Sepsis Treatment


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Sepsis Treatment

  1. 1. Sepsis Treatment Members of the Midwest Critical Care Collaborative Led by: W. Christopher Bandy, MD Katie Burenheide, PharmD
  2. 2. Objectives <ul><li>Reviewing Sepsis Bundle Management </li></ul><ul><ul><li>Early Goal Directive Therapy </li></ul></ul><ul><ul><li>Corticosteroids </li></ul></ul><ul><ul><li>Antibiotics </li></ul></ul><ul><ul><li>ARDSnet </li></ul></ul><ul><ul><li>Stress Ulcer Prophylaxis </li></ul></ul><ul><ul><li>Deep Vein Thrombosis </li></ul></ul><ul><ul><li>Drotrecogin alpha (Xigris  ) </li></ul></ul>
  3. 3. What is a Bundle? <ul><li>Group of interventions that when performed together to treat a disease process results in better outcome then when performed individually </li></ul><ul><li>Each component of the bundle should have a level of evidence-based research supporting its inclusion </li></ul>
  4. 4. Bundle Examples <ul><li>Sepsis Bundle </li></ul><ul><li>Early Goal Directed Therapy </li></ul><ul><li>Stress Ulcer Prophylaxis </li></ul><ul><li>Deep Vein Thrombosis Prophylaxis </li></ul><ul><li>Aggressive oral hygeine </li></ul><ul><li>ARDsNet </li></ul><ul><li>Steroids </li></ul><ul><li>Adequate Glycemic Control </li></ul><ul><li>Ventilator Associated Pneumonia (VAP) Bundle </li></ul><ul><li>Head of bed > 30 degrees </li></ul><ul><li>Ventilator Weaning </li></ul><ul><li>Sedation Scale </li></ul><ul><li>Use of Evac endotracheal Tube </li></ul><ul><li>Aggressive oral hygiene </li></ul><ul><li>Oral gastric tubes </li></ul><ul><li>Stress Ulcer prophylaxis </li></ul>
  5. 5. Adapted from Univ of Ks. Hospital
  6. 6. Early Goal Directed Therapy: Adequate Resuscitation The Key to Hypoperfusion/Hypotension Management due to Sepsis!
  7. 7. EARLY GOAL DIRECTED THERAPY (within 6 hours of diagnosis) <ul><li>SvO2 capable central line or pulmonary artery catheter placement and arterial line are required immediately upon diagnosis of sepsis. </li></ul><ul><ul><li>CVP 8-12 mmHg </li></ul></ul><ul><ul><li>Mean arterial pressure (MAP)  65 mmHg </li></ul></ul><ul><ul><li>SBP  90 mmHg </li></ul></ul><ul><ul><li>SvO2 > 70% </li></ul></ul><ul><ul><li>UOP greater than 0.5mL/kg/hr </li></ul></ul>
  8. 8. Optimization Of Central Venous Pressure (CVP) <ul><li>Check CVP. </li></ul><ul><ul><li>CVP <4 mmHg: Give albumin 5%, 250 ml X 1 </li></ul></ul><ul><ul><li>CVP < 8 mmHg: Administer 500 ml, NS bolus. </li></ul></ul><ul><ul><ul><li>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. </li></ul></ul></ul><ul><ul><li>Target goal CVP of 8-12 mmHg (or 12-16 mmHg if on mechanical ventilation) achieved: </li></ul></ul><ul><ul><ul><li>Continue NS at 2 mL/kg/hr to maintain CVP of 8-12 mmHg. </li></ul></ul></ul>Continue to OPTIMIZATION OF MAP
  9. 9. Optimization of Mean Arterial Pressure (MAP) <ul><li>Check MAP. </li></ul><ul><ul><li>MAP < 65 mmHg, give vasopressor to maintain a MAP > 65 mmHg. </li></ul></ul><ul><ul><ul><li>Norepinephrine 2-20 mcg/min; THEN </li></ul></ul></ul><ul><ul><ul><li>Dopamine 5-20 mcg/kg/min; THEN </li></ul></ul></ul><ul><ul><ul><li>Phenylephrine 40-200 mcg/minute; THEN </li></ul></ul></ul><ul><ul><ul><ul><li>preferred if HR >120 beats/minute </li></ul></ul></ul></ul><ul><ul><ul><li>Vasopressin 0.01-0.06 units/min; THEN </li></ul></ul></ul><ul><ul><ul><ul><li>If on another vasopressor; </li></ul></ul></ul></ul><ul><ul><ul><li>Epinephrine 1-10 mcg/min </li></ul></ul></ul><ul><ul><ul><ul><li>May increase lactate levels.  </li></ul></ul></ul></ul>When goal MAP of > 65 mmHg is achieved continue to OPTIMIZATION OF SvO2.
  10. 10. Optimization of Mean Arterial Pressure (MAP) <ul><li>Additional Tidbits: </li></ul><ul><ul><li>Ask physician if next vasopressor should be added or if it replaces a previous vasopressor. </li></ul></ul><ul><ul><li>Pharmacy: Maximum concentration on all vasopressor drips. </li></ul></ul>
  11. 11. Optimization of SvO2 (Mixed venous O2 Sat) <ul><li>Check SvO2. </li></ul><ul><ul><li>SvO2 < 70% and Hg is less than 10 grams: </li></ul></ul><ul><ul><ul><li>Transfuse packed red blood cells until Hg is > 10 grams and recheck SvO2 and CBC after transfusion. </li></ul></ul></ul><ul><ul><li>SvO2 is less than 70% and Hg is > 10 grams : </li></ul></ul><ul><ul><ul><li>Infuse dobutamine 2.5mcg/kg/min and increase every 30 minutes until SvO2 is at least 70%. </li></ul></ul></ul><ul><ul><ul><li>Maximum dose of dobutamine not to exceed 20 mcg/kg/min. (Usual dose 2.5-10 mcg/kg/min) </li></ul></ul></ul><ul><ul><li>SvO2 is > 70%: </li></ul></ul><ul><ul><ul><li>Early goal directed therapy is complete. </li></ul></ul></ul>
  12. 12. EARLY GOAL DIRECTED THERAPY (within 6 hours of diagnosis) <ul><li>Reassess Each Step Every </li></ul><ul><li>30 Minutes To Maintain </li></ul><ul><li>Optimization Goals. </li></ul>
  13. 13. Monitoring Lactate Levels During Resuscitation
  14. 14. Lactate Measurements <ul><li>Hyperlactatemia is typically present in patients with severe sepsis or septic shock and may be secondary to anaerobic metabolism due to hypoperfusion.  </li></ul><ul><li>The prognostic value of raised blood lactate levels has been well established in septic shock patients , particularly if the high levels persist. </li></ul><ul><li> </li></ul>
  15. 15. Lactate Measurements <ul><li>In addition, blood lactate levels have been shown to have greater prognostic value than oxygen-derived variables.   </li></ul><ul><li>Obtaining serum lactate is essential to identifying tissue hypoperfusion in patients who are not yet hypotensive but who are at risk for septic shock. </li></ul><ul><li> </li></ul>
  16. 16. Bundle Management: ARDSnet Ventilator Management
  17. 17. Rationale <ul><li>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.    </li></ul><ul><li>High tidal volumes that are coupled with high plateau pressures should be avoided in acute lung injury (ALI)/ acute respiratory distress syndrome (ARDS).   </li></ul><ul><li> </li></ul>
  18. 18. Ventilator Settings <ul><li>Mode: </li></ul><ul><ul><li>Assist Control </li></ul></ul><ul><ul><li>SIMV </li></ul></ul><ul><li>Tidal Volume </li></ul><ul><ul><li>6-8 ml/kg; Adjust to keep P pl <30 cm H 2 O </li></ul></ul><ul><li>Rate </li></ul><ul><ul><li>Adjust to keep P a CO 2  35 </li></ul></ul><ul><li>PEEP </li></ul><ul><ul><li>5-15 cm H 2 O </li></ul></ul><ul><ul><li>Adjust to keep </li></ul></ul><ul><ul><li>SpO 2 > 92% and </li></ul></ul><ul><ul><li>P pl <30 cm H 2 O </li></ul></ul><ul><li>FiO2 100% </li></ul><ul><ul><li>Titrate to 60% keeping SpO 2 >92%) </li></ul></ul>
  19. 19. Other Respiratory Management Measures <ul><li>NTS every 6 hours and PRN X 24 hours </li></ul><ul><li>Chest percussion/postural drainage (CPPD) </li></ul><ul><li>Bronchodilators </li></ul><ul><ul><li>Albuterol 2.5 mg in 3 ml NS nebulized every 4-8 hours </li></ul></ul><ul><ul><li>Ipratropium (Atrovent) 0.5 mg nebulized every 6-8 hours (may be given with albuterol) </li></ul></ul>
  20. 20. Bundle Management: Broad-Spectrum Antibiotics
  21. 21. <ul><li>Suspect MRSA: </li></ul><ul><ul><li>Vancomycin 1000 mg IV Q12H </li></ul></ul><ul><ul><ul><li>Trough after third dose </li></ul></ul></ul><ul><ul><ul><li>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. </li></ul></ul></ul><ul><ul><li>If Vancomycin allergy </li></ul></ul><ul><ul><ul><li>Linezolid (Zyvox) 600 mg IV Q12H </li></ul></ul></ul><ul><li>Suspect Fungal Infection </li></ul><ul><ul><li>Fluconazole (Diflucan) 800 mg IV X1 dose, then 400 mg IV daily </li></ul></ul>
  22. 22. <ul><li>Life-Threatening & etiology unclear (suspect intra-abdominal or skin source) </li></ul><ul><ul><li>Meropenem (Merrem) 500 mg IV Q6H </li></ul></ul><ul><ul><ul><li>If carbapenem allergy: </li></ul></ul></ul><ul><ul><ul><ul><li>Levofloxacin (Levaquin) 750 mg IV daily + metronidazole (Flagyl) 500 mg IV Q8H </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Vancomycin 1 gram IV Q12H </li></ul></ul></ul></ul><ul><ul><ul><ul><li>If vancomycin allergy: </li></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>linezolid (Zyvox) 600 mg IV Q12H </li></ul></ul></ul></ul></ul>
  23. 23. <ul><li>Biliary Source: </li></ul><ul><ul><li>Ampicillin/sublactam (Unasyn) 3 grams IV Q6H </li></ul></ul><ul><ul><li>If PCN allergy </li></ul></ul><ul><ul><ul><li>Levofloxacin (Levaquin) 750 mg IV Daily + Metronidazole (Flagyl) 500 mg IV Q8H </li></ul></ul></ul><ul><ul><li>May need an antifungal agent. </li></ul></ul><ul><li>Intrabdominal source: </li></ul><ul><ul><li>Meropenem (Merrem) 500 mg IV Q6H </li></ul></ul><ul><ul><li>If carbapenem allergy: </li></ul></ul><ul><ul><ul><li>Levofloxacin (Levaquin) 750 mg IV Daily + Metronidazole (Flagyl) 500 mg IV Q8H </li></ul></ul></ul>
  24. 24. <ul><li>Petechial rash: </li></ul><ul><ul><li>Ceftriaxone (Rocephin) 2 grams IV Q12H </li></ul></ul><ul><li>Urinary Source: </li></ul><ul><ul><li>Piperacillin/tazobactam ( Zosyn) 4.5 grams IV Q8H </li></ul></ul><ul><ul><li>If penicillin allergy: </li></ul></ul><ul><ul><ul><li>Levofloxacin (Levaquin) 750 mg IV daily </li></ul></ul></ul>
  25. 25. <ul><li>Pulmonary Source: </li></ul><ul><ul><li>Piperacillin/tazobactram (Zosyn) 4.5 grams IV Every 6 hours </li></ul></ul><ul><ul><li>+ Levofloxacin (Levaquin) 750 mg IV Daily </li></ul></ul><ul><ul><li>If penicillin allergy: </li></ul></ul><ul><ul><ul><li>Levofloxacin (Levaquin) 750 mg IV Daily + tobramycin pharmacy to dose </li></ul></ul></ul>
  26. 26. Bundle Management: Blood Glucose Control
  27. 27. Rationale: Adequate blood sugar management reduces <ul><li>Blood stream infections </li></ul><ul><li>Prolonged inflammation </li></ul><ul><li>Acute renal failure requiring dialysis or hemofiltration </li></ul><ul><li>Critical illness polyneuropathy </li></ul><ul><li>Transfusion requirements </li></ul><ul><li>Prolonged mechanical ventilation </li></ul><ul><li>Intensive care length of stay </li></ul><ul><li>Mortality from multiple-organ failure with sepsis regardless of whether there was a history of diabetes or hyperglycemia. </li></ul>
  28. 28. American College Of Endocrinology And American Diabetes Association Consensus Statement <ul><li>Critically Ill patients – recommend insulin infusion and converting patient to subcutaneous insulin when able to. </li></ul><ul><li>“ Sliding Scale is not recommended” – especially as the sole type of insulin therapy. </li></ul>
  29. 29. American College Of Endocrinology And American Diabetes Association Consensus Statement <ul><li>Instead of sliding scale, recommend calling additional insulin needed with regular or Humalog/Novolog “correction insulin”. </li></ul><ul><li>Recommend basal replacement insulin with NPH, Lantus or Levemir with additional correction insulin. </li></ul>
  30. 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. 31. Bundle Management Corticosteroids
  32. 32. Steroids <ul><li>Rationale </li></ul><ul><ul><li>IV corticosteroids recommended in patients with septic shock who despite adequate fluid replacement require vasopressor therapy to maintain adequate blood pressure. </li></ul></ul><ul><li>Mineralocorticoid Effects Recommended </li></ul><ul><ul><li>Hydrocortisone </li></ul></ul><ul><ul><ul><li>IV 100mg every 8 hours </li></ul></ul></ul><ul><ul><li>Fludrocortisone </li></ul></ul><ul><ul><ul><li>0.05mg PO/NG daily in addition to IV hydrocortisone. </li></ul></ul></ul>
  33. 33. Cortisol Levels – Draw Baseline <ul><li>If random cortisol >25 mcg/d </li></ul><ul><ul><li>D/C Hydrocortisone and fludrocortisone </li></ul></ul><ul><li>If random cortisol 15-25 mcg/dl </li></ul><ul><ul><li>Initiate Cosyntropin Stimulation test </li></ul></ul><ul><ul><ul><li>Administer 0.25 mg of cosyntropin </li></ul></ul></ul><ul><ul><ul><li>Repeat cortisol levels every 30 minutes X 2 and 6 hours after cosyntropin </li></ul></ul></ul><ul><ul><ul><li>Normal response = cortisol level doubles in reponse to cosyntropin  D/C all steroid </li></ul></ul></ul><ul><ul><ul><li>Adrenal insufficiency = serum cortisol levels fail to rise more than 9 mcg/dl  Continue all steroids </li></ul></ul></ul><ul><li>If random cortisol < 15 mcg/dl </li></ul><ul><ul><li>Continue hydrocortisone and fludrocortisone </li></ul></ul>
  34. 34. Discontinue steroids once patient is off vasopressors
  35. 35. Bundle Management: Stress Ulcer Prophylaxis
  36. 36. Stress Ulcer Prophylaxis <ul><li>Medications (Either) </li></ul><ul><ul><li>H 2 receptor antagonist </li></ul></ul><ul><ul><ul><li>Famotidine (Pepcid) 20 mg IV BID </li></ul></ul></ul><ul><ul><ul><ul><li>Watch Platelets! Can cause/worsen thrombocytopenia </li></ul></ul></ul></ul><ul><ul><li>Proton Pump Inhibitor </li></ul></ul><ul><ul><ul><li>Esomeprazole (Nexium) 40 mg IV Daily </li></ul></ul></ul>
  37. 37. Bundle Management: Deep Vein Thrombosis Prophylaxis
  38. 38. Deep Vein Prophylaxis <ul><li>Mechanical </li></ul><ul><ul><li>Sequential Compression devices </li></ul></ul><ul><ul><li>Foot Pumps </li></ul></ul><ul><ul><li>Inferior Vena Cava filter (IVC) </li></ul></ul><ul><li>Medications </li></ul><ul><ul><li>Unfractionated Heparin 5000 units SQ Q8H </li></ul></ul><ul><ul><li>Enoxaparin (Lovenox) </li></ul></ul><ul><ul><ul><li>40 mg SQ Daily or </li></ul></ul></ul><ul><ul><ul><li>30 mg SQ BID </li></ul></ul></ul>
  39. 39. Bundle Management: Drotrecogin alpha (Xigris  )
  40. 40. Drotrecogin- α Mechanism of Action <ul><li>Recombinant form of human activated protein C </li></ul><ul><ul><li>Possesses profibrinolytic, antithrombotic, and antiinflammatory activities which may abrogate many systemic responses seen in septic patients </li></ul></ul><ul><li>Activated protein C levels are reduced in septic patients </li></ul>
  41. 41. Drotrecogin alpha (Xigris  ) Criteria for use <ul><li>SIRS Criteria </li></ul><ul><li>(Must have at least 3) </li></ul><ul><ul><li>Temperature </li></ul></ul><ul><ul><li>Heart rate </li></ul></ul><ul><ul><li>Respiratory rate </li></ul></ul><ul><ul><li>WBC </li></ul></ul><ul><li>Organ Dysfunction </li></ul><ul><li>(Must have at least 1) </li></ul><ul><ul><li>Cardiovascular </li></ul></ul><ul><ul><li>Renal </li></ul></ul><ul><ul><li>Respiratory </li></ul></ul><ul><ul><li>Hematological </li></ul></ul><ul><ul><li>Unexplained Metabolic Acidosis </li></ul></ul>
  42. 42. Contraindications <ul><li>EXCLUSION CRITERIA </li></ul><ul><li>(Patients must NOT meet ANY of the following criteria. </li></ul><ul><li>Double check with prescribing physician if any checked criteria.) </li></ul><ul><li>• Age ≤ 18 </li></ul><ul><li>• Life expectancy < 28 days (Due to </li></ul><ul><li>end-stage or advanced disease) </li></ul><ul><li>• Active internal bleeding </li></ul><ul><li>• Hemorrhagic stroke within 3 months </li></ul><ul><li>• Intracranial or spinal surgery within </li></ul><ul><li>2 months </li></ul><ul><li>• Severe head trauma within </li></ul><ul><li>2 months </li></ul><ul><li>• Trauma with increased risk of </li></ul><ul><li>life-threatening bleeding </li></ul><ul><li>• Epidural catheter in place </li></ul><ul><li>• Intracranial neoplasm or evidence of </li></ul><ul><li>cerebral herniation or mass lesion </li></ul><ul><li>RELATIVE CONTRAINDICATIONS </li></ul><ul><li>(Risk should outweighed benefits. </li></ul><ul><li>Patients not included in studies.) </li></ul><ul><li>• Pregnancy </li></ul><ul><li>• Breastfeeding </li></ul><ul><li>• Systemic thrombolytics < 3 days prior </li></ul><ul><li>• Glycoprotein IIb/IIIa antagonists < 7 days prior </li></ul><ul><li>• Oral anticoagulants < 7 days prior </li></ul><ul><li>• Aspirin > 650 mg/day or oral platelets inhibitors </li></ul><ul><li>< 7 days prior </li></ul><ul><li>• Ischemic stroke within 3 months </li></ul><ul><li>• Intracranial arteriovenous malformation aneurysm </li></ul><ul><li>• Known bleeding diathesis </li></ul><ul><li>• INR > 3 </li></ul><ul><li>• Platelets <30,000 </li></ul><ul><li>• Gastrointestinal bleed with 6 weeks </li></ul><ul><li>• Chronic severe hepatic disease </li></ul><ul><li>• Major surgery within 12 hours </li></ul><ul><li>• Concurrent therapeutic dosing of heparin to treat </li></ul><ul><li>active thrombotic or embolic event </li></ul>
  43. 43. Drotrecogin- α Dosing <ul><li>For patients < 135 kg: </li></ul><ul><ul><li>Drotrecogin alpha 24mcg/kg/hour continuous IV infusion X 96 hours based on total body weight </li></ul></ul><ul><li>For patients > 135 kg: </li></ul><ul><ul><li>Drotrecogin alpha 24mcg/kg/hour continuous IV infusion X 96 hours based on adjusted body weight </li></ul></ul>
  44. 44. Trouble Shooting <ul><li>Percutaneous Procedure </li></ul><ul><ul><li>Hold Drotrecogin Alpha (Xigris) infusion 2 hours before and after any percutaneous procedure. </li></ul></ul><ul><li>Major Surgery </li></ul><ul><ul><li>Hold Drotrecogin Alpha (Xigris) infusion 2 hours before and 12 hours after major surgery. </li></ul></ul>
  45. 45. Treating Sepsis Management Time is Crucial – Just like……… <ul><li>Trauma </li></ul><ul><ul><li>Golden hour! </li></ul></ul><ul><li>Myocardial Infarction </li></ul><ul><ul><li>Time is tissue! </li></ul></ul><ul><ul><li>Chain of survival </li></ul></ul><ul><ul><li>Door to balloon time </li></ul></ul><ul><li>Neurology </li></ul><ul><ul><li>Time is brain! </li></ul></ul><ul><li>Sepsis </li></ul><ul><ul><li>Time is organ function! </li></ul></ul><ul><ul><li>Time to ▲ “mentality” </li></ul></ul>
  46. 46. References <ul><li>Rivers E, Nguyen B, et al. Early Goal-Directed Therapy in the Treatment of Severe Sepsis and Septic Shock. The Early Goal-Directed Therapy Collaborative Group. NEJM 2001; 354-1368:1377. </li></ul><ul><li>Rivers E, Nguyen B, et al. Stop Sepsis Tool kit. http:// / </li></ul><ul><li>  Angus DE et al; Epidemiology of severe sepsis in the United States: analysis of incidence, outcome and associated costs of care. Critical Care Medicine 2001; 29:1303-1310. </li></ul><ul><li>Surviving Sepsis Campaign Guidelines for management of severe sepsis and septic shock Care Med 2004 March;32(3):858-873 </li></ul><ul><li>  Kansas Critical Care Collaborative. </li></ul><ul><li>Sepsis Bundle. . 2005 </li></ul><ul><li>Dellinger RP, Carlet JM, Masur H, Gerlach H, al. e. Surviving sepsis campaign guidelines for management of severe sepsis and septic shock. Crit Care Med 2004; 32:858-72. </li></ul><ul><li>Gilber DN, Moellering RC, Eliopoulos GM & Sande Merle A. The Sanford Guide to Antimicrobial Therapy 2006. Antimicrobial Therapy Inc. </li></ul><ul><li>Eli Lilly Sepsis website. </li></ul><ul><li>Annane D, Sebille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. Jama 2002; 288:862-71. </li></ul><ul><li>Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001; 344:699-709. </li></ul><ul><li>Introduction to Cardiovascular Pharmacology. </li></ul>
  47. 47. References – Cont’d <ul><li>ACE/ADA Task Force on Inpatient Diabetes. Endocrine Practice 2006 12(4):459-468. </li></ul><ul><li>Orlando Regional HealthCare. Hyperglycemic Control in Critically Ill. </li></ul><ul><li>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. </li></ul><ul><li>A Malhota. Intensive Insulin in Intensive Care. New England Journal of Medicine 2006 354(5): 516-518. </li></ul><ul><li>JS Krinsley & RL Jones. Cost analysis of intensive glycemic control in critically ill adult patients. Chest 2006; 129:644-650. </li></ul><ul><li>M Brownlee & IB Hirsch. Glycemic Variability: a hemoglobin A1C-Indepented Risk Factor for diabetic complications. JAMA 2006; 295(14) 1707-1708. </li></ul><ul><li>G Van den Berghe, A Wilmer, et al. Intensive Insulin Therapy in the Medical ICU. 2006; 354(5): 449-61. </li></ul>