Sirs

Systemic Inflammatory Response Syndrome (SIRS)

Dr. Madhu Aryal

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

SIRS criteria + suspected or proven infection

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.


MODS(Multiple Organ Dysfunction Syndrome)

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


Severe Sepsis

Sepsis with organ hypoperfusion one of the criteria of MODS

Septic Shock- Severe sepsis + Hypotension Refractory septic Shock- shock not controlled by IV fluids

and pressor agents


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.

Organ Dysfunction Lungs Kidneys CVS CNS PNS Coagulation GI Liver Endocrine Skeletal Muscle

Adult Respiratory Distress Syndrome Acute Tubular Necrosis Shock Metabolic encephalopathy Critical Illness Polyneuropathy Disseminated Intravascular Coagulopathy Gastroparesis and ileus Cholestasis Adrenal insufficiency Rhabdomyolysis

Specific therapy exists

Response of body to inflamation Physiology

Heart rate Respiration Fever Blood pressure Cardiac output WBC Hyperglycemia

Markers of Inflammation TNF IL-1 IL-6 Procalcitonin PAF

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)

Haptoglobins, C-Reactive proteins, ESR



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


Pathogenesis of sepsis and septic shock

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

Homeostasis Is Unbalanced in

Severe Sepsis

Carvalho AC, Freeman NJ. J Crit Illness. 1994;9:51-75; Kidokoro A et al. Shock. 1996;5:223-8; Vervloet MG et al. Semin Thromb Hemost. 1998;24:33-44.

QO2 = Flow * O2 content

BP=CO * SVR

Intra Organ Distribution

regional distribution

Microcirculation

Cardiac Output

Intra Organ Distribution

regional distribution

Microcirculation

Regulation of oxygen delivery

Cardiac output

Normal Abnormal

Oxygen Delivery

Delivery:Demand mismatch Diffusion limitation (edema)

Oxygen Consumption

III

NADH + H+

NAD+ADP + Pi

1/2 O2 + H+

ATP

I

H+ Cytc

H2O

H+

H+

H+ H+

Q IV

•Pyruvate Dehydrogenase (PDH) activity decreased

•Decreased delivery of Acetyl CoA to TCA cycle

•Mitochondrial dysfunction

Inflammatory Response to Sepsis

NEJM 2006;355:1699-1713.

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.


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.

Surviving Sepsis Campaign

Guidelines for Management of Severe Sepsis and Septic Shock

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

Case presentation

43-year-old male Flu-like symptoms for 1

day In ER

Temp 39.5 Pulse 130 Blood pressure 70/30 Respirations 32 Petechial rash Chest, CV, Abdominal

exam normal

Case presentation - 2

Laboratory pH 7.29, PaO2 82,

PaCO2 29 Investigations pending

Blood, urine cultures Orally intubated and

placed on mechanical ventilation

Central venous catheter inserted Cefotaxime 2 g iv Normal saline 2 litres

initially, repeated Admitted to ICU


In ICU: Noradrenaline started to

support blood pressure Additional fluid (saline

and pentastarch) given based on low CVP

Pulmonary artery catheter inserted to aid further hemodynamic management

Despite therapy patient remained anuric Continuous venovenous

hemofiltration initiated


Early gram stain on blood revealed gram negative rods

Patient started on: Hydrocortisone 100 mg iv q8h Recombinant activated protein C 24g/kg/hour for

96 hours Enrolled in RCT (double-blind) of vasopressin vs

norepinephrine for BP support Enteral nutrition via nasojejunal feeding tube Prophylaxis for stress ulcers, deep venous

thromboses

Case Presentation - Resolution

Patient gradually stabilized and improved with complete resolution of organ dysfunction over 5 days

Final cultures confirmed diagnosis as meningococcemia

Severe Sepsis: Management of Our Case

Endothelial Dysfunction and Microvascular Thrombosis

Hypoperfusion/Ischemia

Acute Organ Dysfunction (Severe Sepsis)

Death

rhAPCCorticosteroids

FluidsVasopressors

CVVHFEnteral nutrition

Survival

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


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


Education

Sirs