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Amjad Bani Hani

S IR S , S EP S IS , A N D
M ODS

O bjectives
 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. 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 . PaO2 82. PaCO2 29  Investigations pending  Blood.29.

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 .

deep venous thromboses .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 – Enteral nutrition via nasojejunal feeding tube – Prophylaxis for stress ulcers.

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 ofa bigger
picture

Infection:

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

Infection

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

SIRS:System ic Infl
am m atory Response
Syndrom e
 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
Adapted from: Bone RC et al. Chest. 1992;101:1644-55.
Opal SM et al. Crit Care Med. 2000;28:S81-2.

. 1992.Sepsis:M ore Than Just Infl am m ation  Sepsis:  Known or suspected infection  SIRS criteria Adapted from: Bone RC et al. Chest.101:1644-55.

101:1644-55. 1992. .Severe Sepsis:Acute O rgan D ysfunction  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 Adapted from: Bone RC et al.acidosis Chest.

Sepsis:A Com plex D isease Adapted from: Bone RC et al. 1992. Crit Care Med. 2000. Chest.28:S81-2.101:1644-55. . Opal SM et al.

Jargon 2002: PIRO Predisposition Insult Response Infection Inflammation Physiologic Biochemical Severe Sepsis Specific Organ Severity Organ Dysfunction .

Pulmonary. Renal  HIV  Age (extremes of age)  Gender (males)  Genetics  TNF polymorphisms (TNF promoter high secretor genotype) .Predisposition  Pre-existing disease  Cardiac.

Response  Physiology  Heart rate  Respiration  Fever  Blood pressure  Cardiac output  WBC  Hyperglycemia  Markers of Inflammation  TNF  IL-1  IL-6  Procalcitonin  PAF .

O rgan D ysfunction  Lungs  Kidneys  CVS  CNS  PNS  Coagulation  GI  Liver  Adult Respiratory Distress Syndrome  Acute Tubular Necrosis  Shock  Metabolic encephalopathy  Critical Illness Polyneuropathy  Disseminated Intravascular Coagulopathy  Gastroparesis and ileus  Cholestasis  Endocrine  Skeletal Muscle  Adrenal insufficiency  Rhabdomyolysis Specific therapy exists .

3% of all deaths  Equals deaths after acute myocardial infarction .M agnitude ofthe Problem  Estimated 215. drugs)  Estimated 20 day LOS.000 deaths from US 1995 data  High cost for management (ICU care.000 cost  Represents 9. $22. diagnostic testing.

3 percent over the last ten years. severe sepsis will likely take 215.  This year. .The Incidence ofSepsis in the U nited States  The incidence of sepsis has increased 91.000 lives.  Sepsis is the leading cause of death in the non-coronary ICU.

 One of every three patients who develop severe sepsis will die within a month. and prostate cancer combined. Source: Society of Critical Care . colon/rectal. Severe sepsis takes more lives than breast. pancreatic.

Severe Sepsis is deadly .

Severe Sepsis is C om m on .

Severe Sepsis is increasing in incidence .

1992.000/mm3 or ≤4.101:1644. .000/mm3 or >10% immature neutrophils SIRS = systemic inflammatory response syndrome. including 2 of the following: Sepsis Severe Sepsis SIRS with a presumed or confirmed infectious process  Temperature ≥38oC or ≤36oC  HR ≥90 beats/min  Respirations ≥20/min  WBC count ≥12. Chest. Bone et al.Sepsis:D efi ning a D isease Continuum Infection/ Trauma SIRS A clinical response arising from a nonspecific insult.

Chest. N Engl J Med. . 1999. Wheeler and Bernard. 1992.101:1644.340:207.Sepsis:D efi ning a D isease Continuum Infection/ Trauma SIRS Sepsis Shock Severe Sepsis • Sepsis with ≥1 sign of organ failure – Cardiovascular (refractory hypotension) – Renal – Respiratory – Hepatic – Hematologic – CNS – Unexplained metabolic acidosis Bone et al.

Int Care Med 2002 .Epidem iology ofSepsis The InternationalCohort Study Infectio n Sepsis Severe Sepsis Septic Shock Percent of cases within each category 18 28 24 30 35% mortality 8353 patients with LOS > 24h 4277 infections (2696 on admission) Alberti.

org : Source .  The infection can originate from anywhere in the body. parasitic.Causes ofSepsis  Bacterial infections are the most common cause of sepsis. or viral infections.clevelandclinic. but sepsis can also be caused by fungal. www.

Sources ofSepsis The InternationalCohort Study Severe Sepsis Respiratory Septic Shock 66 53 9 20 Bacteremia 14 16 Urinary 11 11 Multiple - - Abdomen .

M icrobiology ofSepsis The InternationalCohort Study Severe Sepsis Septic Shock Gram-positive 44 40 Gram-negative 47 47 Fungal 9 13 Polymicrobial - - .

Pathogenesis ofSIRS/M O D S Preoperative Illness Trauma or Operation Tissue Injury optimal oxygen delivery and support Recovery Excessive Inflammatory Response Inadequate Resuscitation SIRS/MODS .

Initiation ofInfl am m atory Response From Wheeler & Bernard. NEJM 1999 .

M ediators of Septic R esponse .

P ro-inf a lm m atory M ediators  Bacterial Endotoxin  TNF-α  Interleukin-1  Interleukin-6  Interleukin-8  Platelet Activating Factor (PAF)  Interferon-Gamma  Prostaglandins  Leukotrienes  Nitric Oxide .

A nti-inf a lm m atory M ediators Interleukin-10  PGE2  Protein C  Interleukin-6  Interleukin-4  Interleukin-12  Lipoxins  GM-CSF  TGF  IL-1RA  .

and can lead to organ failure or tissue damage.  Blood clotting during sepsis causes reduced blood flow to limbs and vital organs.Pathophysiology ofSepsis  Sepsis can lead to widespread inflammation and blood clotting. 2004 . Source: Critical Care Nurse Supplement.

coagulation.Pathophysiology ofSepsis In simple terms  sepsis can be viewed as an imbalance of inflammation. and .fibrinolysis In normal patients  homeostasis is maintained when .these are balanced .

Pathophysiology ofSepsis During a normal response to bacteria in the blood the immune system releases inflammatory mediators to promote recovery of the tissue. 2003 . These mediators are known as:      Tumor Necrosis Factor (TNF) Interleukins (IL) Cytokines Prostaglandins Platelet Activating Factor Source: New England Journal of Medicine.

inhibitors are released to suppress fibrinolysis or breakdown.Pathophysiology ofSepsis  The release of the inflammatory mediators starts the Coagulation Cascade leading to the development of a clot. This is necessary to have time for the body to destroy the bacteria before the clot is gone. 2004 .  To maintain this clot. Source: Critical Care Nurse Supplement.

the pro-inflammatory mediators attract neutrophils or WBCs which attack the antigen and try to . engulf it Graphics: Delores Zittel. 2006 .Pathophysiology ofSepsis Once the bacteria or antigen is isolated.

2004 .Pathophysiology ofSepsis To prevent the response from damaging normal tissue. antiinflammatory mediators are released including transforming growth factors and interleukins (IL-4). This balance of inflammatory and anti-inflammatory mediators restricts the inflammation .response to the local site of infection Source: Critical Care Nurse Supplement.

Pathophysiology ofSepsis When the body is unable to maintain the appropriate balance. the immune response is no longer local but becomes systemic. 2004 . Source: Critical Care Nurse Supplement. Inflammation and altered clotting quickly spread through the body.

not corrected .Pathophysiology ofSepsis The person with the infection which was once localized could become critically ill if this process is .

Freeman NJ. . Semin Thromb Hemost. 1994. Vervloet MG et al.5:223-8. Shock.24:33-44. Kidokoro A et al. 1996. 1998.9:51-75.H om eostasis Is Unbalanced in Severe Sepsis Carvalho AC. J Crit Illness.

344. NEJM 2001.10:699-709 . GR.Coagulation and Fibrinolysis Bernard.

Let’s Look a Little D eeper There are 3 integrated responses to sepsis Activation of Inflammation ê Activation of Coagulation ê Impairment of Fibrinolysis .

Interleukin-6 (IL-6) and Platelet activating . Interleukin-1(IL-1).factor .Activation ofInfl am m ation Inflammation is the body’s response to . mediators of inflammation Inflammatory mediators include: Tumor necrosis factor-a.infection When this occurs white blood cells (WBCs) generate and release cytokines or .

Anti-inflammatory cytokines include interleukin -4 (IL-4) and interleukin-10 (IL10) .IL-6) play a critical role to fight off infection the body tries to reestablish balance by releasing anti-inflammatory cytokines as well. IL-1.Activation ofInfl am m ation Although these cytokines (TNF.

In sepsis. continued release of proinflammatory cytokines overwhelms the antiinflammatory cytokines.inflammatory components of the body.Activation ofInfl am m ation There is basically a tugPro-inflammatory (IL-1. Anti-inflammatory (IL-4.TNF) of war going on between the pro-inflammatory and anti. IL10) .IL-6.

This results in the forming of the enzyme thrombin. . This produces clotting in the body. The cytokines from inflammation stimulate coagulation pathways.Activation ofCoagulation Inflammation and coagulation are closely linked.

perfusion .Activation ofCoagulation The enhanced clotting continues making tiny clots or “microthrombi” in the vascular system which impairs blood flow and organ .

Activation ofFibrinolysis Fibrinolysis. is the body’s response to the increased clotting and inflammation. These mediators are called:  Plasminogen Activator Inhibitor-1 (PAI- 1)  Thrombin Activatable Fibrinolysis Inhibitor (TAFI) . or the breakdown of clots. In sepsis this breakdown is inhibited or slowed because of mediators.

suppress fibrinolysis even more creating a state of “coagulopathy”. . Plasminogen Activator Inhibitor1(PAI-1) and Thrombin Activatable Fibrinolysis Inhibitor (TAFI).Activation ofFibrinolysis The increase levels of these two inhibitors.

The Inflammatory. and Fibrolytic Response to Infection Graphics: Delores Zittel. Coagulation. 2006 .

2006 .M aking M atters W orse The Role ofEndothelium in Sepsis Graphic: Delores Zittel.

endothelium also plays a role in the inflammatory. coagulation.components of sepsis .M aking M atters W orse The Role ofEndothelium in Sepsis Normal endothelium has anticoagulant abilities and plays a role in the body’s homeostasis abilities including:  Vasomotor tone  Movement of cells and nutrients  Maintaining blood fluidity When activated. and fibrinolytic .

M aking M atters W orse  In sepsis the endothelium becomes damaged which makes the “inflammatory process” worse by releasing more cytokines (TNF-a and IL1) causing neutrophils to stick to its’ lining.  The “activation” of the capillary endothelium leads to increased permeability causing fluid to “leak” out of the capillaries and into the extracellular spaces. .

2006 .D am aged Endothelium Graphics: Delores Zittel.

Coagulation. . and Fibrinolysis and the effects on endothelium can lead to organ failure even death if left undetected or untreated.Putting it allTogether The imbalance of Inflammation.

Pathogenesis ofSIRS/M O D S Preoperative Illness Trauma or Operation Tissue Injury optimal oxygen delivery and support Recovery Excessive Inflammatory Response Inadequate Resuscitation SIRS/MODS .

Regulation ofoxygen delivery Normal Cardiac output Abnormal BP=CO * SVR Cardiac Output regional distribution regional distribution Intra Organ Distribution Intra Organ Distribution Microcirculation Microcirculation QO2 = Flow * O2 content .

O xygen D elivery  Delivery:Demand mismatch  Diffusion limitation (edema) .

O xygen Consum ption H+ H+ I Q NADH + H+ H+ NAD+ Cytc III H+ IV 1/2 O2 + H+ H2O ADP + Pi •Pyruvate Dehydrogenase (PDH) activity decreased • Decreased delivery of Acetyl CoA to TCA cycle •Mitochondrial dysfunction H+ ATP .

Q uestion: W hy do Septic ?Patients D ie Answer: Organ Failure .

et al. (1986): • Direct correlation between number of organ systems failed and mortality. • Mortality Data: #OSF 1 2 3 D1 D2 D3 D4 D5 D6 D7 22% 31% 34% 35% 40% 42% 41% 52% 67% 66% 62% 56% 64% 68% 80% 95% 93% 96% 100 100 100 % % % .O rgan Failure and M ortality •Knaus.

Sedation. Transfusion. Analgesia. Organ Replacement . DVT Prophylaxis.Evidence-B ased Sepsis G uidelines  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.

Evidence-B ased Sepsis G uidelines .

Severe Sepsis: The FinalCom m on Pathw ay Endothelial Dysfunction and Microvascular Thrombosis Hypoperfusion/Ischemia Acute Organ Dysfunction (Severe Sepsis) Death .

Severe Sepsis: M anagem ent ofO ur Case Endothelial Dysfunction and Microvascular Thrombosis rhAPC Corticosteroids Hypoperfusion/Ischemia Fluids Vasopressors Acute Organ Dysfunction (Severe Sepsis) Death CVVHF Enteral nutrition Survival .