Sepsis/Shock

Sepsis

Sepsis is a complex condition that occurs as a result of the systemic manifestation of infection Severe sepsis, which occurs when sepsis progresses to involve acute organ system dysfunction, contributes to increased severity of illness, length of stay and mortality rates of 20% to 50%

Angus et al Crit Care Med 2001;29:1303-1310; Linde-Zwirble et al Crit Care Med 2004;8:222-226; Weycker et al Crit Care Med 2003;31:2316-2323

Mortality in Severe Sepsis

In the US, 1 patient dies of severe sepsis every 3 minutes (500/day)*

* Angus DC, et al. Crit Care Med. 2001;29:1303-10. American Heart Association, 2000. American Cancer Society, 2001. National Center for Health Statistics, 2001.

Severe Sepsis-Associated Mortality Increases With the Number of Organ Dysfunctions

Angus DC, et al. Crit Care Med. 2001;29:1303-10. Vincent JL, et al. Crit Care Med. 1998;21:1793-800.

Sepsis: Scope of the Problem

Annual expenditure estimated at almost $17 billion/year Sepsis is an acquired disease

Compounds underlying comorbidities

Angus DC, et al. Crit Care Med 2001. In Press. Natanson C, et al. Crit Care Med 1998;1927-31.

Sepsis Source

Lung: tracheobronchial tree colonized within 48 hours GI: translocation of Gram-negative organisms GU: Foley catheter colonized within 72 hours

Wound Other nosocomial sources: invasive lines/procedures Primary source not found in 30% of patients

Sepsis Terms & Definitions

Infection Sepsis Severe Sepsis MODS

Clinical Evidence of Sepsis

SIRS = the Systemic Inflammatory Response Syndrome

Manifested by 2 or more of the following:

Fever (>38C) or hypothermia (<36C) Tachycardia, heart rate >90 beats/minute Tachypnea, respiratory rate >20/min or PaCO2 <32 mm Hg WBC >12,000 or <4,000 mm3 or >10% bands

Bone RC, et al. Chest 1992;101:1644-55.

ACCP/SCCM Consensus Definitions

Infection
Inflammatory response to microorganisms, or Invasion of normally sterile tissues

Severe Sepsis
Sepsis Organ dysfunction Sepsis Hypotension despite fluid resuscitation

Septic shock

Systemic Inflammatory Response Syndrome (SIRS)

Systemic response to a variety of processes Infection plus 2 SIRS criteria

Multiple Organ Dysfunction Syndrome (MODS)

Altered organ function in an acutely ill patient Homeostasis cannot be maintained without intervention

Sepsis

Bone RC et al. Chest. 1992;101:1644-55.

Pathophysiology of Severe Sepsis

Systemic Inflammation

Coagulation

Impaired Fibrinolysis

Severe Sepsis

Inflammation:
Bodys

normal response to infection WBCs (monocytes & macrophages)

Perform phagocytosis Generate & release cytokines Nonspecific mediators of inflammation

Severe Sepsis
Cytokines low molecular weight glycoproteins that act as intracellular messengers
TNF- (tumor necrosis factor alpha) IL (interleukins) Interferons, chemokines & others

Play a role in host defense by attracting activated neutrophils to site of infection Entry into systemic circulation is associated with SIRS

Sepsis & the Endothelium

Role of endothelium Lines blood vessels Reacts to mediators
In sepsis: see vascular permeability
Physical disruption allows capillary leak into interstitial space Vasodilation

Endothelial Cell Biology

Endothelium plays an active role in hemostasis, cellular trafficking & vasomotor tone Normally anticoagulant, anti-adhesive & vasodilatory phenotype Activated endothelial cells express procoagulant, pro-adhesive, & altered vasomotor properties Nature of endothelial response varies among different vascular beds
Aird. Critical Care Medicine 30 (5), 2002.

Endothelial Cell Biology

The endothelium is an active component of the immune response to bacterial invasion
Initiates the transcription of inflammatory genes Toll-like receptors (transmembrane proteins) are believed to be the link between binding of microbial components to the endothelium and activation
Henneke & Golenbock, Critical Care Medicine 30 (5), 2002.

Sepsis-targeting microbial mediators-LPS

4 million LPS molecules/cell 75% of outer membrane

LPS LPS Early Signaling Events of Innate Immunity are now increasingly understood

Mj Mj

DNA DNA

NFkB NFkB

nuclear localization sequence

Host response-antimicrobial defense programs

Sepsis-Associated Coagulopathy

formation of microthrombi
clot breakdown (impaired fibrinolysis) Results in:

Widespread coagulopathy Microvascular thrombosis Multiple organ dysfunction

Sepsis

Sepsis initiates an excessive inflammatory response that is characterized by:

Hemodynamic derangements including arterial hypotension, peripheral vasodilation, hypovolemia from capillary leak and myocardial depression

Endothelial damage

Capillary permeability Organ system dysfunction & edema formation

Stimulation of Mediator Release via WBC

Journal of Critical Illness, 1991

Interruption of Endothelium Integrity

Journal of Critical Illness, 1991

Progression of Endothelial Dysfunction

Journal of Critical Illness, 1991

Pathogenic insult resulting in infection

Inflammatory/Immune System Response
Specific genetic signaling

Insult phase Molecular activation phase

Neutrophil and Monocyte activation

Endothelial cell activation

Platelet dysfunction

Effector molecule release

Enhanced expression of adhesion molecules

System dysfunction phase

Massive cytokine production

Quadrad of dysfunction in sepsis

Coagulation Fibrinolysis
Apoptosis

Imbalance between inflammation and antiinflamation Reduced tissue/cellular perfusion

Organ dysfunction phase

Oxygen & Endothelial damage Microthrombi formation Capillary permeability and edema formation

substrate debt

Organ dysfunction

Pathophysiologic Consequences
Progression of endothelial dysfunction Altered microcirculatory perfusion Widespread inflammation Sepsis-associated coagulopathy Impairment of fibrinolysis

Multiple Organ Dysfunction Syndrome

Progression of sepsis can lead to MODS

Major cause of mortality in sepsis Results from:
Inadequate tissue/organ perfusion Cellular injury Ischemia

Criteria for Acute Organ Dysfunction

Bernard GR, et al. N Engl J Med. 2001;344:699-709.

Identification of High-Risk Severe Sepsis

Clinical

indicators can alert you to high risk of death.* APACHE II score > 25 OR requiring vasopressors

* The mortality rate (risk of death) of standard therapy patients who had an APACHE II score of 25 in the trial was 25%. The mortality rate of standard therapy patients who required vasopressors was 32%.

Need for dopamine > 5 g/kg/min or norepinephrine, epinephrine, or phenylephrine at any dose. Single organ dysfunction alone may not represent high risk of death.

Sepsis Treatment
Goal = Immediate Stabilization of the Patient
Circulatory support with fluid, inotropes and vasopressors Supportive treatment with oxygenation, ventilation Locate and treat focus of infection
Antibiotics & source control Appropriate antibiotic therapy reduces septic mortality by 10%-15%

Targeting Sepsis
Evidence based guidelines for the treatment of sepsis were released in 2004 and updated in 2008 Surviving Sepsis Campaign Guidelines have been promoted to improve outcomes for patients with severe sepsis

Townsend et al 2005 Implementing the Surviving Sepsis Campaign. Society of Critical Care Medicine, the European Society of Intensive Care Medicine, and the International Sepsis Forum; Dellinger et al 2008 CCM 36:296-327.

Targeting Sepsis

The severe sepsis bundles form the main components for implementation

Sepsis resuscitation bundle

First 6 hours

Sepsis management bundle

First 24 hours

Townsend et al 2005 Implementing the Surviving Sepsis Campaign. Society of Critical Care Medicine, the European Society of Intensive Care Medicine, and the International Sepsis Forum. 2005. www.ihi.org

Sepsis Bundles
6 Hour Bundle: These tasks should be implemented immediately and within the first 6 hours of identification of severe sepsis: Measure serum lactate

ED lactate predicts mortality Results available in minutes

Townsend et al 2005. Implementing The Surviving Sepsis Campaign

Role of Biomarkers in the Detection of Disease

A diagnostic tool to optimize and expedite clinical diagnosis Biomarkers can allow for better outcome prediction Can lead to more targeted therapies for a clinical condition

Biomarkers Definitions Working Group Clin Pharmacol Therap 2001;69:89-95;

Common Biomarkers in Clinical Use

D-dimer

in DVT/PE BNP in heart failure Troponin in MI Rheumatoid factor in Rheumatoid arthritis Cortisol response to ACTH in adrenal insufficiency

Biomarkers in Sepsis

While >100 different biomarkers have been proposed or evaluated for their use in diagnosis, management, or prognostic ability in patients with sepsis and septic shock; It is not known which of these provide truly useful information nor even how such utility is best established

Marshall JC et al. Crit Care Med 2009;37:2290-8; Marshall JD et al Crit Care Med 2003;31:1560-7.

Serum Lactate & Mortality in Severe Sepsis

50
P = 0.001 P = 0.022 P < 0.001

45
28-Day Mortality (%)
Initial

ED serum lactate evaluated in 839 adults admitted with severe sepsis initial serum lactate associated with mortality regardless of presence of shock or MODS

40 35 30 25

20
15 10 5 0

P = 0.024

High

Low Int High Non-Shock

Low Int High Shock

Mikkelsen ME et al. Crit Care Med 2009;37:1670-1677.

Initial Lactate in Septic Shock

8

Lactate (mmol/L)

6
P < 0.05
Nonsurvivors P < 0.05 P < 0.01

2
0

Survivors

INITIAL +8h

+16h

+24h

FINAL

Time

Bakker J et al. Am J Surg. 1996;171:221-6.

Diagnostic Accuracy of Sepsis Markers

1

Sensitivity

Calcitonin Precursors (N-ProCT assay)

C-Reactive Protein
Interleukin-6 Lactate

0 1

Specificity

Muller B et al. Swiss Med Wkly. 2001;131:595-602.

CRP Levels Correlate With Mortality & Organ Failure in Critically Ill Patients
30

30 P = 0.001 P = 0.002

CRP mg/dL

CRP mg/dL
0 1 2 3
(20/19)

20

20

10

10

>4
(4/4)

0 Day 0 Survivors Non-Survivors Day 2

(116/115) (111/110) (56/56)

Number of Organ Failures * P < 0.05

CRP Day 0 CRP Day 2 Lobo SM et al. Chest. 2003;123:2043-9.

PCT Levels are Associated with the presence of bacterial infections

100

Amino-ProCT (ng/mL; n=651)

10

0.1

0.01

No SIRS No Infection

SIRS

Sepsis
.

Severe Sepsis

Septic Shock

40

Mller B, Crit Care Med 2000

Sepsis resuscitation bundle (0-6 hrs)

Blood cultures before antibiotics Time to broad spectrum antibiotics

Within 3 hours for ED admission Within 1 hour for ward admission

Delay in initiation of antibiotic therapy is associated with mortality in severe sepsis

Townsend et al 2005. Implementing The Surviving Sepsis Campaign

Mortality Risk with Increasing Delays in Initiating Antimicrobial Therapy

Kumar A et al Crit Care Med 2006;34:1589-1596

Duration of Hypotension Before Initiation of Antibiotics is a Critical Determinant of Survival In Septic Shock

Kumar A et al Crit Care Med 2006;34:1589-1596

Sepsis Bundles
6 Hour Bundle (continued): For hypotension and/or lactate > 4 mmol/L:

Administer an initial minimum of 20 ml/kg of crystalloid

(or colloid equivalent) Administer vasopressor for hypotension not responding to initial fluid resuscitation to maintain mean arterial pressure > 65 mm Hg With persistent hypotension despite fluid resuscitation and/or lactate > 4 mmol/L

Achieve a central venous pressure (CVP) > 8 mm Hg

Achieve a central venous oxygen saturation (SCVO2) of > 70%
Townsend et al 2005. Implementing The Surviving Sepsis Campaign

Sepsis resuscitation bundle (0-6 hrs)

Rivers protocol (Early Goal Directed Therapy)
Refractory to fluid challenge/ elevated lactate

Rivers E. et al NEJM 2001;345:1368-1377

24 Hour Sepsis Bundle

Administer low-dose steroids for septic shock based on a standardized ICU policy Administer drotrecogin alfa (activated) based on a standardized ICU policy Maintain glucose control > lower limit of normal, but <150 mg/dL Maintain inspiratory plateau pressures <30 mm H20 for mechanically ventilated patients

Townsend et al 2005. Implementing The Surviving Sepsis Campaign

Surviving Sepsis Campaign Guidelines

Diagnosis

Obtain cultures: 2 blood cultures - 1 drawn percutaneously & 1 drawn through each vascular access device; obtain cultures of other sites such as urine, wounds, and respiratory secretions before initiating antibiotic therapy

Dellinger et al Critical Care Medicine 2008 36:296-327

Surviving Sepsis Campaign Guidelines

Antibiotic

therapy

Empiric antibiotics 1 HOUR within diagnosis of refractory shock (ie. Fluid challenge) Gram-positive and Gram-negative coverage

Dellinger et al Critical Care Medicine 2008 36:296-327

Surviving Sepsis Campaign Guidelines

Source Identification and Control

Within 1st 6 hours of presentation

Recombinant Human Activated Protein C (rhAPC) (Xigris)

for patients with sepsis-induced multiple organ failure with no absolute contraindication related to bleeding risk

Dellinger et al Critical Care Medicine 2008; 36:296-327

Surviving Sepsis Campaign Guidelines

Mechanical ventilation

lung protective ventilation for acute lung injury/acute respiratory distress syndrome (eg. Low tidal volume 6mL per kg of predicted body weight with the goal of maintaining end inspiratory plateau pressure <30 cm H20)

Dellinger et al Critical Care Medicine 2008; 36:296-327

Surviving Sepsis Campaign Guidelines

Blood product administration

For Hgb < 7.0 g/dL

Steroid Therapy

For septic shock when hypotension responds poorly to resuscitation

Dellinger et al Critical Care Medicine 2008; 36:296-327

Surviving Sepsis Campaign Guidelines

Renal replacement

for acute renal failure

Prophylaxis measures
deep vein thrombosis stress ulcer

Dellinger et al Critical Care Medicine 2008; 36:296-327

Surviving Sepsis Campaign Guidelines

Consideration for limitation of support

Discuss end-of-life care for critically ill patients Promote family communication to discuss use of life-sustaining therapies

Dellinger et al Critical Care Medicine 2008; 36:296-327

Treatment Goals in Sepsis: Prevention

Universal precautions Handwashing Measures to prevent nosocomial infections

Oral care Proper positioning Invasive catheter care/wound care

Evidence-Based Practices

Supine body position as a risk factor for pneumonia

86 intubated and mechanically ventilated patients randomized to:

Semirecumbent (n=39) or Supine (n=47)

Results:
rates of nosocomial pneumonia in semirecumbent group (8% vs. 34% in supine)

Drakulovic et al 1999

Evidence-Based Practices

Oral Care

Plaque is source of bacteria for oral colonization which can cause VAP
Foam swabs or toothettes are ineffective in plaque removal Toothbrushing with toothpaste is more effective However, nurses report oral care in nonintubated patients (5 times a day) versus intubated patients (2-3 times a day)

Grap et al 2006; Munro et al 2008

Failed Trials of Agents for Severe Sepsis

Over 30 clinical trials have been conducted None with significant reduction in mortality

Steroid therapy Anti-TNF monoclonal antibodies factor Anti- LPS Platelet activating factor inhibitor Antithrombin (ATIII) Tissue factor pathway inhibitor (TFPI)

?Role of blocking TLR

Implications for Acute Care Practitioners

Assessment:
Knowledge of S/S of sepsis is important for all Advanced Practice Providers, regardless of practice setting Early detection is key Recognition of SIRS criteria Recognition of clinical evidence of sepsis

Implications for Acute Care Practitioners

Formulating the Differential Diagnosis:
History
Helps in determining if infection was community or nosocomially acquired Helps in identifying if patient is immunocompromised

Thorough Physical Exam Laboratory Data

Implications for Acute Care Practitioners

Treatment:
Circulatory support Oxygenation/ventilation Antibiotic therapy Organ support therapies Surviving Sepsis Guidelines

Critical Care Challenges: Which Patients Are Candidates for Treatment?

Summary:Optimizing Outcomes in Severe Sepsis

Role of Astute Clinical Assessment EARLY:

Recognition Treatment
Appropriate Therapy Use

Resources
www.sepsis.com www.sepsisforum.org www.ards.org www.ccforum.com www.survivingsepsis.com Critical Care Medicine (journal) Sepsis (journal)