Programme in Critical CareUniversity of Western Ontario

London, Ontario, Canada

SIRS, Sepsis, and MODS

Claudio Martin, MSc, MD

Objectives

• To know definitions of SIRS, sepsis, septic shock, MODS

• To become familiar with the epidemiology of sepsis

• To learn basic pathophysiology (inflammation, cardiovascular physiology) of SIRS and sepsis

But first, a real case:

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

Case presentation - 3

• 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

Case presentation - 4

• 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

Infection: Part of a bigger picture

• Infection:– Presence of organisms in a

closed space or location where not normally found

Adapted from: Bone RC et al. Chest. 1992;101:1644-55.Opal SM et al. Crit Care Med. 2000;28:S81-2.

Infection

SIRS: Systemic Inflammatory Response Syndrome

• SIRS: A clinical response arising from a nonspecific insult manifested by 2 of the following:– Temperature

38°C or 36°C– HR 90 beats/min– Respirations 20/min– WBC count

12,000/mL or 4,000/mL or >10% immature neutrophilsAdapted from: Bone RC et al. Chest. 1992;101:1644-55.

Opal SM et al. Crit Care Med. 2000;28:S81-2.

Sepsis: More Than Just Inflammation

• Sepsis:– Known or suspected

infection– SIRS criteria

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

Severe Sepsis: Acute Organ Dysfunction

• Severe Sepsis = Sepsis with signs of acute organ dysfunction in any of the following systems: – Cardiovascular (septic

shock)– Renal– Respiratory– Hepatic– Hemostasis– CNS– Unexplained metabolic

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

Sepsis: A Complex Disease

Adapted from: Bone RC et al. Chest. 1992;101:1644-55.Opal SM et al. Crit Care Med. 2000;28:S81-2.

Jargon 2002: PIRO

InfectionInflammation

PhysiologicBiochemical

SevereSepsis

Specific OrganSeverity

Predisposition

• Pre-existing disease– Cardiac, Pulmonary, Renal– HIV

• Age (extremes of age) • Gender (males)• Genetics

– TNF polymorphisms (TNF promoter high secretor genotype)

Response

• Physiology– Heart rate– Respiration– Fever– Blood pressure– Cardiac output– WBC– Hyperglycemia

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

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

Magnitude of the Problem

• Estimated 215,000 deaths from US 1995 data• High cost for management (ICU care,

diagnostic testing, drugs)– Estimated 20 day LOS; $22,000 cost

• Represents 9.3% of all deaths• Equals deaths after acute myocardial infarction

Sepsis: Defining a Disease Continuum

A clinical response arisingfrom 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 SIRS = systemic inflammatory response SIRS = systemic inflammatory response

syndrome.syndrome.

Bone et al. Bone et al. Chest.Chest. 1992;101:1644. 1992;101:1644.

SIRS with a presumed or confirmed infectious process

SepsisSepsisSIRSSIRSInfection/Infection/TraumaTrauma Severe SepsisSevere Sepsis

Sepsis: Defining a Disease Continuum

Bone et al. Bone et al. Chest.Chest. 1992;101:1644; Wheeler and Bernard. 1992;101:1644; Wheeler and Bernard. N Engl J MedN Engl J Med. 1999;340:207. . 1999;340:207.

SepsisSepsisSIRSSIRSInfection/Infection/TraumaTrauma Severe SepsisSevere Sepsis

• Sepsis with ≥1 sign of organ failure– Cardiovascular (refractory

hypotension)– Renal– Respiratory– Hepatic– Hematologic– CNS– Unexplained metabolic

acidosis

ShockShock

Epidemiology of SepsisThe International Cohort Study

SepsisSepsisInfectionInfection Severe Severe SepsisSepsis

Septic Septic ShockShock

18 28 24 30

35% mortality

8353 patients with LOS > 24h4277 infections (2696 on admission)

Percent of cases within each category

Alberti, Int Care Med 2002

Sources of SepsisThe International Cohort Study

Severe Severe SepsisSepsis

Septic Septic ShockShock

Respiratory 66 53

Abdomen 9 20

Bacteremia 14 16

Urinary 11 11

Multiple - -

Microbiology of SepsisThe International Cohort Study

Severe Severe SepsisSepsis

Septic Septic ShockShock

Gram-positive 44 40

Gram-negative 47 47

Fungal 9 13

Polymicrobial - -

Inadequate Resuscitation

Preoperative Illness

Trauma or Operation

Tissue Injury

optimal oxygen delivery and

support

Recovery

Excessive Inflammatory

Response

SIRS/MODS

Pathogenesis of SIRS/MODS

Initiation of Inflammatory Response

From Wheeler & Bernard, NEJM 1999

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.

Coagulation and Fibrinolysis

Bernard, GR. NEJM 2001;344;10:699-709

Inadequate Resuscitation

Preoperative Illness

Trauma or Operation

Tissue Injury

optimal oxygen delivery and

support

Recovery

Excessive Inflammatory

Response

SIRS/MODS

Pathogenesis of SIRS/MODS

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

Severe Sepsis: The Final Common Pathway

Endothelial Dysfunction and Microvascular Thrombosis

Hypoperfusion/Ischemia

Acute Organ Dysfunction (Severe Sepsis)

Death

Severe Sepsis: Management of Our Case

Endothelial Dysfunction and Microvascular Thrombosis

Hypoperfusion/Ischemia

Acute Organ Dysfunction (Severe Sepsis)

Death

rhAPCCorticosteroids

FluidsVasopressors

CVVHFEnteral nutrition

Survival