SIRS and the Septic Response

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

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

3. Case 1 • 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% • Diffusely tender abdomen, coarse air entry bilaterally • What now?

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

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

6. Case 2 • Same patient, but normal amylase

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

8. 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 • 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): • Temp >38ºC or <35ºC • HR>90bpm • RR>20bpm or PaCO2<32mmHg • WBC>12, <4 or >10% immature (band) forms

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

12. SIRS • 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 Bacteremia • 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 • 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: • Areas of mottled skin • Capillary refill > 3 seconds • Urine output < 0.5cc/kg/hr for at least one hour or renal replacement therapy • Elevated lactate (>2 to 3) • Abrupt change in mental status • Abnormal EEG findings • Platelet count <100, 000 • DIC • ARDS • Cardiac dysfunction

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

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

19. Definitions • 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

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

21. Sepsis • Characteristics that influence outcome in the septic patient include: • 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) • APACHE II score • Advanced age • Site of infection: Lung/gut 50% Urine 30% • Community acquired vs healthcare acquired • Organism involved • Antibiotics—timing and type • Rapidity and adequacy of response

22. Sepsis--Pathogenesis Pathogenesis • Process of malignant intravascular inflammation • Uncontrolled, unregulated, self-sustaining • 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 • 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 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 • 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

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

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

30. Specific Organ Involvement Circulation • 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) • Impaired compensatory secretion of ADH (vasopressin) may also contribute

31. Circulation • 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

32. Circulation • 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 • 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 • 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

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

35. GI Tract • 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 • 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 • Can get reticuloendothelial system dysfunction from the sepsis syndrome • Increased LFT’s/transaminases

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

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

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

40. Treatment • 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 • “Hit them early, hit them hard”

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

42. Treatment • Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock: 2008 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 • Resuscitation goals • CVP 8-12 mmHg • MAP >65 mmHg • U/O > 0.5ml/kg/hr • SVC O2 sat >70% • 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 • 2 or more BCs • One BC from each access device >48hr old • Other sites as indicated

45. Treatment Antibiotics • As early as possible and always within 1hr • Broad spectrum, covering all likely pathogens then narrow as clinically indicated • 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) • Choose source control with max efficacy and min physiologic upset • Remove all intravascular devices if potentially infected

47. Treatment Fluid Therapy • Crystalloid or colloid • Use fluid challenge technique while associated with hemodynamic improvement • 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

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

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