MANAGEMENT OF SEVERE SEPSIS

MANAGEMENT MANAGEMENT OF SEVERE OF SEVERE

SEPSISSEPSISVirginia Chung, MDVirginia Chung, MD

Director, MICUDirector, MICU

Jacobi Medical CenterJacobi Medical Center

INTRODUCTIONINTRODUCTION Sepsis is a clinical syndrome that Sepsis is a clinical syndrome that

complicates severe infection and is complicates severe infection and is characterized by systemic inflammation and characterized by systemic inflammation and widespread tissue injury.widespread tissue injury.

Tissues remote from the original insult Tissues remote from the original insult display signs of inflammation, including display signs of inflammation, including vasodilation, increased microvascular vasodilation, increased microvascular permeability, and leukocyte accumulation.permeability, and leukocyte accumulation.

Tissue injury due to activation of the Tissue injury due to activation of the inflammatory system may also complicate inflammatory system may also complicate noninfectious disorders such as acute noninfectious disorders such as acute pancreatitis or trauma.pancreatitis or trauma.

TERMINOLOGYTERMINOLOGY In 1992, the ACCP/SCCM consensus panel In 1992, the ACCP/SCCM consensus panel

defined the following terms:defined the following terms: InfectionInfection – microbial phenomenon – microbial phenomenon

characterized by an inflammatory response characterized by an inflammatory response to the presence of microorganisms or the to the presence of microorganisms or the invasion of normally sterile host tissue by invasion of normally sterile host tissue by those organisms.those organisms.

BacteremiaBacteremia – presence of viable bacteria in – presence of viable bacteria in the bloodthe blood

SIRSSIRS (Systemic Inflammatory Response (Systemic Inflammatory Response Syndrome) – is a widespread inflammatory Syndrome) – is a widespread inflammatory response to a variety of severe clinical response to a variety of severe clinical insults, manifested by 2 or more of the insults, manifested by 2 or more of the following:following:

TERMINOLOGYTERMINOLOGY

SIRSSIRS Temperature > 38ºC or < 36ºCTemperature > 38ºC or < 36ºC Heart rate > 90 beats/minHeart rate > 90 beats/min Respiratory rate > 20 breaths/min or PaCO2 < Respiratory rate > 20 breaths/min or PaCO2 <

32 mmHg32 mmHg WBC count > 12,000/mm3, <4,000/mm3, or > WBC count > 12,000/mm3, <4,000/mm3, or >

10% immature forms10% immature forms SepsisSepsis – is the systemic response to an – is the systemic response to an

infection, i.e., SIRS + infection.infection, i.e., SIRS + infection. Severe SepsisSevere Sepsis – sepsis associated with organ – sepsis associated with organ

dysfunction, hypoperfusion, or hypotension. dysfunction, hypoperfusion, or hypotension.

TERMINOLOGYTERMINOLOGY Organ Dysfunction CriteriaOrgan Dysfunction Criteria::

CardiovascularCardiovascular – SBP <= 90 mmHg or MAP <= 70 – SBP <= 90 mmHg or MAP <= 70 mmHg for at least 1 hour despite adequate volume mmHg for at least 1 hour despite adequate volume resuscitation, or the use of vasopressors to achieve resuscitation, or the use of vasopressors to achieve the same goals.the same goals.

RenalRenal – urine output < 0.5 ml/kg of body weight for 1 – urine output < 0.5 ml/kg of body weight for 1 hour despite adequate volume resuscitation.hour despite adequate volume resuscitation.

PulmonaryPulmonary – PaO2/FiO2 <= 250 if other organ – PaO2/FiO2 <= 250 if other organ dysfunction present or <= 200 if the lung is the only dysfunction present or <= 200 if the lung is the only dysfunctional organ.dysfunctional organ.

HematologicHematologic – platelet count < 80,000/mm3 or – platelet count < 80,000/mm3 or decreased by 50% over 3 days.decreased by 50% over 3 days.

MetabolicMetabolic – pH<= 7.30 or base deficit > 5.0 mmol/l – pH<= 7.30 or base deficit > 5.0 mmol/l AND plasma lactate > 1.5 x upper limit of normal.AND plasma lactate > 1.5 x upper limit of normal.

CNSCNS – acute alteration in mental status – acute alteration in mental status

TERMINOLOGYTERMINOLOGY Septic ShockSeptic Shock – –

a subset of severe sepsis with a subset of severe sepsis with hypotension despite hypotension despite adequate fluid resuscitation combined with adequate fluid resuscitation combined with perfusion abnormalitiesperfusion abnormalities. .

patients requiring inotropic or vasopressor agents patients requiring inotropic or vasopressor agents may no longer be hypotensive by the time they may no longer be hypotensive by the time they exhibit organ dysfunction, but are nonetheless exhibit organ dysfunction, but are nonetheless considered to be in septic shock.considered to be in septic shock.

form of vasodilatory or distributive shock resulting form of vasodilatory or distributive shock resulting from a marked reduction in systemic vascular from a marked reduction in systemic vascular resistance; it is often associated with an increased resistance; it is often associated with an increased cardiac output but some patients can present with cardiac output but some patients can present with decreased cardiac output due to sepsis-induced decreased cardiac output due to sepsis-induced cardiac dysfunction. cardiac dysfunction.

SIRS & SEPSISSIRS & SEPSIS

A clinical response A clinical response arising from a arising from a nonspecific insult, nonspecific insult, including including 2 of the 2 of the following:following:

• Temperature Temperature 3838ooC or C or 3636ooCC

• HR HR 90 beats/min90 beats/min• Respirations Respirations 20/min20/min• WBC count WBC count 12,000/mm12,000/mm33

oror 4,000/mm4,000/mm33 or >10% or >10% immature neutrophilsimmature neutrophils

SIRS = Systemic Inflammatory Response Syndrome

SIRS with a presumed or confirmed infectious process

SepsisSepsisSIRSSIRSInfection/Infection/TraumaTrauma Severe SepsisSevere Sepsis

Adapted from: Bone RC, et al. Chest 1992;101:1644Opal SM, et al. Crit Care Med 2000;28:S81

SEVERE SEPSISSEVERE SEPSIS

Bone et al. Chest 1992;101:1644; Wheeler and Bernard. N England J Med 1999;340:207

SepsisSepsisSIRSSIRSInfection/Infection/TraumaTrauma Severe SepsisSevere Sepsis

Sepsis with 1 sign of organ failure

Cardiovascular (refractory hypotension)

RenalRespiratoryHepaticHematologicCNSMetabolic acidosis

ShockShock

WORLDWIDEWORLDWIDE

Incidence of severe sepsis is 3.0 cases / 1,000Incidence of severe sepsis is 3.0 cases / 1,000 18 million cases of severe sepsis annually.18 million cases of severe sepsis annually. Kills approximately 1,400 people each day.Kills approximately 1,400 people each day. Leading cause of death in non-coronary ICUsLeading cause of death in non-coronary ICUs Number of cases of severe sepsis is growing Number of cases of severe sepsis is growing

at the rate of 1.5% per year.at the rate of 1.5% per year. This translates to an additional 1 million cases This translates to an additional 1 million cases

per year in the USA alone by 2020.per year in the USA alone by 2020.

RISK FACTORSRISK FACTORS Factors potentially responsible for the Factors potentially responsible for the

growing incidence of severe sepsis and growing incidence of severe sepsis and septic shock:septic shock: Increased awareness and sensitivity for the Increased awareness and sensitivity for the

diagnosis.diagnosis. Increased number of immunocompromised Increased number of immunocompromised

individuals: individuals: HIV/AIDSHIV/AIDS Increased use of cytotoxic and immunosuppressant Increased use of cytotoxic and immunosuppressant

agentsagents MalnutritionMalnutrition AlcoholismAlcoholism Diabetes MellitusDiabetes Mellitus

RISK FACTORSRISK FACTORS

Increased number of transplant recipients and Increased number of transplant recipients and transplantation procedures.transplantation procedures.

Increased use of aggressive invasive Increased use of aggressive invasive procedures in patient management and procedures in patient management and diagnosis.diagnosis.

Increased number of resistant Increased number of resistant microorganisms.microorganisms.

Increased number of elderly patients.Increased number of elderly patients. Increased number of institutionalized Increased number of institutionalized

individuals.individuals.

Mortality

Septic Shock

53-63%

20-53%Severe Sepsis300,000

7-17%Sepsis

400,000

Incidence

Balk, R.A. Crit Care Clin 2000;337:52

MORTALITYMORTALITY

Approximately 200,000 patients including 70,000 Medicare patients have septic shock annually

WHAT CAN WE DO AS WHAT CAN WE DO AS HEALTHCARE PROVIDERS HEALTHCARE PROVIDERS

TO IMPROVE THESE TO IMPROVE THESE MORTALITY STATISTICSMORTALITY STATISTICS ? ?

IHI / SSCIHI / SSC To expedite Quality Improvement (QI) in health care, To expedite Quality Improvement (QI) in health care,

the Institute for Healthcare Improvement (IHI) launched the Institute for Healthcare Improvement (IHI) launched the the 100,000 Lives Campaign100,000 Lives Campaign in December 2004. in December 2004.

This was a national initiative that had a goal of saving This was a national initiative that had a goal of saving 100,000 lives among patients in hospitals through 100,000 lives among patients in hospitals through improvements in the safety and effectiveness of health improvements in the safety and effectiveness of health care by June 18, 2006.care by June 18, 2006.

A “life saved” was defined as a patient successfully A “life saved” was defined as a patient successfully discharged from a hospital who, absent the changes discharged from a hospital who, absent the changes achieved through the campaign, would not have achieved through the campaign, would not have survived. survived.

All 5,759 hospitals in the U.S. were invited to join this All 5,759 hospitals in the U.S. were invited to join this campaign. The Health and Hospitals Corporation (HHC) campaign. The Health and Hospitals Corporation (HHC) with its 11 member hospitals (including Jacobi and with its 11 member hospitals (including Jacobi and NCB) were participantsNCB) were participants

IHI / SSCIHI / SSC

IHI Campaign Interventions:IHI Campaign Interventions: Deploy Rapid Response Teams (RRT/MET)Deploy Rapid Response Teams (RRT/MET) Deliver Reliable Evidence-Based Care for Deliver Reliable Evidence-Based Care for

Acute MIAcute MI Prevent Adverse Drug Events Through Prevent Adverse Drug Events Through

Medication Reconciliation.Medication Reconciliation. Prevent Central Line Infections.Prevent Central Line Infections. Prevent Surgical Site Infections.Prevent Surgical Site Infections. Prevent Ventilator-Associated PneumoniaPrevent Ventilator-Associated Pneumonia

IHI / SSCIHI / SSC At the same time, the Critical Care community formed At the same time, the Critical Care community formed

a working group, launched the Surviving Sepsis a working group, launched the Surviving Sepsis Campaign (SSC), and published their Campaign (SSC), and published their “Guidelines for “Guidelines for Management of Severe Sepsis and Septic Shock”Management of Severe Sepsis and Septic Shock” in in the March 2004 issue of Critical Care Medicine.the March 2004 issue of Critical Care Medicine.

IHI and the SSC working group have since teamed up IHI and the SSC working group have since teamed up to “wage war” on sepsis; their goal is to to “wage war” on sepsis; their goal is to “achieve a “achieve a 25% reduction in sepsis mortality by 2009”.25% reduction in sepsis mortality by 2009”.

To implement these evidence-based guidelines, 3 core To implement these evidence-based guidelines, 3 core strategies are recommended:strategies are recommended: Model for improvement : Plan-Do-Study-Act (PDSA) cyclesModel for improvement : Plan-Do-Study-Act (PDSA) cycles Using “Bundles” to simplify the complex process of caring for Using “Bundles” to simplify the complex process of caring for

patients with severe sepsis by grouping specific management patients with severe sepsis by grouping specific management elements together.elements together.

Enhancing reliability of the bundled elements.Enhancing reliability of the bundled elements.

SEVERE SEPSIS SEVERE SEPSIS BUNDLESBUNDLES

A “bundle” is a group of interventions related A “bundle” is a group of interventions related to a specific disease process that, when to a specific disease process that, when executed together, result in better outcomes executed together, result in better outcomes than when implemented individually. The than when implemented individually. The elements of the bundle are based upon elements of the bundle are based upon evidence-based practice and should be evidence-based practice and should be considered generally accepted practice.considered generally accepted practice.

There are 2 different Severe Sepsis Bundles. There are 2 different Severe Sepsis Bundles. Each bundle articulates objectives to be Each bundle articulates objectives to be accomplished within specific timeframes:accomplished within specific timeframes: Severe Sepsis Resuscitation BundleSevere Sepsis Resuscitation Bundle Severe Sepsis Management BundleSevere Sepsis Management Bundle

Resuscitation BundleResuscitation Bundle Describes 7 tasks that should begin Describes 7 tasks that should begin

immediately, but must be accomplished immediately, but must be accomplished within the first 6 hours of presentation within the first 6 hours of presentation for patients with severe sepsis, septic for patients with severe sepsis, septic shock, or a lactate > 4 mmol/l.shock, or a lactate > 4 mmol/l. 1. Measure serum lactate1. Measure serum lactate – hyperlactatemia – hyperlactatemia

is typically present and may be secondary to is typically present and may be secondary to anaerobic metabolism due to hypoperfusion; anaerobic metabolism due to hypoperfusion; obtaining a level is essential to identifying obtaining a level is essential to identifying tissue hypoperfusion in patients who are not tissue hypoperfusion in patients who are not yet hypotensive, but who are at risk for yet hypotensive, but who are at risk for septic shock.septic shock.

Resuscitation BundleResuscitation Bundle 2. Blood Cultures Obtained Prior to Antibiotic 2. Blood Cultures Obtained Prior to Antibiotic

AdministrationAdministration – 30-50% of these patients will – 30-50% of these patients will have positive blood cultures; best hope of have positive blood cultures; best hope of identifying the organism causing severe sepsis. identifying the organism causing severe sepsis. Two or more blood cultures are recommended. Two or more blood cultures are recommended.

In patients with suspected catheter-related In patients with suspected catheter-related infection, blood cultures should be drawn infection, blood cultures should be drawn simultaneously through the catheter hub and simultaneously through the catheter hub and from a peripheral site. If the same organism is from a peripheral site. If the same organism is recovered and the culture drawn from the line recovered and the culture drawn from the line is positive much earlier than the peripheral is positive much earlier than the peripheral culture, then it is likely that the catheter is the culture, then it is likely that the catheter is the source of infection.source of infection.

Resuscitation BundleResuscitation Bundle 3. 3. Improve Time to Broad-Spectrum AntibioticsImprove Time to Broad-Spectrum Antibiotics – early – early

administration of appropriate antibiotics reduces administration of appropriate antibiotics reduces mortality in patients with Gram(+) and Gram(-) mortality in patients with Gram(+) and Gram(-) bacteremias. Therefore, broad-spectrum antibiotics bacteremias. Therefore, broad-spectrum antibiotics should be given should be given within 3 hourswithin 3 hours from time of from time of presentation to the E.D. or presentation to the E.D. or within 1 hourwithin 1 hour for ward for ward patients transferred to the ICU.patients transferred to the ICU.

Major sources of infection in severe sepsis or septic Major sources of infection in severe sepsis or septic shock are pneumonia and intra-abdominal infections; shock are pneumonia and intra-abdominal infections; other sources accounting for < 5% of cases. other sources accounting for < 5% of cases.

Choice of antibiotics should be guided by the Choice of antibiotics should be guided by the susceptibility patterns of likely pathogens in the susceptibility patterns of likely pathogens in the community or hospital as well as any specific community or hospital as well as any specific knowledge about the patient. The regimen should knowledge about the patient. The regimen should cover all likely pathogens since there is little margin cover all likely pathogens since there is little margin for error in critically ill patients. Re-evaluate at 48-72 for error in critically ill patients. Re-evaluate at 48-72 hours.hours.

Resuscitation BundleResuscitation Bundle 4. Treat Hypotension and/or Elevated Lactate with 4. Treat Hypotension and/or Elevated Lactate with

fluidsfluids – patients may experience ineffective arterial – patients may experience ineffective arterial circulation due to vasodilatation or impaired circulation due to vasodilatation or impaired cardiac output; poorly perfused tissue beds result in cardiac output; poorly perfused tissue beds result in global tissue hypoxia leading to an elevated serum global tissue hypoxia leading to an elevated serum lactate level.lactate level.

Lactate > 4 mmol/l or 36 g/dl is correlated with Lactate > 4 mmol/l or 36 g/dl is correlated with increased severity of illness and poorer outcomes increased severity of illness and poorer outcomes even if hypotension is not yet present.even if hypotension is not yet present.

Initial administration of at least of 20 ml/kg of Initial administration of at least of 20 ml/kg of crystalloid as a fluid challenge should be given crystalloid as a fluid challenge should be given ASAP to these patients; boluses should be repeated ASAP to these patients; boluses should be repeated as necessary.as necessary.

Resuscitation BundleResuscitation Bundle Fluid ChallengeFluid Challenge – describes the initial volume – describes the initial volume

expansion period in which the patient response is expansion period in which the patient response is closely monitored; 4 components are:closely monitored; 4 components are:

1. Fluid type – crystalloid vs. colloid1. Fluid type – crystalloid vs. colloid 2. Infusion rate – 500-1,000 ml over 15-30 minutes2. Infusion rate – 500-1,000 ml over 15-30 minutes 3. End points – MAP > 65 or 70 mmHg, hr < 110 3. End points – MAP > 65 or 70 mmHg, hr < 110

beats/minbeats/min 4. Safety limits – pulmonary edema4. Safety limits – pulmonary edema

Crystalloid vs. ColloidCrystalloid vs. Colloid – the volume of – the volume of distribution for crystalloids is much larger distribution for crystalloids is much larger than for colloids, hence a larger volume of than for colloids, hence a larger volume of crystalloids will be required to achieve the crystalloids will be required to achieve the same goals and could result in more edema.same goals and could result in more edema.

A Comparison of Albumin A Comparison of Albumin and Saline for Fluid and Saline for Fluid Resuscitation in the Resuscitation in the Intensive Care UnitIntensive Care Unit

The SAFE (Saline versus Albumin The SAFE (Saline versus Albumin Fluid Evaluation) Study Fluid Evaluation) Study

InvestigatorsInvestigators

NEJM 2004; 350: 2247-56NEJM 2004; 350: 2247-56

SAFE STUDYSAFE STUDY Multicenter, randomized, double-blind trial comparing the Multicenter, randomized, double-blind trial comparing the

effect of fluid resuscitation with 4% albumin versus effect of fluid resuscitation with 4% albumin versus normal saline on 28-day mortality in the 16 ICUs in normal saline on 28-day mortality in the 16 ICUs in Australia & New Zealand.Australia & New Zealand.

7,000 patients age 18 or older were randomized.7,000 patients age 18 or older were randomized. 3 were mistakenly randomized twice, leaving 6,997 3 were mistakenly randomized twice, leaving 6,997

patients in the study; 3,497 received 4% albumin and patients in the study; 3,497 received 4% albumin and 3,500 received NS.3,500 received NS.

Results: 726 deaths in the albumin group and 729 in NS Results: 726 deaths in the albumin group and 729 in NS group (relative risk of death 0.99; p=0.87); additionally, group (relative risk of death 0.99; p=0.87); additionally, there was no significant differences in ICU days, hospital there was no significant differences in ICU days, hospital days, mechanical ventilation days, renal-replacement days, mechanical ventilation days, renal-replacement therapy days, or development of new single or multiorgan therapy days, or development of new single or multiorgan failures. failures.

Resuscitation BundleResuscitation Bundle End Points of Fluid ResuscitationEnd Points of Fluid Resuscitation – for refractory – for refractory

hypotension not responding to fluids or lactate > 4 hypotension not responding to fluids or lactate > 4 mmol/l, patients should now enter the mmol/l, patients should now enter the Early Goal Early Goal Directed Therapy (EGDT)Directed Therapy (EGDT) phase of the Resuscitation phase of the Resuscitation Bundle where central venous pressure Bundle where central venous pressure (CVP) >= 8 (CVP) >= 8 mmHgmmHg and central venous saturation and central venous saturation (ScvO2) >= 65-(ScvO2) >= 65-70 %70 % are the goals. are the goals.

Rivers, et al., demonstrated a 34% reduction in Rivers, et al., demonstrated a 34% reduction in hospital mortality for the patients in the EGDT group hospital mortality for the patients in the EGDT group versus those in the standard therapy group.versus those in the standard therapy group.

The degree of intravascular volume deficit in septic The degree of intravascular volume deficit in septic patients varies; with venodilation and ongoing patients varies; with venodilation and ongoing capillary leak, most patients require aggressive fluid capillary leak, most patients require aggressive fluid resuscitation during the first 24 hours of resuscitation during the first 24 hours of management.management.

Resuscitation BundleResuscitation Bundle 5. Apply Vasopressors for Ongoing 5. Apply Vasopressors for Ongoing

Hypotension (Shock)Hypotension (Shock) – when an appropriate – when an appropriate fluid challenge fails to restore an adequate fluid challenge fails to restore an adequate arterial pressure and organ perfusion, therapy arterial pressure and organ perfusion, therapy with vasopressors should be started; with vasopressors should be started; vasopressors may be required transiently to vasopressors may be required transiently to sustain life even when hypovolemia has not sustain life even when hypovolemia has not been corrected or when a fluid challenge is in been corrected or when a fluid challenge is in progress.progress.

MAP (mean arterial pressure) >= 65 mmHgMAP (mean arterial pressure) >= 65 mmHg Place arterial catheter for continuous blood Place arterial catheter for continuous blood

pressure measurements; ABGs, lactates readily pressure measurements; ABGs, lactates readily availableavailable

Resuscitation BundleResuscitation Bundle

Choice of Vasopressors: Choice of Vasopressors: either either norepinephrine or dopamine is the first-norepinephrine or dopamine is the first-choice vasopressor agent to correct choice vasopressor agent to correct hypotension in septic shock; epinephrine hypotension in septic shock; epinephrine and phenylephrine should not be used as and phenylephrine should not be used as first-line vasopressors because they first-line vasopressors because they decrease splanchnic blood flow significantlydecrease splanchnic blood flow significantly

Vasopressin can be added when patients Vasopressin can be added when patients are still in shock despite adequate fluid are still in shock despite adequate fluid resuscitation and high-dose conventional resuscitation and high-dose conventional vasopressors. vasopressors.

VasopressorsVasopressors DopamineDopamine – natural precursor of NE and Epi and possesses – natural precursor of NE and Epi and possesses

several dose-dependent pharmacologic effects.several dose-dependent pharmacologic effects. Low doses (< 5 mcg/kg/min) – stimulates dopaminergic DA1 Low doses (< 5 mcg/kg/min) – stimulates dopaminergic DA1

receptors in the renal, mesenteric, and coronary beds, resulting in receptors in the renal, mesenteric, and coronary beds, resulting in vasodilation.vasodilation.

Intermediate doses (5-10 mcg/kg/min) – β-adrenergic effects Intermediate doses (5-10 mcg/kg/min) – β-adrenergic effects predominate, resulting in an increase in cardiac contractility and predominate, resulting in an increase in cardiac contractility and heart rateheart rate

High doses (>10 mcg/kg/min) – α-adrenergic effects predominate, High doses (>10 mcg/kg/min) – α-adrenergic effects predominate, leading to arterial vasoconstriction and an increase in blood leading to arterial vasoconstriction and an increase in blood pressure.pressure.

Systemic hemodynamic effects of dopamine in septic patients : Systemic hemodynamic effects of dopamine in septic patients : increases MAP primarily by increasing cardiac index with minimal increases MAP primarily by increasing cardiac index with minimal effects on SVR; SV increases more than heart rate.effects on SVR; SV increases more than heart rate.

Very high doses (>20 mcg/kg/min) – increases heart rate and right Very high doses (>20 mcg/kg/min) – increases heart rate and right heart pressures; consider alternative agent. heart pressures; consider alternative agent.

VasopressorsVasopressors Norepinephrine (NE)Norepinephrine (NE) – is a potent α-adrenergic agonist – is a potent α-adrenergic agonist

with some β-adrenergic agonist effects; increases MAP with some β-adrenergic agonist effects; increases MAP due to vasoconstrictive effects, with little change in due to vasoconstrictive effects, with little change in heart rate or cardiac output, leading to increased SVR.heart rate or cardiac output, leading to increased SVR.

In open label trials, NE was shown to increase MAP in In open label trials, NE was shown to increase MAP in hypo-tensive patients resistant to fluid resuscitation hypo-tensive patients resistant to fluid resuscitation and dopamine.and dopamine.

In the past, there was concern that NE may have In the past, there was concern that NE may have negative effects on splanchnic and renal blood flow negative effects on splanchnic and renal blood flow leading to regional ischemia; however, recent leading to regional ischemia; however, recent experience does not support this.experience does not support this.

In hyperdynamic septic shock, NE markedly improves In hyperdynamic septic shock, NE markedly improves MAP and glomerular filtration; after restoration of MAP and glomerular filtration; after restoration of systemic hemodynamics urine output increases and systemic hemodynamics urine output increases and renal function improves in most patients. renal function improves in most patients.

Resuscitation BundleResuscitation Bundle 6. Maintain Adequate Central Venous Pressure6. Maintain Adequate Central Venous Pressure – in – in

the event of persistent hypotension despite fluid the event of persistent hypotension despite fluid resuscitation (septic shock) and/or lactate > 4 mmol/l resuscitation (septic shock) and/or lactate > 4 mmol/l (36 mg/dl) achieve CVP >= 8 mmHg. (36 mg/dl) achieve CVP >= 8 mmHg.

Patients should receive the initial minimum of 20 Patients should receive the initial minimum of 20 ml/kg fluid challenge prior to placement of a Central ml/kg fluid challenge prior to placement of a Central Venous Catheter (CVC) and attempts to optimize CVP.Venous Catheter (CVC) and attempts to optimize CVP.

For patients who are hypovolemic and anemic with a For patients who are hypovolemic and anemic with a Hct < 30, consider transfusing packed RBCs; blood is Hct < 30, consider transfusing packed RBCs; blood is a better volume expander and increases oxygen a better volume expander and increases oxygen carrying capacity.carrying capacity.

In mechanically ventilated patients, a higher target In mechanically ventilated patients, a higher target CVP > 12 mmHg is recommended because positive CVP > 12 mmHg is recommended because positive pressure ventilation causes increases in intrathoracic pressure ventilation causes increases in intrathoracic pressures and decreases venous return. pressures and decreases venous return.

Resuscitation BundleResuscitation Bundle 7. Maintain Adequate Central Venous Oxygen 7. Maintain Adequate Central Venous Oxygen

Saturation (ScvO2)Saturation (ScvO2) – in the event of persistent – in the event of persistent hypotension despite fluid resuscitation (septic shock) hypotension despite fluid resuscitation (septic shock) and/or lactate > 4 mmol/l (36 g/dl) achieve a and/or lactate > 4 mmol/l (36 g/dl) achieve a ScvO2 > ScvO2 > 70% OR70% OR a mixed venous oxygen saturation a mixed venous oxygen saturation (SvO2) via (SvO2) via PA catheter > 65%.PA catheter > 65%.

Strategies to achieve target ScvO2:Strategies to achieve target ScvO2: If the CVP > 8 mmHg and Hct < 30, transfuse If the CVP > 8 mmHg and Hct < 30, transfuse

PRBCs to increase oxygen carrying capacity and PRBCs to increase oxygen carrying capacity and hence oxygen delivery to the tissues.hence oxygen delivery to the tissues.

If the patient has underlying cardiac dysfunction or If the patient has underlying cardiac dysfunction or has developed sepsis-induced cardiac dysfunction, has developed sepsis-induced cardiac dysfunction, then add an inotrope (dobutamine) provided the then add an inotrope (dobutamine) provided the patient has been fluid resuscitated and transfused patient has been fluid resuscitated and transfused (if indicated). Increasing cardiac output increases (if indicated). Increasing cardiac output increases oxygen delivery to the tissues.oxygen delivery to the tissues.

Early Goal-Directed Early Goal-Directed Therapy in the Treatment Therapy in the Treatment

of Severe Sepsis and of Severe Sepsis and Septic ShockSeptic Shock

Rivers, E., M.D., M.P.H., Nguyen, B., Rivers, E., M.D., M.P.H., Nguyen, B., M.D., et. al., for the Early Goal-Directed M.D., et. al., for the Early Goal-Directed

Therapy Collaborative Group; NEJM, Therapy Collaborative Group; NEJM, 2001, 345:1368-1377.2001, 345:1368-1377.

EGDTEGDT Randomized, controlled, predominantly blinded study in Randomized, controlled, predominantly blinded study in

the E.D. of an 850-bed tertiary referral center (Henry the E.D. of an 850-bed tertiary referral center (Henry Ford Hospital, Detroit, MI) over a 3-yr period (3/1997-Ford Hospital, Detroit, MI) over a 3-yr period (3/1997-3/2000).3/2000).

Enrollment criteria: 2 of 4 SIRS criteria with a SBP < 90 Enrollment criteria: 2 of 4 SIRS criteria with a SBP < 90 mmHg after a 20-30 ml/kg fluid challenge or a blood mmHg after a 20-30 ml/kg fluid challenge or a blood lactate level > 4 mmol/l (36 g/dl).lactate level > 4 mmol/l (36 g/dl).

Patients either received 6 hours of standard therapy or 6 Patients either received 6 hours of standard therapy or 6 hours of goal-directed therapy before admission to the hours of goal-directed therapy before admission to the ICU; clinicians subsequently involved in the care of the ICU; clinicians subsequently involved in the care of the study patients were blinded to the treatment arm of the study patients were blinded to the treatment arm of the study.study. Control group followed an existing protocol for Control group followed an existing protocol for

hemodynamic support: CVP 8-12 mmHg, MAP > 65 hemodynamic support: CVP 8-12 mmHg, MAP > 65 mmHg, urine output > 0.5 ml/kg/hr; 500 ml fluid mmHg, urine output > 0.5 ml/kg/hr; 500 ml fluid boluses and vasopressors were used.boluses and vasopressors were used.

EGDTEGDT Treatment group had the same aims as the Treatment group had the same aims as the

control group PLUS they had to achieve a central control group PLUS they had to achieve a central venous oxygen saturation (ScvO2) > 70%:venous oxygen saturation (ScvO2) > 70%:

If the ScvO2 < 70 % andIf the ScvO2 < 70 % and Hct < 30, transfuse PRBCsHct < 30, transfuse PRBCs MAP > 90 mmHg, give vasodilators until MAP <= MAP > 90 mmHg, give vasodilators until MAP <=

90 mmHg90 mmHg If CVP, Hct, and MAP were in the optimal range and If CVP, Hct, and MAP were in the optimal range and

ScvO2 still < 70%, start dobutamine 2.5 mcg/kg/min ScvO2 still < 70%, start dobutamine 2.5 mcg/kg/min (inotrope) and titrate it up by 2.5 mcg/kg/min every (inotrope) and titrate it up by 2.5 mcg/kg/min every 30 min until ScvO2 > 70% or a maximum dose of 20 30 min until ScvO2 > 70% or a maximum dose of 20 mcg/kg/min is reached. The dose was decreased or mcg/kg/min is reached. The dose was decreased or d/c’ed if MAP < 65 mmHg or hr > 120 beats/mind/c’ed if MAP < 65 mmHg or hr > 120 beats/min

Finally, to decrease O2 demand, sedate and Finally, to decrease O2 demand, sedate and mechanically ventilate the patient.mechanically ventilate the patient.

EGDTEGDT Results: Results: 263 patients randomized – 133 received standard 263 patients randomized – 133 received standard

therapy and 130 received EGDT; Temp, hr, urine output, therapy and 130 received EGDT; Temp, hr, urine output, BP, CVP were measured cont. for 6 hours, then q 12h for BP, CVP were measured cont. for 6 hours, then q 12h for 72 hrs. 72 hrs.

During the initial 6 hours, the EGDT group received more During the initial 6 hours, the EGDT group received more IV fluids, red cell transfusions, and inotropic therapy than IV fluids, red cell transfusions, and inotropic therapy than the control group.the control group.

During the subsequent 66 hours, the control group During the subsequent 66 hours, the control group received more transfusions, more vasopressors, and had a received more transfusions, more vasopressors, and had a greater requirement for mechanical ventilation and PA greater requirement for mechanical ventilation and PA catheterizationcatheterization..

This showed that the control group was relatively under-This showed that the control group was relatively under-resuscitated initially.resuscitated initially.

In-hospital mortality was significantly higher in the control In-hospital mortality was significantly higher in the control group than in the EGDT group – 46.5 % versus 30.5% group than in the EGDT group – 46.5 % versus 30.5% (p=0.009). (p=0.009).

Resuscitation BundleResuscitation Bundle To summarize, for patients presenting with To summarize, for patients presenting with

severe sepsis, septic shock, or lactate > 4 mmol/l, severe sepsis, septic shock, or lactate > 4 mmol/l, the following 7 tasks need to be accomplished the following 7 tasks need to be accomplished within the first 6 hours of presentation:within the first 6 hours of presentation: 1. Measure serum lactate.1. Measure serum lactate. 2. Obtain blood cultures prior to antibiotic 2. Obtain blood cultures prior to antibiotic

administration.administration. 3. Improve time to broad-spectrum antibiotics (< 3 3. Improve time to broad-spectrum antibiotics (< 3

hrs).hrs). 4. Treat hypotension and/or elevated lactate with 4. Treat hypotension and/or elevated lactate with

fluids.fluids. 5. Apply vasopressors for ongoing hypotension.5. Apply vasopressors for ongoing hypotension. 6. Maintain adequate CVP (>= 8 mmHg).6. Maintain adequate CVP (>= 8 mmHg). 7. Maintain adequate ScvO2 (>= 70%).7. Maintain adequate ScvO2 (>= 70%).

Management BundleManagement Bundle Describes 4 tasks that must be completed within Describes 4 tasks that must be completed within

24 hours of presentation for patients with severe 24 hours of presentation for patients with severe sepsis, septic shock, and/or lactate >4 mmol/l.sepsis, septic shock, and/or lactate >4 mmol/l. 1. Administer Low-Dose Steroids by a Standard Policy1. Administer Low-Dose Steroids by a Standard Policy

– IV corticosteroids (hydrocortisone 200-300 mg/day, – IV corticosteroids (hydrocortisone 200-300 mg/day, for 7 days in 3-4 divided doses) may be given in for 7 days in 3-4 divided doses) may be given in patients with septic shock who despite adequate fluid patients with septic shock who despite adequate fluid replacement require vasopressor therapy to maintain replacement require vasopressor therapy to maintain adequate blood pressure.adequate blood pressure.

The use of fludrocortisone in addition to low-dose The use of fludrocortisone in addition to low-dose hydrocortisone is considered optional. Absolute hydrocortisone is considered optional. Absolute primary adrenal insufficiency is rare in septic shock primary adrenal insufficiency is rare in septic shock (0-3%).(0-3%).

Management BundleManagement Bundle In refractory septic shock, the prevalence of In refractory septic shock, the prevalence of Relative Relative

Adrenal Insufficiency (RAI)Adrenal Insufficiency (RAI) may be as high as 50-75%. may be as high as 50-75%. RAI may be present when the increase in serum cortisol RAI may be present when the increase in serum cortisol level is < 9 mcg/dl, 30-60 min after a 250- mcg ACTH level is < 9 mcg/dl, 30-60 min after a 250- mcg ACTH stimulation.stimulation.

Low dose Corticosteroids (CS)promote shock reversal.Low dose Corticosteroids (CS)promote shock reversal. Their effects on vascular tone were recognized well Their effects on vascular tone were recognized well before their anti-inflammatory properties. In patients before their anti-inflammatory properties. In patients with septic shock, low dose CS significantly reduces with septic shock, low dose CS significantly reduces nitrite/nitrate plasma concentrations, indicating nitrite/nitrate plasma concentrations, indicating inhibition of NO formation.inhibition of NO formation.

Median time to cessation of vasopressors in one study Median time to cessation of vasopressors in one study decr. from 13 to 4 days and 7 to 3 days in another. decr. from 13 to 4 days and 7 to 3 days in another. Another study showed that Another study showed that MAP and SVR increasedMAP and SVR increased and and HR, CI, and NE requirement decreasedHR, CI, and NE requirement decreased with the use of with the use of low-dose CS.low-dose CS.

Effect of Treatment with Low Effect of Treatment with Low Doses of Hydrocortisone and Doses of Hydrocortisone and Fludrocortisone on Mortality Fludrocortisone on Mortality in Patients with Septic Shockin Patients with Septic Shock

Annane, D., Sebille, V., Annane, D., Sebille, V., Charpentier, C., et al., JAMA, Charpentier, C., et al., JAMA,

2002; 288: 862-8712002; 288: 862-871

Low Dose CSLow Dose CS Placebo-controlled, randomized, double-Placebo-controlled, randomized, double-

blind, parallel-group trial performed in 19 blind, parallel-group trial performed in 19 ICUs in France from 1995-1999.ICUs in France from 1995-1999.

1326 pts were assessed for eligibility; 1026 1326 pts were assessed for eligibility; 1026 were ineligible; 300 randomized to receive were ineligible; 300 randomized to receive either hydrocortisone 50 mg IV q6h and either hydrocortisone 50 mg IV q6h and fludrocortisone 50 mcg po qd or matching fludrocortisone 50 mcg po qd or matching placebos for 7 days.placebos for 7 days.

Corticotropin testCorticotropin test was performed in all was performed in all patients; RAI was defined as a response of patients; RAI was defined as a response of 9 9 mcg/dl or lessmcg/dl or less. RAI pts were deemed . RAI pts were deemed NonrespondersNonresponders while those who had a while those who had a >9 >9 mcg/dl increase were Responders.mcg/dl increase were Responders.

Low Dose CSLow Dose CS Mortality rates:Mortality rates:

All patientsAll patients – there was no significant effect of CS on – there was no significant effect of CS on 28-day, ICU, hospital, and 1-year mortality rates.28-day, ICU, hospital, and 1-year mortality rates.

Responders (>9 mcg/dl incr.)Responders (>9 mcg/dl incr.) – there was no – there was no significant effect of CS on 28-day, ICU, hospital, and significant effect of CS on 28-day, ICU, hospital, and 1-year mortality rates.1-year mortality rates.

Nonresponders (<= 9 mcg/dl incr.)Nonresponders (<= 9 mcg/dl incr.) – – 28 days : placebo 73 (63%)28 days : placebo 73 (63%) CS 60 (53%) deaths CS 60 (53%) deaths

p=.04 p=.04 ICU: placebo 81 (70%) CS 66 (58%) deaths ICU: placebo 81 (70%) CS 66 (58%) deaths

p=.02p=.02 Hospital: placebo 83 (72%) CS 70 (61%) deaths Hospital: placebo 83 (72%) CS 70 (61%) deaths

p=.04p=.04 1-year: placebo 88 (77%) CS 77 (68%) deaths 1-year: placebo 88 (77%) CS 77 (68%) deaths

p=.07 p=.07

Low Dose CSLow Dose CS Median Time-to-Vasopressor-Therapy Median Time-to-Vasopressor-Therapy

WithdrawalWithdrawal – – All patients – 9 days (placebo) , 7 days (CS) , p=.01All patients – 9 days (placebo) , 7 days (CS) , p=.01 Responders – 7 days (placebo) , 9 days (CS) , Responders – 7 days (placebo) , 9 days (CS) ,

p=.49p=.49 Nonresponders – 10 days (placebo) , 7 days (CS) , Nonresponders – 10 days (placebo) , 7 days (CS) ,

p=.001p=.001 No significant differences between the 2 No significant differences between the 2

groups in the rates of adverse events related groups in the rates of adverse events related to CS (infection, GI bleed, psychiatric d/o).to CS (infection, GI bleed, psychiatric d/o).

Conclusion: in pressor-dependent septic Conclusion: in pressor-dependent septic shock, administer low dose CS and shock, administer low dose CS and fludrocortisone for 7 days in those with RAI.fludrocortisone for 7 days in those with RAI.

Hydrocortisone Therapy Hydrocortisone Therapy for Patients with Septic for Patients with Septic

Shock Shock (CORTICUS)(CORTICUS)

Sprung, C., Annane, D., Keh, D., Sprung, C., Annane, D., Keh, D., et. al., for the CORTICUS Study et. al., for the CORTICUS Study

Group, NEJM, 2008, 358: 111-124Group, NEJM, 2008, 358: 111-124

CORTICUSCORTICUS Multicenter, randomized, double-blind, Multicenter, randomized, double-blind,

placebo-controlled study conducted in 52 placebo-controlled study conducted in 52 ICUs across Europe and Israel from 3/02 to ICUs across Europe and Israel from 3/02 to 11/05.11/05.

Purpose:Purpose: evaluate the efficacy and safety of evaluate the efficacy and safety of low-dose hydrocortisone in pts with septic low-dose hydrocortisone in pts with septic shock.shock.

Eligibility:Eligibility: onset of septic shock w/i previous onset of septic shock w/i previous 72 hrs with evidence of hypoperfusion or 72 hrs with evidence of hypoperfusion or organ dysfunction attributable to sepsis.organ dysfunction attributable to sepsis.

Exclusions:Exclusions: underlying disease with poor underlying disease with poor prognosis, moribund (death w/i 24 hrs), prognosis, moribund (death w/i 24 hrs), immunosuppressed, long-term CS within 6 immunosuppressed, long-term CS within 6 months or short term CS within 4 weeks.months or short term CS within 4 weeks.

CORTICUSCORTICUS Lab data:Lab data: corticotropin test performed with 0.25mg corticotropin test performed with 0.25mg

cosyntropin with blood samples collected at time 0 cosyntropin with blood samples collected at time 0 and at 60 minutes; samples were frozen and cortisol and at 60 minutes; samples were frozen and cortisol levels measured just before interim and final levels measured just before interim and final analysis.analysis.

Protocol:Protocol: study drug (50 mg hydrocortisone) given study drug (50 mg hydrocortisone) given q6h x 5 days, then q12h x 3 days, then q24h x 3 days q6h x 5 days, then q12h x 3 days, then q24h x 3 days – 29 total doses.– 29 total doses.

End Points: End Points: Primary - 28 day mortality rate in pts who DID Primary - 28 day mortality rate in pts who DID

NOT have a response to corticotropin. NOT have a response to corticotropin. Secondary – 28 day mortality rate in pts who DID Secondary – 28 day mortality rate in pts who DID

respond to corticotropin ; ICU mortality and respond to corticotropin ; ICU mortality and hospital mortality for all patients.hospital mortality for all patients.

CORTICUSCORTICUS Results: Results:

500 pts randomized – 252 received HC (1 500 pts randomized – 252 received HC (1 w/d consent) and 248 received placebo.w/d consent) and 248 received placebo.

Of the 499 pts, 233 (46.7%) did NOT have a Of the 499 pts, 233 (46.7%) did NOT have a response to ACTH – 125 in the study group, response to ACTH – 125 in the study group, 108 in placebo group108 in placebo group

254 (50.9%) did have a response to ACTH – 254 (50.9%) did have a response to ACTH – 118 in the study group, 136 in placebo 118 in the study group, 136 in placebo groupgroup

12 remaining pts – 8 in study group, 4 in 12 remaining pts – 8 in study group, 4 in placebo group had no data for cosyntropin placebo group had no data for cosyntropin test. test.

CORTICUSCORTICUS

HydrocortisoHydrocortisonene

PlaceboPlacebo p p valuevalue

resporespondnd

non-non-resres

resporespondnd

non-non-resres

# # patientspatients

118118 125125 136136 108108

Deaths @ Deaths @ 28 days28 days

49 (39%)49 (39%) 39 (36%)39 (36%) 0.690.69


34 (29%)34 (29%) 39 (29%)39 (29%) 1.001.00


86 (34.3%) 78 (31.5%)78 (31.5%) 0.510.51

Shock Shock rev.rev.

95 (76%)95 (76%) 76 (70%)76 (70%) 0.410.41


100 100 (85%)(85%)

104 104 (77%)(77%)

0.130.13


200 (79.7 %)200 (79.7 %) 184 (74.2 %)184 (74.2 %) 0.180.18

CORTICUSCORTICUS

Results (cont) :Results (cont) : Time to shock resolution was shorter in Time to shock resolution was shorter in

all patients (p<0.001) who received all patients (p<0.001) who received hydrocortisone regardless of whether or hydrocortisone regardless of whether or not they were responders (p<0.001) or not they were responders (p<0.001) or non-responders. (p =0.06)non-responders. (p =0.06) All pts ( 3.3 days vs. 5.8 days )All pts ( 3.3 days vs. 5.8 days ) Responders ( 2.8 days vs. 5.8 days )Responders ( 2.8 days vs. 5.8 days ) Non-responders ( 3.9 days vs. 6.0 days)Non-responders ( 3.9 days vs. 6.0 days)

CORTICUSCORTICUS Results (cont) :Results (cont) :

Adverse events: in the hydrocortisone group, there Adverse events: in the hydrocortisone group, there was an increased incidence of superinfections with was an increased incidence of superinfections with OR=1.37 (CI of 1.05 to 1.79), hyperglycemia, OR=1.37 (CI of 1.05 to 1.79), hyperglycemia, hypernatremia; weakness was rarely reported.hypernatremia; weakness was rarely reported.

Conclusions :Conclusions : Hydrocortisone (HC) cannot be recommended as Hydrocortisone (HC) cannot be recommended as

general adjuvant therapy for septic shockgeneral adjuvant therapy for septic shock Corticotropin testing is also not recommended to Corticotropin testing is also not recommended to

determine which patients should receive HC determine which patients should receive HC therapy therapy

HC may have a role among patients who are HC may have a role among patients who are treated early after onset of septic shock who treated early after onset of septic shock who remain hypotensive despite high dose remain hypotensive despite high dose vasopressors.vasopressors.

Management BundleManagement Bundle

2. Administer Drotrecogin Alfa (Activated) 2. Administer Drotrecogin Alfa (Activated) by a Standard Policyby a Standard Policy – the inflammatory – the inflammatory response in severe sepsis is integrally response in severe sepsis is integrally linked to procoagulant activity and linked to procoagulant activity and endothelial activation. In a large, endothelial activation. In a large, multicenter RCT, multicenter RCT, recombinant human recombinant human Activated Protein C (rhAPC)Activated Protein C (rhAPC) – an – an endogenous profibrinolytic anticoagulant endogenous profibrinolytic anticoagulant with anti-inflammatory properties- with anti-inflammatory properties- improved survival in patients with sepsis-improved survival in patients with sepsis-induced organ dysfunction. induced organ dysfunction.

Efficacy and Safety of Efficacy and Safety of Recombinant Human Recombinant Human

Activated Protein C for Activated Protein C for Severe SepsisSevere Sepsis

Bernard, G., Vincent, J., Laterre, Bernard, G., Vincent, J., Laterre, P., et al., for the PROWESS study P., et al., for the PROWESS study

group, NEJM, 2001; 344: 699-group, NEJM, 2001; 344: 699-709.709.

PROWESSPROWESS Randomized, double-blind, placebo-controlled trial Randomized, double-blind, placebo-controlled trial

conducted at 164 centers in 11 countries from 7/1998 conducted at 164 centers in 11 countries from 7/1998 through 6/2000 evaluating rhAPC (24 mcg/kg/hr for 96 through 6/2000 evaluating rhAPC (24 mcg/kg/hr for 96 hours) in patients with severe sepsis.hours) in patients with severe sepsis.

Inclusion criteriaInclusion criteria: known or suspected infection PLUS 3 : known or suspected infection PLUS 3 of 4 SIRS criteria PLUS at least one organ dysfunction of 4 SIRS criteria PLUS at least one organ dysfunction (cardiac, renal, respiratory, hematologic) or presence of (cardiac, renal, respiratory, hematologic) or presence of lactic acidosis.lactic acidosis.

Exclusion criteriaExclusion criteria: pregnancy, breast-feeding, age<18, : pregnancy, breast-feeding, age<18, weight>135 kg, platelet < 30,000, increased risk of weight>135 kg, platelet < 30,000, increased risk of bleeding, known hypercoagulable condition, AIDS with bleeding, known hypercoagulable condition, AIDS with CD4<50, moribund state with imminent death, CRF on CD4<50, moribund state with imminent death, CRF on HD/PD, liver failure, acute pancreatitis w/o infection, HD/PD, liver failure, acute pancreatitis w/o infection, very recent use of anticoagulants or thrombolytics, high very recent use of anticoagulants or thrombolytics, high dose ASA. dose ASA.

PROWESSPROWESS Primary efficacy end point was death from any Primary efficacy end point was death from any

cause and was assessed 28 days after the cause and was assessed 28 days after the initiation of the infusion; Powered to detect a initiation of the infusion; Powered to detect a 15% reduction in the RR of 28-day all-cause 15% reduction in the RR of 28-day all-cause mortality.mortality.

Trial was suspended at the time of the 2Trial was suspended at the time of the 2ndnd interim analysis after 1,520 patients had been interim analysis after 1,520 patients had been enrolled. There were enrolled. There were 259 (30.8%) deaths in the 259 (30.8%) deaths in the placebo group versus 210 (24.7%) deaths in the placebo group versus 210 (24.7%) deaths in the rhAPC group yielding an absolute 6.1% mortality rhAPC group yielding an absolute 6.1% mortality reduction and 19.4% reduction in RR of death. reduction and 19.4% reduction in RR of death.

16 patients would need to be treated to save one 16 patients would need to be treated to save one (1) life in this study population. (1) life in this study population.

PROWESSPROWESS When subgroup analysis was performed, those When subgroup analysis was performed, those

patients with patients with APACHE II scores > 25APACHE II scores > 25 (quartile (quartile 3 & 4), there was an 3 & 4), there was an absolute mortality absolute mortality reduction of 13% (44 vs 31) and RR reduction reduction of 13% (44 vs 31) and RR reduction of 29.5%.of 29.5%.

8 patients would need to be treated to save one 8 patients would need to be treated to save one (1) life.(1) life.

Adverse events: serious bleeding eventsAdverse events: serious bleeding events (ICH, (ICH, life-threatening bleed, transfusion of 3 units life-threatening bleed, transfusion of 3 units prbc/day for 2 days, or assessed as serious by prbc/day for 2 days, or assessed as serious by the investigator) occurred in 20 (2.4%) of the the investigator) occurred in 20 (2.4%) of the rhAPC group versus 8 (1.0%) in the placebo rhAPC group versus 8 (1.0%) in the placebo group.group.

PROWESSPROWESS In November 2001, the US FDA narrowly In November 2001, the US FDA narrowly

approved rhAPC for sepsis-induced organ approved rhAPC for sepsis-induced organ dysfunction associated with high risk of death, dysfunction associated with high risk of death, such as APACHE II score > 25. (APACHE II = such as APACHE II score > 25. (APACHE II = Acute Physiology and Chronic Health Evaluation)Acute Physiology and Chronic Health Evaluation)

In Europe, the European Agency for the In Europe, the European Agency for the Evaluation of Medicinal Products, approved Evaluation of Medicinal Products, approved rhAPC for the treatment of adult patients with rhAPC for the treatment of adult patients with >= 2 organ dysfunction.>= 2 organ dysfunction.

Very expensive drug, costing approximately US Very expensive drug, costing approximately US $7,000 per 96 hour infusion.$7,000 per 96 hour infusion.

Drotrecogin Alfa Drotrecogin Alfa (Activated) for Adults with (Activated) for Adults with Severe Sepsis and a Low Severe Sepsis and a Low

Risk of DeathRisk of DeathAbraham, E., Laterre, P., Garg, R., Abraham, E., Laterre, P., Garg, R.,

et al., for the ADDRESS study et al., for the ADDRESS study group, NEJM, 2005; 353: 1332-group, NEJM, 2005; 353: 1332-

41.41.

ADDRESSADDRESS After approving rhAPC, the FDA required a study to After approving rhAPC, the FDA required a study to

evaluate the efficacy of rhAPC in adults with severe sepsis evaluate the efficacy of rhAPC in adults with severe sepsis and low risk of death, i.e., and low risk of death, i.e., APACHE II < 25 or single APACHE II < 25 or single organ dysfunction.organ dysfunction.

516 centers in 34 countries participated. The study began 516 centers in 34 countries participated. The study began in 9/02 and was terminated early in 2/04 because it was in 9/02 and was terminated early in 2/04 because it was clear a significant reduction in 28-day mortality would not clear a significant reduction in 28-day mortality would not be shown.be shown.

Mortality: rhAPC 18.5% vs. Placebo 17.0% p=.34Mortality: rhAPC 18.5% vs. Placebo 17.0% p=.34 Serious Bleeding: rhAPC 2.4% vs. Placebo 1.2% p=.02Serious Bleeding: rhAPC 2.4% vs. Placebo 1.2% p=.02 Patients who had recent surgery (< 30 days) and single Patients who had recent surgery (< 30 days) and single

organ dysfunction and received rhAPC had a higher organ dysfunction and received rhAPC had a higher mortality rate than those who received placebo, although mortality rate than those who received placebo, although it did not achieve significance. it did not achieve significance.


3. Maintain Adequate Glycemic Control3. Maintain Adequate Glycemic Control – 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. Continuous infusions of insulin mg/dl. Continuous infusions of insulin and glucose are given. Glucose should and glucose are given. Glucose should be monitored frequently after initiating be monitored frequently after initiating the protocol (q 30-60 min) and on a the protocol (q 30-60 min) and on a regular basis (q4h) once blood glucose regular basis (q4h) once blood glucose concentration has stabilized.concentration has stabilized.

Intensive Insulin Intensive Insulin Therapy in Critically Ill Therapy in Critically Ill

PatientsPatientsVan den Berghe, G., Wouters, P., Van den Berghe, G., Wouters, P., Weekers, F., et al., NEJM, 2001, Weekers, F., et al., NEJM, 2001,

345: 1359-67.345: 1359-67.

I I T (SICU)I I T (SICU) Prospective, single center, randomized, controlled study Prospective, single center, randomized, controlled study

involving adults admitted to the SICU (Leuven, Belgium) involving adults admitted to the SICU (Leuven, Belgium) requiring mechanical ventilation between 2/2/00 and requiring mechanical ventilation between 2/2/00 and 1/18/01.1/18/01.

1548 patients were enrolled. 63% were cardiothoracic 1548 patients were enrolled. 63% were cardiothoracic patients.patients.

783 received conventional treatment where the insulin 783 received conventional treatment where the insulin drip was started only if the blood glucose level > 215 drip was started only if the blood glucose level > 215 mg/dl; subsequent blood sugars were maintained between mg/dl; subsequent blood sugars were maintained between 180 and 200 mg/dl.180 and 200 mg/dl.

765 received intensive insulin therapy where the insulin 765 received intensive insulin therapy where the insulin drip was started for blood glucose > 110 mg/dl; blood drip was started for blood glucose > 110 mg/dl; blood sugars were then maintained between 80-110 mg/dl.sugars were then maintained between 80-110 mg/dl.

I I T (SICU)I I T (SICU) Patients received IV glucose for the first Patients received IV glucose for the first

24 hrs in the SICU, then were enterally 24 hrs in the SICU, then were enterally and/or parenterally fed thereafter.and/or parenterally fed thereafter.

39.2% of pts. in the conventional group 39.2% of pts. in the conventional group was started on an insulin drip versus was started on an insulin drip versus 98.7% in the intensive group (only 10 pts 98.7% in the intensive group (only 10 pts did not get IIT)did not get IIT)

Morning blood sugars: Morning blood sugars: Conventional – 153 mg/dl (all); 173 mg/dl Conventional – 153 mg/dl (all); 173 mg/dl

(insulin)(insulin) Intensive Rx – 103 mg/dl (all, insulin) Intensive Rx – 103 mg/dl (all, insulin)

I I T (SICU)I I T (SICU)

Mortality:Mortality: conventconvent intenseintense p-valuep-value ICUICU 63(8.0%)63(8.0%) 35(4.6%)35(4.6%) <0.04 <0.04 ICU<=5 d.ICU<=5 d. 14(1.8%)14(1.8%) 13(1.7%)13(1.7%) 0.9 0.9 ICU> 5 d.ICU> 5 d.49(20.2%)49(20.2%) 22(10.6%)22(10.6%)

0. 0050. 005 Hosp(all)Hosp(all) 85(10.9%)85(10.9%) 55(7.2%)55(7.2%) 0.01 0.01 Hosp+ICU>5d. 64(26.3)Hosp+ICU>5d. 64(26.3) 35(16.8%)35(16.8%)

0.010.01 Cause/death:Cause/death:

MOF + SepsisMOF + Sepsis 3333 8 8 MOF w/o SepsisMOF w/o Sepsis 1818 14 14

I I T (SICU)I I T (SICU) IIT also reduced bloodstream infections by IIT also reduced bloodstream infections by

46%, ARF requiring HD by 41%, median # of 46%, ARF requiring HD by 41%, median # of RBC transfusion by 50%, and critical illness RBC transfusion by 50%, and critical illness polyneuropathy by 44%; required less days in polyneuropathy by 44%; required less days in the SICU and less mechanical ventilation days.the SICU and less mechanical ventilation days.

Hypoglycemia (< 40 mg/dl) occurred in 39 pts Hypoglycemia (< 40 mg/dl) occurred in 39 pts in IIT group vs. 6 in conventional group. 2/39 in IIT group vs. 6 in conventional group. 2/39 were symptomatic with sweating and agitation.were symptomatic with sweating and agitation.

Post-hoc analysis confirmed best results with Post-hoc analysis confirmed best results with blood glucose 80-110 mg/dl, but blood glucose blood glucose 80-110 mg/dl, but blood glucose < 150 mg/dl was also beneficial (less risk for < 150 mg/dl was also beneficial (less risk for hypoglycemia). hypoglycemia).

Intensive Insulin Intensive Insulin Therapy in the Medical Therapy in the Medical

ICUICUVan den Berghe, G., Wilmer, A., Van den Berghe, G., Wilmer, A.,

Hermans, G., et al., NEJM, 2006; Hermans, G., et al., NEJM, 2006; 354: 449-61.354: 449-61.

I I T (MICU)I I T (MICU)

Prospective, single center, randomized, Prospective, single center, randomized, controlled study of controlled study of adult MICU patients who adult MICU patients who would likely need intensive care for at least 3 would likely need intensive care for at least 3 days.days.

Intention to treat analysis of 1200 pts. enrolled Intention to treat analysis of 1200 pts. enrolled between 3/02 and 5/05.between 3/02 and 5/05.

605 received conventional treatment: insulin 605 received conventional treatment: insulin drip for blood glucose > 215 mg/dl; then kept drip for blood glucose > 215 mg/dl; then kept 180-200 mg/dl.180-200 mg/dl.

595 received IIT: insulin drip started for blood 595 received IIT: insulin drip started for blood glucose > 110 mg/dl; then kept 80-110 mg/dl.glucose > 110 mg/dl; then kept 80-110 mg/dl.

I I T (MICU)I I T (MICU) Morbidity was significantly reduced in the IIT Morbidity was significantly reduced in the IIT

group: less days of mechanical ventilation, group: less days of mechanical ventilation, fewer MICU days, fewer hospital days, fewer fewer MICU days, fewer hospital days, fewer instances of ARF.instances of ARF.

Mortality: no difference in the intention-to-treat Mortality: no difference in the intention-to-treat group (26.8% vs. 24.2%, p=0.31); for those who group (26.8% vs. 24.2%, p=0.31); for those who did stay in the MICU for 3 or more days, the IIT did stay in the MICU for 3 or more days, the IIT group had better outcomes (31.3% vs. 38.1%, group had better outcomes (31.3% vs. 38.1%, p=0.05)p=0.05)

These differences held for in-hospital and 90-These differences held for in-hospital and 90-day mortality as well.day mortality as well.

IIT will benefit those MICU patients who remain IIT will benefit those MICU patients who remain in the MICU for at least 3 daysin the MICU for at least 3 days (cannot be (cannot be predicted reliably upon admission).predicted reliably upon admission).

Intensive versus Intensive versus Conventional Glucose Conventional Glucose Control in Critically Ill Control in Critically Ill

PatientsPatientsThe NICE-SUGAR Study The NICE-SUGAR Study

InvestigatorsInvestigators

NEJM 2009, 360 : 1283-1297NEJM 2009, 360 : 1283-1297

NICE-SUGARNICE-SUGAR NICE-SUGAR : NICE-SUGAR : Normoglycemia in Intensive Care Normoglycemia in Intensive Care

Evaluation-Survival Using Glucose Algorithm Regulation Evaluation-Survival Using Glucose Algorithm Regulation was designed to see if intensive glucose control reduced was designed to see if intensive glucose control reduced mortality at 90 days.mortality at 90 days.

Multicenter, parallel-group, randomized, controlled trial Multicenter, parallel-group, randomized, controlled trial involving adult medical and surgical patents admitted to involving adult medical and surgical patents admitted to the ICUs of 42 hospitals in Australia, New Zealand, and the ICUs of 42 hospitals in Australia, New Zealand, and Canada.Canada.

Eligible patients were admitted to the ICU within the Eligible patients were admitted to the ICU within the preceding 24 hrs and were expected to say at least 3 days preceding 24 hrs and were expected to say at least 3 days in the ICUin the ICU

Patients were randomly assigned to either the :Patients were randomly assigned to either the : Intensive control group – target range of 81 – 108 mg/dlIntensive control group – target range of 81 – 108 mg/dl Conventional control group – target range of 180 mg/dl or less.Conventional control group – target range of 180 mg/dl or less. Both groups were to follow specific treatment algorithms Both groups were to follow specific treatment algorithms

NICE-SUGARNICE-SUGAR Patients were randomly assigned to either the :Patients were randomly assigned to either the :

IntensiveIntensive control group – target range of control group – target range of 81 – 108 mg/dl81 – 108 mg/dl ConventionalConventional control group – target range of control group – target range of 180 mg/dl or less.180 mg/dl or less. Both groups were to follow specific treatment algorithms Both groups were to follow specific treatment algorithms

Primary outcome Primary outcome : : death from any cause within 90 death from any cause within 90 days after randomizationdays after randomization

Secondary outcome : Secondary outcome : survival time during first 90 days, survival time during first 90 days, cause-specific death, and duration of mechanical cause-specific death, and duration of mechanical ventilation, RRT, ICU stay, & hospital stay.ventilation, RRT, ICU stay, & hospital stay.

Tertiary outcomes : Tertiary outcomes : death from any cause within 28 death from any cause within 28 days after randomization, place of death, incidence of days after randomization, place of death, incidence of new organ failure, positive blood cultures, red-cell new organ failure, positive blood cultures, red-cell transfusions.transfusions.

NICE-SUGARNICE-SUGAR Serious Adverse Events Serious Adverse Events : : Blood glucose level < 40 Blood glucose level < 40

mg/dlmg/dl Results :Results : 40,171 pts were assessed; 6104 patients were 40,171 pts were assessed; 6104 patients were

successfully randomized between 12/04 through 11/08; successfully randomized between 12/04 through 11/08; 3054 to the Intensive group and 3050 to the Conventional group; 3054 to the Intensive group and 3050 to the Conventional group; over 99% pts in each followed he preset algorithm for glucose over 99% pts in each followed he preset algorithm for glucose

management.management. 97.2% of the Intensive group received insulin vs. 69% of 97.2% of the Intensive group received insulin vs. 69% of

the Conventional group (p<0.001).the Conventional group (p<0.001). Mean daily insulin dose was larger in the Intensive group Mean daily insulin dose was larger in the Intensive group

( 50.2 +/- 38.1 units vs 16.9 +/- 29.0 units, p<0.001)( 50.2 +/- 38.1 units vs 16.9 +/- 29.0 units, p<0.001) More pts in the Intensive group rec’d CS (34.6 vs 31.7%, More pts in the Intensive group rec’d CS (34.6 vs 31.7%,

p=.02)p=.02)

NICE-SUGARNICE-SUGAR

Results : 90 days after randomizationResults : 90 days after randomization 829 / 3010 (27.5%) in the Intensive group died829 / 3010 (27.5%) in the Intensive group died 751 / 3012 (24.9%) in the Conventional group died751 / 3012 (24.9%) in the Conventional group died OR for death for Intensive Rx was 1.14 , p=0.02OR for death for Intensive Rx was 1.14 , p=0.02 Median survival time was shorter in the Intensive Median survival time was shorter in the Intensive

group, OR=1.11, p=0.03group, OR=1.11, p=0.03 Proximate causes of death were similar, but the Proximate causes of death were similar, but the

Intensive group had more CV deaths (41.6% vs 35.8%, Intensive group had more CV deaths (41.6% vs 35.8%, p=0.02)p=0.02)

66% pts died in ICU, 26% died in non-critical areas, 66% pts died in ICU, 26% died in non-critical areas, 7.5% died after hospital discharge.7.5% died after hospital discharge.

90% of pts who died had life-sustaining treatments 90% of pts who died had life-sustaining treatments withheld or withdrawnwithheld or withdrawn


Results (cont) :Results (cont) : No significant difference between 2 groups in median LOS in No significant difference between 2 groups in median LOS in

ICU or hospitalICU or hospital Number of pts who developed new organ failures were similar Number of pts who developed new organ failures were similar

for both groupsfor both groups No significant difference in the number of ventilator days, No significant difference in the number of ventilator days,

RRT, rates of + blood cultures, or PRBC transfusions between RRT, rates of + blood cultures, or PRBC transfusions between the 2 groups.the 2 groups.

For 90-day mortality, there was no difference between For 90-day mortality, there was no difference between operative and non-operative pts, those with or without DM, operative and non-operative pts, those with or without DM, those with or without severe sepsis, and those with APACHE those with or without severe sepsis, and those with APACHE II scores < or >= 25.II scores < or >= 25.

Severe hypoglycemia occurred in 6.8% of the Intensive group Severe hypoglycemia occurred in 6.8% of the Intensive group vs 0.5% in the Conventional group; 272 episodes vs 16 vs 0.5% in the Conventional group; 272 episodes vs 16 episodes.episodes.


Conclusions :Conclusions : Intensive glucose control in adult ICU pts, as Intensive glucose control in adult ICU pts, as

compared with Conventional glucose control, compared with Conventional glucose control, increased the absolute risk of death at 90 days by increased the absolute risk of death at 90 days by 2.6% 2.6% NN to harm = 38. NN to harm = 38.

Severe hypoglycemia was significantly more Severe hypoglycemia was significantly more common with Intensive glucose control.common with Intensive glucose control.

A goal of normoglycemia does not necessarily A goal of normoglycemia does not necessarily benefit ICU pts and may be harmful.benefit ICU pts and may be harmful.

A blood glucose target of < 180 mg/dl resulted in A blood glucose target of < 180 mg/dl resulted in lower mortality than a target of 81-108 mg/dl – lower mortality than a target of 81-108 mg/dl – Don’t use the lower target in critically ill adults.Don’t use the lower target in critically ill adults.

Management BundleManagement Bundle 4. Prevent Excessive Inspiratory Plateau 4. Prevent Excessive Inspiratory Plateau

PressuresPressures – inspiratory plateau pressures – inspiratory plateau pressures should be maintained < 30 cm H2O for should be maintained < 30 cm H2O for mechanically ventilated patients.mechanically ventilated patients.

Most patients with severe sepsis and septic Most patients with severe sepsis and septic shock will require intubation and shock will require intubation and mechanical ventilationmechanical ventilation

Nearly 50% of these patients will develop Nearly 50% of these patients will develop acute lung injury (ALI) or acute respiratory acute lung injury (ALI) or acute respiratory distress syndrome (ARDS)distress syndrome (ARDS) Bilateral patchy infiltrates on CXRBilateral patchy infiltrates on CXR Low PaO2/FiO2 ratios (ALI < 300, ARDS < 200)Low PaO2/FiO2 ratios (ALI < 300, ARDS < 200) PCWP < 18 mmHg PCWP < 18 mmHg

Ventilation with Lower Tidal Ventilation with Lower Tidal Volumes as Compared with Volumes as Compared with

Traditional Tidal Volumes for Traditional Tidal Volumes for ALI and ARDSALI and ARDS

The Acute Respiratory Distress The Acute Respiratory Distress Syndrome Network, NEJM, 2000; Syndrome Network, NEJM, 2000;

342: 1301-08.342: 1301-08.

ARDSARDS Largest trial of a volume- and pressure-limited Largest trial of a volume- and pressure-limited

strategy that showed a strategy that showed a 9% decrease (31% vs. 9% decrease (31% vs. 39.8%)of all-cause mortality in patients 39.8%)of all-cause mortality in patients ventilated with tidal volumes of 6 ml/kgventilated with tidal volumes of 6 ml/kg of of estimated LBW (as opposed to 12 ml/kg) while estimated LBW (as opposed to 12 ml/kg) while aiming for a plateau pressure of < 30 cm H2O.aiming for a plateau pressure of < 30 cm H2O.

Hypercapnia is well tolerated in patients with Hypercapnia is well tolerated in patients with ALI/ARDS if necessary to minimize plateau ALI/ARDS if necessary to minimize plateau pressures and tidal volumes. A pH 7.20-7.25 is pressures and tidal volumes. A pH 7.20-7.25 is reasonable, but this has not been studied reasonable, but this has not been studied prospectively.prospectively.

Positive end-expiratory pressure (PEEP) prevents Positive end-expiratory pressure (PEEP) prevents alveoli from collapsing at end-expiration; alveoli from collapsing at end-expiration; “recruits” or opens atelectatic areas to “recruits” or opens atelectatic areas to participate in gas exchange. participate in gas exchange.


To summarize: 4 elements that must be To summarize: 4 elements that must be addressed or completed within the first 24 addressed or completed within the first 24 hours of presentation; can run hours of presentation; can run concurrently with the resuscitation bundle.concurrently with the resuscitation bundle. 1. Administer low dose CS by a standard 1. Administer low dose CS by a standard

policy.policy. 2. Administer DroAA (rhAPC) by a standard 2. Administer DroAA (rhAPC) by a standard

policy.policy. 3. Maintain Adequate Glycemic Control.3. Maintain Adequate Glycemic Control. 4. Prevent Excessive Inspiratory Plateau 4. Prevent Excessive Inspiratory Plateau

Pressures.Pressures.

ConclusionsConclusions

Severe sepsis and septic shock have Severe sepsis and septic shock have mortality rates between 30-50%.mortality rates between 30-50%.

To have any chance of reducing this To have any chance of reducing this significantly, we must apply best significantly, we must apply best practices as stipulated in the literature.practices as stipulated in the literature.

By “bundling” the elements together, By “bundling” the elements together, we will be more successful in we will be more successful in accomplishing the many necessary accomplishing the many necessary tasks in treating these critically ill tasks in treating these critically ill patients.patients.

APACHE IIAPACHE II Age in yearsAge in years

under 44-------------------0 Pointsunder 44-------------------0 Points45-54-----------------------2 Points 45-54-----------------------2 Points 55-64-----------------------3 Points 55-64-----------------------3 Points 65-74-----------------------5 Points 65-74-----------------------5 Points over 74---------------------6 Pointsover 74---------------------6 Points

History History of severe organ insufficiency or immunocompromised?of severe organ insufficiency or immunocompromised?Yes, and non-operative or emergency post-operative patient-----Yes, and non-operative or emergency post-operative patient-----5 Points 5 Points Yes, and elective post-operative patient----2 Points Yes, and elective post-operative patient----2 Points No--------------------------0 PointsNo--------------------------0 Points

Rectal Temperature Rectal Temperature over 40.9-------------------4 Points over 40.9-------------------4 Points 39-40.9--------------------3 Points 39-40.9--------------------3 Points 38.5-38.9------------------1 Points 38.5-38.9------------------1 Points 36-38.4--------------------0 Points 36-38.4--------------------0 Points 34-35.9--------------------1 Points 34-35.9--------------------1 Points 32-33.9--------------------2 Points 32-33.9--------------------2 Points 30-31.9--------------------3 Points 30-31.9--------------------3 Points below 30-------------------4 Pointsbelow 30-------------------4 Points

Heart rate Heart rate over 179-------------------4 Points over 179-------------------4 Points 140-179--------------------3 Points 140-179--------------------3 Points 110-139--------------------2 Points 110-139--------------------2 Points 70-109---------------------0 Points 70-109---------------------0 Points 55-69----------------------2 Points 55-69----------------------2 Points 40-54----------------------3 Points 40-54----------------------3 Points below 40------------------4 Points below 40------------------4 Points

Mean arterial pressure over 159-------------------4 Points 130-159--------------------3 Points 110-129--------------------2 Points 70-109---------------------0 Points 50-69----------------------2 Points below 50------------------4 Points

Respiratory Rate over 49---------------------4 Points 35-49-----------------------3 Points 25-34-----------------------1 Points 12-24-----------------------0 Points 10-11-----------------------1 Points 6-9-------------------------2 Points below 6--------------------4 Points

Arterial pHover 7.69-------------------4 Points 7.60-7.69-------------------3 Points 7.50-7.59-------------------1 Points 7.33-7.49-------------------0 Points 7.25-7.32-------------------2 Points 7.15-7.24-------------------3 Points below 7.15-----------------4 Points

White blood count White blood count over 39---------------------4 Pointsover 39---------------------4 Points20-39.9--------------------2 Points 20-39.9--------------------2 Points 15-19.9--------------------1 Points 15-19.9--------------------1 Points 3.0-14.9-------------------0 Points 3.0-14.9-------------------0 Points 1.0-2.9---------------------2 Points 1.0-2.9---------------------2 Points below 1.0------------------4 Points below 1.0------------------4 Points

Hematocrit over 59.9-------------------4 Points 50-59.9---------------------2 Points 46-49.9---------------------1 Points 30-45.9---------------------0 Points 20-29.9---------------------2 Points below 20-------------------4 Points

Serum sodium over 179-------------------4 Points 160-179-------------------3 Points 155-159-------------------2 Points150-154-------------------1 Points130-149-------------------0 Points 120-129-------------------2 Points111-119-------------------3 Pointsbelow 111-----------------4 Points

Serum Creatinine over 3.4 & acute renal fail---8 Points 2.0-3.4 & acute renal fail----6 Points over 3.4 & chronic renal fail-4 Points 1.5-1.9 & acute renal fail----4 Points 2.0-3.4 and chronic---------3 Points 1.5-1.9 and chronic---------2 Points 0.6-1.4---------------------0 Points below 0.6-------------------2 Points

Oxygenation Oxygenation (use PaO2 if FiO2 < 50%, (use PaO2 if FiO2 < 50%, otherwise use A-a gradient)otherwise use A-a gradient)A-a gradient over 499------4 PointsA-a gradient over 499------4 PointsA-a gradient 350-499------3 Points A-a gradient 350-499------3 Points A-a gradient 200-349------2 Points A-a gradient 200-349------2 Points A-a below 200 (if FiO2 A-a below 200 (if FiO2 over 49%) or pO2 more than 70 over 49%) or pO2 more than 70 (if FiO2 less than 50%)-----0 Points (if FiO2 less than 50%)-----0 Points pO2 = 61-70---------------1 Points pO2 = 61-70---------------1 Points pO2 = 55-60---------------3 Points pO2 = 55-60---------------3 Points pO2 below 55--------------4 PointspO2 below 55--------------4 Points

Serum potassium over 6.9-------------------4 Points6-6.9-----------------------3 Points 5.5-5.9---------------------1 Points 3.5-5.4---------------------0 Points 3-3.4-----------------------1 Points 2.5-2.9---------------------2 Points below 2.5------------------4 Points

MANAGEMENT OF SEVERE SEPSIS

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