Sirs present

Systemic Inflammatory Response Syndrome (SIRS)

PRANEE SITAPOSA, MD.

SEPSIS and It’s Disease spectrum

Various stages of disease Bacteremia SIRS Sepsis syndrome Sepsis shock : early and refractory

Definition

Infection Presence of microorganisms in a normally

sterile site. Bacteremia

Cultivatable bacteria in the blood stream. Sepsis

The systemic response to infection. If associated with proven or clinically suspected infection, SIRS is called “sepsis”.

American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference Committee. Crit Care Med. 1992;20:864-874.

SIRS (Systemic Inflammatory Response Syndrome)

The systemic response to a wide range of stresses. Temperature >38°C (100.4°) or <36°C (96.8°F). Heart rate >90 beats/min. Respiratory rate >20 breaths/min or

PaCO2 <32 mmHg.

White blood cells > 12,000 cells/ml or < 4,000 cells/ml or >10% immature (band) forms.

Note Two or more of the following must be present. These changes should be represent acute alterations from

baseline in the absence of other known cause for the abnormalities.


Severe Sepsis

Sepsis with organ hypoperfusion one of the followings : SBP < 90 mmHg Acute mental status change PaO2 < 60 mmHg on RA (PaO2 /FiO2 < 250) Increased lactic acid/acidosis Oliguria DIC or Platelet < 80,000 /mm3

Liver enzymes > 2 x normal


MODS(Multiple Organ Dysfunction Syndrome)

Sepsis with multiorgan hypoperfusion

Two or more of the followings: SBP < 90 mmHg Acute mental status change PaO2 < 60 mmHg on RA (PaO2 /FiO2 < 250) Increased lactic acid/acidosis Oliguria DIC or Platelet < 80,000 /mm3

Liver enzymes > 2 x normal


Relationship between SIRS and Sepsis

Bone RC et al, Chest1992;101:164-55.

The Sepsis Continuum

A clinical response arising from a nonspecific insult, with 2 of the following: T >38oC or <36oC HR >90 beats/min RR >20/min WBC >12,000/mm3 or

<4,000/mm3 or >10% bands

SIRS = systemic inflammatory response syndrome

SIRS with a presumed or confirmed infectious process

Chest 1992;101:1644.

SepsisSIRSSevere Sepsis

SepticShock

Sepsis with organ failure

Refractoryhypotension

Mortality rate in SIRS

Rangel-Frausto, et al. JAMA 273:117-123, 1995.

The Response to Pathogens “Cross-Talk”

NEJM 2003;348:138-150.

Inflammatory Response to Sepsis

NEJM 2006;355:1699-1713.

Procoagulant Response in Sepsis

NEJM 2006;355:1699-1713.

Pathogenesis of sepsis and septic shock

Angus DC, et al. Crit Care Med 2001, 29:1303-1310.

Pathogenesis of Severe Sepsis

InfectionInfection

Microbial ProductsMicrobial Products(exotoxin/endotoxin)(exotoxin/endotoxin)

Cellular ResponsesCellular Responses

OxidasesOxidasesPlateletPlatelet

ActivationActivationKininsKinins

ComplementComplement

Coagulopathy/DICCoagulopathy/DICVascular/Organ System InjuryVascular/Organ System Injury

Multi-Organ FailureMulti-Organ Failure

DeathDeath

EndothelialEndothelial damagedamage Endothelial damageEndothelial damage

CoagulationCoagulationActivationActivation

CytokinesCytokinesTNF, IL-1, IL-6TNF, IL-1, IL-6

Normal Systemic Response to Infection and Injury (1)

Leukocytosis Mobilizes neutrophils into the circulation Tachycardia Increases cardiac output, blood flow to

injuried tissue Fever Raises core temperature; peripheral

vasoconstriction shunts blood flow to injuried tissue. Occurs much more often when infection is the trigger for systemic responses

Mandell et al. Principals and Practice of Infectious Diseases6th ed;906:906-926.


Acute-Phase Responses Anti-infective

Increases synthesis of complement factors, microbe pattern-recognition molecules(mannose-binding lectin, LBP, CRP, CD14, Others)

Sequesters iron (lactoferrin) and zinc (metallothionein)



Anti-inflammatory Releases anti-inflammatory neuroendocrine hormones

(cortisol, ACTH, epinephrine, α-MSH) Increases synthesis of proteins that help prevent

inflammation within the systemic compartmentCytokine antagonists (IL-1Ra, sTNF-Rs)Anti-inflammatory mediators (e.g.,IL-4, IL-6, IL-6R, IL-

10, IL-13, TGF-β)Protease inhibitors (e.g.,α1-antiprotease)Antioxidants (haptoglobin)

Reprograms circulating leukocytes (epinephrine, cortisol, PGE2, ?other)



Procoagulant Walls off infection, prevents systemic spread

Increases synthesis or release of fibrinogen, PAI-1, C4b Decreases synthesis of protein C, anti-thrombin III Metabolic

Preserves euglycemia, mobilizes fatty acids, amino acids Epinephrine, cortisol, glucagon, cytokines

Thermoregulatory Inhibits microbial growth

Fever


Risk factors of sepsis

aggressive oncological chemotherapy and radiation therapy use of corticosteroid and immunosuppressive therapies for organ

transplants and inflammatory diseases longer lives of patients predisposed to sepsis, the elderly, diabetics,

cancer patients, patients with major organ failure, and with granulocyopenia.

Neonates are more likely to develop sepsis (ex. group B Streptococcal infections).

increased use of invasive devices such as surgical protheses, inhalation equipment, and intravenous and urinary catheters.

indiscriminate use of antimicrobial drugs that create conditions of overgrowth, colonization, and subsequent infection by aggressive, antimicrobial-resistant organisms.


Patients at increased risks of developing sepsis

Underlying diseases: neutropenia, solid tumors, leukemia, dysproteinemias, cirrhosis of the liver, diabetes, AIDS, serious chronic conditions.

Surgery or instrumentation: catheters. Prior drug therapy: Immuno-suppressive drugs, e

specially with broad-spectrum antibiotics. Age: males, above 40 y; females, 20-45 y. Miscellaneous conditions: childbirth, septic aborti

on, trauma and widespread burns, intestinal ulceration.


Source (usually an endogenous source of infection)

intestinal tract oropharynx instrumentation sites contaminated inhalation therapy equipment IV fluids. Most frequent sites of infection: Lungs, abdo

men, and urinary tract. Other sources include the skin/soft tissue and t

he CNS.


Diagnosis History

community or nosocomially acquired infection immunocompromised patient exposure to animals, travel, tick bites, occupational h

azards, alcohol use, seizures, loss of consciousness, medications

underlying diseases ; specific infectious agents Some clues to a septic event include

Fever or unexplained signs with malignancy or instrumentation

Hypotension Oliguria or anuria Tachypnea or hyperpnea Hypothermia without obvious cause Bleeding


Specific Infectious agents

Splenectomy (traumatic or functional) S pneumoniae, H influenzae, N meningitidis

Neutropenia (<500 neutrophil/ml) Gram-negative, including P aeruginosa, gram-

positives, including S aureus Fungi, especially Candida species

Hypogammaglobulinemia (e.g.,CLL) S pneumoniae, E coli

Burns MRSA, P aeruginosa, resistant gram-negatives

MacArthur RD, et al. Mosby, 2001:3-10. Wheeler AP, et al. NEJM 1999;340:207-214. Chaowagul W, et al. J Infect Dis 1989;159:890-899.

Specific Infectious agents

Aids P aeuginosa (if neutropenic), S aureus, PCP

pneumonia Intravascular devices

S aureus, S epidermidis Nosocomial infections

MRSA, Enterococcus species, resistant gram-negative, Candida species

Septic patients in NE of Thailand Burkholderia pseudomallei

MacArthur RD, et al. Mosby, 2001:3-10. Wheeler AP, et al. NEJM 1999;340:207-214. Chaowagul W, et al. J Infect Dis 1989;159:890-899.

Diagnosis

Physical Examination essential In all neutropenic patients and in patients wit

h as suspected pelvic infection the physical exam should include rectal, pelvic, and genital examinations

perirectal, and/or perineal abscesses pelvic inflammatory disease and/or absce

sses, or prostatitis


Signs and Symptoms

Nonspecific symptoms of sepsis : not pathognomonic fever chills constitutional symptoms of fatigue, malaise anxiety or confusion

absent symptoms in serious infections, especially in elderly individuals


Complications

Adult respiratory distress syndrome (ARDS) Disseminated Intravascular Coagulation (DIC) Acute Renal failure (ARF) Intestinal bleeding Liver failure Central Nervous System dysfunction Heart failure Death


Surviving Sepsis Campaign

Guidelines for Management of Severe Sepsis and Septic Shock

Dellinger RP, et al. Crit Care Med 2004; 32:858-873.

Before the initiation of antimicrobial therapy, at least two blood cultures should be obtained

At least one drawn percutaneously At least one drawn through each vascular access device if

inserted longer than 48 hours Other cultures such as urine, cerebrospinal fluid, wounds, respiratory

secretions or other body fluids should be obtained as the clinical situation dictates

Other diagnostic studies such as imaging and sampling should be performed promptly to determine the source and causative organism of the infection

may be limited by patient stabilityWeinstein MP. Rev Infect Dis 1983;5:35-53

Blot F. J Clin Microbiol 1999; 36: 105-109.

Diagnosis

Dellinger, et. al. Crit Care Med 2004, 32: 858-873.

Sepsis resuscitation bundle

Serum lactate measured Blood cultures obtained before antibiotics administered Improve time to broad-spectrum antibiotics In the event of hypotension or lactate > 4 mmol/L (36 mg/dL)

a. Deliver an initial minimum of 20 mL/kg of crystaloid (or colloid equivalent)

b. apply vasopressors for ongoing hypotension In the event of persistent hypotension despite fluid

resuscitation or lactate > 4 mmol/L (36 mg/dL) a. achieve central venous pressure of > 8 mmHg b. achieve central venous oxygen saturation of > 70%

Hurtado FJ. et al. Crit Care Clin;2006; 22:521-9.

Sepsis management bundle

Fluid resuscitation

Appropriate cultures prior to antibiotic administration

Early targeted antibiotics and source control

Use of vasopressors/inotropes when fluid

resuscitation optimized

Surviving Sepsis Campaign Management Guidelines Committee. Crit Care Med 2004; 32:858-873.

Sepsis management bundle

Evaluation for adrenal insufficiency Stress dose corticosteroid administration Recombinant human activated protein C (xigris)

for severe sepsis Low tidal volume mechanical ventilation for

ARDS Tight glucose control


Infection Control

Appropriate cultures prior to antibiotic

administration Early targeted antibiotics and source control


CVP : central venous pressure MAP : mean arterial pressure

ScvO2: central venous oxygen saturation

Early Goal-Directed Therapy

NEJM 2001;345:1368-77.

49.2%

33.3%

0

10

20

30

40

50

60

Standard Therapy n=133

EGDTn=130

P = 0.01*

*Key difference was in sudden CV collapse, not MODS

28-day Mortality

Early Goal-Directed Therapy Results

NEJM 2001;345:1368-77.

Antibiotic use in Sepsis (1)

The drugs used depends on the source of the sepsis Community acquired pneumonia

third (ceftriaxone) or fourth (cefepime) generation cephalosporin is given with an aminoglycoside (usually gentamicin)

Nosocomial pneumonia Cefipime or Imipenem-cilastatin and an aminoglycoside

Abdominal infection Imipenem-cilastatin or Pipercillin-tazobactam and

aminoglycoside



Nosocomial abdominal infection Imipenem-cilastatin and aminoglycoside or Pipercillin

-tazobactam and Amphotericin B Skin/soft tissue

Vancomycin and Imipenem-cilastatin or Piperacillin-tazobactam

Nosocomial skin/soft tissue Vancomycin and Cefipime

Urinary tract infection Ciprofloxacin and aminoglycoside



Nosocomial urinary tract infection: Vancomycin and Cefipime

CNS infection: Vancomycin and third generation cephalosporin or

Meropenem Nosocomial CNS infection:

Meropenem and Vancomycin Drugs will change depending on the most likely cause of the patient

's sepsis Single drug regimens are usually only indicated when the organism

causing sepsis has been identified and antibiotic sensitivity testing


New Drug in Treating Severe Sepsis

It is the first agent approved by the FDA effective in the treatment of severe sepsis proven to reduce mortality. Activated Protein C (Xigris) mediates many actions of body homeostasis. It is a potent agent for the: suppression of inflammation

prevention of microvascular coagulation reversal of impaired fibrinolysis


NEJM;355:1699-1723.

Sepsis Cascade

Activated Protein C (Xigris)

NEJM;355:1640, October 19, 2006.

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