Rachel Hinerman, MD FCCP

DefinitionsSepsis = suspected or proven infection and

some of the following:General VariablesInflammatory VariablesHemodynamic VariablesOrgan Dysfunction VariablesTissue Perfusion Variables

Sepsis VariablesGeneral InflammatoryFeverHypothermiaTachycardiaAltered Mental StatusEdemaHyperglycemia

LeukocytosisLeukopeniaNormal WBC with > 10

% immature formsC-reactive protein > 2

SDProcalcitonin > 2 SD

Sepsis VariablesHemodynamic Organ DysfunctionSBP <90MAP < 70SBP decrease > 40

Tissue PerfusionLactate > 1MottlingDecreased Capillary

Refill

P/F < 300UO < .5 ml/kg for 2

hours despite volume resuscitation

Cr increase > .5INR > 1.5IleusPlt < 100 KBili > 4

Severe Sepsis DefinitionSepsis induced organ dysfunction,

hypoperfusion, or hypotension Hypotension Elevated Lactic Acid Oliguria ALI with P/F < 250 without pneumonia ALI with P/F < 200 with pneumonia Cr > 2 Bili > 2 Plt < 100K INR > 1.5

Septic ShockSepsis-induced hypotension that persists despite

adequate fluid resuscitation

*All definitions cited from “Surviving Sepsis Campaign” published in Critical Care Medicine Feb 2013

Dellinger, RP. et al. Dellinger, RP. et al. Crit Care MedCrit Care Med 2004;32 2004;32

SepsisSepsisInfectioInfectionn

Severe Severe SepsisSepsis

Septic Septic ShockShock

A National Health Concern?Myocardial Infarction

Incidence 900,000Deaths 225,000Mortality 25%

Cerebrovascular AccidentIncidence 700,000Deaths 163,5000Mortality 23%

TraumaIncidence 2,900,000Deaths 42,643Mortality 1.5%

Severe SepsisIncidence 751,000Deaths 215,000Mortality 40-60%

Angus, DC. et al Crit Care Med 2000;29National Highway Traffic Safety Commission, 2003

AHA- Heart Disease and Stroke Statistics, 2005 update

Angus DC et al. Crit Care Med 2001; 29. American Cancer Society

Karon et al. Am J Public Health 2001; 91. American Heart Assoc., 2001

Deaths/Year

Source control is most vital factorAdequate resuscitation or re-established

perfusion in 6 hoursAppropriate antibiotic therapy within 1 hr of

hypotension

Determinants of Mortality

InterventionsEarly Goal Directed Therapy (EGDT)

Anti-microbialsSteroidsGlucose ControlLung Protective Ventilation

%

Bernard et al. NEJM 2001; 344. Van den Berghe et al. NEJM 2001; 345. Rivers et al. NEJM 2001; 345Annane et al. JAMA 2002; 288. ARDS-Net Investigators, NEJM; 2000

EGDT ResuscitationBegin at onset of hypotension or lactate >4Do not delay while awaiting ICU admissionInitial bolus is 30 ml/kg crystalloid

Rivers E et al. N Engl J Med 2001; 345:1368–1377

EGDTInitial Resuscitation targets

CVP 8-12 (12-15 if mechanically ventilated)Mean arterial pressure ≥65Urine output ≥ 0.5 ml/kg/hourCentral venous oxygen saturation ≥ 65%If venous oxygen target still not achieved:

trial of fluid or transfuse PRBCs to HCT ≥30% and/or start dobutamine infusion

Rivers, NEJM 2001; 345:1368

EGDT Outcomes

Rivers, E et al. N Engl J Med 2001; 345

EGDT Cost23% reduction in hospital cost

Most cost effective if patient volume > 16 cases/year

Mean reduction of 4 days per hospital admission

Cost per life saved of approximately $32,336

Reduction in hospital charges from $135,000 to $82,000

Treciak S et al. Chest 2006;129:225-232

Huang DT, et al Crit Care 2003;7:S116

Shapiro N, et al. Crit Care Med 2006;34:1025-1032

What to Use?SAFE study: 28 day outcomes

RCT n=6997, 4% albumin or normal saline Albumin group, 726 deaths - Saline group, 729

deaths New organ failure was similar in the two groups No difference: ICU or hospital LOS, mechanical

ventilation days, or days of renal-replacement therapy

Guideline: colloid or crystalloid may be usedSchierhout G et al. BMJ 1998;

316:961–964 Finfer S et al. N Engl J Med 2004;

350:2247–2256

EGDT (and we mean EARLY)Retrospective analysis of 212 patientsDiagnosis: septic shock and ALI within 72 hours Adequate initial fluid resuscitation (AIFR) group

Administration of an initial fluid bolus of ≥ 20 mL/kg prior to and achievement of a central venous pressure of ≥ 8 mm Hg within 6 h after the onset of therapy with a vasopressor

Conservative late fluid management (CLFM) Even-to-negative fluid balance measured on at

least 2 consecutive days during the first 7 days after septic shock onset

Murphy C V et al. Chest 2009;136:102-109

Mean daily fluid balance days 1 through 7

Murphy C V et al. Chest 2009;136:102-109

NONSURVIVO

RS

SURVIVOR

S

Hospital mortality for AIFR, CLFM, both, or neither

Murphy CV et al. Chest 2009; 136:102-109

18%

57%

42%

77%

EGDT & Intubation

No difference: P/F ratio at 6h; EGDT with higher P/F at 72hNo difference in intubation rates at 6 hours 7-72 hour intubation rate: EGDT 2% vs. standard 16.8%

Rivers, E et al. N Engl J Med 2001; 345

Otero R, et al. Chest 2006;130:1579-1595

VasopressorsMean arterial pressure (MAP) maintained ≥

65First choice: norepinephrine or epinephrineVasopressin 0.03 units/min may be added

VasopressinVASST Trial

Hypothesis: VP will increase survival compared to NE at 28d

779 patients in septic shock requiring vasopressors for ≥6 hours

Randomization to vasopressin or norepinephrineNo difference in 28-day survival (35.4% v 39.3%, P =.27).

When groups were stratified by severity of hypotension Low-dose NE improved survival with VP 26% v 35%, P .05 Result persisted at 90 days: mortality of 36% vs. 46 %, P =.04

Russell J et al. NEJM2008;358,9.

InotropesDobutamine infusion for suspected

myocardial dysfunction suggested by elevated cardiac filling pressures and low cardiac output

Recommend against a strategy to increase cardiac index to supranormal levels

Gattinoni L, et al. New Engl J Med 1995; 333:1025-32Hayes MA, et al. New Engl J Med 1994; 330:1717-22

InterventionsEarly Goal Directed Therapy (EGDT)

Anti-microbialsSteroidsGlucose Control

AntimicrobialsBegin therapy within the first hour of

recognizing severe sepsis or septic shockBroad spectrum: one or more agents against

likely bacterial or fungal pathogensConsider combination therapy for potentially

resistant gram negative pathogensConsider combination therapy in neutropenic

patientsNarrow coverage when culture data available

Garnacho-Montero J et al. CCM2007;25:1888-1895

AntimicrobialsStudy objective: to determine the impact of initial

antimicrobial therapy on survival in patients with septic shock

Data: 5,715 cases between 1996 and 2005 Community-acquired = 55%; nosocomial origin =

45%Appropriate empiric antimicrobial therapy = 80% Overall rate of survival to hospital discharge =

43%The survival rates:

Appropriate initial therapy 52% Inappropriate initial therapy 10%

Kumar A et al. Chest 2009;136:1237-1248

InterventionsEarly Goal Directed Therapy (EGDT)Anti-microbials

SteroidsGlucose Control

2012 Steroid GuidelinesThe ACTH stimulation test should not be

used to identify the subset of adults with septic shock who should receive hydrocortisone.

Do not use corticosteroids in the treatment of sepsis in the absence of shock.

Corticosteroid therapy may be weaned when vasopressors are no longer required.

Recommended: hydrocortisone 50 mg iv q 6 hours

Dellinger RP, et al Crit Care Med 2008;36:296-327

InterventionsEarly Goal Directed Therapy (EGDT)Anti-microbialsSteroids

Glucose Control

Glucose ControversyLeuven protocol: 80-

110Cardiac-surgical ICUReduced ICU LOSLess organ dysfunctionHypoglycemia 6.2%Decreased Mortality

3.4% ARR all patients9.4% ARR LOS >5 days

Leuven protocol: 80-110

Medical ICU Reduced ICU LOSLess ventilator daysLess acute renal injuryHypoglycemia 18%Mortality difference

Overall: no difference LOS > 3 days: ↓

mortality

Van den Berghe G, et al. NEJM 2006; 354:449-461

Van den Berghe G, et al. NEJM 2001;345:1359-1367

NICE-SUGARRCT open-label comparing intensive BS 80-110

vs.. conventional BS <180 6,104 ICU heterogeneous patientsPrimary end point: 90-day mortalitySecondary end points:

Hypoglycemia Infection Need for organ support Intensive care unit and hospital length of stay

The NICE-SUGAR Study Investigators NEJM 2008; Volume 360:1283-1297

2012 Glucose Control GuidelinesPatients with severe sepsis and

hyperglycemia in the ICU should receive intravenous insulin.

Use validated protocol for insulin dose adjustment with a target glucose <180.

All patients on intravenous insulin receive a glucose calorie source.

Dellinger RP, et al Crit Care Med 2008;36:296-327

Resuscitation “Bundles”Severe Sepsis 3 Hour Bundle

RecognitionFluid ResuscitationAntimicrobial TherapyOxygen Delivery

Severe Sepsis 6 Hour BundleLow-dose Steroids Glucose ControlLung Protective Ventilation

NYS Sepsis InitiativeHospitals shall have in place evidence-based

protocols for the early recognition and treatment of severe sepsis and septic shock.

Hospitals shall have a process for screening all adult and pediatric patients for sepsis, severe sepsis, and septic shock in the ED and hospital.

Quality measures will be collected and reported.