1. SIRS and the Septic Response Manoj Sayal, MD FRCSC March 5, 2008

2. Agenda 1. A brief review of SIRS (systemic inflammatory response syndrome) 2. SIRS and it’s role in sepsis 3. Definitions of the sepsis syndrome 4. Current sepsis guidelines

3. Case 1 67yo male, presents to ER with 2 day history of N+V, abdo pain 67yo male, presents to ER with 2 day history of N+V, abdo pain In ER, looks unwell: HR 130, BP 80/60 RR 36 SPO2 84% on room air; supplemental O2 applied, sats increase to 92% In ER, looks unwell: HR 130, BP 80/60 RR 36 SPO2 84% on room air; supplemental O2 applied, sats increase to 92% Diffusely tender abdomen, coarse air entry bilaterally Diffusely tender abdomen, coarse air entry bilaterally What now? What now?

4. Case 1 2 large bore IV’s—normal saline 1 litre 2 large bore IV’s—normal saline 1 litre Labs drawn Labs drawn CXR (portable), EKG, ABGs CXR (portable), EKG, ABGs Diagnosis? Diagnosis?

5. Case 1 CXR: RLL infiltrate CXR: RLL infiltrate WBC 22.4 Hb 108 Pl 98 WBC 22.4 Hb 108 Pl 98 Lytes normal; transaminases normal Lytes normal; transaminases normal Amylase 700 Amylase 700 What now? What now?

6. Case 2 Same patient, but normal amylase Same patient, but normal amylase

7. Case 3 Same patient but involved in a major house fire, normal amylase Same patient but involved in a major house fire, normal amylase What’s wrong with each of these patients? What’s wrong with each of these patients? Does their management differ significantly (initially)? Does their management differ significantly (initially)?

8. They are all manifesting evidence of the SIRS response They are all manifesting evidence of the SIRS response

9. SIRS for Dummies (or Surgeons) Dysregulation of the normal response with massive and uncontrolled release of proinflammatory mediators creating a chain of events that leads to widespread tissue injury Dysregulation of the normal response with massive and uncontrolled release of proinflammatory mediators creating a chain of events that leads to widespread tissue injury Results in MODS (Multiple Organ Dysfunction Syndrome) that causes the extremely high morbidity and mortality in this situation Results in MODS (Multiple Organ Dysfunction Syndrome) that causes the extremely high morbidity and mortality in this situation

10. SIRS SIRS is a clinical diagnosis, recognized by 2 or more of the following (in the appropriate setting): SIRS is a clinical diagnosis, recognized by 2 or more of the following (in the appropriate setting): 1. Temp >38ºC or 38ºC or <35ºC 2. HR>90bpm 3. RR>20bpm or PaCO2 20bpm or PaCO2<32mmHg 4. WBC>12, 10% immature (band) forms

11. SIRS Causes Causes Acute pancreatitis, autoimmune disorders, vasculitis, thromboembolism, burns, surgery, pulmonary contusion, SEPSIS) Acute pancreatitis, autoimmune disorders, vasculitis, thromboembolism, burns, surgery, pulmonary contusion, SEPSIS)

12. SIRS How does this relate to infection or the response to infection? How does this relate to infection or the response to infection?

13. Definitions Infection an inflammatory response to microorganisms or the invasion of normally sterile host tissue by these organisms an inflammatory response to microorganisms or the invasion of normally sterile host tissue by these organismsBacteremia viable bacteria in the blood viable bacteria in the blood

14. Definitions Sepsis In sepsis, clinical signs of SIRS are present and are due to either a culture proven infection or a suspected infection In sepsis, clinical signs of SIRS are present and are due to either a culture proven infection or a suspected infection Clinical syndrome that complicates severe infection and represents the systemic response to the infection Clinical syndrome that complicates severe infection and represents the systemic response to the infection

15. Definitions Severe Sepsis Sepsis plus at least one of the following: Sepsis plus at least one of the following: 1. Areas of mottled skin 2. Capillary refill > 3 seconds 3. Urine output < 0.5cc/kg/hr for at least one hour or renal replacement therapy 4. Elevated lactate (>2 to 3) 5. Abrupt change in mental status 6. Abnormal EEG findings 7. Platelet count <100, 000 8. DIC 9. ARDS 10. Cardiac dysfunction

16. Definitions Septic Shock Severe sepsis plus at least one of the following: Severe sepsis plus at least one of the following: 1. MAP<65mmHg despite adequate fluid resuscitation 2. Maintaining MAP>60-65mmHg requires vasopressors: Dopamine > 5μg/kg/min Dopamine > 5μg/kg/min Norepinephrine < 0.25μg/kg/min Norepinephrine < 0.25μg/kg/min Epinephrine < 0.25mg/min Epinephrine < 0.25mg/min

17. Definitions Refractory Septic Shock Septic shock that requires higher doses of the ionotropes to keep the MAP>65mmHg: Septic shock that requires higher doses of the ionotropes to keep the MAP>65mmHg: Dopamine > 15μg/kg/min Dopamine > 15μg/kg/min Norepinephrine > 0.25μg/kg/min Norepinephrine > 0.25μg/kg/min Epinephrine >0.25mg/min Epinephrine >0.25mg/min

18. Definitions Multiple Organ Failure/MODS Presence of altered organ functions in an acutely ill patient such that homeostasis cannot be maintained without intervention Presence of altered organ functions in an acutely ill patient such that homeostasis cannot be maintained without intervention Primary: secondary to a well defined insult in which organ dysfunction occurs early and can be directly attributable to the insult itself (eg ARF from rhabdomyolysis) Primary: secondary to a well defined insult in which organ dysfunction occurs early and can be directly attributable to the insult itself (eg ARF from rhabdomyolysis) Secondary: organ failure not in direct response to the insult itself but as a consequence of a host response to the insult (eg ARDS in pancreatitis) Secondary: organ failure not in direct response to the insult itself but as a consequence of a host response to the insult (eg ARDS in pancreatitis)

19. Definitions Note that NO positive blood cultures are needed in the definition Note that NO positive blood cultures are needed in the definition You only get positive cultures in 17-69% of all septic/septic shock patients You only get positive cultures in 17-69% of all septic/septic shock patients

20. Sepsis Getting more frequent (increasing by 8% per year since the 1970’s) with increasing severity Getting more frequent (increasing by 8% per year since the 1970’s) with increasing severity 2% of all hospitalized patients 2% of all hospitalized patients Up to 75% of all ICU patients Up to 75% of all ICU patients 20-50% mortality, depending on the degree: 20-50% mortality, depending on the degree: SIRS alone 7% SIRS alone 7% Sepsis 16% Sepsis 16% Severe sepsis 20% Severe sepsis 20% Septic shock 46% Septic shock 46% Rangud-Feausto, MS et al, Rangud-Feausto, MS et al, JAMA 1995; 273:117 JAMA 1995; 273:117

21. Sepsis Characteristics that influence outcome in the septic patient include: Characteristics that influence outcome in the septic patient include: Host response: is the host able to mount a fever or WBC response? Host response: is the host able to mount a fever or WBC response? Underlying disease: comorbidities (NIDDM, kidney failure, hepatic failure, cancer, EtOH abuse, immune suppression) Underlying disease: comorbidities (NIDDM, kidney failure, hepatic failure, cancer, EtOH abuse, immune suppression) APACHE II score APACHE II score Advanced age Advanced age Site of infection: Lung/gut 50% Urine 30% Site of infection: Lung/gut 50% Urine 30% Community acquired vs healthcare acquired Community acquired vs healthcare acquired Organism involved Organism involved Antibiotics—timing and type Antibiotics—timing and type Rapidity and adequacy of response Rapidity and adequacy of response

22. Sepsis--Pathogenesis Pathogenesis Process of malignant intravascular inflammation Process of malignant intravascular inflammation Uncontrolled, unregulated, self-sustaining Uncontrolled, unregulated, self-sustaining Exaggerated response of the normal inflammatory response Exaggerated response of the normal inflammatory response

23. Sepsis--Pathogenesis When tissue is injured, or infected, there is the simultaneous release of proinflammatory and antiinflammatory elements—the balance of these helps facilitate tissue repair and healing When tissue is injured, or infected, there is the simultaneous release of proinflammatory and antiinflammatory elements—the balance of these helps facilitate tissue repair and healing Remote tissue injury may ensue when this equilibrium in the inflammatory process is lost and these mediators exert systemic effects Remote tissue injury may ensue when this equilibrium in the inflammatory process is lost and these mediators exert systemic effects

24. Sepsis--Pathogenesis The significant consequences of a systemic proinflammatory reaction include endothelial damage, microvascular dysfuntion, impaired tissue oxygenation and subsequent organ damage or injury The significant consequences of a systemic proinflammatory reaction include endothelial damage, microvascular dysfuntion, impaired tissue oxygenation and subsequent organ damage or injury The consequences of an excessive antiinflammatory response include anergy and immunosuppression The consequences of an excessive antiinflammatory response include anergy and immunosuppression

25. Sepsis--Pathogenesis Normal inflammation involves the regulation of PMN rolling, adhesion, diapedesis, chemotaxis, phagocytosis and killing of invading bacteria Normal inflammation involves the regulation of PMN rolling, adhesion, diapedesis, chemotaxis, phagocytosis and killing of invading bacteria These processes are highly controlled through proinflammatory and antiinflammatory cytokines released by activated macrophages These processes are highly controlled through proinflammatory and antiinflammatory cytokines released by activated macrophages

26. Sepsis--Pathogenesis As a result of dysregulation of this process, an autodestructive process ensues to involve otherwise remote normal tissue and results in the sepsis syndrome As a result of dysregulation of this process, an autodestructive process ensues to involve otherwise remote normal tissue and results in the sepsis syndrome

27. Sepsis--Pathogenesis This involves many factors: This involves many factors: Proinflammatory cytokines (TNFα, IL-6 etc) Proinflammatory cytokines (TNFα, IL-6 etc) Bacterial factors—direct effect of invading microorganisms or their toxic products: Bacterial factors—direct effect of invading microorganisms or their toxic products: Endotoxin (gm neg bacteria) Endotoxin (gm neg bacteria) Cell wall components (peptoglycans, muramyl dipeptide, lipoteichoic acid) Cell wall components (peptoglycans, muramyl dipeptide, lipoteichoic acid) Enterotoxins (staph), exotoxin (pseudomonas), M protein (GAS), toxic shock toxin etc Enterotoxins (staph), exotoxin (pseudomonas), M protein (GAS), toxic shock toxin etc Complement activation (C5a) Complement activation (C5a)

28. Sepsis--Pathogenesis This results in cellular injury and subsequent organ dysfunction This results in cellular injury and subsequent organ dysfunction The precise mechanism is not known, but proposed mechanisms include: The precise mechanism is not known, but proposed mechanisms include: Cellular ischemia (O2 lack relative to need) Cellular ischemia (O2 lack relative to need) Direct cell injury by inflammatory mediators and other products of inflammation Direct cell injury by inflammatory mediators and other products of inflammation Increased rate of apoptosis (programmed cell death) Increased rate of apoptosis (programmed cell death)

29. Sepsis--Pathogenesis If the mediators balance each other out and the initial infectious insult is overcome, homeostasis will be restored If the mediators balance each other out and the initial infectious insult is overcome, homeostasis will be restored The initial insult may be so severe that it directly induces SIRS and MODS The initial insult may be so severe that it directly induces SIRS and MODS In most patients, a balance is not established and one of the 2 predominates In most patients, a balance is not established and one of the 2 predominates

30. Specific Organ Involvement Circulation Derangement in metabolic autoregulation occurs (process that matches O2 availability to need) Derangement in metabolic autoregulation occurs (process that matches O2 availability to need) Vasoactive mediators are released that cause microvascular permeability and vasodilation (prostacyclin and NO) Vasoactive mediators are released that cause microvascular permeability and vasodilation (prostacyclin and NO) Impaired compensatory secretion of ADH (vasopressin) may also contribute Impaired compensatory secretion of ADH (vasopressin) may also contribute

31. Circulation In central circulation, early manifestations include changes in systolic and diastolic ventricular function In central circulation, early manifestations include changes in systolic and diastolic ventricular function Initially, CO increases to compensate for the vasodilation until the patient is no longer able to do so Initially, CO increases to compensate for the vasodilation until the patient is no longer able to do so

32. Circulation In the regional circulation, there is heterogeneity in normal distribution of blood flow and loss of regulation In the regional circulation, there is heterogeneity in normal distribution of blood flow and loss of regulation The microcirculation is a key (if not the most important) target organ for injury in the sepsis syndrome The microcirculation is a key (if not the most important) target organ for injury in the sepsis syndrome There is a decrease in the number of functional capillaries which causes an inability to extract O2 maximally There is a decrease in the number of functional capillaries which causes an inability to extract O2 maximally

33. Circulation Panendothelial activation leads to widespread tissue edema, which is rich in protein Panendothelial activation leads to widespread tissue edema, which is rich in protein Hypotension is the most serious expression of the circulatory dysfunction that results (reduced arterial tone, increased permeability) Hypotension is the most serious expression of the circulatory dysfunction that results (reduced arterial tone, increased permeability) Other changes include venous dilatation (decreasing venous return to the heart) and the release of myocardial depressant factors Other changes include venous dilatation (decreasing venous return to the heart) and the release of myocardial depressant factors

34. Lung Endothelial injury leads to disturbed capillary blood flow and enhanced microvascular permeability and subsequent interstitial and alveolar edema Endothelial injury leads to disturbed capillary blood flow and enhanced microvascular permeability and subsequent interstitial and alveolar edema PMN entrapment amplifies this damage PMN entrapment amplifies this damage ALI/ARDS ALI/ARDS

35. GI Tract May provided positive feedback loop in injury from sepsis from various sources: May provided positive feedback loop in injury from sepsis from various sources: Bacterial overgrowth in UGI tract leading to VAP if patients not fed or prophylaxed Bacterial overgrowth in UGI tract leading to VAP if patients not fed or prophylaxed Translocation through gut wall of bacteria from circulatory abnormalities depressing the gut’s barrier funtion Translocation through gut wall of bacteria from circulatory abnormalities depressing the gut’s barrier funtion

36. Liver Liver dysfunction can worsen sepsis by preventing bacterial clearance Liver dysfunction can worsen sepsis by preventing bacterial clearance Can get reticuloendothelial system dysfunction from the sepsis syndrome Can get reticuloendothelial system dysfunction from the sepsis syndrome Increased LFT’s/transaminases Increased LFT’s/transaminases

37. Kidney ATN (systemic hypotension, direct renal vasoconstriction, cytokine release etc may all cause) ATN (systemic hypotension, direct renal vasoconstriction, cytokine release etc may all cause) Likelihood of death increases dramatically if renal failure accompanies sepsis Likelihood of death increases dramatically if renal failure accompanies sepsis

38. Nervous System CNS: altered sensorium CNS: altered sensorium PNS: peripheral neuropathy PNS: peripheral neuropathy Limb muscle weakness and atrophy Limb muscle weakness and atrophy Reduced DTR’s Reduced DTR’s Loss of peripheral sensation to light touch and pin prick Loss of peripheral sensation to light touch and pin prick Preservation of cranial nerve function Preservation of cranial nerve function

39. Blood Thrombocytopenia Thrombocytopenia DIC DIC Hyponatremia Hyponatremia Anemia Anemia Elevated or decreased WBC Elevated or decreased WBC

40. Treatment Try to get the patient back to homeostasis as quickly and safely as possible Try to get the patient back to homeostasis as quickly and safely as possible Fluid is your best ionotrope…do not be afraid of it Fluid is your best ionotrope…do not be afraid of it “Hit them early, hit them hard” “Hit them early, hit them hard”

41. Treatment Early Goal Directed Therapy in the Treatment of Severe Sepsis and Septic Shock Early Goal Directed Therapy in the Treatment of Severe Sepsis and Septic Shock Emmanuel Rivers, NEJM 2001 Emmanuel Rivers, NEJM 2001

42. Treatment Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock: 2008 Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock: 2008 Crit Care Med 2008 Vol 36 No 1 Crit Care Med 2008 Vol 36 No 1

43. Treatment Initial resuscitation (within first 6h) Begin resuscitation immediately in patients with hypotension or elevated lactate (>4)—do not delay until pending ICU admission Begin resuscitation immediately in patients with hypotension or elevated lactate (>4)—do not delay until pending ICU admission Resuscitation goals Resuscitation goals CVP 8-12 mmHg CVP 8-12 mmHg MAP >65 mmHg MAP >65 mmHg U/O > 0.5ml/kg/hr U/O > 0.5ml/kg/hr SVC O2 sat >70% SVC O2 sat >70% If venous O2 sat not achieved, consider futher fluid, PRBC (to keep Hct >30%) or dobutamine If venous O2 sat not achieved, consider futher fluid, PRBC (to keep Hct >30%) or dobutamine

44. Treatment Diagnosis Obtain appropriate cultures providing it does not delay antibiotic administration Obtain appropriate cultures providing it does not delay antibiotic administration 2 or more BCs 2 or more BCs One BC from each access device >48hr old One BC from each access device >48hr old Other sites as indicated Other sites as indicated

45. Treatment Antibiotics As early as possible and always within 1hr As early as possible and always within 1hr Broad spectrum, covering all likely pathogens then narrow as clinically indicated Broad spectrum, covering all likely pathogens then narrow as clinically indicated Stop if not infectious cause, otherwise 7- 10 days Stop if not infectious cause, otherwise 7- 10 days

46. Treatment Source Control Identify anatomic site of infection as soon as possible (within 6hr of presentation) Identify anatomic site of infection as soon as possible (within 6hr of presentation) Choose source control with max efficacy and min physiologic upset Choose source control with max efficacy and min physiologic upset Remove all intravascular devices if potentially infected Remove all intravascular devices if potentially infected

47. Treatment Fluid Therapy Crystalloid or colloid Crystalloid or colloid Use fluid challenge technique while associated with hemodynamic improvement Use fluid challenge technique while associated with hemodynamic improvement 1000cc crystalloid or 300-500cc colloid over 30 mins 1000cc crystalloid or 300-500cc colloid over 30 mins Rate of fluid administration should be reduced if cardiac filling pressures increase without concurrent hemodynamic improvement Rate of fluid administration should be reduced if cardiac filling pressures increase without concurrent hemodynamic improvement

48. Treatment Vasopressors Maintain MAP > 65mmHg Maintain MAP > 65mmHg Norepinephrine or dopamine initially Norepinephrine or dopamine initially Then can add epinephrine or vasopressin Then can add epinephrine or vasopressin Art line when practical Art line when practical No low-dose dopamine for renal protection No low-dose dopamine for renal protectionIonotropes Dobutamine in patients with depressed myocardial function Dobutamine in patients with depressed myocardial function

49. Treatment Steroids Low dose in patients who respond poorly to fluids and vasopressors Low dose in patients who respond poorly to fluids and vasopressors No ACTH stim test needed No ACTH stim test needed Use HC with or without FC Use HC with or without FC Stop once patient is off vasopressors Stop once patient is off vasopressors

50. Treament Activated Protein C Consider in patients with sepsis induced organ dysfunction and high risk of death (APACHE II >24 or MODS) if there are no contraindications Consider in patients with sepsis induced organ dysfunction and high risk of death (APACHE II >24 or MODS) if there are no contraindications

51. Treatment Blood Product Administration Give RBC if Hb < 70 to target 70-90 Give RBC if Hb < 70 to target 70-90 Do not use FFP unless there is bleeding or planned invasive procedures Do not use FFP unless there is bleeding or planned invasive procedures Give platelets when counts are <5000, or between 5000 and 30000 and there is significant bleeding risk Give platelets when counts are <5000, or between 5000 and 30000 and there is significant bleeding risk

52. Treatment Mechanical Ventilation Lung protective strategies, using ARDSnet guidelines Lung protective strategies, using ARDSnet guidelines SBT’s once patient ready for them SBT’s once patient ready for them HOB at 30-45 degrees HOB at 30-45 degrees

53. Treatment Others Sedation as necessary Sedation as necessary DVT/Stress ulcer prophylaxis DVT/Stress ulcer prophylaxis Glucose control (keep 5-8.3) Glucose control (keep 5-8.3)

54. Summary A large and diverse topic A large and diverse topic Will be a common occurrence in any surgical practice Will be a common occurrence in any surgical practice Needs to be recognized and dealt with quickly to minimize morbidity and mortality Needs to be recognized and dealt with quickly to minimize morbidity and mortality

55. Treatment