1. SIRS, Sepsis, and MODS
Claudio Martin, MSc, MD

2. 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:

3. 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

4. Case presentation - 2 Laboratory Investigations pending
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

5. Case presentation - 3 In ICU: Despite therapy patient remained anuric
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

6. Case presentation - 4
Early gram stain on blood revealed gram negative rods
Patient started on:
Hydrocortisone 100 mg iv q8h
Recombinant activated protein C 24g/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

7. Case Presentation - Resolution
Patient gradually stabilized and improved with complete resolution of organ dysfunction over 5 days
Final cultures confirmed diagnosis as meningococcemia

8. Infection: Part of a bigger picture
Presence of organisms in a closed space or location where not normally found
Infection
Infection is the presence of organisms in a location where they would not normally be found. Culture results have to be carefully interpreted in some circumstances to distinguish colonization or contamination from true infection.
Adapted from: Bone RC et al. Chest. 1992;101:
Opal SM et al. Crit Care Med. 2000;28:S81-2.

9. 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 neutrophils
The systemic inflammatory response syndrome (SIRS) is a clinical response arising from a nonspecific insult manifested by two or more of the following:
Fever or hypothermia
Tachycardia
Tachypnea
Leukocytosis, leukopenia, or a left-shift (increase in immature neutrophilic leukocytes in the blood)
Recent evidence indicates that hemostatic changes play a significant role in many SIRS-linked disorders.
Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest. 1992;101:
Opal SM, Thijs L, Cavaillon JM, et al. Relationships between coagulation and inflammatory processes. Crit Care Med. 2000; 28:S81-2.
Adapted from: Bone RC et al. Chest. 1992;101:
Opal SM et al. Crit Care Med. 2000;28:S81-2.

10. Sepsis: More Than Just Inflammation
Known or suspected infection
SIRS criteria
The original ACCP/SCCM criteria for the diagnosis of sepsis required the presence of known or suspected infection plus two or more SIRS criteria.
Climbing a flight of stairs can produce two SIRS criteria (tachypnea, tachycardia) in a normal sedentary individual.
The critical distinction for diagnosis of sepsis is that SIRS is associated with proven or clinically-suspected infection.
Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest. 1992;101:
Adapted from: Bone RC et al. Chest. 1992;101:

11. 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 acidosis
Severe sepsis is sepsis plus signs and symptoms of acute organ dysfunction, hypoperfusion, or hypotension. Hypoperfusion and perfusion abnormalities may include, but are not limited to, lactic acidosis, oliguria, or an acute alteration in mental status.
Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest. 1992;101:
Adapted from: Bone RC et al. Chest. 1992;101:

12. Sepsis: A Complex Disease
This conceptual framework shows the interrelationships between infection, non-infectious disorders, SIRS, sepsis, and severe sepsis. Components of the process not discussed on the following slides include:
Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest. 1992;101:
Opal SM, Thijs L, Cavaillon JM, et al. Relationships between coagulation and inflammatory processes. Crit Care Med. 2000;28:S81-2.
Adapted from: Bone RC et al. Chest. 1992;101:
Opal SM et al. Crit Care Med. 2000;28:S81-2.

13. Predisposition Jargon 2002: PIRO Insult Response Organ Dysfunction
Infection
Physiologic
Inflammation
Biochemical
Severe
Sepsis
An updated consensus conference still agreed that the concept of SIRS and sepsis was valid and useful. But expansion of the framework was needed to account for new knowledge and a broader approach to measurement of physiologic response (I.e. not restricted to just the 4 SIRS criteria). The presence of infection, response and organ dysfunction thus still defines severe sepsis. The central part of the diagram could also be labelled with ‘severe SIRS’ if the insult is not infectious.
Specific Organ
Severity
Organ Dysfunction

14. Predisposition Pre-existing disease Cardiac, Pulmonary, Renal HIV
Age (extremes of age)
Gender (males)
Genetics
TNF polymorphisms (TNF promoter high secretor genotype)
Various innate factors are now known to have independent effects on the risk for sepsis and the outcome.

15. Response Physiology Markers of Inflammation Heart rate Respiration
Fever
Blood pressure
Cardiac output
WBC
Hyperglycemia
Markers of Inflammation
TNF
IL-1
IL-6
Procalcitonin
PAF
These clinical and laboratory markers of inflammation have all been associated with SIRS or sepsis. Procalcitonin is claimed to have reasonable diagnostic value for infection. Combinations of response markers may also be able to distinguish between sepsis and SIRS.

16. Organ Dysfunction Lungs Adult Respiratory Distress Syndrome 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

17. 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

18. Sepsis: Defining a Disease Continuum
Infection/ Trauma
SIRS
Sepsis
Severe Sepsis
A clinical response arising from 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 with a presumed or confirmed infectious process
The definitions for SIRS and sepsis can also be used to describe a disease continuum with respect to the severity of the illness.
SIRS = systemic inflammatory response syndrome.
Bone et al. Chest. 1992;101:1644.

19. Sepsis: Defining a Disease Continuum
Infection/ Trauma
SIRS
Sepsis
Severe Sepsis
Sepsis with ≥1 sign of organ failure
Cardiovascular (refractory hypotension)
Renal
Respiratory
Hepatic
Hematologic
CNS
Unexplained metabolic acidosis
Septic shock is a subset of severe sepsis. Note that current definitions have dropped the term ‘septicemia’ that may still be found in older textbooks. Bacteremia is the term for when organisms are cultured from blood.
Shock
Bone et al. Chest. 1992;101:1644; Wheeler and Bernard. N Engl J Med. 1999;340:207.

20. Epidemiology of Sepsis The International Cohort Study
Severe Sepsis
Septic Shock
Infection
Sepsis
Percent of cases within each category 18 28 24 30
35% mortality
8353 patients with LOS > 24h
4277 infections (2696 on admission)
Alberti, Int Care Med 2002

21. Sources of Sepsis The International Cohort Study
Severe Sepsis
Septic Shock
Respiratory 66 53
Abdomen 9 20
Bacteremia 14 16
Urinary 11
Multiple -
This chart shows the site of infection for cases within the categories of severe sepsis or septic shock. This information is useful for guiding investigations and initial empiric treatment.

22. Microbiology of Sepsis The International Cohort Study
Severe Sepsis
Septic Shock
Gram-positive 44 40
Gram-negative 47
Fungal 9 13
Polymicrobial -
This chart shows the organisms responsible for cases of severe sepsis or septic shock. This information is useful for guiding initial empiric therapy.

23. Pathogenesis of SIRS/MODS
Preoperative Illness
Trauma or Operation
Tissue Injury
optimal oxygen delivery and support
Sepsis and organ injury can occur through direct inflammatory-mediated mechanisms or due to tissue oxygen delivery that is inadequate to support metabolic demand (which may be increased by the inflammatory response).
Inadequate Resuscitation
Excessive Inflammatory Response
Recovery
SIRS/MODS

24. Initiation of Inflammatory Response
From Wheeler & Bernard, NEJM 1999

25. Homeostasis Is Unbalanced in Severe Sepsis
In simplified terms, sepsis can be conceptualized as a dysfunction of opposing mechanisms of coagulation/inflammation and fibrinolysis. In normal patients homeostasis is maintained because these mechanisms balance each other.
Patients with severe sepsis have increased coagulation and increased inflammation. Manifestations of these include:
Circulating proinflammatory mediators
Endothelial injury
Expression of tissue factor by monocytes and possibly a subset of endothelial cells
Thrombin generation
Patients with severe sepsis also have decreased fibrinolysis. Manifestations of these include:
Increased levels of PAI-1
Increased levels of TAFI
Carvalho AC, Freeman NJ. How coagulation defects alter outcome in sepsis: survival may depend on reversing procoagulant conditions. J Crit Illness. 1994;9:51-75.
Kidokoro A, Iba T, Fukunaga M, et al. Alterations in coagulation and fibrinolysis during sepsis. Shock. 1996;5:223-8.
Vervloet MG, Thijs LG, Hack CE. Derangements of coagulation and fibrinolysis in critically ill patients with sepsis and septic shock. Semin Thromb Hemost. 1998;24:
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.

26. Coagulation and Fibrinolysis
This diagram shows the interaction between the inflammatory, coagulation and fibrinolytic pathways. Activated protein C, an endogenous protein, has multiple sites of action. These include inhibition of neutrophil adhesion, inhibition of tissue factor, inhibition of thrombin generation, and inhibition of inhibitors of fibrinolysis (PAI-1: plasminogen activator inhibitor; TAFI: thrombin activatable fibrinogen inhibitor). The net result is anti-inflammatory and anti-coagulant.
Bernard, GR. NEJM 2001;344;10:

27. Pathogenesis of SIRS/MODS
Preoperative Illness
Trauma or Operation
Tissue Injury
optimal oxygen delivery and support
Tissue injury can also occur as a result of inadequate tissue oxygen delivery or uptake.
Inadequate Resuscitation
Excessive Inflammatory Response
Recovery
SIRS/MODS

28. Regulation of oxygen delivery
Normal
Abnormal
Intra Organ Distribution
regional distribution
Microcirculation
Cardiac Output
Cardiac output
BP=CO * SVR
Abnormalities in oxygen delivery in sepsis have been described at all levels of the circulation. The parameters that can be measured clinically (cardiac output, blood pressure) are indicative of the central circulation, but distribution between and within organs is altered. There are no reliable methods to monitor the microcirculation.
QO2 = Flow * O2 content

29. Oxygen Delivery Delivery:Demand mismatch Diffusion limitation (edema)
The result is a mismatch in oxygen delivery relative to tissue demand, similar to the mismatch that occurs in the lung between ventilation and perfusion. Factors that contribute to this mismatch include shunting (likely physiologic due to high flow rather than anatomic shunts). Decreased capillary perfusion and increased edema increase the diffusion distance for oxygen.
Delivery:Demand mismatch
Diffusion limitation (edema)

30. Oxygen Consumption III NADH + H+ NAD+ ADP + Pi 1/2 O2 + H+ ATP I Cytc
H2O Q IV
Mitochondrial injury and dysfunction has also been described, so even if oxygen delivery is adequate, the cell may not use it effectively to generate ATP. In experimental models, this can be monitored by measuring NADH or cytochrome c fluorescence.
Pyruvate Dehydrogenase (PDH) activity decreased
Decreased delivery of Acetyl CoA to TCA cycle
Mitochondrial dysfunction

31. Severe Sepsis: The Final Common Pathway
Endothelial Dysfunction and Microvascular Thrombosis
Hypoperfusion/Ischemia
The endothelial cell is the focal point of interactions between the inflammatory events and disordered hemostasis of patients with severe sepsis.
Although vascular bed-specific factors are operative, endothelial cell injury or death can shift the cell’s phenotype from antithrombotic to prothrombotic and induce sequestration of inflammatory cells and platelets in the damaged vessel(s).
The resultant hypoperfusion/ischemia produces acute organ dysfunction. Uninterrupted, a viscous cycle ensues that can end in death.
Acute Organ Dysfunction
(Severe Sepsis)
Death

32. Severe Sepsis: Management of Our Case
rhAPC
Corticosteroids
Endothelial Dysfunction and Microvascular Thrombosis
Fluids
Vasopressors
Hypoperfusion/Ischemia
Therapy that can interfere with this process has been described for each level. This combination of specific sepsis and general ICU treatment is expected to lead to better patient survival.
CVVHF
Enteral nutrition
Acute Organ Dysfunction
(Severe Sepsis)
Survival
Death