Sepsis TreatmentSepsis Treatment

Members of the Midwest Critical Care CollaborativeMembers of the Midwest Critical Care CollaborativeLed by:Led by:

W. Christopher Bandy, MDW. Christopher Bandy, MDKatie Burenheide, PharmDKatie Burenheide, PharmD

ObjectivesObjectives

• Reviewing Sepsis Bundle Management– Early Goal Directive Therapy– Corticosteroids– Antibiotics – ARDSnet– Stress Ulcer Prophylaxis– Deep Vein Thrombosis– Drotrecogin alpha (Xigris)

What is a Bundle?What is a Bundle?

• Group of interventions that when performed together to Group of interventions that when performed together to treat a disease process results in better outcome then treat a disease process results in better outcome then when performed individuallywhen performed individually

• Each component of the bundle should have a level of Each component of the bundle should have a level of evidence-based research supporting its inclusionevidence-based research supporting its inclusion

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

Adapted fromAdapted fromUniv of Ks. HospitalUniv of Ks. Hospital

Early Goal Directed Therapy: Early Goal Directed Therapy: Adequate ResuscitationAdequate Resuscitation

The Key to The Key to Hypoperfusion/Hypotension Hypoperfusion/Hypotension Management due to Sepsis!Management due to Sepsis!

EARLY GOAL DIRECTED THERAPY EARLY GOAL DIRECTED THERAPY

(within 6 hours of diagnosis)(within 6 hours of diagnosis) SvO2 capable central line or pulmonary artery SvO2 capable central line or pulmonary artery

catheter placement and arterial line are required catheter placement and arterial line are required immediately upon diagnosis of sepsis.immediately upon diagnosis of sepsis.• CVP 8-12 mmHgCVP 8-12 mmHg• Mean arterial pressure (MAP) Mean arterial pressure (MAP) 65 mmHg65 mmHg• SBP SBP 90 mmHg90 mmHg• SvO2 SvO2 >> 70% 70%• UOP greater than 0.5mL/kg/hrUOP greater than 0.5mL/kg/hr

Optimization Of Optimization Of Central Venous Pressure (CVP)Central Venous Pressure (CVP)

• Check CVP.Check CVP.– CVP <4 mmHg: Give albumin 5%, 250 ml X 1CVP <4 mmHg: Give albumin 5%, 250 ml X 1– CVP < 8 mmHg: Administer 500 ml, NS bolus.CVP < 8 mmHg: Administer 500 ml, NS bolus.

• Recheck CVP every 15 minutes and Recheck CVP every 15 minutes and repeat 500ml NS bolus repeat 500ml NS bolus q 15 min times 3 doses q 15 min times 3 doses until CVP is 8-12 mmHg. Call until CVP is 8-12 mmHg. Call physician if further fluid resuscitation required.physician if further fluid resuscitation required.

– Target goal CVP of 8-12 mmHg (or 12-16 mmHg if on Target goal CVP of 8-12 mmHg (or 12-16 mmHg if on mechanical ventilation) achieved: mechanical ventilation) achieved:

• Continue NS at 2 mL/kg/hr to maintain CVP of 8-12 mmHg.Continue NS at 2 mL/kg/hr to maintain CVP of 8-12 mmHg.

Continue to Continue to OPTIMIZATION OF MAPOPTIMIZATION OF MAP

Optimization ofOptimization ofMean Arterial Pressure (MAP)Mean Arterial Pressure (MAP)

• Check MAP.Check MAP.– MAP < 65 mmHg, give vasopressor to maintain a MAP < 65 mmHg, give vasopressor to maintain a

MAP MAP >> 65 mmHg. 65 mmHg.• Norepinephrine 2-20 mcg/min; THENNorepinephrine 2-20 mcg/min; THEN• Dopamine 5-20 mcg/kg/min; THENDopamine 5-20 mcg/kg/min; THEN• Phenylephrine 40-200 mcg/minute; THEN Phenylephrine 40-200 mcg/minute; THEN

– preferred if HR >120 beats/minutepreferred if HR >120 beats/minute

• Vasopressin 0.01-0.06 units/min; THENVasopressin 0.01-0.06 units/min; THEN– If on another vasopressor; If on another vasopressor;

• Epinephrine 1-10 mcg/min Epinephrine 1-10 mcg/min – May increase lactate levels. May increase lactate levels. 

When goal MAP of When goal MAP of >> 65 mmHg is achieved 65 mmHg is achieved continue to continue to OPTIMIZATION OF SvO2.OPTIMIZATION OF SvO2.

Optimization ofOptimization ofMean Arterial Pressure (MAP)Mean Arterial Pressure (MAP)

• Additional Tidbits:Additional Tidbits:– Ask physician if next vasopressor should be Ask physician if next vasopressor should be

added or if it replaces a previous vasopressor. added or if it replaces a previous vasopressor. – Pharmacy: Maximum concentration on all Pharmacy: Maximum concentration on all

vasopressor drips. vasopressor drips.

Optimization of SvO2 Optimization of SvO2 (Mixed venous O2 Sat)(Mixed venous O2 Sat)

Check SvO2.Check SvO2.– SvO2 < 70% and Hg is less than 10 grams: SvO2 < 70% and Hg is less than 10 grams:

• Transfuse packed red blood cells until Hg is Transfuse packed red blood cells until Hg is >> 10 grams 10 grams and recheck SvO2 and CBC after transfusion. and recheck SvO2 and CBC after transfusion.

– SvO2 is less than 70% and Hg is SvO2 is less than 70% and Hg is >>10 grams10 grams: : • Infuse dobutamine 2.5mcg/kg/min and increase every 30 Infuse dobutamine 2.5mcg/kg/min and increase every 30

minutes until SvO2 is at least 70%. minutes until SvO2 is at least 70%. Maximum dose of dobutamine not to exceed 20 Maximum dose of dobutamine not to exceed 20

mcg/kg/min. (Usual dose 2.5-10 mcg/kg/min)mcg/kg/min. (Usual dose 2.5-10 mcg/kg/min)

– SvO2 is SvO2 is >> 70%: 70%: • Early goal directed therapy is complete.Early goal directed therapy is complete.

EARLY GOAL DIRECTED THERAPY EARLY GOAL DIRECTED THERAPY

(within 6 hours of diagnosis)(within 6 hours of diagnosis)

Reassess Each Step Every Reassess Each Step Every

30 Minutes To Maintain30 Minutes To Maintain

Optimization Goals. Optimization Goals.

Monitoring Lactate Levels During Resuscitation

Lactate MeasurementsLactate Measurements

• Hyperlactatemia is typically present in Hyperlactatemia is typically present in patients with severe sepsis or septic shock patients with severe sepsis or septic shock and may be secondary to anaerobic and may be secondary to anaerobic metabolism due to hypoperfusion.  metabolism due to hypoperfusion. 

• The prognostic value of raised blood The prognostic value of raised blood lactate levels has been well established in lactate levels has been well established in septic shock patients , particularly if the septic shock patients , particularly if the high levels persist. high levels persist.

http://www.ihi.org/IHI/Topics/CriticalCare/Sepsis/Changes/IndividualChanges/SerumLactateMeasured.htm

Lactate MeasurementsLactate Measurements

• In addition, blood lactate levels have been In addition, blood lactate levels have been shown to have greater prognostic value than shown to have greater prognostic value than oxygen-derived variables.   oxygen-derived variables.  

• Obtaining serum lactate is essential to Obtaining serum lactate is essential to identifying tissue hypoperfusion in patients identifying tissue hypoperfusion in patients who are not yet hypotensive but who are at who are not yet hypotensive but who are at risk for septic shock.risk for septic shock.

http://www.ihi.org/IHI/Topics/CriticalCare/Sepsis/Changes/IndividualChanges/SerumLactateMeasured.htm

Bundle Management:ARDSnet Ventilator Management

RationaleRationale• Patients with sepsis are at increased risk for Patients with sepsis are at increased risk for

developing acute respiratory failure, and developing acute respiratory failure, and most patients with severe sepsis and septic most patients with severe sepsis and septic shock will require endotracheal intubation shock will require endotracheal intubation and mechanical ventilation.   and mechanical ventilation.   

• High tidal volumes that are coupled with High tidal volumes that are coupled with high plateau pressures should be avoided in high plateau pressures should be avoided in acute lung injury (ALI)/ acute respiratory acute lung injury (ALI)/ acute respiratory distress syndrome (ARDS).distress syndrome (ARDS).    

http://www.ihi.org/IHI/Topics/CriticalCare/Sepsis/Changes/IndividualChanges/PreventExcessiveInspiratoryPlateauPressures.htmhttp://www.ihi.org/IHI/Topics/CriticalCare/Sepsis/Changes/IndividualChanges/PreventExcessiveInspiratoryPlateauPressures.htm

Ventilator SettingsVentilator Settings• Mode: Mode:

– Assist ControlAssist Control– SIMV SIMV

• Tidal VolumeTidal Volume– 6-8 ml/kg; Adjust to 6-8 ml/kg; Adjust to

keep Pkeep Pplpl <30 cm H <30 cm H22OO

• RateRate– Adjust to keep PAdjust to keep PaaCOCO22

3535

• PEEPPEEP– 5-15 cm H5-15 cm H22OO

– Adjust to keep Adjust to keep

SpOSpO22 > 92% and > 92% and

PPplpl <30 cm H <30 cm H22OO

• FiO2 100%FiO2 100%– Titrate to 60% keeping Titrate to 60% keeping

SpOSpO22 >92%) >92%)

Other Respiratory Management Other Respiratory Management MeasuresMeasures

• NTS every 6 hours and PRN X 24 hours NTS every 6 hours and PRN X 24 hours • Chest percussion/postural drainage (CPPD) Chest percussion/postural drainage (CPPD) • BronchodilatorsBronchodilators

– Albuterol 2.5 mg in 3 ml NS nebulized every 4-8 hours Albuterol 2.5 mg in 3 ml NS nebulized every 4-8 hours – Ipratropium (Atrovent) 0.5 mg nebulized every 6-8 Ipratropium (Atrovent) 0.5 mg nebulized every 6-8

hours (may be given with albuterol)hours (may be given with albuterol)

Bundle Management: Bundle Management: Broad-Spectrum AntibioticsBroad-Spectrum Antibiotics

• 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

• 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

• 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

• 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

• 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

Bundle Management:Blood Glucose Control

Rationale:Rationale:Adequate blood sugar management reducesAdequate blood sugar management reduces

• Blood stream infections Blood stream infections • Prolonged inflammationProlonged inflammation• Acute renal failure Acute renal failure

requiring dialysis or requiring dialysis or hemofiltrationhemofiltration

• Critical illness Critical illness polyneuropathypolyneuropathy

• Transfusion Transfusion requirementsrequirements

• Prolonged mechanical Prolonged mechanical ventilationventilation

• Intensive care length of Intensive care length of staystay

• Mortality from multiple-Mortality from multiple-organ failure with sepsis organ failure with sepsis regardless of whether regardless of whether there was a history of there was a history of diabetes or diabetes or hyperglycemia.hyperglycemia.

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.

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.

Surviving Sepsis Campaign Surviving Sepsis Campaign RecommendsRecommends

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

Bundle ManagementBundle ManagementCorticosteroidsCorticosteroids

SteroidsSteroids• RationaleRationale

– IV corticosteroids recommended in patients IV corticosteroids recommended in patients with septic shock who despite adequate fluid with septic shock who despite adequate fluid replacement require vasopressor therapy to replacement require vasopressor therapy to maintain adequate blood pressure.maintain adequate blood pressure.

• Mineralocorticoid Effects RecommendedMineralocorticoid Effects Recommended– Hydrocortisone Hydrocortisone

• IV 100mg every 8 hours IV 100mg every 8 hours

– Fludrocortisone Fludrocortisone • 0.05mg PO/NG daily in addition to IV hydrocortisone.0.05mg PO/NG daily in addition to IV hydrocortisone.

Cortisol Levels – Draw BaselineCortisol 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

Discontinue steroids once patient is off vasopressors

Bundle Management:Bundle Management:Stress Ulcer Prophylaxis Stress Ulcer Prophylaxis

Stress Ulcer ProphylaxisStress Ulcer Prophylaxis

• Medications (Either)Medications (Either)– HH22 receptor antagonist receptor antagonist

• Famotidine (Pepcid) 20 mg IV BIDFamotidine (Pepcid) 20 mg IV BID– Watch Platelets! Can cause/worsen thrombocytopeniaWatch Platelets! Can cause/worsen thrombocytopenia

– Proton Pump InhibitorProton Pump Inhibitor• Esomeprazole (Nexium) 40 mg IV DailyEsomeprazole (Nexium) 40 mg IV Daily

Bundle Management:Bundle Management:Deep Vein Thrombosis ProphylaxisDeep Vein Thrombosis Prophylaxis

Deep Vein ProphylaxisDeep Vein Prophylaxis

• MechanicalMechanical– Sequential Compression devicesSequential Compression devices– Foot PumpsFoot Pumps– Inferior Vena Cava filter (IVC)Inferior Vena Cava filter (IVC)

• MedicationsMedications– Unfractionated Heparin 5000 units SQ Q8HUnfractionated Heparin 5000 units SQ Q8H– Enoxaparin (Lovenox) Enoxaparin (Lovenox)

• 40 mg SQ Daily or40 mg SQ Daily or• 30 mg SQ BID 30 mg SQ BID

Bundle Management:Bundle Management:Drotrecogin alpha (XigrisDrotrecogin alpha (Xigris))

Drotrecogin-Drotrecogin-ααMechanism of ActionMechanism of Action

• Recombinant form of human activated Recombinant form of human activated protein C protein C – Possesses profibrinolytic, antithrombotic, and Possesses profibrinolytic, antithrombotic, and

antiinflammatory activities which may antiinflammatory activities which may abrogate many systemic responses seen in abrogate many systemic responses seen in septic patients septic patients

• Activated protein C levels are reduced in Activated protein C levels are reduced in septic patientsseptic patients

Drotrecogin alpha (XigrisDrotrecogin alpha (Xigris) ) Criteria for useCriteria 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

ContraindicationsContraindicationsEXCLUSION CRITERIAEXCLUSION CRITERIA

(Patients must NOT meet ANY of the following criteria.(Patients must NOT meet ANY of the following criteria. Double check with prescribing physician if any checked criteria.)Double check with prescribing physician if any checked criteria.)

• • Age ≤ 18Age ≤ 18• • Life expectancy < 28 days (Due toLife expectancy < 28 days (Due to end-stage or end-stage or advancedadvanced disease) disease)• • Active internal bleedingActive internal bleeding• • Hemorrhagic stroke within 3 monthsHemorrhagic stroke within 3 months• • Intracranial or spinal surgery withinIntracranial or spinal surgery within 2 months2 months• • Severe head trauma withinSevere head trauma within 2 months2 months• • Trauma with increased risk ofTrauma with increased risk of life-threatening bleedinglife-threatening bleeding• • Epidural catheter in placeEpidural catheter in place• • Intracranial neoplasm or evidence ofIntracranial neoplasm or evidence of cerebral herniation or mass lesioncerebral herniation or mass lesion

RELATIVE CONTRAINDICATIONSRELATIVE CONTRAINDICATIONS(Risk should (Risk should outweighedoutweighed benefits. benefits.Patients not included in studies.)Patients not included in studies.)

• • PregnancyPregnancy• • BreastfeedingBreastfeeding• • Systemic thrombolytics < 3 days priorSystemic thrombolytics < 3 days prior• • Glycoprotein IIb/IIIa antagonists < 7 days priorGlycoprotein IIb/IIIa antagonists < 7 days prior• • Oral anticoagulants < 7 days priorOral anticoagulants < 7 days prior• • Aspirin > 650 mg/day or oral platelets inhibitors Aspirin > 650 mg/day or oral platelets inhibitors < 7 days prior< 7 days prior• • Ischemic stroke within 3 monthsIschemic stroke within 3 months• • Intracranial arteriovenous malformation aneurysmIntracranial arteriovenous malformation aneurysm• • Known bleeding diathesisKnown bleeding diathesis• • INR > 3INR > 3• • Platelets <30,000Platelets <30,000• • Gastrointestinal bleed with 6 weeksGastrointestinal bleed with 6 weeks• • Chronic severe hepatic diseaseChronic severe hepatic disease• • Major surgery within 12 hoursMajor surgery within 12 hours• • Concurrent therapeutic dosing of heparin to treatConcurrent therapeutic dosing of heparin to treat active thrombotic or embolic eventactive thrombotic or embolic event

Drotrecogin-Drotrecogin-αα DosingDosing

• For patients < 135 kg:For patients < 135 kg:– Drotrecogin alpha 24mcg/kg/hour continuous Drotrecogin alpha 24mcg/kg/hour continuous

IV infusion X 96 hours based on total body IV infusion X 96 hours based on total body weightweight

• For patients > 135 kg:For patients > 135 kg:– Drotrecogin alpha 24mcg/kg/hour continuous Drotrecogin alpha 24mcg/kg/hour continuous

IV infusion X 96 hours based on adjusted IV infusion X 96 hours based on adjusted body weightbody weight

Trouble ShootingTrouble Shooting

• Percutaneous ProcedurePercutaneous Procedure– Hold Drotrecogin Alpha (Xigris) infusion 2 hours Hold Drotrecogin Alpha (Xigris) infusion 2 hours

before and after any percutaneous procedure.before and after any percutaneous procedure.

• Major SurgeryMajor Surgery– Hold Drotrecogin Alpha (Xigris) infusion 2 hours Hold Drotrecogin Alpha (Xigris) infusion 2 hours

before and 12 hours after major surgery.before and 12 hours after major surgery.

Treating Sepsis Management Treating Sepsis Management Time is Crucial – Just like………Time is Crucial – Just like………

• TraumaTrauma– Golden hour!Golden hour!

• Myocardial InfarctionMyocardial Infarction– Time is tissue!Time is tissue!– Chain of survivalChain of survival– Door to balloon timeDoor to balloon time

• NeurologyNeurology– Time is brain!Time is brain!

• SepsisSepsis– Time is organ function!Time is organ function!– Time to Time to ▲▲ “mentality” “mentality”

ReferencesReferences• Rivers E, Nguyen B, et al. Early Goal-Directed Therapy in the Treatment of Severe Sepsis and 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-Septic Shock. The Early Goal-Directed Therapy Collaborative Group. NEJM 2001; 354-1368:1377.1368:1377.

• Rivers E, Nguyen B, et al. Stop Sepsis Tool kit. Rivers E, Nguyen B, et al. Stop Sepsis Tool kit. http://www.llu.edu/llumc/emergency/patientcare/

•   Angus DE et al; Epidemiology of severe sepsis in the United States: analysis of incidence, 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. outcome and associated costs of care. Critical Care Medicine 2001; 29:1303-1310.

• Surviving Sepsis Campaign Guidelines for management of severe sepsis and septic shock Care Med 2004 March;32(3):858-873 Care Med 2004 March;32(3):858-873

•   Kansas Critical Care Collaborative. Kansas Critical Care Collaborative. http://www.kscritcare.org/ • Sepsis Bundle. Sepsis Bundle. http://www.ihi.org/IHI/Topics/CriticalCare/Sepsis. 2005. 2005• Dellinger RP, Carlet JM, Masur H, Gerlach H, al. e. Surviving sepsis campaign guidelines for 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. management of severe sepsis and septic shock. Crit Care Med 2004; 32:858-72. http://www.sccm.org/professional_resources/guidelines/table_of_contents/Documents/FINAL.pdf

• Gilber DN, Moellering RC, Eliopoulos GM & Sande Merle A. The Sanford Guide to Antimicrobial Gilber DN, Moellering RC, Eliopoulos GM & Sande Merle A. The Sanford Guide to Antimicrobial Therapy 2006. Antimicrobial Therapy Inc. Therapy 2006. Antimicrobial Therapy Inc.

• Eli Lilly Sepsis website. http://www.sepsis.com/index.jspEli Lilly Sepsis website. http://www.sepsis.com/index.jsp• Annane D, Sebille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone 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.and fludrocortisone on mortality in patients with septic shock. Jama 2002; 288:862-71.• Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of recombinant human activated 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.protein C for severe sepsis. N Engl J Med 2001; 344:699-709.• Introduction to Cardiovascular Pharmacology. Introduction to Cardiovascular Pharmacology.

http://www.orhs.org/classes/nursing/CVPharm05.pdf

References – Cont’dReferences – Cont’d• ACE/ADA Task Force on Inpatient Diabetes. Endocrine Practice 2006 12(4):459-468.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. 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 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): inpatient care: how do we stop the insanity?” Society of Hospital Medicine 2006 1(3): 141-144. 141-144.

• A Malhota. Intensive Insulin in Intensive Care. New England Journal of Medicine A Malhota. Intensive Insulin in Intensive Care. New England Journal of Medicine 2006 354(5): 516-518.2006 354(5): 516-518.

• JS Krinsley & RL Jones. Cost analysis of intensive glycemic control in critically ill JS Krinsley & RL Jones. Cost analysis of intensive glycemic control in critically ill adult patients. Chest 2006; 129:644-650. adult patients. Chest 2006; 129:644-650.

• M Brownlee & IB Hirsch. Glycemic Variability: a hemoglobin A1C-Indepented Risk M Brownlee & IB Hirsch. Glycemic Variability: a hemoglobin A1C-Indepented Risk Factor for diabetic complications. JAMA 2006; 295(14) 1707-1708. 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. G Van den Berghe, A Wilmer, et al. Intensive Insulin Therapy in the Medical ICU. 2006; 354(5): 449-61. 2006; 354(5): 449-61.