1. Systemic Inflammatory Response Syndrome,MODS,Sepsis
Dr Amit Gupta
Additional Professor
Dept of Surgery

2. Infection
Infection
Presence of organisms in a closed space or location
where not normally found
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.

3. SIRS: Systemic Inflammatory Response Syndrome
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.

4. 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:

5. 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:

6. 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.

7. Septic Shock:
Sepsis induced with hypotension despite adequate resuscitation along with
the presence of perfusion abnormalities which may include, but are not limited
to lactic acidosis, oliguria, or an acute alteration in mental status

8. Multiple Organ Dysfunction Syndrome (MODS):
Presence of altered organ function in an acutely ill patient such that homeostasis cannot be maintained without intervention

9. Predisposition 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

10. Predisposition Pre-existing disease Age (extremes of age)
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.

11. Response Markers of Inflammation Physiology TNF Heart rate IL-1
Procalcitonin
PAF
Physiology
Heart rate
Respiration
Fever
Blood pressure
Cardiac output
WBC
Hyperglycemia
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.

12. 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

13. 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.

14. 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

15. Pathogenesis of SIRS/MODS
Inadequate Resuscitation
Preoperative Illness
Trauma or Operation
Tissue Injury
optimal oxygen delivery and support
Recovery
Excessive Inflammatory Response
SIRS/MODS
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).

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

17. 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.

18. 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:

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

20. 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

21. 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)

22. 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

23. 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

25. Early Goal-Directed Therapy
Components:
Early Recognition
Early Goal-Directed Therapy
Monitoring
Resuscitation
Pressor / Inotropic Support
Steroid Replacement
Recombinant Activated Protein C
Source Control
Glycemic Control
Nutritional Support
Adjuncts:
Stress Ulcer Prophylaxis, DVT Prophylaxis, Transfusion, Sedation, Analgesia, Organ Replacement