Sepsis and MODS

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Sepsis and MODS

• Wen-Lin Su, MD, MPH
• Division of MICU RCC, Department of Critical
  Care Medicine Division of Pulmonary Medicine,
  Department of Medicine. Tri-Service General
  Hospital,
• National Defense Medical Center

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Crit Care Med 1992 20864
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ACCP/SCCM Consensus Conference Definitions

• 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 the presence of viable bacteria in
  the blood.

Crit Care Med 1992 20864
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Systemic inflammatory response syndrome (SIRS)

• The systemic inflammatory response to a variety
  of severe clinical insults. The response is
  manifested by two or more of the followings
• Temperature gt38C or lt36C
• Heart rate gt90 beats/min
• Respiratory rate gt20 breaths/min or PaCO2 lt32
  mmHg
• WBC gt12,000 cells/mm3, lt4000cells/mm3, or gt10
  immature (band) forms

Crit Care Med 1992 20864
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Sepsis vs Severe Sepsis

• Sepsis the systemic response to infection. That
  is, SIRS with definitive evidence of infection.
• Severe sepsis Sepsis associated with organ
  dysfunction, hypoperfusion, or hypotension.
• The manifestations of hypoperfusion may include,
  but are not limited to, lactic acidosis,
  oliguria, or an acute alteration in mental status.

Crit Care Med 1992 20864
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Septic Shock

• Septic shock sepsis induced hypotension despite
  adequate fluid resuscitation along with perfusion
  abnormalities that may include, but are not
  limited to, lactic acidosis, oliguria, or an
  acute alteration in mental status.
• Patients who are on inotropic or vasopressor
  agents may not be hypotensive at the time that
  perfusion abnormalities are measured.
• Hypotension systolic BP of lt90 mmHg or a
  reduction of ?40 mmHg from baseline in the
  absence of other causes for the fall in blood
  pressure.
• 1 L/hour x 2 hours

Crit Care Med 1992 20864
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Definition
Sepsis
Infection/Trauma
Severe Sepsis
SIRS

• Sepsis with 1 sign of organ failure
• Cardiovascular (refractory hypotension)
• Renal
• Respiratory
• Hepatic
• Hematologic
• CNS
• Unexplained metabolic acidosis

Bone et al. Chest. 19921011644 Wheeler and
Bernard. N Engl J Med. 1999340207.
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Multiple Organ Dysfunction Syndrome (MODS/MOF)

• MODS/MOF the presence of altered organ function
  in an acutely ill patient such that homeostasis
  cannot be maintained without intervention.
• Primary MODS a well-defined insult, occurs
  early and can be directly attributable to the
  insult itself (eg, renal failure due to
  rhabdomyolysis).
• Secondary MODS not in direct response to the
  insult itself, but as a consequence of a host
  response. MODS represents the more severe end of
  severity of illness characterized by SIRS/sepsis.

Crit Care Med 1992 20864
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Homeostasis Is Unbalanced in Severe Sepsis
Carvalho AC, Freeman NJ. J Crit Illness.
1994951-75 Kidokoro A et al. Shock.
19965223-8 Vervloet MG et al. Semin Thromb
Hemost. 19982433-44.
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Crit Care Med 2000 28(4)N3-N12
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Cytokine Storm ?
Incomplete Rx or relapse ???
Corticosteroid
Good side remove virus
High viral load
Bad side ARDS MODS
Genetic predisposition to immune hyperstimulation
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Identifying Acute Organ Dysfunction as a Marker
of Severe Sepsis
Altered Consciousness Confusion Psychosis
Tachycardia Hypotension ? CVP ? PAOP
Tachypnea PaO2 lt70 mm Hg SaO2 lt90 PaO2/FiO2 ?300
Oliguria Anuria ? Creatinine
? Platelets ? PT/APTT ? Protein C ? D-dimer
Jaundice ? Enzymes ? Albumin ? PT
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SIRS
Infection
Immune Response
Sepsis
Uncontrolled Pro-inflammatory Mechanisms
Dysregulated anti-inflammatory Mechanisms
MODS/MOF
Crit Care Med 2000, 28(4)N105-N113 with
modification
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Severe Sepsis The Final Common Pathway
Cytokine storm
Endothelial Dysfunction and Microvascular
Thrombosis
Hypoperfusion/Ischemia
Acute Organ Dysfunction (Severe Sepsis)
Death
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Dysoxia

• Pressure ? Perfusion ? Oxygenation
• (Vessel) (Tissue) (Cell)
• Hypovolemic Hypoxemic Cytopathic
• hypoxia hypoxia hypoxia

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Mechanism of regional tissue dysoxia (Cytopathic
hypoxia)
BP drop CO drop SVR drop
Lact up PaO2 drop VO2 drop
Tissue pO2 up
ATP turnover
Microcirculatory shunting
Global hypoperfusion
Mitochondrial failure
Crit Care Med 1995 23 1217 Lancet 2002 360 219
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Surviving Sepsis

• A global program to
• Reduce mortality rates in severe sepsis
• The Surviving Sepsis Campaign was initiated in
  2002 by the European Society of Intensive Care
  Medicine, the International Sepsis Forum, and the
  Society of Critical Care Medicine with the intent
  to reduce mortality rates in severe sepsis by 25
  in 5 years

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Surviving Sepsis Campaign International
guidelines for management of severe sepsis and
septic shock 2008

• R. Phillip Dellinger, MD Mitchell M. Levy, MD
  Jean M. Carlet, MD Julian Bion, MD Margaret M.
  Parker, MD Roman Jaeschke, MD Konrad Reinhart,
  MD Derek C. Angus, MD, MPH Christian
  Brun-Buisson, MD Richard Beale, MD Thierry
  Calandra, MD, PhD Jean-Francois Dhainaut, MD
  Herwig Gerlach, MD Maurene Harvey, RN John J.
  Marini, MD John Marshall, MD Marco Ranieri, MD
  Graham Ramsay, MD Jonathan Sevransky, MD B.
  Taylor Thompson, MD Sean Townsend, MD Jeffrey
  S. Vender, MD Janice L. Zimmerman, MD
  Jean-Louis Vincent, MD, PhD for the
  International Surviving Sepsis Campaign
  Guidelines Committee
• Crit Care Med 200836296-327
• available online at
• www.springerlink.com
• www.sccm.org
• www.sepsisforum.com

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1 2
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Guidelines for Management of Severe Sepsis and
Septic Shock

• I. MANAGEMENT OF SEVERE SEPSIS
• Initial Resuscitation
• Diagnosis
• Antibiotics Therapy
• Source Control
• Fluid therapy
• Vasopressors
• Inotropic Therapy
• Corticosteroid
• Recombinant Human Activated Protein C (rhAPC)
• Blood Product Administration

• II. SUPPORTIVE THERAPY OF SEVERE SEPSIS
• Mechanical Ventilation of Sepsis-induced ALI/ARDS
• Sedation, Analgesia, and N-M Blockade in Sepsis
• Glucose Control
• Renal Replacement
• Bicarbonate Therapy
• DVT Prophylaxis
• Stress Ulcer Prophylaxis
• Selective Digestive Tract Decontamination (SDD)
• Consideration for Limitation of Support
• III. Pediatric Consideration

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• MANAGEMENT OF
• SEVERE SEPSIS

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Initial Resuscitation
Figure B, page 948, reproduced with permission
from Dellinger RP. Cardiovascular management of
septic shock. Crit Care Med 200331946-955.
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Early Goal-Directed Therapy

• 1000 ml of crystalloid or 300-500 ml bolus of
  colloid q 30 min to keep CVP 8-12 mmHg
• Vasoactive agents (MAP ? 65 mmHg)
• Vasopressors if MAP lt 65 mmHg
• Vasodilator if MAP gt 90 mmHg
• Transfusion (? Hct gt 30) and Dobutamine if ScvO2
  lt 70 or mixed venous lt 65
• Keep urine output ? 0.5 ml.kg-1.hr-1
• In hospital mortality was 30.5 vs. 46.5 in
  control group

River et al. N Engl J Med, 2001
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EGDT first 6 hours in ER
500ml bolus of colloid every 30min Dobutamin
started at 2.5 ug/kg/min, increase by
2.5ug/kg/min every 30 min, or until maximal dose
20ug/kg/min given Decrease dobutamin dose if MAP
gt65mmHg or HRgt 120bpm
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Initial Resuscitation (2008)

• Initial resuscitation (first 6 hrs)
• Begin resuscitation immediately in patients with
  hypotension or elevated serum lactate 4 mmol/L
  do not delay pending ICU admission (1C)
• Resuscitation goals (1C)
• CVP 812 mm Hg a
• Mean arterial pressure 65 mm Hg
• Urine output 0.5 mL/kg/hr
• Central venous (superior vena cava) oxygen
  saturation 70 or mixed venous 65
• If venous oxygen saturation target is not
  achieved (2C)
• Consider further fluid
• Transfuse packed red blood cells if required to
  hematocrit of 30 and/or
• Start dobutamine infusion, maximum 20 µg/kg/min

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Diagnosis (2008)

• Obtain appropriate cultures before starting
  antibiotics provided this does not significantly
  delay antimicrobial administration (1C)
• Obtain two or more BCs
• One or more BCs should be percutaneous
• One BC from each vascular access device in place
  48 hrs
• Culture other sites as clinically indicated
• Perform imaging studies promptly to confirm and
  sample any source of infection, if safe to do so
  (1C), (ex. Sonography suitable, transport outside
  unit may be dangerous)

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Role of Infection Control

• Right Drugs for Right patients at Right time
• De-Escalation Therapy (For severe infection in
  ICU)
• Why
• How
• Outcomes
• Resistance

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Controversial Clinical Definitions

• Appropriate
• The etiologic organism is sensitive to the
  therapeutic agent
• Adequate
• Correct antibiotic
• Optimal dose-All patients should receive a full
  loading
• dose of each antimicrobial.
• Correct route of administration to ensure
  penetration at the site of infection
• Use of combination therapy if necessary

ATS/IDSA. Am J Respir Crit Care Med 2005 171
388-416
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Need for adequate antibiotic coverage

• Major concerns is nosocomial infections
• Pseudomonas aeruginosa
• ESBL
• Acinetobacter spp
• MRSA
• VRE (in certain countries)
• Candidas
• fungus

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Antibiotic Therapy (2008)

• Begin intravenous antibiotics as early as
  possible and always within the first hour of
  recognizing severe sepsis (1D) and septic shock
  (1B)
• In the presence of septic shock, each hour delay
  in achieving administration of effective
  antibiotics is associated with a measurable
  increase in mortality
• Broad-spectrum one or more agents active against
  likely bacterial/fungal pathogens and with good
  penetration into presumed source (1B)
• Watch out MRSA in some communities and healthcare
  settings

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Antibiotic Therapy (2008)

• Reassess antimicrobial regimen daily to optimize
  efficacy, prevent resistance, avoid toxicity, and
  minimize costs (1C)
• Consider combination therapy in Pseudomonas
  infections (2D)
• Consider combination empiric therapy in
  neutropenic patients (2D)

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Antibiotic Therapy (2008)

• Combination therapy 35 days and de-escalation
  following susceptibilities (To single therapy)
  (2D)
• Duration of therapy typically limited to 710
  days longer if response is slow or there are
  undrainable foci of infection or immunologic
  deficiencies (1D)
• Stop antimicrobial therapy if cause is found to
  be noninfectious (1D)

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Source identification and control (2008)

• A specific anatomic site of infection should be
  established as rapidly as possible (1C) and
  within first 6 hrs of presentation (1D)
• E.g., necrotizing fascitis, diffuse peritonitis,
  cholangitis, intestinal infarction)
• Formally evaluate patient for a focus of
  infection amenable to source control measures
  (e.g. abscess drainage, tissue debridement,
  removal of a potentially infected device, or the
  definitive control of a source of ongoing
  microbial contamination) (1C)

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Source identification and control (2008)

• Implement source control measures as soon as
  possible following successful initial
  resuscitation (1C) (exception infected
  pancreatic necrosis, where surgical intervention
  is best delayed) (2B)
• Choose source control measure with maximum
  efficacy and minimal physiologic upset (1D)
• e.g., percutaneous rather than surgical drainage
  of an abscess
• Remove intravascular access devices if
  potentially infected (1C)
• Prompt remove after other vascular access had
  been established

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Fluid Therapy (2008)

• Fluid resuscitation may consist of natural or
  artificial colloids or crystalloids (1B)

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Figure 2, page 206, reproduced with permission
from Choi PT, Yip G, Quinonez L, Cook DJ.
Crystalloids vs. colloids in fluid resuscitation
A systematic review. Crit Care Med 1999
27200210
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Fluid Therapy (2008)

• Resuscitation initially target a central venous
  pressure of 8 mm Hg (12 mm Hg in mechanically
  ventilated patients) (1C)
• A fluid challenge technique be applied wherein
  fluid administration is continued as long as the
  hemodynamic improvement (e.g., arterial pressure,
  heart rate, urine output) continues (1D)

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Fluid Therapy (2008)

• Fluid challenge over 30 min
• ?1000 ml crystalloid
• 300500 ml colloid
• More rapid administration and greater amounts of
  fluid may be needed in patients with
  sepsis-induced tissue hypoperfusion
• (1D)

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Fluid Therapy (2008)

• The rate of fluid administration be reduced
  whencardiac filling pressures (central venous
  pressure or pulmonary artery balloon-occluded
  pressure) increase without concurrent hemodynamic
  improvement
• (1D)

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Effects of Dopamine, Norepinephrine,and
Epinephrine on the SplanchnicCirculation in
Septic Shock
Figure 2, page 1665, reproduced with permission
from De Backer D, Creteur J, Silva E, Vincent JL.
Effects of dopamine, norepinephrine, and
epinephrine on the splanchnic circulation in
septic shock Which is best? Crit Care Med 2003
311659-1667
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Vasopressors (2008)

• Mean arterial pressure (MAP) be maintained 65 mm
  Hg (? 65) (1C)
• Sustain life and maintain perfusion in the face
  of life-threatening hypotension
• Either NOREPI or DOPA administered through a
  central catheter is the initial vasopressor of
  choice (1C)
• Epinephrine, phenylephrine, or vasopressin should
  not be administered as the initial vasopressor in
  septic shock (2C). Vasopressin 0.03 units/min may
  be subsequently added to norepinephrine with
  anticipation of an effect equivalent to
  norepinephrine alone

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Vasopressors (2008)

• Epinephrine be the first chosen alternative agent
  in septic shock that is poorly responsive to
  norepinephrine or dopamine (2B)
• Do not use low-dose dopamine for renal perfusion
  (1A)
• Bellomo et al. Lancet 2000
• In patients requiring vasopressors, place an
  arterial catheter as soon as possible.(1D)

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Relative vasopressin deficiency

• Low doses of vasopressin may be effective in
  raising blood pressure in patients refractory to
  other vasopressors and may have other potential
  physiologic benefits
• Higher doses of vasopressin have been associated
  with cardiac, digital, and splanchnic ischemia
  and should be reserved for situations where
  alternative vasopressors have failed (96).
• Cardiac output measurement to allow maintenance
  of a normal or elevated flow is desirable when
  these pure vasopressors are instituted.
• 2008 surviving sepsis campaign Grade 1D

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Vasopressors (2004)

• Norepinephrine
• Less tachycardia
• Increased cardiac index
• No deleterious effect on cerebral perfusion
  pressure
• No effect on the hypothalamic-pituitary axis
• More effective and better outcome as compared
  with dopamine
• Amelioration of splanchnic hypoperfusion
• Increased glomerular filtration pressure
• Decreased serum lactate concentration

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Vasopressin and Septic Shock (2004)

• Versus cardiogenic shock
• Decreases or eliminates requirements of
  traditional pressors
• As a pure vasopressor expected to decrease
  cardiac output

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Vasopressors (2004) Vasopressin

• Not a replacement for norepinephrine or dopamine
  as a first-line agent
• Consider in refractory shock despite high-dose
  conventional vasopressors
• If used, administer at 0.01-0.04 units/minute in
  adults
• Grade E

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During Septic Shock
Images used with permission from Joseph E.
Parrillo, MD
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Inotropic Therapy (2008)

• Use dobutamine in patients with myocardial
  dysfunction as supported by elevated cardiac
  filling pressures and low cardiac output (1C)
  (check cardiac output)
• Do not increase cardiac index to predetermined
  supranormal levels (1B)

(Yu et al. Crit Care Med, 1993) (Hayes et al.
NEJM, 1994) Gattinoni et al. NEJM, 1995)
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Steroid Therapy
Figure 2A, page 867, reproduced with permission
from Annane D, Sébille V, Charpentier C, et al.
Effect of treatment with low doses of
hydrocortisone and fludrocortisone on mortality
in patients with septic shock. JAMA 2002
288862-871
54

• Annane, Bollaert and Briegel
• Different doses, routes of administration and
  stopping/tapering rules
• Annane
• Required hypotension despite therapeutic
  intervention
• Bollaert and Briegel
• Required vasopressor support only

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Use of corticosteroid therapy in patients with
sepsis and septic shock An evidence-based review
Keh et al. Crit Care Med 2004 Vol. 32, No. 11
(Suppl.)
56
Corticosteroid in Septic Shock

• High doses of corticosteroids do not improve
  survival and may worsen outcomes by increasing
  the frequency of secondary infections
• Low-dose (?physiologic?) steroids may be
  beneficial because of relative adrenal
  insufficiency
• Treat patients who still require vasopressors
  despite fluid replacement with hydrocortisone
  200-300 mg/day, for 7 days in three or four
  divided doses or by continuous infusion

Bone, et al. NEJM 1987 317-658 VA Systemic
Sepsis Cooperative Study Group. NEJM 1987
317659-665
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Hydrocortisone Therapy for Patients with Septic
Shock

• In the multicenter, randomized, double-blind,
  placebo-controlled trial
• 251 patients 50 mg hydrocortisone iv q6h for 5
  days, the dose was then tapered during a 6-day
  period
• 248 patients iv placebo
• 28-day mortality, 86/251 (34.3) in the
  hydrocortisone group vs 78/248 (31.5) in the
  placebo group (P0.51)
• In the hydrocortisone group, shock was reversed
  more quickly than in the placebo group
• However, there were more episodes of
  superinfection, including new sepsis and septic
  shock.

Sprung et al. NEJM 358(2) 111, 2008
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Corticosteroid in ARDS

• These results do not support the routine use of
  methylprednisolone for persistent ARDS despite
  the improvement in cardiopulmonary physiology. In
  addition, starting methylprednisolone therapy
  more than two weeks after the onset of ARDS may
  increase the risk of death.
• Anonymous et al. NEJM 354(16) 1671, 2006

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Steroid treatment in ARDS a critical appraisal
of the ARDS network trial and the recent
literature

• To compare the design and results of randomized
  trials investigating prolonged glucocorticoid
  treatment ( 7 days) in patients with ALI-ARDS
• Trials were retrieved from the Cochrane Central
  Register of Controlled Trials (CENTRAL)
• Five selected trials ( n 518) consistently
  reported significant improvement in gas exchange,
  reduction in markers of inflammation, and
  decreased duration of mechanical ventilation and
  intensive care unit stay (all p lt 0.05)
• Three larger trials did not reproduce the marked
  reductions observed in the earlier trials (RR
  0.84 95 CI 0.68-1.03 p 0.09, I 2 9.1),
  but achieved a distinct reduction in the RR of
  death in the larger subgroup of patients ( n
  400) treated before day 14 of ARDS 82/214 (38)
  vs. 98/186 (52.5), RR 0.78 95 CI 0.64-0.96
  p 0.02
• A distinct survival benefit when initiated before
  day 14 of ARDS

Meduri et al, Intensive Care Medicine, 2008
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Corticosteroid (2008)

• Consider intravenous hydrocortisone for adult
  septic shock when hypotension responds poorly to
  adequate fluid resuscitation and vasopressors
  (2C)
• ACTH stimulation test is not recommended to
  identify the subset of adults with septic shock
  who should receive hydrocortisone (2B)
• Hydrocortisone is preferred to dexamethasone
  (2B)

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Corticosteroid (2008)

• Fludrocortisone (50 g orally once a day) may be
  included if an alternative to hydrocortisone is
  being used that lacks significant
  mineralocorticoid activity. Fludrocortisone if
  optional if hydrocortisone is used (2C)
• Steroid therapy may be weaned once vasopressors
  are no longer required (2D)
• Hydrocortisone dose should be 300 mg/day (1A)
• Do not use corticosteroids to treat sepsis in the
  absence of shock unless the patients endocrine
  or corticosteroid history warrants it (1D)

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Human Activated Protein CEndogenous Regulator of
Coagulation
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Human Activated Protein C in Septic Shock

• Activated protein C had anti-thrombotic,
  anti-inflammatory and pro-fibrinolytic properties
• Drotrecogin Alfa is the first anti-inflammatory
  agent that proved effective in the treatment of
  sepsis

From Recombinant human activated protein c
worldwide evaluation in severe sepsis (PROWESS)
study group Bernard et al. NEJM, 2001
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Results 28-Day All-Cause Mortality
Primary analysis results 2-sided p-value
0.005 Adjusted relative risk reduction
19.4 Increase in odds of survival 38.1
Adapted from Table 4, page 704, with permission
from Bernard GR, Vincent JL, Laterre PF, et al.
Efficacy and safety of recombinant human
activated protein C for severe sepsis. N Engl J
Med 2001 344699-709
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Mortality and APACHE II Quartile
Adapted from Figure 2, page S90, with permission
from Bernard GR. Drotrecogin alfa (activated)
(recombinant human activated protein C) for the
treatment of severe sepsis. Crit Care Med 2003
31Suppl.S85-S90
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Mortality and Numbers of Organs Failing
Adapted from Figure 4, page S91, with permission
from Bernard GR. Drotrecogin alfa (activated)
(recombinant human activated protein C) for the
treatment of severe sepsis. Crit Care Med 2003
31Suppl.S85-S90
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FDA labelingRecombinant human activated protein
C (rhAPC)

• Patients who have severe sepsis and with a high
  risk of death
• Such as with an APACHE II score of at least 25
• Evidence of end-organ dysfunction
• Shock, acidosis, oliguria, or hypoxemia
• Be given within 24 hours of the first organ
  failure
• Not be given to mild-to-moderate sepsis who do
  not have evidence of end-organ injury

Bernard et al. Crit Care Med, 2003
68
rhAPC (2004)

• High risk of death
• APACHE II ? 25
• Sepsis-induced multiple organ failure
• Septic shock
• Sepsis induced ARDS
• No absolute contraindications
• Weigh relative contraindications

Grade B
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Human Activated Protein C(2008)

• Consider rhAPC in adult patients with
  sepsis-induced organ dysfunction with clinical
  assessment of high risk of death (typically
  APACHE II gt25 or multiple organ failure) if there
  are no contraindications (2B, 2C for
  postoperative patients within 30 days).
• Adult patients with severe sepsis and low risk of
  death (typically, APACHE II lt 20 or one organ
  failure) should not receive rhAPC (1A)

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Contraindications to Use of Recombinant Human
Activated Protein C (rhAPC)

• Active internal bleeding
• Recent (within 3 months) hemorrhagic stroke
• Recent (within 2 months) intracranial or
  intraspinal surgery, or severe head trauma
• Trauma with an increased risk of life threatening
  bleeding
• Presence of an epidural catheter
• Intracranial neoplasm or mass lesion or evidence
  of cerebral herniation
• Known hypersensitivity to rhAPC or any component
  of the product

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Transfusion Strategyin the Critically Ill
Figure 2A, page 414, reproduced with permission
from Hebert PC, Wells G, Blajchman MA, et al. A
multicenter, randomized, controlled clinical
trial of transfusion requirements in critical
care. N Engl J Med 1999 340409-417
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Blood Product Administration(2008) Red Blood
Cells

• Give red blood cells when hemoglobin decreases to
  7.0 g/dL (70 g/L) to target a hemoglobin of
  7.09.0 g/dL in adults (1B). A higher hemoglobin
  level may be required in special circumstances
  (e.g., myocardial ischaemia, severe hypoxemia,
  acute hemorrhage, cyanotic heart disease, or
  lactic acidosis)

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Blood Product Administration (2008)

• Do not use erythropoietin to treat sepsis-related
  anemia. Erythropoietin may be used for other
  accepted reasons (chronic renal failure). (1B)
• Do not use fresh frozen plasma to correct
  laboratory clotting abnormalities unless there is
  bleeding or planned invasive procedures (2D)
• Do not use antithrombin therapy (1B)

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Blood Product Administration (2008)

• Administer platelets when (2D)
• Counts are 5000/mm3 (5x 109/L) regardless of
  bleeding
• Counts are 500030,000/mm3 (530x109/L) and there
  is significant bleeding risk
• Higher platelet counts (50,000/mm3 50x 109/L)
  are required for surgery or invasive procedures

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Mechanical Ventilation of Sepsis-Induced ALI/ARDS
(2008)
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ARDSnet Mechanical Ventilation Protocol Results
Mortality
Mortality
Adapted from Figure 1, page 1306, with permission
from The Acute Respiratory Distress Syndrome
Network. N Engl J Med 20003421301-1378
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Mechanical Ventilation ofSepsis-Induced ALI/ARDS

• Target a tidal volume of 6 mL/kg (predicted) body
  weight in patients with ALI/ARDS (1B)
• Target an initial upper limit plateau pressure 30
  cm H2O. Consider chest wall compliance when
  assessing plateau pressure (1C)
• If plateau pressure remain gt 30 after reduction
  of tidal volume to 6 ml/kg PBW, tidal volume
  should be reduced further to as low as 4 ml/kg

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• Allow PaCO2 to increase above normal, if needed,
  to minimize plateau pressures and tidal volumes
  (1C)
• Permissive hypercapnia
• Be limited in patients with preexisting metabolic
  acidosis and contraindicated in patients with
  increased initracranial pressure.
• Set PEEP to avoid extensive lung collapse at
  end-expiration (1C)
• Titrate PEEP based on
• Bedside measurement of thoracopulmonary
  compliance
• Guided by the FiO2 required to maintain adequate
  oxygenation
• PEEP gt 5 cm H20 to avoid lung collapse

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The Role of Prone Positioning in ARDS

• 70 of prone patients improved oxygenation
• 70 of response within 1 hour
• 10-day mortality rate in quartile with lowest
  PaO2FIO2 ratio (?88)
• Prone 23.1
• Supine 47.2

Gattinoni L, et al. N Engl J Med 2001345568-73
Slutsky AS. N Engl J Med 2001345610-2.
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The Role of Prone Positioning in ARDS

• Consider prone positioning in ARDS when
• Potentially injurious levels of F1O2 or plateau
  pressure exist
• Not at high risk from positional changes
• (2C)

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Mechanical Ventilationof Severe Sepsis

• Maintain mechanically ventilated patients in a
  semirecumbent position (head of the bed raised to
  45) unless contraindicated (to limit aspiration
  risk and to prevent the development of VAP) (1B),
  between 30 and 45 (2C)
• Drakulovic et al. Lancet 1999 3541851-1858

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• Noninvasive mask ventilation (NIV) only be
  considered in that minority of ALI/ARDS patients
  with
• mild-moderate hypoxemic respiratory failure with
  stable hemodynamics who can be made comfortable
  and are easliy arousable
• Able to protect the airway and spontaneously
  clear the airway of secretions
• expected to recover rapidly
• 2B

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Mechanical Ventilationof Septic Patients

• Use a weaning protocol and an SBT regularly to
  evaluate the potential for discontinuing
  mechanical ventilation (1A)
• Ely, et al. NEJM 1996 3351864-1869
• Esteban, et al. AJRCCM 1997 156459-465
• Esteban, et al. AJRCCM 1999 159512-518

87
Prior to SBT, patients should

• a) Arousable
• b) Hemodynamically stable (without vasopressor
  agents)
• c) No new potentially serious conditions
• d) Low ventilatory and end-expiratory pressure
  requirements
• Requiring levels of FIO2 that could be safely
  delivered with a face mask or nasal cannula

88
Mechanical Ventilation of Septic Patients

• SBT options
• Low level of pressure support (7) with continuous
  positive airway pressure 5 cm H2O
• T-piece

89
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90

• Routine use of the pulmonary artery catheter for
  patient with ALI/ARDS is not recommanded.
• Potential benefits may be confounded by
• Differences in interpretation of results
• Lack of correlation of PAOP with clinical
  response
• Absence of a proven strategy to use catheter
  results to improve patient outcomes
• Grade 1A

91

• Conservative fluid strategy for patients with
  established acute lung injury who do not have
  evidence of tissue hypoperfusion
• Less weight gain, and
• fluid-conservative strategy based on either a CVP
  or a pulmonary artery catheter along with
  clinical variables
• ? led to fewer days of mechanical ventilation
• Only used in patients with established ALI
• Grade 1C

92
Sedation and Analgesia in Sepsis (2008)

• Use sedation protocols with a sedation goal for
  critically ill mechanically ventilated patients
  (1B)
• Ramsay score daytime 2-3, night time 4-5
• Use either intermittent bolus sedation or
  continuous infusion sedation to predetermined end
  points (sedation scales), with daily
  interruption/ lightening to produce awakening.
  Re-titrate if necessary (1B)
• Kollef, et al. Chest 1998 114541-548
• Brook, et al. CCM 1999 272609-2615
• Kress, et al. NEJM 2000 3421471-1477

93
Neuromuscular Blockers

• Avoid neuromuscular blockers where possible
• Risk of prolonged neuromuscular blockade
  following discontinuation
• Monitor depth of block with train-of-four when
  using continuous infusions (1B)

94
The Role of IntensiveInsulin Therapy in the
Critically Ill

• At 12 months, intensive insulin therapy reduced
  mortality by 3.4 (Plt0.04)

Adapted from Figure 1B, page 1363, with
permission from van den Berghe G, Wouters P,
Weekers F, et al. Intensive insulin therapy in
critically ill patients. N Engl J Med
20013451359-67
95
Glucose Control

• After initial stabilization
• Glucose be maintained lt150 mg/dl
• Continuous infusion insulin and glucose or
  feeding (enteral preferred)
• Monitoring
• Initially q30-60 mins
• After stabilizaiton q4h

Van den Berghe et al. NEJM, 2001 Finney et al.
JAMA, 2003 Krinsley. Mayo Clin Proc. 2004
96

• Use intravenous insulin to control hyperglycemia
  in patients with severe sepsis following
  stabilization in the ICU (1B)
• Aim to keep blood glucose lt 150mg/dL (8.3 mmol/L)
  using a validated protocol for insulin dose
  adjustment (2C)
• Provide a glucose calorie source and monitor
  blood glucose values every 1-2 hrs (4 hrs when
  stable) in patients receiving intravenous insulin
  (1C)
• Interpret with caution low glucose levels
  obtained with point of care testing of capillary
  blood, as these techniques may overestimate
  arterial blood or plasma glucose values (1B)

97
Renal Replacement
2008 update

• Absence of hemodynamic instability
• Intermittent hemodialysis and continuous
  venovenous filtration equal (CVVH)
• Hemodynamic instability
• CVVH preferred --- to facilitate management
  of fluid balance in septic
  patients, no improved in regional perfusion and
  survival benefit

Grade 2B
Grade 2D
98
Renal Replacement
2008 update

• Whether the dose of continuous renal replacement
  affects outcomes in patients with acute renal
  failure ?
• Increased the rate of ultrafiltration can
  improved mortality
• Limitation not specifically in sepsis
• Two very large multicenter randomized trials will
  be available in 2008 --- greatly inform practive

99
Bicarbonate Therapy

• Bicarbonate therapy not recommended to improve
  hemodynamics in patients with hypoperfusion-induce
  d lactic acidemia pH gt7.15
• Will increase Na, fluid overload, increase
  lactate and PCO2
• Grade 1B
• Cooper, et al. Ann Intern Med 1990 112492-498
• Mathieu, et al. CCM 1991 191352-1356

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Changing pH Has Limited Value

• Treatment Before After
• NaHCO3 (2 mEq/kg)
• pH 7.22 7.36
• PAOP 15 17
• Cardiac output 6.7 7.5
• 0.9 NaCl
• pH 7.24 7.23
• PAOP 14 17
• Cardiac output 6.6 7.3

Cooper DJ, et al. Ann Intern Med 1990
112492-498
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Deep Vein Thrombosis Prophylaxis

• Heparin (either UFH 2-3times perday or LMWH once
  daily) was recommended in patients with severe
  sepsis unless contraindications (1A)
• If contraindication for heparin, use mechanical
  prophylactic device (1A)
• Mechanical device (unless contraindicated)
• such as graduated compression stockings or
  intermittent compression devices

102
Deep Vein Thrombosis Prophylaxis
2008 update

• High risk patients (severe sepsis and history of
  DVT, trauma, or orthopedic surgery)
• Combination pharmacologic and mechanical
• In patient at very high risk, LMWH be used rather
  than UFH

Grade 2C
Grade 2C
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Primary Stress Ulcer Risk Factors Frequently
Present in Severe Sepsis

• Mechanical ventilation
• Coagulopathy
• Hypotension

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Stress Ulcer prophylaxis
2008 update

• H2 blocker
• Proton pump inhibitor
• The benefit of prevention of upper GI bleed must
  be weighed against the potential effect of an
  increased stomach pH on development of
  ventilator-associated pneumonia

Grade 1A
Grade 1B
Intensive Care Med 2006321151-1158
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Selective Digestive Tract Decontamination (SDD)
New Issue
2008 update

• SDD (enteral nonabsorbable antimicrobials and
  short-course intravenous antibiotics)
• --- reduces infections, mainly pneumonia,
  and mortality in general population of critically
  ill and trauma patients

106
Selective Digestive Tract Decontamination (SDD)
New Issue
2008 update

• As the main effect of SDD is in preventing
  ventilator-associated pneumonia, studies
  comparing SDD with nonantimicrobial interventions
  are needed
• Vancomycin --- a safe and effective regimen
• concerns persist about the potential for
• emergence of resistant Gram() infection

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Consideration forLimitation of Support

• Advance care planning, including the
  communication of likely outcomes and realistic
  goals of treatment, should be discussed with
  patients and families. Decisions for less
  aggressive support or withdrawal of support may
  be in the patients best interest.
• Grade 1D

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Summary gain in mortality in sepsis

• Activated protein C 31 vs 25 (-6)
• Bernard et al. NEJM 2001 344 699-709
• Early goal 47 vs 30 (-17)
• River et al. NEJM 2001 345 1368-73
• Hydrocortisone 63 vs 53 (-10)
• Annane et al. JAMA 2002 288 862-871
• Adequate antibiotics therapy 63 vs 31 (-32)
• Valles J et al. Chest 2003 123 1615-1624

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Sepsis BundlesSevere Sepsis/Septic Shock Bundles

• 6 hours (Sepsis Resuscitation Bundles)
• 24 hours (Sepsis Management Bundles)
• STOP Strategies to Timely Obviate the
  Progression of Sepsis
• H. Bryant Nguyen, MD, MS
• For the STOP Sepsis Working Group
• Loma Linda University Medical Center, Loma Linda,
  California
• MUST Multiple Urgent Sepsis Therapies
• BEST Better and Early Sepsis Treatment
• MOST Multiple Organ Success Therapy

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Sepsis Resuscitation Bundle

• Serum lactate measured
• Blood cultures obtained prior to antibiotic
  administration
• From the time of presentation, broad-spectrum
  antibiotics administered within 3 hours for ED
  admissions and 1 hour for non-ED ICU admissions

111
Sepsis Resuscitation Bundle

• In the event of hypotension and/or lactate gt4
  mmol/L (36 mg/dl)
• Deliver an initial minimum of 20 ml/kg of
  crystalloid (or colloid equivalent)
• Apply vasopressors for hypotension not responding
  to initial fluid resuscitation to maintain mean
  arterial pressure (MAP) ?65 mm Hg

See the individual chart measurement tool for an
equivalency chart.
112
Perfusion and Pressure
113
Sepsis Resuscitation Bundle

• In the event of persistent hypotension despite
  fluid resuscitation (septic shock) and/or lactate
  gt 4 mmol/L (36 mg/dl)
• Achieve central venous pressure (CVP) of 8 mm Hg
• Achieve central venous oxygen saturation (ScvO2)
  of ? 70

Achieving a mixed venous oxygen saturation
(SvO2) of 65 is an acceptable alternative.
114
Sepsis Management Bundle

• Low-dose steroids administered for septic shock
  in accordance with a standardized ICU policy
• Drotrecogin alfa (activated) administered in
  accordance with a standardized ICU policy

See the individual chart measurement tool for an
equivalency chart.
115
Sepsis Management Bundle

• Glucose control maintained ? lower limit of
  normal, but lt 150 mg/dl (8.3 mmol/L)
• Inspiratory plateau pressures maintained lt 30 cm
  H2O for mechanically ventilated patients.

116
A clinician, armed with the sepsis bundles,
attacks the three heads of severe sepsis
hypotension, hypoperfusion and organ dysfunction.
Crit Care Med 2004 320(Suppl)S595-S597
117
7-3 RuleAnalg Anesth 1979 38 124-132

• Initial PCWP
• lt10?200ml x 10 min
• 10-15?100ml
• gt15?50ml

• Response in PCWP
• gt7?Stop
• 3-7?wait 10min
• lt3?Continue

118
PAC-Guided Treatment Protocol
Adapted from Pinsky Vincent. Crit care Med 33
1119-22, 2005
119
Pathways and Mediators of Sepsis, Potential
Treatments, and Results of Randomized, Controlled
Trials (RCTs)
Russell, NEJM 355(16) 1699, 2006
120
Pathways and Mediators of Sepsis, Potential
Treatments, and Results of Randomized, Controlled
Trials (RCTs)
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