MANAGEMENT OF SEVERE SEPSIS

1
MANAGEMENT OF SEVERE SEPSIS

• Virginia Chung, MD
• Director, MICU
• Jacobi Medical Center

2
INTRODUCTION

• Sepsis is a clinical syndrome that complicates
  severe infection and is characterized by systemic
  inflammation and widespread tissue injury.
• Tissues remote from the original insult display
  signs of inflammation, including vasodilation,
  increased microvascular permeability, and
  leukocyte accumulation.
• Tissue injury due to activation of the
  inflammatory system may also complicate
  noninfectious disorders such as acute
  pancreatitis or trauma.

3
TERMINOLOGY

• In 1992, the ACCP/SCCM consensus panel defined
  the following terms
• Infection microbial phenomenon characterized by
  an inflammatory response to the presence of
  microorganisms or the invasion of normally
  sterile host tissue by those organisms.
• Bacteremia presence of viable bacteria in the
  blood
• SIRS (Systemic Inflammatory Response Syndrome)
  is a widespread inflammatory response to a
  variety of severe clinical insults, manifested by
  2 or more of the following

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TERMINOLOGY

• SIRS
• Temperature gt 38ºC or lt 36ºC
• Heart rate gt 90 beats/min
• Respiratory rate gt 20 breaths/min or PaCO2 lt 32
  mmHg
• WBC count gt 12,000/mm3, lt4,000/mm3, or gt 10
  immature forms
• Sepsis is the systemic response to an
  infection, i.e., SIRS infection.
• Severe Sepsis sepsis associated with organ
  dysfunction, hypoperfusion, or hypotension.

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TERMINOLOGY

• Organ Dysfunction Criteria
• Cardiovascular SBP lt 90 mmHg or MAP lt 70 mmHg
  for at least 1 hour despite adequate volume
  resuscitation, or the use of vasopressors to
  achieve the same goals.
• Renal urine output lt 0.5 ml/kg of body weight
  for 1 hour despite adequate volume resuscitation.
• Pulmonary PaO2/FiO2 lt 250 if other organ
  dysfunction present or lt 200 if the lung is the
  only dysfunctional organ.
• Hematologic platelet count lt 80,000/mm3 or
  decreased by 50 over 3 days.
• Metabolic pHlt 7.30 or base deficit gt 5.0
  mmol/l AND plasma lactate gt 1.5 x upper limit of
  normal.
• CNS acute alteration in mental status

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TERMINOLOGY

• Septic Shock
• a subset of severe sepsis with hypotension
  despite adequate fluid resuscitation combined
  with perfusion abnormalities.
• patients requiring inotropic or vasopressor
  agents may no longer be hypotensive by the time
  they exhibit organ dysfunction, but are
  nonetheless considered to be in septic shock.
• form of vasodilatory or distributive shock
  resulting from a marked reduction in systemic
  vascular resistance it is often associated with
  an increased cardiac output but some patients can
  present with decreased cardiac output due to
  sepsis-induced cardiac dysfunction.

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SIRS SEPSIS
Infection/Trauma
Sepsis
Severe Sepsis
SIRS

• A clinical response arising from a nonspecific
  insult, including ? 2 of the following
• Temperature ?38oC or ?36oC
• HR ?90 beats/min
• Respirations ?20/min
• WBC count ?12,000/mm3 or ?4,000/mm3 or gt10
  immature neutrophils

SIRS with a presumed or confirmed infectious
process
SIRS Systemic Inflammatory Response Syndrome
Adapted from Bone RC, et al. Chest
19921011644 Opal SM, et al. Crit Care Med
200028S81
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SEVERE SEPSIS
Infection/Trauma
Sepsis
SIRS
Severe Sepsis
Sepsis with ?1 sign of organ failure Cardiovascul
ar (refractory hypotension) Renal Respiratory Hepa
tic Hematologic CNS Metabolic acidosis
Bone et al. Chest 19921011644 Wheeler and
Bernard. N England J Med 1999340207
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WORLDWIDE

• Incidence of severe sepsis is 3.0 cases / 1,000
• 18 million cases of severe sepsis annually.
• Kills approximately 1,400 people each day.
• Leading cause of death in non-coronary ICUs
• Number of cases of severe sepsis is growing at
  the rate of 1.5 per year.
• This translates to an additional 1 million cases
  per year in the USA alone by 2020.

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RISK FACTORS

• Factors potentially responsible for the growing
  incidence of severe sepsis and septic shock
• Increased awareness and sensitivity for the
  diagnosis.
• Increased number of immunocompromised
  individuals
• HIV/AIDS
• Increased use of cytotoxic and immunosuppressant
  agents
• Malnutrition
• Alcoholism
• Diabetes Mellitus

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RISK FACTORS

• Increased number of transplant recipients and
  transplantation procedures.
• Increased use of aggressive invasive procedures
  in patient management and diagnosis.
• Increased number of resistant microorganisms.
• Increased number of elderly patients.
• Increased number of institutionalized individuals.

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MORTALITY
Mortality
Incidence
Approximately 200,000 patients including 70,000
Medicare patients have septic shock annually
Balk, R.A. Crit Care Clin 200033752
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WHAT CAN WE DO AS HEALTHCARE PROVIDERS TO IMPROVE
THESE MORTALITY STATISTICS ?
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IHI / SSC

• To expedite Quality Improvement (QI) in health
  care, the Institute for Healthcare Improvement
  (IHI) launched the 100,000 Lives Campaign in
  December 2004.
• This was a national initiative that had a goal of
  saving 100,000 lives among patients in hospitals
  through improvements in the safety and
  effectiveness of health care by June 18, 2006.
• A life saved was defined as a patient
  successfully discharged from a hospital who,
  absent the changes achieved through the campaign,
  would not have survived.
• All 5,759 hospitals in the U.S. were invited to
  join this campaign. The Health and Hospitals
  Corporation (HHC) with its 11 member hospitals
  (including Jacobi and NCB) were participants

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IHI / SSC

• IHI Campaign Interventions
• Deploy Rapid Response Teams (RRT/MET)
• Deliver Reliable Evidence-Based Care for Acute MI
• Prevent Adverse Drug Events Through Medication
  Reconciliation.
• Prevent Central Line Infections.
• Prevent Surgical Site Infections.
• Prevent Ventilator-Associated Pneumonia

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IHI / SSC

• At the same time, the Critical Care community
  formed a working group, launched the Surviving
  Sepsis Campaign (SSC), and published their
  Guidelines for Management of Severe Sepsis and
  Septic Shock in the March 2004 issue of Critical
  Care Medicine.
• IHI and the SSC working group have since teamed
  up to wage war on sepsis their goal is to
  achieve a 25 reduction in sepsis mortality by
  2009.
• To implement these evidence-based guidelines, 3
  core strategies are recommended
• Model for improvement Plan-Do-Study-Act (PDSA)
  cycles
• Using Bundles to simplify the complex process
  of caring for patients with severe sepsis by
  grouping specific management elements together.
• Enhancing reliability of the bundled elements.

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SEVERE SEPSIS BUNDLES

• A bundle is a group of interventions related to
  a specific disease process that, when executed
  together, result in better outcomes than when
  implemented individually. The elements of the
  bundle are based upon evidence-based practice and
  should be considered generally accepted practice.
• There are 2 different Severe Sepsis Bundles. Each
  bundle articulates objectives to be accomplished
  within specific timeframes
• Severe Sepsis Resuscitation Bundle
• Severe Sepsis Management Bundle

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Resuscitation Bundle

• Describes 7 tasks that should begin immediately,
  but must be accomplished within the first 6 hours
  of presentation for patients with severe sepsis,
  septic shock, or a lactate gt 4 mmol/l.
• 1. Measure serum lactate hyperlactatemia is
  typically present and may be secondary to
  anaerobic metabolism due to hypoperfusion
  obtaining a level is essential to identifying
  tissue hypoperfusion in patients who are not yet
  hypotensive, but who are at risk for septic shock.

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Resuscitation Bundle

• 2. Blood Cultures Obtained Prior to Antibiotic
  Administration 30-50 of these patients will
  have positive blood cultures best hope of
  identifying the organism causing severe sepsis.
  Two or more blood cultures are recommended.
• In patients with suspected catheter-related
  infection, blood cultures should be drawn
  simultaneously through the catheter hub and from
  a peripheral site. If the same organism is
  recovered and the culture drawn from the line is
  positive much earlier than the peripheral
  culture, then it is likely that the catheter is
  the source of infection.

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Resuscitation Bundle

• 3. Improve Time to Broad-Spectrum Antibiotics
  early administration of appropriate antibiotics
  reduces mortality in patients with Gram() and
  Gram(-) bacteremias. Therefore, broad-spectrum
  antibiotics should be given within 3 hours from
  time of presentation to the E.D. or within 1 hour
  for ward patients transferred to the ICU.
• Major sources of infection in severe sepsis or
  septic shock are pneumonia and intra-abdominal
  infections other sources accounting for lt 5 of
  cases.
• Choice of antibiotics should be guided by the
  susceptibility patterns of likely pathogens in
  the community or hospital as well as any specific
  knowledge about the patient. The regimen should
  cover all likely pathogens since there is little
  margin for error in critically ill patients.
  Re-evaluate at 48-72 hours.

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Resuscitation Bundle

• 4. Treat Hypotension and/or Elevated Lactate with
  fluids patients may experience ineffective
  arterial circulation due to vasodilatation or
  impaired cardiac output poorly perfused tissue
  beds result in global tissue hypoxia leading to
  an elevated serum lactate level.
• Lactate gt 4 mmol/l or 36 g/dl is correlated with
  increased severity of illness and poorer outcomes
  even if hypotension is not yet present.
• Initial administration of at least of 20 ml/kg of
  crystalloid as a fluid challenge should be given
  ASAP to these patients boluses should be
  repeated as necessary.

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Resuscitation Bundle

• Fluid Challenge describes the initial volume
  expansion period in which the patient response is
  closely monitored 4 components are
• 1. Fluid type crystalloid vs. colloid
• 2. Infusion rate 500-1,000 ml over 15-30
  minutes
• 3. End points MAP gt 65 or 70 mmHg, hr lt 110
  beats/min
• 4. Safety limits pulmonary edema
• Crystalloid vs. Colloid the volume of
  distribution for crystalloids is much larger than
  for colloids, hence a larger volume of
  crystalloids will be required to achieve the same
  goals and could result in more edema.

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

• The SAFE (Saline versus Albumin Fluid Evaluation)
  Study Investigators
• NEJM 2004 350 2247-56

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SAFE STUDY

• Multicenter, randomized, double-blind trial
  comparing the effect of fluid resuscitation with
  4 albumin versus normal saline on 28-day
  mortality in the 16 ICUs in Australia New
  Zealand.
• 7,000 patients age 18 or older were randomized.
• 3 were mistakenly randomized twice, leaving 6,997
  patients in the study 3,497 received 4 albumin
  and 3,500 received NS.
• Results 726 deaths in the albumin group and 729
  in NS group (relative risk of death 0.99
  p0.87) additionally, there was no significant
  differences in ICU days, hospital days,
  mechanical ventilation days, renal-replacement
  therapy days, or development of new single or
  multiorgan failures.

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Resuscitation Bundle

• End Points of Fluid Resuscitation for
  refractory hypotension not responding to fluids
  or lactate gt 4 mmol/l, patients should now enter
  the Early Goal Directed Therapy (EGDT) phase of
  the Resuscitation Bundle where central venous
  pressure (CVP) gt 8 mmHg and central venous
  saturation (ScvO2) gt 65-70 are the goals.
• Rivers, et al., demonstrated a 34 reduction in
  hospital mortality for the patients in the EGDT
  group versus those in the standard therapy group.
• The degree of intravascular volume deficit in
  septic patients varies with venodilation and
  ongoing capillary leak, most patients require
  aggressive fluid resuscitation during the first
  24 hours of management.

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Resuscitation Bundle

• 5. Apply Vasopressors for Ongoing Hypotension
  (Shock) when an appropriate fluid challenge
  fails to restore an adequate arterial pressure
  and organ perfusion, therapy with vasopressors
  should be started vasopressors may be required
  transiently to sustain life even when hypovolemia
  has not been corrected or when a fluid challenge
  is in progress.
• MAP (mean arterial pressure) gt 65 mmHg
• Place arterial catheter for continuous blood
  pressure measurements ABGs, lactates readily
  available

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Resuscitation Bundle

• Choice of Vasopressors either norepinephrine or
  dopamine is the first-choice vasopressor agent to
  correct hypotension in septic shock epinephrine
  and phenylephrine should not be used as
  first-line vasopressors because they decrease
  splanchnic blood flow significantly
• Vasopressin can be added when patients are still
  in shock despite adequate fluid resuscitation and
  high-dose conventional vasopressors.

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Vasopressors

• Dopamine natural precursor of NE and Epi and
  possesses several dose-dependent pharmacologic
  effects.
• Low doses (lt 5 mcg/kg/min) stimulates
  dopaminergic DA1 receptors in the renal,
  mesenteric, and coronary beds, resulting in
  vasodilation.
• Intermediate doses (5-10 mcg/kg/min)
  ß-adrenergic effects predominate, resulting in an
  increase in cardiac contractility and heart rate
• High doses (gt10 mcg/kg/min) a-adrenergic
  effects predominate, leading to arterial
  vasoconstriction and an increase in blood
  pressure.
• Systemic hemodynamic effects of dopamine in
  septic patients increases MAP primarily by
  increasing cardiac index with minimal effects on
  SVR SV increases more than heart rate.
• Very high doses (gt20 mcg/kg/min) increases
  heart rate and right heart pressures consider
  alternative agent.

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Vasopressors

• Norepinephrine (NE) is a potent a-adrenergic
  agonist with some ß-adrenergic agonist effects
  increases MAP due to vasoconstrictive effects,
  with little change in heart rate or cardiac
  output, leading to increased SVR.
• In open label trials, NE was shown to increase
  MAP in hypo-tensive patients resistant to fluid
  resuscitation and dopamine.
• In the past, there was concern that NE may have
  negative effects on splanchnic and renal blood
  flow leading to regional ischemia however,
  recent experience does not support this.
• In hyperdynamic septic shock, NE markedly
  improves MAP and glomerular filtration after
  restoration of systemic hemodynamics urine output
  increases and renal function improves in most
  patients.

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Resuscitation Bundle

• 6. Maintain Adequate Central Venous Pressure in
  the event of persistent hypotension despite fluid
  resuscitation (septic shock) and/or lactate gt 4
  mmol/l (36 mg/dl) achieve CVP gt 8 mmHg.
• Patients should receive the initial minimum of 20
  ml/kg fluid challenge prior to placement of a
  Central Venous Catheter (CVC) and attempts to
  optimize CVP.
• For patients who are hypovolemic and anemic with
  a Hct lt 30, consider transfusing packed RBCs
  blood is a better volume expander and increases
  oxygen carrying capacity.
• In mechanically ventilated patients, a higher
  target CVP gt 12 mmHg is recommended because
  positive pressure ventilation causes increases in
  intrathoracic pressures and decreases venous
  return.

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Resuscitation Bundle

• 7. Maintain Adequate Central Venous Oxygen
  Saturation (ScvO2) in the event of persistent
  hypotension despite fluid resuscitation (septic
  shock) and/or lactate gt 4 mmol/l (36 g/dl)
  achieve a ScvO2 gt 70 OR a mixed venous oxygen
  saturation (SvO2) via PA catheter gt 65.
• Strategies to achieve target ScvO2
• If the CVP gt 8 mmHg and Hct lt 30, transfuse PRBCs
  to increase oxygen carrying capacity and hence
  oxygen delivery to the tissues.
• If the patient has underlying cardiac dysfunction
  or has developed sepsis-induced cardiac
  dysfunction, then add an inotrope (dobutamine)
  provided the patient has been fluid resuscitated
  and transfused (if indicated). Increasing cardiac
  output increases oxygen delivery to the tissues.

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Early Goal-Directed Therapy in the Treatment of
Severe Sepsis and Septic Shock

• Rivers, E., M.D., M.P.H., Nguyen, B., M.D., et.
  al., for the Early Goal-Directed Therapy
  Collaborative Group NEJM, 2001, 3451368-1377.

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EGDT

• Randomized, controlled, predominantly blinded
  study in the E.D. of an 850-bed tertiary referral
  center (Henry Ford Hospital, Detroit, MI) over a
  3-yr period (3/1997-3/2000).
• Enrollment criteria 2 of 4 SIRS criteria with a
  SBP lt 90 mmHg after a 20-30 ml/kg fluid challenge
  or a blood lactate level gt 4 mmol/l (36 g/dl).
• Patients either received 6 hours of standard
  therapy or 6 hours of goal-directed therapy
  before admission to the ICU clinicians
  subsequently involved in the care of the study
  patients were blinded to the treatment arm of the
  study.
• Control group followed an existing protocol for
  hemodynamic support CVP 8-12 mmHg, MAP gt 65
  mmHg, urine output gt 0.5 ml/kg/hr 500 ml fluid
  boluses and vasopressors were used.

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EGDT

• Treatment group had the same aims as the control
  group PLUS they had to achieve a central venous
  oxygen saturation (ScvO2) gt 70
• If the ScvO2 lt 70 and
• Hct lt 30, transfuse PRBCs
• MAP gt 90 mmHg, give vasodilators until MAP lt 90
  mmHg
• If CVP, Hct, and MAP were in the optimal range
  and ScvO2 still lt 70, start dobutamine 2.5
  mcg/kg/min (inotrope) and titrate it up by 2.5
  mcg/kg/min every 30 min until ScvO2 gt 70 or a
  maximum dose of 20 mcg/kg/min is reached. The
  dose was decreased or d/ced if MAP lt 65 mmHg or
  hr gt 120 beats/min
• Finally, to decrease O2 demand, sedate and
  mechanically ventilate the patient.

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EGDT

• Results 263 patients randomized 133 received
  standard therapy and 130 received EGDT Temp, hr,
  urine output, BP, CVP were measured cont. for 6
  hours, then q 12h for 72 hrs.
• During the initial 6 hours, the EGDT group
  received more IV fluids, red cell transfusions,
  and inotropic therapy than the control group.
• During the subsequent 66 hours, the control group
  received more transfusions, more vasopressors,
  and had a greater requirement for mechanical
  ventilation and PA catheterization.
• This showed that the control group was relatively
  under-resuscitated initially.
• In-hospital mortality was significantly higher in
  the control group than in the EGDT group 46.5
  versus 30.5 (p0.009).

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Resuscitation Bundle

• To summarize, for patients presenting with severe
  sepsis, septic shock, or lactate gt 4 mmol/l, the
  following 7 tasks need to be accomplished within
  the first 6 hours of presentation
• 1. Measure serum lactate.
• 2. Obtain blood cultures prior to antibiotic
  administration.
• 3. Improve time to broad-spectrum antibiotics (lt
  3 hrs).
• 4. Treat hypotension and/or elevated lactate with
  fluids.
• 5. Apply vasopressors for ongoing hypotension.
• 6. Maintain adequate CVP (gt 8 mmHg).
• 7. Maintain adequate ScvO2 (gt 70).

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Management Bundle

• Describes 4 tasks that must be completed within
  24 hours of presentation for patients with severe
  sepsis, septic shock, and/or lactate gt4 mmol/l.
• 1. Administer Low-Dose Steroids by a Standard
  Policy IV corticosteroids (hydrocortisone
  200-300 mg/day, for 7 days in 3-4 divided doses)
  may be given in patients with septic shock who
  despite adequate fluid replacement require
  vasopressor therapy to maintain adequate blood
  pressure.
• The use of fludrocortisone in addition to
  low-dose hydrocortisone is considered optional.
  Absolute primary adrenal insufficiency is rare in
  septic shock (0-3).

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Management Bundle

• In refractory septic shock, the prevalence of
  Relative Adrenal Insufficiency (RAI) may be as
  high as 50-75. RAI may be present when the
  increase in serum cortisol level is lt 9 mcg/dl,
  30-60 min after a 250- mcg ACTH stimulation.
• Low dose Corticosteroids (CS)promote shock
  reversal. Their effects on vascular tone were
  recognized well before their anti-inflammatory
  properties. In patients with septic shock, low
  dose CS significantly reduces nitrite/nitrate
  plasma concentrations, indicating inhibition of
  NO formation.
• Median time to cessation of vasopressors in one
  study decr. from 13 to 4 days and 7 to 3 days in
  another. Another study showed that MAP and SVR
  increased and HR, CI, and NE requirement
  decreased with the use of low-dose CS.

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

• Annane, D., Sebille, V., Charpentier, C., et al.,
  JAMA, 2002 288 862-871

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Low Dose CS

• Placebo-controlled, randomized, double-blind,
  parallel-group trial performed in 19 ICUs in
  France from 1995-1999.
• 1326 pts were assessed for eligibility 1026 were
  ineligible 300 randomized to receive either
  hydrocortisone 50 mg IV q6h and fludrocortisone
  50 mcg po qd or matching placebos for 7 days.
• Corticotropin test was performed in all patients
  RAI was defined as a response of 9 mcg/dl or
  less. RAI pts were deemed Nonresponders while
  those who had a gt9 mcg/dl increase were
  Responders.

42
Low Dose CS

• Mortality rates
• All patients there was no significant effect of
  CS on 28-day, ICU, hospital, and 1-year mortality
  rates.
• Responders (gt9 mcg/dl incr.) there was no
  significant effect of CS on 28-day, ICU,
  hospital, and 1-year mortality rates.
• Nonresponders (lt 9 mcg/dl incr.)
• 28 days placebo 73 (63) CS 60 (53)
  deaths p.04
• ICU placebo 81 (70) CS 66
  (58) deaths p.02
• Hospital placebo 83 (72) CS 70 (61)
  deaths p.04
• 1-year placebo 88 (77) CS 77
  (68) deaths p.07

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Low Dose CS

• Median Time-to-Vasopressor-Therapy Withdrawal
• All patients 9 days (placebo) , 7 days (CS) ,
  p.01
• Responders 7 days (placebo) , 9 days (CS) ,
  p.49
• Nonresponders 10 days (placebo) , 7 days (CS) ,
  p.001
• No significant differences between the 2 groups
  in the rates of adverse events related to CS
  (infection, GI bleed, psychiatric d/o).
• Conclusion in pressor-dependent septic shock,
  administer low dose CS and fludrocortisone for 7
  days in those with RAI.

44
Hydrocortisone Therapy for Patients with Septic
Shock (CORTICUS)

• Sprung, C., Annane, D., Keh, D., et. al., for the
  CORTICUS Study Group, NEJM, 2008, 358 111-124

45
CORTICUS

• Multicenter, randomized, double-blind,
  placebo-controlled study conducted in 52 ICUs
  across Europe and Israel from 3/02 to 11/05.
• Purpose evaluate the efficacy and safety of
  low-dose hydrocortisone in pts with septic shock.
• Eligibility onset of septic shock w/i previous
  72 hrs with evidence of hypoperfusion or organ
  dysfunction attributable to sepsis.
• Exclusions underlying disease with poor
  prognosis, moribund (death w/i 24 hrs),
  immunosuppressed, long-term CS within 6 months or
  short term CS within 4 weeks.

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CORTICUS

• Lab data corticotropin test performed with
  0.25mg cosyntropin with blood samples collected
  at time 0 and at 60 minutes samples were frozen
  and cortisol levels measured just before interim
  and final analysis.
• Protocol study drug (50 mg hydrocortisone) given
  q6h x 5 days, then q12h x 3 days, then q24h x 3
  days 29 total doses.
• End Points
• Primary - 28 day mortality rate in pts who DID
  NOT have a response to corticotropin.
• Secondary 28 day mortality rate in pts who DID
  respond to corticotropin ICU mortality and
  hospital mortality for all patients.

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CORTICUS

• Results
• 500 pts randomized 252 received HC (1 w/d
  consent) and 248 received placebo.
• Of the 499 pts, 233 (46.7) did NOT have a
  response to ACTH 125 in the study group, 108 in
  placebo group
• 254 (50.9) did have a response to ACTH 118 in
  the study group, 136 in placebo group
• 12 remaining pts 8 in study group, 4 in placebo
  group had no data for cosyntropin test.

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CORTICUS
Hydrocortisone Hydrocortisone Placebo Placebo p value
respond non-res respond non-res
patients 118 125 136 108
Deaths _at_ 28 days 49 (39) 39 (36) 0.69
Deaths _at_ 28 days 34 (29) 39 (29) 1.00
Deaths _at_ 28 days 86 (34.3) 86 (34.3) 78 (31.5) 78 (31.5) 0.51
Shock rev. 95 (76) 76 (70) 0.41
Shock rev. 100 (85) 104 (77) 0.13
Shock rev. 200 (79.7 ) 200 (79.7 ) 184 (74.2 ) 184 (74.2 ) 0.18
49
CORTICUS

• Results (cont)
• Time to shock resolution was shorter in all
  patients (plt0.001) who received hydrocortisone
  regardless of whether or not they were responders
  (plt0.001) or non-responders. (p 0.06)
• All pts ( 3.3 days vs. 5.8 days )
• Responders ( 2.8 days vs. 5.8 days )
• Non-responders ( 3.9 days vs. 6.0 days)

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CORTICUS

• Results (cont)
• Adverse events in the hydrocortisone group,
  there was an increased incidence of
  superinfections with OR1.37 (CI of 1.05 to
  1.79), hyperglycemia, hypernatremia weakness was
  rarely reported.
• Conclusions
• Hydrocortisone (HC) cannot be recommended as
  general adjuvant therapy for septic shock
• Corticotropin testing is also not recommended to
  determine which patients should receive HC
  therapy
• HC may have a role among patients who are treated
  early after onset of septic shock who remain
  hypotensive despite high dose vasopressors.

51
Management Bundle

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

52
Efficacy and Safety of Recombinant Human
Activated Protein C for Severe Sepsis

• Bernard, G., Vincent, J., Laterre, P., et al.,
  for the PROWESS study group, NEJM, 2001 344
  699-709.

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PROWESS

• Randomized, double-blind, placebo-controlled
  trial conducted at 164 centers in 11 countries
  from 7/1998 through 6/2000 evaluating rhAPC (24
  mcg/kg/hr for 96 hours) in patients with severe
  sepsis.
• Inclusion criteria known or suspected infection
  PLUS 3 of 4 SIRS criteria PLUS at least one organ
  dysfunction (cardiac, renal, respiratory,
  hematologic) or presence of lactic acidosis.
• Exclusion criteria pregnancy, breast-feeding,
  agelt18, weightgt135 kg, platelet lt 30,000,
  increased risk of bleeding, known hypercoagulable
  condition, AIDS with CD4lt50, moribund state with
  imminent death, CRF on HD/PD, liver failure,
  acute pancreatitis w/o infection, very recent use
  of anticoagulants or thrombolytics, high dose
  ASA.

54
PROWESS

• Primary efficacy end point was death from any
  cause and was assessed 28 days after the
  initiation of the infusion Powered to detect a
  15 reduction in the RR of 28-day all-cause
  mortality.
• Trial was suspended at the time of the 2nd
  interim analysis after 1,520 patients had been
  enrolled. There were 259 (30.8) deaths in the
  placebo group versus 210 (24.7) deaths in the
  rhAPC group yielding an absolute 6.1 mortality
  reduction and 19.4 reduction in RR of death.
• 16 patients would need to be treated to save one
  (1) life in this study population.

55
PROWESS

• When subgroup analysis was performed, those
  patients with APACHE II scores gt 25 (quartile 3
  4), there was an absolute mortality reduction of
  13 (44 vs 31) and RR reduction of 29.5.
• 8 patients would need to be treated to save one
  (1) life.
• Adverse events serious bleeding events (ICH,
  life-threatening bleed, transfusion of 3 units
  prbc/day for 2 days, or assessed as serious by
  the investigator) occurred in 20 (2.4) of the
  rhAPC group versus 8 (1.0) in the placebo group.

56
PROWESS

• In November 2001, the US FDA narrowly approved
  rhAPC for sepsis-induced organ dysfunction
  associated with high risk of death, such as
  APACHE II score gt 25. (APACHE II Acute
  Physiology and Chronic Health Evaluation)
• In Europe, the European Agency for the Evaluation
  of Medicinal Products, approved rhAPC for the
  treatment of adult patients with gt 2 organ
  dysfunction.
• Very expensive drug, costing approximately US
  7,000 per 96 hour infusion.

57
Drotrecogin Alfa (Activated) for Adults with
Severe Sepsis and a Low Risk of Death

• Abraham, E., Laterre, P., Garg, R., et al., for
  the ADDRESS study group, NEJM, 2005 353 1332-41.

58
ADDRESS

• After approving rhAPC, the FDA required a study
  to evaluate the efficacy of rhAPC in adults with
  severe sepsis and low risk of death, i.e., APACHE
  II lt 25 or single organ dysfunction.
• 516 centers in 34 countries participated. The
  study began in 9/02 and was terminated early in
  2/04 because it was clear a significant reduction
  in 28-day mortality would not be shown.
• Mortality rhAPC 18.5 vs. Placebo 17.0
  p.34
• Serious Bleeding rhAPC 2.4 vs. Placebo
  1.2 p.02
• Patients who had recent surgery (lt 30 days) and
  single organ dysfunction and received rhAPC had a
  higher mortality rate than those who received
  placebo, although it did not achieve
  significance.

59
Management Bundle

• 3. Maintain Adequate Glycemic Control following
  initial stabilization of patients with severe
  sepsis, blood glucose should be maintained lt 150
  mg/dl. Continuous infusions of insulin and
  glucose are given. Glucose should be monitored
  frequently after initiating the protocol (q 30-60
  min) and on a regular basis (q4h) once blood
  glucose concentration has stabilized.

60
Intensive Insulin Therapy in Critically Ill
Patients

• Van den Berghe, G., Wouters, P., Weekers, F., et
  al., NEJM, 2001, 345 1359-67.

61
I I T (SICU)

• Prospective, single center, randomized,
  controlled study involving adults admitted to the
  SICU (Leuven, Belgium) requiring mechanical
  ventilation between 2/2/00 and 1/18/01.
• 1548 patients were enrolled. 63 were
  cardiothoracic patients.
• 783 received conventional treatment where the
  insulin drip was started only if the blood
  glucose level gt 215 mg/dl subsequent blood
  sugars were maintained between 180 and 200 mg/dl.
• 765 received intensive insulin therapy where the
  insulin drip was started for blood glucose gt 110
  mg/dl blood sugars were then maintained between
  80-110 mg/dl.

62
I I T (SICU)

• Patients received IV glucose for the first 24 hrs
  in the SICU, then were enterally and/or
  parenterally fed thereafter.
• 39.2 of pts. in the conventional group was
  started on an insulin drip versus 98.7 in the
  intensive group (only 10 pts did not get IIT)
• Morning blood sugars
• Conventional 153 mg/dl (all) 173 mg/dl
  (insulin)
• Intensive Rx 103 mg/dl (all, insulin)

63
I I T (SICU)

• Mortality convent intense p-value
• ICU 63(8.0) 35(4.6) lt0.04
• ICUlt5 d. 14(1.8) 13(1.7) 0.9
• ICUgt 5 d. 49(20.2) 22(10.6) 0. 005
• Hosp(all) 85(10.9) 55(7.2) 0.01
• HospICUgt5d. 64(26.3) 35(16.8) 0.01
• Cause/death
• MOF Sepsis 33 8
• MOF w/o Sepsis 18 14

64
I I T (SICU)

• IIT also reduced bloodstream infections by 46,
  ARF requiring HD by 41, median of RBC
  transfusion by 50, and critical illness
  polyneuropathy by 44 required less days in the
  SICU and less mechanical ventilation days.
• Hypoglycemia (lt 40 mg/dl) occurred in 39 pts in
  IIT group vs. 6 in conventional group. 2/39 were
  symptomatic with sweating and agitation.
• Post-hoc analysis confirmed best results with
  blood glucose 80-110 mg/dl, but blood glucose lt
  150 mg/dl was also beneficial (less risk for
  hypoglycemia).

65
Intensive Insulin Therapy in the Medical ICU

• Van den Berghe, G., Wilmer, A., Hermans, G., et
  al., NEJM, 2006 354 449-61.

66
I I T (MICU)

• Prospective, single center, randomized,
  controlled study of adult MICU patients who would
  likely need intensive care for at least 3 days.
• Intention to treat analysis of 1200 pts. enrolled
  between 3/02 and 5/05.
• 605 received conventional treatment insulin drip
  for blood glucose gt 215 mg/dl then kept 180-200
  mg/dl.
• 595 received IIT insulin drip started for blood
  glucose gt 110 mg/dl then kept 80-110 mg/dl.

67
I I T (MICU)

• Morbidity was significantly reduced in the IIT
  group less days of mechanical ventilation, fewer
  MICU days, fewer hospital days, fewer instances
  of ARF.
• Mortality no difference in the
  intention-to-treat group (26.8 vs. 24.2,
  p0.31) for those who did stay in the MICU for 3
  or more days, the IIT group had better outcomes
  (31.3 vs. 38.1, p0.05)
• These differences held for in-hospital and 90-day
  mortality as well.
• IIT will benefit those MICU patients who remain
  in the MICU for at least 3 days (cannot be
  predicted reliably upon admission).

68
Intensive versus Conventional Glucose Control in
Critically Ill Patients

• The NICE-SUGAR Study Investigators
• NEJM 2009, 360 1283-1297

69
NICE-SUGAR

• NICE-SUGAR Normoglycemia in Intensive Care
  Evaluation-Survival Using Glucose Algorithm
  Regulation was designed to see if intensive
  glucose control reduced mortality at 90 days.
• Multicenter, parallel-group, randomized,
  controlled trial involving adult medical and
  surgical patents admitted to the ICUs of 42
  hospitals in Australia, New Zealand, and Canada.
• Eligible patients were admitted to the ICU
  within the preceding 24 hrs and were expected to
  say at least 3 days in the ICU
• Patients were randomly assigned to either the
• Intensive control group target range of 81
  108 mg/dl
• Conventional control group target range of 180
  mg/dl or less.
• Both groups were to follow specific treatment
  algorithms

70
NICE-SUGAR

• Patients were randomly assigned to either the
• Intensive control group target range of 81
  108 mg/dl
• Conventional control group target range of 180
  mg/dl or less.
• Both groups were to follow specific treatment
  algorithms
• Primary outcome death from any cause within 90
  days after randomization
• Secondary outcome survival time during first 90
  days, cause-specific death, and duration of
  mechanical ventilation, RRT, ICU stay, hospital
  stay.
• Tertiary outcomes death from any cause within
  28 days after randomization, place of death,
  incidence of new organ failure, positive blood
  cultures, red-cell transfusions.

71
NICE-SUGAR

• Serious Adverse Events Blood glucose level lt 40
  mg/dl
• Results 40,171 pts were assessed 6104 patients
  were successfully randomized between 12/04
  through 11/08
• 3054 to the Intensive group and 3050 to the
  Conventional group
• over 99 pts in each followed he preset algorithm
  for glucose management.
• 97.2 of the Intensive group received insulin vs.
  69 of the Conventional group (plt0.001).
• Mean daily insulin dose was larger in the
  Intensive group ( 50.2 /- 38.1 units vs 16.9 /-
  29.0 units, plt0.001)
• More pts in the Intensive group recd CS (34.6 vs
  31.7, p.02)

72
NICE-SUGAR

• Results 90 days after randomization
• 829 / 3010 (27.5) in the Intensive group died
• 751 / 3012 (24.9) in the Conventional group died
• OR for death for Intensive Rx was 1.14 , p0.02
• Median survival time was shorter in the Intensive
  group, OR1.11, p0.03
• Proximate causes of death were similar, but the
  Intensive group had more CV deaths (41.6 vs
  35.8, p0.02)
• 66 pts died in ICU, 26 died in non-critical
  areas, 7.5 died after hospital discharge.
• 90 of pts who died had life-sustaining
  treatments withheld or withdrawn

73
NICE-SUGAR

• Results (cont)
• No significant difference between 2 groups in
  median LOS in ICU or hospital
• Number of pts who developed new organ failures
  were similar for both groups
• No significant difference in the number of
  ventilator days, RRT, rates of blood cultures,
  or PRBC transfusions between the 2 groups.
• For 90-day mortality, there was no difference
  between operative and non-operative pts, those
  with or without DM, those with or without severe
  sepsis, and those with APACHE II scores lt or gt
  25.
• Severe hypoglycemia occurred in 6.8 of the
  Intensive group vs 0.5 in the Conventional
  group 272 episodes vs 16 episodes.

74
NICE-SUGAR

• Conclusions
• Intensive glucose control in adult ICU pts, as
  compared with Conventional glucose control,
  increased the absolute risk of death at 90 days
  by 2.6 ? NN to harm 38.
• Severe hypoglycemia was significantly more common
  with Intensive glucose control.
• A goal of normoglycemia does not necessarily
  benefit ICU pts and may be harmful.
• A blood glucose target of lt 180 mg/dl resulted in
  lower mortality than a target of 81-108 mg/dl
  Dont use the lower target in critically ill
  adults.

75
Management Bundle

• 4. Prevent Excessive Inspiratory Plateau
  Pressures inspiratory plateau pressures should
  be maintained lt 30 cm H2O for mechanically
  ventilated patients.
• Most patients with severe sepsis and septic shock
  will require intubation and mechanical
  ventilation
• Nearly 50 of these patients will develop acute
  lung injury (ALI) or acute respiratory distress
  syndrome (ARDS)
• Bilateral patchy infiltrates on CXR
• Low PaO2/FiO2 ratios (ALI lt 300, ARDS lt 200)
• PCWP lt 18 mmHg

76
Ventilation with Lower Tidal Volumes as Compared
with Traditional Tidal Volumes for ALI and ARDS

• The Acute Respiratory Distress Syndrome Network,
  NEJM, 2000 342 1301-08.

77
ARDS

• Largest trial of a volume- and pressure-limited
  strategy that showed a 9 decrease (31 vs.
  39.8)of all-cause mortality in patients
  ventilated with tidal volumes of 6 ml/kg of
  estimated LBW (as opposed to 12 ml/kg) while
  aiming for a plateau pressure of lt 30 cm H2O.
• Hypercapnia is well tolerated in patients with
  ALI/ARDS if necessary to minimize plateau
  pressures and tidal volumes. A pH 7.20-7.25 is
  reasonable, but this has not been studied
  prospectively.
• Positive end-expiratory pressure (PEEP) prevents
  alveoli from collapsing at end-expiration
  recruits or opens atelectatic areas to
  participate in gas exchange.

78
Management Bundle

• To summarize 4 elements that must be addressed
  or completed within the first 24 hours of
  presentation can run concurrently with the
  resuscitation bundle.
• 1. Administer low dose CS by a standard policy.
• 2. Administer DroAA (rhAPC) by a standard policy.
• 3. Maintain Adequate Glycemic Control.
• 4. Prevent Excessive Inspiratory Plateau
  Pressures.

79
Conclusions

• Severe sepsis and septic shock have mortality
  rates between 30-50.
• To have any chance of reducing this
  significantly, we must apply best practices as
  stipulated in the literature.
• By bundling the elements together, we will be
  more successful in accomplishing the many
  necessary tasks in treating these critically ill
  patients.

80
(No Transcript)
81
APACHE II

• Age in yearsunder 44-------------------0
  Points45-54-----------------------2 Points
  55-64-----------------------3 Points
  65-74-----------------------5 Points over
  74---------------------6 Points
• History of severe organ insufficiency or
  immunocompromised?Yes, and non-operative or
  emergency post-operative patient-----5 Points
  Yes, and elective post-operative patient----2
  Points No--------------------------0 Points
• Rectal Temperature over 40.9-------------------4
  Points 39-40.9--------------------3 Points
  38.5-38.9------------------1 Points
  36-38.4--------------------0 Points
  34-35.9--------------------1 Points
  32-33.9--------------------2 Points
  30-31.9--------------------3 Points below
  30-------------------4 Points

82

• Heart rate over 179-------------------4
  Points 140-179--------------------3 Points
  110-139--------------------2 Points
  70-109---------------------0 Points
  55-69----------------------2 Points
  40-54----------------------3 Points below
  40------------------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
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
83
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

• White blood count over 39-------------------
  --4 Points20-39.9--------------------2 Points 
  15-19.9--------------------1 Points 
  3.0-14.9-------------------0 Points 
  1.0-2.9---------------------2 Points  below
  1.0------------------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
84

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