min times 3 doses until CVP is 8-12 mmHg. Call physician if further fluid resuscitation required. Target goal CVP of 8-12 mmHg (or 12-16 mmHg if on mechanical ventilation) achieved: Continue NS at 2 mL/kg/hr to maintain CVP of 8-12 mmHg. Continue to OPTIMIZATION OF MAP

9. Optimization of Mean Arterial Pressure (MAP) Check MAP. MAP < 65 mmHg, give vasopressor to maintain a MAP > 65 mmHg. Norepinephrine 2-20 mcg/min; THEN Dopamine 5-20 mcg/kg/min; THEN Phenylephrine 40-200 mcg/minute; THEN preferred if HR >120 beats/minute Vasopressin 0.01-0.06 units/min; THEN If on another vasopressor; Epinephrine 1-10 mcg/min May increase lactate levels. When goal MAP of > 65 mmHg is achieved continue to OPTIMIZATION OF SvO2.

10. Optimization of Mean Arterial Pressure (MAP) Additional Tidbits: Ask physician if next vasopressor should be added or if it replaces a previous vasopressor. Pharmacy: Maximum concentration on all vasopressor drips.

11. Optimization of SvO2 (Mixed venous O2 Sat) Check SvO2. SvO2 < 70% and Hg is less than 10 grams: Transfuse packed red blood cells until Hg is > 10 grams and recheck SvO2 and CBC after transfusion. SvO2 is less than 70% and Hg is > 10 grams : Infuse dobutamine 2.5mcg/kg/min and increase every 30 minutes until SvO2 is at least 70%. Maximum dose of dobutamine not to exceed 20 mcg/kg/min. (Usual dose 2.5-10 mcg/kg/min) SvO2 is > 70%: Early goal directed therapy is complete.

12. EARLY GOAL DIRECTED THERAPY (within 6 hours of diagnosis) Reassess Each Step Every 30 Minutes To Maintain Optimization Goals.

13. Monitoring Lactate Levels During Resuscitation

14. Lactate Measurements Hyperlactatemia is typically present in patients with severe sepsis or septic shock and may be secondary to anaerobic metabolism due to hypoperfusion. The prognostic value of raised blood lactate levels has been well established in septic shock patients , particularly if the high levels persist. http://www.ihi.org/IHI/Topics/CriticalCare/Sepsis/Changes/IndividualChanges/SerumLactateMeasured.htm

15. Lactate Measurements In addition, blood lactate levels have been shown to have greater prognostic value than oxygen-derived variables. Obtaining serum lactate is essential to identifying tissue hypoperfusion in patients who are not yet hypotensive but who are at risk for septic shock. http://www.ihi.org/IHI/Topics/CriticalCare/Sepsis/Changes/IndividualChanges/SerumLactateMeasured.htm

16. Bundle Management: ARDSnet Ventilator Management

17. Rationale Patients with sepsis are at increased risk for developing acute respiratory failure, and most patients with severe sepsis and septic shock will require endotracheal intubation and mechanical ventilation. High tidal volumes that are coupled with high plateau pressures should be avoided in acute lung injury (ALI)/ acute respiratory distress syndrome (ARDS). http://www.ihi.org/IHI/Topics/CriticalCare/Sepsis/Changes/IndividualChanges/PreventExcessiveInspiratoryPlateauPressures.htm

18. Ventilator Settings Mode: Assist Control SIMV Tidal Volume 6-8 ml/kg; Adjust to keep P pl <30 cm H 2 O Rate Adjust to keep P a CO 2  35 PEEP 5-15 cm H 2 O Adjust to keep SpO 2 > 92% and P pl <30 cm H 2 O FiO2 100% Titrate to 60% keeping SpO 2 >92%)

19. Other Respiratory Management Measures NTS every 6 hours and PRN X 24 hours Chest percussion/postural drainage (CPPD) Bronchodilators Albuterol 2.5 mg in 3 ml NS nebulized every 4-8 hours Ipratropium (Atrovent) 0.5 mg nebulized every 6-8 hours (may be given with albuterol)

20. Bundle Management: Broad-Spectrum Antibiotics

21. Suspect MRSA: Vancomycin 1000 mg IV Q12H Trough after third dose The American Thoracic Society and Infectious Disease Society of America advocate targeting higher vancomycin trough concentrations in pneumonia and recommend vancomycin trough levels between 15-20  g/mL. If Vancomycin allergy Linezolid (Zyvox) 600 mg IV Q12H Suspect Fungal Infection Fluconazole (Diflucan) 800 mg IV X1 dose, then 400 mg IV daily

22. Life-Threatening & etiology unclear (suspect intra-abdominal or skin source) Meropenem (Merrem) 500 mg IV Q6H If carbapenem allergy: Levofloxacin (Levaquin) 750 mg IV daily + metronidazole (Flagyl) 500 mg IV Q8H Vancomycin 1 gram IV Q12H If vancomycin allergy: linezolid (Zyvox) 600 mg IV Q12H

23. Biliary Source: Ampicillin/sublactam (Unasyn) 3 grams IV Q6H If PCN allergy Levofloxacin (Levaquin) 750 mg IV Daily + Metronidazole (Flagyl) 500 mg IV Q8H May need an antifungal agent. Intrabdominal source: Meropenem (Merrem) 500 mg IV Q6H If carbapenem allergy: Levofloxacin (Levaquin) 750 mg IV Daily + Metronidazole (Flagyl) 500 mg IV Q8H

24. Petechial rash: Ceftriaxone (Rocephin) 2 grams IV Q12H Urinary Source: Piperacillin/tazobactam ( Zosyn) 4.5 grams IV Q8H If penicillin allergy: Levofloxacin (Levaquin) 750 mg IV daily

25. Pulmonary Source: Piperacillin/tazobactram (Zosyn) 4.5 grams IV Every 6 hours + Levofloxacin (Levaquin) 750 mg IV Daily If penicillin allergy: Levofloxacin (Levaquin) 750 mg IV Daily + tobramycin pharmacy to dose

26. Bundle Management: Blood Glucose Control

27. Rationale: Adequate blood sugar management reduces Blood stream infections Prolonged inflammation Acute renal failure requiring dialysis or hemofiltration Critical illness polyneuropathy Transfusion requirements Prolonged mechanical ventilation Intensive care length of stay Mortality from multiple-organ failure with sepsis regardless of whether there was a history of diabetes or hyperglycemia.

28. American College Of Endocrinology And American Diabetes Association Consensus Statement Critically Ill patients – recommend insulin infusion and converting patient to subcutaneous insulin when able to. “ Sliding Scale is not recommended” – especially as the sole type of insulin therapy.

29. American College Of Endocrinology And American Diabetes Association Consensus Statement Instead of sliding scale, recommend calling additional insulin needed with regular or Humalog/Novolog “correction insulin”. Recommend basal replacement insulin with NPH, Lantus or Levemir with additional correction insulin.

30. Surviving Sepsis Campaign Recommends Following initial stabilization of patients with severe sepsis, blood glucose should be maintained < 150 mg/dL (8.3 mmol/L).

31. Bundle Management Corticosteroids

32. Steroids Rationale IV corticosteroids recommended in patients with septic shock who despite adequate fluid replacement require vasopressor therapy to maintain adequate blood pressure. Mineralocorticoid Effects Recommended Hydrocortisone IV 100mg every 8 hours Fludrocortisone 0.05mg PO/NG daily in addition to IV hydrocortisone.

33. Cortisol Levels – Draw Baseline If random cortisol >25 mcg/d D/C Hydrocortisone and fludrocortisone If random cortisol 15-25 mcg/dl Initiate Cosyntropin Stimulation test Administer 0.25 mg of cosyntropin Repeat cortisol levels every 30 minutes X 2 and 6 hours after cosyntropin Normal response = cortisol level doubles in reponse to cosyntropin  D/C all steroid Adrenal insufficiency = serum cortisol levels fail to rise more than 9 mcg/dl  Continue all steroids If random cortisol < 15 mcg/dl Continue hydrocortisone and fludrocortisone

34. Discontinue steroids once patient is off vasopressors

35. Bundle Management: Stress Ulcer Prophylaxis

36. Stress Ulcer Prophylaxis Medications (Either) H 2 receptor antagonist Famotidine (Pepcid) 20 mg IV BID Watch Platelets! Can cause/worsen thrombocytopenia Proton Pump Inhibitor Esomeprazole (Nexium) 40 mg IV Daily

37. Bundle Management: Deep Vein Thrombosis Prophylaxis

38. Deep Vein Prophylaxis Mechanical Sequential Compression devices Foot Pumps Inferior Vena Cava filter (IVC) Medications Unfractionated Heparin 5000 units SQ Q8H Enoxaparin (Lovenox) 40 mg SQ Daily or 30 mg SQ BID

39. Bundle Management: Drotrecogin alpha (Xigris  )

40. Drotrecogin- α Mechanism of Action Recombinant form of human activated protein C Possesses profibrinolytic, antithrombotic, and antiinflammatory activities which may abrogate many systemic responses seen in septic patients Activated protein C levels are reduced in septic patients

41. Drotrecogin alpha (Xigris  ) Criteria for use SIRS Criteria (Must have at least 3) Temperature Heart rate Respiratory rate WBC Organ Dysfunction (Must have at least 1) Cardiovascular Renal Respiratory Hematological Unexplained Metabolic Acidosis

42. Contraindications EXCLUSION CRITERIA (Patients must NOT meet ANY of the following criteria. Double check with prescribing physician if any checked criteria.) • Age ≤ 18 • Life expectancy < 28 days (Due to end-stage or advanced disease) • Active internal bleeding • Hemorrhagic stroke within 3 months • Intracranial or spinal surgery within 2 months • Severe head trauma within 2 months • Trauma with increased risk of life-threatening bleeding • Epidural catheter in place • Intracranial neoplasm or evidence of cerebral herniation or mass lesion RELATIVE CONTRAINDICATIONS (Risk should outweighed benefits. Patients not included in studies.) • Pregnancy • Breastfeeding • Systemic thrombolytics < 3 days prior • Glycoprotein IIb/IIIa antagonists < 7 days prior • Oral anticoagulants < 7 days prior • Aspirin > 650 mg/day or oral platelets inhibitors < 7 days prior • Ischemic stroke within 3 months • Intracranial arteriovenous malformation aneurysm • Known bleeding diathesis • INR > 3 • Platelets <30,000 • Gastrointestinal bleed with 6 weeks • Chronic severe hepatic disease • Major surgery within 12 hours • Concurrent therapeutic dosing of heparin to treat active thrombotic or embolic event

43. Drotrecogin- α Dosing For patients < 135 kg: Drotrecogin alpha 24mcg/kg/hour continuous IV infusion X 96 hours based on total body weight For patients > 135 kg: Drotrecogin alpha 24mcg/kg/hour continuous IV infusion X 96 hours based on adjusted body weight

44. Trouble Shooting Percutaneous Procedure Hold Drotrecogin Alpha (Xigris) infusion 2 hours before and after any percutaneous procedure. Major Surgery Hold Drotrecogin Alpha (Xigris) infusion 2 hours before and 12 hours after major surgery.

45. Treating Sepsis Management Time is Crucial – Just like……… Trauma Golden hour! Myocardial Infarction Time is tissue! Chain of survival Door to balloon time Neurology Time is brain! Sepsis Time is organ function! Time to ▲ “mentality”

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47. References – Cont’d ACE/ADA Task Force on Inpatient Diabetes. Endocrine Practice 2006 12(4):459-468. http://www.aace.com/meetings/consensus/IIDC/IDGC0731.pdf#search=%22american%20college%20of%20endocrinology%20consensus%20statement%202006%22 Orlando Regional HealthCare. Hyperglycemic Control in Critically Ill. http://www.surgicalcriticalcare.net/Guidelines/glucose_control.pdf G Umpierrez & G Maynard. Glycemic Chaos (not glycemic control) still the rule for inpatient care: how do we stop the insanity?” Society of Hospital Medicine 2006 1(3): 141-144. A Malhota. Intensive Insulin in Intensive Care. New England Journal of Medicine 2006 354(5): 516-518. JS Krinsley & RL Jones. Cost analysis of intensive glycemic control in critically ill adult patients. Chest 2006; 129:644-650. M Brownlee & IB Hirsch. Glycemic Variability: a hemoglobin A1C-Indepented Risk Factor for diabetic complications. JAMA 2006; 295(14) 1707-1708. G Van den Berghe, A Wilmer, et al. Intensive Insulin Therapy in the Medical ICU. 2006; 354(5): 449-61.