Transcript JOURNAL CLUB

MANAGEMENT OF
SEVERE SEPSIS
Virginia Chung, MD
Director, MICU
Jacobi Medical Center
INTRODUCTION
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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.
TERMINOLOGY
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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:
TERMINOLOGY
SIRS
Temperature > 38ºC or < 36ºC
 Heart rate > 90 beats/min
 Respiratory rate > 20 breaths/min or PaCO2 < 32 mmHg
 WBC count > 12,000/mm3, <4,000/mm3, or > 10%
immature forms
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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
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Organ Dysfunction Criteria:
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Cardiovascular – SBP <= 90 mmHg or MAP <= 70 mmHg
for at least 1 hour despite adequate volume resuscitation, or
the use of vasopressors to achieve the same goals.
Renal – urine output < 0.5 ml/kg of body weight for 1 hour
despite adequate volume resuscitation.
Pulmonary – PaO2/FiO2 <= 250 if other organ dysfunction
present or <= 200 if the lung is the only dysfunctional organ.
Hematologic – platelet count < 80,000/mm3 or decreased by
50% over 3 days.
Metabolic – pH<= 7.30 or base deficit > 5.0 mmol/l AND
plasma lactate > 1.5 x upper limit of normal.
CNS – acute alteration in mental status
TERMINOLOGY
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Septic Shock –
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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 sepsisinduced cardiac dysfunction.
SIRS & SEPSIS
Infection/
Trauma
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 >10% immature
neutrophils
Sepsis Severe Sepsis
SIRS with a presumed
or confirmed
infectious process
SIRS = Systemic Inflammatory Response Syndrome
Adapted from: Bone RC, et al. Chest 1992;101:1644
Opal SM, et al. Crit Care Med 2000;28:S81
SEVERE SEPSIS
Infection/
Trauma
SIRS
Sepsis Severe Sepsis
Sepsis with 1 sign of organ
failure
Cardiovascular (refractory
hypotension)
Renal
Respiratory
Hepatic
Hematologic
CNS
Metabolic acidosis
Shock
Bone et al. Chest 1992;101:1644; Wheeler and Bernard. N England J Med 1999;340:207
WORLDWIDE
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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.
RISK FACTORS
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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:
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HIV/AIDS
 Increased use of cytotoxic and immunosuppressant
agents
 Malnutrition
 Alcoholism
 Diabetes Mellitus
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RISK FACTORS
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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
Incidence
Mortality
Sepsis
400,000
7-17%
Severe Sepsis
300,000
Septic
Approximately 200,000
patients including 70,000 Shock
Medicare patients have
septic shock annually
Balk, R.A. Crit Care Clin 2000;337:52
20-53%
53-63%
WHAT CAN WE DO AS
HEALTHCARE PROVIDERS TO
IMPROVE THESE MORTALITY
STATISTICS ?
IHI / SSC
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To expedite Quality Improvement (QI) in health care, the
Institute for Healthcare Improvement (IHI) launched the
100,000 Lives Campaign in December 2004.
This is a national initiative with 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” is 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. have been invited to join this
campaign. The Health and Hospitals Corporation (HHC) with
its 11 acute care hospitals (incl. Jacobi and NCB) are participants
IHI / SSC
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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
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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. (Recently updated Jan 2008)
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:
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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.
SEVERE SEPSIS BUNDLES
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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:
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Severe Sepsis Resuscitation Bundle
Severe Sepsis Management Bundle
Resuscitation Bundle
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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 > 4 mmol/l.
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1. Measure serum lactate – hyperlactatemia is
typically present and may be secondary to anaerobic
metabolism due to hyperperfusion; obtaining a level
is essential to identifying tissue hypoperfusion in
patients who are not yet hypotensive, but who are at
risk for septic shock.
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
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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. 2008: 1 hour.
Major sources of infection in severe sepsis or septic shock
are pneumonia and intra-abdominal infections; other sources
accounting for < 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.
Resuscitation Bundle
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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 > 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/bolus should be given ASAP to these
patients; boluses should be repeated as necessary.
Resuscitation Bundle
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Fluid Challenge – describes the initial volume expansion
period in which the patient response is closely monitored; 4
componenets are:
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1. Fluid type – crystalloid vs. colloid
2. Infusion rate – 500-1,000 ml over 15-30 minutes
3. End points – MAP > 65 or 70 mmHg, hr < 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.
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
SAFE STUDY
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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; p=0.87); 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.
Resuscitation Bundle
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End Points of Fluid Resuscitation – for refractory
hypotension not responding to fluids or lactate > 4 mmol/l,
patients should now enter the Early Goal Directed Therapy
(EGDT) phase of the Resuscitation Bundle where central
venous pressure (CVP) >= 8-12 mmHg and central venous
saturation (ScvO2) >=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.
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) >= 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 highdose conventional vasopressors.
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Vasopressors
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Dopamine – natural precursor of NE and Epi and possesses
several dose-dependent pharmacologic effects.
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Low doses (< 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) – β-adrenergic effects
predominate, resulting in an increase in cardiac contractility and heart rate
High doses (>10 mcg/kg/min) – α-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 (>20 mcg/kg/min) – increases heart rate and right heart
pressures; consider alternative agent.
Vasopressors
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Norepinephrine (NE) – is a potent α-adrenergic agonist with
some β-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 hypotensive 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.
Vasopressin versus
Norepinephrine Infusion in
Patients with Septic Shock
Russell, JA, MD, et. al., for the VASST
Investigators
NEJM, 2008, 358:877-887.
VASST
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Multicenter, randomized, double-blind trial, comparing the use
of NE alone to NE plus vasopressin at 0.03units/min. on 28 day
mortality.
27 centers in Canada, Australia, and USA participated between
July 2001 and April 2006.
Inclusion criteria: age>16 with septic shock – hypotension
despite fluid resuscitation requiring >= 5 mcg/min NE.
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Less severe septic shock : NE 5-14 mcg/min
More severe septic shock : NE >=15 mcg/min
Of 6229 screened, 802 were randomized :
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396 NE ; 406 vasopressin
Pts were very ill with mean APACHE II scores of 27 and > 3 organ
dysfunction
VASST
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Results: No significant difference in the primary
outcome – rate of death from any cause, 28 days after
start of the infusions- between the VP and the NE
group (35.4 vs 39.3%, p=0.26)
Similarly, there was no difference in 90-day mortality
either (43.9 vs 49.6%, p=0.11)
Sub-group analysis: less severe septic shock pts who
received VP had lower mortality at 28-days (26.5 vs
35.7%, p=0.05) and at 90-days (35.8 vs 46.1%, p=0.04)
Investigators had hypothesized that beneficial effects of
VA would be more pronounced in the more severe
septic shock group
Resuscitation Bundle
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6. Maintain Adequate Central Venous Pressure – in the event
of persistent hypotension despite fluid resuscitation (septic
shock) and/or lactate > 4 mmol/l (36 mg/dl) achieve CVP
>= 8-12 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 <
30, consider transfusing packed RBCs; blood is a better
volume expander and increases oxygen carrying capacity.
In mechanically ventilated patients, a higher target CVP > 12
mmHg is recommended because positive pressure ventilation
causes increases in intrathoracic pressures and decreases
venous return.
Resuscitation Bundle
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7. Maintain Adequate Central Venous Oxygen Saturation
(ScvO2) – in the event of persistent hypotension despite
fluid resuscitation (septic shock) and/or lactate > 4 mmol/l
(36 g/dl) achieve a ScvO2 > 70% OR a mixed venous oxygen
saturation (SvO2) via PA catheter > 65%.
Strategies to achieve target ScvO2:
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If the CVP > 8 mmHg and Hct < 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.
2008 : option of transfusing first or go directly to inotropes
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, 345:1368-1377.
EGDT
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Randomized, controlled, predominantly blinded study in an 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 < 90 mmHg
after a 20-30 ml/kg fluid challenge or a blood lactate level > 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 > 65 mmHg,
urine output > 0.5 ml/kg/hr; 500 ml fluid boluses and
vasopressors were used.
EGDT
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Treatment group had the same aims as the control group
PLUS they had to achieve a central venous oxygen saturation
(ScvO2) > 70%:
 If the ScvO2 < 70 % and
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Hct < 30, transfuse PRBCs
MAP > 90 mmHg, give vasodilators until MAP <= 90 mmHg
If CVP, Hct, and MAP were in the optimal range and ScvO2 still
< 70%, start dobutamine 2.5 mcg/kg/min (inotrope) and titrate
it up by 2.5 mcg/kg/min every 30 min until ScvO2 > 70% or a
maximum dose of 20 mcg/kg/min is reached. The dose was
decreased or d/c’ed if MAP < 65 mmHg or hr > 120 beats/min
Finally, to decrease O2 demand, sedate and mechanically
ventilate the patient.
EGDT
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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 underresuscitated initially.
In-hospital mortality was significantly higher in the control
group than in the EGDT group – 46.5 % versus 30.5%
(p=0.009).
Resuscitation Bundle
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To summarize, for patients presenting with severe
sepsis, septic shock, or lactate > 4 mmol/l, the
following 7 tasks need to be accomplished within the
first 6 hours of presentation:
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1. Measure serum lactate.
2. Obtain blood cultures prior to antibiotic administration.
3. Improve time to broad-spectrum antibiotics (< 3(1) hrs).
4. Treat hypotension and/or elevated lactate with fluids.
5. Apply vasopressors for ongoing hypotension.
6. Maintain adequate CVP (>= 8 mmHg).
7. Maintain adequate ScvO2 (>= 70%).
Management Bundle
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Describes 4 tasks that must be completed within 24
hours of presentation for patients with severe sepsis,
septic shock, and/or lactate >4 mmol/l.
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1. Administer Low-Dose Steroids by a Standard Policy – IV
corticosteroids (hydrocortisone 200-300 mg/day, for 7 days
in 3-4 divided doses) are recommended 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%).
Management Bundle
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In refractory septic shock, the prevalence of Relative Adrenal
Insufficiency (RAI) may be as high as 50-75%. RAI is present
when the increase in serum cortisol level is < 9 mcg/dl, 3060 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.
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
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 >9 mcg/dl increase were Responders.
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Low Dose CS
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Mortality rates:
All patients – there was no significant effect of CS on 28day, ICU, hospital, and 1-year mortality rates.
 Responders (>9 mcg/dl incr.) – there was no significant
effect of CS on 28-day, ICU, hospital, and 1-year mortality
rates.
 Nonresponders (<= 9 mcg/dl incr.) –
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28 days : placebo
ICU:
placebo
Hospital: placebo
1-year: placebo
73 (63%)
81 (70%)
83 (72%)
88 (77%)
CS
CS
CS
CS
60
66
70
77
(53%) deaths p=.04
(58%) deaths p=.02
(61%) deaths p=.04
(68%) deaths p=.07
Low Dose CS
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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
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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.
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Hydrocortisone Therapy for
Patients with Septic Shock
Sprung, CL, MD, Annane, D, MD, et. al., for
the CORTICUS Study Group
NEJM, 2008, 358: 111-124.
CORTICUS
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Multicenter, randomized, double-blind, placebocontrolled trial evaluating the efficacy and safety of
low-dose hydrocortisone (HC) therapy in septic shock.
52 European and Israeli ICUs took part between March
2002 and November 2005.
Inclusion criteria: age >=18 with onset of septic shock
within the previous 72 hrs and hypoperfusion or organ
dysfunction due to sepsis.
Exclusion criteria: underlying disease with poor
prognosis, moribund (life expect < 24hrs),
immunosuppression, Rx with long-term CS within 6
months, or short-term CS within 4 weeks.
CORTICUS
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Protocol: 50 mg IVP q6h x 5days, then q12h x 3 days,
and then q24h x 3 days (both HC and placebo)
Primary end-point was rate of death at 28-days in pts
who DID NOT have a response to ACTH
Secondary end-points: 28-day mortality in pts who
HAD a response to ACTH, and in all pts, ICUmortality, 1 year mortality, reversal of organ failure and
shock, ICU LOS, Hospital LOS.
500 pts enrolled: 252 (HC) and 248 (placebo)
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233 (46.7%) did not respond to ACTH – 125(HC), 108(plac)
254 (50.9%) DID respond to ACTH – 118(HC), 136(plac)
CORTICUS
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Results: No significant difference between the 2 study grps in the
primary outcome – 28 day mortality in ACTH non-responders.
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Likewise, there was no significant difference in 28 day mortality
in the ACTH responders
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HC grp: 49/125 (39.2%) died
Placebo grp: 39/108 (36.1%) died; p=0.69
HC grp: 34/118 (28.8%) died
Placebo grp: 39/136 (28.7%) died; p=1.00
Overall, there were 86/252 (34.3%) deaths in HC grp and
78/248 (31.5%) deaths in Placebo grp ; p=0.51
Of those patients who had reversal of their shock, those who
rec’d HC took less days to do so ( 3.3 vs 5.8 days)
CORTICUS
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Results (cont): ACTH non-responders had a higher 28-day
mortality (38%) than ACTH responders (29%)
Adverse events:
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HC grp: increased incidence of superinfections: new episodes of
sepsis/septic shock (OR 1.37), increased incidence of hyperglycemia and
hypernatremia
Conclusion:
 HC cannot be recommended as general adjuvant therapy for
septic shock (vasopressor responsive) nor can ACTH testing
be recommended to determine which pt should receive HC.
 HC may have a role among pts who are treated early after the
onset of septic shock who remain hypotensive despite the
administration of high-dose vasopressors (vasopressor
unresponsive)
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 propertiesimproved survival in patients with sepsis-induced
organ dysfunction.
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.
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, age<18,
weight>135 kg, platelet < 30,000, increased risk of bleeding,
known hypercoagulable condition, AIDS witth CD4<50,
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.
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.
PROWESS



When subgroup analysis was performed, those patients
with APACHE II scores > 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, lifethreatening 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.
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 >
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 >= 2 organ dysfunction.
Very expensive drug, costing approximately US $7,000
per 96 hour infusion.
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.
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 < 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 (< 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.
Management Bundle

3. Maintain Adequate Glycemic Control – following
initial stabilization of patients with severe sepsis,
blood glucose should be maintained < 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.
Intensive Insulin Therapy in
Critically Ill Patients
Van den Berghe, G., Wouters, P., Weekers, F.,
et al., NEJM, 2001, 345: 1359-67.
IIT




Prospective, 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 > 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 > 110 mg/dl; blood sugars were then
maintained between 80-110 mg/dl.
IIT



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)

IIT

Mortality:
convent
ICU
63(8.0%)
 ICU<=5 d.
14(1.8%)
 ICU> 5 d.
49(20.2%)
 Hosp(all)
85(10.9%)
 Hosp+ICU>5d. 64(26.3)
 Cause/death:

MOF + Sepsis
 MOF w/o Sepsis

33
18
intense
p-value
35(4.6%)
13(1.7%)
22(10.6%)
55(7.2%)
35(16.8%)
<0.04
0.9
0. 005
0.01
0.01
8
14
IIT



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 (< 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 < 150 mg/dl
was also beneficial (less risk for hypoglycemia).
Intensive Insulin Therapy in
the Medical ICU
Van den Berghe, G., Wilmer, A., Hermans,
G., et al., NEJM, 2006; 354: 449-61.
I I T (MICU)




Prospective, 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 traetment: insulin drip for
blood glucose > 215 mg/dl; then kept 180-200 mg/dl.
595 received IIT: insulin drip started for blood glucose
> 110 mg/dl; then kept 80-110 mg/dl.
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%, p=0.31); for those who did stay in
the MICU for 3 or more days, the IIT group had better
outcomes (31.3% vs. 38.1%, p=0.05)
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).
IIT

2008: 2 large Mc-RCTs of IIT underway
(sepsis, MSICU) failed to show mortality
improvement and were stopped early due
to high rates of hypoglycemia and adverse
events in the IIT groups.
Management Bundle
4. Prevent Excessive Inspiratory Plateau Pressures –
inspiratory plateau pressures should be maintained
< 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 < 300, ARDS < 200)
 PCWP < 18 mmHg

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.
ARDS



Largest trial of a volume- and pressure-limited strategy
that showed a 9% decrease 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 < 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.
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. Consider Administering low dose CS for
vasopressor unresponsive shock .
 2. Administer DroAA (rhAPC) by a standard policy.
 3. Maintain Adequate Glycemic Control (<150).
 4. Prevent Excessive Inspiratory Plateau Pressures.

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.
APACHE II

Age in years
under 44-------------------0 Points
45-54-----------------------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
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
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 pH
over 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
over 39---------------------4 Points
20-39.9--------------------2 Points
15-19.9--------------------1 Points
3.0-14.9-------------------0 Points
1.0-2.9---------------------2 Points
below 1.0------------------4 Points
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 Points
150-154-------------------1 Points
130-149-------------------0 Points
120-129-------------------2 Points
111-119-------------------3 Points
below 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
(use PaO2 if FiO2 < 50%,
otherwise use A-a gradient)
A-a gradient over 499------4 Points
A-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 Points
6-6.9-----------------------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

Drotrecogin Alfa (Activated) for Adults with
Severe Sepsis and a Low Risk of Death

NEJM Vol. 353;13:1332-1341 September 29, 2005

Edward Abraham, M.D., Pierre-François Laterre, M.D., Rekha Garg,
M.D., Howard Levy, M.D., Ph.D., Deepak Talwar, M.D., Benjamin L.
Trzaskoma, M.S., Bruno François, M.D., Jeffrey S. Guy, M.D., Martina
Brückmann, M.D., Álvaro Rea-Neto, M.D., Rolf Rossaint, M.D.,
Dominique Perrotin, M.D., Armin Sablotzki, M.D., Ph.D., Nancy
Arkins, R.N., Barbara G. Utterback, M.S., M.B.A., William L.
Macias, M.D., for the Administration of Drotrecogin Alfa (Activated) in
Early Stage Severe Sepsis (ADDRESS) Study Group


10% of ICU admissions worldwide
PROWEESS trial showed 6.1% reduction in 28
day mortality from severe sepsis in patients
treated with Activated Protein C
METHODS




Randomized, double blind, placebo controlled and
multicenter trial
2640 patients with severe sepsis and a low risk of death
defined by APACHE II with score <25 or single organ
dysfunction were enrolled in 516 centers in 34 countries
They were randomized to receive 96 hour of
placebo(0.9NS) or DrotAA
Treatment with the study drug was started within 48
hours of documentation of first organ dysfunction
EXCLUSION CRITERIA






Patients with multiorgan failure in Europe
Patients with APACHE score of 25 or more in
US
If they had an increased risk of bleeding
If they were in moribund state
Or were not expected to survive for 28 days
If patients condition worsened